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1.  Painful fat necrosis resulting from insulin injections 
The case is a 34-year-old woman with long-standing type 1 diabetes mellitus with existing follow-up in the outpatient clinic at the Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, UHCW. She had maintained good glycaemic control and glycaemic stability with basal bolus regimen for many years. She had not developed any diabetes-related complications and had no other co-morbidities. Six months ago, she presented to A&E with sudden-onset, well-localised and severe pain in the right iliac fossa, just lateral to the para-umbilical area. Her biochemistry was normal. Ultrasound scan, however, revealed a right-sided ovarian cyst, which was thought to have caused pain to her. She was discharged from A&E with simple analgesia. On subsequent gynaecological follow-up 4 weeks later, her pain remained severe and examination revealed an exquisitely tender subcutaneous nodule at the same location measuring 2 cm in diameter. Magnetic resonance imaging (MRI) scan at the time revealed a 1 cm mass in the subcutaneous adipose tissue, which co-localised to her pain. The mass demonstrated a central fat signal surrounded by a peripheral ring: observations consistent with fat necrosis. There were other smaller subcutaneous nodules also observed in the left para-umbilical area. Subsequent surgical resection of the main area of fat necrosis was performed. The patient made an excellent recovery and her pain resolved post-operatively. Histology confirmed the presence of fat necrosis. Fat necrosis is a rare complication of s.c. insulin injection. This case illustrates the importance of considering this diagnosis in patients who inject insulin and develop localised injection-site pain.
Learning points
Fat necrosis is a rare complication of insulin injections that can manifest with severe, persistent and well-localised pain.Fat necrosis can masquerade as other pathologies causing diagnostic confusion.The imaging modality of choice for accurate diagnosis of fat necrosis is MRI.Histological confirmation of fat necrosis is important.Appropriate management of localised fat necrosis is surgical excision, with avoidance of further insulin injections into the affected area.
PMCID: PMC4176647  PMID: 25298886
3.  Identification of a novel heterozygous mutation in exon 50 of the COL1A1 gene causing osteogenesis imperfecta 
A 19-year-old woman was diagnosed with osteogenesis imperfecta (OI). She had sustained numerous low-trauma fractures throughout her childhood, including a recent pelvic fracture (superior and inferior ramus) following a low-impact fall. She had the classical blue sclerae, and dual energy X-ray absorptiometry (DEXA) bone scanning confirmed low bone mass for her age in the lumbar spine (Z-score was −2.6). However, despite these classical clinical features, the diagnosis of OI had not been entertained throughout the whole of her childhood. Sequencing of her genomic DNA revealed that she was heterozygous for the c.3880_3883dup mutation in exon 50 of the COL1A1 gene. This mutation is predicted to result in a frameshift at p.Thr1295, and truncating stop codon 3 amino acids downstream. To our knowledge, this mutation has not previously been reported in OI.
Learning points
OI is a rare but important genetic metabolic bone and connective tissue disorder that manifests a diverse clinical phenotype that includes recurrent low-impact fractures.Most mutations that underlie OI occur within exon 50 of the COL1A1 gene (coding for protein constituents of type 1 pro-collagen).The diagnosis of OI is easily missed in its mild form. Early diagnosis is important, and there is a need for improved awareness of OI among health care professionals.OI is a diagnosis of exclusion, although the key diagnostic criterion is through genetic testing for mutations within the COL1A1 gene.Effective management of OI should be instituted through a multidisciplinary team approach that includes a bone specialist (usually an endocrinologist or rheumatologist), a geneticist, an audiometrist and a genetic counsellor. Physiotherapy and orthopaedic surgery may also be required.
PMCID: PMC3922149  PMID: 24616757
4.  Impact of FTO genotypes on BMI and weight in polycystic ovary syndrome: a systematic review and meta-analysis 
Diabetologia  2012;55(10):2636-2645.
FTO gene single nucleotide polymorphisms (SNPs) have been shown to be associated with obesity-related traits and type 2 diabetes. Several small studies have suggested a greater than expected effect of the FTO rs9939609 SNP on weight in polycystic ovary syndrome (PCOS). We therefore aimed to examine the impact of FTO genotype on BMI and weight in PCOS.
A systematic search of medical databases (PubMed, EMBASE and Cochrane CENTRAL) was conducted up to the end of April 2011. Seven studies describing eight distinct PCOS cohorts were retrieved; seven were genotyped for SNP rs9939609 and one for SNP rs1421085. The per allele effect on BMI and body weight increase was calculated and subjected to meta-analysis.
A total of 2,548 women with PCOS were included in the study; 762 were TT homozygotes, 1,253 had an AT/CT genotype, and 533 were AA/CC homozygotes. Each additional copy of the effect allele (A/C) increased the BMI by a mean of 0.19 z score units (95% CI 0.13, 0.24; p = 2.26 × 10−11) and body weight by a mean of 0.20 z score units (95% CI 0.14, 0.26; p = 1.02 × 10−10). This translated into an approximately 3.3 kg/m2 increase in BMI and an approximately 9.6 kg gain in body weight between TT and AA/CC homozygotes. The association between FTO genotypes and BMI was stronger in the cohorts with PCOS than in the general female populations from large genome-wide association studies. Deviation from an additive genetic model was observed in heavier populations.
The effect of FTO SNPs on obesity-related traits in PCOS seems to be more than two times greater than the effect found in large population-based studies. This suggests an interaction between FTO and the metabolic context or polygenic background of PCOS.
PMCID: PMC3433670  PMID: 22801903
BMI; FTO; Meta-analysis; Polycystic ovary syndrome; Systematic review; Weight
5.  Developing and Validating a Predictive Model for Stroke Progression 
Cerebrovascular Diseases Extra  2011;1(1):105-114.
Progression is believed to be a common and important complication in acute stroke, and has been associated with increased mortality and morbidity. Reliable identification of predictors of early neurological deterioration could potentially benefit routine clinical care. The aim of this study was to identify predictors of early stroke progression using two independent patient cohorts.
Two patient cohorts were used for this study – the first cohort formed the training data set, which included consecutive patients admitted to an urban teaching hospital between 2000 and 2002, and the second cohort formed the test data set, which included patients admitted to the same hospital between 2003 and 2004. A standard definition of stroke progression was used. The first cohort (n = 863) was used to develop the model. Variables that were statistically significant (p < 0.1) on univariate analysis were included in the multivariate model. Logistic regression was the technique employed using backward stepwise regression to drop the least significant variables (p > 0.1) in turn. The second cohort (n = 216) was used to test the performance of the model. The performance of the predictive model was assessed in terms of both calibration and discrimination. Multiple imputation methods were used for dealing with the missing values.
Variables shown to be significant predictors of stroke progression were conscious level, history of coronary heart disease, presence of hyperosmolarity, CT lesion, living alone on admission, Oxfordshire Community Stroke Project classification, presence of pyrexia and smoking status. The model appears to have reasonable discriminative properties [the median receiver-operating characteristic curve value was 0.72 (range 0.72–0.73)] and to fit well with the observed data, which is indicated by the high goodness-of-fit p value [the median p value from the Hosmer-Lemeshow test was 0.90 (range 0.50–0.92)].
The predictive model developed in this study contains variables that can be easily collected in practice therefore increasing its usability in clinical practice. Using this analysis approach, the discrimination and calibration of the predictive model appear sufficiently high to provide accurate predictions. This study also offers some discussion around the validation of predictive models for wider use in clinical practice.
PMCID: PMC3343757  PMID: 22566988
Acute stroke care; Predictors of outcome; Stroke outcome
6.  Quantification of Vaginal Support: Are Continuous Summary Scores Better than POPQ Stage? 
This analysis compared 3 continuous variables as summary support loss scores with POPQ ordinal stages.
Study Design
We used pooled baseline data from 1141 subjects in 3 randomized trials (CARE, n=322; OPUS, n = 380; ATLAS, n =439) to test 3 support loss measures. The relative responsiveness was assessed using the standardized response mean of 2-year outcome data from the CARE trial.
Each support loss measure was strongly correlated with POPQ ordinal staging; the single most distal POPQ point had the strongest correlation. Improvements in anatomic support were weakly correlated with improvements in POPDI (r = .17-.24, p <.01 for each) but not with changes in POPIQ for all measures of support loss or POPQ stage.
While continuous, single number summary measures compared favorably to ordinal POPQ staging system, the single most distal POPQ point may be preferable to POPQ ordinal stages to summarize or compare group data.
PMCID: PMC2975822  PMID: 20728072
Pelvic organ prolapse; prolapse; pelvic surgery; outcome measures; quantification of prolapse
7.  Poor outcome in primary intracerebral haemorrhage: results of a matched comparison 
Postgraduate Medical Journal  2004;80(940):89-92.
Background: Primary intracerebral haemorrhage (PICH) is associated with a poorer outcome than cerebral infarction. This study aimed to determine whether this is explained by the clinical severity of stroke.
Methods: An observational study of outcome in consecutive admissions with acute PICH and ischaemic stroke was undertaken. A nested case-control analysis, matched on a 1:2 basis for age, pre-stroke disability, early neurological impairment (Scandinavian Stroke Scale; SSS), and Oxfordshire Community Stroke Project classification was then performed. Follow up was at 30 days and at hospital discharge.
Results: Overall, 679 subjects were included in the analysis. Of these, 53 (8%) had PICH; this group had more severe initial neurological impairment (day 3 SSS 28 v 45 points, p<0.001) and a higher prevalence of total anterior circulation strokes (55% v 21%, p<0.001) than did the group admitted with ischaemic strokes. Outcomes were poorer in the PICH group, with 36% inpatient mortality and 68% of survivors having a day 30 modified Rankin Scale (MRS) of at least 3 (compared with 13% and 52%, respectively, in the ischaemic stroke group). Following matching for baseline clinical characteristics, the PICH group had a higher mortality, but this was not statistically significant; the day 30 MRS and institutionalisation rates in survivors were similar in the matched haemorrhage and infarct groups.
Conclusions: Compared with ischaemic stroke, PICH is associated with higher mortality and increased disability in survivors. The severity of clinical stroke is a major contributor to these poor outcomes; baseline characteristics, however, do not fully explain outcome differences.
PMCID: PMC1742919  PMID: 14970296
8.  Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on loss of weight and lean tissue in cancer cachexia: a randomised double blind trial 
Gut  2003;52(10):1479-1486.
Aim: N-3 fatty acids, especially eicosapentaenoic acid (EPA), may possess anticachectic properties. This trial compared a protein and energy dense supplement enriched with n-3 fatty acids and antioxidants (experimental: E) with an isocaloric isonitrogenous control supplement (C) for their effects on weight, lean body mass (LBM), dietary intake, and quality of life in cachectic patients with advanced pancreatic cancer.
Methods: A total of 200 patients (95 E; 105 C) were randomised to consume two cans/day of the E or C supplement (480 ml, 620 kcal, 32 g protein ± 2.2 g EPA) for eight weeks in a multicentre, randomised, double blind trial.
Results: At enrolment, patients’ mean rate of weight loss was 3.3 kg/month. Intake of the supplements (E or C) was below the recommended dose (2 cans/day) and averaged 1.4 cans/day. Over eight weeks, patients in both groups stopped losing weight (Δ weight E: −0.25 kg/month versus C: −0.37 kg/month; p = 0.74) and LBM (Δ LBM E: +0.27 kg/month versus C: +0.12 kg/month; p = 0.88) to an equal degree (change from baseline E and C, p<0.001). In view of evident non-compliance in both E and C groups, correlation analyses were undertaken to examine for potential dose-response relationships. E patients demonstrated significant correlations between their supplement intake and weight gain (r = 0.50, p<0.001) and increase in LBM (r = 0.33, p = 0.036). Such correlations were not statistically significant in C patients. The relationship of supplement intake with change in LBM was significantly different between E and C patients (p = 0.043). Increased plasma EPA levels in the E group were associated with weight and LBM gain (r = 0.50, p<0.001; r = 0.51, p = 0.001). Weight gain was associated with improved quality of life (p<0.01) only in the E group.
Conclusion: Intention to treat group comparisons indicated that at the mean dose taken, enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved quality of life. Further trials are required to examine the potential role of n-3 enriched supplements in the treatment of cancer cachexia.
PMCID: PMC1773823  PMID: 12970142
cachexia; pancreatic cancer; quality of life; eicosapentaenoic acid; n-3 fatty acids; nutritional support; weight; lean body mass; cytokines
9.  Fits, faints, or fatal fantasy? Fabricated seizures and child abuse 
Archives of Disease in Childhood  2002;86(4):230-233.
PMCID: PMC1719157  PMID: 11919091
10.  The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer 
British Journal of Cancer  2004;90(6):1129-1132.
PMCID: PMC2409662  PMID: 15026790
leptin; interleukin-6; insulin; cortisol; fat oxidation; feeding; weight loss; pancreatic cancer
12.  Diagnosing physical child abuse: the way forward 
Postgraduate Medical Journal  2000;76(902):743-749.
PMCID: PMC1741851  PMID: 11085763
13.  A polymorphism of the interleukin-1 β gene influences survival in pancreatic cancer 
British Journal of Cancer  2000;83(11):1443-1447.
Pro-inflammatory cytokines contribute to the cachexia associated with pancreatic cancer and stimulate the acute phase response which has been associated with shortened survival in such patients. Polymorphisms of cytokine genes may influence their production. The present study examined the effect of a polymorphism of the interleukin (IL)-1b gene upon the inflammatory state and survival in pancreatic cancer. Genomic DNA was obtained from 64 patients with pancreatic cancer and 101 healthy controls. Using the polymerase chain reaction and subsequent TaqI restriction enzyme digestion the subject's genotype for a diallelic polymorphism of the interleukin-1b gene was established. IL-1b production by peripheral blood mononuclear cells and serum C-reactive protein (CRP) levels from patients were also examined and survival noted. Patients homozygous for allele 2 of the IL-1b gene had significantly shorter survival than other groups (P = 0.0001). These patients also exhibited higher IL-1b production (P = 0.022). Possession of allele 2 was also associated with significantly shorter survival (median 144 vs 256 days, P = 0.034) and significantly higher CRP level (P = 0.0003). The possession of a genotype resulting in increased IL-1b production was associated with shortened survival and increased serum CRP level. This may reflect the role of IL-1b in inducing an acute phase protein response and cachexia in cancer or may be related to changes in tumour phenotye. © 2000 Cancer Research Campaign
PMCID: PMC2363418  PMID: 11076651
pancreatic cancer; interleukin-1β; genetic polymorphisms; prognostic factors; C-reactive protein
14.  The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer 
British Journal of Cancer  1999;81(1):80-86.
Previous studies have suggested that administration of oral eicosapentaenoic acid (EPA) will stabilize weight in patients with advanced pancreatic cancer. The aim of the present study was to determine if a combination of EPA with a conventional oral nutritional supplement could produce weight gain in these patients. Twenty patients with unresectable pancreatic adenocarcinoma were asked to consume two cans of a fish oil-enriched nutritional supplement per day in addition to their normal food intake. Each can contained 310 kcal, 16.1 g protein and 1.09 g EPA. Patients were assessed for weight, body composition, dietary intake, resting energy expenditure (REE) and performance status. Patients consumed a median of 1.9 cans day−1. All patients were losing weight at baseline at a median rate of 2.9 kg month−1. After administration of the fish oil-enriched supplement, patients had significant weight-gain at both 3 (median 1 kg, P = 0.024) and 7 weeks (median 2 kg, P = 0.033). Dietary intake increased significantly by almost 400 kcal day−1 (P = 0.002). REE per kg body weight and per kg lean body mass fell significantly. Performance status and appetite were significantly improved at 3 weeks. In contrast to previous studies of oral conventional nutritional supplements in weight-losing cancer patients, this study suggests that an EPA-enriched supplement may reverse cachexia in advanced pancreatic cancer. © 1999 Cancer Research Campaign
PMCID: PMC2374349  PMID: 10487616
pancreatic cancer; cachexia; eicosapentaenoic acid; docosahexaenoic acid; fish oil; nutritional supplementation
15.  Urethrorectal fistula in a horse. 
The Canadian Veterinary Journal  1999;40(2):122-124.
Anomalies of the urethra are uncommon. Urethrorectal fistula in horses has only been reported in foals and only in conjunction with other congenital anomalies. This report describes the diagnosis, surgical management, and possible etiologies of a unique case of urethrorectal fistula in a mature gelding.
PMCID: PMC1539560  PMID: 10065321
16.  Osteochondritis dessicans and subchondral cystic lesions in draft horses: a retrospective study. 
The Canadian Veterinary Journal  1998;39(10):627-633.
The clinical features, radiographic findings, treatment, and outcome in 51 draft horses with osteochondritis dessicans (OCD) or subchondral cystic lesions (SC) are reported. Clydesdale and Percheron were the most commonly affected breeds, and affected animals represented only 5% of the hospital population of draft horses. Horses were most frequently affected in the tibiotarsal joints and 73% (24 of 33 cases) of the horses with tibiotarsal effusion were affected bilaterally. Osteochondritis dessicans of the distal intermediate ridge was the most common lesion found in the tibiotarsal joint. The stifle was also frequently affected; 87% (13 of 15 cases) of horses with femoropatellar OCD only were lame, and lesions were most commonly located on the lateral trochlear ridge. Sixteen cases were managed conservatively, 30 received surgery, and 5 were euthanized. Lameness, effusion, or both clinical signs resolved in more than 50% of surgically treated cases, but clinical signs improved in 30% of conservatively-managed cases.
PMCID: PMC1539460  PMID: 9789673
17.  Prevention of renal injury after induction of ozone tolerance in rats submitted to warm ischaemia. 
Mediators of Inflammation  1999;8(1):37-41.
On the basis that ozone (O3) can upregulate cellular antioxidant enzymes, a morphological, biochemical and functional renal study was performed in rats undergoing a prolonged treatment with O3 before renal ischaemia. Rats were divided into four groups: (1) control, a medial abdominal incision was performed to expose the kidneys; (2) ischaemia, in animals undergoing a bilateral renal ischaemia (30 min), with subsequent reperfusion (3 h); (3) O3 + ischaemia, as group 2, but with previous treatment with O3 (0.5 mg/kg per day given in 2.5 ml O2) via rectal administration for 15 treatments; (4) O2 + ischaemia, as group 3, but using oxygen (O2) alone. Biochemical parameters as fructosamine level, phospholipase A, and superoxide dismutases (SOD) activities, as well as renal plasma flow (RPF) and glomerular filtration rate (GFR), were measured by means of plasma clearance of p-amino-hippurate and inulin, respectively. In comparison with groups 1 and 3, the RPF and GFR were significantly decreased in groups 2 and 4. Interestingly, renal homogenates of the latter groups yielded significantly higher values of phospholipase A activity and fructosamine level in comparison with either the control (1) and the O3 (3) treated groups. Moreover renal SOD activity showed a significant increase in group 3 without significant differences among groups 1, 2 and 4. Morphological alterations of the kidney were present in 100%, 88% and 30% of the animals in groups 2, 4 and 3, respectively. It is proposed that the O3 protective effect can be ascribed to the substantial possibility of upregulating the antioxidant defence system capable of counteracting the damaging effect of ischaemia. These findings suggest that, whenever possible, ozone preconditioning may represent a prophylactic approach for minimizing renal damage before transplantation.
PMCID: PMC1781776  PMID: 10704088
18.  Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. 
Journal of Clinical Investigation  1997;100(3):597-603.
Cholecystokinin (CCK) plays an important role in pancreatic carcinogenesis. While human CCK-A and -B receptors have been fully characterized, their relative roles in human pancreatic adenocarcinoma remain unclear. Thus, expression of CCK-A and -B receptors in normal human pancreas, pancreatic adenocarcinomas, and other human extrapancreatic tissues and malignancies was examined, using reverse transcription followed by the polymerase chain reaction (RT-PCR). mRNA isolated from 15 normal pancreas specimens, 22 pancreatic adenocarcinomas, and 58 extrapancreatic tissues and tumors was subjected to RT-PCR using primers specific for human CCK-A and -B receptors. Expression of CCK-B receptors was detected in all tissues arising from pancreas and in most extrapancreatic tissues and tumors. In contrast, CCK-A receptors exhibited a more selective pattern of expression in gall bladder, intestine, brain, ovary, spleen, and thymus. Of significance, CCK-A receptors were expressed selectively in all pancreatic adenocarcinomas, but not in any normal pancreas specimens. In situ hybridization, using receptor-specific riboprobes, localized CCK-A receptor expression to ductal cells, the presumed origin of most human pancreatic adenocarcinomas. Southern blot analysis revealed no evidence of CCK-A receptor gene amplification or rearrangement in pancreatic adenocarcinomas. Because of its selective expression, the CCK-A receptor may serve as selective biomarker for pancreatic adenocarcinoma.
PMCID: PMC508227  PMID: 9239407
20.  Comparison of herniorrhaphy versus clamping of umbilical hernias in horses: a retrospective study of 93 cases (1982-1994). 
The Canadian Veterinary Journal  1996;37(5):295-298.
Many uncomplicated umbilical hernias have been managed successfully in foals by the application of a hernia clamp. Isolated reports of complications following clamp application have led some authors to suggest that it is an unsuitable method of treatment. Little information has been published comparing the complication rates associated with the use of hernia clamps and herniorrhaphy in the treatment of umbilical hernias. The purpose of this retrospective study was to report the characteristics of clinical cases of umbilical hernia and to compare the complication rates following these 2 treatment approaches. Information was collected from records or from owners to identify the occurrence of complications and owner satisfaction following treatment. Of 93 cases, 10 complicated and 18 uncomplicated hernias were treated by herniorrhaphy, 40 uncomplicated hernias were treated by clamping, 1 originally uncomplicated hernia was treated by both techniques, and 24 cases were untreated. Nineteen percent of uncomplicated hernias treated by herniorrhaphy, and 19% of those clamped developed minor complications. This study demonstrates that although minor complications may be associated with either technique, they generally do not result in significant morbidity.
PMCID: PMC1576383  PMID: 8705974
24.  Blockade of cardiac sodium channels. Competition between the permeant ion and antiarrhythmic drugs. 
Journal of Clinical Investigation  1992;90(2):368-381.
A number of basic and clinical studies suggest that elevation of external sodium concentrations, [Na]o, may reverse the cardiotoxic effect of local anesthetic-class drugs. The mechanisms of reversal are uncertain. The blocking action of lidocaine and disopyramide were studied over a range of [Na]o. Both whole-cell voltage clamp and single-channel recordings were performed on isolated rabbit myocytes at 17 and 22 degrees C, respectively. In the presence of lidocaine, an inactivated channel blocker, the level of steady-state block in response to pulse train stimulation was not affected by variations in [Na]o from 20 to 150 mM. Estimates of the rate of dissociation of drug from the channel also were unaffected. In contrast, steady-state block by disopyramide, a drug that blocks open channels, was decreased as [Na]o was increased. Single-channel measurements suggest that the influence of [Na]o on channel current amplitude was small, 12% for a 25 mM increase in [Na]o. This increase in single-channel current amplitude would affect drug-free channels only, in that our studies suggest that drug-associated channels do not conduct. The association rate constant of disopyramide with open single sodium channels was decreased from 10 x 10(6) to 5 x 10(6)/M per s by an increase in [Na]o from 120 to 180 mM. Elevation of [Na]o may reverse the blocking action of local anesthetic-class drugs by an increase in single-channel current amplitude or by a decrease in drug association rate with the sodium channel. The occurrence of the latter action depends on the mode of block of the specific agent.
PMCID: PMC443111  PMID: 1322937
25.  Subluxation of the Carpus in Thirteen Horses 
The Canadian Veterinary Journal  1984;25(8):311-314.
The records of 13 horses of various breeds with subluxation of the radiocarpal, intercarpal or carpometacarpal joint, or combinations of these were reviewed. Subluxation was most common at the carpometacarpal joint (n = 10) and concomitant fractures of individual carpal bones or metacarpus II and IV were seen (n = 12).
Treatment comprised of immobilization in a full leg plaster cast for from four to 18 weeks. Three animals were euthanized, two because of cast complications and one because of a request by the owner. The remaining ten were saved to function as breeding animals.
PMCID: PMC1790629  PMID: 17422436
Subluxation; carpus; horse

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