The Effect of <Emphasis Type="Italic">LRP5</Emphasis> Polymorphisms on Bone Mineral Density Is Apparent in Childhood

Paget’s disease of bone (PDB) can adversely affect quality of life, but relatively little is known about the clinical predictors of reduced quality of life in patients with the disease. Here, we studied quality of life and its determinants in a large cohort of PDB patients who had been enrolled into the PRISM study, a randomized comparative trial of intensive versus symptomatic treatment for PDB. Health-related quality of life was assessed using the Short-Form 36 (SF36) questionnaire and other validated assessment instruments in 1,324 subjects with PDB. Clinical predictors of quality of life were identified by multivariate regression analysis. The physical summary (mean ± standard deviation) score of the SF36 was substantially reduced in PDB to 36.3 ± 11.3 compared with the expected population norm of 50 (P < 0.001). The mental summary score was only slightly reduced, to 48.7 ± 11.8, in PDB; but this was statistically significant (P < 0.001). Bone pain due to PDB, previous bisphosphonate therapy, and increasing age were identified as negative predictors of the SF36 physical summary score (P < 0.001); but serum levels of total alkaline phosphatase (ALP) did not predict physical summary score. We conclude that PDB has a substantial negative impact on health-related quality of life, which mainly affects physical functioning. The lack of correlation between ALP and quality of life observed in this study emphasizes the importance of addressing quality-of-life issues when treating PDB and not just focussing on response of ALP levels. The PRISM Trial Group. Writing Group: Marion K. Campbell, William D. Fraser, Anne L. Langston, Graeme MacLennan, Stuart H. Ralston, Peter L. Selby. Independent Trial Steering Committee: Maarten Boers (chair), Juliet Compston (member), Philip Hannaford (observer, host institution representative), Marilyn McCallum (member), Graham Russell (member). Data Monitoring Committee: Ade Adebajo, Nigel Arden, Howard Bird, Margaret Byron, Alison Carr, Ernest Choy (chair 2001–06), Peter Croft, Vern Farewell, Ian Harvey, Sarah Hewlett, Shabbar Jaffar, Martyn Lewis, Gary MacFarlane (chair 2006), Chris Roberts, Lee Shepstone, Deborah Symmons. Trial Office Team: Gary Adams (data manager), Daniel Barnett (trial programmer), Marie Cameron (research assistant), Janice Cruden (data manager), Magnus McGee (trial statistician), Donna Patterson (data manager), Clare Robertson (research assistant), Allan Walker (trial programmer), Euan Wiseman (trial programmer). Local Trial Investigators (the following people were responsible for the local coordination of the study at the collaborating hospital sites, *lead consultant): Aberdeen Royal Infirmary, UK, Vera Herd, Stuart H. Ralston*; University Hospital Aintree, UK, Rose McIver, Mashood Siddiqi*; Royal National Hospital for Rheumatic Disease, Bath, UK, Ashok Bhalla,* Diana Cochran, Sharon Grieve, Sara Mills; Musgrave Park Hospital, Belfast, UK, Katrina Hughes, Richard Wallace*; Queen Elizabeth Hospital, Birmingham, UK, Neil Gittoes,* Liz McGregor; Royal Bolton Hospital, UK, Keatley R. H. Adams,* Mary Adams; Ninewells Hospital, Dundee, UK, Vera Herd, Graham Leese,* Ellen Malcolm; University Hospital of North Durham, UK, Sarah Hailwood*; Medway Maritime Hospital, Gillingham, UK, Paul Ryan,* Gwen Worcester; Western Infirmary, Glasgow, UK, Alastair McLellan,* Debby Nelson; Huddersfield Royal Infirmary, UK, Allan Fairclough, Richard Reece*; Raigmore Hospital, Inverness, UK, Fiona McGhie, Malcolm Steven*; Airedale Hospital, Keighley, UK, Annie Cooper,* Stuart H. Ralston*; Leicester Royal Infirmary and Leicester General Hospital, UK, Margaret Coe, S. Javed Iqbal,* Geraldine McHugh; Royal Liverpool University Hospital, UK, William D. Fraser,* Ya-Wen Jessica Huang, Margaret Little, Vinita Mishra, Nicola Wherly; Llandudno General Hospital, UK, Merle Maddison, Lyn Vaterlaws*; Guy’s Hospital, London, UK, Ignac Fogelman,* Nina Prescod; King’s College Hospital, London, UK, Rama Chandra, Tina Mangion, Caje Moniz*; Manchester Royal Infirmary, UK, Susan Harrison, Peter L. Selby*; James Cook University Hospital, Middlesbrough, UK, John N. Fordham,* Val Lunn, Dawn Youll; Freeman Hospital, Newcastle, UK, Roger Francis*; Norfolk & Norwich University Hospital, UK, Jane Leeder, David G. I. Scott*; City Hospital, Nottingham, UK, David Hosking,* Pat San; Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, UK, Michael Davie,* Teresa Jones, Dawn Pugh; Nuffield Orthopaedic Centre, Oxford, UK, Matthew Brown, Vicky Toghill, John Wass,* Jo Young; Llandough Hospital, Penarth, UK, Roz Broadbent, Mike Stone,* Jane Turton; Derriford Hospital, Plymouth, UK, Charles Hutton,* Maggie Jolly; Poole Hospital, UK, Julia Taylor, Paul Thompson*; Harold Wood Hospital, Romford, UK, Kuntal Chakravarty*; Oldchurch Hospital, Romford, UK, Christine Heron, Christopher Kelsey*; Hope Hospital, Salford, UK, Sylvia Mercer, Terence W. O’Neill*; Northern General Hospital, Sheffield, UK, Jenny Cliffe, Linda Kersh, Eugene McCloskey*; Southampton General Hospital, UK, Trish Byng, Janet Cushnaghan, Cyrus Cooper,* Nick Harvey, Karen Walker-Bone; Royal National Orthopaedic Hospital, Stanmore, UK, Richard Keen,* Maggie Partridge; Great Western Hospital, Swindon, UK, Lynne Kerton, Elizabeth Price*; Queen Elizabeth II Hospital, Welwyn Garden City, UK, Jill Lomas, Peter Winocour*; Arrowe Park Hospital, Wirral, UK, E. George, T. D. Kennedy,* Anthony Lake; Yeovil District Hospital, UK, Nita Beacham, Clare Buckley, Jenny Knight, Lisa Martin, T. G. Palferman.*     

Gender differences in the ratio between humerus width and length are established prior to puberty

Summary On a sample of 1,317 children aged 9.9 years we developed a novel method of measuring humeral dimensions from total body dual-energy X-ray absorptiometry (DXA) scans and showed that gender differences in the ratio between humeral width and length are established prior to puberty. Introduction It is recognised that long bone cross-sectional area is greater in males compared to females, which is thought to reflect more rapid periosteal bone growth in boys. However, it is currently unclear whether these findings reflect gender differences in bone size or shape. In the present study, we investigated whether gender differences exist in the balance between longitudinal and periosteal long bone growth in children, leading to gender differences in bone shape, based on a novel method for evaluating shape of the humerus. We also examined whether these differences are established prior to puberty. Methods Length, area and width of the humerus were estimated from total body DXA scans in 1,317 children aged 9.9 ± 0.33 years, who had participated in a nested case-control study of fractures within the Avon Longitudinal Study of Parents and Children (ALSPAC) (a geographically based birth cohort based in South West England). No differences were observed with respect to parameters of humeral geometry according to fracture history, and so both groups were pooled for further analysis. Aspect ratio (AR) of the humerus was calculated as humeral width divided by length. Total body height and weight were measured at the same time as the DXA scan. Puberty was assessed using self-completion questionnaires. Results Humeral width and length were positively associated with age and height in boys and girls combined (P < 0.001), and with Tanner stage in girls (P < 0.002). In contrast, age, height and Tanner stage were not related to humeral AR. We then examined gender differences in humeral shape according to pubertal stage. In prepubertal children (i.e. Tanner stage 1), humeral length was similar in boys and girls, but width (1.92 vs 1.88 cm, P < 0.001) and area (47.7 vs 46.9 cm², P < 0.001) were greater in boys, resulting in a greater AR (7.78 vs 7.53, P < 0.001). Similar gender differences were observed in early pubertal children (i.e. Tanner stage 2). Conclusion We conclude that the greater periosteal diameter of boys compared to girls reflects differences in the balance between longitudinal and periosteal bone growth. Interestingly, resulting gender differences in humeral AR are established in prepubertal children.     

Regulation of fibroblast growth factor-23 in chronic kidney disease.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a circulating factor that regulates the renal reabsorption of inorganic phosphate (Pi) and is increased in chronic kidney disease (CKD). The aim of the current investigation was to study the regulation of FGF23 in CKD subjects with various degree of renal function. As such, we analysed the relationship between FGF23, Pi, calcium, parathyriod hormone (PTH), 25(OH) vitamin D3(25(OH)D3), 1,25(OH)2 vitamin D3(1,25(OH)2D3) and estimated glomerular filtration rate (eGFR). METHODS: Intact FGF23 and other biochemical variables were analysed in 72 consecutive adult out-patients with various stages of CKD (eGFR ranging from 4-96 ml/min.) Association studies were performed using linear univariate and multivariate analysis. RESULTS: FGF23 was significantly elevated at CKD stage 4 (266 +/- 315 pg/ml, P < 0.001) and 5 (702 +/- 489 pg/ml, P < 0.001) compared with CKD 1-2 (46 +/- 43 pg/ml). In CKD 4-5 an independent association between log FGF23 and Pi (P < 0.001), 25(OH)D3 (P < 0.05) as well as eGFR (P < 0.01) was observed. In contrast, in CKD 1-3 log PTH (P < 0.05) was the only independent predictor of log FGF23 in multivariate analysis. In CKD 1-5, Pi (P < 0.00001) and log PTH (P < 0.01) were explanatory variables for log FGF23 in multivariate analysis. CONCLUSIONS: We conclude that serum FGF23 increases in CKD 4-5, in parallel with the emerging hyperphosphataemia. Serum Pi is the most important predictor of FGF23 when GFR is less than 30 ml/min. In contrast, our data suggest that Pi may not be an important determinant of FGF23 in normophosphataemic CKD subjects. Finally, the association between FGF23 and PTH in CKD may suggest a co-regulation that remains to be further elucidated.     

Techniques for experimental heterotopic and orthotopic tracheal transplantations - When to use which model?

BACKGROUND: Different animal models have been developed to study the pathogenesis and treatment of obliterative airway disease (OAD). Here we describe the techniques of heterotopic and orthotopic tracheal transplantations in the rat, comparing the kinetics of systemic host immune response and of histopathologic OAD development. METHODS: Heterotopic and orthotopic tracheal transplantations were performed in both allogeneic (Brown Norway-to-Lewis) and syngeneic (Lewis-to-Lewis) models. Grafts were harvested after 7, 30, and 60 days post-transplant for histologic evaluation and analysis of host cellular and humoral response. RESULTS: Syngeneic tracheal grafts did not develop luminal obliteration and were morphologically indistinguishable from native tracheas. In heterotopic allografts, airway epithelium was rapidly destroyed and OAD progressed with complete luminal occlusion by 30 days. Orthotopic allografts showed enhanced early infiltration (1298+/-45 vs. 674+/-75 cells/high power field, p<0.001) with concomitant greater day 7 luminal narrowing (45+/-6% vs. 14+/-3%, p<0.001). In this model, donor-type BN epithelium (62+/-17%, 21+/-19%, and 1+/-1% on days 7, 30, and 60) was gradually replaced by recipient-type epithelial cells (2+/-4%, 70+/-22%, and 98+/-2%). OAD developed with circular orientation of cells and connective tissue fibers to 45+/-6% obliteration by day 60. Cellular host response, as determined by IFN-gamma-ELISPOT assay (548+/-132 vs. 402+/-197 spots, p=0.046) and anti-donor alloreactive IgM antibody production (2827+/-148 vs. 1565+/-393 mean channel fluorescence, p<0.001) were significantly stronger in rats bearing orthotopic vs. heterotopic allografts. CONCLUSIONS: The orthotopic tracheal transplantation model may be more representative of OAD found in human lung transplant recipients and we therefore encourage the wider use of this model.     

Rapid sequence intubation without a neuromuscular blocking agent in a 14-year-old female patient with myasthenia gravis

The anesthesia care of a 14-year-old female patient with an acute exacerbation of myasthenia gravis (MG) and a full stomach who required emergency surgery for placement of a hemodialysis catheter is described. A nonventilated rapid sequence induction was successful with the use of propofol, lidocaine, remifentanil, cricoid pressure and no neuromuscular blocking agent. Although the use of combinations of i.v. anesthetic agents have been suggested for tracheal intubation without the need for neuromuscular blocking agents, none of these techniques has been advocated for rapid sequence intubation. We review existing literature on the topic of tracheal intubation using remifentanil and propofol without a neuromuscular blocking agent and on the topic of tracheal intubation of patients with MG using i.v. anesthesia and no neuromuscular blocking agents.     

Changes in disc height and posteroanterior displacement after fusion in patients with idiopathic scoliosis: a 9-year follow-up study

INTRODUCTION: In scoliosis patients treated with long segment spinal fusion, degenerative changes like retrolisthesis and disc space narrowing below fusion have been observed. However, there is disagreement concerning their incidence and dependency on the location of the lowest instrumented vertebra. MATERIALS AND METHODS: To evaluate temporal changes in disc height and posteroanterior displacement (indicating listhesis) below fusion, 40 patients with adolescent idiopathic scoliosis, mainly treated with Cotrel-Dubousset instrumentation, were retrospectively investigated in this longitudinal study with a follow-up of on average 9.2 years (median 9.4 y) after surgery. Disc height and displacement were measured from lateral radiographs by means of distortion-compensated roentgen analysis (DCRA). Additionally, a mathematical model was developed to determine the influence of vertebral tilt in scoliosis on disc height and displacement. RESULTS: Overall, no significant decrease in disc height was observed during follow-up. Concerning listhesis a small but significant retrolisthesis was found in segments L2/L3 and L3/L4. Compared with normative data, there was no significant listhesis for the L5/S1 segment. Nevertheless, separating the study group into subsamples of identical distal fusion level revealed a significant correlation between the amount of posteroanterior displacement at L5/S1 and the location of the lowest instrumented vertebra. With a reduction of free motion segments, listhesis increased into posterior direction. Taking the tilt correction into account led to considerably increased values of disc height whereas displacement was affected only to a minor degree. CONCLUSIONS: Long segment spinal fusion in young patients with idiopathic scoliosis did not lead to disc space narrowing during 9.2 years follow-up. However, the observed increase in retrolisthesis potentially indicates the initiation of a degenerative process. These only minimal changes might be referred to the preservation of a physiologic lumbar lordosis. Without correction for vertebral tilt disc space narrowing is overestimated.     

Effect of Surgery on the Outcome of Midgut Carcinoid Disease with Lymph Node and Liver Metastases

We have evaluated survival and tumor-related symptoms in the presence of mesenteric lymph node and liver metastases in relation to surgical procedures in 314 patients (148 women, mean age at diagnosis 61 years; 249 with liver metastases) treated for midgut carcinoid tumors. Of the operated patients, 46% presented with severe abdominal pain and intestinal obstruction and were operated on before the diagnosis. Medical treatment (somatostatin analogs, interferon-a) was initiated in 67% and 86%, respectively. Surgical attempts included small intestine or ileocecal/right-sided colon resection with excision of mesenteric lymph node metastases. Most of the patients (n = 286) had mesenteric lymph node metastases; 33% of them had unresectable mesenteric lymph node metastases and underwent surgery without mesenteric dissection. Patients who underwent resection for the primary tumor had a longer survival than those with no resection (median survival 7.4 vs. 4.0 years; p <0.01). Patients who underwent successful excision of mesenteric metastases had a significantly longer survival than those with remaining lymph node metastases. Patients operated on for a primary tumor but with remaining lymph nodes but no liver metastases and who subsequently received interferon and somatostatin analog treatment had a median survival of 7.4 years. Resection of the primary tumor and the mesenteric lymph node metastases led to a significant reduction in tumor-related symptoms. Surgery to remove the primary intestinal tumor including mesenteric lymph node metastases is supported by the present results, even in the presence of liver metastases. Liver metastases and significant preoperative weight loss are identified as major negative prognostic factors for survival.     

Nephron-sparing surgery in multiple bilateral angiomyolipomas

We report on a 17-year-old white woman with multiple bilateral renal angiomyolipomas (AMLs) in the absence of tuberous sclerosis. Multiple hyperdense lesions were detected in both kidneys by sonography. A computed tomography (CT) scan confirmed mainly fatty tissue. Sparing as much functional tissue as possible, eight AMLs of the right kidney were resected. The largest removed tumour measured 7 x 4 x 2.4 cm. Renal function was completely preserved. An AML is a benign, generally unilateral renal tumour. Treatment is necessary in cases of flank pain, spontaneous bleeding, obstruction by tumour growth and tumours exceeding 4 cm in diameter. Patients who present are often symptomatic due to pain, retroperitoneal bleeding or haematuria. An AML occurs either sporadically or in association with tuberous sclerosis. Bilateral or unilateral multiple AMLs are rare.     

Early Surgery in Prone Position for Associated Injuries in Patients Undergoing Non-operative Management for Splenic and Liver Injuries

Background

In patients undergoing non-operative management (NOM) of blunt splenic and/or liver injuries, no data exist on the safety of same-admission surgery in prone position for concomitant injuries.

Methods

Retrospective study including adult trauma patients with blunt splenic/liver injuries and attempted NOM from 01/2009 to 06/2015 was conducted. Patient and injury characteristics as well as outcomes [failed (f)NOM, mortality] of patients with/without surgery in prone position were compared (‘prone’ vs. ‘non-prone’ group).

Results

A total of 244 patients with blunt splenic/liver injury and attempted NOM were included. Forty patients (16.4%) underwent surgery in prone position on median post-injury day 2.0 [interquartile range (IQR) 3.0]. Surgery in prone position was mostly performed for associated spinal or pelvic injuries. The ISS was significantly higher, and the proportion of patients with high-grade injuries (OIS?≥?3) was significantly less frequent in the ‘prone? group (30.0?±?14.5 vs. 23.9?±?13.2, p?=?0.009 and 27.5 vs. 53.9%, p?=?0.002). In-hospital mortality as well as NOM failure rates were not significantly different between the ‘prone’ and ‘non-prone? group (2.5 vs. 2.9%, p?=?1.000; 0.0 vs. 4.4%, p?=?0.362). Eleven patients with high-grade injuries were operated in prone position at median day 3 (IQR 3.0). None of these patients failed NOM. However, one patient with a grade IV splenic injury required immediate splenectomy after being operated in right-sided position on the day of admission.

Conclusion

In this single-center analysis, surgery in prone position was performed in a substantial number of patients with splenic/liver injuries without increasing the fNOM rate. However, caution should be used in patients with grade IV/V splenic injuries.