Postamputation neuromas and other symptomatic stump abnormalities: detection with CT

One of the potentially troublesome sequelae of limb amputations is the development of stump neuromas at the severed ends of major nerves. The ability to define them and to distinguish them from other causes of stump pain is of considerable clinical significance. Computed tomography was performed on ten lower limb amputees with stump pain. Five patients had neuromas that were manifest as focal or generalized alteration in the caliber, size, or contour of the nerve trunk in the affected stump. The remaining five patients each had an abnormality detected; these abnormalities included heterotopic bone formation, popliteal artery aneurysm, lipoma, scar tissue, and abscess in the contralateral limb.     

The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo

Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony‐stimulating factor (M‐CSF) receptor c‐fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c‐fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague‐Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 µg/kg/6 weeks) subcutaneously. Following 4, 8, and 12 weeks of treatment, serum biochemical, bone morphometric, and histologic analyses were performed. Whole‐body bone mineral density and tibial cortical thickness where unchanged in the dasatinib‐ or ZOL‐treated animals relative to controls. However, micro–computed tomographic (µCT) analysis of cancellous bone at the proximal tibias showed that trabecular volume (BV/TV) and thickness (Tb.Th) were increased in dasatinib‐treated animals at levels comparable with those of the ZOL‐treated group. These changes were associated with a decrease in osteoclast numbers (N.Oc/B.Pm) and surface (Oc.S/BS) and decreased serum levels of the osteoclast marker c‐terminal collagen crosslinks (CTX‐1). Mineral apposition rate (MAR), bone‐formation rate (BFR), and levels of the serum osteoblast markers osteocalcin and N‐terminal propeptide of type I procollagen (P1NP) were not altered significantly in the dasatinib‐treated animals relative to controls. These studies show that dasatinib increases trabecular bone volume at least in part by inhibiting osteoclast activity, suggesting that dasatinib therapy may result in dysregulated bone remodeling. © 2010 American Society for Bone and Mineral Research     

Targeted Disruption of the CXCL12/CXCR4 Axis Inhibits Osteolysis in a Murine Model of Myeloma‐Associated Bone Loss

The plasma cell (PC) malignancy, multiple myeloma (MM), is unique among hematological malignancies in its capacity to cause osteoclast (OC)‐mediated skeletal destruction. We have previously shown that elevated plasma levels of PC‐derived CXCL12 are associated with presence of X‐ray detectable osteolytic lesions in MM patients. To further investigate this relationship, plasma levels of CXCL12 and βCrossLaps, a marker of bone loss, were measured. A strong correlation between levels of CXCL12 and OC‐mediated bone resorption was identified. To confirm the OC‐activating potential of MM PC‐derived CXCL12 in vivo, we established a model of MM‐mediated focal osteolysis, wherein MM PC lines, such as RPMI‐8226, were injected into the tibias of nude mice. Implanting RPMI‐8226 gave rise to osteolytic lesions proximal to the tumor, resulting in a 5% decrease in bone volume (BV) compared with vehicle control. Importantly, bone loss was significantly inhibited with systemic administration of the CXCL12/CXCR4 antagonist T140. Furthermore, implanting CXCL12‐overexpressing RPMI‐8226 cells resulted in a 13% decrease in BV and was associated with increased OC recruitment proximal to the tumor, increased serum matrix metalloproteinase activity, and increased levels of collagen I degradation products. These findings confirm our hypothesis that MM PC‐derived CXCL12 stimulates the recruitment and activity of OC, thereby contributing to the formation of MM osteolytic lesions.     

Measurements of occupational exposure to switched gradient and spatially-varying magnetic fields in areas adjacent to 1.5 T clinical MRI systems

PURPOSE: To determine if magnetic field exposure close to two clinical 1.5 T magnetic resonance imaging (MRI) scanners during image acquisition and when moving in the spatially-varying static magnetic field is compliant with European Union (EU) Directive 2004/40/EC (the Directive). MATERIALS AND METHODS: Using commercially available equipment we measured the magnetic flux density around the scanners during two clinical pulse sequences. The data was compared with frequency-dependent limits that will limit occupational exposure following transposition of the Directive into national law in 2008. The static magnetic field was measured around the scanners and the exposure from movement within this field was simulated. RESULTS: The whole-body exposure experienced when standing close to the face of the magnet exceeds the limits in the Directive on the two scanners tested during clinical sequences. Simulation of movement toward the scanner shows that speeds must be restricted to 1/5 of normal walking speed to comply with the Directive. CONCLUSION: EU Directive 2004/40/EC will have a major impact on the current use and future development of MRI due to limitations on exposure to time-varying gradient fields and movement within the spatially-varying static field. This will make interventional work impossible and routine MRI use impracticable in Europe.     

Melatonin – a pleiotropic molecule involved in pathophysiological processes following organ transplantation

Mammals adjust their physiology in response to seasonal changes to environment (i.e. photoperiod, temperature, food availability). These changes are thought to predominantly occur for the conservation of energy during winter, by pervasive changes such as the inhibition of reproduction. Previous reports have suggested that circannual changes also occur to the immune system. In mammals, this chronological effect may be dependent on photoperiod, and evidence exists to suggest that there is a great deal of immune variation in response to light, or circadian rhythm. This is a clinically relevant, yet under-reported area of human transplantation. The aim of this review is to discuss immune variation, with specific emphasis on melatonin secretion, in the context of organ rejection, infection, neoplasia formation, and immunosuppression.     

Immune deficiencies in chronic intestinal pseudo-obstruction

Aim: Chronic intestinal pseudo-obstruction has been associated with urinary disorders, myopathy, and ophthalmoplegia in adults and cholelithiasis in children. We observed a high percentage of total-parenteral-nutrition-dependent patients with pseudo-obstruction and recurrent infections requiring gammaglobulin infusions. Methods: AH records for 23 children with chronic intestinal pseudo-obstruction (10 females and 13 males, mean age 9.8 y ± 4.9 y, range 4–24 y) referred for a nutritional evaluation from 1992 to 1995 were reviewed. Chronic intestinal pseudo-obstruction was diagnosed by clinical, radiographic findings and antroduodenal manometry. Intestinal full-thickness biopsies were performed in seven children. Results: Hypogammaglobulinemia was diagnosed in 18 patients (78%): 16 patients had various immunoglobulin deficiencies and 2 had selective antibody deficiency. Intravenous gammaglobulin was administered in 14 patients. Other medical conditions affecting the children are summarized as follows: autonomic dysfunction in 10 patients (43%), recurrent hypoglycemia in 9 (39%), asthma in 9 (39%), cholecystitis in 7 (30%), low serum carnitine level in 6 (26%), urinary dysfunction in 6 (26%), pancreatitis in 5 (22%), behavioral problems in 5 (22%), myopathy in 2 (9%), idiopathic thrombocytopenia in 2 (8%), velopharyngeal insufficiency in 1 (4%), oculocutaneous albinism in 1 (4%), Pierre-Robin syndrome in 1 (4%), and protein C deficiency in 1 (4%). Munchausen syndrome was suspected in two patients. Conclusions: Chronic intestinal pseudo-obstruction appears to be associated with immune deficiencies. It is unclear if the immune deficiencies, intestinal pseudo-obstruction, and the other medical conditions have a common underlying etiology. Repeated infections may be due to impaired immune function in children with chronic intestinal pseudo-obstruction. We recommend screening for immune deficiencies in children with chronic intestinal pseudo-obstruction.     

Inter-rater agreement and reliability of the COSMIN (COnsensus-based Standards for the selection of health status Measurement Instruments) Checklist

Background  

The COSMIN checklist is a tool for evaluating the methodological quality of studies on measurement properties of health-related patient-reported outcomes. The aim of this study is to determine the inter-rater agreement and reliability of each item score of the COSMIN checklist (n = 114).     

Quantification of urinary oxalate by liquid chromatography-tandem mass spectrometry with online weak anion exchange chromatography

BACKGROUND: Urinary oxalate is commonly measured with an enzymatic assay that is specific but requires a manual clean-up step to reduce ascorbic acid interference. We developed a urinary oxalate assay that uses liquid chromatography-tandem mass spectrometry (LC-MS/MS) with anion exchange chromatography and simple sample preparation. METHODS: We added calibrator or urine sample (10 microL) to 10 microL of (13)C2 oxalate and 400 microL of water and performed separation on a Waters OASIS WAX column, flow rate 0.6 mL/min, and then elution for 0.3 min with water containing 2 mmol/L ammonium acetate and 1 mL/L formic acid and for 1.0 min with 750 mL/L methanol containing 20 mL/L ammonia. We detected multiple reaction monitoring transitions m/z 88.6 > 60.5 and m/z 90.5 > 61.5 for oxalic acid and 13C2-oxalate, respectively, with a Quattro micro tandem mass spectrometer in electrospray-negative mode. RESULTS: Oxalate and 13C2-oxalate eluted at 1.2 min. Mean recovery was 95%, limit of detection 3.0 micromol/L, lower limit of quantification 100.0 micromol/L, linearity to 2212 micromol/L, imprecision <6%, and bias <3% at 166, 880, and 1720 micromol/L. Oxalate eluted after the main area of ion suppression. Mean response ratios for urine and aqueous samples, enriched at 200 and 1000 micromol/L, were 3.7% and 5.4%, respectively. No interference was observed from other organic acids. Passing and Bablock regression analysis comparing the Trinity Biotech enzymatic reagent set and LC-MS/MS showed LC-MS/MS = 1.06 (enzymatic assay) -21.2, r = 0.964, n = 110. Bland Altman analysis showed general agreement, with a mean bias of -1.9 mumol/L. CONCLUSION: This LC-MS/MS assay is applicable for quantifying urinary oxalate excretion.