Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene

We report the phenotype of mice with targeted disruption of the Trpv6 (Trpv6 KO) epithelial calcium channel. The mice exhibit disordered Ca(2+) homeostasis, including defective intestinal Ca(2+) absorption, increased urinary Ca(2+) excretion, decreased BMD, deficient weight gain, and reduced fertility. Although our Trpv6 KO affects the closely adjacent EphB6 gene, the phenotype reported here is not related to EphB6 dysfunction. INTRODUCTIOn: The mechanisms underlying intestinal Ca(2+) absorption are crucial for overall Ca(2+) homeostasis, because diet is the only source of all new Ca(2+) in the body. Trpv6 encodes a Ca(2+)-permeable cation channel responsible for vitamin D-dependent intestinal Ca(2+) absorption. Trpv6 is expressed in the intestine and also in the skin, placenta, kidney, and exocrine organs. MATERIALS AND METHODS: To determine the in vivo function of TRPV6, we generated mice with targeted disruption of the Trpv6 (Trpv6 KO) gene. RESULTS: Trpv6 KO mice are viable but exhibit disordered Ca(2+) homeostasis, including a 60% decrease in intestinal Ca(2+) absorption, deficient weight gain, decreased BMD, and reduced fertility. When kept on a regular (1% Ca(2+)) diet, Trpv6 KO mice have deficient intestinal Ca(2+) absorption, despite elevated levels of serum PTH (3.8-fold) and 1,25-dihydroxyvitamin D (2.4-fold). They also have decreased urinary osmolality and increased Ca(2+) excretion. Their serum Ca(2+) is normal, but when challenged with a low (0.25%) Ca(2+) diet, Trpv6 KO mice fail to further increase serum PTH and vitamin D, ultimately developing hypocalcemia. Trpv6 KO mice have normal urinary deoxypyridinoline excretion, although exhibiting a 9.3% reduction in femoral mineral density at 2 months of age, which is not restored by treatment for 1 month with a high (2%) Ca(2+) "rescue" diet. In addition to their deranged Ca(2+) homeostasis, the skin of Trpv6 KO mice has fewer and thinner layers of stratum corneum, decreased total Ca(2+) content, and loss of the normal Ca(2+) gradient. Twenty percent of all Trpv6 KO animals develop alopecia and dermatitis. CONCLUSIONS: Trpv6 KO mice exhibit an array of abnormalities in multiple tissues/organs. At least some of these are caused by tissue-specific mechanisms. In addition, the kidneys and bones of Trpv6 KO mice do not respond to their elevated levels of PTH and 1,25-dihydroxyvitamin D. These data indicate that the TRPV6 channel plays an important role in Ca(2+) homeostasis and in other tissues not directly involved in this process.

Does perioperative glucocorticosteroid treatment correlate with disturbance in surgical wound healing after treatment of facial fractures? A retrospective study

PURPOSE: To clarify whether perioperative glucocorticosteroid treatment used in association with repair of facial fractures predisposes to disturbance in surgical wound healing (DSWH). PATIENTS AND METHODS: Retrospective review of records of patients who had undergone open reduction, with or without ostheosynthesis, or had received reconstruction of orbital wall fractures during the 2-year period from 2003 to 2004. RESULTS: Steroids were administered to 100 patients (35.7%) out of a total of 280. Dexamethasone was most often used, with the most common regimen being dexamethasone 10 mg every 8 hours over 16 hours, with a total dose of 30 mg. The overall DSWH rate was 3.9%. The DSWH rate for patients who had received perioperative steroids was 6.0%, and the corresponding rate for patients who did not receive steroids was 2.8%. The difference was not statistically significant. An intraoral surgical approach remained the only significant predictor to DSWH. CONCLUSIONS: With regard to DSWH, patients undergoing operative treatment of facial fractures can safely be administered doses of 30 mg or less of perioperative glucocorticosteroids equivalent to dexamethasone.

Head Reduction Osteotomy With Additional Containment Surgery Improves Sphericity and Containment and Reduces Pain in Legg-Calvé-Perthes Disease.

BACKGROUND Severe femoral head deformities in the frontal plane such as hips with Legg-Calvé-Perthes disease (LCPD) are not contained by the acetabulum and result in hinged abduction and impingement. These rare deformities cannot be addressed by resection, which would endanger head vascularity. Femoral head reduction osteotomy allows for reshaping of the femoral head with the goal of improving head sphericity, containment, and hip function. QUESTIONS/PURPOSES Among hips with severe asphericity of the femoral head, does femoral head reduction osteotomy result in (1) improved head sphericity and containment; (2) pain relief and improved hip function; and (3) subsequent reoperations or complications? METHODS Over a 10-year period, we performed femoral head reduction osteotomies in 11 patients (11 hips) with severe head asphericities resulting from LCPD (10 hips) or disturbance of epiphyseal perfusion after conservative treatment of developmental dysplasia (one hip). Five of 11 hips had concomitant acetabular containment surgery including two triple osteotomies, two periacetabular osteotomies (PAOs), and one Colonna procedure. Patients were reviewed at a mean of 5 years (range, 1-10 years), and none was lost to followup. Mean patient age at the time of head reduction osteotomy was 13 years (range, 7-23 years). We obtained the sphericity index (defined as the ratio of the minor to the major axis of the ellipse drawn to best fit the femoral head articular surface on conventional anteroposterior pelvic radiographs) to assess head sphericity. Containment was assessed evaluating the proportion of patients with an intact Shenton's line, the extrusion index, and the lateral center-edge (LCE) angle. Merle d'Aubigné-Postel score and range of motion (flexion, internal/external rotation in 90° of flexion) were assessed to measure pain and function. Complications and reoperations were identified by chart review. RESULTS At latest followup, femoral head sphericity (72%; range, 64%-81% preoperatively versus 85%; range, 73%-96% postoperatively; p = 0.004), extrusion index (47%; range, 25%-60% versus 20%; range, 3%-58%; p = 0.006), and LCE angle (1°; range, -10° to 16° versus 26°; range, 4°-40°; p = 0.0064) were improved compared with preoperatively. With the limited number of hips available, the proportion of an intact Shenton's line (64% versus 100%; p = 0.087) and the overall Merle d'Aubigné-Postel score (14.5; range, 12-16 versus 15.7; range, 12-18; p = 0.072) remained unchanged at latest followup. The Merle d'Aubigné-Postel pain subscore improved (3.5; range, 1-5 versus 5.0; range, 3-6; p = 0.026). Range of motion was not observed to have improved with the numbers available (p ranging from 0.513 to 0.778). In addition to hardware removal in two hips, subsequent surgery was performed in five of 11 hips to improve containment after a mean interval of 2.3 years (range, 0.2-7.5 years). Of those, two hips had triple osteotomy, one hip a combined triple and valgus intertrochanteric osteotomy, one hip an intertrochanteric varus osteotomy, and one hip a PAO with a separate valgus intertrochanteric osteotomy. No avascular necrosis of the femoral head occurred. CONCLUSIONS Femoral head reduction osteotomy can improve femoral head sphericity. Improved head containment in these hips with an often dysplastic acetabulum requires additional acetabular containment surgery, ideally performed concomitantly. This can result in reduced pain and avascular necrosis seems to be rare. With the number of patients available, function did not improve. Therefore, future studies should use more precise instruments to evaluate clinical outcome and include longer followup to confirm joint preservation. LEVEL OF EVIDENCE Level IV, therapeutic study.