Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial

Background: Calcitriol therapy is the mainstay of therapy for the treatment of secondary hyperparathyroidism. Oral administration of calcitriol is necessary in CAPD patients, but no studies have directly compared different routes of administration in this patient population. Methods: To determine if the peak serum calcitriol level (pulse therapy) is more important than the total delivered dose, we randomized CAPD patients with mild to moderate secondary hyperparathyroidism to receive either pulse (3.0 &mgr;g twice a week, n=10) or daily (0.75 &mgr;g a day, n=8) oral calcitriol in comparable weekly doses. The main comparison was the rate of decline of serum intact parathyroid hormone (PTH) levels to reach the desired end-point of 100 pg/ml. The patients were dialysed with low-calcium dialysate and received only calcium-containing phosphate binders. Results: Pharmacokinetic analysis after a single dose of 3.0 &mgr;g (pulse) vs 0.75 &mgr;g (daily) revealed 1,25(OH)2-vitamin D levels to be higher in the pulse group at 3 and 6 h, but equivalent by 12 h. The area under the curve for 1 week of daily and 1 week of pulse therapy was equal. The patients in the 2 arms had equivalent basal serum levels of PTH (pulse=562±291 vs daily=454±113 pg/ml), calcium (pulse=2.32±0.20 vs daily=2.32±0.12 mmol/l) and phosphorus (pulse=1.32±0.52 vs daily=1.35±0.26 mmol/l). The time required for the PTH to decrease to 100 pg/ml and rate of decline in PTH were similar (time: pulse=14.2±6.8 weeks, daily=12.2±7 weeks; rate: pulse=7.4±4.2 vs daily=8.4±4.2% PTH/week; P=NS). The serum calcium increased similarly in both groups. Hypercalcaemia (>2.9 mmol/l) was rare (pulse=3, daily=2 episodes). Conclusions: This study demonstrates that pulse and daily calcitriol are similarly effective and safe for the treatment of mild to moderate secondary hyperparathyroidism in CAPD patients despite higher peak levels of 1,25(OH)2-vitamin D with pulse therapy. Key words: calcitriol; calcium balance; CAPD; dialysis; hyperparathyroidism; renal osteodystrophy      

Complications of craniofacial resection for malignant tumors of the skull base: report of an International Collaborative Study

BACKGROUND: Advances in imaging, surgical technique, and perioperative care have made craniofacial resection (CFR) an effective and safe option for treating malignant tumors involving the skull base. The procedure does, however, have complications. Because of the relative rarity of these tumors, most existing data on postoperative complications come from individual reports of relatively small series of patients. This international collaborative report examines a large cohort of patients accumulated from multiple institutions with the aim of identifying patient-related and tumor-related predictors of postoperative morbidity and mortality and set a benchmark for future studies. METHODS: One thousand one hundred ninety-three patients from 17 institutions were analyzed for postoperative mortality and complications. Postoperative complications were classified into systemic, wound, central nervous system (CNS), and orbit. Statistical analyses were carried out in relation to patient characteristics, extent of disease, prior radiation treatment, and type of reconstruction to determine factors that predicted mortality or complications. RESULTS: Postoperative mortality occurred in 56 patients (4.7%). The presence of medical comorbidity was the only independent predictor of mortality. Postoperative complications occurred in 433 patients (36.3%). Wound complications occurred in 237 (19.8%), CNS-related complications in 193 (16.2%), orbital complications in 20 (1.7%), and systemic complications in 57 (4.8%) patients. Medical comorbidity, prior radiation therapy, and the extent of intracranial tumour involvement were independent predictors of postoperative complications. CONCLUSIONS: CFR is a safe surgical treatment for malignant tumors of the skull base, with an overall mortality of 4.7% and complication rate of 36.3%. The impact of medical comorbidity and intracranial tumor extent should be carefully considered when planning therapy for patients whose tumors are amenable to CFR.     

Incidence and Characteristics of Atypical Femoral Fractures: Clinical and Geometrical Data

Despite the multitude of studies published on atypical femoral fractures (AFFs), a profile for patients at risk does not exist. This study aimed first at estimating AFF incidence over a 19‐month‐period in Quebec City using the ASBMR Task force criteria to define AFF. The medical records of patients hospitalized for hip or femoral fracture between June 1, 2009, and December 31, 2010, were reviewed. Thirty‐six cases of atypical fractures were identified during the 19‐month period, representing an AFF incidence of 7.0 (range, 4.7 to 9.3) cases per 100,000 person‐years. In the second part of the study, data regarding the characteristics suspected of increasing the risks of AFF were collected from medical and pharmacological records, proximal femur radiographs, and patient interviews. The data regarding each patient with an AFF during years 2008‐2011 were compared to two controls with a hip or femoral fragility fracture or a traumatic fracture, paired for age and sex. Twenty patients with AFF were added to the 36 patients with AFF selected in the first part, thereby 56 patients with AFF were investigated. The association between the occurrence of AFF and bisphosphonates (BPs) use was proven statistically significant in multivariate analysis, odds ratio (OR) = 10.39 (95% CI, 2.22 to 48.58; p = 0.0029). Compared to controls, patients with AFF had excessive femoral offset (43.1 mm versus 38.3 mm, p = 0.0007), proximal femoral neck angle in varus (128.9 degrees versus 134.0 degrees, p < 0.0001), and had greater proximal cortical thickness. This retrospective study confirms the low incidence of AFF, confirms its significant association with exposure to BPs, and reveals the possible contribution of proximal femoral geometry in AFF occurrence. © 2016 American Society for Bone and Mineral Research.     

Growth of bone marrow stromal cells on small intestinal submucosa: an alternative cell source for tissue engineered bladder

OBJECTIVE: To assess the potential use of bone marrow stromal cell (BMSC)-seeded biodegradable scaffold for bladder regeneration in a canine model, by characterizing BMSCs and comparing them to bladder smooth muscle cells (SMCs) by immunohistochemistry, growth capability, and contractility. MATERIALS AND METHODS: Bone marrow was taken by direct needle aspiration from the femurs of five beagle dogs for the in vitro study. Mononuclear cells were isolated by Ficoll-Paque density gradient centrifugation and cultivated in medium 199 with 10% fetal bovine serum. BMSCs were characterized by cell proliferation, in vitro contractility, immunohistochemical analysis, and the growth pattern on small intestinal submucosa (SIS) scaffolds compared to bladder SMC cultures from the same dogs. Another six dogs had a hemicystectomy and bladder augmentation with BMSC-seeded (two), bladder cells including urothelial cells plus SMC-seeded SIS (two) and unseeded SIS scaffolds (two). The six dogs were followed for 10 weeks after augmentation. RESULTS: In vitro BMSCs had a significant contractile response to calcium-ionophore, with a mean (sem) 36 (2)%, relative contraction (P < 0.01), which was similar to bladder SMCs but markedly different from fibroblasts. BMSCs also expressed alpha-smooth muscle actin by immunohistochemical staining and Western blotting, but did not express desmin or myosin. In vivo, both BMSC-seeded and bladder cell-seeded SIS grafts had solid smooth-muscle bundle formation throughout the graft. CONCLUSIONS: BMSCs had a similar cell proliferation, histological appearance and contractile phenotype as primary cultured bladder SMCs. SIS supported three-dimensional growth of BMSCs in vitro, and BMSC-seeded SIS scaffold promoted bladder regeneration in a canine model. BMSCs may serve as an alternative cell source in urological tissue engineering.     

Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts

BACKGROUND: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates. METHODS: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry. RESULTS: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected. CONCLUSIONS: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.     

Primärer endoprothetischer Ellbogengelenkersatz bei komplexen intraartikulären distalen Humerusfrakturen

Introduction

Open reduction and internal fixation of multifragmentary intra-articular fractures of the distal humerus often do not provide satisfactory results in elderly patients with osteoporosis.

Method

From December 2001 to January 2008 a total elbow arthroplasty (Coonrad-Morrey, Zimmer, USA) was performed on 12 patients (average age 81±9  ears) who presented with a type C distal humeral fracture. The mean time of follow-up with clinical and radiological assessment was 28±17 months.

Results

The Mayo score showed a good functional result with an average of 81±9 out of 100. DASH and SECEC scores showed a fair result with respect to elbow function (43±8 and 68±7 points, respectively). The average range of motion of all patients was 120-33-0°. Heterotopic ossifications were found by X-ray examination in 4 cases and asymptomatic radiolucent lines in 4 cases.

Conclusion

Primary total elbow arthroplasty for complex intra-articular distal humerus fractures in elderly patients has good functional results and is an alternative to osteosynthesis.     

Patient satisfaction and functional status after treatment of infection at the site of a total knee arthroplasty with use of the PROSTALAC articulating spacer

BACKGROUND: Two-stage exchange arthroplasty remains the standard treatment of infection at the site of a total knee arthroplasty. The clinical and functional outcomes associated with the use of an articulating antibiotic spacer for two-stage revision for infection are not well established. We conducted a retrospective study to evaluate the outcomes associated with the use of the PROSTALAC articulating spacer between the first and second stages. METHODS: Fifty-eight patients underwent two-stage revision total knee arthroplasty for infection between January 1997 and December 1999. Of these, fifty-four were alive at the time of follow-up and forty-seven were available for inclusion in the present retrospective study. In all patients, a prosthesis of antibiotic-loaded acrylic cement (the PROSTALAC system) was implanted during the first stage after débridement. The amount of osteolysis that occurred between the stages and the range of motion of the knee joint were measured. After two years of follow-up, outcomes were assessed with use of the WOMAC, Oxford-12, and SF-12 instruments as well as a satisfaction questionnaire. RESULTS: At a minimum of two years (average, forty-one months) after revision arthroplasty, two patients (4%) had had a recurrence of infection. The amount of bone loss was unchanged between stages, and the range of movement of the knee improved from 78.2 degrees before the first stage to 87.1 degrees at two years. The average normalized WOMAC function and pain scores were 68.9 and 77.1, respectively; the average Oxford-12 score was 67.3; the average SF-12 mental and physical scores were 53.7 and 41.2, respectively; and the average satisfaction score was 71.7. CONCLUSION: A revision operation for infection at the site of a total knee replacement with use of an articulating spacer was associated with reasonable function and satisfaction scores. These findings may be related to the articulating features of the PROSTALAC system, which permits full active movement of the knee in the early postoperative period.     

Mycophenolate mofetil significantly reduces leukocyte graft infiltration after heterotopic cardiac transplantation in a rat model: comparative study with cyclosporine and FK 506.

BACKGROUND: The purpose of the study was to evaluate the effects of cyclosporine (CsA), FK 506 and mycophenolate mofetil (MMF) on graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) after cardiac transplantation in rats. METHODS: Three hundred forty animals were transplanted and randomly divided into 4 groups: CsA, 3 mg/kg/d (n = 74); MMF, 40 mg/kg/d (n = 96); FK 506, 0.3 mg/kg/d (n = 96); and a control group receiving no immunosuppressive therapy (n = 74). Three or 4 animals from each group were killed at intervals of 1 to 4 days up to Day 60. Immunohistochemistry was performed using monoclonal antibodies (MAb) against CD4, CD8, CD11a and CD18. Positively stained cells were analyzed in the perivascular space (PVS) of intra- and epicardial arteries. Statistical analysis was performed using area-under-the-curve assessment with an extended t-test. RESULTS: CsA and FK 506 reduced the presence graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) in the PVS of intra- and epicardial arteries when compared with control animals. MMF therapy resulted in a further significant reduction in infiltrating leukocytes when compared with the 2 calcineurin inhibitors. MMF had a faster onset of action than the calcineurin inhibitors. CsA and FK 506 required 12 to 20 additional days to achieve the reducing effect of graft infiltration seen in MMF-treated animals. CONCLUSION: MMF possesses potent infiltration-blocking properties and its application leads to a greater reduction of cellular infiltration in the course of transplant rejection when compared with calcineurin inhibitors.