The effect of cyclosporin A on the level of big endothelin in patients one year after orthotopic heart transplantation

Orthotopic heart transplantation (OHTx) is currently an established method for the treatment of end-stage heart failure. Persistent elevated plasma endothelin-1 (ET-1) levels have been reported after successful OHTx, the etiology of which is not yet fully understood. Immunosuppressive therapy is assumed to be one of the possible factors affecting ET-1 levels in the body. The present study evaluated the effect of cyclosporin A (CyA) on big ET-1 levels (a precursor of ET-1) in patients 1 year after successful OHTx. The study population comprised 34 patients after OHTx (28 males, 6 females, mean age 49.56±11.83 years) divided into two groups according to immunosuppressive protocol (17 patients on cyclosporine–azathioprine–prednisone and 17 patients on cyclosporine-mycophenolate mofetil-prednisone therapy). Plasma levels of big ET-1 and CyA were available for all patients. The control groups consisted of 10 healthy individuals (8 males, 2 females, mean age 41.1±11.55 years) and 20 patients with severe heart failure (15 males, 5 females, mean age 54.45±8.49 years), respectively. Big ET-1 plasma levels were found to be elevated in OHTx patients in comparison with healthy controls (13.63±11.3 fmol/ml vs 2.99±1.98 fmol/ml, P=0.005). Big ET-1 plasma levels correlated with plasma CyA levels in patients treated with cyclosporine–azathioprine–prednisone (r=0.53, P=0.03). This was not the case in either in the OHTx patients as a whole or in the subgroup of patients on cyclosporine–mycophenolate mofetil–prednisone therapy. The plasma levels of big ET-1 are dependent on CyA plasma levels 1 year after successful OHTx in patients treated with the immunosuppressive combination of cyclosporine, azathioprine, and prednisone. As this finding was not observed in the mycophenolate group of patients, mycophenolate mofetil might affect the alteration of the endothelin metabolism.     

Influence of donor- and recipient-specific factors on the postoperative course after combined pancreas–kidney transplantation

Introduction  

Simultaneous pancreas–kidney (SPK) transplantation is state-of-the-art therapy for patients with type-1 diabetes mellitus and end-stage renal failure. Improvement of long-term organ function and long-term survival after transplantation is the main focus of current research, but improvement of the early postoperative course is very important for the patient. Pancreas transplantation is associated with postoperative complications. We defined and identified donor- and recipient-specific factors related to postoperative complications.     

Leukemia relapse after allogeneic bone marrow transplantation: how does chronic graft-versus-host disease influence the pattern and onset of relapse?

We describe a pattern of relapse in 601 patients who received an allogeneic hematopoietic stem cell transplant at our institution for acute or chronic leukemia and myelodysplasia over a period of 18 years. We show a correlation between chronic graft-versus-host disease and extramedullary relapse, suggesting that the expected graft versus leukemia effect in patients with chronic graft-versus-host disease may preferentially maintain marrow remission without preventing relapse in extramedullary sites.     

Is the ABO incompatibility a risk factor in bone marrow transplantation?

ABO histo-bloodgroups are strong transplantation antigens. In bone marrow transplantation, foreign ABO red cell antigens are not ignored by the immune system of the host, neither by the immunocompetent cells of the graft. Although ABO incompatibility is not considered a contraindication in bone marrow transplantation (BMT), its clinical consequences are still a matter of investigation. An overview of reports published by different groups is given and discussed. They present conflicting data regarding the role of the ABO match between patient and donor in the haematopoietic stem cell (HSC) transplantation. We report on the clinical outcome of bone marrow transplantation in 223 patients who received grafts from MHC identical siblings. Included are 139 ABO identical, 32 ABO minor mismatched, 34 major mismatched and 13 bi-directionally mismatched pairs. The statistical evaluation of standard parameters used to monitor the post-transplant period gave a proof that in neither group of patients with an ABO incompatible donor the recovery and success rate of transplantation, including the relapse incidence, risk of graft vs. host disease (GVHD) or overall survival, were significantly inferior. However, in all three cohorts of ABO mismatched patients, a delayed recovery of neutrophils was recorded as compared to the group receiving an ABO compatible graft. These finding leads us to the conclusion that the ABO compatibility is not a disadvantage in BMT, whereas the delayed recovery of neutrophils in patients having received an ABO mismatched graft is probably reflecting a transient humoral process leading to immune tolerance and graft accommodation.     

Effects of 3 years treatment with once-yearly zoledronic acid on the kinetics of bone matrix maturation in osteoporotic patients

Summary

Once-yearly administration of intravenous zoledronic acid for 3 years in humans affects the kinetics of matrix filling in by mineral, independent of bone turnover.

Introduction

Yearly 5-mg infusions of zoledronic acid (ZOL) for 3 years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the kinetics of forming bone material properties maturation.

Methods

Iliac crest biopsies from the HORIZON-PFT clinical trial were analyzed by Raman microspectroscopy in actively bone-forming surfaces as a function of tissue age in trabecular and osteonal bone, to determine ZOL’s effect on bone material quality indices maturation kinetics.

Results

Mineral/matrix ratio increased in both groups as a function of tissue age, at both osteonal- and trabecular-forming surfaces; ZOL exhibiting the greatest increase in the trabecular surfaces only. The proteoglycan content showed a dependency on tissue age in both trabecular and osteonal surfaces, with ZOL exhibiting lower values in the tissue age 8–22 days in the trabecular surfaces. Mineral crystallinity (crystallite length and thickness) showed a dependence on tissue age, with ZOL exhibiting lower crystallite length compared with placebo only in the 8- to 22-day-old tissue at trabecular surfaces, while crystal thickness was lower in the 1- to 5-day-old tissue at both osteonal and trabecular surfaces.

Conclusions

The results of the present study suggest that once-yearly administration of intravenous ZOL for 3 years in humans does not exert any adverse effects on the evolution of bone material properties at actively forming osteonal and trabecular surfaces, while it may have a beneficial effect on the progression of the mineral-to-matrix ratio and mineral maturity bone quality indices.     

Hyperphosphaturia after kidney transplantation in syngeneic rats: effects on nephrocalcinosis and bone metabolism?

BACKGROUND: Studies on kidney transplantation have thus far mainly dealt with surgical techniques, immunology, and transplant tolerance. Disturbed mineral metabolism after renal denervation has not received much attention. Basic physiological research in short-term experiments has shown that experimental renal denervation in rats leads to parathormone (PTH)-independent hyperphosphaturia (HPU). HPU and other metabolic complications also have been described after clinical kidney transplantation. Furthermore, there is an unexpected increase in the risk of bone fracture. However, these studies have examined an organism pre-damaged with regard to the parathyroid and immunosuppression. Experimental investigations in syngeneic rats were performed to see whether HPU also occurs after transplantation and thus after denervation and which target organs are involved. METHODS: Thirty-six male Lewis rats subjected to laparotomy (n = 12), unilateral nephrectomy (n = 12), or unilateral transplantation and bilateral nephrectomy (n = 12) were observed for 18 weeks. RESULTS: Animals that underwent transplantation had a significant loss of phosphate in the urine not associated with decreased calcium, phosphate, or magnesium in bone. Stability test showed no deterioration, despite a slight increase in the bone parameters of alkaline phosphatase, cyclic AMP, and hydroxyproline with unchanged calciotropic hormones. Nephrocalcinosis was not observed. Parallel to HPU, there was a compensatory reduction in fecal phosphate excretion. CONCLUSIONS: The loss of phosphate after clinical kidney transplantation in the predamaged parathyroid hormone control system as well as immunosuppression and a surprising increase in the incidence of bone fractures may be explained by the denervation-related loss of phosphate. The lack of intestinal counter-regulation could be an important pathomechanism.     

Study of gelatinized marrow stroma osteoblasts and true bone ceramic active bone

Trueboneceramic(TBC)isacomparativelygoodframematerialinbonetissueengineeringbecauseofitsadvantagesofnaturalbonetrabeculestructure, easydegradation, nonimmunogenicity, easymanufacture, abundantresources, andlowcost, etc1.Owingtoitsfragileness, nonductility, andasmoothsurfaceunfitforseedcelladhesion, itisstilldifficultforwidespreadclinicaluse. Bytakingadvantageofthepeculiaritiesofsodiumalginatethatwilltransformfromliquidstateintogelatinationstateandproducelateralconjunctionwhencombiningwithbiva…     

A complex fracture of the hyoid bone and the larynx after a bicycle accident – Case report and review of literature

Introduction and importanceReports about laryngeal trauma and fractures of the hyoid bone are rare in the literature. Most cases are forensic cases and the results of postmortem analysis. Traumatic larynx and hyoid bone fractures represent a rare but important differential diagnosis of the common symptom hoarseness.Case presentationA 60-year-old female patient presented with unclear dysphonia and globus sensation following intubation for a surgical treatment for a lower leg fracture after a bicycle accident two months ago. Endoscopy and the computed tomography (CT) of the neck revealed a fixed and immobile fractured piece of the larynx, a hyoid bone fracture and a pseudarthrosis between the greater horn of the hyoid bone and the upper edge of the thyroid cartilage. The hyoid bone fracture led to a distortion of the supraglottis. After surgical removal of the fractured part of the hyoid bone and the pseudarthrosis separation, the supraglottis appeared symmetrical again. Four weeks after surgery the patient was symptom-free.Clinical discussionThough combined hyoid bone and larynx fractures after traumatic injuries are rare, they represent an important differential diagnosis in trauma patients with dysphagia or dysphonia. The clinical symptoms can vary and occur immediately or within a latent period taking weeks or months until the proper diagnosis. Depending on the symptoms, surgical management can be effective.ConclusionAn isolated partial resection of the hyoid bone with separation of the pseudarthrosis is a reasonable therapeutic option and can lead to completely resolving symptom. Preoperatively, a CT provides further valuable information.     

Single-dose daily administration of cyclosporin A for relapsing nephrotic syndrome

Cyclosporin A (CsA) has been reported to be effective as a steroid-sparing agent in frequently relapsing nephrotic syndrome (FRNS). However, low efficacy has sometimes been observed in selected patients with steroid-dependent FRNS. We speculated that a low peak level of CsA in the blood might be the cause, and conducted a prospective pilot study on such steroid-dependent FRNS patients to examine whether single-dose daily administration of CsA would yield a sufficient peak blood level, and therefore a satisfactory steroid-sparing effect. Five children with steroid-dependent FRNS, aged 7-16 years, were enrolled in the study. All had been treated with prednisolone combined with twice daily CsA ( T), which was subsequently replaced with the single-dose daily administration protocol ( S), because of a poor steroid-sparing effect. Although the mean daily CsA dosage with the S protocol was significantly lower than with the T protocol ( S 2.4+/-1.1 mg/kg per day vs. T 3.6+/-0.8 mg/kg per day, P<0.05), the mean peak blood level tended to be higher with the S protocol than the T protocol ( S 764+/-122 ng/ml vs. T 358+/-250 ng/ml, P=0.1797) without mean trough blood level elevation. As a result, the minimum dose of prednisolone required for maintenance of clinical remission tended to be lower with the S than the T protocol ( S 0.4+/-0.2 mg/kg on alternate days vs. T 0.6+/-0.4 mg/kg on alternate days, P=0.0656). No evidence of CsA nephrotoxicity was observed in a repeat renal biopsy performed 9 months after commencement of the S protocol in one patient. These clinical observations, although on a small number of patients and preliminary, suggest that single-dose daily administration of CsA might be an attractive protocol in selected patients with steroid-dependent FRNS in whom CsA administration by the conventional protocol is associated with a poor steroid-sparing effect.     

Effects of knee extensor muscle strength on the incidence of osteopenia and osteoporosis after 6 years

The association of knee extensor muscle strength with bone mineral density (BMD) has been reported in cross-sectional epidemiological studies, but it remains unclear whether or not this is the case with longitudinal change. Thus, we investigated whether or not the knee extension strength can predict the incidence of osteopenia or osteoporosis after 6 years, then compared the difference between sexes. Subjects were 1255 community-dwelling Japanese men and menopaused women, aged 40–81 years. BMD of lumbar spine and femoral neck was assessed by dual-energy X-ray absorptiometry twice at 6-year intervals. Subjects were divided into three groups, normal, osteopenia, and osteoporosis, depending on their young adult mean BMD % value. In the cross-sectional analysis the correlations between the knee extension strength and BMD of the two regions were examined, using Pearson’s correlation coefficient. Longitudinal analyses were then conducted to determine the odds ratio, controlled for age and BMI, given that those who were normal in the initial stage developed osteopenia or osteoporosis after 6 years, for every 1 SD decrease in knee extension strength, as well as those who first had normal or osteopenia and then developed osteoporosis. Cross-sectional analysis showed a statistically significant relation between knee extensor muscle strength and BMD at both the lumbar spine (p = 0.02) and the femoral neck (p < 0.0001) only in men. The longitudinal analysis showed the significant effect of muscle strength on the loss of femoral neck BMD from normal to osteopenia or osteoporosis both in men (OR 1.84, 95 % CI 1.36–2.48, p < 0.0001) and in women (OR 1.29, 95 % CI 1.002–1.65, p < 0.05), as well as on the loss of spinal BMD from normal or osteopenia to osteoporosis only in men (OR 2.97, 95 % CI 1.07–8.23, p < 0.05). The results suggest the importance of knee extension strength to maintain the bone health of the proximal femur and spine in aging particularly in men.     

Quantitative trait locus on chromosome X affects bone loss after maturation in mice

Genetic programming is known to affect the peak bone mass and bone loss after maturation. However, little is known about how polymorphic genes on chromosome X (Chr X) modulate bone loss after maturation. We previously reported a quantitative trait locus (QTL) on Chr X, designated Pbd3, which had a suggestive linkage to bone mass, in male SAMP2 and SAMP6 mice. In this study, we aimed to clarify the effects of Pbd3 on the skeletal phenotype. We generated a congenic strain, P2.P6-X, carrying a 45.6-cM SAMP6-derived Chr X interval on a SAMP2 genetic background. The effects of Pbd3 on the bone phenotype were determined by microcomputed tomography (μCT), whole-body dual-energy X-ray absorptiometry (DXA), serum bone turnover markers, and histomorphometric parameters. Both the bone area fraction (BA/TA) on μCT and whole-body DXA revealed reduced bone loss in P2.P6-X compared with that in SAMP2. The serum concentrations of bone turnover markers at 4 months of age were significantly lower in P2.P6-X than in SAMP2, but did not differ at 8 months of age. These results were observed in female mice, but not in male mice. In conclusion, a QTL within a segregated 45.6-cM interval on Chr X is sex-specifically related to the rate of bone loss after maturation.     

Influence of the induced membrane filled with syngeneic bone and regenerative cells on bone healing in a critical size defect model of the rat’s femur

IntroductionThe induced membrane technique for the treatment of large bone defects consists of a 2-stage procedure. In the first stage, a polymethylmethacrylate (PMMA) cement spacer is inserted into the bony defect of a rat’s femur and over a period of 2–4 weeks a membrane forms that encapsulates the defect/spacer. In a second operation the membrane is opened, the PMMA spacer is removed and the resulting cavity is filled with autologous bone.Since little effort has been made to replace the need for autologous bone this study was performed to elucidate the influence of different stem cells and the membrane itself on bone healing in a critical size femur defect model in rats.Especially the question should be addressed whether the use of stem cells seeded on a β-TCP scaffold is equivalent to syngeneic bone as defect filling in combination with the induced membrane technique.Materials and MethodsA total of 96 male Sprague-Dawley (SD) rats received a 10 mm critical size defect of the femur, which was stabilized by a plate osteosynthesis and filled with PMMA cement. In a second step the spacer was extracted and the defects were filled with syngeneic bone, β-TCP with MSC + EPC or BM-MNC. In order to elucidate the influence of the induced membrane on bone defect healing the induced membrane was removed in half of the operated femurs. The defect area was analysed 8 weeks later for bone formation (osteocalcin staining), bone mineral density (BMD) and bone strength (3-point bending test).ResultsNew bone formation, bone mineral density and bone stiffness increased significantly, if the membrane was kept. The transplantation of biologically active material (syngeneic bone, stem cells on b-TCP) into the bone defect mostly led to a further increase of bone healing. Syngeneic bone had the greatest impact on bone healing however defects treated with stem cells were oftentimes comparable.ConclusionFor the first time we demonstrated the effect of the induced membrane itself and different stem cells on critical size defect healing. This could be a promising approach to reduce the need for autologous bone transplantation with its’ limited availability and donor site morbidity.     

Treatment of osteonecrosis of the femoral head by percutaneous decompression and autologous bone marrow mononuclear cell infusion

Osteonecrosisfrequentlycausesfemoralheadcollapseanddisablingarthritis,whichultimatelyleadstototaljointreplacement.Ahighfailurerateofjointreplacementunderscoresthejoint preservingprocedures.Varioussurgicaltechniques havebeenusedasatherapyforosteonecrosisofthe femoralhead,whichincludecoredecompressionalone orwithnonvascualrizedorvascularizedbonegraft(DBM,IBG,vascularizedfibulaetc.).1Sofar,the mechanismoftheosteonecrosisisstillunclear(except traumatic),andthereisnouniversalmethodforit especiall…     

Treatment of transient bone marrow oedema of the hip—a comparative study

Between 1990 and 2000, we treated 43 patients with transient bone marrow oedema of the hip. Five were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and limited weight bearing, and 38 by core decompression followed by limited weight bearing. At follow-up 2-10 years later, all patients were assessed by a structured interview as well as the Harris hip score (HHS) and the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC). Both groups reached the same clinical outcome (HHS and WOMAC). Core decompression enabled a significantly faster recovery. There were no complications, but progression to avascular necrosis was seen in both groups. Core decompression induced fast pain relief, making it the preferable treatment.