Tacrolimus versus cyclosporine induction therapy in pulmonary transplantation in miniature swine.

OBJECTIVE: Tacrolimus has been shown to provide superior immunosuppression in various solid organ transplant settings. The purpose of our study was to compare the survival of porcine lung allografts after induction with either cyclosporine A (CsA) or tacrolimus. METHODS: Single lung transplantation from MHC mismatched donors was performed in 10 minipigs. Immunosuppression included 1.5 mg/kg per day methylprednisolone and 1.0 mg/kg per day azathioprine. CsA (n=5) was adjusted to trough levels of 300-500 ng/ml, tacrolimus (n=5) was adjusted to 16-26 ng/ml. All immunosuppressive drugs were discontinued on postoperative day (POD) 28. Allograft survival was monitored by sequential chest radiographs, bronchoscopy and transbronchial biopsy histology. Peripheral blood leukocytes were scanned for donor chimerism and CD3, CD4, CD8 and CD25 expression. RESULTS: The animals survived a 4-week course of immunosuppression without radiological or histological signs of rejection on POD 28. Median allograft survival in CsA-treated animals was 55+/-15 days and all animals rejected their grafts within 42 days after withdrawal of immunosuppression. In tacrolimus-treated animals, median survival was 152+/-65 days with the longest survivor being electively sacrificed on POD 390 (P=0.0064). The degree of donor leukocyte chimerism and the frequency of CD4+CD25+ T-cells were higher in the tacrolimus group, however, these differences were not statistically significant. CONCLUSION: The results of our study show that primary immunosuppression with tacrolimus is superior to cyclosporine after pulmonary allotransplantation in a large animal model.     

Evaluation of 188 consecutive homografts implanted in pulmonary position after 20 years.

OBJECTIVE: Homografts are considered the gold standard for right ventricular outflow tract reconstruction. Their long-term durability is limited, and alternatives became available. We evaluate their long-term hemodynamic performance to permit comparisons with alternative devices. METHODS: Between 1985 and 2004, 188 homografts were implanted in pulmonary position at our institution. Mean patient age was 24.8 years (range 2 days-75 years); 56 were female and 132 male. Total follow-up time was 1073 years. Fifty-eight percent were Ross procedures (mean age 31.5 years) and 42% were different procedures (mean age 15.6 years); main diagnoses were tetralogy of Fallot (48%), truncus arteriosus (14%), transposition of the great arteries (11%). Twenty-six percent were redo implantations. We evaluated freedom from death, explantation, insufficiency, relevant gradient, degeneration, and the interval between diagnosis of degeneration and therapeutic procedure (therapeutic gap). Results were stratified by indication, age, history, homograft size, and origin. RESULTS: Ten-year-freedom-from explantation was 82% in homografts >19 mm and 45% in smaller ones. Ten-year freedom from degeneration was 68% after Ross procedure and 25% after other operations; it was 83% in patients older than 10 years at implantation and 51% in younger ones. 'Non-Ross-procedure' and 'implantation age below 10 years' were the only independent risk factors for degeneration. The observed trend towards therapeutical gap reduction was not statistically significant. CONCLUSIONS: Homograft implantation in the pulmonary position can be performed with good long-term freedom from explantation. However, freedom from degeneration is a matter of concern. Therefore, alternative valved conduits are required especially for pediatric patients.     

Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations

OBJECTIVE We studied the relationship between plasma level of insulin-like growth hormone I (IGF-I), changes in lean body mass and in adipose mass, and adverse side-effects during human growth hormone (hGH) treatment of elderly men who had low IGF-I levels. DESIGN The first six months was a period of baseline observation. The subjects were then randomized into two groups so that during months 7–18, men in group I received hGH, and men in group II served as untreated controls. SUBJECTS Eighty-three overtly healthy elderly men, who were selected because their plasma IGF-I level was less than 0.35 units/ml. The men were randomly assigned in a ratio of three to one into group I (n= 62) or into group II (n= 21). MEASUREMENTS Plasma IGF-I level was measured monthly. Lean body mass and adipose mass were measured every six months. RESULTS Fifteen men left the study during the baseline period because of personal reasons or intercurrent medical events. In those who received drug (group I), there were a number of adverse reactions which could have been related to the hGH therapy: carpal tunnel syndrome 10, gynaecomastia 4, and hyperglycaemia 3. In total there were 27 dropouts from group I and two dropouts from group II after the six-month point, for a variety of medical and non-medical reasons, the majority probably not related to hGH therapy. During the hGH treatment of group I, plasma IGF-I increased from the range 0.10–0.35 units/ml into the range 0.5–2.2 units/ml. Among the 18 men who completed 12 months of hGH treatment without experiencing one of the three above-noted presumed hGH side-effects, mean and peak plasma IGF-I during treatment were significantly lower than among the 13 men who experienced carpal tunnel syndrome or gynaecomastia (one subject had both) while on hGH. With one exception, neither carpal tunnel syndrome nor gynaecomastia occurred in any individual with a mean IGF-I level less than 10 units/ml during hGH treatment. Twelve months of hGH treatment (group I) caused an increase in lean body mass to 106% of the initial baseline (month one of the protocol), and a reduction in adipose mass to 84% of the baseline. Meanwhile, the lean body mass of the untreated men in group II declined to 97% of the initial baseline. The body composition responses after 12 months of treatment in group I were larger in the men whose mean intra-treatment IGF-I level was 0.5–1.0 units/ ml, than in the men whose mean intra-treatment IGF-I level was 1.0–1.5 units/ml. CONCLUSIONS These observations show that when elderly men with low circulating IGF-I concentrations are treated continuously with hGH, elevation of plasma IGF-I above 10 units/ml is associated with a substantial frequency of carpal tunnel syndrome or gynaecomastia. It may be that the effects of the hormone in expanding lean body mass and reducing adipose mass can be achieved, and the side-effects avoided, by maintaining the mean IGF-I level in the range 0.5–1.0 units/ml.     

Korrektureingriffe am Fuß nach posttraumatischen ischämischen Kontrakturen

Operationsprinzip Korrektur eines Pes equinus adductus durch keilf?rmige Resektion des Chopart-Gelenkes mit Keilbasis dorsolateral. Bei gleichzeitigem Pes varus keilf?rmige Resektion des subtalaren Gelenkes mit Keilbasis lateral (Lange 1962 [7], Myerson et al. 1986 [8], Witt et al. 1985 [13]) (Abbildungen 1a bis 1f). Bei gleichzeitigem Tarsaltunnelsyndrom Dekompression des Nervus tibialis durch Spaltung des Retinaculum musculi flexorum. Zur Korrektur von Krallenzehen Resektion der jeweiligen distalen Grundphalangen nach Hohmann; bei flektierten Endgelenken Resektion der distalen Mittelphalangen. (Auf diese Techniken wird hier nicht eingegangen).      

Myocardial perfusion and function in dogs with moderate coronary stenosis

MRI studies of first-pass contrast enhancement with polylysine-Gd-DTPA and myocardial tagging using spatial modulation of magnetization (SPAMM) were performed to assess the feasibility of a combined regional myocardial blood flow and 2D deformation exam. Instrumented closed-chest dogs were imaged at a baseline control state (Cntl) followed by two interventions: moderate coronary stenosis (St) achieved by partial occlusion of the left anterior descending (LAD) and moderate coronary stenosis with dobutamine loading (StD). Hypoperfusion of the anterior region (ANT) of the myocardium (LAD distribution) relative to the posterior wall (POS) based on the upslope of the signal intensity time curve from the contrast-enhanced MR images was demonstrated only with dobutamine loading (ANT:POS Cntl=1.077 ± 0.15 versus ANT:POS StD=0.477 ± 0.11, P<0.03) and was confirmed with radio-labeled microspheres measurements (ANT:POS Cntl=1.18 ± 0.2 ml/min/g versus ANT:POS StD=0.44 ± 0.1 ml/min/g; P<0.002). Significant changes in regional myocardial shortening were only seen in the StD state (P<0.02); the anterior region showed impaired myocardial shortening with dobutamine loading (P=NS), whereas the nonaffected POS region showed a marked increase in shortening when compared with Cntl (Cntl=0.964 ± 0.02 versus StD=0.884 ± 0.03; P<0.001). These results demonstrate that an integrated quantitative assessment of regional myocardial function and semiquantitative assessment of myocardial blood flow can be performed noninvasively with ultrafast MRI.     

Is the risk of bipolar disorder in twins equal to the risk in singletons? A nationwide register-based study

BACKGROUND: A previous study demonstrated a higher rate of schizophrenia in dizygotic twins than in the general population, and a higher rate of schizophrenia in siblings of dizygotic twins than in siblings of monozygotic twins and singletons, pointing to a common genetic predisposition for dizygotic twinning and schizophrenia. The aim of the present study was to investigate whether these findings also apply to bipolar disorder. METHODS: Through record linkage between The Danish Twin Register, The Danish Psychiatric Central Register and The Danish Civil Registration System, the rate of bipolar disorder (diagnosed for the first time during admission to hospital) in dizygotic and monozygotic twins was compared with the rate in singletons, and the rate in siblings and parents of twins was compared with the rate in siblings and parents of singletons. RESULTS: The rate of bipolar disorder was the same in dizygotic twins, monozygotic twins and singletons as well as for parents and siblings of dizygotic twins, monozygotic twins and singletons. LIMITATIONS: The study is a register-based study, only including hospitalized patients. CONCLUSION: This study shows that there is an equal rate of bipolar disorder in twins and in singletons. Assuming that DZ twinning is under some genetic influence, a differential relationship between schizophrenia and DZ twinning on one hand and bipolar disorder and DZ twinning on the other hand may suggest differences in the genetic basis of the two diseases. The finding that the rate of bipolar disorder in monozygotic twins is the same as the rate of bipolar disorder in singletons supports studies finding no association between bipolar disorder and obstetric complications.     

Interaction of PSD-95 with potassium channels visualized by fluorescence lifetime-based resonance energy transfer imaging

Resonance energy transfer (RET) has been extensively used to estimate the distance between two different fluorophores. This study demonstrates how protein-protein interactions can be visualized and quantified in living cells by time-correlated single-photon counting (TCSPC) imaging techniques that exploit the RET between appropriate fluorescent labels. We used this method to investigate the association of the potassium inward rectifier channel Kir2.1 and the neuronal PDZ protein PSD-95, which has been implicated in subcellular targeting and clustering of ion channels. Our data show that the two proteins not only colocalize within clusters but also interact with each other. Moreover, the data allow a spatially resolved quantification of this protein-protein interaction with respect to the relative number and the proximity between interacting molecules. Depending on the subcellular localization, a fraction of 20 to 60% of PSD-95 molecules interacted with Kir2.1 channels, approximating their fluorescent labels by less than 5 nm.     

Analysis of microdissected prostate tissue with ProteinChip arrays--a way to new insights into carcinogenesis and to diagnostic tools

Prostate carcinomas are one of the most common malignancies in western societies. The pathogenesis of this tumor is still poorly understood. These tumors present with two characteristic features: epithelial-mesenchymal interactions, which play a pivotal role for tumor development and most of clinically manifest cancers arise in prostate proper compared to a minority of tumors which develop in the transitional zone. Deciphering the epithelial-mesenchymal cross talk and identification of molecular pecularities of the sub-populations of cells in different zones can therefore help understanding carcinogenesis and development of new, non-invasive tools for the diagnosis and prognosis of prostate carcinomas which has remained a challenge until today. A ProteinChip array technology (SELDI = surface enhanced laser desorption ionization) has been developed recently by Ciphergen Biosystems enabling analysis and profiling of complex protein mixtures from a few cells. This study describes the analysis of approximately 500-1000 freshly obtained prostate cells by SELDI-TOF-MS (surface enhanced laser desorption ionization time-of-flight mass spectrometry). Pure cell populations of stroma, epithelium and tumor cells were selected by laser assisted microdissection. Multiple specific protein patterns were reproducibly detected in the range from 1.5 to 30 kDa in 28 sub-populations of 4 tumorous prostates and 1 control. A specific 4.3 kDa peak was increased in the prostate tumor stroma compared to normal prostate proper and transitional zone stroma and increased in prostate tumor glands compared to normal prostate proper and transitional zone glands. Coupling laser assisted microdissection with SELDI provides tremendous opportunities to identify cell and tumor specific proteins to understand molecular events underlying prostate carcinoma development. It underlines the vast potential of this technology to better understand pathogenesis and identify potential candidates for new specific biomarkers in general which could help to screen for and distinguish disease entities, i.e. between clinically significant and insignificant carcinomas of the prostate.