Let's talk about...chloroplast import.
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Biological Transport, Active↗
Biomedical subjects
T Becker
Publications and source records attributed to T Becker.
Multiple testing in the context of haplotype analysis revisited: application to case-control data.
We have lately presented a testing procedure for family data which accounts for the multiple testing problem that is induced by the enormous number of different marker combinations that can be analyzed in a set of tightly linked markers. Most methods of haplotype based association analysis already require simulations to obtain an uncorrected P value for a specific marker combination. As shown before, it is nevertheless not necessary to carry out nested simulations to obtain a global P value that properly corrects for the multiple testing of different marker combinations without neglecting the dependency of the tests. We have now implemented this approach for case-control data in our program FAMHAP, as this data structure currently plays a dominant role in the field. We consider different ways to deal with phase ambiguities and two different statistical tests for the underlying single marker combinations to obtain uncorrected P values. One test statistic is chi-square based, the other is a haplotype trend regression. The performance of these different tests in the multiple testing situation is investigated in a large simulation study. We obtain a considerable gain in power with our global P values as opposed to Bonferroni corrected P values for all suggested test statistics. Good power was obtained both with the haplotype trend regression approach as well as with the simpler chi-square based test. Furthermore, we conclude that the better strategy to deal with phase ambiguities is to assign to each individual its list of weighted haplotype explanations, rather than to assign to each individual its most likely haplotype explanation. Finally, we demonstrate the usefulness of our approach by a real data example.
Algorithms↗
Structural and functional evidences for a type 1 TGF-beta sensu stricto receptor in the lophotrochozoan Crassostrea gigas suggest conserved molecular mechanisms controlling mesodermal patterning across bilateria.
The transforming growth factor beta (TGFbeta) superfamily includes bone morphogenetic proteins, activins and TGF-betasensu stricto (s.s.). These ligands have been shown to play a key role in numerous biological processes including early embryonic development and immune regulation. They transduce their signal through a hetromeric complex of type I and type II receptors. Such receptors have been identified in ecdysozoans but none have been found as yet in the other major protostomal clade, the lophotrochozoans. Here, we report the identification of the first lophotrochozoan TGFbetas.s. type I receptor (Cg-TGFbetaRI) from the mollusk Crassostrea gigas. The phylogenetic and structural analyses as well as the expression pattern during early development suggest Cg-TGFbetaRI to belong to the TGFbetas.s./activin type I receptor clade and functional studies corroborate these deductions. The use of the zebrafish embryo as a reporter organism reveals that either Cg-TGFbetaRI or its dominant negative acting truncated form, when overexpressed during gastrulation, resulted in a range of phenotypes displaying severe disturbance of anterioposterior patterning due to a strong modulation of ventrolateral mesoderm patterning. Finally, a Cg-TGFbetaRI cytokine activity during immune regulation in C. gigas has been investigated by real-time PCR in haemocytes and mantle edge during an in vivo bacterial LPS challenge. One piece of evidence from this study suggests that the molecular mechanisms controlling mesodermal patterning and some immune regulations across all bilateria could be conserved through a functional TGF-beta s.s. pathway in lophotrochozoans.
Activin Receptors, Type I↗
[Liver transplantation: deciding between need and donor allocation].
Liver transplantation represents an established therapeutic option for advanced liver diseases. The spectrum of indications encompasses infectious, vascular, immunological and toxic diseases leading to cirrhosis, in addition to genetic, metabolic, developmental and selected neoplastic diseases. On the one hand the timing of liver transplantation is determined by the disease specific course until decompensation and the disease manifestation involving bile ducts or hepatocytes. On the other hand it represents gene therapy of diseases affecting the liver, or entities where the genetic defect lies in the liver. In view of the shortage of donor organs and an increasing requirement for liver transplantation the challenge is to provide an effective and fair waiting list management. Reform of allocation criteria has put the focus on urgency. This in turn leads to an increase in waiting time for elective transplantations, inclusion of end stage diseases and critical patients, higher perioperative costs, problems with the matching of organs and the problem of an effective use of organ resources. Fair allocation and medical necessity therefore define the challenges surrounding the indications for liver transplantation.
Cost-Benefit Analysis↗
[Organ transplantation in endocrinology. Islet cells and pancreas].
Pancreas transplantation is a successful and effective procedure resulting in tight glucose control. Due to the postoperative morbidity and the need for immunosuppression pancreas transplantation should be considered at the time of kidney transplantation. Besides this, pancreas transplantation alone should be considered for patients with unacceptably poor metabolic control and quality of life despite optimal medical treatment. Recently, islet transplantation became a less invasive alternative to pancreas transplantation. Due to the lack of long-term follow-up and due to the need of multiple donor grafts for one recipient, islet transplantation should be performed under experimental settings in experienced centers. New developments in protecting transplanted islets and in the induction of donor-specific tolerance could increase the indication to perform the procedure. Therefore alternative sources of beta-cells have to be identified.
Comorbidity↗
[Subacute proximal entrapment neuropathy of the radial nerve at the hiatus radialis].
Endogenous lesions of the radial nerve at the upper arm level and in the canalis spiralis are exceptional. Entrapment of the radial nerve in the hiatus radialis following forced arm movements, stretching, or as a consequence of pathologies of the surrounding tissue is known. We observed two patients suffering from a painful subacute middle radial nerve palsy with complete axonal degeneration caused by a lesion at the hiatus radialis, demonstrated by EMG, sonography, MRI, and surgical exploration. Successful nerve repair, in one case with a nerve graft, was performed. In both cases the most appropriate explanation was a focal neuritis with swelling of the nerve followed by strangulation at the hiatus radialis. In one case acute neuroborreliosis was the reason for the neuritis.
Adult↗
Update on liver transplantation using cyclosporine.
After the introduction of cyclosporine into liver transplantation in 1983, 1-year patient survival more than doubled. Later, with the improved microemulsified formulation of cyclosporine (Neoral) more stable pharmacokinetics were achieved. Today, C(2) monitoring of cyclosporine blood levels allows a more accurate estimation of the area under the concentration-versus-time curve as the single best indicator of cyclosporine exposure. As a consequence, with better control of side effects as well as desired effects the results of cyclosporine in liver transplantation have been further improved. The introduction of mycophenolate mofetil and basiliximab/daclizumab combination therapy has provided new options for the prevention of allograft rejection. The safety profile of individual immunosuppressive regimens comes more into focus since acute allograft rejection may be controlled successfully with competing strategies. As the focus in liver transplantation is shifting toward greatly improved long-term results, late posttransplant mortality with a functioning graft is a major concern. Prevention of long-term complications associated with highly effective immunosuppressants--posttransplant lymphoproliferative disease, cytomegalovirus infection, diabetes, hypertension, and hyperlipidemia-gains importance. Technical advances in living-related and cadaveric split-liver transplantation have lead to increasing use of segmental liver transplantation with the need to consider the effects of immunosuppression on liver regeneration and metabolism. The individualized orchestration of immunosuppression taking into account the underlying liver disease as well as other individual predispositions remains a future challenge.
Child↗
Early carotid endarterectomy in patients with a nondisabling ischemic stroke: results of a retrospective analysis.
BACKGROUND: There are several recent recommendations not to delay carotid endarterectomy (CEA) for at least 4 weeks in patients experiencing a nondisabling ischemic stroke. Therefore, we re-examined if these patients could be safely operated on earlier: The aim of our study was to review the perioperative stroke and death rates of CEA performed within 30 days of stroke onset. PATIENTS AND METHODS: During a 4 year period until December 2001, in 66 neurologically stable patients suffering a nondisabling stroke ipsilateral to a carotid artery stenosis > 50% CEA was performed after a median interval of 10 (1-28) days. The modified Rankin scale (mRS) was applied to characterize the severity of impairment of daily living activities pre- and postoperatively: Any postoperative deterioration > 24 hours on the mRS was considered as a new stroke. RESULTS: Operative mortality was 0%, and postoperative neurologic worsening > 24 hours occurred in 8/66 patients (12.1%). In 5/8 patients neurologic deterioration resolved within 5 days after surgery, only one stroke was permanent (1.5%). There was no correlation between timing of surgery or the presence of acute ipsilateral cranial CT defects with the occurrence of postoperative stroke. Stroke severity grading on admission according to the mRS, however, emerged to be a significant determinant of postoperative outcome: While 6/23 patients (26%) with an initial deficit > or = 3 on the mRS developed neurologic worsening, this was the case in only 2/43 patients (4.6%) with a deficit < or = 2 (Odds Ratio 7.2; 95% CI 1.32-39.49; two-sided p = 0.01). CONCLUSION: Our results suggest that selected patients with a minor stroke (mRS < or = 2 on admission) can safely undergo early CEA.
Aged↗
Examination of G72 and D-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder.
A recent study has suggested that the brain-expressed genes for G72 and D-amino-acid oxidase (DAAO) exert an influence on susceptibility to schizophrenia. Our aim was to replicate this finding in German schizophrenic patients and to assess whether G72 and DAAO might also contribute to the development of bipolar affective disorder. We genotyped seven single-nucleotide polymorphisms (SNPs) in the G72 gene and three in the DAAO gene in 599 patients (299 schizophrenic, 300 bipolar) and 300 controls. At G72, individual SNPs and a four-marker haplotype were associated with schizophrenia. The most significant SNP as well as the haplotype were also associated with bipolar affective disorder (BPAD). DAAO was associated with schizophrenia, but not with BPAD. The association of variation at G72 with schizophrenia as well as BPAD provides molecular support for the hypothesis that these two major psychiatric disorders share some of their etiologic background.
Adult↗
[Methodolocical issues of naturalistic observational studies on the economic evaluation of neuroleptic treatment for schizophrenic disease].
Methodological problems of prospective natural trials are discussed. The application of adequate methods is demonstrated by analysing the effects of antipsychotic medical treatment on the probability and the costs of inpatient episodes of 307 patients with schizophrenia for 2.5 years. Selection bias is controlled by the propensity score method. Effects of medical treatment on the incidence of inpatient episodes are analysed by means of a random-effect logit model. Effects of medical treatment on the costs of inpatient episodes are analysed by means of a random-effect Tobit model. Results of the study show that antipsychotic medical treatment reduces the probability and the costs of inpatient treatment irrespective of the type of neuroleptic drugs. The hypothesis of a higher effectivity of atypical neuroleptics in comparison to conventional antipsychotics regarding the reduction of the incidence and the costs of inpatient treatment was not supported. Beyond the effects of medical treatment the study results indicate that improving social support and competence for coping with life events as well as providing community mental health services may reduce the risk and the costs of inpatient episodes.
Adolescent↗
[Consensus-recommendations for sirolimus in liver transplantation].
Sirolimus is an m-TOR inhibitor without renal side effects and potentially protects against the development of malignancy. Due to a higher incidence of complications in two trials and an official warning in the drug information, the use of Sirolimus in liver transplantation is limited. The participants of this consensus meeting had to analyse and evaluate the literature with respect to the potential role of Sirolimus in liver transplantation. This consensus statement follows the scheme normally employed for the presentation of guidelines including the grading of evidence (1a-5) and the extent of recommendation (A-C). Moreover, the consensus included the experience of the authors with respect to the handling of Sirolimus after liver transplantation.
Drug Therapy, Combination↗
In vivo properties of the urinary bladder wall and their modulation by estradiol and raloxifene in a rat model.
OBJECTIVES: Urinary incontinence is a common symptom of urogenital aging that affects a considerable proportion of postmenopausal women. Morphological and morphometrical modulation of the bladder by estrogen are known. Yet data showing that this translates into changes of in vivo function of the urinary bladder are missing. METHODS: We measured urodynamic parameters in anaesthetized, surviving rats. Following ovariectomy animals were divided into three groups and fed either an estradiol-, raloxifene-, or unsupplemented soy-free formula for ten weeks. Via a transurethral catheter the intravesical pressure was recorded during a stretch period (the urinary bladder was filled), and a one-minute isometric accommodation period immediately after the filling period. Upon termination of the experiment upper and lower halves of the bladder were processed histologically. RESULTS: The estrogen-, and raloxifene-treated animals showed significantly higher pressures in responses to rapid stretch. Bladder compliance during the isometric period on the other hand was not significantly affected by these treatments. Thickness of the epithelial layer, collagen content and muscle bundles were significantly increased by estrogen and raloxifene treatment. CONCLUSIONS: This is a good animal model to investigate modulation of detrusor muscle contractility and stiffness. Both estradiol and raloxifene increase bladder contractility. Urinary bladder morphology indicates that estrogen acts primarily in the upper half of this organ since significant effects on collagen content and muscle fibers are only found in this part.
Animals↗
[Pro and contra -- vesicoureteral reflux in childhood -- endoscopic administration vs. open reconstruction].
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Age Factors↗
[Gemcitabine/cisplatin vs. MVAC. 5 year survival outcome of the phase III study of chemotherapy of advanced urothelial carcinoma in Germany].
Of 405 patients with stage IV transitional cell carcinoma from an international multicenter phase III trial, 70 were randomized in Germany to receive either gemcitabine/cisplatin or standard MVAC systemic chemotherapy for locally advanced or metastatic urothelial cancer. Overall survival as the primary endpoint of the study was similar in both arms (median survival GC 15.4 months vs MVAC 16.1 months), as were tumor-specific survival and time to progressive disease. In the intent-to-treat analysis, the 5-year overall survival rate was 10% for patients randomized to GC and 18% randomized to MVAC. Tumor overall response rates (GC 54%, MVAC 53%) were similar. The toxic death rate was 0% in the GC arm and 3% (one patient) in the MVAC arm. Significantly more GC than MVAC patients experienced grade 3/4 anemia (GC 52%, MVAC 20%) with significantly more red blood cell transfusions in the GC arm.Significantly more GC than MVAC patients had grade 3/4 thrombocytopenia (GC 54%, MVAC 17%) without grade 3/4 hemorrhage or hematuria in either arm. More MVAC patients experienced grade 3/4 neutropenia (GC 56%, MVAC 61%, p=1.000), neutropenic or leukopenic fever (GC 0%, MVAC 10%, p=0.237), mucositis (GC 0%, MVAC 7%, p=0.495), and alopecia (GC 6%, MVAC 36%, p=0.004). GC represents a reasonable alternative for the palliative treatment of patients with locally advanced and metastatic transitional cell carcinoma. Sustained long-term survival was only found for patients with locally advanced cancer, lymphatic metastases, or solitary distant metastasis but not for visceral metastatic disease.
Adult↗
Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus.
OBJECTIVES: Hormone replacement therapy (HRT) has therapeutic effects on climacteric complaints and prevents osteoporosis. Owing to the increased risks of breast cancer and cardiovascular diseases, patients look for alternatives. Cimicifuga racemosa (CR) preparations might be an alternative, because they proved to reduce climacteric complaints as efficiently as conjugated estrogens without exerting estrogenic effects in the uterus. Whether CR has positive effects on bone and in fat tissue is currently unknown. Therefore, osteoprotective effects of the CR extract BNO 1055 and an influence on fat tissue were studied in ovariectomized rats. METHODS: Bone mineral density (BMD) of the tibia of ovariectomized (ovx) rats was determined by computer-assisted tomography (CT). CT scans of fat depots were perimetrically quantified. Bone turnover (osteocalcin, crosslaps) and lipocyte activity (leptin) were also determined. Uterine weights were measured and gene expression of estrogen-regulated uterine genes (IGF-1, ERbeta) was determined by RT-PCR. RESULTS: Treatment of the ovx rats over a period of 3 months with E(2) and the CR extract BNO 1055 showed osteoprotective effects; both significantly reduced the loss of BMD in tibia. Serum osteocalcin levels were significantly reduced by both treatments, whereas only E(2), but not BNO 1055, reduced serum crosslaps. A paratibial fat depot and serum leptin concentration were also significantly reduced. In contrast to E(2), the CR extract showed no effect on uterine weight and gene expression of E(2)-regulated genes. CONCLUSION: The CR extract BNO 1055 exerted estrogenic effects in the bone (particularly in osteoblasts) and in fat tissue, but not in the uterus of ovx rats. The extract appears to contain rat organ-specific selective estrogen receptor modulators (SERMs), and if these findings can be approved in human it may be an alternative to HRT.
Adipose Tissue↗
Functional nodes in dynamic neural networks for bioprocess modelling.
This contribution presents a novel method for the direct integration of a-priori knowledge in a neural network and its application for the online determination of a secondary metabolite during industrial yeast fermentation. Hereby, existing system knowledge is integrated in an artificial neural network (ANN) by means of 'functional nodes'. A generalized backpropagation algorithm is presented. For illustration, a set of ordinary differential equations describing the diacetyl formation and degradation during the cultivation is incorporated in a functional node and integrated in a dynamic feedforward neural network in a hybrid manner. The results show that a hybrid modelling approach exploiting available a-priori knowledge and experimental data can considerably outperform a pure data-based modelling approach with respect to robustness, generalization and necessary amount of training data. The number of training sets were decreased by 50%, obtaining the same accuracy as in a conventional approach. All incorrect decisions, according to defined cost criteria obtained with the conventional ANN, were avoided.
Journal Article↗
Silymarin is a selective estrogen receptor beta (ERbeta) agonist and has estrogenic effects in the metaphysis of the femur but no or antiestrogenic effects in the uterus of ovariectomized (ovx) rats.
Silymarin is a widely used standardized mixture of flavonolignans and its major component Silybinin binds to cytosolic estrogen receptors. Here, we demonstrate that this binding is exclusive to the estrogen receptor beta (ERbeta). Treatment of ovariectomized (ovx) rats with silymarin or estradiol (E2) may allow differentiation of biological effects mediated by the ERalpha or ERbeta. E2 inhibited serum LH, cholesterol, LDL and HDL concentrations in the blood and increased gene expression of IGF1, HbEGF and C3 in the uterus, while silymarin was totally ineffective or antagonistic in altering these parameters. Both, E2 and silymarin inhibited expression of uterine ERbeta gene. Hence, in the pituitary, liver (where the lipoproteins are synthesized) and uterus E2 acts primarily via the ERalpha. Exclusive estrogenic effects of silymarin were observed in the metaphysis of the femur (MF), on osteoblast parameters (gene expression of IGF1, TGFbeta1, osteoprotegerin, collagen-1alpha1, osteocalcin (OC)) and on the osteoclast activity marker tartrate resistant acid phosphatase (TRAP) gene expression of adult ovx rats. Our RT-PCR method detects ERbeta gene expression in all organs including developing bones but not in the MF of adult ovx rats. We conclude therefore, that the effects of silymarin in this part of the bone cannot be exerted via the ERalpha because it does not bind to this receptor subtype. Despite the failure to detect ERbeta mRNA in the MF of our animals the possibility exists that ERbeta protein is present and may mediate the effects of silymarin. Another possibility may be that the effect of silymarin and therefore possibly also of E2 in the MF may be mediated via other possibly not yet identified receptors or via an ERbeta splice variant which is not detected by our PCR-method.
Animals↗
A longitudinal analysis of the impact of social and clinical characteristics on the costs of schizophrenia treatment.
OBJECTIVE: The aim of the study was the longitudinal analysis of the influence of social and clinical factors on the mid-term costs of schizophrenia treatment. METHOD: Treatment costs as well as clinical and social characteristics of 307 patients with the ICD-10 diagnosis of schizophrenia were assessed at five follow-ups over 2.5 years. Between and within effects of clinical and social characteristics on treatment costs were estimated by error component regression models. RESULTS: Effects caused by differences between individuals were found for age, partnership, in-patient history, objective and subjective role functioning, life-events and psychotic relapse. Effects of idiosyncratic transitory changes of social and clinical characteristics were found for symptoms, psychotic relapse, and for social role-functioning. CONCLUSION: Treatment costs can be reduced to a limited extent not only by the prevention of psychotic symptoms and relapse but also by the improvement of role-functioning capacities.
Adult↗