Low incidence of posttransplant lymphoproliferative disease in children treated with low-dose immunosuppression after liver transplantation.
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Child↗
Biomedical subjects
T Meyer
Publications and source records attributed to T Meyer.
Testing a new staging system for cutaneous melanoma proposed by the American Joint Committee on Cancer.
The American Joint Committee on Cancer (AJCC) recently proposed a new staging system for cutaneous melanoma. We tested its practicability and its prognostic value was compared with the currently used TNM classification. The data of 1976 melanoma patients were used for the testing. 1218 patients (61.6%) could be assigned to the proposed pT classification, 136 patients (90.1%) with lymph node metastases and/or in-transit metastases to the proposed pN classification and all 14 patients with distant metastases to the proposed pM classification. Proposed pathological staging was possible for 971 patients (49%). The number of pT1 patients (399 versus 230) and stage I patients (544 versus 393) was distinctly higher in the proposed classification. In proposed stage II and III groups, subgroups with different prognosis could be identified. The new staging system includes more detailed information on clinical and pathohistological findings. Nevertheless, it is practicable and enables more patients with excellent prognosis to be identified.
Adolescent↗
Imatinib: a selective tyrosine kinase inhibitor.
The understanding of the pathophysiology of a large number of cancer types provides a strategy to target cancer cells with minimal effect on normal cells. Protein phosphorylation and dephosphorylation play a pivotal role in intracellular signaling; to regulate signal transduction pathways, there are approximately 700 protein kinases and 100 protein phosphatases encoded within the human genome. In cancer, as well as in other proliferative diseases, unregulated cell proliferation, differentiation and survival frequently results from abnormal protein phosphorylation. Although it is often possible to identify a single kinase that plays a pivotal role in a given disease, the development of drugs based upon protein kinase inhibition has been hampered by unacceptable side effects resulting from a lack of target selectivity. With the growing understanding of the molecular biology of protein tyrosine kinases and the use of structural information, the design of potential drugs directed towards the bind adenosine triphosphate (ATP)-binding site of a single target has become possible. These advances have transferred emphasis away from the identification of potent kinase inhibitors and more towards issues of target selectivity, cellular efficacy, therapeutic effectiveness and tolerability. In this paper, the relationship between molecular biology and drug discovery methods, as utilized for the identification of anticancer drugs, will be illustrated.
Adenosine Triphosphate↗
Alternative splicing of the 5'-sequences of the mouse EAAT2 glutamate transporter and expression in a transgenic model for amyotrophic lateral sclerosis.
Glutamate-mediated neurotoxicity and a reduced expression of the excitatory amino acid transporter 2 (EAAT2) have been described in the pathogenesis of several acute and chronic neurological conditions. EAAT2 is the major carrier of glutamate in the mammalian brain. However, the principles of EAAT2 expression regulation are not fully understood. For the human brain, extensive alternative splicing of the EAAT2 RNA has been shown. To delineate the complex RNA regulation of EAAT2 we investigated whether the murine species is a suitable model for the study of EAAT2 splicing events. We identified five splice variants (mEAAT2/5UT1-5) encoding different 5'-untranslated sequences and two distinct N-termini of the putative EAAT2 polypeptide. In the murine CNS we found a region-specific expression pattern of the novel 5'-variants of EAAT2 as shown by in situ hybridization, dot blotting and competitive reverse transcription polymerase chain reaction. Furthermore, we performed an expression analysis of the EAAT2 splice variants in the spinal cord of a transgenic model (SOD1G93A) of amyotrophic lateral sclerosis, a motor neurone disease for which altered splicing of EAAT2 has been discussed. We found an increased expression of mEAAT2/5UT4 and a reduction of mEAAT2/5UT5 in the early course of the disease. We conclude that alternative splicing of 5'-sequences may contribute to the regional expression of the EAAT2 RNA and was altered in the pre-symptomatic stage of the SOD1G93A-mouse model for amyotrophic lateral sclerosis.
5' Untranslated Regions↗
Late locoregional recurrence in rectal carcinoma.
AIMS: Locoregional recurrence in rectal carcinoma usually occurs within the first five years of treatment. In recent years we have increasingly diagnosed patients with late locoregional recurrence more than 5 years after primary treatment. METHODS: The data of 978 patients with invasive stage I-III rectal carcinoma who underwent curative resection (R0) between 1978 and 1990 were analysed retrospectively. The median follow-up time was 10 years. RESULTS: The earliest locoregional recurrence was observed at 2 months, the latest at 148 months (extramural locoregional recurrence) after primary treatment. Within 1, 2 and 5 years 34, 64 and 91 per cent of all locoregional recurrences had been diagnosed. The 2-, 5- and 10-year locoregional recurrence rates of all patients increased from 11.3 to 16.7 to 18.8 per cent. The time lapse to diagnosis of locoregional recurrence was significantly influenced by the pN category (pN0: later), grading (low grade: later) and tumour cell dissemination (present: earlier). Locoregional recurrence was also diagnosed significantly earlier in patients undergoing regular follow-up. The curative reoperation rate was 22 per cent (n=37), being higher in patients with intramural locoregional recurrence (49 per cent), after primary anterior resection (32 per cent) and in the absence of distant metastases (29 per cent). CONCLUSION: Long-term follow-up beyond five years demonstrates increasing numbers of late locoregional recurrences.
Adult↗
Clinical evaluation of 5-S-cysteinyldopa testing using a new and optimized detection system as a tumour marker for malignant melanoma.
5-S-cysteinyldopa (5-S-CD) has been described as a tumour marker for the detection of human metastatic melanoma. We investigated the clinical utility of a new and optimized method to detect 5-S-CD by analysing 207 plasma samples derived from 138 patients with clinical stage I/II ( = 60), III ( = 32) or IV ( = 46) melanoma. Control groups consisted of 27 patients with non-melanoma skin diseases and 30 healthy volunteers. 5-S-CD plasma levels were determined using a new analytical technique based on a fully automated solid phase extraction coupled online to a novel high performance liquid chromatography method. In all the samples from the healthy control subjects 5-S-CD plasma concentrations were below 2.0 microg/l. Increased 5-S-CD-levels (>/=2.0 microg/l) were found in 52%, 67% and 81% of the plasma samples from patients with stages I/II, III and IV malignant melanoma, respectively. The mean values of 5-S-CD were found to rise with increasing tumour stage. Among 27 samples from patients with non-melanoma skin disease, slightly elevated 5-S-CD levels between 2.3 and 2.6 microg/l were found in only four samples from patients with multiple dysplastic naevi. In conclusion, our improved analytical technique provides a high sensitivity in all stages of the disease and represents a useful technique for monitoring melanoma patients.
Biomarkers, Tumor↗
Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels.
PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125. PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to >or= twice its nadir level, confirmed by a second sample also >or= twice the nadir. RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression. CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials.
CA-125 Antigen↗
Control of astrocyte Ca(2+) oscillations and waves by oscillating translocation and activation of protein kinase C.
BACKGROUND: Glutamate-induced Ca2+ oscillations and waves coordinate astrocyte signaling responses, which in turn regulate neuronal excitability. Recent studies have suggested that the generation of these Ca2+ oscillations requires a negative feedback that involves the activation of conventional protein kinase C (cPKC). Here, we use total internal reflection fluorescence (TIRF) microscopy to investigate if and how periodic plasma membrane translocation of cPKC is used to generate Ca2+ oscillations and waves. RESULTS: Glutamate stimulation of astrocytes triggered highly localized GFP-PKCgamma plasma membrane translocation events, induced rapid oscillations in GFP-PKCgamma translocation, and generated GFP-PKCgamma translocation waves that propagated across and between cells. These translocation responses were primarily mediated by the Ca2+-sensitive C2 domains of PKCgamma and were driven by localized Ca2+ spikes, by oscillations in Ca2+ concentration, and by propagating Ca(2+) waves, respectively. Interestingly, GFP-conjugated C1 domains from PKCgamma or PKCdelta that have been shown to bind diacylglycerol (DAG) also oscillated between the cytosol and the plasma membrane after glutamate stimulation, suggesting that PKC is repetitively activated by combined oscillating increases in Ca(2+) and DAG concentrations. The expression of C1 domains, which increases the DAG buffering capacity and thereby delays changes in DAG concentrations, led to a marked prolongation of Ca(2+) spikes, suggesting that PKC activation is involved in terminating individual Ca(2+) spikes and waves and in defining the time period between Ca(2+) spikes. CONCLUSIONS: Our study suggests that cPKCs have a negative feedback role on Ca(2+) oscillations and waves that is mediated by their repetitive activation by oscillating DAG and Ca(2+) concentrations. Periodic translocation and activation of cPKC can be a rapid and markedly localized signaling event that can limit the duration of individual Ca(2+) spikes and waves and can define the Ca(2+) spike and wave frequencies.
Animals↗
Restricted accumulation of phosphatidylinositol 3-kinase products in a plasmalemmal subdomain during Fc gamma receptor-mediated phagocytosis.
Phagocytosis is a highly localized and rapid event, requiring the generation of spatially and temporally restricted signals. Because phosphatidylinositol 3-kinase (PI3K) plays an important role in the innate immune response, we studied the generation and distribution of 3' phosphoinositides (3'PIs) in macrophages during the course of phagocytosis. The presence of 3'PI was monitored noninvasively in cells transfected with chimeras of green fluorescent protein and the pleckstrin homology domain of either Akt, Btk, or Gab1. Although virtually undetectable in unstimulated cells, 3'PI rapidly accumulated at sites of phagocytosis. This accumulation was sharply restricted to the phagosomal cup, with little 3'PI detectable in the immediately adjacent areas of the plasmalemma. Measurements of fluorescence recovery after photobleaching were made to estimate the mobility of lipids in the cytosolic monolayer of the phagosomal membrane. Stimulation of phagocytic receptors induced a marked reduction of lipid mobility that likely contributes to the restricted distribution of 3'PI at the cup. 3'PI accumulation during phagocytosis was transient, terminating shortly after sealing of the phagosomal vacuole. Two factors contribute to the rapid disappearance of 3'PI: the dissociation of the type I PI3K from the phagosomal membrane and the persistent accumulation of phosphoinositide phosphatases.
Adaptor Proteins, Signal Transducing↗
Overexpression of monomeric and multimeric GIRK4 subunits in rat atrial myocytes removes fast desensitization and reduces inward rectification of muscarinic K(+) current (I(K(ACh))). Evidence for functional homomeric GIRK4 channels.
K(+) channels composed of G-protein-coupled inwardly rectifying K(+) channel (GIRK) (Kir3.0) subunits are expressed in cardiac, neuronal, and various endocrine tissues. They are involved in inhibiting excitability and contribute to regulating important physiological functions such as cardiac frequency and secretion of hormones. The functional cardiac (K((ACh))) channel activated by G(i)/G(o)-coupled receptors such as muscarinic M(2) or purinergic A(1) receptors is supposed to be composed of the subunits GIRK1 and GIRK4 in a heterotetrameric (2:2) fashion. In the present study, we have manipulated the subunit composition of the K((ACh)) channels in cultured atrial myocytes from hearts of adult rats by transient transfection of vectors encoding for GIRK1 or GIRK4 subunits or GIRK4 concatemeric constructs and investigated the effects on properties of macroscopic I(K(ACh)). Transfection with a GIRK1 vector did not cause any measurable effect on properties of I(K(ACh)), whereas transfection with a GIRK4 vector resulted in a complete loss in desensitization, a reduction of inward rectification, and a slowing of activation. Transfection of myocytes with a construct encoding for a concatemeric GIRK4(2) subunit had similar effects on desensitization and inward rectification. Following transfection of a tetrameric construct (GIRK4(4)), these changes in properties of I(K(ACh)) were still observed but were less pronounced. Heterologous expression in Chinese hamster ovary cells and human embryonic kidney 293 cells of monomeric, dimeric, and tetrameric GIRK4 resulted in robust currents activated by co-expressed A(1) and M(2) receptors, respectively. These data provide strong evidence that homomeric GIRK4 complexes form functional G(beta)gamma gated ion channels and that kinetic properties of GIRK channels, such as activation rate, desensitization, and inward rectification, depend on subunit composition.
Acetylcholine↗
[Symptoms of primary endocardial fibroelastosis in a young adult].
HISTORY AND ADMISSION FINDINGS: A 21-year-old woman with known endocardial fibroelastosis diagnosed when aged 3 months was admitted because of progressive dyspnoea. The physical examination revealed symptoms of heart failure, with pulmonary rales, mild hepatomegaly, and tachyarrhythmia. INVESTIGATIONS: The electrocardiogram showed atrial fibrillation, complete right bundle branch block and right ventricular hypertrophy. Echocardiography indicated hypertrophy and dilatation of the right ventricle (61 mm) with tricuspid regurgitation and hypoplasia of the left ventricle. Heart catheterization confirmed pulmonary hypertension (60/46 mmHg) as well as dilatation and hypokinesia of the right ventricle. Right ventricular biopsy showed severe myocardial hypertrophy resulting from secondary pulmonary hypertension, while no evidence of myocarditis or idiopathic dilated cardiomyopathy was found. TREATMENT AND COURSE: Symptoms of heart failure improved under medical treatment with digitalis, angiotensin-converting enzyme inhibitor and diuretics. CONCLUSION: Primary endocardial fibroelastosis of the contracted type must be included in the differential diagnosis of heart failure occurring in young adults.
Adult↗
Efficacy of balloon valvuloplasty in patients with critical aortic stenosis and cardiogenic shock--the role of shock duration.
BACKGROUND: Because of limited long-term success, aortic balloon valvuloplasty is considered to be a palliative procedure, including patients at excessive risk for standard therapy-aortic valve replacement-that is, those in cardiogenic shock. HYPOTHESIS: The study was undertaken to evaluate the outcome of balloon valvuloplasty for critical aortic stenosis complicated by cardiogenic shock. METHODS: Over a 10-year-period, we followed 14 patients (age 74+/-11 years, range 50-91) presenting in cardiogenic shock and critical aortic stenosis, who underwent valvuloplasty, together with 19 patients with critical aortic stenosis requiring urgent major noncardiac surgery. RESULTS: In patients in shock, calculated aortic valve area could be increased successfully by at least 0.3 cm2, from 0.38+/-0.09 to 0.81+/-0.12 cm2, with an insignificant increase in cardiac index from 1.89+/-0.33 to 2.01+/-0.41 l/min * m2. In-hospital mortality was 71% (10 patients). Two patients underwent valve replacement within 16 days and survived after 1 year, as did two patients refusing surgery. By multivariate logistic regression analysis, only an interval between onset of shock symptoms and valvuloplasty of > 48 h was significantly associated with fatal outcome (p < 0.01). In those patients requiring noncardiac surgery, this was possible after valvuloplasty in 95% who survived 1 year after hospital discharge. One patient in this group died of pulmonary embolism the day after the procedure. CONCLUSION: These data support the concept of causal treatment in patients with cardiogenic shock, as well as in the setting of cardiogenic shock and critical aortic stenosis, at the earliest possible convenience.
Aged↗
Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects.
RATIONALE: Several clinical studies suggest antidepressive and anxiolytic effects of regular aerobic exercise. OBJECTIVES: The present study examines the effects of a 10-week protocol of moderate aerobic exercise (3-4 miles jogging 3 times per week) on central serotonergic receptor sensitivity. METHODS: Neuroendocrine challenges using oral doses of meta-chlorophenylpiperazine (m-CPP; 0.4 mg/kg), ipsapirone (0.3 mg/kg), and placebo were performed in 12 untrained healthy volunteers before and after 10 weeks of moderate aerobic exercise. RESULTS: Before training, administration of the non-selective serotonergic agonist m-CPP, which exerts a number of well-reproducible effects mainly via its action on 5-HT2C receptors, was associated with a significant increase of cortisol and prolactin (but not adrenaline or noradrenaline) in comparison with the placebo condition. After the 10-week training period, administration of m-CPP was followed by a blunted cortisol response which was not significantly increased in comparison to the placebo challenge. In contrast, the increases of cortisol observed after administration of the 5-HT1A agonist ipsapirone were of the same magnitude during the pre- and post-training challenge sessions. The behavioral response to ipsapirone and the mean maximal increases of plasma adrenaline and noradrenaline did not change during the training period. CONCLUSIONS: Regular aerobic exercise is associated with a blunted cortisol response to m-CPP, which might reflect a downregulation of central 5-HT2C receptors.
Adult↗
The risk of haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours--a prospective study.
OBJECTIVE: To analyze prospectively the frequency and the risk of symptomatic and asymptomatic haemorrhage after image guided stereotactic biopsy of intra-axial brain tumours. METHODS: The study was conducted within a time frame of 24 months (April 1998-April 2000). 326 patients (150 males, 176 females; mean age 56.8 years) were included and 345 computerized tomography (CT)-guided stereotactic biopsies were performed/supervised by a specialized stereotactic neurosurgeon. A modified Riechert Stereotaxy System and a workstation for multiplanar trajectory planning were used in all patients. Serial biopsies (median, 5 samples) were done with small forceps (diameter 1 mm), smear preparations of the biopsy specimens were intra-operatively examined. Frequency, size, and location of any detectable bleeding were analyzed by post-biopsy CT-scan investigation. For risk estimation, logistic regression analysis was performed. The chi-square statistic was used for comparative analysis of the study results with available data from the literature. RESULTS: A conclusive tissue diagnosis could be achieved in 98%. Overall treatment morbidity was 3.1%. There was no mortality. Haemorrhage related morbidity was 0.9%. Age, Karnofsky score, mass effect of the tumour, tumour histology, tumour location and the number of specimens taken did not have any prognostic significance. The clinically silent bleeding rate was 9.6% and more often seen in patients with high grade gliomas (p = 0.03). Both the silent and non-silent bleeding rate were significantly lower as compared to available prospective data in the literature (p < 0.01). CONCLUSION: Using multiplanar image guided trajectory planning, small biopsy forceps and intra-operative smear preparations the risk of major haemorrhage related morbidity after stereotactic brain tumour biopsy is extremely low (<1%) in experienced hands.
Adolescent↗
Depressed mood, physician-rated prognosis, and comorbidity as independent predictors of 1-year mortality in consecutive medical inpatients.
OBJECTIVE: To determine the independent effects of depressed mood and markers of medical disease severity on mortality in consecutive medical inpatients. METHODS: Consecutive general medical inpatients were asked to complete the Hospital Anxiety and Depression Scale (HADS) at admission. Prognostic indicators were obtained from patients' records and physicians' ratings. The study endpoint was mortality from all causes at 1 year. RESULTS: The baseline assessment was completed by 575 patients (87.7%). Survival data were available for 572 of these (86 deaths). HADS depression scores and several physical risk indicators predicted mortality. In multivariate analyses, physicians' rating of prognosis was the best predictor of mortality [adjusted odds ratio (OR) 3.6; 95% confidence interval (CI), 2.5--5.4]. Other independent predictors included a principal diagnosis of hemato-oncological disease, comorbidity scores, and HADS depression (adjusted OR 1.75; 95% CI, 1.10--2.79). CONCLUSION: Our data demonstrate an independent prognostic effect of depressed mood on mortality in general medical inpatients. Screening for depression may improve risk stratification in these patients over and above that obtained by routinely available physical parameters and physicians' clinical judgement.
Adult↗
Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition.
Synaptic inhibition by GABA(A) and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Several potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl(-)](i), including the neuronal isoform KCC2. We show that KCC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnormal spontaneous electrical activity and altered spinal cord responses to peripheral electrical stimuli. In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses. Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition.
Action Potentials↗
Responsiveness of subjective quality of life assessment in schizophrenic patients: a quasi-experimental pilot study.
Responsiveness of quality of life (QOL) assessments in chronic schizophrenic patients was investigated by a quasi-experimental pilot study. Satisfaction ratings were assessed over five time points with an externally imposed disturbing stimulus at the second time point. Despite a markedly high stability, the disturbance provoked a temporally limited decrease in QOL.
Chronic Disease↗
Subcellular targeting by membrane lipids.
The reversible localization of signaling proteins to both the plasma and the internal membranes of cells is critical for the selective activation of downstream functions and depends on interactions with both proteins and membrane lipids. New structural and biochemical analyses of C1, C2, PH, FYVE, FERM and other domains have led to an unprecedented amount of information on the molecular interactions of these signaling proteins with regulatory lipids. A wave of studies using GFP-tagged membrane binding domains as reporters has led to new quantitative insights into the kinetics of these signaling mechanisms.
Animals↗