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Biomedical subjects

M Stalder

Publications and source records attributed to M Stalder.

At least 19 recordsLinked to original sources
PubMed2006

Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.

Idiopathic hypereosinophilic syndrome (IHES) is a disease that is difficult to classify, and diagnosis is one of exclusion. The identification of a cytogenetically invisible interstitial deletion resulting in the fusion of FIP1-Like-1 (FIP1L1) to platelet-derived growth factor receptor alpha (PDGFRA) has enabled many IHES cases to be reclassified as chronic eosinophilic leukemia. As it is likely that PDGFRA may fuse to other partner genes, we established a reverse transcriptase-PCR test to detect specific overexpression of the PDGFRA kinase domain as an indicator of the presence of a fusion gene. Overexpression was detected in 12/12 FIP1L1-PDGFRA-positive patients, plus 9/217 (4%) patients with hypereosinophilia who had tested negative for FIP1L1-PDGFRA. One of the positive cases was investigated in detail and found to have a complex karyotype involving chromosomes 3, 4 and 10. Amplification of the genomic breakpoint by bubble PCR revealed a novel fusion between KIF5B at 10p11 and PDGFRA at 4q12. Imatinib, a known inhibitor of PDGFRalpha, produced a complete cytogenetic response and disappearance of the KIF5B-PDGFRA fusion by PCR, from both genomic DNA and mRNA. This study demonstrates the utility of screening for PDGFRA kinase domain overexpression in patients with IHES and has identified a third PDGFRA fusion partner in chronic myeloproliferative disorders.

Antineoplastic Agents↗
PubMed2005

Use of echocardiography to assess function of hDAF-transgenic pig cardiac xenografts.

The current standard of hand palpation may not be a sensitive method to detect rejection in heterotopic heart xenotransplants (HHTx). We sought to assess the use of echocardiography to detect rejection of pig heart xenografts. Four cynomolgus monkeys received HHTx from hDAF-transgenic pigs. Immunosuppression was cyclophosphamide induction, cyclosporine, steroids, sodium mycophenolate, alphaGal trisaccharide polymer, +/-soluble complement receptor type 1. Echocardiography was performed immediately after HHTx and three times a week postoperatively. Contractility on echo was scored as 1(none), 2(severely impaired), 3(moderate to severely impaired), 4(moderately impaired), 5(mild to moderately impaired), 6(mildly impaired), or 7(normal). Left ventricle wall thickness (LVWT) was measured in the anterior, inferior, posterior, lateral, and septal walls, the average was calculated. Impaired contractility or increase in LVWT were considered rejection and treated with steroids (solumedrol 15 mg/kg IV for 3-5 days). Palpation score (4-strong to 1-none) was recorded daily. Myocardial biopsies were obtained infrequently. At the time of first rejection, all four monkeys had an increase in LVWT and a decrease in contractility on echocardiography. Steroid treatment enhanced contractility in four monkeys and decreased LVWT in three monkeys. Palpation score remained at four of four during initial rejection episodes. Decrease in contractility and increase in LVWT on echocardiography appear to signify graft injury because steroid treatment results in improvement. Compared to palpation, echocardiography is more sensitive for assessing function of heterotopic pig heart xenografts. Echocardiography has, therefore, the potential to detect and treat early rejection episodes of heterotopic heart xenografts in nonhuman primates. This may help to achieve longer graft survival.

Animals↗
PubMed2005

Miniaturization (0.2 g) and evaluation of attachment techniques of telemetry transmitters.

We have developed a miniaturized very high frequency (VHF) transmitter design for radio-tagging small animals. The average mass of the circuitry is 0.084 g (range 0.081-0.087), hence, with the smallest power cell, complete tags weigh 0.2 g and have a life of 18-22 days. We further demonstrate that with such small tags the technique of attaching the device to the animal's body strongly affects the effective radiated power, and thus transmission ranges. Ideally the attachment couples the electronics to the animal's body as a ground plane for improved radiation. The transmitter allows the application of radio-tracking to be expanded to new taxa whose spatial behaviour and population dynamics are largely unknown, for example arthropods, reptiles or amphibians. The new design is also suitable for miniature implants and signal modulation with sensors.

Electronics↗
PubMed2004

Resistant pure red cell aplasia after allogeneic stem cell transplantation with major ABO mismatch treated by escalating dose donor leukocyte infusion.

We report a case of pure red cell aplasia (PRCA) following allogeneic stem cell transplantation (SCT) with major ABO mismatch which proved resistant to all standard treatment options such as change in immunosuppressive treatment, high-dose erythropoietin (EPO) or plasma exchange. We therefore proceeded to administer five cycles of Rituximab therapy, without success. Finally, escalating doses of donor-derived leukocyte infusion (DLI) resolved the PRCA of our patient 415 d after bone-marrow transplantation (BMT) and 140 d after the first infusion of donor leukocytes. A review of the literature shows the efficacy of various treatments; the role of DLI and other treatment options are discussed. Furthermore, the underlying pathophysiological mechanisms especially with regard to the role of NK cells in alloreactivity after allogeneic SCT are explained.

ABO Blood-Group System↗
PubMed2001

Immunoelectron microscopic localization of the neural recognition molecules L1, NCAM, and its isoform NCAM180, the NCAM-associated polysialic acid, beta1 integrin and the extracellular matrix molecule tenascin-R in synapses of the adult rat hippocampus.

We have investigated the possibility that morphologically different excitatory glutamatergic synapses of the "trisynaptic circuit" in the adult rodent hippocampus, which display different types of long-term potentiation (LTP), may express the immunoglobulin superfamily recognition molecules L1 and NCAM, the extracellular matrix molecule tenascin-R, and the extracellular matrix receptor constituent beta1 integrin in a differential manner. The neural cell adhesion molecules L1, NCAM (all three major isoforms), NCAM180 (the largest major isoform with the longest cytoplasmic domain), beta1 integrin, polysialic acid (PSA) associated with NCAM, and tenascin-R were localized by pre-embedding immunostaining procedures in the CA3/CA4 region (mossy fiber synapses) and in the dentate gyrus (spine synapses) of the adult rat hippocampus. Synaptic membranes of mossy fiber synapses where LTP is expressed presynaptically did not show detectable levels of immunoreactivity for any of the molecules/epitopes studied. L1, NCAM, and PSA, but not NCAM180 or beta1 integrin, were detectable on axonal membranes of fasciculating mossy fibers. In contrast to mossy fiber synapses, spine synapses in the outer third of the molecular layer of the dentate gyrus, which display postsynaptic expression mechanisms of LTP, were both immunopositive and immunonegative for NCAM, NCAM180, beta1 integrin, and PSA. Those spine synapses postsynaptically immunoreactive for NCAM or PSA also showed immunoreactivity on their presynaptic membranes. NCAM180 was not detectable presynaptically in spine synapses. L1 could not be found in spine synapses either pre- or postsynaptically. Also, the extracellular matrix molecule tenascin-R was not detectable in synaptic clefts of all synapses tested, but was amply present between fasciculating axons, axon-astrocyte contact areas, and astrocytic gap junctions. Differences in expression of the membrane-bound adhesion molecules at both types of synapses may reflect the different mechanisms for induction and/or maintenance of synaptic plasticity.

Animals↗
PubMed2001

Abeta-induced inflammatory processes in microglia cells of APP23 transgenic mice.

A microglial response is part of the inflammatory processes in Alzheimer's disease (AD). We have used APP23 transgenic mice overexpressing human amyloid precursor protein with the Swedish mutation to characterize this microglia response to amyloid deposits in aged mice. Analyses with MAC-1 and F4/80 antibodies as well as in vivo labeling with bromodeoxyuridine demonstrate that microglia in the plaque vicinity are in an activated state and that proliferation contributes to their accumulation at the plaque periphery. The amyloid-induced microglia activation may be mediated by scavenger receptor A, which is generally elevated, whereas the increased immunostaining of the receptor for advanced glycation end products is more restricted. Although components of the phagocytic machinery such as macrosialin and Fc receptors are increased in activated microglia, efficient clearance of amyloid is missing seemingly because of the lack of amyloid-bound autoantibodies. Similarly, although up-regulation of major histocompatibility complex class II (IA) points toward an intact antigen-presenting function of microglia, lack of T and B lymphocytes does not indicate a cell-mediated immune response in the brains of APP23 mice. The similar characteristics of microglia in the APP23 mice and in AD render the mouse model suitable to study the role of inflammatory processes during AD pathogenesis.

Amyloid beta-Peptides↗
PubMed1999

Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid.

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology, namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid beta (Abeta) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer's disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of Abeta in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways rather than local production or blood uptake of Abeta as a primary mechanism underlying cerebrovascular amyloid formation. APP23 mice on an App-null background developed a similar degree of both plaques and CAA, providing further evidence that a neuronal source of APP/Abeta is sufficient to induce cerebrovascular amyloid and associated neurodegeneration.

Aging↗
PubMed1999

Cerebral amyloid induces aberrant axonal sprouting and ectopic terminal formation in amyloid precursor protein transgenic mice.

A characteristic feature of Alzheimer's disease (AD) is the formation of amyloid plaques in the brain. Although this hallmark pathology has been well described, the biological effects of plaques are poorly understood. To study the effect of amyloid plaques on axons and neuronal connectivity, we have examined the axonal projections from the entorhinal cortex in aged amyloid precursor protein (APP) transgenic mice that exhibit cerebral amyloid deposition in plaques and vessels (APP23 mice). Here we report that entorhinal axons form dystrophic boutons around amyloid plaques in the entorhinal termination zone of the hippocampus. More importantly, entorhinal boutons were found associated with amyloid in ectopic locations within the hippocampus, the thalamus, white matter tracts, as well as surrounding vascular amyloid. Many of these ectopic entorhinal boutons were immunopositive for the growth-associated protein GAP-43 and showed light and electron microscopic characteristics of axonal terminals. Our findings suggest that (1) cerebral amyloid deposition has neurotropic effects and is the main cause of aberrant sprouting in AD brain; (2) the magnitude and significance of sprouting in AD have been underestimated; and (3) cerebral amyloid leads to the disruption of neuronal connectivity which, in turn, may significantly contribute to AD dementia.

Amyloid beta-Protein Precursor↗
PubMed1999

Association of microglia with amyloid plaques in brains of APP23 transgenic mice.

Microglia are a key component of the inflammatory response in the brain and are associated with senile plaques in Alzheimer's disease (AD). Although there is evidence that microglial activation is important for the pathogenesis of AD, the role of microglia in cerebral amyloidosis remains obscure. The present study was undertaken to investigate the relationship between beta-amyloid deposition and microglia activation in APP23 transgenic mice which express human mutated amyloid-beta precursor protein (betaPP) under the control of a neuron-specific promoter element. Light microscopic analysis revealed that the majority of the amyloid plaques in neocortex and hippocampus of 14- to 18- month-old APP23 mice are congophilic and associated with clusters of hypertrophic microglia with intensely stained Mac-1- and phosphotyrosine-positive processes. No association of such activated microglia was observed with diffuse plaques. In young APP23 mice, early amyloid deposits were already of dense core nature and were associated with a strong microglial response. Ultrastructurally, bundles of amyloid fibrils, sometimes surrounded by an incomplete membrane, were observed within the microglial cytoplasm. However, microglia with the typical characteristics of phagocytosis were associated more frequently with dystrophic neurites than with amyloid fibrils. Although the present observations cannot unequivocally determine whether microglia are causal, contributory, or consequential to cerebral amyloidosis, our results suggest that microglia are involved in cerebral amyloidosis either by participating in the processing of neuron-derived betaPP into amyloid fibrils and/or by ingesting amyloid fibrils via an uncommon phagocytotic mechanism. In any case, our observations demonstrate that neuron-derived betaPP is sufficient to induce not only amyloid plaque formation but also amyloid-associated microglial activation similar to that reported in AD. Moreover, our results are consistent with the idea that microglia activation may be important for the amyloid-associated neuron loss previously reported in these mice.

Animals↗
PubMed1997

Cladribine (2-CDA) given as subcutaneous bolus injections is active in pretreated Waldenström's macroglobulinaemia. Swiss Group for Clinical Cancer Research (SAKK).

Clinical trials with intravenous cladribine infusions in pretreated patients with Waldenström's macroglobulinaemia have shown a response rate of 40%. Our pharmacokinetic studies revealed that the bioavailability of subcutaneous cladribine is complete but that the concentration-time profile is very different from intravenous administration. We designed this phase II multi-institutional trial to study the activity and toxicity of cladribine given as s.c. bolus injections in patients with symptomatic Waldenström's macroglobulinaemia. Between May 1993 and October 1995, 25 patients were accrued: male/female 18/7, median age 65 years (range 44-85). All except one patient had been pretreated with more than one regimen (median 2, range 0-10). 18 patients had progressed under previous therapy and six were in relapse. All patients received cladribine for a total dose of 0.5 mg/kg per cycle as s.c. bolus injections divided over 5 d at > or = 4 week intervals, for a maximum of six cycles. All 25 patients were evaluable for toxicity and response. A total of 67 cycles were administered (median 3 cycles, range 1-6). Overall response rate including disease stabilization which had been progressive under previous therapy was 68%. 10 patients (40%, 95% CI 21-61%) achieved a partial remission. Seven responders had been progressive under previous therapy. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range 0.5-33) and 8 months (5-29), respectively. Four patients (16%) suffered from infections W.H.O. grade > or = 2 (pneumonia grade 2, Staphylococcus septicaemia grade 3, viral encephalitis and pneumonia, both grade 4 with complete resolution). No other severe adverse events were observed. Cladribine given as s.c. 5 d bolus injections was found to be active in pretreated Waldenström's macroglobulinaemia and resulted in durable remissions.

Adult↗
PubMed1997

Systemic mastocytosis following a malignant ovarian germ cell tumour.

Cases of mediastinal germ cell tumours associated with haematological disorders (two cases of systemic mastocytosis included) have been reported previously. This combination is more frequent than would be expected by chance alone. We report the case of a 30-year-old woman, who presented with a systemic mastocytosis following a malignant ovarian germ cell tumour which was treated by chemo- and radiotherapy. The patient predominantly complained of skeletal pains, which led to an erroneous radiological diagnosis of fibrous dysplasia for years. An aggressive variant of systemic mastocytosis was diagnosed on bone marrow examination. Systemic mastocytosis was confirmed by splenectomy, liver biopsy and finally autopsy. The present case is unique because of the ovarian location of the germ cell tumour. We suggest our observation could be related to the broad group of haematological malignancies associated with germ cell tumours.

Adolescent↗
PubMed1996

[History of gynecologic treatment of infertility].

Within less than 20 years this branch of the infertility treatment by new reproductive medical technologies has left behind the original concept of bypassing blocked tubes. It has started to bypass nature. As the extracorporal way, however of shortest duration within the human prenatal development, exposes the human being to external influences, the discussion about the pros and cons of the new technologies is already abundant and still rising. The field named infertility-treatment was once in the middle and in the heart of the gynecologic discipline. It gave rise to the most intellectual branch of gynecology, the gynecologic endocrinology. Undoubtedly, there are tendencies at present to make "Reproductive Medicine" an independent discipline splitting from gynecology and obstetrics, with only the core remaining gynecology, but with the addition of essential constituents coming from genetics, human biology, andrology, medical ethics, even from sociology and law. Gynecology would tremendously suffer from this loss. The field "Reproductive Medicine" has gained the most attentive audience far beyond the scope of our gynecologic profession. One thinks it should have calm and peace to grow further in the same way other fields of medicine flourish, guided by science, concience and compassion. The juxta-medical expansion of the field could as well not have been foreseen one-hundred years ago.

Europe↗
PubMed1995

Noninvasive assessment of the effect of xenobiotics on mitochondrial function in human beings: studies with acetylsalicylic acid and ethanol with the use of the carbon 13-labeled ketoisocaproate breath test.

Studies in experimental animals and morphologic data in patients suggest that mitochondria are a prime target of the toxicity of ethanol and acetylsalicylic acid. However, the effects of socially consumed amounts of ethanol and therapeutic doses of acetylsalicylic acid on mitochondrial function in human beings are not known. The alpha-ketoisocaproic acid (KICA) breath test noninvasively assesses a mitochondrial function, the decarboxylation of KICA, by following the exhalation of labeled carbon dioxide after the administration of labeled KICA. The decarboxylation of I-[13C]KICA was measured in two groups of eight healthy volunteers after ingestion of 0.5 gm/kg of ethanol or 30 mg/kg of acetylsalicylic acid, respectively. Breath samples were collected at intervals for the determination of [13C] carbon dioxide in breath. The ingestion of ethanol resulted in peak concentrations of ethanol in plasma of 17.3 +/- 2.4 mmol/L (mean +/- 95% confidence interval) and increased the lactate/pyruvate ratio in peripheral venous blood. Although the 13C enrichment of circulating KICA and leucine were similar in the presence and absence of ethanol, the decarboxylation KICA was significantly lower (p < 0.01) at each time point in the presence of ethanol. The fraction decarboxylated in 2 hours was 6.3% +/- 1.9% of the administered dose after administration of ethanol and 14.2% +/- 3.9% (p < 0.001) in the control period. In contrast, the ingestion of acetylsalicylic acid, which resulted in plasma concentrations of 0.9 mmol/L salicylate significantly increased the decarboxylation of KICA to 19.3% +/- 3.1% of the administered dose exhaled in 2 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[The value of anticardiolipin antibody assessment].

Anticardiolipin antibodies (ACL) are associated with the presence of several clinical conditions. To determine the clinical interest of their evaluation, we reviewed all the results of ACL determinations performed in our laboratory during 1990 and 1991. 266 analyses (232 patients) were carried out. Determinations of IgG and IgM type ACL were performed by ELISA. ACL values were positive or slightly positive in 40% of the analyzed samples. Diagnosis was mentioned as the grounds for 212 requests (186 patients). ACL were positive (> m + 3SD) in about 40% of patients with autoimmune disease or with at least two of the following pathologies: autoimmune disease, venous or arterial thromboembolism, recurrent abortion.

Abortion, Habitual↗