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Biomedical subjects

R König

Publications and source records attributed to R König.

At least 19 recordsLinked to original sources
PubMed2005

MRI brain volumetry in Rasmussen encephalitis: the fate of affected and "unaffected" hemispheres.

Rasmussen encephalitis (RE) is regarded as a unihemispheric disease. Serial three-dimensional MRIs of 18 patients under immunotherapy were analyzed volumetrically and planimetrically. Median volume loss was significantly higher in the affected than in the unaffected hemispheres (29.9 cm3/y vs 6.8 cm3/y). Correlation of the planimetrically and volumetrically assessed hemispheric ratios (HRs) was significant. The results support the concept of RE as a basically unilateral disease. Planimetric HR assessment is valid and time efficient.

Adolescent↗
PubMed2002

New advanced operational regime on the W7-AS stellarator.

A promising new plasma operational regime on the Wendelstein stellarator W7-AS has been discovered. It is extant above a threshold density and characterized by flat density profiles, high energy and low impurity confinement times, and edge-localized radiation. Impurity accumulation is avoided. Quasistationary discharges with line-averaged densities n(e) to 4 x 10(20) m(-3), radiation levels to 90%, and partial plasma detachment at the divertor target plates can be simultaneously realized. Energy confinement is up to twice that of a standard scaling. At B(t) = 0.9 T, an average beta value of 3.1% is achieved. The high n(e) values allow demonstration of electron Bernstein wave heating using linear mode conversion.

Journal Article↗
PubMed2001

A novel lentivirus vector derived from apathogenic simian immunodeficiency virus.

The improvement of gene transfer efficiency in growth-arrested cells using human immunodeficiency virus type 1 (HIV-1)-derived vectors led to the development of vectors derived from other members of the lentivirus family. Here we report the generation of a lentiviral vector derived from the apathogenic molecular virus clone SIVagm3mc of the simian immunodeficiency virus from African green monkeys (Cercocebus pygerythrus). Upon pseudotyping with the G-protein of vesicular stomatitis virus (VSV-G), the SIVagm-derived vector was shown to transduce proliferating and growth-arrested mammalian cell lines, including human cells. After in vivo inoculation into the striatum of the adult rat brain, the vector was shown to transduce terminally differentiated neurons and oligodendrocytes as well as quiescent and reactive astrocytes. Moreover, SIVagm transfer vector mRNA was efficiently packaged by HIV-1 vector particles. Homologous [SIV(SIV)] vectors generated by using the SIVagm-derived envelope glycoproteins allowed selective gene transfer into human CD4(+)/CCR5(+) cells. Thus, the SIVagm3mc-derived vector is a useful alternative to HIV-1-derived lentiviral vectors in somatic gene therapy.

Animals↗
PubMed2001

Effects of cadmium and vanadium ions on antigen-induced signaling in CD4(+) T cells.

Heavy metal environmental pollutants modulate antigen-directed responses by T lymphocytes, but the molecular mechanisms by which certain metal ions exert their effects are only poorly understood. We tested the hypothesis that cadmium and vanadium ions alter antigen-induced T cell signal transduction pathways in CD4(+) T helper cells. We used CD4(+) primary T lymphocytes and splenic T cells from DO.11.10 T cell receptor transgenic mice. We determined the effects of cadmium chloride and sodium orthovanadate at concentrations that did not induce apoptotic cell death, but affected cytokine or proliferation responses to antigenic stimulation. We used electrophoretic mobility shift assays to measure effects of cadmium and vanadium ions on antigen-induced activation of the nuclear transcriptional regulator proteins, nuclear factor-kappaB, cyclic AMP response element binding protein, nuclear factor of activated T cells, and activator protein-1. Different signaling pathways lead to activation of these transcription factors. Our results suggest that the two heavy metal ions differentially affect signaling pathways. This knowledge will help in the development of molecular epidemiological assays.

Animals↗
PubMed2001

Effects of heavy metal ions on resting and antigen-activated CD4(+) T cells.

Heavy metal environmental pollutants increase susceptibility of affected individuals to bacterial and viral infections, but the mechanisms responsible for this effect are not known. We established cellular in vitro systems to identify molecular targets for the action of heavy metal ions. We used two model systems to determine the effects of heavy metal ions on antigen-induced T lymphocyte responses. The first system was representative of primary antigen responses and utilized CD4(+) primary T lymphocytes derived from DO.11.10 T cell receptor transgenic mice. The second system represented a memory T cell phenotype and utilized the CD4(+) T helper 1 clone, pGL2. We measured the effects of the four heavy metals cadmium, lead, mercury, and vanadium on cytokine and proliferation responses by purified CD4(+) T cell to antigenic stimulation. Cytokine responses were differentially affected by lead and vanadium at concentrations that did not affect T cell proliferation in response to antigen. We also determined whether the metal ions induced apoptotic cell death. Mercury induced apoptosis at concentrations as low as 0.5 microM, whereas cadmium required a concentration of 100 microM. Lead (maximal concentration tested was 200 microM) and vanadium (100 microM) did not induce apoptosis. The results suggested that the different heavy metal ions differentially affected antigen-stimulated responses in T helper cells. These in vitro systems can now be applied to test whether heavy metal ions alter antigen-induced T cell signal transduction pathways in CD4(+) T helper cells.

Air Pollutants↗
PubMed2001

[Obstruction of surgical portosystemic shunts in the early postoperative phase: interventional treatment by angioplasty with stent implantation].

PURPOSE: Recurrent variceal bleeding in patients treated with surgical porto-systemic shunting is most often due to shunt stenoses or occlusion. Radiological interventional procedures are a possible method of therapy and our experience herein is described in this report. PATIENTS AND METHODS: From 1997 to 1999 54 patients with recurrent variceal bleeding were treated with a surgical porto-systemic shunt procedure. Of these early shunt occlusion occurred in 5 patients, which was treated with percutaneous transcatheter techniques. RESULTS: In only one patient was PTA alone sufficient to reestablish shunt patency, in four patient stent placement was necessary in addition. In the follow-up period 1 patient died 26 month after intervention with (autopsy-proven) patent shunt, in one patient shunt reocclusion occurred after 11 months and in 3 patients the shunt is still patent. CONCLUSIONS: PTA, if necessary in combination with stent placement, is an attractive alternative method of therapy in case of an early surgical porto-systemic shunt occlusion.

Adult↗
PubMed2001

Solvent entropy-driven searching for protein modeling examined and tested in simplified models.

Solvent entropy is a force to consider in protein folding and protein design but is difficult to model. It is investigated here in the context of the hp model: Two types of residues, hydrophobic and hydrophilic, are modeled on a lattice. Nine chains and two- and three-dimensional simulations are compared. We show that considering solvent entropy alone, efficient folding of lattice chains (identification of the native fold) can be achieved by an entropy-driven simulation on its own. Moreover, in a detailed comparison over a wide range of parameters, entropy-guided searching outperforms an energy-driven search in the model. The combination of energy- and entropy-driven search yields the most efficient searching. It is compared in detail with the above results, indicating also how this solvent shell model may advantageously be implemented in more complex protein modeling simulations.

Computer Simulation↗
PubMed2001

Post-thymic selection of peripheral CD4+ T-lymphocytes on class II major histocompatibility antigen-bearing cells.

Following positive and negative selection in the thymus, mature CD4+ T-cells emigrate into peripheral lymphoid organs. Whether resting T-cells require periodic stimulation to remain viable in the absence of antigen is important for understanding peripheral T-cell homeostasis. A prerequisite for T-cell receptor (TCR)-mediated signals in maintaining peripheral CD4+ T-cell longevity has been demonstrated. Here, we show in mice expressing a mutant I-Abeta transgene on an I-Abeta knockout background that naïve CD4+ T-cells also require engagement of their CD4 coreceptors by peripheral, class II MHC-bearing cells for their survival. The transgene's product combines with endogenous Aalpha, but this mutant AalphaAbeta heterodimer cannot interact with CD4 molecules, although it efficiently presents antigens to TCRs. Resting CD4+ T-lymphocytes from mutant Abeta transgenic mice die by apoptosis at a much higher rate than do CD4+ T-cells from normal mice. Apoptosis of CD4+ T-cells in mutant Abeta transgenic mice is partially mediated by Fas. Adoptive transfer experiments revealed that the increase in apoptosis is due to a lack of interactions with mutant MHC class II rather than to an intrinsic defect in the CD4+ T-cells selected on mutant Abeta-expressing thymic epithelial cells. Thus, interactions between CD4 and MHC class II molecules contribute to the regulation of homeostasis in the peripheral immune system. Our results further suggest that thymic emigrant cells are continuously retested in the periphery for appropriate coreceptor interactions. Peripheral selection may be important in eliminating potentially autoreactive T-cells.

Animals↗
PubMed2000

OFD II, OFD VI, and Joubert syndrome manifestations in 2 sibs.

We present 2 sibs with manifestations of oral-facial-digital syndromes (OFD) and Joubert syndrome. The index patient was the 5th child of healthy nonconsanguineous Turkish parents. At birth this female patient had large hydrocephalus, hypertelorism, deep-set eyes, nystagmus, broad mouth, thick oral frenula, cleft palate, hamartomas of the tongue, postaxial polydactyly of fingers, normal toes, and hypotonia. Cranial MRI showed hydrocephalus and Dandy-Walker malformation. The child had no psychomotor development, was unable to swallow and had severe seizures. She died at 2 months of recurrent apneic episodes. At birth the brother of the index patient showed prominent forehead, broad, deep nasal bridge, cleft palate, multiple hamartomas of the tongue, irregular alveolar ridges, retrognathia, bilateral postaxial polydactyly of the hands and feet, and broad halluces. He had an abnormal breathing pattern with phases of tachypnea and apnea. Cranial MRI showed hydrocephalus, hypoplasia of the cerebellar vermis, Dandy-Walker malformation, and hypomyelination of the corpus callosum. Renal ultrasonography demonstrated multiple small cysts. Ocular fixation was absent and he had a mild nystagmus.

Abnormalities, Multiple↗
PubMed2000

MLV-derived retroviral vectors selective for CD4-expressing cells and resistant to neutralization by sera from HIV-infected patients.

Retroviral vectors derived from amphotropic murine leukemia viruses (MLV) mediate gene transfer into almost all human cells and are thus not suitable for in vivo applications in gene therapy in which cell-specific gene delivery is required. We and others recently reported the generation of MLV-derived vectors pseudotyped by variants of the envelope glycoproteins (Env) of human immunodeficiency virus type 1 (HIV-1), thus displaying the CD4-dependent tropism of the parental lentivirus (Mammano et al., 1997, J. Virol. 71, 3341-3345; Schnierle et al., 1997, Proc. Natl. Acad. Sci. USA 76, 8640-8645). However, because of their HIV-1-derived envelopes these vectors are neutralized by HIV-specific antibodies present in some infected patients. To circumvent this problem, we pseudotyped MLV capsid particles with variants of Env proteins derived from the apathogenic simian immunodeficiency virus (SIVagm) of African green monkeys (AGM; Chlorocebus pygerythrus). Truncation of the C-terminal domain of the transmembrane protein was found to be necessary to allow formation of infectious pseudotype vectors. These [MLV(SIVagm)] vectors efficiently transduced various human CD4-expressing cell lines using the coreceptors CCR5 and Bonzo to enter target cells. Moreover, they were resistant to neutralization by antibodies directed against HIV-1. Therefore, [MLV(SIVagm)] vectors will be useful to study the mechanisms of SIVagm cell entry and for the selective gene transfer into CD4+ T-cells of AIDS patients.

Amino Acid Sequence↗
PubMed2000

[Hypomelanosis Ito in translocation trisomy 9/mosaicism (46,XX/46,XX,t(9;9)(p24;p24)). Spontaneous remission in childhood].

A 4 5/12 years old girl with hypomelanosis of Ito (HI) presented on the 3rd day of life with hypopigmented streaks and whorls following the lines of Blaschko on the back, the arms and the legs. In addition, patchy depigmented areas were present on the trunk. Extracutaneous manifestations included dystopia of the right kidney, atrial septal defect, persistent ductus arteriosus, hearing impairment, EEG abnormalities, and asymmetric dilatation of the ventricle system and a vermal atrophy as documented in the MRT of the brain. Cytogenetic analysis showed a mosaic 46,XX/46,XX,t(9;9)(p24;p24) present in the lymphocytes and skin fibroblasts. The mother's karyotype in her lymphocytes was normal. At reexamination at the age of 4 5/12 years the girl was retarded. In particular, the speech development was severely delayed. Interestingly we found only very small areas of hypopigmentation, which, unless one knew the previous findings, would not have been diagnostic.

Child, Preschool↗
PubMed2000

[The diagnostic problems in magnetic resonance tomography of the bone marrow in patients with malignomas under G-CSF therapy].

AIM: To study the effect of G-CSF therapy directly by MRI and 1H MRS in the lumbar and femoral bone marrow and differentiate between malignant bone marrow infiltration (MBMI) and reconversion of red marrow. METHODS: Thirteen patients could be examined twice, before and during G-CSF medication and another six only during treatment. T1 weighted spin-echo and opposed-phase gradient-echo images as well as the spectroscopic data (T2 values, water content) were analysed. RESULTS: After G-CSF a pathologic bone marrow signal intensity was seen in 8/13 (lumbar) and 11/13 (femoral) patients respectively. The majority of the signal alterations were diffuse (6 and 8), the minority focal (2 and 3). If a patient was successfully stimulated, a significant increase in water content occurred (21% lumbar, 34% femoral). T2 values did not change significantly, nor did they correlate with the stimulation success. CONCLUSIONS: MR tomography and -spectroscopy are suitable to detect lumbar and femoral bone marrow stimulation by G-CSF quantitatively and qualitatively. The changes may simulate MBMI. The adequate judgement of G-CSF treated bone marrow without pretherapeutic images is not possible.

Adult↗
PubMed2000

Familial syndromic esophageal atresia maps to 2p23-p24.

Esophageal atresia (EA) is a common life-threatening congenital anomaly that occurs in 1/3,000 newborns. Little is known of the genetic factors that underlie EA. Oculodigitoesophageoduodenal (ODED) syndrome (also known as "Feingold syndrome") is a rare autosomal dominant disorder with digital abnormalities, microcephaly, short palpebral fissures, mild learning disability, and esophageal/duodenal atresia. We studied four pedigrees, including a three-generation Dutch family with 11 affected members. Linkage analysis was initially aimed at chromosomal regions harboring candidate genes for this disorder. Twelve different genomic regions covering 15 candidate genes (approximately 15% of the genome) were excluded from involvement in the ODED syndrome. A subsequent nondirective mapping approach revealed evidence for linkage between the syndrome and marker D2S390 (maximum LOD score 4.51 at recombination fraction 0). A submicroscopic deletion in a fourth family with ODED provided independent confirmation of this genetic localization and narrowed the critical region to 7.3 cM in the 2p23-p24 region. These results show that haploinsufficiency for a gene or genes in 2p23-p24 is associated with syndromic EA.

Abnormalities, Multiple↗
PubMed2000

An HDR (hypoparathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14.

Partial monosomy 10p is a rare chromosomal condition and a significant proportion of patients show features of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). A critical haploinsufficiency region for DGS/VCFS was defined on 10p (DGCR2). We performed molecular deletion analysis of two further patients with partial monosomy 10p, who showed hypoparathyroidism, deafness, and renal dysplasia or renal insufficiency, but no cardiac defect, cleft palate, or reduced T cell levels. Previously, the combination of hypoparathyroidism, deafness, and renal dysplasia has been proposed to represent a specific syndrome (MIM 146255) under the acronym HDR. In addition to the two patients in this report, at least four published cases with partial monosomy 10p show the triad of HDR and 14 other patients present with at least two of the three features. We therefore conclude that HDR syndrome can be associated with partial monosomy 10p. Based on molecular deletion analysis and the clinical data, we suggest that the DGS/VCFS phenotype associated with 10p deletion can be considered as a contiguous gene syndrome owing to haploinsufficiency of two different regions. Hemizygosity of the proximal region, designated DGCR2, can cause cardiac defect and T cell deficiency. Hemizygosity of the distal region, designated HDR1, can cause hypoparathyroidism and in addition sensorineuronal deafness and renal dysplasia/insufficiency or a subset of this triad.

Adult↗
PubMed1999

Requirement for efficient interactions between CD4 and MHC class II molecules for survival of resting CD4+ T lymphocytes in vivo and for activation-induced cell death.

Regulation of homeostasis in the immune system includes mechanisms that promote survival of resting T lymphocytes, and others that control activation-induced cell death (AICD). In this study, we report on the use of a transgenic mouse model to test the role of CD4-MHC class II interactions for the susceptibility of CD4+ T lymphocytes to AICD, and for the survival of resting CD4+ T cells in peripheral lymphoid organs. The only I-Abeta gene expressed in these mice is an Abetak transgene with a mutation that prevents MHC class II molecules from interacting with CD4. We show increased apoptosis in CD4+ T lymphocytes derived from wild-type, but not from mutant Abetak transgenic mice following stimulation with staphylococcal enterotoxin A. Therefore, AICD may be impaired in CD4+ T cells derived from mutant Abetak transgenic mice. Importantly, we observed much higher apoptosis in resting CD4+ T cells from mutant Abetak transgenic mice than from wild-type mice. Furthermore, resting CD4+ T cells from mutant Abetak transgenic mice expressed higher levels of cell surface CD95 (Fas, APO-1). Ab-mediated cross-linking of CD95 further increased apoptosis in CD4+ T cells from mutant Abetak transgenic mice, but not from wild-type mice, suggesting apoptosis involved CD95 signaling. When cocultured with APC-expressing wild-type MHC class II molecules, apoptosis in resting CD4+ T lymphocytes from mutant Abetak transgenic mice was reduced. Our results show for the first time that interactions between CD4 and MHC class II molecules are required for the survival of resting CD4+ T cells in peripheral lymphoid organs.

Animals↗
PubMed1999

Detection of TSPY protein in a unilateral microscopic gonadoblastoma of a Turner mosaic patient with a Y-derived marker chromosome.

Gonadoblastomas are seen almost exclusively in dysgenetic gonads of patients with a chromosomal mosaicism of 45,X and an additional Y-bearing cell line. This paper presents a case of a Turner mosaic patient with 45,X/46,X,+mar karyotype, who developed a unilateral microscopic gonadoblastoma. Cytogenetic and molecular analysis confirmed a Y-chromosomal origin of the marker chromosome, with a deletion of the distal Yq arm and the proposed region of a so far undefined gonadoblastoma locus (GBY) present. One of the candidate genes within the postulated GBY region is TSPY (testis-specific protein Y-encoded). To study the TSPY protein expression, an anti-fusion protein antibody was used for immunohistochemistry of the patient's gonads. In contrast to the dysgenetic gonad, an intense immunoreaction was found in gonadoblastoma tumour cells of the other gonad. These results confirm the high level of TSPY protein expression by these cells and demonstrate the value of this antibody as an additional marker to confirm the diagnosis of gonadoblastoma.

Adolescent↗