42 results on '"Georgia Lahr"'
Search Results
2. Prevalence and phenotypic characterization of MC4R variants in a large pediatric cohort
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J. von Schnurbein, Heike Vollbach, Georgia Lahr, S. Brandt, Klaus-Michael Debatin, Christian Denzer, and Martin Wabitsch
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Adult ,Male ,0301 basic medicine ,Nonsynonymous substitution ,Pediatric Obesity ,medicine.medical_specialty ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Nonsense mutation ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Polymorphism, Single Nucleotide ,Childhood obesity ,Frameshift mutation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Gene Frequency ,Loss of Function Mutation ,Germany ,Internal medicine ,Prevalence ,medicine ,Humans ,Outpatient clinic ,Genetic Predisposition to Disease ,Age of Onset ,Child ,Retrospective Studies ,Nutrition and Dietetics ,business.industry ,Infant, Newborn ,Infant ,medicine.disease ,Growth hormone secretion ,Phenotype ,030104 developmental biology ,Case-Control Studies ,Child, Preschool ,Cohort ,Receptor, Melanocortin, Type 4 ,Female ,business ,Body mass index - Abstract
We aimed to determine the prevalence of melanocortin-4 receptor (MC4R) variants in a large German cohort of children with obesity in a pediatric outpatient clinic and to ascertain whether there is a specific phenotype associated with loss-of-function variants as previously reported. Eight hundred and ninety-nine patients from our pediatric obesity clinic were screened for MC4R variants by DNA sequencing after PCR amplification. Retrospective statistical analysis of anthropometric and metabolic characteristics was performed, comparing patients with and without MC4R variants across the entire cohort (n=586) as well as in case–control analysis using patients with common sequence MC4R individually matched for age, sex and body mass index standard deviation score (SDS) (n=11 case–control pairs). We identified heterozygous variants within the coding region of the MC4R gene in n=22 (2.45%) patients. Fourteen (1.56%) had a variant that impaired receptor function. One new frameshift (p.F152Sfs), an yet unpublished nonsense mutation (p.Q156X) and one nonsynonymous variation (p.V65E) described in the Mouse Genome Database were detected. Across the whole cohort, at all ages, mean height SDS in subjects with impaired receptor function was higher than in patients with common sequence MC4R. In matched individuals, this trend persisted (8 of the 11 pairs) within the case–control setting. No differences were found regarding metabolic characteristics. The observed prevalence of mutations causing impaired receptor function in this large cohort is comparable to other pediatric cohorts. MC4R deficiency tends to lead to a taller stature, confirming previous clinical reports. The association of MC4R mutations with a distinct phenotype concerning metabolic characteristics remains questionable. more...
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- 2016
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3. Biologically Inactive Leptin and Early-Onset Extreme Obesity
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Barbara Moepps, Georgia Lahr, Martin Wabitsch, Petra Vatter, Peter Gierschik, Klaus-Michael Debatin, Pamela Fischer-Posovszky, Belinda Lennerz, Jan-Bernd Funcke, and Ursula Kuhnle-Krahl
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medicine.medical_specialty ,Leptin Deficiency ,Leptin receptor ,Leptin ,digestive, oral, and skin physiology ,General Medicine ,Biology ,Metreleptin ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Mutant protein ,Internal medicine ,Aspartic acid ,medicine ,Tyrosine ,Receptor ,hormones, hormone substitutes, and hormone antagonists - Abstract
Mutations in the gene encoding leptin (LEP) typically lead to an absence of circulating leptin and to extreme obesity. We describe a 2-year-old boy with early-onset extreme obesity due to a novel homozygous transversion (c.298G→T) in LEP, leading to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y) and high immunoreactive levels of leptin. Overexpression studies confirmed that the mutant protein is secreted but neither binds to nor activates the leptin receptor. The mutant protein failed to reduce food intake and body weight in leptin-deficient ob/ob mice. Treatment of the patient with recombinant human leptin (metreleptin) rapidly normalized eating behavior and resulted in weight loss. more...
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- 2015
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4. NOD2 Polymorphism Predicts Response to Treatment in Crohn’s Disease—First Steps to a Personalized Therapy
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Benjamin Mayer, Ulrike Spaniol, Jochen Klaus, Georgia Lahr, Georg B T von Boyen, Johannes Stephani, Carolin Pflüger, Jan Hendrik Niess, and N. Degenkolb
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Oncology ,Crohn’s disease ,Adult ,Male ,medicine.medical_specialty ,Heterozygote ,Adolescent ,Genotype ,Physiology ,Drug Resistance ,Nod2 Signaling Adaptor Protein ,Disease ,NOD2 ,Young Adult ,Refractory ,Crohn Disease ,Polymorphism (computer science) ,Internal medicine ,Medicine ,Humans ,Young adult ,Precision Medicine ,Glucocorticoids ,Step-up ,Crohn's disease ,Polymorphism, Genetic ,business.industry ,Tumor Necrosis Factor-alpha ,Gastroenterology ,Antibodies, Monoclonal ,Hepatology ,Middle Aged ,medicine.disease ,Top-down ,digestive system diseases ,TNF-α antagonist ,Phenotype ,Immunology ,Mutation ,Original Article ,Female ,Personalized medicine ,business ,Immunosuppressive Agents - Abstract
Background and Aims Great efforts have been made to predict disease behavior over time and the response to treatment in Crohn’s disease (CD). Such understanding could personalize therapy. Early introduction of more aggressive therapies to patients at high risk and no introduction of predictable refractory treatments could become possible. We hence tested the influence of the NOD2 carrier status on treatment response. Patients and Methods In 185 CD patients (age 45 ± 9.8 years, female n = 108, minimum disease duration 10 years), the three most common polymorphisms (p.Arg702Trp, p.Gly908Arg, p.Leu1007fsX1008) of NOD2 were tested by polymerase chain reaction and sequencing. Detailed clinical and medical history were obtained with a standardized questionnaire and by reviewing the medical charts. Treatments introduced were chosen by physicians blinded to genotype data. Results The frequency of the NOD2 variant allele was about one-third (67, 30.2%) of CD patients. NOD2 carriers were more often treated with systemic and locally active steroids and with an immunosuppressant (Azathioprine/6-MP). NOD2 mutation carrier status was more often associated with systemic steroid [8.9% vs. wild-type (WT) 1.2%, P = 0.0086] and local-steroid refractory (14.9% vs. WT 3.5%; P = 0.001). The WT patients were significantly higher refractory to immunosuppressant (12.8% vs. NOD2 carriers, 0.5%, P = 0.03). Most WT patients were treated with TNF-α antagonists and remission rates were significantly higher in this group after 1 year of treatment (84% vs. NOD2 carriers, 33%, P = 0.07). Conclusions The study presents first hints for the NOD2 carrier status to be predictive for response to therapy. A higher percentage of CD patients with NOD2 mutation carrier status was steroid refractory but could be treated well with immunosuppressants. The WT status showed a higher response to steroids and remission rates within 1 year of anti-TNF-α therapy. On the way to personalized medicine, this approach should be further investigated in larger studies. more...
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- 2011
5. Severe Early-Onset Obesity Due to Bioinactive Leptin Caused by a p.N103K Mutation in the Leptin Gene
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Martin, Wabitsch, Jan-Bernd, Funcke, Julia, von Schnurbein, Friederike, Denzer, Georgia, Lahr, Inas, Mazen, Mona, El-Gammal, Christian, Denzer, Anja, Moss, Klaus-Michael, Debatin, Peter, Gierschik, Vanisha, Mistry, Julia M, Keogh, I Sadaf, Farooqi, Barbara, Moepps, and Pamela, Fischer-Posovszky more...
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Leptin ,Male ,digestive, oral, and skin physiology ,Body Weight ,Hyperphagia ,Special Features ,Mutation ,Humans ,Female ,Obesity ,Child ,hormones, hormone substitutes, and hormone antagonists - Abstract
Context: Congenital leptin deficiency is a very rare cause of severe early-onset obesity. We recently characterized a mutation in the leptin gene (p.D100Y), which was associated with detectable leptin levels and bioinactivity of the hormone. Case Description: We now describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity and hyperphagia, both homozygous for a c.309C>A substitution in the leptin gene leading to a p.N103K amino acid exchange in the protein and detectable circulating levels of leptin. In vitro experiments in a heterologous cell system demonstrated that the mutated protein was biologically inactive. Treatment with sc recombinant human leptin led to rapid improvement of eating behavior and weight loss. Conclusions: Sequencing of the leptin gene may need to be considered in hyperphagic, severely obese children with detectable levels of circulating leptin. more...
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- 2015
6. Immunological reconstitution in a patient with ZAP-70 deficiency following transfusion of blood lymphocytes from a previously transplanted sibling without conditioning
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A. Schulz, Georgia Lahr, Catharina Schuetz, Eva-Maria Jacobsen, W. Friedrich, Klaus Schwarz, Markus Rojewski, Klaus-Michael Debatin, and Manfred Hönig
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Transplantation ,Hematopoietic cell ,business.industry ,T-cell receptor ,Hematology ,Early infancy ,Humoral immunity ,Immunology ,Medicine ,Signal transduction ,Sibling ,business ,CD8 - Abstract
SCID is a clinically defined group of monogenetic diseases characterized by life-threatening infections in early infancy. One variant of SCID is due to defects in the Zeta-chain-associated protein (ZAP-70; MIM+176947), which results in deficient signal transduction from the TCR to the nucleus and abnormal maturation and function of thymocytes. A characteristic finding is a complete lack of circulating CD8+ T cells, whereas CD4+ T cells are present, but without function.1 Although ZAP-70 is not expressed in B cells, humoral immunity is indirectly affected because of inadequate T-cell help. Currently, hematopoietic cell transplantation represents the only curative treatment.1 more...
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- 2011
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7. Laser-mediated microdissection of paraffin sections from Xenopus embryos allows detection of tissue-specific expressed mRNAs
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Georgia Lahr, Yukiko Imamichi, and Doris Wedlich
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Embryo, Nonmammalian ,Paraffin Embedding ,animal structures ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Lasers ,Embryogenesis ,Ectoderm ,Biology ,Molecular biology ,Marker gene ,Xenopus laevis ,medicine.anatomical_structure ,Genetics ,medicine ,biology.protein ,Animals ,RNA, Messenger ,Endoderm ,Sonic hedgehog ,Microdissection ,DNA Primers ,Developmental Biology ,Laser capture microdissection ,Floor plate - Abstract
One of the key end points for understanding the molecular basis of embryogenesis is the analysis of spatiotemporal patterns of gene expression. Methodical limitations due to low mRNA levels often prevent a tissue-specific resolution. In this study, we developed an improved laser microdissection technique and RT-PCR that allows marker gene detection in small tissue areas from sections of formalin-fixed paraffin-embedded Xenopus embryos. Tissue pieces were isolated by laser microbeam microdissection and captured by laser pressure catapulting. Neither laser treatment nor conventional histological or immunochemical staining impaired subsequent RNA analysis. Transcripts of tissue-specific marker genes such as endodermin (endoderm), epidermal cytokeratin (epidermal ectoderm), N-CAM (neural tube), myoD (somites), and sonic hedgehog (floor plate) were amplified by nested RT-PCR analysis from small areas of single sections. more...
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- 2001
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8. Identification of expressed genes by laser-mediated manipulation of single cells
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Georgia Lahr and Karin Schütze
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Cell ,Biomedical Engineering ,Bioengineering ,Cell Separation ,Adenocarcinoma ,Biology ,Polymerase Chain Reaction ,Applied Microbiology and Biotechnology ,Deoxyribonuclease HpaII ,Gene expression ,medicine ,Humans ,Point Mutation ,RNA, Messenger ,Codon ,Deoxyribonucleases, Type II Site-Specific ,Gene ,Microdissection ,Messenger RNA ,Lasers ,Point mutation ,Microtomy ,Microbeam ,Molecular biology ,Reverse transcriptase ,Genes, ras ,medicine.anatomical_structure ,Colonic Neoplasms ,Molecular Medicine ,Biotechnology - Abstract
We describe a rapid noncontact method for the capture of single cells or small tissue areas of any size or shape directly within the cap of a common microfuge tube. Prior to the laser-mediated transfer, the specimen is isolated by laser microbeam microdissection, forming a clear-cut gap around the selected area. Laser treatment does not impair subsequent RNA analysis. We have used this method to isolate a single cell from archival colon adenocarcinoma, and were able to detect point mutations within codon 12 of c-Ki-ras2 mRNA after nested RT-PCR analysis. more...
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- 1998
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9. The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain
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Anette Mayer, Dick F. Swaab, Georgia Lahr, Christof Pilgrim, Ingrid Reisert, Other departments, and Netherlands Institute for Neuroscience (NIN)
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Male ,Gonad ,Transcription, Genetic ,Restriction Mapping ,Hypothalamus ,Kruppel-Like Transcription Factors ,Biology ,Polymerase Chain Reaction ,Cellular and Molecular Neuroscience ,Y Chromosome ,Genes, Regulator ,Genetics ,medicine ,Humans ,RNA, Messenger ,Gene ,Transcription factor ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Temporal cortex ,Sexual differentiation ,Brain ,Nuclear Proteins ,Human brain ,Middle Aged ,Sex Determination Processes ,Sex-Determining Region Y Protein ,Temporal Lobe ,Human genetics ,Frontal Lobe ,DNA-Binding Proteins ,medicine.anatomical_structure ,Testis determining factor ,Female ,Transcription Factors - Abstract
Sexual differentiation of the brain is thought to be regulated by hormonal signals from the developing male gonad. However, more-recent experimental and clinical data throw some doubt on the general validity of the "classical" steroid hypothesis and suggest that additional intervening factors or mechanisms need to be considered. In particular, it is now envisaged that neurons are capable of acquiring sex-specific properties independently of their hormonal environment. Here we show that two Y-chromosomal genes involved in sex determination of the gonad, SRY and ZFY, are transcribed in hypothalamus, and frontal and temporal cortex of the adult male human brain. These genes are candidates for male-specific transcriptional regulators that could confer upon human brain cells the potential for hormone-independent realization and maintenance of genetic sex. more...
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- 1998
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10. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series
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Ban Mousa Rashid, Beston F. Nore, Ansgar Schulz, Nawshirwan Gafoor Rashid, and Georgia Lahr
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Genetics ,Medicine(all) ,business.industry ,lcsh:R ,lcsh:Medicine ,Osteopetrosis ,Case Report ,General Medicine ,medicine.disease ,Penetrance ,CLCN7 gene ,TCIRG1 ,Dominant allele ,Exon ,Consanguineous marriage ,Mutation (genetic algorithm) ,Autosomal dominant osteopetrosis ,Medicine ,Missense mutation ,Allele ,business ,Aunt - Abstract
Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (C GG>T GG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T). Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense mutation (C GG>T GG) located in exon 15 (c.1225C>T) of the Chloride channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T). In addition to the clinical diagnosis of both cases, the missense mutation we identified in one allele of the Chloride channel 7 gene could be linked to autosomal dominant osteopetrosis-II because the symptoms appear in late childhood or adolescence. Conclusion In this family, the molecular diagnosis was confirmed after identification of the same mutation in the older son (sibling). Furthermore, we detected that the father and his brother (the uncle) are carriers of the same mutation, whereas the mother and her sister (the aunt) do not carry any mutation of the Chloride channel 7 gene. Thus, the disease penetrance is at least 60% in the family. The mother and father are cousins and a further consanguineous marriage between the aunt and the uncle is not recommended because the dominant allele of the Chloride channel 7 gene will be transferred to the progeny. However, a similar risk is also expected following a marriage between the uncle and an unrelated woman. The p.R409W mutation in the Chloride channel 7 gene has not yet been described in the literature and it possibly has a dominant-negative impact on the protein. more...
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- 2013
11. Infantile malignant osteopetrosis: a rare cause of neonatal hypocalcemia
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Bulent Alioglu, Yıldız Dallar Bilge, İnci Arikan, Semra Kara, Ozlem Engiz, Denizhan Bagrul, and Georgia Lahr
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Male ,endocrine system ,Pathology ,medicine.medical_specialty ,Pediatrics ,Vacuolar Proton-Translocating ATPases ,Bone disease ,Endocrinology, Diabetes and Metabolism ,Hepatosplenomegaly ,Mutation, Missense ,Bone and Bones ,Frontal Bossing ,Endocrinology ,medicine ,Humans ,Neonatal hypocalcemia ,Hypocalcemia ,business.industry ,Infant, Newborn ,Osteopetrosis ,Optic Nerve ,medicine.disease ,Pancytopenia ,Radiography ,Pediatrics, Perinatology and Child Health ,medicine.symptom ,Generalized osteosclerosis ,business ,Infantile malignant osteopetrosis - Abstract
Infantile malignant osteopetrosis (IMO; OMIM 259700) is a rare inherited bone disease characterized by reduced or dysregulated activity of osteoclasts, resulting in generalized osteosclerosis. The disease usually presents within the first few months of life with anemia, hepatosplenomegaly, frontal bossing, nystagmus, blindness, deafness, and bone fractures. Children with IMO are at risk of developing hypocalcemia, with attendant tetanic seizures. We report the case of a baby boy who presented with neonatal hypocalcemia. Skeletal radiographs demonstrated sclerotic bones and a dense base of the skull with typical "space alien" face confirming the diagnosis of IMO. Pancytopenia developed at 2 months of age. Visual evoked potential showed severe bilateral optic nerve damage. Genetic mutation study revealed a new mutation in exon 13 of the TCIRG1 gene. Neonatal hypocalcemia can occur as result of IMO, which is easily missed out by clinicians. This causes delay in establishing the diagnosis and starting necessary treatment. Therefore, osteopetrosis should be kept in mind as a rare cause of neonatal hypocalcemia. more...
- Published
- 2012
12. Expression and alternative splicing of the neural cell adhesion molecule NCAM in human granulosa cells during luteinization
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U. Fröhlich, Manfred Gratzl, K. Sterzik, Georgia Lahr, Artur Mayerhofer, and R. Zienecker
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Lung Neoplasms ,Granulosa cell ,Gene Expression ,Polymerase Chain Reaction ,Biochemistry ,Cell membrane ,Structural Biology ,Tumor Cells, Cultured ,Carcinoma, Small Cell ,NCAM ,Cell adhesion molecule ,Single-Strand Specific DNA and RNA Endonucleases ,Cell biology ,Neural cell adhesion molecule ,Folliculogenesis ,Luteinization ,medicine.anatomical_structure ,Adhesion ,Female ,Human ,Gene isoform ,endocrine system ,medicine.medical_specialty ,DNA, Complementary ,Cell Adhesion Molecules, Neuronal ,Molecular Sequence Data ,Biophysics ,Biology ,Corpus Luteum ,Luteal Cells ,Internal medicine ,Genetics ,medicine ,Humans ,RNA, Messenger ,Molecular Biology ,Messenger RNA ,Granulosa Cells ,Base Sequence ,Cell Membrane ,Alternative splicing ,RNA Probes ,Cell Biology ,Microscopy, Electron ,Endocrinology ,nervous system - Abstract
Freshly aspirated human granulosa cells from pre-ovulatory follicles and granulosa cells luteinized in culture possess the neural cell adhesion molecule (NCAM) of approximate molecular mass of 140,000 and NCAM mRNA as confirmed by S1-nuclease protection assays and RT-PCR. Moreover, in the process of luteinization the NCAM isoform pattern is modified. Isoforms containing an insert of 10 amino acids (termed VASE) in the extracellular domain of NCAM were supplemented by alternatively spliced isoforms without this insert. NCAM immunoreactivity, at light and electron microscope levels, was associated with the cell membrane of most granulosa cells which formed clusters. During time in culture an increasing subpopulation of granulosa cells, devoid of NCAM immunoreactivity, spread out and formed monolayers. This differential expression and the alternative splicing of NCAM during luteinization of granulosa cells raise the possibility that NCAM could be involved in folliculogenesis and the formation of the corpus luteum in the human. more...
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- 1994
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13. Loss of enteroendocrine cells in autoimmune-polyendocrine-candidiasis-ectodermal-dystrophy (APECED) syndrome with gastrointestinal dysfunction
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Annette Findeisen, J. von Schnurbein, Stephan Buderus, Carsten Posovszky, Catharina Schütz, Martin Wabitsch, Thomas F. E. Barth, Klaus-Michael Debatin, C. Schröder, A. Schulz, and Georgia Lahr
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Male ,medicine.medical_specialty ,Malabsorption ,Adolescent ,Gastrointestinal Diseases ,Endocrinology, Diabetes and Metabolism ,Biopsy ,Enteroendocrine Cells ,Clinical Biochemistry ,DNA Mutational Analysis ,Down-Regulation ,Enteroendocrine cell ,Cell Count ,Biochemistry ,Gastroenterology ,Inflammatory bowel disease ,Cohort Studies ,Dysgenesis ,Endocrinology ,Internal medicine ,medicine ,Humans ,Child ,Polyendocrinopathies, Autoimmune ,biology ,medicine.diagnostic_test ,business.industry ,Stomach ,Biochemistry (medical) ,Chromogranin A ,Infant ,medicine.disease ,medicine.anatomical_structure ,Child, Preschool ,biology.protein ,Female ,Gastrointestinal function ,business - Abstract
Enteroendocrine (EE) cells are necessary for the regulation of gastrointestinal function. The lack of intestinal enteroendocrine cells in enteroendocrine cell dysgenesis causes severe malabsorptive diarrhea. Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) is often accompanied by gastrointestinal (GI) symptoms.We hypothesized that an autoimmune attack against the cells of the GI-associated diffuse endocrine system may be a specific feature of GI dysfunction in APECED disorders.Biopsies were obtained during routine diagnostic endoscopy from 35 pediatric patients with gastrointestinal symptoms as well as from five healthy controls; biopsies were immunostained for chromogranin A and serotonin. Four patients were classified as APECED syndrome on molecular and clinical grounds.Immunohistological analysis of biopsies along the GI tract (stomach, duodenum, colon) immunostained with chromogranin A and serotonin revealed a widespread reduction or complete loss of EE cells in all four patients with APECED syndrome suffering from severe diarrhea, vomiting, malabsorption, or constipation. In contrast, EE cells were present in pediatric patients with similar gastrointestinal symptoms caused by inflammatory bowel disease, celiac disease, lymphocytic colitis, and autoimmune disorders without endocrinopathy or graft vs. host disease of the gut.The reduction of EE cells is a specific and important early event in the pathogenesis of APECED with GI dysfunction. We propose a diagnostic algorithm integrating clinics, genetics and immunohistology. more...
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- 2011
14. Loss of Gastrointestinal Endocrine Cells in Patients with Autoimmune Polyendocrine Syndromes and Gastrointestinal Dysfunction
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Carsten Posovszky, Thomas Barth, Georgia Lahr, Julia Schnurbein, Stephan Buderus, Annette Findeisen, Catharina Schutz, Carmen Schroder, Ansgar Schulz, Klaus Michael Debatin, and Martin Wabitsch
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- 2011
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15. Early Relapse in ALL Is Identified by Time to Leukemia in NOD/SCID Mice and Is Characterized by a Gene Signature Involving Survival Pathways
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Georgia Lahr, Andrea Zangrando, Jana Stursberg, Karsten Stahnke, Anja Möricke, Karlheinz Holzmann, Giuseppe Basso, Johann M. Kraus, Martin Schrappe, Geertruy te Kronnie, Martin Zimmermann, Elena Vendramini, SM Eckhoff, André Schrauder, Klaus-Michael Debatin, Hans A. Kestler, Lüder Hinrich Meyer, Manon Queudeville, and Marco Giordan more...
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Transplantation, Heterologous ,Apoptosis ,Mice, SCID ,Nod ,Cohort Studies ,Mice ,Mice, Inbred NOD ,Recurrence ,Internal medicine ,medicine ,Animals ,Humans ,Child ,PI3K/AKT/mTOR pathway ,Survival analysis ,business.industry ,Gene Expression Profiling ,Infant, Newborn ,Infant ,Cell Biology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Survival Analysis ,Phenotype ,Transplantation ,Gene expression profiling ,Leukemia ,Child, Preschool ,Immunology ,Female ,business - Abstract
SummaryWe investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients. more...
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- 2011
16. Successful HLA haploidentical hematopoietic SCT in chronic granulomatous disease
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Manfred Hoenig, Dückers G, Niehues T, Klaus-Michael Debatin, Wilhelm Friedrich, Markus Wiesneth, Ingrid Furlan, Georgia Lahr, Catharina Schütz, Eva-Maria Jacobsen, Ansgar Schulz, and Siepermann K
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Transplantation ,Pathology ,medicine.medical_specialty ,business.industry ,Hematology ,Human leukocyte antigen ,medicine.disease ,Haematopoiesis ,Graft-versus-host disease ,Chronic granulomatous disease ,Immunology ,Medicine ,Stem cell ,Progenitor cell ,business - Published
- 2014
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17. Successful second haploidentical SCT in osteopetrosis
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Natalia Simanovsky, Georgia Lahr, Polina Stepensky, Igor B. Resnick, Reuven Or, Ansgar Schulz, Michael Weintraub, Simcha Samuel, and Rebecca Brooks
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Male ,Transplantation ,medicine.medical_specialty ,Transplantation Conditioning ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant ,Osteopetrosis ,Hematology ,Haploidy ,medicine.disease ,Surgery ,Cell transplantation ,Medicine ,Humans ,Transplantation, Homologous ,business - Published
- 2010
18. A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T cell responsiveness
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Julia von Schnurbein, Barbara Moepps, Gudrun Strauss, Peter Gierschik, Jan Kassubek, Hannes Mühleder, Pamela Fischer-Posovszky, Martin Wabitsch, Thomas F. E. Barth, Georgia Lahr, Klaus-Michael Debatin, and Peter Möller more...
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Leptin ,medicine.medical_specialty ,DNA, Complementary ,Adolescent ,Endocrinology, Diabetes and Metabolism ,T-Lymphocytes ,Clinical Biochemistry ,Mutant ,Blotting, Western ,Mutation, Missense ,Adipokine ,Biology ,Motor Activity ,medicine.disease_cause ,Transfection ,Biochemistry ,Exon ,Eating ,Endocrinology ,Internal medicine ,medicine ,Pressure ,Missense mutation ,Humans ,Obesity ,Cloning, Molecular ,Adiposity ,Cell Proliferation ,Mutation ,Leptin receptor ,Hypogonadism ,digestive, oral, and skin physiology ,Biochemistry (medical) ,Calorimetry, Indirect ,medicine.disease ,Immunohistochemistry ,Cold Temperature ,Cytokines ,Female ,Energy Intake ,Energy Metabolism - Abstract
Objective: Leptin, a protein product of adipocytes, plays a critical role in the regulation of body weight, immune function, pubertal development, and fertility. So far, only three homozygous mutations in the leptin gene in a total of 13 individuals have been found leading to a phenotype of extreme obesity with marked hyperphagia and impaired immune function. Design: Serum leptin was measured by ELISA. The leptin gene (OB) was sequenced in patient DNA. The effect of the identified novel mutation was assessed using HEK293 cells. Results: We describe a 14-yr-old child of nonobese Austrian parents without known consanguinity. She had a body mass index of 31.5 kg/m2 (+2.46 sd score) and undetectable leptin serum levels. Sequencing of the leptin gene revealed a hitherto unknown homozygous transition (TTA to TCA) in exon 3 of the LEP gene resulting in a L72S replacement in the leptin protein. RT-PCR, Western blot, and immunohistochemical analysis indicated that the mutant leptin was expressed in the patient’s adipose tissue but retained within the cell. Using a heterologous cell system, we confirmed this finding and demonstrated that the side chain of Leu72 is crucial for intracellular leptin trafficking. Our patient showed signs of a hypogonadotropic hypogonadism. However, in contrast to the literature, she showed only mild obesity and a normal T cell responsiveness. Conclusions: These findings shed a new light on the clinical consequences of leptin deficiency. Congenital leptin deficiency should be considered possible in pediatric patients with mild obesity even if parents are lean and unrelated. more...
- Published
- 2010
19. Secretory vesicle and cell surface markers for human endocrine pancreatic and pituitary tumors
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Georgia Lahr, Manfred Gratzl, Otmar Gratzl, C. Vereczkey, and Keith Langley
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Chromogranins ,Enteroendocrine cell ,General Medicine ,Biology ,Synaptic vesicle ,Secretory Vesicle ,Pathology and Forensic Medicine ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,medicine ,Endocrine system ,Pancreas ,Secretory pathway ,Hormone - Abstract
9 1992 Blackwell Scientific Publications, Inc. The pancreatic islet and the adenohypophysis are endocrine tissues sharing several properties. These organs are both composed of different endocrine cells secreting a variety of hormones. These are stored within the cells in dense core secretory vesicles and are released by appropriate stimuli. In addition to dense core secretory vesicles, endocrine pancreatic and adenohypophyseal cells contain small translucent vesicles, which are very similar to synaptic vesicles not only in their morphological appearance but also with regard to their protein constituents [31, 64]. Indeed, several lines of evidence suggest that pancreatic and adenohypophyseal endocrine cells have an additional secretory pathway for neurotransmitters besides the classic exocytotic pathway for hormone release [31, 54, 60]. Proteins present in the dense core vesicles containing hormones, such as chromogranins and secretogranins, have also been detected in their counterparts within neurons (for refs. see [30, 37, 38, 61]). This indicates that neurons and endocrine ceils are very similar with respect to the composition of their characteristic small secretory vesicles (SSV) and large secretory vesicles (LSV) besides having a variety of molecular, biochemical, and functional similarities [25]. Neurons and endocrine cells also share proteins exposed on the external surface. The best documented proteins of this class are members of the family of neural cell adhesion molecules (NCAMs), which are present in endocrine cells of the adult, including pancreatic islet and adenohypophyseal cells [2, 39-41]. While tumors derived from the endocrine pancreas are rare [35], pituitary tumors are frequently observed [27, 35, 73]. Besides symptoms produced locally by the tumors, overproduction of their hormones and their subsequent effects in the body often permit a straightforward diagnosis. However, a significant percentage of endocrine pancreatic and pituitary tumors do not cause elevated serum hormone levels and thus are hormonally inactive [27, 29, 73]. In such cases additional characteristic constituents of endocrine cells are critical in providing information on the nature, location, and distribution of endocrine tumor cells in the body. Here we summarize recent findings concerning the expression of membrane proteins of SSV and of the cell surface antigen NCAM by normal and neoplastic endocrine cells. more...
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- 1992
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20. Leydig Cells Express Neural Cell Adhesion Molecules in Vivo and in Vitro1
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Annette Christoph, Georgia Lahr, Artur Mayerhofer, Klaus Seidl, Wolfgang Wille, Dagmar Barthels, Manfred Gratzl, and Dieter Bitter-Suermann
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Gene isoform ,endocrine system ,Cell type ,Leydig cell ,Cell adhesion molecule ,Embryogenesis ,Cell Biology ,General Medicine ,Biology ,Molecular biology ,In vitro ,Blot ,medicine.anatomical_structure ,nervous system ,Reproductive Medicine ,medicine ,Neural cell adhesion molecule - Abstract
The neural cell adhesion molecule (NCAM) polypeptides are expressed by numerous tissues during embryonic development, where they are involved in cell-cell interactions. In the adult, NCAM expression is confined to a few cell types, including neurons and peptide-hormone-producing cells. Here we demonstrate that the Leydig cells of the adult rat, mouse, and hamster testes express NCAM as well. Western blotting showed that an NCAM of approximately 120 kDa was present in the adult testes of all three species investigated. This form was also found in freshly isolated mouse Leydig cells and in Leydig cells after 2 days in culture. After 4 days in culture, mouse Leydig cells expressed additional NCAM isoforms of approximately 140 and 180 kDa, indicating changes in alternative splicing of NCAM primary transcripts. Also, NCAM mRNA of all isoforms, as detected by S1-nuclease protection assays, increased with time in culture. The expression of the cell adhesion molecule NCAM by adult Leydig cells may explain the aggregation of Leydig cells in clusters in rodent testes, which could be a prerequisite for functional coordination of groups of Leydig cells. Furthermore, the presence of this neural and endocrine marker may indicate a closer relationship between Leydig cells and neural and peptide-hormone-producing cells than is considered to exist at the present time. more...
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- 1992
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21. Osteopetrosis due to homozygous chloride channel ClCN7 mutation mimicking metabolic disease with haematological and neurological impairment
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Robert Weinzettel, Georgia Lahr, Georg Ebetsberger, Ansgar Schulz, Olaf Rittinger, Dieter Furthner, Kenneth Schmitt, and Ariane Biebl
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Male ,Pathology ,medicine.medical_specialty ,Anemia ,DNA Mutational Analysis ,Hepatosplenomegaly ,Genes, Recessive ,Disease ,Diagnosis, Differential ,Fatal Outcome ,Chloride Channels ,Creatine Kinase, BB Form ,Medicine ,Humans ,Codon ,Chromosome Aberrations ,Epilepsy ,biology ,business.industry ,Homozygote ,Skull ,Osteopetrosis ,Neurodegenerative Diseases ,Exons ,medicine.disease ,Haemolysis ,Alkaline Phosphatase ,Pancytopenia ,Spine ,Radiography ,Child, Preschool ,Hematopoiesis, Extramedullary ,Pediatrics, Perinatology and Child Health ,biology.protein ,CLCN7 ,medicine.symptom ,business ,Rare disease - Abstract
UNLABELLED We report on the fatal clinical course of a 3 year old male Turkish patient suffering from osteopetrosis caused by a homozygous mutation in the chloride channel gene ClCN7 with developing pancytopenia and severe neurological impairment. Hepatosplenomegaly due to extramedullary hematopoesis, severe transfusion-dependent anemia and growth failure initially suggested metabolic or oncologic disorder. Particular haematological parameters like tear drop cells basophilic punctation of the polymorphonuclear cells in the absence of haemolysis caused the diagnostic X-ray investigations of the skull and vertebral column. Raised serum creatinkinase-BB isoenzyme and genetic testing were in line with the diagnose of osteopetrosis at an age of 2(1/2) years. CONCLUSION Osteopetrosis is a rare but considerable differential diagnose for unclarified change in haematopoetic cell lines combined with severe neurological symptoms mimicking metabolic or haematological disease. Because of this rare disease a consensus protocol for diagnostics, treatment and follow up of patients suffering from osteopetrosis is recently worked out from the European Group of Blood and Marrow Transplantation (EBMT) and the European Society for Immundeficiencies (ESID) to build up a central registry for this disease (available by ansgar.schulz@uniklinik-ulm.de). more...
- Published
- 2009
22. Expression of the Neural Cell Adhesion Molecule in Endocrine Cells of the Ovary*
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Artur Mayerhofer, Manfred Gratzl, and Georgia Lahr
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endocrine system ,medicine.medical_specialty ,Cell Adhesion Molecules, Neuronal ,Blotting, Western ,Morphogenesis ,Gene Expression ,Enteroendocrine cell ,Ovary ,Biology ,Immunoenzyme Techniques ,Endocrinology ,Estrus ,Pregnancy ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Ovarian follicle ,Cell adhesion ,Granulosa Cells ,Cell adhesion molecule ,Single-Strand Specific DNA and RNA Endonucleases ,Nucleic Acid Hybridization ,Rats, Inbred Strains ,Rats ,Microscopy, Electron ,medicine.anatomical_structure ,nervous system ,Theca Cells ,Female ,Neural cell adhesion molecule ,Corpus luteum - Abstract
In the adult mammalian ovary morphogenesis and differentiation processes are under hormonal control and, thus, occur in a highly regulated way during the sexual cycle. Cell-cell interactions, such as cell adhesion and cell separation, are crucial during these events. Here we show that the ovarian endocrine cells, which are prototypes of steroid-producing cells, express neural cell adhesion molecules (NCAMs). The combined use of in situ hybridization histochemistry, immunocytochemistry at the light and electron microscope levels, S1 nuclease protection assays, and Western blotting revealed that in the ovary of the adult rat during the estrus cycle and pregnancy, NCAM mRNA and the 140-kDa isoform of this protein are expressed mainly in granulosa cells of growing preantral and antral follicles and in corpora lutea. Since the granulosa cells lining the forming antrum and the antral fluid were strongly immunoreactive, a role for NCAM in the formation of the follicular antrum is proposed. The expression of NCAM was also associated with luteal cells of the active corpus luteum, indicating a role for NCAM in the morphogenesis of this endocrine compartment. Moreover, thecal cells of large follicles and hypertrophic thecal cells of atretic follicles expressed NCAM, as did interstitial cells, which are derived from thecal cells of atretic follicles. We propose that the adhesion molecule, NCAM, is an important factor involved in the recognition and intercellular interaction of ovarian endocrine cells and, thus, participates in the regulation of the cyclic remodeling processes of the ovarian endocrine compartments. more...
- Published
- 1991
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23. Expression of synaptophysin during the prenatal development of the rat spinal cord: Correlation with basic differentiation processes of neurons
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Mathias Bergmann, Artur Mayerhofer, Manfred Gratzl, and Georgia Lahr
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Aging ,Blotting, Western ,Immunocytochemistry ,Central nervous system ,Synaptophysin ,Gestational Age ,Synaptic vesicle ,Neuroblast ,Pregnancy ,medicine ,Animals ,RNA, Messenger ,Neurons ,biology ,General Neuroscience ,Single-Strand Specific DNA and RNA Endonucleases ,Embryogenesis ,Membrane Proteins ,Nucleic Acid Hybridization ,Cell Differentiation ,Rats, Inbred Strains ,RNA Probes ,Spinal cord ,Immunohistochemistry ,Rats ,Cell biology ,Neuroepithelial cell ,medicine.anatomical_structure ,Spinal Cord ,nervous system ,biology.protein ,Female ,DNA Probes ,Neuroscience - Abstract
The development of the spinal cord involves the proliferation of neurons, their migration to well-defined areas, fiber outgrowth and synapse formation. The present study was designed to correlate the spatiotemporal pattern of expression of synaptophysin, an integral membrane protein of small synaptic vesicles, with these basic processes occurring during the embryonic development of the rat spinal cord. Thoracic segments of spinal cords from embryonic days 12, 14, 16, 18, 20 and of adult spinal cords were studied. S1 nuclease protection assays and immunoblots revealed minute amounts of specific mRNA and synaptophysin at embryonic day 12. There was a steep increase of mRNA between embryonic days 14 and 16, after which levels reached a plateau. A rise in the amount of synaptophysin in the spinal cord occurred between embryonic days 12 and 14, and the levels changed only slightly until the end of embryonic development. Even higher levels of synaptophysin, found in the adult spinal cord, may indicate that its biosynthesis continued after birth. In situ hybridization histochemistry revealed the localization of specific synaptophysin mRNA in the neuroepithelium. However, immunocytochemistry failed to detect synaptophysin in the neuroepithelial cells. Following migration of the neuroblasts, synaptophysin was found in neurons concomitantly with the onset of fiber outgrowth. Thus, already at embryonic day 12, outgrowing fibers of the dorsal root sensory neurons and of motoneurons were synaptophysin positive. From embryonic day 14 throughout the prenatal period, strong synaptophysin immunoreactivity was seen in the ventrolateral and dorsal parts of the marginal layer. Most likely this staining pattern indicates transient functional synaptic contacts because, in the adult spinal cord, the corresponding region, the white matter, exhibited only faint synaptophysin immunoreactivity. In the intermediate layer of the embryonic spinal cord, which corresponds to the gray matter of the adult spinal cord, synaptophysin-positive fibers were observed prior to the formation of functional synapses. The latter are most likely permanent, since synaptophysin in the adult spinal cord is mainly confined to the gray matter. Our data (i) show transcription and translation of synaptophysin within the neurons of the spinal cord and correlate these processes with proliferation, migration, fiber outgrowth and the formation of transient or permanent synapses, and (ii) prove that synaptophysin is a marker for fiber outgrowth in addition to synapse formation. more...
- Published
- 1991
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24. Residual CD95-pathway function in children with autoimmune lymphoproliferative syndrome is independent from clinical state and genotype of CD95 mutation
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Georgia Lahr, H Fuchs, Thomas Boehler, Carsten Posovszky, Jutte van der Werff ten Bosch, Klaus-Michael Debatin, and Pediatrics
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Death Domain Receptor Signaling Adaptor Proteins ,Herpesvirus 4, Human ,Genotype ,T-Lymphocytes ,chemical and pharmacologic phenomena ,Apoptosis ,Biology ,medicine.disease_cause ,Autoimmune Diseases ,Pathogenesis ,hemic and lymphatic diseases ,medicine ,Humans ,fas Receptor ,Caspase 10 ,Staphylococcal Protein A ,Gene ,CD95-pathway function ,Children ,Cells, Cultured ,Mutation ,B-Lymphocytes ,Caspase 8 ,clinical state ,hemic and immune systems ,Syndrome ,Fas receptor ,medicine.disease ,Cell Transformation, Viral ,Penetrance ,autoimmune lymphoproliferative syndrome ,biological factors ,Lymphoproliferative Disorders ,Phenotype ,Autoimmune lymphoproliferative syndrome ,Pediatrics, Perinatology and Child Health ,Immunology ,biological phenomena, cell phenomena, and immunity ,CD95 mutation - Abstract
Human autoimmune lymphoproliferative syndrome (ALPS) is caused by defective CD95-mediated apoptosis of lymphocytes. In most patients, heterozygous mutations within the CD95 gene are found. Mutated proteins interfere with CD95-signaling in a dominant-negative way. However, the penetrance of clinical disease is variable. We describe 13 patients out of nine families with the clinical presentation of ALPS. Eight different mutations were detected. Sensitivity to CD95-induced cell-death, assembly of the CD95-death-inducing signaling complex (DISC), and activity of initiator caspases-8 and -10 were compared in EBV-transformed B-lymphoblastoid cells of these patients. All CD95-mutations led to a reduced DISC formation and diminished initiator caspase activity upon CD95-stimulation, whereas a marked heterogeneity in sensitivity to CD95-induced killing was found. Residual apoptosis sensitivity to almost normal levels could be achieved upon cross-linking by addition of protein A. Thus, no correlation between residual CD95 sensitivity and clinical phenotype or genotype of ALPS was found. This observation is only partially explained by the variable effects of the CD95-mutations themselves. It also points to a pronounced influence of additional factors, such as modifier pathways or exogenous effects apart from the CD95 pathway in the pathogenesis of ALPS. more...
- Published
- 2008
25. Chromogranin a in the olfactory system of the rat
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C. Heiss, Robert J. Parmer, K. Schilling, Artur Mayerhofer, Georgia Lahr, Daniel T. O'Connor, and Manfred Gratzl
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Male ,Olfactory system ,endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Blotting, Western ,Molecular Sequence Data ,Immunocytochemistry ,Hippocampus ,In situ hybridization ,Primary olfactory cortex ,Olfactory nerve ,Internal medicine ,Adrenal Glands ,Chromogranins ,medicine ,Animals ,Amino Acid Sequence ,RNA, Messenger ,Brain Chemistry ,biology ,Immune Sera ,General Neuroscience ,Brain ,Nucleic Acid Hybridization ,Chromogranin A ,Rats, Inbred Strains ,Olfactory Bulb ,digestive system diseases ,Rats ,Olfactory bulb ,Cell biology ,Molecular Weight ,Endocrinology ,nervous system ,Pituitary Gland ,biology.protein ,Female ,DNA Probes - Abstract
The olfactory bulb of the rat contains chromogranin A at a similar level as the adrenal gland or the hypophysis as revealed by immunoblots. Olfactory chromogranin A also displays the same size as chromogranin A of endocrine cells. In the hippocampus and other brain regions, we could not detect chromogranin A by immunoblotting. In contrast, chromogranin A messenger ribonucleic acid (using S1 nuclease protection assays) was observed in all brain regions examined, including the olfactory bulb. By in situ hybridization histochemistry with a complementary ribonucleic acid probe (280 nucleotides), and by immunocytochemistry, chromogranin A synthesis could be localized to cell bodies of the mitral cell layer, of the external plexiform layer and of the periglomerular region of the olfactory bulb. Immunocytochemically, chromogranin A was also detected in the central projection areas of mitral and tufted cells in the primary olfactory cortex and the anterior amygdaloid area but not in the olfactory glomeruli, where the incoming olfactory nerve fibers of the primary olfactory neurons establish synaptic contacts. Taken together the data show that chromogranin A, following biosynthesis in the perikarya of the mitral and tufted cells, is specifically transported into their axonal terminals but not into their primary dendrites. We propose that the rat olfactory system could serve as a model for the study of chromogranin A regulation and function in neurons. more...
- Published
- 1990
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26. Obesity and Weight Regulation
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Martin Wabitsch, Malaika Fuchs, Sina Horenburg, Julia von Puttkamer, Anja Moss, Georgia Lahr, and Pamela Fischer-Posovszky
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- 2007
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27. Identical phenotype in patients with somatic and germline CD95 mutations requires a new diagnostic approach to autoimmune lymphoproliferative syndrome
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Anselm Enders, Georgia Lahr, Hans Fuchs, Andreas Heitger, Stephan Ehl, Karl Winkler, Jochen Rössler, Charlotte M. Niemeyer, and Matthias V. Kopp
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Somatic cell ,CD3 ,Receptors, Antigen, T-Cell, alpha-beta ,DNA Mutational Analysis ,Apoptosis ,Germline ,Autoimmune Diseases ,Immunophenotyping ,Diagnosis, Differential ,Germline mutation ,T-Lymphocyte Subsets ,Medicine ,Humans ,Lymphocyte Count ,fas Receptor ,Child ,Gene ,Germ-Line Mutation ,biology ,business.industry ,medicine.disease ,Phenotype ,Lymphoproliferative Disorders ,Interleukin 10 ,Autoimmune lymphoproliferative syndrome ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,business ,Algorithms - Abstract
In a patient with a somatic mutation in the CD95 gene, the long-term evolution of the clinical phenotype was indistinguishable from that of patients with autoimmune lymphoproliferative syndrome caused by germline CD95 mutations. A new diagnostic algorithm for autoimmune lymphoproliferative syndrome is suggested incorporating studies on sorted TCRalpha/beta+CD3+CD8-CD4- T cells. more...
- Published
- 2005
28. The role of microsatellite instability in cervical intraepithelial neoplasia and squamous cell carcinoma of the cervix
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Vivian W. Wang, Mei Yung Yu, So Fan Yim, Yick Fu Wong, Tony K.H. Chung, Georgia Lahr, Keith W.K. Lo, James C. B. Li, Kin Yan Poon, and Tak Hong Cheung
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Oncology ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Uterine Cervical Neoplasms ,Cervical intraepithelial neoplasia ,Polymerase Chain Reaction ,Internal medicine ,medicine ,Carcinoma ,Humans ,neoplasms ,Cervix ,Neoplasm Staging ,Intraepithelial neoplasia ,business.industry ,nutritional and metabolic diseases ,Obstetrics and Gynecology ,Microsatellite instability ,Cancer ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,Uterine Cervical Dysplasia ,digestive system diseases ,medicine.anatomical_structure ,Epidermoid carcinoma ,Dysplasia ,Carcinoma, Squamous Cell ,Female ,business ,Microsatellite Repeats - Abstract
Objectives This study was conducted to define the role of microsatellite instability (MSI) in cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC) of the cervix. We also tested the validity of using markers recommended for MSI study in colonic carcinoma by the National Cancer Institute (NCI) for cervical neoplasm. Methods Twenty normal cervical, 24 low-grade CIN (CIN-L), 59 high-grade CIN (CIN-H), and 93 SCC tissues were examined for MSI after microdissection. A polymerase chain reaction based MSI detection was performed using five markers recommended by the NCI for colonic cancer (panel one) as well as five other markers (panel two) found to be informative in earlier studies. High-frequency MSI (MSI-H) was defined as instability in ≥2 of 5 loci if one panel was used and ≥30% of loci when more than five loci were used. Low-frequency MSI (MSI-L) was diagnosed if instability was noted but did not meet the criteria of MSI-H. Findings were correlated with clinicopathologic information. Results The combined use of panel one and two markers showed no MSI in normal cervical or CIN-L tissue, MSI-L in 1 CIN-H (1.7%), MSI-L in 16 (17.2%), and MSI-H in 11 (11.8%) SCC, respectively. The NCI-recommended panel alone detected 19 of 27 MSI-positive SCC. MSI-positive was not related to patient age, disease stage, and tumor grade. The overall survival of MSI-positive patients was significantly worse than that of microsatellite stable patients (P = 0.02). An increasing trend of MSI-H rate with higher disease stages was noted (P = 0.035) but MSI-H was not associated with poor prognosis. Conclusions The NCI recommended panel of markers might not be useful in MSI study for SCC and using more than five markers improves the MSI detection. MSI is rare in cervical dysplasia but is present in a subset of SCC. The association between MSI-positivity and prognosis awaits future confirmation. more...
- Published
- 2003
29. Going in vivo with laser microdissection
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Anette, Mayer, Monika, Stich, Dieter, Brocksch, Karin, Schütze, and Georgia, Lahr
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Micromanipulation ,Lasers ,Cell Culture Techniques ,Tumor Cells, Cultured ,Humans ,Cell Separation - Published
- 2002
30. [3] Going in vivo with laser microdissection
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Anette Mayer, Dieter Brocksch, Karin Schütze, Monika Stich, and Georgia Lahr
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Chemistry ,In vivo ,Molecular biology ,Microdissection ,Laser capture microdissection - Published
- 2002
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31. [23] Analysis of specific gene expression
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Anna Starzinski-Powitz, Anal Anette Mayer, and Georgia Lahr
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Genetics ,Gene expression profiling ,Regulation of gene expression ,Gene knockdown ,Expression quantitative trait loci ,Pair-rule gene ,Gene targeting ,Biology ,Gene dosage ,Regulator gene - Published
- 2002
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32. RT-PCR from archival single cells is a suitable method to analyze specific gene expression
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Georgia Lahr
- Subjects
Genetics ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression ,Reproducibility of Results ,Cell Biology ,Biology ,Adenocarcinoma ,Molecular biology ,Reverse transcriptase ,Pathology and Forensic Medicine ,law.invention ,Real-time polymerase chain reaction ,Investigation methods ,law ,RNA analysis ,Gene expression ,Colonic Neoplasms ,Humans ,RNA ,Molecular Biology ,Polymerase chain reaction ,Microdissection ,Isolated cell - Published
- 2000
33. Age-of-onset-dependent influence of NOD2 gene variants on disease behaviour and treatment in Crohn’s disease
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Benjamin Mayer, Carsten Posovszky, Jan Hendrik Niess, Georgia Lahr, Georg B T von Boyen, Jochen Klaus, Veronika Pfalzer, and Klaus-Michael Debatin
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Crohn’s disease ,Adult ,Male ,Bone density ,Adolescent ,Osteoporosis ,Anti-Inflammatory Agents ,Nod2 Signaling Adaptor Protein ,610 Medicine & health ,Disease ,Inflammatory bowel disease ,Severity of Illness Index ,NOD2 ,Young Adult ,Crohn Disease ,Thinness ,Bone Density ,Medicine ,Humans ,Allele ,Age of Onset ,Child ,Alleles ,Crohn's disease ,business.industry ,Homozygote ,Gastroenterology ,Genetic Variation ,General Medicine ,CARD 15 ,Middle Aged ,medicine.disease ,digestive system diseases ,Immunology ,Pediatric-onset ,Female ,Age of onset ,business ,Immunosuppressive Agents ,Research Article - Abstract
BACKGROUND: Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn's disease (CD). METHODS: 85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD). RESULTS: Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213). CONCLUSIONS: These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants. more...
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- 2013
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34. Transcription of the Y chromosomal gene, Sry, in adult mouse brain
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Ingrid Reisert, Christof Pilgrim, Stephen C. Maxson, Anette Mayer, Georgia Lahr, and Walter Just
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Male ,Transcription, Genetic ,Central nervous system ,Molecular Sequence Data ,Hypothalamus ,Mice, Inbred Strains ,Biology ,Y chromosome ,Cellular and Molecular Neuroscience ,Mice ,Transcription (biology) ,Mesencephalon ,Y Chromosome ,Gene expression ,Testis ,medicine ,Animals ,Sexual Maturation ,Molecular Biology ,Gene ,Transcription factor ,Genetics ,Sexual differentiation ,Base Sequence ,medicine.anatomical_structure ,Testis determining factor ,Genetic Code ,Female - Abstract
The Y chromosomal gene Sry encodes a putative transcription factor which appears to serve as a master switch initiating testicular development. Here we show that this gene is transcribed in hypothalamus, midbrain, and testis of adult male but not adult female mice. In contrast to its circular transcripts in adult testis, those in brain are linear and may be translated. We propose that Sry exerts a role in the regulation of sex differentiation of the mammalian nervous system. more...
- Published
- 1995
35. Expression of the Neural Cell Adhesion Molecule NCAM by Peptide- and Steroid-Producing Endocrine Cells and Tumors: Alternatively Spliced Forms and Polysialylation
- Author
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Artur Mayerhofer and Georgia Lahr
- Subjects
Gene isoform ,endocrine system ,medicine.medical_specialty ,Messenger RNA ,Endocrinology, Diabetes and Metabolism ,Alternative splicing ,Enteroendocrine cell ,General Medicine ,Biology ,Primary transcript ,Pathology and Forensic Medicine ,Cell biology ,Exon ,Endocrinology ,nervous system ,Internal medicine ,medicine ,Endocrine system ,Neural cell adhesion molecule - Abstract
The adhesive properties of neural cell adhesion molecules (NCAMs) can be modified by alternative splicing of the primary transcript or by posttranslational modifications, such as sialylation. In this article, we describe distinct forms of alternative splicing and posttranslational modification of the extracellular domain of NCAM of various endocrine tissues and derived tumor cells of the rat and of steroid- and peptide-hormone producing endocrine cells in humans. NCAM-140 is the major isoform expressed in the rat adrenal gland, adenohypophysis, and in granulosa and granulosa-lutein cells. NCAM-180 is predominant in the neurohypophysis. Polysialylated NCAM is expressed in different endocrine tissues and tumor cells of the rat. Different amounts of NCAM mRNA containing the "extra-exon" VASE at the exon 7/8 splice boundary were detected in endocrine cells of rats. Human granulosa cells in culture undergo luteinization. During this process, the VASE-containing NCAM isoform is supplemented by an alternatively spliced isoform without this insert. Thus, modifications of NCAM may be important for adhesive interactions in normal and neoplastic endocrine cells. In addition, the differential expression and the alternative splicing of NCAM during luteinization of granulosa cells raise the possibility that NCAM could be involved in folliculogenesis and the formation of the corpus luteum in humans. more...
- Published
- 1995
36. Neural cell adhesion molecules in rat endocrine tissues and tumor cells: distribution and molecular analysis
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Manfred Gratzl, Artur Mayerhofer, D. Barthels, Georgia Lahr, S. Bucher, and W. Wille
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medicine.medical_specialty ,Pituitary gland ,Cell Adhesion Molecules, Neuronal ,Molecular Sequence Data ,Gene Expression ,Enteroendocrine cell ,In situ hybridization ,Biology ,PC12 Cells ,Polymerase Chain Reaction ,Cell Line ,Rats, Sprague-Dawley ,Exon ,Endocrinology ,Internal medicine ,Adrenal Glands ,medicine ,Tumor Cells, Cultured ,Animals ,Pituitary Neoplasms ,RNA, Messenger ,Base Sequence ,Polysialic acid ,Immune Sera ,Alternative splicing ,Antibodies, Monoclonal ,Genetic Variation ,Exons ,RNA Probes ,Immunohistochemistry ,Rats ,Alternative Splicing ,medicine.anatomical_structure ,nervous system ,Oligodeoxyribonucleotides ,Pituitary Gland ,Neural cell adhesion molecule ,Female ,DNA Probes ,Endocrine gland - Abstract
The adhesive properties of neural cell adhesion molecules (NCAMs) can be modified by alternative splicing of the primary transcript or posttranslational modifications. In the present study, we describe distinct forms of alternative splicing and posttranslational modification of the extracellular domain of NCAM of various endocrine tissues and derived tumor cells of the rat. Using an antiserum detecting the immunoglobulin-like domains of NCAM as well as a monoclonal antibody recognizing the NCAM-specific polysialic acid (PSA), we observed a similar staining pattern in adrenals, pituitary, and neoplastic endocrine cells. In endocrine tumor cells [pheochromocytoma (PC12), insulinoma (RINA2), and pituitary tumor cells (GH3)], NCAM immunoreactivity was most intense at contact sites between the cells. The immunocytochemical data were substantiated by results of in situ hybridization histochemistry. Specifically, higher levels of NCAM mRNA were detected in the adrenal cortex than in the medulla. In the pituitary, NCAM mRNA was more abundant in the anterior and intermediate lobes than in the neural lobe. The sequence of NCAM mRNAs in endocrine cells was analyzed by polymerase chain reaction and S1 nuclease protection assays. We found that major exons 4-13 of the NCAM mRNA in endocrine tissues and related tumor cell lines were homologous to those in the brain. However, PC12, RINA2, and GH3 tumor cells; normal rat pituitaries; and adrenals contained different amounts of NCAM mRNA with an alternative extra exon, termed VASE (also called pi in mouse) between constitutive exons 7 and 8. In addition, in pituitaries, we detected an alternative exon in splice site a between the constitutive exons 12 and 13, termed a15, with or without an AAG triplett. These sites are thought to be important for the adhesive properties of NCAM. Therefore, these results suggest that modifications of NCAM may be important for adhesive interactions in normal and neoplastic endocrine cells. more...
- Published
- 1993
37. Membrane Proteins as Markers for Normal and Neoplastic Endocrine Cells
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Georgia Lahr and Manfred Gratzl
- Subjects
Membrane protein ,Polysialic acid ,Distribution (pharmacology) ,Tumor cells ,Neural cell adhesion molecule ,Enteroendocrine cell ,Biology ,Synaptic vesicle ,Cell biology - Abstract
Neurons, endocrine cells and their neoplastic derivatives share a variety of similar or even identical characteristic proteins. The analysis of these cellular constituents provides valuable information on the nature, location and distribution of tumor cells in the body. more...
- Published
- 1993
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38. Chromogranin A in neurons of the rat cerebellum and spinal cord: quantification and sites of expression
- Author
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Manfred Gratzl, Artur Mayerhofer, M. A. Takiyyuddin, Georgia Lahr, and Mathias Bergmann
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Male ,medicine.medical_specialty ,Cerebellum ,endocrine system ,Histology ,Central nervous system ,In situ hybridization ,Deep cerebellar nuclei ,Internal medicine ,medicine ,Chromogranins ,Animals ,RNA, Messenger ,Neurons ,biology ,Chromogranin A ,Rats, Inbred Strains ,Spinal cord ,Olfactory bulb ,Rats ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Spinal Cord ,Cerebellar cortex ,biology.protein ,Anatomy - Abstract
Chromogranin A (CGA) is an abundant protein of dense-cored secretory vesicles in endocrine and neuronal cells. The present study, for the first time, compares CGA of neurons of the central nervous system with the CGA of adrenal origin. By S1 nucleus protection assay, we found that the 3' part of the CGA mRNA between exons 5-8 of the cerebellum and the spinal cord of the rat is homologous to that of the adrenal. In situ hybridization histochemistry revealed that CGA mRNA in the cerebellar cortex is present in cell bodies of Purkinje cells and in neurons of the deep cerebellar nuclei. The perikarya of these cells also exhibit CGA-like immunoreactivity. CGA mRNA and CGA-like immunoreactivity are also present in the motoneurons of the ventral, lateral, and dorsal horns of the rat spinal cord. The amounts of CGA, as determined by radioimmunoassay in cerebellum and spinal cord, were about one tenth of the amounts detected in the adrenal, adenohypophysis, or the olfactory bulb. The sites of CGA expression suggest that CGA may be involved in signal transduction in the motor system. more...
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- 1992
39. Time to Leukaemia (TTL) Assessed in NOD/SCID Mice Transplanted with Primary ALL Leukaemia Cells Determines Early Relapse in Patients and Is Identified by a Specific Gene Signature
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Lüder Hinrich Meyer, Martin Zimmermann, Manon Dammé, Martin Schrappe, Klaus Michael Debatin, Karsten Stahnke, SM Eckhoff, André Schrauder, and Georgia Lahr
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Gene signature ,medicine.disease ,Biochemistry ,Log-rank test ,Leukemia ,medicine.anatomical_structure ,Prednisone ,Internal medicine ,Relative risk ,medicine ,Bone marrow ,Risk factor ,business ,B cell ,medicine.drug - Abstract
Poor response to induction therapy is the major risk factor identified in ALL and is used within the ALL BFM study to identify high risk groups (e.g. prednisone poor response, PPR: more than 1000 blasts/μl peripheral blood after treatment with prednisone systemically for 8 days and MTX intrathecally once on day 1). Despite the efforts achieved by the stratification strategies the majority of relapses are recruited from the group of initially good responding patients (in ALL BFM the standard and medium risk, SR and MR groups) emphasising the need for additional independent stratification factors. In our study we transplanted primary leukaemia cells from 50 children with newly diagnosed B cell precursor ALL (BCP-ALL) into NOD/SCID mice. Time to leukaemia was determined for each patient sample transplanted as weeks from date of transplant to date of clinical manifestation of the disease. Leukaemia was verified in spleen and bone marrow by flow cytometry staining for human CD19 and CD45. Time to leukaemia of less than 10 weeks (short TLL) was observed in 6 patient samples whereas 44 leukaemia samples took more than 10 weeks until appearance of leukaemia (long TTL). A clear cut in relapse free survival (Kaplan Meier analysis, N=50, log rank: P= .0000) was found for patients whose leukaemia cell samples showed short TTL (N=6, mean survival: 12.1 months, SE: 3.9, CI: 4.6–19.6) in contrast to patients with long TTL (N=44, mean survival: 54.3 months, SE: 2.9, CI: 48.6–60.1). Of note, the same distinct difference in relapse free survival was observed considering the SR and MR groups only (N=40, log rank P= .0000, long TTL: 44.9 months; short TTL: 12.5 months). By multivariate analysis (N=50, 3-years relapse free survival) patients exhibiting short TTL in the xenotransplant model exhibited a strongly increased risk for relapse with a risk ratio of 18.31 (CI: 5.03–66.72, P= .000). Interestingly, patients in our cohort showing prednisone poor response known as important clinical risk factor revealed only a risk ratio of 6.59 (CI: 1.32–32.75, P= .021). None of the patients with long TTL encountered early relapse. These findings in 50 directly transplanted samples were confirmed transplanting different cryopreserved BCP-ALL samples. In order to further characterise the biological properties of the leukaemia cell in the two groups, gene expression profiles of samples with short or long TTL in the xenograft model were investigated using a human whole genome array (Affymetrix U133 Plus 2.0). We identified a signature of differentially expressed genes distinguishing both groups. The differential expression was confirmed for selected genes by semi-quantitative PCR. Taken together, estimation of time to leukaemia (TTL) of leukaemia samples transplanted onto NOD/SCID mice is a new promising factor in paediatric ALL. Using an expression array approach patient samples displaying short TTL can be discriminated from those with long TTL by a unique gene expression signature. This allows direct identification of patients with increased risk for relapse by this new independent risk factor avoiding transplant in the mouse model. more...
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- 2007
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40. Stem Cell Transplantation in Children with Infantile Osteopetrosis Is Associated with a High Incidence of VOD, Which Could Be Prevented with Defibrotide
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S Stöhr, Manfred Hönig, Wilhelm Friedrich, Georgia Lahr, Selim Corbacioglu, G Berry, and Ansgar Schulz
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Male ,medicine.medical_specialty ,Pediatrics ,Hepatic veno-occlusive disease ,Premedication ,medicine.medical_treatment ,Immunology ,Population ,Hepatic Veno-Occlusive Disease ,Hematopoietic stem cell transplantation ,Defibrotide ,Biochemistry ,Polydeoxyribonucleotides ,medicine ,Humans ,education ,Transplantation ,education.field_of_study ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Infant ,Osteopetrosis ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,Graft-versus-host disease ,Treatment Outcome ,surgical procedures, operative ,Female ,Complication ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Background: Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder of osteoclast function, which can be reversed by hematopoietic stem cell transplantation (SCT). In recent studies defibrotide (DF) demonstrated superior efficacy in the treatment of hepatic veno-occlusive disease (VOD). Methods: Twenty children with MIOP were consecutively transplanted in our centre between 1996 and 2005. Eleven of these patients were transplanted between 1996 and 2001 without any VOD prophylaxis. Thereafter nine patients were transplanted between 2001 and 2005 with prophylactic DF from the first day of conditioning until 30 days after SCT because we observed a high incidence of VOD in transplanted patients and explored the prevention of this complication by using DF as a prophylaxis. Results: Patients without DF experienced an overall incidence of VOD of 63.6% (7/11). VOD was severe in three patients and one patient succumbed to VOD related multiorgan failure (MOF). In nine patients consecutively transplanted between 2001 and 2005 only one patient (11.1%) was diagnosed with moderate VOD. Conclusion: SCT in patients with MIOP is associated with a very high risk to develop VOD. Prophylactic DF was implemented in our current transplant protocol and reduced the VOD rate dramatically in this high risk population. more...
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- 2006
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41. Basic fibroblast growth factor (bFGF) in rodent testis Presence of bFGF mRNA and of a 30 kDa bFGF protein in pachytene spermatocytes
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Sabine Bucher, Klaus Seidl, Georgia Lahr, Manfred Gratzl, Claudia Grothe, Artur Mayerhofer, and Walter Knöchel
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Male ,Mouse ,Ratón ,mRNA ,Basic fibroblast growth factor ,Blotting, Western ,Biophysics ,Cell Separation ,Biology ,Fibroblast growth factor ,Biochemistry ,chemistry.chemical_compound ,Mice ,Western blot ,Structural Biology ,Spermatocytes ,Testis ,Genetics ,medicine ,Animals ,RNA, Messenger ,Molecular Biology ,Messenger RNA ,medicine.diagnostic_test ,Single-Strand Specific DNA and RNA Endonucleases ,Leydig Cells ,Cell Biology ,RNA Probes ,Molecular biology ,Rats ,Blot ,Fibroblast Growth Factors ,Meiosis ,medicine.anatomical_structure ,chemistry ,cardiovascular system ,Spermatogenesis ,Germ cell - Abstract
We have previously described a 30 kDa basic fibroblast growth factor (bFGF)-like protein in rodent testicular homogenates and have shown that pachytene spermatocytes are the sites of predominant immunoreactivity for this bFGF-like protein (Mayerhofer, A., Russell, L.D., Grothe, C., Rudolf, M. and Gratzl, M. (1991) Endocrinology 129, 921–924). We have now addressed the question whether this 30 kDa bFGF-like protein is a large bFGF form and whether it is produced by pachytene spermatocytes. We detected bFGF mRNA in homogenates of isolated mouse spermatocytes (which consisted mainly of pachytene spermatocytes) using S1 nuclease protection assays. As shown by Western blot analyses, the bFGF mRNA in mouse spermatocytes is translated into bFGF of an approximate molecular weight of 30 kDa. Neither bFGF mRNA, nor bFGF itself, was observed in isolated mouse Leydig cells. These results indicate that the immunoreactive bFGF-like protein observed previously in germ cells of the murine testis is identical to bFGF. Thus, germ cells of the testis produce bFGF, which may exert regulatory function in the process of spermatogenesis. more...
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42. Novel homozygous AIRE mutation in a German patient with severe APECED
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J. von Schnurbein, Martin Wabitsch, Georgia Lahr, Klaus-Michael Debatin, and Carsten Posovszky
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Male ,medicine.medical_specialty ,Hypoparathyroidism ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,Autoimmune hepatitis ,Vitiligo ,Gene mutation ,medicine.disease_cause ,Frameshift mutation ,PTPN22 ,Exon ,Endocrinology ,Addison Disease ,Internal medicine ,medicine ,Humans ,Chronic mucocutaneous candidiasis ,Polyendocrinopathies, Autoimmune ,Family Health ,Mutation ,business.industry ,Candidiasis, Chronic Mucocutaneous ,Homozygote ,Syndrome ,medicine.disease ,Pedigree ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,Female ,business ,Transcription Factors - Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder typically presenting with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure variably accompanied by other symptoms. APECED is caused by a mutation in the autoimmune regulator gene (AIRE). Today over 60 different mutations are known world-wide, most of them localized in exons 2, 8, and 10. We report here a German girl with rheumatoid factor positive arthritis, chronic mucocutaneous candidiasis, autoimmune hepatitis, chronic diarrhea, vitiligo, hypothyroidism, hypoparathyroidism, and adrenal failure who is homozygous for a novel mutation at the end of exon 3 of the AIRE gene (c.462G>A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.Pro154fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo. more...
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