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Showing papers by "Charité published in 2000"


Journal ArticleDOI
Markus Schuelke1
TL;DR: A poor man's approach to genotyping for research and high-throughput diagnostics and how it can be applied to medicine and science.
Abstract: A poor man's approach to genotyping for research and high-throughput diagnostics.

3,421 citations


Journal ArticleDOI
08 Mar 2000-JAMA
TL;DR: In this study of patients with symptomatic heartfailure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being.
Abstract: For editorial comment see p 1335. Context Results from recent studies on the effects of b1-blockade in patients with heart failure demonstrated a 34% reduction in total mortality. However, the effect of b1-blockade on the frequency of hospitalizations, symptoms, and quality of life in patients with heart failure has not been fully explored. Objective To examine the effects of the b1-blocker controlled-release/extendedrelease metoprolol succinate (metoprolol CR/XL) on mortality, hospitalization, symptoms, and quality of life in patients with heart failure.

1,289 citations


Journal ArticleDOI
01 Jun 2000-Brain
TL;DR: Characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators and quantifying axonal reduction and signs of acute axonal damage in early lesion development of chronic multiple sclerosis found it to be independent of demYelinating activity and inflammation.
Abstract: Damage to axons is taken as a key factor of disability in multiple sclerosis, but its pathogenesis is largely unknown. Axonal injury is believed to occur as a consequence of demyelination and was recently shown to be a feature even of the early disease stages. The present study was aimed at characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multiple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pronounced axonal injury, whereas primary progressive multiple sclerosis patients surprisingly showed relatively little acute axonal injury. Acute axonal damage, as defined by the accumulation of amyloid precursor protein (APP), was found to occur not only in active demyelinating but also in remyelinating and inactive demyelinated lesions with a large inter-individual variability. Only few remyelinating lesions were adjacent to areas of active demyelination. In this minority of lesions, axonal damage may have originated from the neighbourhood. APP expression in damaged axons correlated with the number of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-alpha) or inducible nitric oxide synthase (iNOS). Axonal injury is therefore, at least in part, independent of demyelinating activity, and its pathogenesis may be different from demyelination. This has major implications for therapeutic strategies, which aim at preventing both demyelination and axonal loss.

885 citations


Journal ArticleDOI
TL;DR: Assessment of sT NF-R1 may be useful in identifying patients who are at high risk of death and in monitoring patients undergoing anti-TNF-alpha treatment, independent of established markers of CHF severity.
Abstract: BACKGROUND: Inflammatory immune activation is an important feature in chronic heart failure (CHF). Little is known about the prognostic importance of tumor necrosis factor-alpha (TNF-alpha), soluble TNF-receptor 1 and 2 (sTNF-R1/sTNF-R2), interleukin-6 (IL-6), and soluble CD14 receptors (sCD14) in CHF patients. METHODS AND RESULTS: In 152 CHF patients (age 61+/-1 years, New York Heart Association [NYHA] class 2.6+/-0.1, peak VO(2) 17.3+/-0.6 mL. kg(-1). min(-1), mean+/-SEM) plasma concentrations of immune variables were prospectively assessed. During a mean follow-up of 34 months (>12 months in all patients), 62 patients (41%) died. Cumulative mortality was 28% at 24 months. In univariate analyses, increased total and trimeric TNF-alpha, sTNF-R1, and sTNF-R2 (all P

749 citations


Journal ArticleDOI
TL;DR: As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD–AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.
Abstract: The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5, 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD-AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

678 citations


Journal ArticleDOI
TL;DR: Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine, and almost allIL-17-producing Th cells simultaneously produced TNF-α and most IL- 17+ Th cells also produced GM-CSF, also observed in humans.
Abstract: Naive Th cells can be directed in vitro to develop into Th1 or Th2 cells by IL-12 or IL-4, respectively. In vivo, chronic immune reactions lead to polarized Th cytokine patterns. We found earlier that Borrelia burgdorferi , the spirochaete that causes Lyme disease, induces Th1 development in αβ TCR-transgenic Th cells. Here, we used TCR-transgenic Th cells and oligonucleotide arrays to analyze the differences between Th1 cells induced by IL-12 vs those induced by B. burgdorferi . Transgenic Th cells primed with peptide in the presence of B. burgdorferi expressed several mRNAs, including the mRNA encoding IL-17, at significantly higher levels than Th cells primed with peptide and IL-12. Cytometric single-cell analysis of Th cell cytokine production revealed that IL-17 cannot be categorized as either Th1 or Th2 cytokine. Instead, almost all IL-17-producing Th cells simultaneously produced TNF-α and most IL-17 + Th cells also produced GM-CSF. This pattern was also observed in humans. Th cells from synovial fluid of patients with Lyme arthritis coexpressed IL-17 and TNF-α upon polyclonal stimulation. The induction of IL-17 production in Th cells is not restricted to B. burgdorferi . Priming of TCR-transgenic Th cells in the presence of mycobacterial lysates also induced IL-17/TNF-α coproduction. The physiological stimulus for IL-17 production was hitherto unknown. We show here for the first time that microbial stimuli induce the expression of IL-17 together with TNF-α in both murine and human T cells. Chronic IL-17 expression induced by microbes could be an important mediator of infection-induced immunopathology.

617 citations


Journal ArticleDOI
TL;DR: There are profound abnormalities in the various B cell compartments in SLE that respond differently to immunosuppressive therapy, and CD27high plasma cells showed a similar degree of somatic hypermutation, but preferentially employed VH4 family members.
Abstract: In patients with active systemic lupus erythematosus (SLE), a marked B lymphocytopenia was identified that affected CD19(+)/CD27(-) naive B cells more than CD19(+)/CD27(+) memory B cells, leading to a relative predominance of CD27-expressing peripheral B cells CD27(high)/CD38(+)/CD19(dim)/surface Ig(low)/CD20(-)/CD138(+) plasma cells were found at high frequencies in active but not inactive SLE patients Upon immunosuppressive therapy, CD27(high) plasma cells and naive CD27(-) B cells were markedly decreased in the peripheral blood Mutational analysis of V gene rearrangements of individual B cells confirmed that CD27(+) B cells coexpressing IgD were memory B cells preferentially using V(H)3 family members with multiple somatic mutations CD27(high) plasma cells showed a similar degree of somatic hypermutation, but preferentially employed V(H)4 family members These results indicate that there are profound abnormalities in the various B cell compartments in SLE that respond differently to immunosuppressive therapy

598 citations


Journal ArticleDOI
TL;DR: There is an optimum lipoprotein concentration below which lipid reduction would, on balance, be detrimental, and it is proposed that, in patients with CHF, a non-lipid-lowering statin (with ancillary properties such as immune modulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowered statin.

509 citations


Journal ArticleDOI
TL;DR: Subcutaneous rhuIL-10 administered daily for 28 days to patients with mild to moderately active Crohn's disease is safe, well-tolerated, and shows clinical and endoscopic improvement.

485 citations


Journal ArticleDOI
TL;DR: In this paper, a simple pretest procedure for choosing the number of bootstrap samples so as to minimize experimental randomness is proposed, which has been shown to work well in practice.
Abstract: In practice, bootstrap tests must use a finite number of bootstrap samples. This means that the outcome of the test will depend on the sequence of random numbers used to generate the bootstrap samples, and it necessarily results in some loss of power. We examine the extent of this power loss and propose a simple pretest procedure for choosing the number of bootstrap samples so as to minimize experimental randomness. Simulation experiments suggest that this procedure will work very well in practice.

434 citations


Journal ArticleDOI
TL;DR: It is demonstrated that the antioxidant pyrrolidine dithiocarbamate inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
Abstract: We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P 95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.

Journal ArticleDOI
TL;DR: The lamin A/C gene was examined in the MDDC1 family and a single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion.
Abstract: Background—Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. Familial transmission of the disease is frequently observed, and genetic heterogeneity is indicated by clinical and morphological variability in the disease phenotype. In the family MDDC1 reported here, the disease phenotype is severe and characterized by an autosomal dominant pattern of transmission. In addition, the majority of affected family members show signs of mild skeletal muscle involvement. Methods and Results—On the basis of the clinical observation of both cardiac and skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was examined in this kindred. Coding regions were polymerase chain reaction–amplified from genomic DNA and sequenced. A single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion. Conclusions—Heterozygosity for a single nucleotide deletion in exon 6 of...

Journal ArticleDOI
TL;DR: The results confirmed the previous contention that HCMV IE‐1 is an important CD8 T cell target and the technical improvement made in order to address this question has clearly wider implications.
Abstract: The frequencies of human cytomegalovirus (HCMV) protein-specific CD8 T cells, identified by the presence of intracellular IFN-gamma, were measured by flow cytometry following stimulation of freshly isolated peripheral blood mononuclear cells (PBMC) with comprehensive peptide pools. These pools spanned the entire amino acid sequences of the HCMV pp65 and major immediate early (IE-1) proteins and consisted of 15-amino acid peptides with at least nine overlaps between neighboring peptides. As a result all potential CD8 T cell epitopes contained in these proteins were provided by the complete pools and, therefore, unlike with single epitopes, testing was independent of donor HLA type. Individual stimulating peptides from the same pools were identified in parallel experiments. Thus we found that our results with the complete pools using PBMC from 26 healthy HCMV-seropositive donors were 100% sensitive and specific with respect to predicting the presence of recognized epitopes in the respective proteins. In addition, cells from 15 renal transplant patients were tested with complete pools alone. While our results confirmed our previous contention that HCMV IE-1 is an important CD8 T cell target, the technical improvement we made in order to address this question has clearly wider implications. Similar pools may be applied to examine the role of proteins from other pathogens, in autoimmune disease or following vaccination.

Journal ArticleDOI
TL;DR: Neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene, as determined in this study.
Abstract: More than 500 unrelated patients with neurofibromatosis type 1 (NF1) were screened for mutations in the NF1 gene. For each patient, the whole coding sequence and all splice sites were studied for aberrations, either by the protein truncation test (PTT), temperature-gradient gel electrophoresis (TGGE) of genomic PCR products, or, most often, by direct genomic sequencing (DGS) of all individual exons. A total of 301 sequence variants, including 278 bona fide pathogenic mutations, were identified. As many as 216 or 183 of the genuine mutations, comprising 179 or 161 different ones, can be considered novel when compared to the recent findings of Upadhyaya and Cooper, or to the NNFF mutation database. Mutation-detection efficiencies of the various screening methods were similar: 47.1% for PTT, 53.7% for TGGE, and 54.9% for DGS. Some 224 mutations (80.2%) yielded directly or indirectly premature termination codons. These mutations showed even distribution over the whole gene from exon 1 to exon 47. Of all sequence variants determined in our study, T or G-->A transitions within a CpG dinucleotide, and only six different mutations also occur in NF1 pseudogenes, with five being typical C-->T transitions in a CpG. Thus, neither frequent deamination of 5-methylcytosines nor interchromosomal gene conversion may account for the high mutation rate of the NF1 gene. As opposed to the truncating mutations, the 28 (10.1%) missense or single-amino-acid-deletion mutations identified clustered in two distinct regions, the GAP-related domain (GRD) and an upstream gene segment comprising exons 11-17. The latter forms a so-called cysteine/serine-rich domain with three cysteine pairs suggestive of ATP binding, as well as three potential cAMP-dependent protein kinase (PKA) recognition sites obviously phosphorylated by PKA. Coincidence of mutated amino acids and those conserved between human and Drosophila strongly suggest significant functional relevance of this region, with major roles played by exons 12a and 15 and part of exon 16.

Journal ArticleDOI
TL;DR: Using RT-PCR and RACE, the human cDNA homologue, designated CNGB3, was identified and cloned, which encodes an 809 amino acid polypeptide and was present on 11 of 22 disease chromosomes segregating in families.
Abstract: Achromatopsia is an autosomal recessive disorder featuring total colour blindness, photophobia, reduced visual acuity and nystagmus. While mutations in the CNGA3 gene on chromosome 2q11 are responsible for achromatopsia in a subset of patients, previous linkage studies have localized another achromatopsia locus, ACHM3, on chromosome 8q21. Using achromatopsia families in which CNGA3 mutations have been excluded, we refined the ACHM3 locus to a 3.7 cM region enclosed by markers D8S1838 and D8S273. Two yeast artificial chromosome (YAC) contigs covering nearly the entire ACHM3 interval were constructed. Database searches with YAC content sequences identified two overlapping high throughput genomic sequencing phase (HTGS) entries which contained sequences homologous to the murine cng6 gene encoding the putative beta-subunit of the cone photoreceptor cGMP-gated channel. Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide. Northern blot analysis revealed a major transcript of approximately 4.4 kb specifically expressed in the retina. The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence. Analysis of the CNGB3 gene in achromats revealed six different mutations including a missense mutation (S435F), two stop codon mutations (R203X and E336X), a 1 bp and an 8 bp deletion (1148delC and 819-826del) and a putative splice site mutation of intron 13. The 1148delC mutation was identified recurrently in several families, and in total was present on 11 of 22 disease chromosomes segregating in our families.

Journal ArticleDOI
TL;DR: The findings suggest that the mutant allele of the RANTES gene contributes to the development of atopic dermatitis and its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.
Abstract: Up-regulation of C-C chemokine expression characterizes allergic inflammation and atopic diseases. A functional mutation in the proximal promoter of the RANTES gene has been identified, which results in a new consensus binding site for the GATA transcription factor family. A higher frequency of this allele was observed in individuals of African descent compared with Caucasian subjects (p < 0.00001). The mutant allele was associated with atopic dermatitis in children of the German Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient transfections of the human mast cell line HMC-1 and the T cell line Jurkat with reporter vectors driven by either the mutant or wild-type RANTES promoter showed an up to 8-fold higher constitutive transcriptional activity of the mutant promoter. This is the first report to our knowledge of a functional mutation in a chemokine gene promoter. Our findings suggest that the mutation contributes to the development of atopic dermatitis. Its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.

Journal ArticleDOI
TL;DR: It is demonstrated that MTase activity contributes to poor tissue outcome after mild ischemic brain injury and DNA methylation was not enhanced, and reduceddnmt gene expression was not protective in an ischemia model of excitotoxic/necrotic cell death.
Abstract: DNA methylation is important for controlling the profile of gene expression and is catalyzed by DNA methyltransferase (MTase), an enzyme that is abundant in brain. Because significant DNA damage and alterations in gene expression develop as a consequence of cerebral ischemia, we measured MTase activity in vitro and DNA methylation in vivo after mild focal brain ischemia. After 30 min middle cerebral artery occlusion (MCAo) and reperfusion, MTase catalytic activity and the 190 kDa band on immunoblot did not change over time. However, [3H]methyl-group incorporation into DNA increased significantly in wild-type mice after reperfusion, but not in mutant mice heterozygous for a DNA methyltransferase gene deletion (DnmtS/+).DnmtS/+ mice were resistant to mild ischemic damage, suggesting that increased DNA methylation is associated with augmented brain injury after MCA occlusion. Consistent with this formulation, treatment with the MTase inhibitor 5-aza-2′-deoxycytidine and the deacetylation inhibitor trichostatin A conferred stroke protection in wild-type mice. In contrast to mild stroke, however, DNA methylation was not enhanced, and reduceddnmt gene expression was not protective in an ischemia model of excitotoxic/necrotic cell death. In conclusion, our results demonstrate that MTase activity contributes to poor tissue outcome after mild ischemic brain injury.

Journal ArticleDOI
Andreas Schmeling1, Walter Reisinger1, D Loreck1, K Vendura, W Markus1, G. Geserick1 
TL;DR: It was concluded that skeletal maturation takes place in phases which are identically defined for all ethnic groups and time-related differences in passing those stages of skeletal m maturity within the relevant age group appear to be unaffected by ethnic identity.
Abstract: An X-ray of the hand is an important method in forensic science for estimation of the age of juvenile suspects with uncertain date of birth. Relevant X-ray standards for evaluation of skeletal maturity are available for white US Americans as well as for North and Central Europeans. The applicability of these standards to members of ethnic groups different from the reference population has been the subject of controversial discussion. More than 80 publications were analysed with the view to finding out whether skeletal maturation is affected by ethnic identity. It was concluded that skeletal maturation takes place in phases which are identically defined for all ethnic groups. Time-related differences in passing those stages of skeletal maturation within the relevant age group appear to be unaffected by ethnic identity. It is the socioeconomic status of a given population which is of decisive importance to the rate of ossification. The application of X-ray standards to individuals of a socio-economic status lower than that of the reference population usually leads to underestimation of that person's age. In terms of criminal responsibility, this is of no adverse effect on the person concerned.

Journal ArticleDOI
01 Mar 2000-Leukemia
TL;DR: It is described here that constitutively activated NF-κB complexes are found in the vast majority of childhood acute lymphoblastic leukemia (ALL) without any subtype restriction, and strongly suggests a critical role of this factor for leukemia cell survival.
Abstract: The pleiotropic transcription factor NF-kappaB controls cellular apoptotic and growth processes and increasing evidence suggests a role in tumorigenesis. We describe here that constitutively activated NF-kappaB complexes are found in the vast majority (39 out of 42 samples) of childhood acute lymphoblastic leukemia (ALL) without any subtype restriction. Electrophoretic shift analysis further demonstrates that these complexes are composed of p50-p50 and p65-p50 dimers. Proteasome inhibition in primary ALL cultures results in a hyperphosphorylated form of IkappaBalpha, indicating that activation of upstream kinases, which trigger IkappaBalpha degradation, has led to nuclear translocation of NF-kappaB. Careful inhibition of cellular proteolytic activities is of importance when analyzing extracts from primary ALL cells. Degradation of p65 and other proteins in ALL samples could be specifically suppressed by alpha-1 antitrypsin. Constitutive NF-kappaB activation is thus a common characteristic of childhood ALL and strongly suggests a critical role of this factor for leukemia cell survival.

Journal ArticleDOI
Kaufmann O1, Manfred Dietel1
TL;DR: This study tested if anti‐TTF‐1 can also be used to verify a pulmonary origin of neuroendocrine carcinomas, placing emphasis on the discrimination of pulmonary small cell carcinomas (SCCs) from extrapulmonary SCCs and the distinction of S CCs from Merkel cell carcinoma of the skin.
Abstract: Aims The thyroid transcription factor-1 (TTF-1) is a highly specific immunohistochemical marker for the identification of pulmonary adenocarcinomas and non-neuroendocrine large cell carcinomas, especially in patients presenting with metastatic carcinomas of unknown primary site. In this study we tested if anti-TTF-1 can also be used to verify a pulmonary origin of neuroendocrine carcinomas, placing emphasis on the discrimination of pulmonary small cell carcinomas (SCCs) from extrapulmonary SCCs and the distinction of SCCs from Merkel cell carcinomas of the skin. Methods and results We studied 37 pulmonary SCCs, 15 SCCs of extrapulmonary origin, 4 pulmonary large cell neuroendocrine carcinomas (LCNECs), four extrapulmonary LCNECs, six medullary thyroid carcinomas, 16 Merkel cell carcinomas, and a total of 32 carcinoids/low-grade neuroendocrine carcinomas of pulmonary (12 cases) and extrapulmonary (20 cases) origin. Using the commercially available monoclonal antibody 8G7G3/1, TTF-1 was immunohistochemically detectable in 81% of pulmonary SCCs but also in 80% of extrapulmonary SCCs. Furthermore, anti-TTF-1 showed a positive staining in 50% of all pulmonary carcinoids, in one gastric carcinoid, in 2/4 of pulmonary, and 1/4 of extrapulmonary LCNECs. All medullary thyroid carcinomas were also TTF-1-positive. Merkel cell carcinomas were consistently TTF-1-negative. Conclusions Our results suggest that in contrast to non-neuroendocrine carcinomas, anti-TTF-1 cannot be used to prove or to exclude a pulmonary origin of SCCs or LCNECs of unknown or uncertain primary site. Therefore, before using anti-TTF-1 as a marker for pulmonary carcinomas one should be sure to have excluded SCC and LCNEC. On the other hand, anti-TTF-1 might be used to specifically discriminate SCCs of various origin from Merkel cell carcinomas.

Journal ArticleDOI
Kaufmann O1, Manfred Dietel1
TL;DR: Antibodies against the thyroid transcription factor‐1 (TTF‐1) and the surfactant proteins A and B (SPA, SPB) were compared as paraffin‐reactive immunohistochemical markers for non‐small cell carcinomas of pulmonary origin.
Abstract: Aims Antibodies against the thyroid transcription factor-1 (TTF-1) and the surfactant proteins A and B (SPA, SPB) were compared as paraffin-reactive immunohistochemical markers for non-small cell carcinomas of pulmonary origin. Methods and results We studied 138 carcinomas of pulmonary origin (98 adenocarcinomas, 20 non-neuroendocrine large cell carcinomas, 20 squamous cell carcinomas) and a total of 276 extrapulmonary carcinomas of various primary origins. Using the monoclonal antibody 8G7G3/1, TTF-1 was detectable in 75% of non-mucinous pulmonary adenocarcinomas and in 40% of large cell carcinomas but in only 10% of mucinous adenocarcinomas and not in squamous cell carcinomas. In contrast, both SPA and SPB were positive in only 45% of pulmonary adenocarcinomas and in 10% and in 5% of the large cell carcinomas, respectively. TTF-1 had a specificity of 0.98 for pulmonary carcinomas as 5/7 thyroid carcinomas were the only TTF-1-positive extrapulmonary tumours. Anti-SPB and anti-SPA had specificities of 1.00 and 0.97, respectively. Conclusions The monoclonal antibody 8G7G3/1 against TTF-1 should be the first choice as a component of an antibody panel aiming to prove or to exclude the pulmonary origin of non-mucinous adenocarcinomas and non-neuroendocrine poorly differentiated carcinomas, especially in patients presenting with metastatic carcinomas of unknown primary site.

Journal ArticleDOI
TL;DR: In this paper, photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory.
Abstract: Analysis of photon transit time for low-power light passing into the head, and through both skull and brain, of human subjects allowed for tomographic imaging of cerebral hemoglobin oxygenation based on photon diffusion theory. In healthy adults, imaging of changes in hemoglobin saturation during hand movement revealed focal, contralateral increases in motor cortex oxygenation with spatial agreement to activation maps determined by functional magnetic resonance imaging; in ill neonates, imaging of hemoglobin saturation revealed focal regions of low oxygenation after acute stroke, with spatial overlap to injury location determined by computed tomography scan. Because such slow optical changes occur over seconds and co-localize with magnetic resonance imaging vascular signals whereas fast activation-related optical changes occur over milliseconds and co-localize with EEG electrical signals, optical methods offer a single modality for exploring the spatiotemporal relationship between electrical and vascular responses in the brain in vivo, as well as for mapping cortical activation and oxygenation at the bedside in real-time for clinical monitoring.

Journal ArticleDOI
TL;DR: Investigating the hemodynamic effects of immunoadsorption and subsequent immunoglobulin G (IgG) substitution in comparison with the effects of conventional medical treatment in patients with dilated cardiomyopathy found it to improve cardiovascular function in DCM.

Journal ArticleDOI
TL;DR: As SPIO accumulates in plaques with increased endothelial permeability and a high macrophage content, two established features of plaque inflammation, it may have a potential for noninvasive assessment of inflammatory atherosclerotic plaques.
Abstract: Schmitz SA, Coupland SE, Gust R, et al. Superparamagnetic iron oxide–enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits. Invest Radiol 2000;35:460–471.RATIONALE AND OBJECTIVES.Inflammatory atherosclerotic plaques are characterized by increased endothelial permeabi

Journal ArticleDOI
TL;DR: Allogeneic stem cell transplantation from an HLA‐identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors.
Abstract: Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.

Journal ArticleDOI
Peter A. Reichart1
TL;DR: Prevalence of oral mucosa lesions changes with age and increases with general morbidity, routine examinations of oral cavities of the aging are mandatory particularly to detect early precancerous and other mucosal lesions.
Abstract: –Objectives: To determine prevalence of oral mucosal lesions in a cross-sectional study among aging Germans. Methods: Three specially trained dental teams examined adults (35–44 yrs, Group 1) and senior individuals (65–74 yrs, Group 2) in 90 sample points of which 60 were located in the former West and 30 in the former East part of Germany. The spectrum comprised 28 different oral lesions with subforms. Results: 655 individuals in Group 1 (35–44 yrs) and 1367 individuals in Group 2 (65–74 yrs) were studied. 33.8% (Group 1) and 33.9% (Group 2) were without any pathology of the oral mucosa. Several lesions were not recorded in both Groups like oral hairy leukoplakia and gingival hyperplasia (Group 1 and two) and xerostomia (Group 1). In Group 1 history for labial herpetic lesions (31.7%), Fordyce granules (26.6%), history for recurrent aphthous ulceration (18.3%) and lip and/or cheek biting (10.1%) were recorded. In Group 2 Fordyce granules (23.7%), history of labial herpes (20.0%), plicated tongue (19.0%) and denture stomatitis (18.3%) were those lesions most frequently recorded. Leukoplakia was seen in 1.8% (West) and 0.9% (East) respectively; men were more often affected than women (2.3% versus 0.0% P<0.05, Group 1; 2.3% versus 0.9%, Group 2. There was association between the prevalence of leukoplakia and a lower (3.3%) or higher educational level (0.5%). Denture associated lesions were seen in 18.3% (Group 2) compared to 2.5% (Group 1) (P<0.001). Other age-related lesions were lip and/or cheek biting being more prevalent in Group 1 10.1% versus 1.9% (P<0.001), plicated tongue 19.0% in Group 2 versus 3.8% in Group 1 (P<0.001). Conclusions: The present study has shown prevalence to be comparable to other relevant Western European studies. Since the spectrum of oral mucosal lesions changes with age and increases with general morbidity, routine examinations of oral cavities of the aging are mandatory particularly to detect early precancerous and other mucosal lesions.

Journal ArticleDOI
TL;DR: The data suggest that rO CT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.
Abstract: Renal excretion and reabsorption of organic cations are mediated by electrogenic and electroneutral organic cation transporters, which belong to a recently discovered family of polyspecific transporters. These transporters are electrogenic and exhibit differences in substrate specificity. In rat, the renal expression of the polyspecific cation transporters rOCT1 and rOCT2 was investigated. By in situ hybridization, significant amounts of both rOCT1 and rOCT2 mRNA were detected in S1, S2, and S3 segments of proximal tubules. By immunohistochemistry, expression of the rOCT1 protein was mainly observed in S1 and S2 segments of proximal tubules, with lower expression levels in the S3 segments. At variance, rOCT2 protein was mainly expressed in the S2 and S3 segments. Both transporters were localized to the basolateral cell membrane. Neither rOCT1 nor rOCT2 was detected in the vasculature, the glomeruli, and nephron segments other than proximal tubules. The data suggest that rOCT1 and rOCT2 are responsible for basolateral cation uptake in the proximal tubule, which represents the first step in cation secretion.

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TL;DR: For assessment of protein malnutrition in patients with cirrhosis, body cell mass determination by use of BIA offers a considerable advantage over other widely available but less accurate methods like anthropometry or the creatinine approach.

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TL;DR: In univariate and multivariate analyses, having received adequate therapy and experiencing late infection (>63 days after HSCT) were associated with a lower risk of dying from toxoplasmosis.
Abstract: In immunocompromised individuals, toxoplasmosis mostly occurs as a reactivation of a latent infection, causing severe to life-threatening disease. Thus, recipients who are seropositive for Toxoplasma gondii before an allogeneic hematopoietic stem cell transplant (HCT) are at highest risk, although primary infections may also cause severe toxoplasmosis. The disease most often affects the central nervous system, but in HCT recipients other organs are involved in more than half of the cases. Because of the alteration of the immune response in these patients, serodiagnosis is not sufficiently reliable in the diagnosis of post-HCT toxoplasmosis, and direct detection of the causative agent is required for an etiologic diagnosis (ideally by microscopy, but most commonly through detection of its DNA by PCR). If inadequately treated or left untreated, toxoplasmosis generally has a fatal outcome in HCT recipients. Therefore, treatment must be started as early as possible. However, due to the high mortality of established disease, preemptive treatment using routine blood PCR monitoring seems effective in detecting infection early and preventing disease, especially in seropositive high-risk alloHCT recipients when chemo-prophylaxis is not possible. The gold standard both in the treatment of reactivation and disease is the combination of pyrimethamine–sulfadiazine–folinic acid, while cotrimoxazole is the agent of choice in the primary prophylaxis for high-risk patients.

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TL;DR: The main components which are thought to be relevant to the pathogenesis of CHF are cytokines, adhesion molecules, autoantibodies, nitric oxide, and endothelin-1, and this review will concentrate on these factors.