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Biomedical subjects

C Schumacher

Publications and source records attributed to C Schumacher.

At least 19 recordsLinked to original sources
PubMed2006

[Pituitary metastases from lung cancer. Five cases].

Pituitary metastases are rare and generally asymptomatic. We studied 5 patients with pituitary metastases from lung cancer, illustrating the different clinical features. These metastases were in these cases symptomatic with the manifestation being diabetes insipidus or visual field defect. Histological subtypes from our five patients were as well small cell or non small cell lung cancer. After diagnosis of pituitary metastasis, prognosis seems to be linked to the histological subtype and the stage of lung cancer, rather than to the presence of such metastases.

Adult↗
PubMed2001

Identification of SCAN dimerization domains in four gene families.

Zinc-finger transcription factors are often accompanied by modular sequence motifs such as the Kruppel-associated box (KRAB) and the SCAN domain. The KRAB domain mediates transcriptional repression while the SCAN domain mediates selective protein dimerization. The hypoalphalipoproteinemia susceptibility gene ZNF202 encodes a SCAN box and a KRAB domain followed by eight Cys2-His2 zinc-finger motifs. In order to identify the existence of genes which encode proteins of structural homology to ZNF202, a mouse lambda library was screened with a human ZNF202 cDNA probe. The isolated cDNA clones represented three SCAN-domain-encoding gene families. We purified three novel cDNAs that encode a SCAN-KRAB-(Cys2-His2)x domain alignment and one cDNA that encodes a SCAN-(Cys2-His2)x domain alignment. In addition, we identified one cDNA sequence with a predicted protein sequence containing a KRAB-SCAN-KRAB-(Cys2-His2)x domain alignment. Therefore, when combined with the recently discovered family of isolated SCAN-domain-encoding genes, four SCAN domain gene families can be distinguished. The consensus sequences for the murine SCAN and KRAB domains are highly conserved within the mammalian phylogenetic tree which may be useful in elucidating the biological function of these protein modules and the crucial residues responsible for their binding specificity.

Amino Acid Sequence↗
PubMed2001

The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux.

The zinc finger gene 202 (ZNF202) located within a hypoalphalipoproteinemia susceptibility locus on chromosome 11q23 is a transcriptional repressor of various genes involved in lipid metabolism. To provide further evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia, we investigated the effect of ZNF202 expression on ATP binding cassette transporter A1 (ABCA1) and ABCG1. ABCA1 is a key regulator of the plasma high density lipoprotein pool size, whereas ABCG1 is another mediator of cellular cholesterol and phospholipid efflux in human macrophage. We demonstrate here that the full-length ZNF202m1 isoform binds to GnT repeats within the promotors of ABCA1 (-229/-210) and ABCG1 (-572/-552). ZNF202m1 expression in HepG2 cells dose-dependently repressed the promotor activities of ABCA1 and ABCG1. This transcriptional effect required the presence of the SCAN domain in ZNF202 and the functional integrity of a TATA box at position -24 of ABCA1, whereas the presence of GnT binding motifs was nonessential. The state of ZNF202 SCAN domain oligomerization affected the ability of the adjacent ZNF202 Krüppel-associated box domain to recruit the transcriptional corepressor KAP1. Overexpression of ZNF202m1 in RAW264.7 macrophages prevented the induction of ABCA1 gene expression by 20(S)OH-cholesterol and 9-cis-retinoic acid, further substantiating the interference of ZNF202 in critical elements of transcriptional activation. Finally, HDL and apoAImediated lipid efflux was significantly reduced in RAW264.7 cells stably expressing ZNF202m1. In conclusion, we have identified ABCA1 and ABCG1 as target genes for ZNF202-mediated repression and thus, provide evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia.

ATP Binding Cassette Transporter 1↗
PubMed2001

[Conservative treatment of choroidal melanoma using iodine-125 brachytherapy, technique and preliminary analysis of 78 patients].

PURPOSE: Iodine 125 curietherapy is one of the conservative treatments of uveal melanoma. The technique used to achieve these results was simplified through the physical characteristics of the radioelement and the optimized-dosimetry program employed. PATIENTS AND METHODS: 78 patients with choroidal melanoma were treated with iodine 125. About 100 Gy were delivered to the superior pole of the tumour. The minimal length of follow-up was 17 months and the average, 67 months. RESULTS: There was 88% local control, leading to lowered visual acuity in 76% of the cases. Radiation retinopathy, directly related to proximity to the macula, is the principle etiology. Seven patients died of hepatic metastasis, five patients were enucleated. Four patients were further treated with protontherapy to make up for noncontrol locally. CONCLUSION: One dose of 100 Gy to the superior pole of the tumor seemed to lead to good local control, with the exception of complications related to proximity to the macula and the optic nerve. In this attempt to optimize irradiation, the time lapse between any benefit in local control derived from irradiation and posttherapeutic complications observed remains insufficient to evaluate any relationship.

Adult↗
PubMed2001

Norepinephrine induces action potential prolongation and early afterdepolarizations in ventricular myocytes isolated from human end-stage failing hearts.

AIMS: Congestive heart failure is characterized by high levels of norepinephrine which is considered to be arrhythmogenic. It is unclear whether increased norepinephrine is only a marker of the severity of heart failure or whether it directly triggers ventricular arrhythmias. METHODS AND RESULTS: Ventricular myocytes were isolated from eight explanted hearts of patients with end-stage heart failure (ischaemic or dilated cardiomyopathy). With the whole-cell configuration of the patch-clamp technique the effect of 1 micromol x l(-1)norepinephrine on action potentials and membrane currents was studied. The cells had a membrane capacitance of 256 +/- 25 pF (n = 26) and action potential duration (APD90) during control conditions was 620 +/- 45 ms at 1 Hz (n = 14). Norepinephrine induced action potential prolongation in all cells and early afterdepolarizations in 50% of them. Norepinephrine significantly increased the calcium current but had no effect on the delayed rectifier current, the inward rectifier current or the transient outward current. Norepinephrine also significantly increased the steady-state calcium window-current measured between -40 and 0 mV. CONCLUSIONS: In contrast to many animal species, norepinephrine induces action potential prolongation in ventricular myocytes from human failing hearts, as well as early afterdepolarization, by an increase in both the calcium peak current and window current. Thus norepinephrine seems to be an important arrhythmogenic factor in congestive heart failure.

Action Potentials↗
PubMed2000

The SCAN domain mediates selective oligomerization.

The SCAN domain is described as a highly conserved, leucine-rich motif of approximately 60 amino acids found at the amino-terminal end of zinc finger transcription factors. Although no specific biological function has been attributed to the SCAN domain, its predicted amphipathic secondary structure led to the suggestion that this domain may mediate protein-protein associations. A yeast two-hybrid screen identified members of two SCAN domain protein families that interact with the SCAN domain of the zinc finger protein ZNF202. The interacting ZNF191 protein represents the family of SCAN domain-containing zinc finger proteins, whereas the novel SDP1 protein establishes a new family of genes that encode an isolated SCAN domain. Isolated SCAN domain proteins may form asymmetric homodimers in solution. Biochemical binding studies confirmed the associations of ZNF191 and SDP1 with ZNF202 and established the SCAN domain as a selective hetero- and homotypic oligomerization domain. SCAN mediated protein associations might therefore represent a new regulatory mechanism of transcriptional activity.

Amino Acid Sequence↗
PubMed2000

A broad role for the zinc finger protein ZNF202 in human lipid metabolism.

The ZNF202 gene resides in a chromosomal region linked genetically to low high density lipoprotein cholesterol in Utah families. Here we show that the ZNF202 gene product is a transcriptional repressor that binds to elements found predominantly in genes that participate in lipid metabolism. Among its targets are structural components of lipoprotein particles (apolipoproteins AIV, CIII, and E), enzymes involved in lipid processing (lipoprotein lipase, lecithin cholesteryl ester transferase), and several genes involved in processes related to energy metabolism and vascular disease. Based on the linkage and apparent transcriptional function of ZNF202, we propose that ZNF202 is a candidate susceptibility gene for human dyslipidemia.

Alternative Splicing↗
PubMed2000

Prognostic implications of a positive bronchial resection margin.

OBJECTIVE: This retrospective study evaluates probability of survival and mode of recurrence in patients with a microscopically positive bronchial resection margin following resection for primary bronchogenic carcinoma, as well as influence of radiotherapy on survival. METHODS: From January 1986 to July 1997, 40 patients had a microscopically positive bronchial resection margin following a macroscopically complete resection (17 lobectomies, three bilobectomies, four sleeve-lobectomies, and 16 pneumonectomies). Tissue diagnosis was squamous cell carcinoma in 32 patients, adenocarcinoma in four, adenosquamous carcinoma in two and neuroendocrine carcinoma in two. Lymph node status was N0 in 14 patients, N1 in 10, and N2 in 16. The bronchial margin contained carcinoma in situ in 20 patients, invasive mucosal carcinoma in five, and peribronchial infiltration in 15. All patients except the three most recent underwent adjuvant radiation therapy. RESULTS: At the conclusion of the study (January 31st, 1999), 30 patients had died: two with post-operative complications, 17 with progressive disease, ten without relation to cancer, and one under undefined circumstances. Six of 10 unrelated deaths were interpreted as respiratory complications of radiotherapy. Recurrent disease appeared in 24 patients (60%). Nineteen had progression of initial disease (47.5%): metastatic spread in 12 (30%), isolated local recurrence in four (10%), and combined local recurrence and metastases in three (7.5%). Five patients developed metachronous cancer, with bronchial location in four (10%) and laryngeal in one (2.5%). 5-year survival (Kaplan-Meier) in 20 patients with carcinoma in situ was 38.7+/-13.7% (median 31 months), but rose to 55.0+/-16. 6% when excluding seven deaths not related to cancer (five of whom were secondary to radiotherapy) (chi(2)=3.080; P=0.0792). Survival in 13 patients classified N0 was 51.3+/-16.3% (median 61 months), and 71.1+/-18.0% following exclusion of unrelated deaths (chi(2)=3. 939; P=0.0472). Adverse prognosis of peribronchial infiltration was correlated to a positive N status (13 N2 and 2 N1), 5-year survival being 20.0+/-10.3% (median: 18 months). CONCLUSIONS: Prognosis of peribronchial infiltration is similar to N2 disease. In situ carcinoma does not influence survival per se. Local control of disease is probably in part due to radiotherapy. However, the high prevalence of unrelated late deaths suggests an adverse impact of radiotherapy on survival.

Adenocarcinoma↗
PubMed2000

Changes of beta-adrenergic signaling in compensated human cardiac hypertrophy depend on the underlying disease.

In human heart failure, desensitization of the beta-adrenergic signal transduction has been reported to be one of the main pathophysiological alterations. However, data on the beta-adrenergic system in human compensated cardiac hypertrophy are very limited. Therefore, we studied the myocardial beta-adrenergic signaling in patients suffering from hypertrophic obstructive cardiomyopathy (HOCM, n = 9) or from aortic valve stenosis (AoSt, n = 8). beta-Adrenoceptor density determined by [(125)I]iodocyanopindolol binding was reduced in HOCM and AoSt compared with nonhypertrophied, nonfailing myocardium (NF) of seven organ donors. In HOCM the protein expression of stimulatory G protein alpha-subunit (G(s)alpha) measured by immunoblotting was unchanged, whereas the inhibitory G protein alpha-subunit (Galpha(i-2)) was increased. In contrast, in AoSt, Galpha(i-2) protein was unchanged, but G(s)alpha protein was increased. Adenylyl cyclase stimulation by isoproterenol was reduced in HOCM but not in AoSt. Plasma catecholamine levels were normal in all patients. In conclusion, both forms of hypertrophy are associated with beta-adrenoceptor downregulation but with different changes at the G protein level that occur before symptomatic heart failure due to progressive dilatation of the left ventricle develops and are not due to elevated plasma catecholamine levels.

Adaptation, Physiological↗
PubMed1999

Functional loss of E-cadherin and cadherin-11 alleles on chromosome 16q22 in colonic cancer.

Proteins of the cadherin family regulate cellular adhesion and motility and are believed to act as tumour suppressors. Previous studies have identified frequent mutation and allelic inactivation of the E-cadherin (cadherin-1) locus in diffuse gastric cancer. At least two other cadherin genes, P-cadherin (cadherin-3) and OB-cadherin (cadherin-11), have been mapped close to the E-cadherin gene on chromosome 16q22. As this region of the genome is frequently deleted in malignancy, multiple cadherin loci may be affected by losses of chromosome 16q22. The expression of mRNA transcripts from polymorphic alleles of the E-cadherin and cadherin-11 genes was examined in 30 cases of colonic, gastric, and renal carcinoma. In gastric cancer, loss of expression of one allele was restricted to the E-cadherin locus, whilst in renal carcinoma neither locus was affected. In colonic cancers, loss of expression of one E-cadherin allele was detected in 5 of 22 cases, whilst loss of a cadherin-11 allele was seen in 5 of 23 cases. This functional loss of cadherin gene expression may be due to gene deletion, inactivation or recombination. As no evidence of cadherin gene mutation was observed in the remaining transcripts, we can conclude that these two genes are only indirectly involved in the pathogenesis of colorectal cancer.

Blotting, Northern↗
PubMed1999

Altered force-frequency relation in hypertrophic obstructive cardiomyopathy.

The present study was designed to test the hypothesis that in hypertrophied myocardium of patients with hypertrophic obstructive cardiomyopathy (HOCM) a reduced contractile reserve provided by frequency dependent potentiation of force of contraction contributes to the myocardial dysfunction. Myectomy was performed in 8 HOCM patients with normal systolic left ventricular function at rest. Nonfailing myocardium from the hearts of three multiorgan donors was investigated for comparison. In thin myocardial strips we measured the inotropic effects of different stimulation frequencies (0.5-3.0 Hz) at different extracellular Ca2+ concentrations (1.8-16.2 mmol/l). At 1.8 mmol/l extracellular Ca2+ concentration, increasing stimulation rates had no positive inotropic effect in HOCM myocardium, whereas in nonfailing myocardium force of contraction increased up to 3 Hz. Increasing extracellular Ca2+ concentrations induced a positive force-frequency relation in HOCM with a maximum at 5.4 mmol/l Ca2+. A further increase to 16.2 mmol/l Ca2+ resulted in a negative force-frequency relation in these specimens. The time to peak tension and the time to relaxation decreased at increasing stimulation frequencies at all Ca2+ concentrations investigated. In conclusion, in hypertrophied myocardium of HOCM patients increasing stimulation frequencies failed to have a positive inotropic effect at physiological extracellular Ca2+ concentrations. The induction of a positive force-frequency relation by higher Ca2+ concentrations suggests that an abnormal cellular Ca2+ handling may play an important pathophysiological role.

Calcium↗
PubMed1999

Calcium-sensitivity of the SR calcium release channel in failing and nonfailing human myocardium.

BACKGROUND: Altered Ca2+ metabolism of the sarcoplasmic reticulum results in changes of the contractile behavior in failing human myocardium. The ryanodine-sensitive Ca2+ release channel of the sarcoplasmic reticulum plays a key role in the intracellular Ca2+ handling in cardiac myocytes. Recently, we showed that the density of 3H-ryanodine binding sites which correspond to the SR Ca2+ release channel in human myocardial homogenates is unchanged in failing human myocardium. However, the sensitivity of the channel towards Ca2+, which acts as the trigger signal of channel activation and thereby initiates contraction, has not yet been investigated in failing and nonfailing myocardium. METHODS: Homogenates (100 micrograms protein) from hearts with dilated (DCM, n = 10) or ischemic (ICM, n = 9) cardiomyopathy were incubated with a saturating concentration of 3H-ryanodine (12 nM) in the presence of different Ca2+ concentrations ranging from 1 nM to 10 mM. For comparison, myocardium of 8 nonfailing hearts which could not be transplanted for technical reasons was investigated. Non-specific binding was determined in the presence of a high concentration (10 microM) of unlabeled ryanodine. RESULTS: 3H-ryanodine binding to the Ca2+ release channel showed a bell-shaped pattern with an increase in specific binding at submicromolar Ca2+ concentrations and a decrease at higher Ca2+ concentrations than 0.5 mM, whereas nonspecific binding was not influenced by different Ca2+ concentrations. In nonfailing myocardium, maximal 3H-ryanodine binding (Bmax) was 85.2 +/- 3.1 fmol/mg protein and half-maximal binding was reached at a free Ca2+ concentration of 0.25 (0.22-0.30) microM (EC50). Neither EC50 values nor maximal specific 3H-ryanodine binding differed between nonfailing and failing myocardium of both etiologies. EC50 values were 0.24 (0.23-0.26) microM (DCM, n = 10) or 0.28 (0.25-0.31) microM (ICM, n = 9), respectively. Caffeine (2 mM) and the ATP-analogon AMP-PCP (1 mM) led to a shift towards lower Ca2+ concentrations consistent with an activation of the channel by these compounds, whereas Mg2+ (0.7 mM) shifted the Ca(2+)-dependence of 3H-ryanodine binding towards higher Ca2+ concentrations indicating inhibition of channel opening. After activation of the Ca2+ release channel by caffeine or AMP-PCP as well as after the inhibition with Mg2+ EC50 values were the same in failing and nonfailing myocardium. CONCLUSION: Caffeine and AMP-PCP sensitize, whereas Mg2+ desensitizes the myocardial Ca2+ release channel to Ca2+. The determination of Ca(2+)-dependent 3H-ryanodine binding to the human myocardial Ca2+ release channel is a useful tool to investigate its open probability. Furthermore, the Ca(2+)-sensitivity and the pharmacological behavior of the human SR Ca2+ release channel are similar in failing and nonfailing myocardium.

Calcium↗
PubMed1998

Thyroid function in lead smelter workers: absence of subacute or cumulative effects with moderate lead burdens.

OBJECTIVE: To evaluate the effect of low to moderate occupational lead exposure on thyroid function we conducted a cross-sectional study of 151 male lead smelter workers. METHODS: Parameters of thyroid function were assessed in relation to both subacute and cumulative lead exposure over a 10-year employment period. Blood lead levels, obtained from plant surveillance records, were used to establish four ordinal levels of current and cumulative exposure (< 15, 15-24, 25-39, and > or =40 microg/dl). RESULTS: Mean values for the lowest as compared with the highest current exposure group were similar for thyroxine (T4: 6.8 versus 6.1 microg/dl), estimated free thyroxine (EFT4: 1.6 ng/dl in both groups), and thyroid-stimulating hormone (TSH: 1.8 versus 1.7 mIU/l); there was no evidence of a significant trend for diminished thyroid function associated with increasing current lead exposure. Similarly, no significant difference was observed for T4, EFT4, or TSH in relation to the 10-year cumulative exposure or for adjusted analyses controlling for potential confounders, including age and alcohol use. CONCLUSION: In contrast to studies observing thyroid dysfunction in the setting of high lead exposure and related clinical poisoning, our findings weigh against a significant physiologic effect on thyroid function at lower levels (< 60 microg/dl) of occupational lead exposure.

Adult↗
PubMed1998

Halothane, but not isoflurane, impairs the beta-adrenergic responsiveness in rat myocardium.

BACKGROUND: The aim of this study was to identify the mechanisms by which halothane and isoflurane change the myocardial beta-adrenergic signal transduction pathway. METHODS: The authors investigated the influence of volatile anesthetics on the isometric force of contraction of rat papillary muscles. Concentration-response curves for isoproterenol and epinephrine were studied under control conditions and in the presence of halothane or isoflurane. In radioligand receptor-binding studies, the beta-adrenoceptor affinities for isoproterenol and epinephrine were investigated with and without guanosine triphosphate. In addition, the isoproterenol-induced cyclic adenosine monophosphate accumulations in viable cardiomyocytes in the absence and in the presence of halothane were determined by radioimmunoassays. RESULTS: The half-maximal positive inotropic effect of isoproterenol was reached at a half-maximal effective concentration (EC50 value) of 68 nM (33-141 nM; n = 10). A minimum alveolar concentration of 1.3 halothane reduced the positive inotropic potency of isoproterenol (EC50 = 158 nM [118-214 nM; n = 10; P < 0.01 vs. control]), whereas isoflurane did not changed it. This observation held true when the force of contraction was stimulated with epinephrine. Halothane (1.3 minimum alveolar concentration) depressed beta-adrenoceptor high-affinity binding and beta-adrenoceptor agonist affinity in radioligand binding assays, an effect not seen with isoflurane. Halothane shifted the intracellular cyclic adenosine monophosphate response curve of isoproterenol to the right. CONCLUSION: Halothane, but not isoflurane, impairs the beta-adrenergic responsiveness in rat myocardium by reducing the agonist affinity of the beta-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1998

Exposure of human vascular smooth muscle cells to Raf-1 antisense oligodeoxynucleotides: cellular responses and pharmacodynamic implications.

To characterize the pharmacodynamic properties of CGP 69846A/ISIS 5132, an antisense oligodeoxynucleotide directed against the mitogenic signal transducer Raf-1 kinase, we investigated the elicited biological responses in human coronary artery smooth muscle cells. Cell exposure to CGP 69846A resulted in a reversible time- and concentration-dependent down-regulation of cellular Raf-1 gene expression and, ultimately, inhibition of cell cycle progression. The highest potencies of this compound to reduce Raf-1 mRNA and protein levels were observed after 24 and 48 hr of cell exposure, respectively, with corresponding IC50 values of approximately 100 and approximately 300 nM. Proliferation was inhibited with an IC50 value of approximately 300 nM after 72 hr. We interpreted the recovery rate of Raf-1 mRNA after cell exposure to antisense ODNs as the half-life (t1/2 approximately 50 hr) of active intracellular CGP 69846A in our cell culture system. The endogenous Raf-1 turnover half-life of approximately 30 hr, as assessed by monitoring metabolically labeled Raf-1 protein, correlated kinetically with the antisense-induced protein decay rate (50% decay in approximately 33 hr), indicating that the efficiency of CGP 69846A in decreasing Raf-1 protein levels was rate-limited by the endogenous protein turnover rate. The pharmacodynamic effects of CGP 69846A antisense ODNs are therefore limited by the duration of its intracellular activity rather than by its ability to transiently decrease mRNA levels. Local steady state exposure to CGP 69846A may represent a new approach to prevent the transition of quiescent vascular smooth muscle cells into the pathologically hyperproliferating cells seen after angioplasty.

Antineoplastic Agents↗
PubMed1998

First North American field release of a vaccinia-rabies glycoprotein recombinant virus.

Following nearly 10 yr of extensive laboratory evaluation, a vaccinia-rabies glycoprotein (V-RG) vaccine was the first recombinant virus to undergo limited North American field release on 20 August 1990. The free-ranging raccoon population on Parramore Island (Virginia, USA) was exposed to a high density (10 baits/ha) of vaccine-laden baits distributed on a 300 ha vaccination area. An annual total of 887 raccoons were live-trapped for sedation, physical examination and blood collection for rabies antibody determination; there was no evidence of adverse effects or lesions due to the vaccine. Age and sex distributions, mean body weights, and live-capture histories of raccoons from the vaccination and non-baited control areas were compared. There were no statistically significant differences in survivorship between the baited and non-baited areas, nor between rabies antibody-positive and antibody-negative raccoons from the vaccination area. There was no trend in field mortality that suggested an association with either tetracycline or sulfadimethoxine, used as biomakers, or with vaccine contact determined by antibody status. No gross or histopathologic lesions due to the vaccine were demonstrated among a subsample of live-trapped raccoons collected for gross necropsy, biomarker analysis, histopathologic examination, and V-RG virus isolation attempts. Recovery of V-RG virus was limited to the tonsils of two biomarker-positive, clinically healthy raccoons collected from the vaccination area for postmortem examination on days 2 and 4 following bait distribution. These data reinforce the extensive body of safety data on the V-RG virus and extend it to include field evaluation where vaccine is offered free-choice in abundance, in baits designed to attract free-ranging raccoons, in a relatively simple ecosystem.

Administration, Oral↗