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Biomedical subjects

L Ehrlich

Publications and source records attributed to L Ehrlich.

At least 19 recordsLinked to original sources
PubMed2001

Early experience in intermediate-risk penile cancer with sentinel node identification using the gamma probe.

OBJECTIVES: To report the initial experience with sentinel node identification using the gamma probe in patients with intermediate-risk penile cancer (T2NXM0, or T1 with intermediate or high-grade disease) and impalpable groin nodes. METHODS: Technetium-99m-labeled sulfur colloid was injected at the site of primary penile carcinoma 1 hour before surgery. The sentinel lymph nodes were located using the gamma probe and excised through a 3-cm inguinal incision. A full groin dissection was performed only in cases in which frozen section of the node demonstrated metastasis. RESULTS: Nine sentinel nodes were identified by the gamma probe and excised in 5 men. In 3 patients, the sentinel nodes were negative bilaterally. In 2 patients, the sentinel node, although grossly normal, showed a single focus of metastasis by frozen section analysis. In both of these patients, a full groin dissection was carried out and revealed no other nodal metastases. All 5 remained free of recurrence (median follow-up 18 months, range 16 to 23). CONCLUSIONS: In patients with microscopic involvement of a single lymph node only (confirmed by full groin dissection), gamma probe identification was 100% accurate. None of the patients with negative sentinel nodes had a recurrence. Biopsy of the sentinel nodes using the gamma probe can predict the presence or absence of inguinal node metastasis in patients with intermediate-risk penile cancer, sparing many patients the long-term morbidity of a full groin dissection. These initial results suggest further study is warranted.

Adult↗
PubMed2001

Combined large cell neuroendocrine carcinoma and spindle cell carcinoma of the lung.

We report a unique case of a combined pulmonary large-cell neuroendocrine carcinoma and spindle-cell carcinoma. The patient was a 54-year-old female smoker who presented with a 4-month history of increased left-sided chest pain and exertional dyspnea. The left upper lobectomy specimen revealed an 8.0-cm mass with central necrosis. Microscopically, the epithelial areas were composed of well-defined nests of large cells with peripheral palisading expressing low-molecular-weight keratin, synaptophysin, chromogranin, and neuron-specific enolase. The spindle-cell component consisted of pleomorphic cells arranged in fibrosarcoma and malignant fibrous histiocytoma-like patterns. These spindle cells were positive for low-molecular-weight keratin and vimentin with focal expression of CD68 and muscle-specific actin. Electron microscopy in the spindle-cell areas showed cell junctions and numerous tonofilaments, indicative of epithelial differentiation. The tumor behaved aggressively and the patient died with extensive metastases 4 months after surgery. The combination of neuroendocrine malignancies and spindle-cell carcinomas appears to be uncommon in the lung. Previous reports have described this association in single case reports of anaplastic small-cell carcinoma and atypical carcinoid, but not in large-cell neuroendocrine carcinoma.

Biopsy, Needle↗
PubMed1999

StarDOM: from STAR format to XML.

StarDOM is a software package for the representation of STAR files as document object models and the conversion of STAR files into XML. This allows interactive navigation by using the Document Object Model representation of the data as well as easy access by XML query languages. As an example application, the entire BioMagResBank has been transformed into XML format. Using an XML query language, statistical queries on the collected NMR data sets can be constructed with very little effort. The BioMagResBank/XML data and the software can be obtained at http://www.nmr.embl-heidelberg.de/nmr/StarDOM linge@embl-heidelberg.de

Databases, Factual↗
PubMed1998

Comparative kinetic analysis of FLP and cre recombinases: mathematical models for DNA binding and recombination.

The integrase class site specific recombinases FLP from Saccharomyces cerevisiae, and Cre from bacteriophage P1, have been extensively used to direct DNA rearrangements in heterologous organisms. Although their reaction mechanisms have been relatively well characterised, little comparative analysis of the two enzymes has been published. We present a comparative kinetic analysis of FLP and Cre, which identifies important differences. Gel mobility shift assays show that Cre has a higher affinity for its target, loxP (7. 4x10(10) M-1), than FLP for its target, FRT (8.92x10(8) M-1). We show that both recombinases bind the two halves of their target sites cooperatively, and that Cre shows approximately threefold higher cooperativity than FLP. Using a mathematical model describing the sequential binding of recombinase monomers to DNA, we have determined values for the association and dissociation rate constants for FLP and Cre.FLP and Cre also showed different characteristics in in vitro recombination assays. In particular, approximately tenfold more active FLP was required than Cre to optimally recombine a given quantity of excision substrate. FLP was able to reach maximum excision levels approaching 100%, whilst Cre-mediated excision did not exceed 75%. To investigate possible reasons for these differences a mathematical model describing the excision recombination reaction was established. Using measured DNA binding parameters for FLP and Cre in the model, and comparing simulated and experimental recombination data, the values of the remaining unknown parameters were determined. This analysis indicates that the synaptic complex is more stable for Cre than for FLP.

Allosteric Regulation↗
PubMed1998

Prediction of protein hydration sites from sequence by modular neural networks.

The hydration properties of a protein are important determinants of its structure and function. Here, modular neural networks are employed to predict ordered hydration sites using protein sequence information. First, secondary structure and solvent accessibility are predicted from sequence with two separate neural networks. These predictions are used as input together with protein sequences for networks predicting hydration of residues, backbone atoms and sidechains. These networks are trained with protein crystal structures. The prediction of hydration is improved by adding information on secondary structure and solvent accessibility and, using actual values of these properties, residue hydration can be predicted to 77% accuracy with a Matthews coefficient of 0.43. However, predicted property data with an accuracy of 60-70% result in less than half the improvement in predictive performance observed using the actual values. The inclusion of property information allows a smaller sequence window to be used in the networks to predict hydration. It has a greater impact on the accuracy of hydration site prediction for backbone atoms than for sidechains and for non-polar than polar residues. The networks provide insight into the mutual interdependencies between the location of ordered water sites and the structural and chemical characteristics of the protein residues.

Amino Acid Sequence↗
PubMed1997

A Brownian dynamics model for the chromatin fiber.

MOTIVATION: We describe a Brownian dynamics model for the folding of the chromatin fiber based on the model of Woodcock et al. (Proc Natl Acad Sci USA, 90, 9021-9025, 1993). The model takes into account the elastic properties of the DNA as well as the electrostatic interaction and nucleosomal excluded-volume interaction. The solvent is described as a viscous medium, the electrostatic interactions by a screened Coulomb potential. RESULTS: The hydrodynamic properties and their dependence on the solvent's ionic strength are accurately reproduced by the model for nucleosome di- and tetramers. Ionic strength-dependent changes in mobility can be attributed to partial screening of the electrostatic repulsion between different segments of linker DNA. Formation of fiber-like structures occurs on time scales of several hundred microseconds for a linear configuration of 25 nucleosomes. The model was implemented by creating user-defined data types. Use of this so-called object-oriented paradigm allowed for a high degree of component reuse in simulation, analysis and visualization contexts. AVAILABILITY: The described software is available on request from the authors. Additional information can be found on the WWW at http:/(/)www.dkfz-heidelberg.de/Macromol/ehrlich /chromatin.htm/.

Chromatin↗
PubMed1997

Progressive unilateral mandibular swelling in adolescence: a diagnostic dilemma.

Asymmetrical swelling of the mandible in adolescence may pose a significant diagnostic dilemma. The differential diagnosis ranges from traumatic, infectious, and metabolic processes to benign and malignant tumors. Among them, fibrous dysplasia, osteomyelitis, and malignancy may present with similar clinical and radiological features, making an accurate diagnosis quite difficult. This is an illustrative case involving a 14-year-old girl who initially presented with diffuse fibrous dysplasia of the mandible and in whom a superimposed osteomyelitis of the left side subsequently developed. Multiple investigations and several biopsies were required to arrive at a diagnosis. Similarities in clinical and radiographic findings of fibrous dysplasia, osteomyelitis, and malignancy are presented, and implications for treatment are discussed.

Adolescent↗
PubMed1995

Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors.

The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases; however, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1beta and TNF-alpha in combination caused marked neuronal injury. Brain cell cultures treated with IL-1beta plus TNF-alpha generated substantial amounts of NO. Blockade of NO production with a NO synthase inhibitor was accompanied by a marked reduction (about 45%) of neuronal injury, suggesting that NO production by astrocytes plays a role in cytokine-induced neurotoxicity. Addition of N-methly-D-aspartate (NMDA) receptor antagonists to brain cell cultures also blocked IL-1beta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the involvement of NMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1beta plus TNF-alpha was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity. These in vitro findings suggest that agents which suppress NO production or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases.

2-Amino-5-phosphonovalerate↗
PubMed1991

Deletion of sequences upstream of the proteinase improves the proteolytic processing of human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 expresses structural proteins and replicative enzymes within gag and gag-pol precursor polyproteins. Specific proteolytic processing of the precursors by the viral proteinase is essential for maturation of infectious viral particles. We have studied the activity of proteinase in its immature form, as part of a gag-pol fusion protein, in an in vitro expression system. We found that deletion of p6*, the region in pol upstream of proteinase, resulted in improved processing of the precursor. A modified proteinase is released, but it functions less efficiently than wild type. Improved autoprocessing correlates with increased accessibility of the active site region in the polyprotein carrying the p6* deletion. Our results suggest that p6* is involved in the regulation of proteinase activation, perhaps as a region limiting the interaction of the active site and substrate binding domain with the remainder of the polyprotein. Release of p6* inhibition may be an activation step necessary for infectious particle maturation.

Amino Acid Sequence↗
PubMed1991

Adjuvant therapy for neuroendocrine small cell carcinoma of the cervix: review of the literature.

Neuroendocrine cell carcinoma of the cervix is a virulent tumor associated with an extremely poor prognosis. Even in clinical Stage I disease, there may be subclinical hematogenous and lymphatic metastases with frequent recurrences. Adjuvant postoperative external pelvic radiotherapy has been reported to offer some degree of local control; however, most patients succumb to distant disease. Following radical abdominal hysterectomy and pelvic lymphadenectomy, with confirmation of the neuroendocrine tumor by electron microscopy and immunohistochemical staining, two patients were given adjuvant systemic chemotherapy with concurrent pelvic radiotherapy, employing regimens with documented activity against small cell carcinoma of the lung of neuroendocrine origin. Despite severe myelotoxicity and persistent neuropathy, both patients are alive without clinical evidence of disease at 28+ and 47+ months.

Adult↗
PubMed1990

Mutational analysis of a native substrate of the human immunodeficiency virus type 1 proteinase.

Proteolytic processing of the gag/pol precursor by the human immunodeficiency virus type 1 proteinase is essential for the production of infectious viral particles. Although the sites of virus-specific cleavages have been determined, the primary amino acid sequences surrounding these sites are heterogeneous and the determinants that direct the cleavage specificity exhibited by human immunodeficiency virus type 1 proteinase remain largely undefined. We performed mutational analysis of the Tyr/Pro site, which produces the amino terminus of the viral capsid protein, and the Phe/Pro site, which produces the amino terminus of the proteinase. Mutations were made in a clone encoding a frameshift mutation that results in the expression of equimolar amounts of the substrate and proteinase in the form of a truncated gag/pol precursor. After single-amino-acid substitutions were made, their effects on proteolytic processing were examined by in vitro transcription and in vitro translation of the synthetic mRNA; translation products were then processed by exogenously added purified proteinase. Single-amino-acid substitutions yielded both substrates which were processed with wild-type efficiency and substrates on which processing was impaired. At the Tyr/Pro site in gag, processing was severely inhibited by substitutions within the P4, P2, P1, and P2' positions. The Phe/Pro site in pol, however, demonstrated far greater tolerance to amino acid substitution. These data suggest that the primary amino acid sequence around a scissile bond is more critical for cleavage of the Tyr/Pro site than the Phe/Pro site.

Amino Acid Sequence↗
PubMed1990

Practical aspects of mammographic-pathological correlation: experience with needle localization.

Preoperative mammographic needle localization of a lesion and specimen radiography facilitate accurate excisional biopsy of a nonpalpable breast lesion. The pathological diagnosis must be correlated with the mammographic indication for biopsy to ensure optimal patient care. We describe our approach to pathological correlation and outline the practical aspects and potential pitfalls of our practice. Optimal mammographic-pathological correlation requires cooperation between radiologist, surgeon and pathologist.

Adult↗
PubMed1989

Comparison of dopamine and fenoldopam effects on renal blood flow and prostacyclin excretion in normal and essential hypertensive subjects.

We recently reported that a low dose dopamine (DA) infusion in normal subjects increased renal blood flow (RBF) via prostacyclin (PGI2) formation without changes in PGE2 levels. The present study explores whether this mechanism is mediated by the DA1 receptor and evaluates the effect of DA on RBF and PGs in subjects with essential hypertension (EH). A low dose of DA (1 microgram/kg.min), which previously did not alter hemodynamics in normal subjects was infused into eight patient with EH to determine the role of DA stimulation in hypertensives. To assess the effect of DA1 stimulation, fenoldopam, a selective DA1 agonist, was infused (0.1 microgram/kg.min) into 10 normal and 10 hypertensive patients. Fenoldopam, unlike DA, significantly decreased diastolic blood pressure in hypertensives (96 +/- 3 to 85 +/- 2 mm Hg; P less than 0.01) along with a significant increase in pulse rate (68 +/- 2 vs. 73 +/- 2 beats/min; P less than 0.01). RBF measured by para-aminohippurate clearance increased only in normals during fenoldopam infusion from 1185 +/- 71 to 1533 +/- 84 L/min.m2 (PGI(2)01), and this was associated with an increase in PGI2 (6-keto-PGF1) excretion (149 +/- 19 vs. 214 +/- 32 ng/g creatinine; P less than 0.02). These effects of fenoldopam were similar to DA effects on RBF and PGI2 excretion in normals. In contrast, in hypertensive subjects, neither fenoldopam (867 +/- 113 vs. 1054 +/- 177 L/min.m2; P greater than 0.1) nor DA (1098 +/- 85 vs. 1061 +/- 101 L/min.m2; P greater than 0.1) increased RBF. Similarly, neither the DA nor the fenoldopam infusion stimulated PGI2 excretion in the hypertensives. The fenoldopam infusion in the hypertensives produced a significant natriuresis (22 +/- 3 to 49 +/- 9 mmol/3 h; P less than 0.05). Similar effects on Na+ excretion in this group were noted during DA infusion (17 +/- 3 to 36 +/- 3 mmol/3 h; P less than 0.05), suggesting that DA-induced natriuresis is not directly linked to DA-induced changes in RBF or PG excretion. The present study shows that in normal subjects, fenoldopam, a specific DA1 agonist, like DA, stimulates renal PGI2 release and RBF. In contrast, neither DA nor fenoldopam alters PGI2 or RBF in patients with EH, suggesting an alteration of dopaminergic tone in some hypertensives that is characterized by a defect in DA1 receptor sensitivity.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Mechanisms of blood pressure regulation by magnesium in man.

In order to determine the effect and mechanism of Mg on vascular tone, a 3-hour infusion of Mg (200 mg/h) was administered to normal subjects. The Mg infusion resulted in a drop in blood pressure (BP), a rise in renal blood flow, and an increase in urinary 6-keto-PGF1 alpha excretion. Cyclooxygenase inhibition with indomethacin and the calcium channel blocker, nifedipine, prevented these vascular effects of Mg. These data suggest that prostacyclin release via changes in Ca2+ flux may be the mechanism of Mg vasodilatory action. Since angiotensin II (AII) acts via the Ca2+ messenger system, we also studied the effects of Mg loading and dietary Mg depletion on AII responses. Mg loading blunted the rise in BP and the aldosterone-stimulating effect of AII, whereas Mg depletion significantly enhanced these AII effects. These results support the hypothesis that Mg may be an antagonist of the pressor and steroidogenic effects of AII.

Adult↗
PubMed1988

The renal vasodilating effect of dopamine is mediated by calcium flux and prostacyclin release in man.

A low dose of dopamine (DA; 1 microgram/kg.min for 3 h) was infused into 10 normal subjects to determine whether vasodilator prostaglandins might be involved in the vascular action of this vasoactive hormone. Although this DA dose did not alter blood pressure, pulse, or cardiac index, it significantly increased renal blood flow (RBF), as estimated by para-amino-hippurate clearance [1.40 +/- 0.10 (+/- SE) to 1.93 +/- 0.18 L/min.1.73 m2; P less than 0.02]. This increase was due to DA receptor action since it was blocked by metoclopramide, a DA antagonist, and was not altered by prazosin, an alpha-adrenergic antagonist. DA simultaneously increased the urinary excretion rate of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin [PGI2; 79 +/- 16 to 154 +/- 32 ng/g creatinine (2 +/- 0.40 to 3.88 +/- 0.78 pmol/mumol creatinine); P less than 0.02], but there was no change in PGE2 excretion. This dose of DA increased urinary Na+ and K+ excretion and slightly increased creatinine clearance from 0.12 +/- 0.01 to 0.16 +/- 0.02 L/min.1.73 m2 (P less than 0.05). Metoclopramide also blocked the increase in PGI2 excretion, indicating that this increase was due to DA. The relationship between RBF and PGI2 was supported by studies in which either indomethacin or ibuprofen, both cyclooxygenase inhibitors, blocked the increase in both RBF and PGI2 excretion rate. Since some DA actions may be mediated through calcium flux, we also administered nifedipine, a calcium channel-blocking drug, and found that the DA effect on RBF and PGI2 was significantly reduced. These studies suggest that the DA effect on RBF is mediated by calcium flux, which probably activates renal vascular phospholipase, leading to release of arachidonic acid and synthesis of PGI2, a potent vasodilator.

Adult↗
PubMed1988

Plasma atrial natriuretic hormone levels in patients with the syndrome of inappropriate antidiuretic hormone secretion.

This study explored whether atrial natriuretic hormone (ANH) might be involved in the escape from salt and water retention that occurs in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Sixteen patients with low serum Na+ concentrations [123 +/- 1 (+/- SE) mmol/L] were studied. Each patient excreted urine that was hyperosmolar (mean, 391 +/- 4 mosmol/kg) in relation to serum osmolality (mean, 258 +/- 4 mosmol/kg). Sodium excretion (81 +/- 20 mmol/L) also was inappropriate to the low serum Na+ level. The probable causes of SIADH were head trauma (4), pneumonia (5), lung cancer (3), and chlorpropamide therapy (4). In the nontumor patients, plasma and/or urinary vasopressin (AVP) concentrations were in the normal range, but inappropriate for serum osmolality. Urinary AVP values of 50 pg/mL or more (greater than 46 pmol/L) were found in the three tumor patients. The mean plasma ANH concentration was 6-fold higher than that in normal subjects [296 +/- 51 vs. 51 +/- 13 pg/mL (100 +/- 20 vs. 17 +/- 4 pmol/L); P less than 0.01]. Six SIADH patients were studied again after brief (1-3 days) water restriction. Although serum osmolality increased in each, their plasma AVP concentrations decreased very little, and urinary AVP excretion and plasma ANH did not change. These results indicate that plasma ANH levels are markedly increased in patients with SIADH. Their increased ANH secretion may antagonize water retention resulting from the inappropriate AVP secretion.

Adult↗