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Biomedical subjects

E Levine

Publications and source records attributed to E Levine.

At least 55 records · Page 3Linked to original sources
PubMed1997

A basic compositional requirement of agents having heparin-like cell-modulating activities.

Heparin has been recognized as possessing a large variety of cell-modulating activities. Using compositionally simple, structurally rigid, and low molecular weight saccharide molecules (cyclodextrins), we demonstrated that these activities depend primarily on a single, gross compositional parameter: a minimum intramolecular density of neighboring anionic (sulfate) groups. This same critical parameter is shown to be involved in achieving cell-modulating behavior as diverse as angiogenesis, endothelial proliferation, inhibition of smooth muscle cell growth, and cell protection against virus invasion. Physical chemical evidence is presented that associates this property with multi-ionic complex formation between the clusters of anionic and cationic sites on the complexing partners. These observations revive early suggestions of the decisive role of electrostatic complexation capabilities of glycosaminoglycans like heparin; taken together with numerous observations on heparinoids and other agents reported in diverse specialized fields of cell biology and medicine, they provide evidence that molecular agents of critical anionic (sulfate) density (MACADs) represent a broad class of molecules that, in contrast to proteins, do not rely on structural detail for their cell biological activities, but function by ionic complexation with proteinic agents (e.g. growth factors), thereby modifying their structure-specific activities.

Alcian Blue↗
PubMed1997

Renal cystic diseases.

Renal cystic disease comprises a mixed group of heritable, developmental, and acquired disorders. Because of their diverse etiology, histology, and clinical presentation, no single scheme of classification has gained acceptance. Conditions include autosomal dominant polycystic kidney disease, acquired renal cystic disease, medullary sponge kidney, autosomal recessive polycystic kidney disease, multicystic dysplastic kidney, medullary cystic disease, tuberous sclerosis, cysts of the renal sinus, and von Hippel-Lindau's disease. An awareness of the pathology of each cystic disease is helpful in the understanding of the corresponding radiological images. Imaging techniques used in evaluating renal cystic disease include intravenous urography, sonography, CT, MRI, nuclear medicine, and renal angiography. Many types of cystic disease show similar imaging features. Meticulous attention to subtle radiological findings is therefore essential for reaching a correct diagnosis. Imaging features requiring analysis include whether the cysts are unilateral or bilateral, renal size and functional status, cyst distribution in the kidneys, and the presence of hemorrhagic and calcified renal cysts, solid renal masses, renal sinus cysts, and cysts in adjacent organs. Radiological findings should be carefully correlated with clinical features such as patient age, family history, symptoms, physical findings, and renal functional status before a diagnosis is attempted.

Adult↗
PubMed1997

Current concepts and controversies in imaging of renal cystic diseases.

Renal cystic disease compromises a diverse group of inherited and acquired entities. This article reviews the clinical, pathologic, and radiologic findings of eight renal cystic diseases. For each entity, the current concepts of pathogenesis and pathophysiology are discussed. When appropriate, controversies concerning terminology, management, and malignant potentials are addressed. Renal cystic diseases that are discussed include autosomal dominant and autosomal recessive polycystic kidney disease, medullary sponge kidney, medullary cystic disease, multicystic, dysplastic kidney, von Hippel-Lindau disease, acquired cystic kidney disease, and tuberous sclerosis.

Humans↗
PubMed1997

Metastatic bladder cancer: advances in treatment.

At present, a combination of cisplatin, methotrexate, vinblastine and doxorubicin is the most widely used chemotherapy for metastatic bladder cancer. However, long-term follow-up shows that this combination may have little effect on survival. In addition, this regimen is toxic. New agents are needed which combine efficacy with good safety profiles. Agents which have been investigated include gallium nitrate, interferon-alpha and paclitaxel both as single agents and in combination with established cytotoxic drugs. A number of studies have been conducted in bladder cancer with the novel nucleoside analogue, gemcitabine. Response rates of up to 33% have been recorded in two phase II studies. Gemcitabine was well tolerated in both studies with few of the side-effects normally associated with cytotoxic drugs. A third study is ongoing.

Adult↗
PubMed1997

Unusual central nervous system toxicity in a phase I study of N1N11 diethylnorspermine in patients with advanced malignancy.

The objectives of this study were to determine the dose limiting toxicity (DLT) and other major toxicities, the maximum tolerated dose (MTD) and the human pharmacokinetics of N1N11 diethylnorspermine (DENSPM), a new polyamine analog which in experimental systems inhibits the biosynthesis of intracellular polyamines and promotes their degradation by inducing the enzyme spermine/spermidine N-acetyl transferase. These objectives were incompletely achieved because of the occurrence of an unusual syndrome of acute central nervous system toxicity which forms the basis of the present report. Fifteen patients with advanced solid tumors were entered into a phase I study of DENSPM given by a 1 h i.v. infusion every 12 h for 5 days (10 doses). The starting dose was 25 mg/m2/day (12.5 mg/m2/dose) with escalation by a modified Fibonacci search. Doses of 25 and 50 mg/m2/day were tolerated with only minor side effects of facial flushing, nausea, headache and dizziness (all grade I). At doses of 83 and 125 mg/m2/day, a symptom complex of headache, nausea and vomiting, unilateral weakness, dysphagia, dysarthria, numbness, paresthesias, and ataxia, was seen in 3 patients, one after 2 courses of 83 and 2 after 1 course of 125 mg/m2/day. This syndrome occurred after drug administration was complete and the patients had returned home. Lesser CNS toxicity was seen in 2 other patients at lower daily doses. Preliminary pharmacokinetics of DESPM measured in plasma by HPLC in 8 patients showed linearity with dose and a rapid plasma decay with a t1/2 of 0.12 h. We conclude that great caution is warranted in administering DENSPM on this schedule at doses of > or = 83 mg/m2/day.

Adenocarcinoma↗
PubMed1997

Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy.

The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1996

Functional trkB neurotrophin receptors are intrinsic components of the adult brain postsynaptic density.

Neurotrophins have long been thought to act as target-derived factors that regulate the survival and differentiation of afferent neurons. Recently, brain-derived neurotrophic factor (BDNF) was shown to elicit rapid increases in synaptic activity of cultured hippocampal neurons by enhancing responsiveness to excitatory input. These findings suggest a postsynaptic localization of neurotrophin receptors. In this study, we examined the expression of trkB, a high-affinity receptor for BDNF, in the postsynaptic density (PSD), a proteinaceous specialization of the postsynaptic membrane. Western blot analyses with antibodies to trkB revealed localization to the PSD in adult rat cerebral cortex and hippocampus. Only the full-length, active form of trkB was detected in PSD samples. BDNF treatment of the adult cortical PSD resulted in a 5-fold increase in trkB autophosphorylation, supporting the contention that the PSD contains functional trkB. Truncated trkB, which does not contain the tyrosine kinase signaling domain, though present in membrane fractions, was undetectable in the PSD. The presence of trkB in the PSD is consistent with a role for neurotrophins in the regulation of synaptic activity via direct postsynaptic mechanisms.

Animals↗
PubMed1996

Acquired cystic kidney disease.

ACKD is characterized by the development of many fluid-filled renal cysts and sometimes neoplasms in the kidneys of individuals with chronic renal failure but without a history of hereditary cystic disease. The condition is seen mainly in dialysis patients, but often begins in patients with ESRD before dialysis is started. Most patients with ACKD are asymptomatic, but the disorder may be associated with such serious complications as retroperitoneal hemorrhage and metastatic renal cell carcinoma. The diagnosis of ACKD and its complications is best achieved by CT scanning, although US and MR imaging may be useful in evaluation, particularly in patients not treated with dialysis. Cyst hemorrhage is common in ACKD and may cause flank pain and hematuria. Hemorrhagic cysts may be recognized by their CT scan, sonographic, or MR imaging features. Hemorrhagic cysts may rupture into the perinephric space causing large perinephric hematomas. These can usually be treated-conservatively. Patients with ACKD, particularly those treated with dialysis, have an increased risk of renal cell carcinoma. Renal cell carcinoma may also develop in the native kidneys of renal transplant recipients with good graft function many years after transplantation. Annual imaging of the native kidneys of all dialysis patients or of transplant recipients for the development of carcinoma is not justified, however, because it has not been shown to have a significant effect on patient outcome. Screening may, however, be useful in selected dialysis patients with good general medical condition and who have known risk factors for renal cell carcinoma including prolonged dialysis, large kidneys, ACKD, and male gender. Screening of the native kidneys of transplant recipients may be performed when they are referred for US evaluation of the renal allograft.

Humans↗
PubMed1995

Glycosylphosphatidylinositol-modified murine B7-1 and B7-2 retain costimulator function.

Glycosylphosphatidylinositol (GPI)-modified variants of murine B7-1 and B7-2 cell surface costimulators were produced via chimerization with alternative GPI-modification signal sequences from decay-accelerating factor (DAF). GPI anchorage was verified by demonstrating phosphatidylinositol-specific phospholipase C (PI-PLC) sensitivity of the chimeric polypeptides in both immunofluorescence/flow-cytometric and immunoprecipitation analyses. The various GPI-modified chimeric B7-1:DAF and B7-2:DAF polypeptides were shown to retain costimulator function, in both an in vitro proliferation assay and an in vivo triggering of cytotoxicity assay. The findings indicate that costimulator function for both B7-1 and B7-2 is not dependent upon native hydrophobic transmembrane anchorage. Moreover, the functionality of the GPI-modified variants in enhancing the immunogenicity of the murine T lymphoma line EL-4 suggests a novel route for generating APC-centered immunotherapeutics, including cellular cancer vaccines, that is based upon protein transfer of GPI-modified costimulators.

Animals↗
PubMed1995

Therapy for inflammatory breast cancer: impact of doxorubicin-based therapy.

BACKGROUND: Inflammatory breast cancer (IBC) carries an ominous prognosis. Before 1988, women with IBC at our institution were treated with neoadjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without vincristine and prednisone (CMF/VP). After 1988, women with IBC were treated with cyclophosphamide, doxorubicin, and 5-fluorouracil (FAC). This study compares these two regimens with regard to response and survival. METHODS: The records of all women presenting between January 1973 and December 1991 with a stage IIIB (T4d, any N, MO) breast cancer with proven dermal lymphatic invasion by tumor cells were reviewed retrospectively. RESULTS: The study comprised 38 women; 28 received CMF (22 CMF, 6 CMF/VP), and 10 received FAC. The overall response rate to induction chemotherapy in the CMF/VP group was 57% (40% PR, 17% CR), and 100% (60% PR, 40% CR) in the FAC group. The median overall survival for women receiving CMF/VP was 18 months compared with 30 months for women receiving FAC (p = 0.02). The median disease-free survivals for the CMF/VP and FAC groups were 6 and 24 months, respectively (p < 0.001). When comparing responders and nonresponders with CMF/VP induction therapy, the responders had a significantly longer overall median survival (24 versus 10 months) (p < 0.001) and disease-free median survival (8 versus 2 months) (p < 0.001). All of the five patients remaining alive received FAC with 80% (four of five) having a complete response. These four patients subsequently underwent mastectomy and radiation. CONCLUSION: This study suggests that a doxorubicin-containing chemotherapy regimen improves overall and disease-free median survivals when compared with the previously used CMF combination in the treatment of IBC. A favorable response to induction chemotherapy also appeared to be associated with an improved survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Phase I study of paclitaxel and carboplatin: implications for trials in head and neck cancer.

An ongoing phase I and pharmacokinetic trial of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin is evaluating the maximum tolerated dose (MTD) of a 3-hour paclitaxel infusion combined with fixed doses of carboplatin in previously treated and untreated patients with a variety of advanced cancers. A patient's previous treatment status determines the fixed carboplatin dose: target area under the concentration-time curves of 4.0 and 4.5 mg.min/mL in previously treated and untreated patients, respectively. Studies 1 and 2 entered previously treated patients to establish the paclitaxel MTD without and with cytokine support: study 1 established 135 mg/m2 paclitaxel as the MTD without such support. In study 2, granulocyte colony-stimulating factor is administered, and the MTD has not yet been reached with paclitaxel doses of 135 mg/m2 to 230 mg/m2 assessed thus far and 250 mg/m2 now being evaluated. Objective responses have been seen in three of five patients with squamous cell carcinoma of the head and neck and in patients with non-small cell lung cancer and metastatic cancer of unknown primary site as well. Myelosuppression has been the dose-limiting toxicity, although significant nausea and vomiting and myalgia have been documented occasionally. Paclitaxel apparently has nonlinear pharmacokinetics with a beta half-life of 6.7 hours (SD +/- 1.3 hours). Future trials of paclitaxel/carboplatin will address the management of squamous cell carcinoma of the head and neck and non-small cell carcinoma of the lung.

Adenocarcinoma↗
PubMed1994

Selective disruption of E-cadherin function in early Xenopus embryos by a dominant negative mutant.

E-cadherin function was disrupted in vivo in developing Xenopus laevis embryos through the expression of a mutant E-cadherin protein lacking its cytoplasmic tail. This truncated form of E-cadherin was designed to act as a dominant negative mutant by competing with the extracellular interactions of wild-type endogenous E-cadherin. Expression of truncated E-cadherin in the early embryo causes lesions to develop in the ectoderm during gastrulation. In contrast, expression of a similarly truncated N-cadherin protein failed to cause the lesions. The ectodermal defect caused by the truncated E-cadherin is rescued by overexpression of wild-type E-cadherin, by co-injection of full-length E-cadherin RNA along with the RNA for the truncated form. Overexpression of full-length C-cadherin, however, is unable to compensate for the disruption of E-cadherin function and can actually cause similar ectodermal lesions when injected alone, suggesting that there is a specific requirement for E-cadherin. Therefore, E-cadherin seems to be specifically required for maintaining the integrity of the ectoderm during epiboly in the gastrulating Xenopus embryo. Differential cadherin expression reflects, therefore, the requirement for distinct adhesive properties during different morphogenetic cell behaviors.

Amino Acid Sequence↗
PubMed1994

Needs assessment for advanced practice nurses for the uniformed services.

An assessment was made of the need for advanced practice nurses (APNs) in the uniformed services of the Department of Defense and the United States Public Health Service. The purpose of the assessment was to determine the role of the Graduate School of Nursing (GSN) at the Uniformed Services University of the Health Sciences in educating APNs for the uniformed services. The assessment focused on three categories of APNs: certified registered nurse anesthetists (CRNAs), certified nurse-midwives (CNMs), and nurse practitioners (NPs). The assessment found that current authorizations for APNs in the three military services exceeded inventory by 192 APNs: 148 CRNAs, 4 CNMs, and 40 NPs. In addition, losses through attrition in fiscal year 1993 were 154 APNs: 97 CRNAs, 7 CNMs, and 50 NPs. Thus, there is a need for educational support to prepare APNs for the uniformed services. The GSN can usefully supplement other educational programs in meeting this need.

Education, Nursing↗
PubMed1994

Acute renal and urinary tract disease.

Patients with acute urinary tract disorders often present with acute abdominal symptoms. Sonography and CT are often the first investigations performed when the clinical nature of the symptoms is unclear. However, excretory urography and cystography, scintigraphy, and angiography all play useful roles in evaluating patients with acute urinary tract disorders. Patients with suspected acute renal obstruction due to ureteric calculi are best assessed by excretory urography. If the latter study is contraindicated, sonography with duplex Doppler analysis of small intra-renal arteries may suggest the diagnosis by showing a dilated collecting system and an elevated resistive index. Patients with acute renal trauma are best imaged by CT, although excretory urography is an appropriate alternative if a mild exclusively renal injury is suspected. Patients with refractory acute renal infections require imaging to identify either pyonephrosis or large renal or perinephric abscesses that require immediate intervention. CT and sonography are most useful for identifying these complications. Acute renal vascular disorders, including renal hemorrhage, renal infarction, and renal vein thrombosis are readily diagnosed by contrast-enhanced CT. Both sonography and MR imaging help in the diagnosis of acute renal vein thrombosis. Most acute bladder disorders are diagnosed clinically. Cystography, however, is essential for the diagnosis of traumatic bladder rupture. Pelvic CT is a useful alternative to cystography for diagnosing bladder rupture in patients who undergo CT as their first imaging study because of suspected head or abdominal injuries.

Abdomen, Acute↗
PubMed1993

Asymmetry of gap junction formation along the animal-vegetal axis of Xenopus oocytes.

Functional expression of gap junction proteins (connexins) in paired oocytes exhibits a strong polar preference: oocyte pairs with their vegetal poles in apposition have higher junctional conductances than equivalent pairs contacting at their animal poles. This asymmetry of cell-cell channel formation is probably due to a corresponding asymmetric distribution of the connexin proteins along the vegetal-animal axis as indicated by immunohistochemical localization. The asymmetry can be influenced by the membrane potential of the oocytes and also by applying an electrical field. A key determinant is the charge of the connexin protein. Mutant connexins in which the net positive charge of the presumed cytoplasmic portion of connexin32 is abolished or reversed to a net negative charge (by addition of negatively charged amino acids to the carboxyl terminus) show loss of asymmetry or reversal of it, respectively. This change of asymmetry of channel formation is paralleled by a change in the distribution of the mutant proteins.

Amino Acid Sequence↗