Separation of an overtube from the bite block during band ligation of esophageal varices.
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Aged↗
Biomedical subjects
R Levy
Publications and source records attributed to R Levy.
Re-evaluation of the functional anatomy of the basal ganglia in normal and Parkinsonian states.
In the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative.
Animals↗
Neutrophil superoxide release and interleukin 8 in acute myocardial infarction: distinction between complicated and uncomplicated states.
Superoxide release in neutrophils and sera levels of interleukin 8 (IL-8) were determined in 15 patients with complicated acute myocardial infarction (MI) and 15 patients with uncomplicated MI. All patients showed increased superoxide release in unstimulated and stimulated neutrophils compared with healthy control subjects, indicating priming of these cells. Superoxide release of unstimulated or stimulated neutrophils was found to be significantly higher in patients with complicated MI than in patients with uncomplicated MI. Thrombolytic therapy did not affect the rates of superoxide release. The neutrophil chemoattractant/activator IL-8 was detected in the sera of all patients, with significantly higher levels in those with complicated MI. The highest levels of IL-8 were detected at admission to the Coronary Care Unit and significantly decreased thereafter, suggesting its contribution to neutrophil-mediated tissue injury. The high levels of IL-8 may be one of the major contributors to the priming of neutrophils in these patients.
Aged↗
Impaired neutrophil functions in patients with leukocytoclastic vasculitis.
BACKGROUND: Leukocytoclastic vasculitis (LV) is characterized by segmental inflammation of small blood vessels, resulting in ischemic damage to the surrounding tissue. It is considered to be related to a type III hypersensitivity reaction, although the exact etiologic mechanism is not clear. OBJECTIVE: The purpose of this study was to evaluate neutrophil functions in patients with LV in order to understand their role in the pathogenesis of the disease. METHODS: Neutrophil functions were examined in 25 LV patients. The patients were divided into two groups: Group A consisted of 14 patients with drug-induced LV and Group B consisted of 11 patients where LV was induced by other factors. RESULTS: Both groups of patients showed significantly reduced chemotaxis and phagocytosis. Superoxide generation was significantly lower (P < 0.001) only in neutrophils from patients in Group A: 5.8 +/- 0.5 nmoles O2/10(6) cells/min compared to 9.08 +/- 0.8 nmoles O2/10(6) cells/min in the controls. Preincubation on normal neutrophils with the patients' sera caused an increase in their superoxide generation in accordance with the high IL-8 levels in these sera. CONCLUSIONS: Neutrophil functions were significantly impaired in patients with LV. It is likely that factors present in LV plasma may chronically activate neutrophils, so that they become refractory to further stimulation. Our study showed that neutrophil superoxide generation is low only in drug-induced LV; this test may assist in distinguishing such patients from those with LV induced by other causes.
Acetaminophen↗
Infection by parvovirus B 19 during pregnancy: a review.
Fetal infection by Parvovirus B 19 is a common cause of fetal anemia and nonimmune hydrops fetalis and may result in fetal death. Recent improvements in diagnosing parvovirus infections by sensitive molecular biology techniques now allow for a new insight into its pathogenic rule, immunology, and the varied clinical manifestations. The estimated overall risk of fetal loss after maternal exposure is about 6.5 percent, which is much less than previously thought. Inasmuch as complete spontaneous reversal of fetal hydrops has been commonly described, controversy exists regarding the management of the fetus with clinical signs of infection by Parvovirus B 19. According to the experience that has accumulated, it seems that only cases with severe fetal anemia or signs of fetal compromise should be managed by intrauterine transfusion. This procedure, however, is not without risk. Although an association between fetal viral infection and structural abnormalities has been described, it has not been proved yet. However, infection by Parvovirus B 19 has been recently proposed as a causative factor for congenital red blood cell aplasia.
Female↗
A controlled family study of late-onset non-affective psychosis (late paraphrenia).
BACKGROUND: The relationship between those schizophrenia-like conditions that have their onset in late life and early-onset schizophrenia is unclear. Very few family history studies of patients with late-onset psychosis have been reported, and it is not known whether their relatives have an increased risk of psychosis. METHOD: Information was collected on the psychiatric morbidity of 269 first-degree relatives of patients with schizophrenia or delusional disorder with an onset after the age of 60 (late paraphrenia), and 272 first-degree relatives of healthy elderly control subjects, using a research diagnostic instrument. RESULTS: With a narrow age range (15-50 years) at risk, the estimated lifetime risk of schizophrenia was 1.3% in the relatives of both cases and controls. With a wider age range (15-90 years) at risk, estimated lifetime risk of schizophrenia was 2.3% for the relatives of cases and 2.2% for the relatives of controls. However, depression was significantly more common among the relatives of cases than controls. CONCLUSIONS: Those schizophrenia-like psychoses with onset in late life are not genetically associated with schizophrenia.
Adult↗
IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma.
PURPOSE: To evaluate the safety, pharmacokinetics, and biologic effect of multiple doses of the chimeric anti-CD20 monoclonal antibody (mAb) IDEC-C2B8 in patients with relapsed B-cell lymphoma. PATIENTS AND METHODS: Twenty patients with relapsed low-grade (n = 15) or intermediate-/high-grade (n = 5) lymphoma received weekly infusions times four of 125 mg/m2 (n = 3), 250 mg/m2 (n = 7), or 375 mg/m2 (n = 10) of IDEC-C2B8. RESULTS: Infusional side effects during the initial infusion were mainly grade I/II fever, asthenia, chills, nausea, rash, and urticaria. More serious events were rare. Peripheral-blood B cells were rapidly depleted and slowly recovered over 3 to 6 months. There was no change in mean immunoglobulin (Ig) levels. Antibody serum half-life (and maximum concentration [Cmax]) generally increased between the first and fourth infusions (33.2 hours v 76.6 hours, respectively) following the 375-mg/m2 doses. Six of 18 assessable patients had a partial remission (PR), with a median time to disease progression of 6.4 months (range, 3 to 21.7). Minor responses (MRs) were observed in five patients and progressive disease (PD) in seven. Tumor responses occurred in peripheral blood, bone marrow (BM), spleen, bulky lymph nodes, and extranodal sites, and in patients who had relapsed following high-dose myeloablative chemotherapy. Six of 14 patients (40%) with a low-grade histology responded. Four of six with bulky disease had a PR. CONCLUSION: IDEC-C2B8 chimeric anti-CD20 mAb therapy is well tolerated and has clinical activity in patients with relapsed B-cell lymphoma. The 375-mg/m2 dose has been selected for a phase II trial in patients with relapsed low-grade or follicular B-cell lymphoma.
Adult↗
[Efficacy of interferon alpha in primary prevention of preneoplastic lesions in a transgenic murine model of hepatocellular carcinoma related to the interaction between woodchuck hepatitis viruses and c-myc oncogene].
OBJECTIVES: C-myc oncogene overexpression by near insertion of hepatitis B virus is important in woodchuck hepatocarcinogenesis. This DNA fragment was transferred in mice who developed hepatocellular carcinoma via preneoplastic lesions. In the present study, we tested the preventive effect of alpha interferon on the incidence of hepatocyte dysplasia. METHODS: Human recombinant alpha interferon hybrid B/D was continuously administered at increasing doses (0 to 10,000 IU/g) in a transgenic mouse model. One cohort was treated from day 21 to day 80. A histological liver examination was performed and the transgene expression was assessed by hybridization with or without previous genic amplification, and by indirect immunofluorescence. RESULTS: At day 15, histological liver examination was normal. Interferon treatment decreased the expression of viral sequences, but not of c-myc. At day 80, interferon treatment resulted in a reduction of the incidence and severity of dysplasic lesions, and a marked decrease in c-myc overexpression. CONCLUSION: In this transgenic mouse model, alpha interferon treatment decreased the incidence and severity of precancerous lesions, due to a reduction in c-myc overexpression. This prophylaxis could be of interest in human hepatocarcinogenesis where c-myc overexpression is frequent.
Animals↗
length of clinical trials of dementia drugs. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.
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Aged↗
Rationale for adjuvant idiotypic vaccination after high-dose therapy for multiple myeloma.
With conventional therapy, multiple myeloma (MM) has a poor prognosis. During the last few years, it has become clear that high-dose chemotherapy with autologous stem cell support can increase overall survival of MM patients, but further improvement in outcome is desperately needed. The monoclonal immunoglobulin (Ig) produced by the MM cells called idiotypes (Id) is a tumor-specific antigen due to unique antigenic determinants that are localized in the variable regions of the Ig molecule. Conceivably, Id immunization of MM patients in complete remission could further increase survival. Here we review the scientific basis for such Id immunization.
Adjuvants, Immunologic↗
A nine-amino acid peptide from IL-1beta augments antitumor immune responses induced by protein and DNA vaccines.
The idiotypic determinants of B cell lymphoma provide a tumor-specific Ag and a target for immunotherapy. We have developed several generations of idiotype vaccines that were tested in an animal model, the 38C13 mouse B cell lymphoma. Initially we showed that effective tumor immunity was elicited by the syngeneic Id when it was conjugated to a carrier protein and mixed with an adjuvant. A subsequent generation of Id vaccines eliminated the need for a carrier protein and for an adjuvant by incorporating cytokines into fusion proteins containing the Id. A third generation of vaccines consisting of naked DNA encoding the Id-granulocyte-macrophage colony-stimulating factor (GM-CSF) fusion proteins was equally effective in inducing tumor immunity. To determine whether Ig variable regions, in the absence of constant regions, could be immunotherapeutic in this model, we tested the use of single-chain Fv (scFv). scFv proteins, produced in bacteria, and naked DNA encoding scFv were used in this study. scFv was tested alone or fused to GM-CSF or an immunoenhancing peptide derived from IL-1beta. Here we demonstrate that scFv-GM-CSF was effective only when injected as a protein, not as a DNA vaccine. In contrast, both scFv-IL-1beta peptide fusion protein and naked DNA encoding it induced tumor immunity that protected mice from tumor challenge.
Animals↗
Local intraluminal infusion of biodegradable polymeric nanoparticles. A novel approach for prolonged drug delivery after balloon angioplasty.
BACKGROUND: Several perfusion balloon catheters are under investigation for local drug delivery; however, sustained tissue drug levels are difficult to achieve with these techniques. To overcome this problem, sustained-release, biodegradable nanoparticles represent a potential alternative for prolonged local delivery. METHODS AND RESULTS: A biodegradable polylactic-polyglycolic acid (PLGA) copolymer was used to formulate nanoparticles. Fluorescent-labeled nanoparticles were intraluminally administered in a single, 180-second infusion after balloon injury in the rat carotid model. Localization and retention at different time points and biocompatibility of nanoparticles were evaluated. To evaluate the potential of the system in the prevention of neointimal formation, dexamethasone was incorporated into the particles and delivered locally as above. Nanoparticles were seen in the three layers of the artery at 3 hours and 24 hours. At 3 days, they were mainly present in the adventitial layer, decreasing at 7 days, with no fluorescent activity at 14 days. The PLGA nanoparticles appeared to be fully biocompatible. In the dexamethasone nanoparticle study, a significant amount of dexamethasone was present in the treated segment for up to 14 days after a single infusion, with no plasma levels detected after the first 3 hours. There was a 31% reduction in intima-media ratio in animals treated with local dexamethasone nanoparticles compared with control. CONCLUSIONS: Nanoparticles successfully penetrated into the vessel wall and persisted for up to 14 days after a short, single intraluminal infusion. Local administration of nanoparticles with incorporated dexamethasone significantly decreased neointimal formation. This methodology appears to have important potential for clinical applications in local drug delivery.
Angioplasty, Balloon, Coronary↗
Injury produces early rise in lipoprotein lipase activity in rabbit aorta.
The mechanisms following intimal injury predisposing towards atherosclerotic changes have not been fully elucidated. We speculated that a local increase in the enzyme lipoprotein lipase (LPL) might explain a higher susceptibility of the damaged intima to lipid accretion, and so we investigated the effect of balloon endothelial denudation on LPL activity and cholesterol content (LPLa and Cholc, respectively), in aortas from normolipidemic male New Zealand white rabbits. Arteries were obtained from injured and control animals after 2, 6, 8 and 10 weeks to evaluate the shortest period after de-endothelialization necessary to detect LPLa changes. Injury resulted in a 4-fold LPLa rise (P < 0.01), as early as 2 weeks, and the enzymatic activity remained increased throughout the study period. A mild but significant 22% Cholc increase (P < 0.03) was found after 2 weeks of injury, even in this normolipidemic rabbit model. We conclude that physical damage to the intima markedly and soon increases LPLa. This finding might account for the higher lipid accumulation by injured vessels, providing additional support to the hypothesis of LPL as an atherogenic mediator.
Animals↗
Chronic opioid treatment induces adenylyl cyclase V superactivation. Involvement of Gbetagamma.
It has been known for some time that chronic treatment of neuronal cells and tissues with opioids, contrary to their acute effect, leads to an increase in cAMP accumulation. This phenomenon, defined as adenylyl cyclase superactivation, has been implicated in opiate addiction, yet the mechanism by which it is induced remains unclear. Here, we show that this phenomenon can be reproduced and studied in COS-7 cells cotransfected with adenylyl cyclase type V and mu-opioid receptor cDNAs. These cells display acute opioid inhibition of adenylyl cyclase activity, whereas prolonged exposure to the mu-agonist morphine or [-Ala2, N-methyl-Phe4, Gly-ol5]enkephalin leads to a time-dependent superactivation of adenylyl cyclase. This superactivated state is reversible, because it is gradually lost following agonist withdrawal. Adenylyl cyclase superactivation can be prevented by pertussis toxin pretreatment, indicating the involvement of Gi/o proteins, or by cotransfection with the carboxyl terminus of beta-adrenergic receptor kinase or with alpha-transducin (scavengers of Gbetagamma dimers), indicating a role for the G protein betagamma dimers in adenylyl cyclase superactivation. However, contrary to several other Gbetagamma-dependent signal transduction mechanisms (e.g. the extracellular signal-regulated kinase 2/MAP kinase pathway), adenylyl cyclase superactivation is not affected by the Ras dominant negative mutant N17-Ras.
Adenylate Cyclase Toxin↗
Tumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin's lymphoma.
Patients with non-Hodgkin's B-cell lymphoma who received an antitumor vaccine of idiotypic ig protein showed humoral and proliferative immune responses. Because immunity to some antigens, including tumor antigens and human pathogenic viruses, may be better correlated with the cytolytic cellular immune response, we evaluated 16 non-Hodgkin's lymphoma patients immunized with autologous idiotypic ig molecules for changes in tumor-specific cytotoxic T-lymphocyte precursor (CTLp) frequency using limiting dilution analysis. Eleven patients had a significant increase in tumor-specific CTLp. Eight of these 11 patients remain without evidence of disease or with stable minimal disease. In contrast, all five patients who did not have a significant change in tumor-specific CTLp have developed progressive disease. Patient vaccination with tumor associated protein antigens can increase tumor-specific CTLp frequencies. The correlation of increased tumor specific CTLp with freedom from progression is significant at P = .002. This study indicates that measurement of CTLp frequencies are relevant to the clinical evaluation of human tumor vaccines and suggests that cell-mediated cytolytic immune responses may be an important determinant of vaccine efficacy.
Adult↗
Contribution of arginine residues in the RP135 peptide derived from the V3 loop of gp120 to its interaction with the Fv fragment of the 0.5beta HIV-1 neutralizing antibody.
The construction, expression, and purification of an active Fv fragment of the 0.5beta monoclonal human immunodeficiency virus type 1 (HIV-1) neutralizing antibody is reported. The interaction between the Fv fragment and the RP135 peptide derived from the V3 loop of gp120 from HIV-1IIIB was studied by varying the salt concentration and by mutating arginine residues in the peptide. The mutations R4A, R8A and R11A (which correspond to residues 311, 315, and 318 in gp120 of HIV-1IIIB) reduce the binding free energy by 0.22 (+/- 0. 20), 4.32 (+/- 0.16), and 1.58 (+/- 0.17) kcal mol-1, respectively. The salt-dependent components of their contributions to binding are 0.02 (+/- 0.22), -0.55 (+/- 0.18), and -0.97 (+/- 0.19) kcal mol-1, respectively. The magnitudes of the mutational effects and the extent of shielding by 1 M NaCl suggest that Arg-8 is involved in a buried salt bridge in the peptide-Fv fragment complex, whereas Arg-11 is involved in a more solvent-exposed electrostatic interaction.
Amino Acid Sequence↗
Translocation of annexin I to plasma membranes and phagosomes in human neutrophils upon stimulation with opsonized zymosan: possible role in phagosome function.
Annexin I in the cytosol of resting neutrophils was translocated to the plasma membranes upon addition of opsonized zymosan (OZ). Maximum translocation could be detected 1 min after stimulation with OZ, and decreased thereafter. Subcellular fractionation studies demonstrated that annexin I could not be detected in the granule fractions in either resting or activated cells, but was found in association with the phagosome fraction. The marked translocation of annexin I was unique to OZ, since formyl-Met-Leu-Phe induced only slight translocation of annexin I to the plasma membranes, and phorbol 12-myristate 13-acetate had no effect at all. The mechanism regulating the translocation of annexin I is not clear. Annexin I is not phosphorylated in resting or stimulated cells. The correlation between the elevation in the intracellular calcium ion concentration ([Ca2+]i) and the degree of translocation of annexin I to the plasma membranes induced by the different stimuli, together with the inhibition of these processes by the addition of EGTA, indicate that the translocation of annexin I can probably be attributed to the rise in [Ca2+]i. However, this cannot be the sole mechanism since ionomycin, which caused an increase in [CA2+]i similar to that induced by OZ, was less efficient than OZ in inducing translocation of annexin I. The induction of annexin I translocation to the plasma membrane by OZ, which was the only agent that induced phagosome formation, and the detection of annexin I in the phagosome fraction, suggest that annexin I participates in phagosome function.
Annexin A1↗
Pharmacological basis for functional selectivity of partial muscarinic receptor agonists.
Muscarinic receptor agonists activate phosphoinositide hydrolysis and adenylate cyclase in Chinese hamster ovary cells transfected with cDNAs encoding the human muscarinic ml and m3 receptors. Whereas carbachol activates similarly both receptor subtypes, 4-[3-chlorophenyl-carbamoyloxy]-2-butynyltrimethyl ammonium chloride (McN-A-343) preferentially activates the m1 subtype over m3, in regard to both phosphoinositide hydrolysis and adenylate cyclase activity. On the other hand, oxotremorine activates phosphoinositide hydrolysis to a similar extent in both cell lines, but it activates preferentially adenylate cyclase in m1 versus m3 receptor expressing cells. Relative to carbachol, both McN-A-343 and oxotremorine activate preferentially phosphoinositide hydrolysis over adenylate cyclase in both cell lines. Prolonged incubation of cells with either carbachol, McN-A-343, or oxotremorine down-regulated the m1 receptors. This was accompanied by a parallel decrease in adenylate cyclase activity, whereas phosphoinositide hydrolysis remained relatively high. Inactivation of the receptors by alkylation with acetylethylcholine mustard, or by blocking with atropine, reduced carbachol-stimulated adenylate cyclase activity more effectively than carbachol-induced phosphoinositide hydrolysis in both m1 and m3 receptor expressing cells. These findings imply that the receptor reserve in these cell lines is greater for phosphoinositide hydrolysis response than for adenylate cyclase response. Yet, the receptor reserve for each of these responses is similar in both m1 and m3 receptor expressing cells. Since the binding affinities of McN-A-343 and of oxotremorine to m1 and m3 receptors are very similar, and since both cell lines contain similar amounts of spare receptors, we propose that the preferential activation of muscarinic m1 over m3 receptor by partial agonists is related to differences in the abilities of the two receptor subtypes to undergo conformational changes following agonist binding. This hypothesis is supported by results showing that the muscarinic m1 but not m3 receptor exhibits two affinity states in a competition binding assay.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗