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Biomedical subjects

S Levy

Publications and source records attributed to S Levy.

At least 109 records · Page 6Linked to original sources
PubMed1997

Dose-ranging study of the clinical efficacy of twice-daily triamcinolone acetonide inhalation aerosol in moderately severe asthma.

OBJECTIVES: This multicenter, double-blind, placebo-controlled study evaluated the dose response to 6 weeks of triamcinolone acetonide inhalation aerosol (TAA, 100 microg per puff) in patients with moderately severe asthma. STUDY DESIGN: A total of 285 patients were randomly assigned to treatment with 1, 2, 4, or 8 puffs TAA (total daily doses of 200, 400, 800, and 1,600 microg, respectively), administered twice daily, or matching placebos. Efficacy was assessed by changes in FEV1, asthma symptom scores, albuterol use, and peak flow rates. RESULTS: Linear trend analyses showed a dose response for all efficacy variables across the dose range of 200 to 1,600 microg daily. Therapeutic activity was evident at a dose of 200 microg daily for all variables, with significant clinical efficacy (p<0.05) demonstrated for all doses except for reduction in inhaled albuterol use which achieved statistical significance at 400 microg/d. Daily doses of 400 microg and higher showed response plateaus at 3 weeks of treatment that were maintained for the remainder of the trial. The incidence of adverse events was similar in all treatment groups, although more patients treated with TAA reported pharyngitis in a dose-related manner. CONCLUSIONS: Our findings suggest that most patients with chronic, moderately severe asthma can be treated adequately with doses of TAA between 200 microg (1 puff bid) and 800 microg (4 puffs bid) daily. At this dose range, clinically significant improvements are evident in symptoms, pulmonary function, and rescue medication use.

Administration, Inhalation↗
PubMed1997

The tetraspanin superfamily: molecular facilitators.

A legacy of molecular evolution is the formation of gene families encoding proteins that often serve related functions. One such family gaining recent attention is the tetraspanin superfamily, whose membership has grown to nearly 20 known genes since its discovery in 1990. All encode cell-surface proteins that span the membrane four times, forming two extracellular loops. Some of these genes are found in organisms as primitive as schistosomes and nematodes. Alternately known as the transmembrane 4 (TM4) superfamily or the TM4SF, 4TM, or tetraspan family, we propose here that the name tetraspanins be used for the purpose of standardization. What do the tetraspanins do? Awaiting definitive functional studies, we can only put together pieces of a puzzle that has been built by raising antibodies against these proteins and looking at their distribution, associations, and functions. A brief overview indicates that some tetraspanins are found in virtually all tissues (CD81, CD82, CD9, CD63), whereas others are highly restricted, such as CD37 (B cells) or CD53 (lymphoid and myeloid cells). Many of these proteins have a flair for promiscuous associations with other molecules, including lineage-specific proteins, integrins, and other tetraspanins. In terms of function, they are involved in diverse processes such as cell activation and proliferation, adhesion and motility, differentiation, and cancer. We propose that these functions may all relate to their ability to act as "molecular facilitators," grouping specific cell-surface proteins and thus increasing the formation and stability of functional signaling complexes.

Animals↗
PubMed1996

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↗
PubMed1996

Novel unconventional binding site in the variable region of immunoglobulins.

The variable immunoglobulin (Ig) domains contain hypervariable regions that are involved in the formation of the antigen binding site. Besides the canonical antigen binding site, so-called unconventional sites also reside in the variable region that bind bacterial and viral proteins. Docking to these unconventional sites does not typically interfere with antigen binding, which suggests that these sites may be a part of the biological functions of Igs. Herein, a novel unconventional binding site is described. The site is detected with 8-azidopurine nucleotide photoaffinity probes that label antibodies efficiently and under mild conditions. Tryptic peptides were isolated from photolabeled monoclonal antibodies and aligned with the variable antibody domains of heavy and light chains. The structure of a variable Ig fragment was used to model the binding of the purine nucleotide to invariant residues in a hydrophobic pocket of the Ig molecule at a location distant from the antigen binding site. Monoclonal and polyclonal antibodies were biotinylated with the photoaffinity linker and used in fluorescence-activated cell sorter and ELISA analyses. The data support the utility of this site for tethering diagnostic and therapeutic agents to the variable Ig fragment region without impairing the structural and functional integrity of antibodies.

Affinity Labels↗
PubMed1996

Dynamic simulations of the molecular conformations of wild type and mutant xanthan polymers suggest that conformational differences may contribute to observed differences in viscosity.

Xanthan gum is an exopolysaccharide secreted by the bacterium Xanthamonas campestris whose ability to make solutions viscous at low concentrations and over a pH and temperature range have generated much interest in both academic and industrial environments. Mutant Xanthamonas strains have been derived that produce xanthan gums with an altered or variant subunit chemical structure and different measured viscosities when compared with the wild type (wt) form of the polymer. Two variant gums were targeted as potentially interesting in this study, these being the nonacetylated tetramer (natet) and the acetylated tetramer (atet), which both lack a side-chain terminal mannose residue and in one case (natet) lacks an acetate group on an internal mannose residue. Solutions of these tetrameric gums possess viscosities higher (natet) and lower (atet) than the wt gum, and therefore we have attempted to determine whether these molecules possess unique conformational preferences when compared with the wt and with each other. In this manner we can initiate an understanding of how a polysaccharide's conformation contributes to its solution properties. The GEGOP software permits a sampling of the static and dynamic equilibrium states of carbohydrate molecules, and this software was employed to calculate equilibrium states of representative oligosaccharides with chemical structures representative of xanthan-like molecules. Energy minimization techniques revealed similar local minima for all three molecules. Some of these minima are comprised of elongate backbone conformations (A type) in which side chains fold onto backbone surfaces. Other minima with A backbones possessed side chains in less intimate backbone contact especially when calculations were performed with a low dielectric constant. This phenomenon was particularly pronounced in the wt molecule where an increased number of negatively charged side-chain residues experience charge repulsion resulting in reduced side-chain-backbone contact. Metropolis Monte Carlo (MMC) dynamic simulations performed with an elevated temperature factor (1000 K) allowed a better qualitative representation of conformational space than 300 K simulations. Employing a nonhierarchical cluster analysis method (population density profile: PDP) coupled with a classification scheme, it was possible to partition resulting MMC data sets into conformational families. This analysis revealed that in simulations performed with different dielectric constant values (10, 25, and infinity) all molecules possessed primarily A-type backbones. Less elongate, more open helical backbone forms (B, C, D, J, and Flat-a) did occur during the simulations but were populated to a lesser extent. In the natet molecule significantly open helical backbones existed (E, F, G, H, and I) that did not occur in the lower viscosity wt and atet molecules. PDP clustering methods and subsequent conformational classification applied to the first residue (mannose) of the side chain permitted a determination of side-chain orientation. Comparison of all three molecules indicated a larger population of side-chain conformational families in less direct backbone contact for the wt molecule than either of the variant molecules (natet/atet) suggesting that the side chains in the wt are more flexible. Thus, a major conformational difference between the high viscosity natet and the lower viscosities of the wt/atet is the increased amount of open helical backbone in the natet. In addition, the significant difference between the higher viscosity wt and the lower viscosity atet is the increase side-chain flexibility in the wt. We hypothesize that conformational differences of this kind could form a partial explanation of the observed differences in viscosity between these xanthan-like polymers.

Carbohydrate Conformation↗
PubMed1996

Ligation of TAPA-1 (CD81) or major histocompatibility complex class II in co-cultures of human B and T lymphocytes enhances interleukin-4 synthesis by antigen-specific CD4+ T cells.

We have previously shown that CD4+ T cells from allergic individuals are predisposed to producing interleukin (IL)-4 in response to allergens. IL-4 production could be modulated by antigen concentration as well as by the type of antigen-presenting cells (APC), with B lymphocytes inducing greater quantities of IL-4 than monocytes. Using this system we examined IL-4 synthesis after culture of CD4+ T cells with B cells, monocytes, or both, as APC in the presence of allergen and a monoclonal antibody against CD81 (TAPA-1), a member of the TM4 superfamily of proteins that regulates activation, proliferation and trafficking of B cells. Addition of anti-CD81 mAb during culture enhanced IL-4 synthesis by 2- to 70-fold over that using an isotype-matched control mAb. Furthermore, anti-CD81 mAb enhanced IL-4 synthesis in CD4+ T cells only when CD4+ T cells were cultured with B cells but not monocytes as APC, indicating that anti-CD81 mAb affected IL-4 synthesis in T cells via interactions with B cells. However, pretreatment of either population separately with anti-CD81 mAb prior to culture had no effect on subsequent IL-4 synthesis, suggesting a requirement for temporal or cooperative interactions between T and B lymphocytes. In addition, anti-CD81 mAb enhanced IL-4 production but reduced CD4+ T cell antigen-specific proliferation, demonstrating that IL-4 production and proliferation by CD4+ T cells were inversely related. Finally, mAb to major histocompatibility complex class II but not to anti-CD19 also enhanced IL-4 synthesis when B lymphocytes were used as APC. In all instances, enhancement of CD4+ IL-4 synthesis correlated with the presence of large cell aggregates in T-B lymphocyte cocultures. These results indicate that the capacity of B cells to induce IL-4 can be significantly enhanced by ligation of particular molecules on their surface and should aid in the design of treatments for diseases in which modulation of the cytokine profile would be beneficial.

Antibodies, Monoclonal↗
PubMed1996

Estrogen replacement may be an alternative to parathyroid surgery for the treatment of osteoporosis in elderly postmenopausal women presenting with primary hyperparathyroidism: a preliminary report.

Parathyroid surgery is indicated in patients presenting with primary hyperparathyroidism (PHPT) and osteoporosis (defined as bone mineral density more than 2 standard deviations below normal). Many are elderly women with complex medical problems, either unwilling or considered unfit for surgery. Estrogen replacement therapy (ERT) may potentially be an alternative form of therapy in this group. We studied 15 consecutive postmenopausal women presenting with PHPT and osteoporosis. Group 1 comprised 5 women who elected to be treated with ERT (conjugated equine estrogen, 0.3-0.625 mg/day). The other 10 women underwent successful parathyroidectomy. These 10 patients were randomly subdivided into group 2 (5 patients who received calcitriol 0.25 micrograms b.i.d. for 12 months following surgery) and group 3 (5 patients who received elemental calcium 1 g/day for 12 months following surgery). Lumbar spine and femoral neck bone mineral density (BMD) were measured prior to and after 12 months of therapy, using a dual-energy X-ray absorptiometer (Lunar DPX-L). The three groups did not differ with respect to their ages (group mean 71.8 years), or baseline serum calcium (group mean 2.77 mmol/l), serum parathyroid hormone (group mean 11.0 pmol/l), lumbar spine BMD (group mean 0.93 g/cm2) and femoral neck BMD (group mean 0.73 g/cm2). Serum calcium normalized in all patients who underwent surgery and none developed hypoparathyroidism. A non-significant decrease in serum calcium was seen in patients treated with ERT only. Lumbar spine (+5.3% per year; 95% CI, 1.1% to 9.6%) and femoral neck BMD (+5.5% per year; 95% CI, -2.1% to 13.2%) increased significantly after 12 months of ERT (p < 0.001 compared with pre-therapy values). These increases in BMD did not differ significantly from those in patients who underwent successful parathyroidectomy followed by either calcitriol therapy or calcium replacement (lumbar spine BMD increase of +6.2% per year, 95% CI 3.1% to 9.4%; and femoral neck BMD increase of +3% per year, 95% CI 0 to 6%). In summary, increases in lumbar spine and femoral neck BMD occur following treatment of PHPT. ERT appeared as effective as parathyroidectomy (combined with either calcitriol or calcium supplements) for the treatment of osteoporosis in elderly postmenopausal women presenting with PHPT.

Aged↗
PubMed1996

Complex SMAS-platysma and senility.

Following an anatomic study of 18 hemifaces, the authors show the modifications to and the behavior of the complex SMAS-platysma in the process of senility. Through this investigation, they succeeded in better understanding the anatomic modifications to the face's deep structures caused by the loss of tonicity and consequent flaccidity of the integument upon them. The investigation also showed the ligamentary fixations existing among the SMAS, the parotid-masseteric fascia, the major and minor zygomatic muscles, and the adherences of the platysma to the mandible periosteum.

Adult↗
PubMed1996

Limulus ventral photoreceptors contain two functionally dissimilar inositol triphosphate-induced calcium release mechanisms.

Injections of inositol 1,4,5 triphosphate (InsP3) into Limulus ventral photoreceptors give rise to a rapid depolarization and an elevation of intracellular calcium concentration (Cai). This response to InsP3 is followed by a period of desensitization that persists as long as Cai remains elevated (feedback inhibition). Limulus ventral photoreceptors have two types of lobe: a light-sensitive rhabdomeric lobe (R lobe), and a light-insensitive arhabdomeric lobe (A lobe). Evidence showing the presence of feedback inhibition has been so far demonstrated only in the R lobe. In this study, simultaneous measurements of Cai were made using aequorin and double-barreled calcium-sensitive electrodes in each type of lobe. We carefully checked the location of the R lobe and A lobe by scanning a microspot of light across the whole photoreceptor. We then inserted a double-barreled calcium-sensitive microelectrode with InsP3 in either type of lobe. In the R lobe, injections of InsP3 led to a large Cai increase, a rapid depolarization and feedback inhibition; a brief flash of light induced a rapid depolarization and a Cai increase measured by both aequorin and the calcium-sensitive electrode. In the A lobe, injection of InsP3 led to an increase in Cai measured by the calcium-sensitive electrode but to no depolarization or aequorin luminescence. Further there was no evidence of feedback inhibition in the A lobe; the elevation of Cai caused by the first injection did not desensitize the photoreceptor to a second injection of InsP3 3 s later. To verify that the aequorin and the cell membrane respond to an increase in Cai, we presented a brief flash of light. Following a uniform illumination, there is indeed a typical large luminescence increase and a receptor potential. The calcium-sensitive electrode measures a small and slow Cai increase because its tip is located in the A lobe and it is measuring Ca2+ diffusing from the R lobe. Our observation that the InsP3-induced Cai increase in the A lobe is not apparently accompanied by a subsequent desensitization to InsP3 may suggest that there are more than one type of InsP3 receptor in the same cell. Alternatively, the InsP3 receptor could be the same but some additional factor, which confers feedback inhibition, could be missing in the A lobe.

Aequorin↗
PubMed1995

Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators.

The efficacy of trimetazidine, an antianginal agent with a direct effect on ischemic myocardium, has been tested alone or in combination with beta blockers or nifedipine. The combination with diltiazem, a widely used calcium antagonist, has not been studied. The aim of this study was to evaluate the potential benefit of oral trimetazidine (20 mg 3 times daily) in combination with oral diltiazem (60 mg three times daily). This was a multicenter, placebo-controlled study with a follow-up period of 6 months. Patients with stable angina and a positive exercise electrocardiogram before and after 15 days of diltiazem therapy were included. The 67 patients were randomized to diltiazem plus placebo (group I, 35 patients) and diltiazem plus trimetazidine (group II, 32 patients). Follow-up included a bicycle ergometer maximal exercise test and a physical examination at inclusion and at 3 and 6 months. The 2 groups were similar in terms of ergometric parameters, except for the ischemic threshold, defined as the time to 1-mm ST-segment depression. The latter was shorter in group II. Comparison of exercise tests performed at inclusion and after 6 months of therapy in both groups showed that the ischemic threshold was significantly prolonged (2 minutes 41 seconds; p < 0.001) in group II. This was not the case for group I, which showed a 41-second prolongation only (difference not significant). The work (kPM) produced at 1-mm ST-segment depression was also significantly increased in group II (1,445.9 kPM; p < 0.001) compared with group I (563.7 kPM; p = 0.012).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Circular dichroism of ferriprotoporphyrin IX-morphine complexes in aqueous solution.

Complexes of ferriprotoporphyrin IX (FP) with (-)-morphine exhibit large optical activity in aqueous solution. Several CD bands of different signs were recorded under different conditions in the wavelength range of 300 to 450 nm. The largest CD band, centered at about 364 nm, showed molar ellipticities of about -5 x 10(5) deg.cm2.dmol-1 based on FP (rotational strength of about -3 DBM). An optimum pH range of 7.4 to 7.8 with regard to optical activity of the complex has been observed. Concomitantly with the formation of optically active complexes, large aggregates are being formed as determined by ultracentrifugation. A mole ratio of 1 between FP and morphine in the complex was estimated from both CD titration and measurement of the amounts of aggregate formed upon variation of the mole fraction of the complex components. Derivatives of morphine such as heroin or codeine do not form optically active complexes and aggregates under similar conditions. As in the analogous FP-quinine and FP-quinidine complexes investigated previously, the optical activity observed is considered to originate at least in part from optical interactions between FP molecules arrayed chirally in the FP-(-)-morphine aggregates.

Circular Dichroism↗
PubMed1995

[Comparative effects of cibenzoline and hydroquinidine in the prevention of auricular fibrillation. A randomized double-blind study].

The objective of this study was to compare the efficacy and safety of cibenzoline (130 mg twice a day) and sustained-release hydroquinidine (300 mg twice a day) in the prevention of recurrent atrial fibrillation (AF). This randomized double-blind study was conducted in 87 patients, with a mean age of 62 years, presenting with a history of AF for 72 hours to a maximum of 3 years. After restoration of sinus rhythm, in order for the subjects to be included in the study, echocardiography had to reveal a left ventricular shortening fraction of more than 20%. Patients were followed for one year by clinical examination, ECG and 24-hour Holter monitoring performed 7 days after inclusion, then after 3, 6, 9 and 12 months. The two groups, treated with either cibenzoline (n = 40) or hydroquinidine (n = 44), were comparable. The AF recurrence rates with cibenzoline or hydroquinidine were 34.9% had 36.4% at 6 months, and 41.9% and 43.2% at 12 months, respectively (NS). Most recurrences occurred during the first month. Adverse effects were reported in 10 patients (23.3%) with cibenzoline and 12 patients (27.3%) with hydroquinidine. They led to discontinuation of treatment in 6 patients (14%) treated with cibenzoline and 5 patients (11.4%) treated with hydroquinidine. Serious adverse events included one death from hypoglycaemic coma and one case of persistent ventricular tachycardia with hydroquinidine. In conclusion, oral cibenzoline demonstrated the same antiarrhythmic activity as hydroquinidine in the long-term prevention of recurrent atrial fibrillation, with a similar degree of safety. This drug can therefore constitute an alternative to conventional antiarrhythmics in this context.

Adult↗
PubMed1995

A phase I and pharmacokinetic study of a new camptothecin derivative, 9-aminocamptothecin.

Camptothecins are the only available antitumor agents which target the nuclear enzyme topoisomerase I. 9-Aminocamptothecin (9-AC) is a water-insoluble derivative of camptothecin which has demonstrated impressive antitumor activity in preclinical models. While two other water-soluble derivatives, CPT-11 and topotecan, have successfully completed Phase I and Phase II testing, biochemical and tissue culture studies suggest that camptothecin analogues differ in characteristics which may be important in determining antitumor activity. We performed a Phase I trial of 9-AC to determine the pharmacokinetics, dose-limiting toxicity, and maximum tolerated dose of this agent when administered as a 72-h continuous i.v. infusion. Thirty-one patients with resistant solid cancers received 5-60 microgram/m2/h 9-AC for 72 h, repeated at 3-week intervals. The drug was administered in a vehicle containing dimethylacetamide, polyethylene glycol, and phosphoric acid. Blood samples were collected and the lactone (closed ring) form of 9-AC was quantitated. The maximum tolerated dose of 9-AC was determined to be 45 microgram/m2/h. Dose-limiting toxicity consisted of neutropenia. Thrombocytopenia was also prominent. There were no significant nonhematological toxicities. Minimal responses were seen in patients with gastric, colon, and non-small cell lung cancer. Although significant interpatient variation in plasma 9-AC lactone levels was observed, pooled data were fit to a two-compartment model, with a terminal half-life of 36 h. Analyses of topoisomerase protein levels in peripheral blood cells indicated decreases in topoisomerase I accompanied by increases in topoisomerase II in two of three patients. 9-AC is an active antitumor agent and may be administered safely as a 72-h infusion in patients with cancer. Although Phase II trials with a 72-h infusion of 9-AC are warranted, alternate schedules should be evaluated given the dramatic preclinical activity seen with more prolonged administrations.

Adult↗
PubMed1994

The use of HPLC to evaluate the variations of blood coronary adenosine levels during percutaneous transluminal angioplasty.

Although it is well established that adenosine is released during acute ischemia, little is known of the behaviour of adenosine levels following treatment of coronary lesion by percutaneous transluminal coronary angioplasty (PTCA). Using high performance liquid chromatography, we measured intracoronary adenosine levels before and 5 min after PTCA in ten patients with one-vessel disease and a significant (> 70%) coronary stenosis. Adenosine levels decrease in all patients after PTCA. Nevertheless, more studies are now necessary to evaluate the possible predictive value (with regard to restenosis) of coronary adenosine levels after PTCA.

Adenosine↗
PubMed1994

The fluoride content of bottled drinking waters.

Sales of bottled drinking waters in the United Kingdom have tripled over the last 5 years. The fluoride content of 12 bottled waters purchased from two Leeds supermarkets was determined by both the direct and acid diffusion methods and found to vary from 0.10-0.80 mg/l fluoride (ie ppm fluoride). This article shows that bottled drinking waters contain differing concentrations of fluoride. There is no apparent difference between the direct and acid diffusion methods for the determination of fluoride concentrations of drinking waters. The manufacturers' labelling of fluoride concentrations are mainly inaccurate. Dentists should be aware of the fluoride concentrations of the drinking water of their child patients, be they municipal or bottled drinking water, when prescribing fluoride supplements. Also, some parents are using bottled waters to prepare baby milk formulations which themselves may contain high levels of fluoride and subject their children to the risk of dental fluorosis.

Fluorides↗