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B Enders

Publications and source records attributed to B Enders.

At least 19 recordsLinked to original sources
PubMed1998

Immunization of Aotus monkeys with recombinant Plasmodium falciparum hybrid proteins does not reproducibly result in protection from malaria infection.

Plasmodium falciparum antigens SERP, HRPII, MSAI, and 41-3 have shown promise as vaccine components. This study aimed at reproducing and extending previous results using three hybrid molecules. Antibody responses were reproduced in Aotus monkeys, but solid protection from a P. falciparum blood-stage challenge that showed an unintendedly enhanced pathogenicity was not observed.

Animals↗
PubMed1994

Role of diprotonated phosphate in evoking muscle reflex responses in cats and humans.

Lactic acid and H+ evoke muscle reflexes that raise sympathetic nerve activity. Whether these substances are direct afferent stimulants or markers for the acidification of other substances is unknown. Diprotonated phosphate (H2PO4-), a possible mediator of fatigue, increases as the cell acidifies and phosphate is produced. Its role in evoking muscle reflexes is unknown. We used 31P-nuclear magnetic resonance to measure forearm muscle H+ and H2PO4- and microneurography to measure muscle sympathetic nerve activity (MSNA, peroneal nerve) during a handgrip protocol designed to dissociate H+ from H2PO4-. Ischemic handgrip (50% maximal voluntary contraction x 2 min) was followed by a 1-min rest period during which the muscle was freely perfused. This was followed by a second bout of ischemic handgrip and a 5-min recovery. In seven of eight subjects, MSNA correlated with H2PO4-, whereas it correlated with pH in only one subject. To determine whether muscle reflex responses are evoked by H+, lactic acid, monoprotonated phosphate (HPO4(2-), or H2PO4-, we injected H+, lactate, H2PO4- [all 50 mM in 10 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) buffered to pH 6], and HPO4(2-) (50 mM, pH 7.5 in 10 mM HEPES) into the arterial supply of the triceps surae of the cat (n = 9) as we measured mean arterial blood pressure (MAP). H2PO4- increased MAP more than HPO4(2-), H+, or lactate (27.1 +/- 3.7 vs. 5.0 +/- 1.3, 4.6 +/- 3.1, and 7.7 +/- 3.2 rise in mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Comparison of the effects of adjuvants and adjuvant doses on the quantitative and qualitative antibody response to selected antigens in New World squirrel monkeys Saimiri sciureus.

The effect of several adjuvants and of adjuvant doses on the quantitative and qualitative antibody response to tetanus toxoid (TT) and a recombinant herpes simplex virus peptide (HSVgD) was evaluated in the New World monkey Saimiri sciureus. All adjuvant formulations were effective in inducing a strong antibody response to these antigens. The qualitative antibody response, as defined by monoclonal antibodies 3A2/G6 and 4G3/B5, was determined. Only 3A2/G6+ antibodies were induced after immunization with HSVgD irrespective of the adjuvant used and after immunization with TT alone. However, both types of antibodies were induced against TT in the presence of the adjuvants tested. These data suggest that both adjuvant and antigens can intervene in driving the quality of the antibody response induced after immunization. Strong antibody response to TT was induced at any adjuvant dose tested, suggesting that lower doses are as effective as higher doses. These findings can have implications on the design of future trials of vaccine candidate constructs in monkeys and eventually in human beings.

Adjuvants, Immunologic↗
PubMed1993

Acute and chronic antiarrhythmic efficacy of d-sotalol in patients with sustained ventricular tachyarrhythmias.

To evaluate the clinical efficacy of d-sotalol, 84 patients with a history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), who had inducible sustained VT/VT at baseline electrophysiologic study (EPS), were investigated after intravenous (IV) d-sotalol (1.5-2.5 mg.kg-1). A total of 29 additional patients received only oral d-sotalol, (400-600 mg.day-1). Acute success of antiarrhythmic therapy was defined as suppression of inducible sustained VT/VF. The overall success rate of IV d-sotalol was 38% (32/84) after a mean of 4.3 drugs failed to suppress inducibility. A 78% success rate (31/40) was demonstrated in patients who were also assessed after oral d-sotalol. Torsade de pointes type VT was seen in one patient. After 1 year, only 16% of patients with a positive EPS had a recurrence compared to 43% of patients with a negative EPS (P < 0.05). Estimated survival rates were 95 and 88% after 1 and 2 years of follow-up, respectively. Only five of 56 patients discontinued d-sotalol therapy because of adverse effects. IV d-sotalol appears to be an effective antiarrhythmic agent. Its long-term efficacy is predictable on the basis of therapy guided by electrophysiologic testing in patients with refractory ventricular tachyarrhythmias. The efficacy of d-sotalol seems comparable to that reported for d,l-sotalol.

Cardiac Pacing, Artificial↗
PubMed1993

Limb congestion and sympathoexcitation during exercise. Implications for congestive heart failure.

During static exercise, heart failure (HF) subjects activate the sympathetic nervous system differently than normal controls. HF causes metaboreceptor desensitization with either enhanced mechanoreceptor activity or central command. In this report, we examined whether increased muscle interstitial pressure, as seen in HF, augments other neural systems. We measured muscle sympathetic nerve activity (MSNA; peroneal nerve) in 10 normals during static exercise (40% maximal voluntary grip) and posthandgrip circulatory arrest (PHG-CA). This was repeated after venous congestion (VC; cuff inflation to 90 mmHg). VC increased forearm volume (plethysmography) by 4.7%. MSNA responses to exercise were greater after VC (150.5 +/- 41.8 vs. 317.3 +/- 69.9 arbitrary units; P < 0.01). However, MSNA responses during PHG-CA were not affected by VC, and 31P nuclear magnetic resonance (n = 5) demonstrated no effect of VC on pH or H2PO4-. Similar effects of VC on MSNA were noted after ischemic exercise (n = 7), excluding flow alterations as the explantation. VC probably sensitized mechanically sensitive afferents since MSNA during involuntary biceps contractions increased after VC (n = 6), and skin sympathetic nerve responses during handgrip, an index of central command, were not increased by VC (n = 6).

Adult↗
PubMed1992

Strategies for the development of an antimalarial vaccine.

Susceptible Aotus monkeys were immunized with Escherichia coli-derived fusion proteins containing partial sequences of the proteins MSAI, SERP, HRPII and with a group of three recombinant antigens isolated by screening with an antiserum raised against the protective 41 kDa protein band. HRPII, the combination of the fusion proteins of the 41 kDa group and a mixture of two sequences of SERP conferred significant protection against a challenge infection with Plasmodium falciparum blood stages. Based on the protective capacity of these recombinant antigens we have expressed two hybrid proteins (MS2/SERP/HRPII and SERP/MSAI/HRPII) in E. coli containing selected partial sequences. In two independent immunization trials it was shown that immunization of Aotus monkeys with either of the two hybrid proteins can protect the animals from an experimental P. falciparum infection.

Amino Acid Sequence↗
PubMed1992

Protection of Aotus monkeys from malaria infection by immunization with recombinant hybrid proteins.

On the basis of investigations of the malarial blood-stage antigens SERP, HRPII, and MSAI from Plasmodium falciparum, we chose two Escherichia coli-expressed hybrid proteins containing selected partial sequences of these antigens. Antibodies raised against both hybrid proteins in rabbits and Aotus monkeys recognize the corresponding P. falciparum polypeptides. In two independent trials with 13 animals, immunization of Aotus monkeys with either of the two hybrid proteins administered in a well-tolerated oil-based formulation protected the animals from an experimental P. falciparum infection.

Animals↗
PubMed1992

Protection of Aotus monkeys after immunization with recombinant antigens of Plasmodium falciparum.

The genus Aotus spp. (owl monkey) is one of the WHO recommended experimental models for Plasmodium falciparum blood stage infection, especially relevant for vaccination studies with asexual blood stage antigens of this parasite. For several immunization trials with purified recombinant merozoite/schizont antigens, the susceptible Aotus karyotypes II, III, IV and VI were immunized with Escherichia coli derived fusion proteins containing partial sequences of the proteins MSAI (merozoite surface antigen I), SERP (serine-stretch protein) and HRPII (histidine alanine rich protein II) as well as with a group of recombinant antigens obtained by an antiserum raised against a protective 41 kD protein band. The subcutaneous application (3x) of the antigen preparations was carried out in intact animals followed by splenectomy prior to challenge, in order to increase the susceptibility of the experimental hosts to the parasite. A partial sequence of HRPII, the combination of three different fusion proteins of the 41 kD group and a mixture of two sequences of SERP in the presence of a modified Al(OH)3 adjuvant conferred significant protection against a challenge infection with P. falciparum blood stages (2-5 x 10(6)) i. RBC). Monkeys immunized with the MS2-fusion protein carrying the N-terminal part of the 195 kD precursor of the major merozoite surface antigens induced only marginal protection showing some correlation between antibody titer and degree of parasitaemia. Based on the protective capacity of these recombinant antigens we have expressed two hybrid proteins (MS2/SERP/HRPII and SERP/MSAI/HRPII) in E. coli containing selected partial sequences of SERP, HRPII and MSAI. Antibodies raised against both hybrid proteins in rabbits and Aotus monkeys recognize the corresponding schizont polypeptides. In two independent immunization trials using 13 animals (age 7 months to 3 years) we could show that immunization of Aotus monkeys with either of the two hybrid proteins administered in an oil-based well tolerated formulation protected the animals from a severe experimental P. falciparum (strain Palo Alto) infection.

Amino Acid Sequence↗
PubMed1992

Effect of pH and inorganic phosphate on creatine kinase inactivation: an in vitro 31P NMR saturation-transfer study.

The pseudo-first-order rate constant of rabbit muscle creatine kinase (CK), in the direction of ATP synthesis (kf), was determined by saturation-transfer 31P NMR. When pH was varied between 6.0 and 7.4, kf increased linearly at both 20 degrees C and 37 degrees c. The corresponding flux is very small between pH 6.0 and 6.5, in contrast to previous studies. Up to 50 h exposure of the CK enzyme to high concentrations of inorganic phosphate (Pi), a known inhibitor in certain situations, had negligible effect on enzymatic flux in the physiological pH range. Thus under in vivo conditions, such as in stroke, where pH falls as low as 6.2 and Pi rises to high levels, the rate of the CK reaction may be severely reduced due to pH but not due to high Pi concentrations.

Adenosine Triphosphate↗
PubMed1991

Coagulation disorders in experimentally induced acute mouse malaria.

The development of coagulation disorders was studied in murine malaria. Plasmodium vinckei was chosen following an initial experiment because onset and duration of parasitemia were more suitable for hemostasiological studies than in the short-lasting infection, caused by P. berghei. Evaluation of the time courses of hematocrit, platelets, antithrombin (AT) III activity, Factor V activity and parasitemia showed a significant decrease in platelets, hematocrit, Factor V and AT III activity during the course of infection. The obtained data strongly suggest the development of a disseminated intravascular coagulation in mice during the terminal phase of murine malaria.

Animals↗
PubMed1991

A recombinant hybrid protein as antigen for an anti-blood stage malaria vaccine.

Based on investigations on several blood stage antigens from Plasmodium falciparum we have expressed a hybrid protein in E. coli containing 262 amino acids of the serine-stretch protein SERP and 189 amino acids of the histidine alanine rich protein HRPII. Antibodies raised against the hybrid protein by immunization of rabbits and Aotus monkeys react with both corresponding schizont polypeptides. Two Aotus monkeys immunized with the SERP/HRPII hybrid protein showed only low parasitemias after challenge infection with P. falciparum, compared to the control group. The result suggests that hybrid proteins of this type may be the basis for the development of a malaria vaccine.

Animals↗
PubMed1989

Antimalarial activity of new floxacrine-related acridinedione derivatives: studies on blood schizontocidal action of potential candidates against P. berghei in mice and P. falciparum in vivo and in vitro.

Deoxyfloxacrine derivatives (1-hydrazone: S 83 0083; 1-imine: S 84 7277) and floxacrine derivatives (10-methoxy-floxacrine: L 84 7667; 1-imine: L 84 7693) selected from a series of newly synthesized 3-aryl-7-chloro-3,4-dihydro-1,9(2H,10H)-acridinediones were evaluated for blood schizontocidal activities in mice infected with asexual stages of various drug-resistant lines of P. berghei and in New World monkeys infected with blood schizonts of different chloroquine-resistant strains of P. falciparum. All compounds tested showed high activity against drug-resistant lines of P. berghei (ED50: 1.0-4.4 mg/kg x 5, per os) and were distinctly superior in their antimalarial potency to floxacrine. Compounds L 84 7667 and L 84 7693 proved to be highly active against the FCBR strain of P. falciparum in vitro (IC50: 0.73-1.78 nmol); they effected temporary clearance of parasitemias due to the Palo Alto strain of P. falciparum in squirrel monkeys at oral doses of 15 mg/kg given daily for 5 consecutive days. Compounds S 83 0083 and S 84 7277, showing moderate in vitro effects (12.9-24.8 nmol), cleared parasitemias of the FCBR strain of P. falciparum in owl monkeys at oral doses of 20 mg/kg (S 84 7277) given daily for 5 or 7 consecutive days (follow-up period, 17 and 30 days, respectively) or at doses of 20 mg/kg (x 4) (S 83 0083) followed by doses of 40 mg/kg (x 3) within a follow-up period of 30 days. These observations suggest that the range of doses required for the cure of established P. falciparum infections is probably too large to cover infections with strains of the least susceptibility and might evoke toxic reactions by the potential candidates tested.

Acridines↗
PubMed1989

Antithrombin III substitution affects survival rate in a murine malaria model.

The effect of AT III substitution on survival time was studied in P. vinkei infected mice. One hundred mice were infected, randomly selected and allocated to two groups of 40 animals each on day 13 after infection. One group was placebo treated, the other group received 3 IU AT III daily on days 13 to 19. Comparison of the survival time in the log rank test showed a prolongation of the median survival time (5 versus 9 days, P less than 0.01). It is concluded that AT III might be beneficial in the treatment of severe malaria cases.

Animals↗
PubMed1988

A histidin alanine rich recombinant antigen protects Aotus monkeys from P. falciparum infection.

We have isolated a cDNA clone coding for 165 amino acids of a histidine alanine rich protein. An extended repeat region of this clone codes for the tripeptide Ala-His-His, which is extremely conserved, and for the tripeptide Ala-Ala-Asp, which shows only slight variability among the repeat units. This antigen exhibits high homology to the HRPII antigen described by Wellems and Howard (1986). The coding region was expressed in E. coli as a MS2-polymerase fusion protein, which was purified and used for immunization of Aotus monkeys. The animals immunized with this fusion protein showed only low parasitemias (less than 2%) after infection with P. falciparum, while animals from the control group or animals immunized with a MS2-fusion protein carrying other malaria specific sequences were not protected. The result suggests that this antigen is a good candidate for a malaria vaccine.

Amino Acid Sequence↗
PubMed1987

Trypanothione reductase from Trypanosoma cruzi. Purification and characterization of the crystalline enzyme.

The structural differences between trypanothione reductase of Trypanosoma cruzi and human glutathione reductase, an enzyme of known three-dimensional structure, offer an opportunity for rational drug design against Chagas' disease. As a first step in the analysis of the parasite enzyme we report its purification and characterization. 2.2 mg trypanothione reductase was extracted from 33 g wet weight of cultured epimastigotes or from 4 g lyophilized cells. The flavoenzyme was purified 2400-fold to homogeneity in three steps with an overall yield of 45%. The enzyme is a dimer with a subunit Mr of 50,000. Using NADPH (Km = 5 microM) and trypanothione disulfide (Km = 45 microM) as substrates, a turnover number of 14,200 min-1 was estimated. Trypanothione reductase, the parasite enzyme, and glutathione reductase, the host enzyme, exhibit mutually exclusive specificities for their respective disulfide substrates. When screening cell cultures or column eluates for the presence of trypanothione reductase, a microassay based on Ellman's reagent as indicator was used. A mixture of regioisomeric glutathionylspermidine disulfides isolated from Escherichia coli served as substrate in this microassay. Experimentally, the catalytic cycle of the enzyme can be subdivided into the half-reactions Eox + NADPH + H+----EH2 + NADP+, and EH2 + trypanothione disulfide----Eox + dihydrotrypanothione. This is also true for the crystallized enzyme in the presence of 2 M (NH4)2SO4. The spectral properties of trypanothione reductase both in the oxidized form (Eox) and in the two-electron-reduced form (EH2) closely resemble those of human glutathione reductase. Both proteins contain a flavin and a redox-active disulfide at the catalytic site. After reduction of Eox to EH2, trypanothione reductase can be inactivated by specifically alkylating one of the nascent active-site thiols.

Animals↗
PubMed1987

Toxic effect of isolated glycophorin A on the in vitro growth of Plasmodium falciparum.

We have examined the inhibitory potencies of glycophorin A, a mixture of glycophorins B and C, chymotryptic fragments of GpA, desialylated GpA, alkaliborohydride treated GpA, and the O-linked tetrasaccharide isolated from GpA on the invasion of human red blood cells by synchronous Plasmodium falciparum (strain FCB). 50% inhibition of invasion, as measured by 3H-hypoxanthine incorporation into parasites, was achieved at 14 and 155 microM for GpA and GpA-CH1, respectively. We have noticed, however, that isolated GpA exhibits a toxic effect on the intraerythrocytic growth of the parasite whereas the chymotryptic fragment (amino acid residues 1-64 of GpA) does not. Thus the inhibitory potency of isolated GpA during erythrocyte invasion by the merozoite should be regarded as the result of both an inhibitory and a toxic effect. The inhibitory effect should be attributed to the carbohydrate-rich outer portion of GpA carrying clusters of neuraminic acid. The toxic effect should be attributed to the hydrophobic region of GpA which might be capable of inserting into the membrane of free merozoites and/or erythrocytes. Our data suggest that results previously obtained with glycoprotein inhibitors carrying hydrophobic portions may have to be questioned.

Erythrocytes↗
PubMed1987

Intermediate host (Biomphalaria alexandrina) antigens partly protect against subcutaneous infections with cercariae of Schistosoma mansoni but are ineffective in infections by percutaneous invasion.

Mice were immunized against hepatopancreas homogenate of Biomphalaria alexandrina, using Al(OH)3 as adjuvant, and challenged by subcutaneous (s.c.) injection of Schistosoma mansoni cercariae, percutaneous invasion of cercariae and intravenous (i.v.) injection of mechanically prepared schistosomula of different ages. Significantly reduced (about 50%) numbers of adult S. mansoni were found 42 days after challenge in immunized animals infected by s.c. injection of cercariae. Protective effects were detectable as early as 4 days after infection when the numbers of schistosomules in the lungs were reduced in immunized animals. However, immunized animals lacked protective immunity against S. mansoni when infected via the percutaneous route with cercariae or by i.v. injection of schistosomules of different ages. Experiments show that immunization of hosts against intermediate host antigens does not protect against S. mansoni infection via the natural route.

Animals↗