Misoprostol dose and route after mifepristone for early medical abortion: a randomised controlled noninferiority trial.

OBJECTIVE: To compare 400 and 800 microg sublingual or vaginal misoprostol 24 hours after 200 mg mifepristone for noninferiority regarding efficacy in achieving complete abortion for pregnancy termination up to 63 days of gestation. DESIGN: Placebo-controlled, randomised, noninferiority factorial trial, stratified by centre and length of gestation. Misoprostol 400 or 800 microg, administered either sublingually or vaginally, with follow up after 2 and 6 weeks. SETTING: Fifteen obstetrics/gynaecology departments in ten countries. POPULATION: Pregnant women (n = 3005) up to 63 days of gestation requesting medical abortion. METHODS: Two-sided 95% CI for differences in failure of complete abortion and continuing pregnancy, with a 3% noninferiority margin, were calculated. Proportions of women with adverse effects were recorded. OUTCOME MEASURES: Complete abortion without surgical intervention (main); continuing live pregnancies, induction-to-abortion interval, adverse effects, women's perceptions (secondary). RESULTS: Efficacy outcomes analysed for 2962 women (98.6%): 90.5% had complete abortion after 400 microg misoprostol, 94.2% after 800 microg. Noninferiority of 400 microg misoprostol was not demonstrated for failure of complete abortion (difference: 3.7%; 95% CI 1.8-5.6%). The 400-microg dose showed higher risk of incomplete abortion (P < 0.01) and continuing pregnancy (P < 0.01) than 800 microg. Vaginal and sublingual routes had similar risks of failure to achieve complete abortion (P = 0.47, difference in sublingual minus vaginal -0.7%, 95% CI -2.6-1.2%). A similar pattern was observed for continuing pregnancies (P = 0.21). Fewer women reported adverse effects with vaginal than sublingual administration and with the 400-microg dose than the 800-microg dose. Of the women, 94% were satisfied or highly satisfied with the regimens, 53% preferred the sublingual route and 47% preferred the vaginal route. CONCLUSIONS: A 400-microg dose of misoprostol should not replace the 800-microg dose when administered 24 hours after 200 mg mifepristone for inducing abortion in pregnancies up to 63 days. Sublingual and vaginal misoprostol have similar efficacy, but vaginal administration is associated with a lower frequency of adverse effects.

Sleep disordered breathing and nocturnal hypoxemia are very prevalent in a lung cancer screening population and may condition lung cancer screening findings: results of the prospective Sleep Apnea In Lung Cancer Screening (SAILS) study.

OBJECTIVE: Obstructive sleep apnea (OSA) can influence the appearance and proliferation of some tumors. The Sleep Apnea In Lung Cancer Screening (SAILS) study (NCT02764866) evaluated the prevalence of OSA and nocturnal hypoxemia in a high-risk population enrolled in a lung cancer screening program. METHODS: This was a prospective study of the prevalence of OSA in a lung cancer screening program. Subjects met the National Lung Screening Trial (NLST) age and smoking criteria (age 55-75 years; pack-years >30). Participants in the study were offered annual screening with low-dose computed tomography (LDCT) and pulmonary function testing, as well as home sleep apnea testing (HSAT) and a sleep-specific questionnaire. Sleep study-related variables, symptoms, and epidemiologic data were recorded. RESULTS: HSAT was offered to 279 subjects enrolled in our lung cancer screening program. HSAT results were available for 236 participants (mean age 63.6 years; mean tobacco exposure: 45 pack-years), of whom 59% were male and 53% were active smokers. Emphysema (74%) and chronic obstructive pulmonary disease (COPD) (62%) were common and in most cases mild in severity. OSA, including moderate to severe disease, was very common in this patient population. AHI distributions were as follows: AHI <5 (22.5%); 5-15 (36.4%); 15-30 (23.3%); and >30 (17.8%). Nocturnal hypoxemia (T90) (p = 0.003), diffusing capacity for carbon monoxide (DLCO) (p = 0.01), tobacco exposure (p = 0.024), and COPD (p = 0.023) were associated with OSA severity. Positive screening findings (nodules ≥6 mm) were associated with nocturnal hypoxemia on multivariate analysis adjusted for confounders (OR = 2.6, 95% CI = 1.12-6.09, p = 0.027). CONCLUSION: Moderate to severe OSA is very prevalent in patients enrolled in a lung cancer screening program. Nocturnal hypoxemia more than doubles the risk of positive screening findings.

Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing fabs.

BACKGROUND: The third hypervariable (V3) loop of HIV-1 gp120 has been termed the principal neutralizing determinant (PND) of the virus and is involved in many aspects of virus infectivity. The V3 loop is required for viral entry into the cell via membrane fusion and is believed to interact with cell surface chemokine receptors on T cells and macrophages. Sequence changes in V3 can affect chemokine receptor usage, and can, therefore, modulate which types of cells are infected. Antibodies raised against peptides with V3 sequences can neutralize laboratory-adapted strains of the virus and inhibit syncytia formation. Fab fragments of these neutralizing antibodies in complex with V3 loop peptides have been studied by X-ray crystallography to determine the conformation of the V3 loop. RESULTS: We have determined three crystal structures of Fab 58.2, a broadly neutralizing antibody, in complex with one linear and two cyclic peptides the amino acid sequence of which comes from the MN isolate of the gp120 V3 loop. Although the peptide conformations are very similar for the linear and cyclic forms, they differ from that seen for the identical peptide bound to a different broadly neutralizing antibody, Fab 59.1, and for a similar peptide bound to the MN-specific Fab 50.1. The conformational difference in the peptide is localized around residues Gly-Pro-Gly-Arg, which are highly conserved in different HIV-1 isolates and are predicted to adopt a type II beta turn. CONCLUSIONS: The V3 loop can adopt at least two different conformations for the highly conserved Gly-Pro-Gly-Arg sequence at the tip of the loop. Thus, the HIV-1 V3 loop has some inherent conformational flexibility that may relate to its biological function.

WITHDRAWN: Response from original author: Reproducibility of first trimester three-dimensional placental measurements; a methodological issue.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, DOI of original article: http://dx.doi.org/10.1016/j.ejogrb.2016.07.485. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Short side chain sterols from the tunicate Polizoa opuntia.

The sterol composition of the Patagonian tunicate Polizoa opuntia was examined, and twenty-four compounds were identified as having either a delta 5, delta 7, or delta 0 nucleus. Two of them, the rare 20-methylpregn-5-en-3 beta-ol and 20-ethylpregn-5-en-3 beta-ol, were previously unreported as natural products from tunicates. These compounds were present only as trace components; therefore, their structures were confirmed by synthesis from suitable precursors and by comparison of the spectral and chromatographic constants of the synthetic and natural compounds.

Misoprostol 3, 4, or 5 days after methotrexate for early abortion. A randomized trial.

A randomized trial was conducted including 287 pregnant women seeking elective abortion to compare the efficacy of misoprostol given 3, 4, or 5 days after methotrexate for abortion at < or = 63 days' gestation. Subjects received 50 mg/m2 methotrexate intramuscularly and were randomly allocated to self-administer vaginally 800 micrograms of misoprostol 3, 4, or 5 days after the methotrexate. The misoprostol dose was repeated 48 and 96 h later if the abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), and side effects. Eighty-six cases (93%; 95% confidence interval [CI] 85%-97%) aborted in Group I; 90 cases (92%; 95% CI 84%-96%) aborted in Group II (relative risk [RR] = 1.09; RR 95% CI 0.38-3.14); and 89 (93%; 95% CI 86%-97%) cases aborted in Group III (RR = 0.97; RR 95% CI 0.33-2.87). No significant statistical differences were obtained for the success rates when misoprostol was given days 3, 4, or 5 after the administration of methotrexate (p = 0.97) nor with any of the characteristics of the subjects. Complete abortion occurred in 265/287 (92%; 95% CI 89%-95%) patients. Twenty-two cases (8%; 95% CI 5%-11%) resulted in failure. Side effects for methotrexate were minimal while for misoprostol they were moderate. This combination could be an alternative to surgical abortion or the use of antiprogestins and prostaglandins for medical abortion.

PIP: A randomized trial was conducted including 287 pregnant women seeking elective abortion to compare the efficacy of misoprostol given 3, 4, or 5 days after methotrexate for abortion at 63 days or less gestation. Subjects received 50 mg/sq. m methotrexate intramuscularly and were randomly allocated to self-administer vaginally 800 mcg of misoprostol 3, 4, or 5 days after methotrexate administration. The misoprostol dose was repeated 48 and 96 hours later if the abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure) and side effects. 86 cases [93%; 95% confidence interval (CI), 85-97%] aborted in Group I; 90 cases (92%; 95% CI, 84-96%) aborted in Group II [relative risk (RR) = 1.09; RR 95% CI, 0.38-3.14]; and 89 cases (93%; 95% CI, 86-97%) aborted in Group III (RR = 0.97; RR 95% CI, 0.33-2.87). No significant statistical differences were obtained for the success rates when misoprostol was given days 3, 4, or 5 after methotrexate administration (p = 0.97) nor with any of the characteristics of the subjects. Complete abortion occurred in 265/287 patients (92%; 95% CI, 89-95%). 22 cases (8%; 95% CI, 5-11%) resulted in failure. Side effects for methotrexate were minimal, while for misoprostol they were moderate. This combination could be an alternative to surgical abortion or the use of antiprogestins and prostaglandins for medical abortion.

Early abortion with 800 micrograms of misoprostol by the vaginal route.

The objective of this study was to confirm the effectiveness and safety of self-administration of misoprostol every 24 h, for abortion up to 9 weeks of gestation. A group of 720 volunteer subjects with gestations from 35 to 63 days received 800 micrograms of vaginal misoprostol every 24 h up to a maximum of three main doses for abortion. Outcome measures assessed included successful abortion (complete abortion without requiring surgery), side effects, decrease in hemoglobin, mean time of vaginal bleeding, and mean time of return of menses. Complete abortion occurred in 644 of 720 (89.4%, 95% CI 87, 92) subjects. The mean decrease in hemoglobin was statistically significant (p = 0.0001). There were 14 subjects with clinically significant decreases in hemoglobin, but only two required transfusions. Vaginal bleeding lasted 6.7 +/- 3.9 days, spotting 8.1 +/- 4 days, and total bleeding 14 +/- 5.3 days. Mean expulsion time was 8.0 +/- 3.4 h. Although mifepristone remains unavailable, given the low price and availability of misoprostol in > 72 countries of the world, this latter drug constitutes an abortion alternative, provided that a minimum clinical network is nearby or accessible.

Oral methotrexate and vaginal misoprostol for early abortion.

A prospective trial including 300 pregnant women seeking elective abortion was conducted to evaluate the safety and efficacy of methotrexate and misoprostol for abortion at < or = 63 days' gestation. Subjects received methotrexate 50 mg orally and were randomly allocated to receive 800 micrograms of misoprostol vaginally 3, 4, or 5 days after administration of the methotrexate. The misoprostol dose was repeated 48 and 96 h later if abortion did not occur. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure) and side effects. Complete abortion occurred in 273 of 300 patients (91%, 95%, CI 87, 94%) patients. No significant statistical differences were found in the success rates when misoprostol was given days 3, 4, or 5 after the administration of methotrexate (p = 0.69). Vaginal bleeding lasted 7.1 +/- 3.8 days, spotting 4.1 +/- 2.5 days, and total bleeding 11.2 +/- 4.1 days. Side effects for methotrexate were minimal, whereas, for misoprostol they were mild and transient except for pain. The use of methotrexate and misoprostol together could be an alternative to the intramuscular use of methotrexate or the use of antiprogestins and prostaglandin for medical abortion.

PIP: The safety and effectiveness of oral methotrexate and vaginal misoprostol for early abortion were evaluated in a prospective study of 300 women who presented to the Cuidad de la Habana (Havana, Cuba) for termination of a pregnancy of a gestational age of 63 days or less. All women were given 50 mg of methotrexate at study entry and then were randomly allocated to receive 800 mcg of misoprostol either 3, 4, or 5 days later. If abortion did not occur, misoprostol was readministered 48 and 96 hours later. Complete abortion occurred in 273 women (91%); the success rate was 72% (216 cases) after just one dose of misoprostol. There were no significant differences in abortion rates based on the day on which misoprostol was administered. Vaginal bleeding lasted an average of 7.1 +or- 3.8 days, spotting continued for 4.1 +or- 2.5 days, and total bleeding persisted for 11.2 +or- 4.1 days. Side effects for methotrexate included nausea (9.7%), vomiting (6.7%), dizziness (10.3%), fatigue (6.3%), headache (5.3%), and chills (5.3%). For misoprostol, side effects included nausea (23.0%), vomiting (25.3%), diarrhea (51.7%), dizziness (18.3%), headache (18.0%), chills (60.0%), and pelvic pain (97.3%). All signs and symptoms were of low intensity and short duration, however. These results suggest that combined use of methotrexate and misoprostol represents a feasible alternative to the intramuscular use of methotrexate or of antiprogestins and prostaglandin for medical abortion. The efficacy and safety of this new regimen are very close to those of RU-486, but the cost is considerably less.

Vaginal misoprostol for late first trimester abortion.

A group of 120 women with gestations from 64 to 84 days received 800 micrograms of vaginal misoprostol every 24 h for a maximum of three doses without performing postexpulsion systematic preventive curettage. Outcome measures included successful abortion (complete abortion without requiring a surgical procedure), side effects, and mean time of expulsion and vaginal bleeding. Complete abortion occurred in 104 of 120 (87%, 95% CI 79, 92) subjects. The decrease of hemoglobin was statistically significant (p = 0.0001) but clinically unimportant: 12.2 mg/dL (SD 1.1) before treatment and 11.6 mg/dL (SD 1.0) after treatment. Statistically significant differences were found only between the success rates for white women in comparison with nonwhite women, in which case the success rates were higher for white than for nonwhite women. Vaginal bleeding lasted 8 +/- 5 days, spotting 4 +/- 3, and total bleeding 12 +/- 4 days. The acceptable expulsion time, the fact that postabortion systematic curettage was not needed, the clinically insignificant hemoglobin loss, and the success rate obtained show that misoprostol administered vaginally may be a valid method for interrupting gestations of 10-12 weeks.

PIP: The effectiveness and safety of vaginal misoprostol, without the need for postexpulsion systematic curettage, were investigated in 120 Cuban women seeking late first-trimester abortion (10-12 weeks). Women received 800 mcg of misoprostol vaginally every 24 hours, for a maximum of three doses. Complete abortion occurred in 104 women (87%); 87 women (73%) aborted after a single dose, 11 (9%) required two doses, and 6 (5%) received a third dose. The remaining 16 women (13%) underwent surgical abortion. Mean hemoglobin decreased from 12.2 mg/dl before treatment to 11.6 mg/dl after abortion--a difference that was statistically but not clinically significant. Side effects--which disappeared within 2 hours--included nausea (22%), vomiting (17%), diarrhea (54%), dizziness (25%), headache (19%), and chills (72%). Although 99% of subjects reported pelvic pain (99%), only 10% requested an analgesic for pain relief. Vaginal bleeding persisted for a mean of 8 days. According to logistic regression analysis, the only variable significantly associated with treatment success was race. The success rate was 94% among White women compared with 73% among Black and Black Cuban women. The acceptable expulsion period, the fact that a postabortion systematic curettage was not required, the clinically insignificant hemoglobin loss, and the high success rate all demonstrate that misoprostol administered vaginally may be a valid method for interrupting late first-trimester pregnancies.

Medical versus surgical abortion.

OBJECTIVE: To evaluate the safety, efficacy, and acceptability of an oral drug regimen of medical abortion compared with surgical abortion. MATERIALS AND METHODS: 500 women with amenorrhea < 56 days chose either surgical abortion or 600 mg of mifepristone (RU-486) followed by 400 microg of misoprostol after 48 h. RESULTS: Medical regimen had more side effects than surgical abortion, including bleeding, cramping, nausea and vomiting. Only fever was more frequent in the surgical method. The failure rates for medical abortion exceeded those for surgical abortion, 16.0% vs. 4.0%. The adolescents' failure rate in the medical regimen group was only 1.7%. Several failures on medical abortion were not true drug failures, but surgical interventions not medically necessary (misdiagnosis). Women were satisfied with either method, but more preferred medical abortion. CONCLUSION: Medical methods are safe, effective, simpler and potentially allow greater privacy than surgical abortion methods. Therefore, medical methods could be the method of choice for abortion, particularly for adolescents.

Present and future of maternal mortality in Latin America.

Twenty-three thousand maternal deaths per year in Latin America and the Caribbean reflects clearly the critical situation in this part of the world. Although we don't know exactly how many women die every year from pregnancy and childbirth, it is clear that the majority of these women are from low socioeconomic backgrounds, live in remote places and have a low level of education. Hemorrhages, infections and hypertension induced by pregnancy are the most common causes of maternal mortality. These pathologies can in many cases be prevented if there is a will for a positive change that involves different sectors related with health. The role of the scientific societies, and the role of FIGO through the 'Save the Mothers' Project are of extreme importance, assuming a chief role and compromise that can help in the right way to be able to revert this situation.

[Orbital endoscopic surgery: experimental model for foreign bodies extraction]. / Cirugía endoscópica de la órbita: modelo experimental para extracción de cuerpos extraños.

PURPOSE: Endoscopy is a useful technique that may be applied to study orbital pathology because it is safe. In this paper we describe the surgical technique using endoscopy for orbital foreign body extraction. METHODS: In an experimental model in the dog we inserted a spheric metallic foreign body into the intraconal portion of the orbit. After general anesthesia we performed a 2 mm. peritomy in the conjuntiva. Then we introduced the optic system connected to a TV monitor. Associated to the optic system we fixed a 14-G Abbocath to introduce a 1.7 mm foreign body forceps. RESULTS: After a complete endoscopic exam of the orbit we identified the metallic foreign body. With the 1.7 mm forceps we could take out the foreign body. The extractions were very simple and the technique was not traumatic for the orbit. CONCLUSIONS: Endoscopic surgery of the orbit is a useful and safe technique to extract orbital foreign bodies in this experimental model.

[Experimental study about the effects of exploratory endoscopical technique on the posterior orbit]. / Estudio experimental sobre la aplicación de la técnica exploratoria endoscópica en la órbita posterior.

PURPOSE: To determine the effects of the orbital endoscopic technique in the dog (IOP, vascularization). METHODS: Eight dogs were used to examine the four quadrants of the posterior orbit that we have established as a theoretical division of the orbit. Thus, two examinations were performed for each region. In order to observe the effects of the current technique, a rigorous control on the visual parameters was established, paying special attention to the effects of the blood supply in the vessels of the eyeball, measuring the posterior ciliary arteries (in the dog, the central artery of the retina is very rudimentary) with the Doppler color and Power Doppler echography. RESULTS: The results compiled on the examination of the visual function, ocular mobility, the general examination of reflexes, examination of the ocular fundus and general condition did not show any significant alteration. Conjunctival chemosis occurred in one case, but spontaneously disappeared 76 hours after the operation. The IOP only showed a mild increase after the surgery in two cases. The PSV and EDV blood flow values increased in the immediate post-surgery, above all in the vessel belonging to the region operated in 6 out the 8 subjects, but had decreased at 7 days post-surgery. CONCLUSIONS: The results obtained did not show any significant alterations when the orbital endoscopic technique for the posterior orbit was used. A mild increase is observed in the blood velocity values of the posterior ciliary arteries after the surgery that seems to indicate a certain compression. However, these values are reduced significantly when the method is repeated within 7 days.

Effects of free fatty acid infusion on rabbit pulmonary surfactant. Influence of corticosteroids.

We studied the effect of free fatty acids (FFA) i.v. on alveolar lung surfactant content of rabbits. A FFA mixture was given in doses from 0.1 to 20 mg X kg-1 X min-1 during 15 min in seven different experimental series (n = 45). Disaturated phosphatidylcholine (DSPC) content in lung airway lavage fluid was measured as an index of alveolar surfactant pool. DSPC was significantly increased (p less than 0.05) by 86% in the series receiving 20 mg FFA X kg-1 X min-1 as compared to control values (means +/- SD: 4.4 +/- 1.1 mg DSPC X kg-1 body weight). Smaller doses of FFA did not change DSPC, but induced a dose-related pulmonary oedema. All the rabbits receiving 20 mg FFA X kg-1 X min-1 died before completion of the 15 min infusion; they were hypoxaemic, hyperventilated and had a decrease in lung compliance. Hydrocortisone (20 mg X kg-1 i.v.) and methylprednisolone (30 mg X kg-1 i.v.) administered 2 h before FFA blocked the increase of DSPC induced by 20 mg FFA X kg-1 X min-1. Both drugs decreased pulmonary oedema and tended to normalize some of the pulmonary function indices, although they did not modify the lethality. In conclusion, acute i.v. infusion of FFA increased alveolar surfactant pool and produced pulmonary oedema; pretreatment with corticosteroids reduced these effects and protected the lung from some of the noxious effects of FFA.

A structure-based approach to a synthetic vaccine for HIV-1.

The generation of neutralizing antibodies by peptide immunization is dependent on achieving conformational compatibility between antibodies and native protein. Consequently, approaches are needed for developing conformational mimics of protein neutralization sites. We replace putative main-chain hydrogen bonds (NH --> O=CRNH) with a hydrazone link (N-N=CH-CH(2)CH(2)) and scan constrained peptides for fit with neutralizing monoclonal antibodies (MAbs). To explore this approach, a V3 MAb 58.2 that potently neutralizes T-cell lab-adapted HIV-1(MN) was used to identify a cyclic peptide, [JHIGPGR(Aib)F(D-Ala)GZ]G-NH(2) (loop 5), that binds with >1000-fold higher affinity than the unconstrained peptide. NMR structural studies suggested that loop 5 stabilized beta-turns at GPGR and R(Aib)F(D-Ala) in aqueous solvent implying considerable conformational mimicry of a Fab 58.2 bound V3 peptide determined by X-ray crystallography [Stanfield, R. L. et al. (1999) Structure 142, 131-142]. Rabbit polyclonal antibodies (PAbs) generated to loop 5 but not to the corresponding uncyclized peptide bound the HIV-1(MN) envelope glycoprotein, gp120. When individual rabbit antisera were scanned with linear and cyclic peptides, further animal-to-animal differences in antibody populations were characterized. Loop 5 PAbs that most closely mimicked MAb 58.2 neutralized HIV-1(MN) with similar potency. These results demonstrate the remarkable effect that conformation can have on peptide affinity and immunogenicity and identify an approach that can be used to achieve these results. The implications for synthetic vaccine and HIV-1 vaccine research are discussed.

Studying the acceptability and feasibility of medical abortion.

PIP: Various approaches of measuring acceptability used in contraception research can be used to measure acceptability of abortions induced by RU-486. The primary acceptance method determines whether women will or will not choose RU-486 in the absence of other abortion methods, if offered it, and how many women will indeed undergo a medical abortion. The comparative acceptance method determines how many women will choose RU-486 if other methods are available. Another acceptability approach is interviewing women to learn if they suffered any side effects or have any complaints. Researchers can also see if women think that they would choose RU-486 again should the need arise. This method would work best with women who have undergone both surgical and medical abortions. It is important to examine acceptability because medical service delivery systems in developing countries cannot always perform safe and effective surgical abortions and individual choice is important in matters concerning stressful and intimate issues, such as abortion. Research is beginning to show that women in both developed and developing countries tend to be motivated by the same issues when choosing RU-486 over surgical abortion. For example, women in Cuba, India, and Europe chose RU-486 because it avoids surgery and hospital admission and is easy and convenient. More than 90% of the women in studies in India and Cuba considered their RU-486 experience to be at least satisfactory. 83% who had earlier undergone a surgical abortion preferred RU-486 induced abortion. 90% of repeat abortion seekers would choose RU-486 again. Feasibility studies examine whether medical institutions can handle medical abortion technology. Feasibility depends on cost, clinic facilities (e.g., availability of sonograms), clinic management, professional training, and the presence of back-up systems (e.g., high quality surgical services with transfusion capability). Researchers also need to determine whether medical abortion burdens medical systems and patients.^ieng

Induction of protective immunity against experimental infection with malaria using synthetic peptides.

Synthetic peptides are potential vaccine candidates because they may be able to induce high antibody titres and specific cellular immune responses against native proteins and thus the whole invading organism. In a previous study we showed that immunization with molecules of relative molecular mass (Mr) 155,000 (155K) 83K, 55K and 35K, specific for the late schizont and merozoite stages of Plasmodium falciparum, could elicit either partial or total protection in Aotus trivirgatus monkeys experimentally infected with P. falciparum. Here we have chemically synthesized 18 peptides corresponding to different fragments of these proteins to immunize Aotus trivirgatus monkeys. Some peptides gave partial protection from challenge with P. falciparum parasites, but none provided complete protection individually. A combination of three partially protective peptides gave complete or almost complete protection, however, suggesting that this particular combination of peptides is a good candidate for a malaria vaccine.

The conformational restriction of synthetic vaccines for malaria.

The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites.