The effects of pre-sleep consumption of casein protein on next-morning measures of RMR and appetite compared between sedentary pre- and postmenopausal women.

The purpose of the present study was to compare next-morning responses of RMR and appetite to pre-sleep consumption of casein protein (CP) in pre- and postmenopausal women. The study was a randomised, crossover, double-blind, placebo-controlled trial. Seven sedentary premenopausal (age: 19·9 (sd 1·2) years; BMI: 23·1 (sd 2·6) kg/m2) and seven sedentary postmenopausal (age: 56·4 (sd 4·9) years; BMI: 26·3 (sd 3·5) kg/m2) women participated. During visit one, anthropometrics and body composition were measured. Following visit one, subjects consumed either CP (25 g) or placebo (PL) ≥2 h after their last meal and ≤30 min prior to sleep on the night before visits two and three. Visits two and three occurred ≥1 week after visit one and were 48 h apart. During visits two and three, RMR (VO2), RER and appetite were measured via indirect calorimetry and visual analogue scale, respectively. Anthropometrics and body composition were analysed by one-way ANOVA. RMR and measures of appetite were analysed using a 2 × 2 (menopause status × CP/PL) repeated-measures ANOVA. Significance was accepted at P ≤ 0·05. RMR was significantly lower in postmenopausal compared with premenopausal women under both conditions (P = 0·003). When consumed pre-sleep CP did not alter RMR, RER or appetite compared with PL when assessed next morning in pre- and postmenopausal women. These data contribute to growing evidence that pre-sleep consumption of protein is not harmful to next-morning metabolism or appetite. In addition, these data demonstrate that menopause may not alter next-morning RMR, RER or appetite after pre-sleep consumption of CP.

Body composition and bone mineral density in breast cancer survivors and non-cancer controls: A 12- to 15-month follow-up.

While prognosis for breast cancer in women has improved, adverse side effects of treatments may negatively affect body composition and bone mineral density (BMD). This study assessed body composition and BMD changes in breast cancer survivors (BCS) (n = 10, 57.9 ± 5.7 years) and age-matched women (non-cancer, n = 10, 56.5 ± 4.3 years) over a 12- to 15-month period via dual-energy X-ray absorptiometry. No differences were observed between groups at baseline except forearm BMD values were lower in BCS (BCS: 0.462 ± 0.070 g/cm2 ; Control: 0.539 ± 0.052 g/cm2 , p = .012). Body fat increased in both groups compared to baseline (BCS: 38.3-39.6 kg, p = .013; Control: 38.2-39.5 kg, p = .023) at the follow-up. Significant decreases in BMD at the lumbar spine, femoral neck, total femur and ulna were observed in both groups. Breast cancer survivors had a greater decrease in left femoral neck BMD. While BCS demonstrated lower baseline forearm BMD values and a greater decrease in left femoral neck BMD, both groups showed an increase in body fat and decrease in forearm BMD. These findings support the implementation of interventions to improve body composition and BMD in both BCS and women without cancer.

Supplementation with a combination of beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine is safe and could improve hematological parameters.

BACKGROUND: Combining the amino acids arginine and glutamine with the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) has been shown to reverse lean tissue loss in cancer and acquired immunodeficiency syndrome (AIDS) patients. Although each of these nutrients has been shown to be safe, the safety of this mixture has not been reported. Three double-blind studies examined the safety of the combination of HMB, arginine and glutamine on blood chemistries, hematology, emotional profile, and adverse events. METHODS: Study 1 was conducted in healthy adult males (n = 34), study 2 was in HIV patients with AIDS-associated weight loss (n = 43), and study 3 was in cancer patients with wasting (n = 32). Volunteers were assigned to either a placebo or a mixture of 3 g HMB, 14 g arginine, and 14 g glutamine per day. RESULTS: Across the 3 studies, HMB, arginine, and glutamine supplementation was not associated with any adverse indicators of health. The only significant changes noted were positive indicators of health status. HMB, arginine, and glutamine supplementation was associated with an improvement in emotional profile (p = .05), a decreased feeling of weakness (p = .03), and increased red blood cells, hemoglobin, hematocrit, lymphocytes, and eosinophils (p < .05) when compared with placebo-supplemented subjects. Blood creatinine levels were not changed. However, blood urea nitrogen increased (p = .01) with HMB, arginine, and glutamine supplementation, which was possibly caused by the additional nitrogen consumed or to the fact that ureagenesis is influenced by arginine and glutamine supplementation. CONCLUSION: These results show that HMB, arginine, and glutamine can be safely used to treat muscle wasting associated with AIDS and cancer.

Effects of resistance training on cardiovascular responses to lower body negative pressure in the elderly.

The purpose of the present study was to determine whether resistance training alters the cardiovascular responses to submaximal lower body negative pressure (LBNP) in the elderly. Twenty-one subjects were randomized into a control (C: n=10; 70 +/- 3 years, mean +/- SD) or a resistance training (TR: n=11; 67 +/- 7 years) group. Subjects in the TR underwent 12 weeks of training consisting of three sets of 8-12 contractions at approximately 60-80% of their initial maximal one repetition, three times per week, on 10 different machines. Before (Pre) and after (Post) training, all subjects underwent exposures of LBNP of -10, -20 and -40 Torr and muscle biopsy sampling at the vastus lateralis. TR increased (P< or =0.05) knee extension (Pre=379 +/- 140 N, Post=534 +/- 182 N) and chest press (Pre=349 +/- 137 N, Post=480 +/- 192 N) strength. Neither body weight nor percentage body fat were altered (P >0.05) by training. Resistance training increased (P< or =0.05) cross-sectional area in both Type I (4203 +/- 1196 to 5248 +/- 1728 microm2) and Type II (3375 +/- 1027 to 4286 +/- 1892 microm2) muscle fibres. Forearm blood flow, forearm vascular conductance, mean arterial pressure, and heart-rate responses to LBNP were not altered by the training. These data suggest that the cardiovascular responses of elderly to LBNP are unaffected by 12 weeks of whole-body resistance training despite increases in muscle strength and size.

The Andro Project: physiological and hormonal influences of androstenedione supplementation in men 35 to 65 years old participating in a high-intensity resistance training program.

BACKGROUND: Since the passage of The Dietary Supplement Health and Education Act in 1994, there has been a flood of new "dietary" supplements promoting anti-aging benefits such as the enhancement of growth hormone or testosterone levels. Androstenediol and androstenedione are such products. This study's purpose was to elucidate the physiological and hormonal effects of 200 mg/d of oral androstenediol and androstenedione supplementation in men aged 35 to 65 years while participating in a 12-week high-intensity resistance training program. METHODS: Fifty men not consuming any androgenic-enhancing substances and with normal total testosterone levels, prostate-specific antigen, hemoglobin, and hematocrit, and with no sign of cardiovascular or metabolic diseases participated. Subjects were randomly assigned to a placebo, androstenediol (diol), or androstenedione (dione) group using a double-blind study design. Main outcomes included serum sex hormone profile, body composition assessment, muscular strength, and blood lipid profiles. RESULTS: During the 12 weeks of androstenedione or androstenediol use, a significant increase in the aromatization by-products estrone and estradiol was observed in both groups (P =.03). In the dione group, total testosterone levels significantly increased 16% after 1 month of use, but by the end of 12 weeks, they returned to pretreatment levels. This return to baseline levels resulted from increases in aromatization and down-regulation in endogenous testosterone synthesis based on the fact that luteinizing hormone was attenuated 18% to 33% during the treatment period. Neither androstenediol nor androstenedione enhanced the adaptations to resistance training compared with placebo for body composition or muscular strength. However, both androstenediol and androstenedione supplementation adversely affected high-density lipoprotein cholesterol (HDL-C) levels, coronary heart disease risk (representing a 6.5% increase), and each group's respective (low-density lipoprotein cholesterol [LDL-C]/HDL-C)/(apolipoprotein A/apolipoprotein B) lipid ratio (diol: +5.2%; dione: +10.5%; P =.05). In contrast, the placebo group's HDL-C levels increased 5.1%, with a 12.3% decline in the (LDL-C/HDL-C)/(apolipoprotein A/apolipoprotein B) lipid ratio. These negative and positive lipid effects occurred despite no significant alterations in body composition or dietary intakes in the supplemental groups or placebo group, respectively. CONCLUSIONS: Testosterone precursors do not enhance adaptations to resistance training when consumed in dosages recommended by manufacturers. Testosterone precursor supplementation does result in significant increases in estrogen-related compounds, dehydroepiandrosterone sulfate concentrations, down-regulation in testosterone synthesis, and unfavorable alterations in blood lipid and coronary heart disease risk profiles of men aged 35 to 65 years.

Nutritional supplementation of the leucine metabolite beta-hydroxy-beta-methylbutyrate (hmb) during resistance training.

The effects of supplementation of the leucine metabolite beta-hydroxy-beta-methylbutyrate (HMB) were examined in a resistance training study. Thirty-nine men and 36 women between the ages of 20-40 y were randomized to either a placebo (P) supplemented or HMB supplemented (3.0 g HMB/d) group in two gender cohorts. All subjects trained three times per week for 4 wk. In the HMB group, plasma creatine phosphokinase levels tended to be suppressed compared to the placebo group following the 4 wk of resistance training (HMB:174. 4 +/- 26.8 to 173.5 +/- 17.0 U/L; P:155.0 +/- 20.8 to 195.2 +/- 23.5 U/L). There were no significant differences in strength gains based on prior training status or gender with HMB supplementation. The HMB group had a greater increase in upper body strength than the placebo group (HMB:7.5 +/- 0.6 kg; P:5.2 +/- 0.6 kg; P = 0.008). The HMB groups increased fat-free weight by 1.4 +/- 0.2 kg and decreased percent fat by 1.1% +/- 0.2% while the placebo groups increased fat-free weight by 0.9 +/- 0.2 kg and decreased percent fat by 0.5% +/- 0.2% (fat-free weight P = 0.08, percent fat P = 0.08, HMB compared to placebo). In summary, this is the first short-term study to investigate the roles of gender and training status on the effects of HMB supplementation on strength and body composition. This study showed, regardless of gender or training status, HMB may increase upper body strength and minimize muscle damage when combined with an exercise program.

Effects of beta-hydroxy-beta-methylbutyrate on muscle damage after a prolonged run.

This study examined the effects of supplemental beta-hydroxy-beta-methylbutyrate (HMB) on muscle damage as a result of intense endurance exercise. Subjects (n = 13) were paired according to their 2-mile run times and past running experience. Each pair was randomly assigned a treatment of either HMB (3 g/day) or a placebo. After 6 wk of daily training and supplementation, all subjects participated in a prolonged run (20-km course). Creatine phosphokinase and lactate dehydrogenase (LDH) activities were measured before and after a prolonged run to assess muscle damage. The placebo-supplemented group exhibited a significantly greater (treatment main effect, P = 0.05) increase in creatine phosphokinase activity after a prolonged run than did the HMB-supplemented group. In addition, LDH activity was significantly lower (treatment main effect, P = 0.003) with HMB supplementation compared with the placebo-supplemented group. In conclusion, supplementation with 3.0 g of HMB results in a decreased creatine phosphokinase and LDH response after a prolonged run. These findings support the hypothesis that HMB supplementation helps prevent exercise-induced muscle damage.

beta-hydroxy-beta-methylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors.

The leucine metabolite, beta-hydroxy-beta-methylbutyrate (HMB) enhances the effects of exercise on muscle size and strength. Although several reports in animals and humans indicate that HMB is safe, quantitative safety data in humans have not been reported definitively. The objective of this work was to summarize safety data collected in nine studies in which humans were fed 3 g HMB/d. The studies were from 3 to 8 wk in duration, included both males and females, young and old, exercising or nonexercising. Organ and tissue function was assessed by blood chemistry and hematology; subtle effects on emotional perception were measured with an emotional profile test (Circumplex), and tolerance of HMB was assessed with a battery of 32 health-related questions. HMB did not adversely affect any surrogate marker of tissue health and function. The Circumplex emotion profile indicated that HMB significantly decreased (improved) one indicator of negative mood (Unactivated Unpleasant Affect category, P < 0.05). No untoward effects of HMB were indicated. Compared with the placebo, HMB supplementation resulted in a net decrease in total cholesterol (5.8%, P < 0.03), a decrease in LDL cholesterol (7.3%, P < 0.01) and a decrease in systolic blood pressure (4.4 mm Hg, P < 0.05). These effects of HMB on surrogate markers of cardiovascular health could result in a decrease in the risk of heart attack and stroke. In conclusion, the objective data collected across nine experiments indicate that HMB can be taken safely as an ergogenic aid for exercise and that objective measures of health and perception of well-being are generally enhanced.

Relative heart rate, heart rate reserve, and VO2 during submaximal exercise in the elderly.

BACKGROUND: The purpose of this study was to examine the relationships among relative maximal heart rate (%HRmax), maximal heart rate reserve (%HRmax reserve), and maximal oxygen uptake (%VO2max) during submaximal exercise by elderly subjects. METHODS: VO2max and HRmax were determined on 36 women and 19 men, 60 to 80 yrs of age, by a maximal treadmill test to volitional exhaustion. On a separate day, subjects underwent a submaximal treadmill protocol consisting of three 6-min exercise stages at treadmill speeds and grades estimated to elicit 40%, 60%, and 80% of HRmax reserve. Cardiorespiratory responses were determined during mins 4-5 and 5-6 of each stage. RESULTS: Measured exercise intensities expressed by the three methods were: %HRmax reserve = 36, 55, and 79%; %HRmax = 65, 75, and 88%; %VO2max = 53, 69, and 88%. %HRmax was greater (p < .05) than %VO2max at 53 and 69% of VO2max. %HRmax reserve was less (p < .05) than %VO2max for all three intensities. Slopes and intercepts for the linear regression equations relating %VO2max with %HRmax and with %HRmax reserve differed between men and women (p < .05). The regression equation relating %VO2max and %HRmax was y = -22.8 + 1.2 (%HRmax) -13.0 (Gender) + 0.2 (%HRmax x Gender): standard error of the estimate (SEE) = 9.7% and R2 = .71. The regression equation relating %VO2max and %HRmax reserve was y = 32.4 + 0.7 (%HRmax reserve) -10.9 (Gender) + 0.2 (%HRmax reserve x Gender): SEE = 9.8% and R2 = .70 (Gender: F = 0; M = 1). CONCLUSIONS: The data indicate that there is considerable variability among methods of expressing exercise intensity and that %HRmax more closely represents %VO2max than does %HRmax reserve (p < .05) in older adults. These results are in contrast to what has been shown with younger subjects and with American College of Sports Medicine guidelines for exercise prescription.

The lack of effect of aerobic exercise training on propranolol pharmacokinetics in young and elderly adults.

The effects of exercise training on the pharmacokinetics of orally administered propranolol were studied in young and elderly healthy volunteers. Twenty-three young (30 +/- 5 years of age) and 20 elderly (67 +/- 5 years of age) adults were randomly assigned to endurance training (N = 12 young subjects, 10 elderly subjects) or nonexercising control (N = 11 young subjects, 10 elderly subjects) groups. Training consisted of treadmill walking, stair climbing, or both three times per week for 40 minutes at 70-85% of maximal heart rate reserve for 16 weeks. Resting plasma propranolol concentrations after a single dose of 80 mg of oral propranolol were measured by high performance liquid chromatography with fluorescence detection, and estimated hepatic blood flow measured was measured using indocyanine green during supine test. Aerobic training increased maximal oxygen uptake (VO2 max) by 13% and 14% in the exercising young and elderly groups, respectively. There was no change in VO2 max in either control group. Adjusted mean estimated hepatic blood flow after exercise corrected for body weight for the young subjects who did not exercise (15.6 mL/min/Kg) and those who did (18.2 mL/min/Kg) groups were of borderline significance. No statistical differences were detected in the experimental propranolol pharmacokinetic parameters (maximal concentration, time of maximal concentration, terminal half-life, area under the curve, and protein binding) or derived pharmacokinetic parameters (intrinsic clearance, bioavailability, clearance, and volume of distribution). These results provide evidence that changes in aerobic fitness do not produce corresponding changes in propranolol pharmacokinetics in young or elderly adults.

An RFLP map of the Plasmodium falciparum genome, recombination rates and favored linkage groups in a genetic cross.

We report a genetic linkage map of the Plasmodium falciparum genome, using the inheritance patterns of nearly 90 RFLP markers in a genetic cross. Markers were assigned to polymorphic loci on all 14 nuclear chromosomes. Genetic recombination between parental markers was detected in each of the progeny, indicating that progeny from cross-fertilization events were favored over progeny from self-fertilization of either parent alone. Inheritance patterns among the markers suggested that certain parental linkage groups on chromosomes 2, 3, 12 and 13 were favored in the cross. Recombination frequencies on five chromosomes indicated an approximate map unit size of 15-30 kb per centiMorgan for P. falciparum.

A test for genetic exchange in mixed infections of Leishmania major in the sand fly Phlebotomus papatasi.

We tested if genetic exchange was observable between two strains of Leishmania major (Trypanosomatidae) during mixed infection of the sand fly Phlebotomus papatasi. Previous studies suggested that genetic exchange may occur in natural populations of Leishmania at a low frequency, but experimental crosses examining small numbers of progeny (less than 60) did not reveal hybrid parasites. Accordingly, a strategy was devised to increase the number of progeny that could be screened by 100-fold. Clonal derivatives from two strains that were infective to flies and contained numerous restriction fragment length polymorphisms were characterized and selected for resistance to methotrexate or tunicamycin by gene amplification. A successfully mixed infection of P. papatasi was obtained, and a method was developed for directly plating promastigotes from the gut contents of infected flies onto selective media. Twenty-five hundred independent progeny were scored for the presence of both drug resistance markers. No hybrid parasites were observed, indicating that the frequency of genetic exchange in this cross must be less than 4 x 10(-4). The lines and methods established in this work may prove useful in future studies of the mechanism and frequency of gene exchange in Leishmania.

Genetic mapping of the chloroquine-resistance locus on Plasmodium falciparum chromosome 7.

The resurgence of malaria in recent decades has been accompanied by the worldwide spread of resistance to chloroquine, a drug once uncontested as the first-line antimalarial agent because of its efficacy and low toxicity. Chloroquine-resistant strains of Plasmodium falciparum counter the drug by expelling it rapidly via an unknown mechanism. In the absence of explicit biochemical knowledge of this efflux mechanism, reverse genetics provides a powerful approach to the molecular basis of chloroquine resistance. Here we report genetic linkage analysis in which 85 restriction fragment length polymorphism markers were used to examine inheritance of the 14 P. falciparum chromosomes in a laboratory cross between a chloroquine-resistant and a chloroquine-sensitive parasite. Inheritance data from 16 independent recombinant progeny show that the rapid efflux, chloroquine-resistant phenotype is governed by a single locus within an approximately 400-kilobase region of chromosome 7. Identification and characterization of genes within this region should lead to an understanding of the chloroquine-resistance mechanism.

New approaches to addressing information needs in local public health agencies.

For local Public Health agencies to be fully responsive to community needs, staff must have ready access to up-to-date and accurate information. During the last several years, the Hamilton-Wentworth Department of Public Health Services (DPHS), a Teaching Health Unit affiliated with McMaster University, has been developing new information services including establishment of a specialized library on site; education sessions on the use of information stored in this library and in the Hamilton-Wentworth Health Library Network; innovative approaches to tailoring information services to staff needs including on-site access to on-line literature databases; and establishment of a group to retrieve and report community health data. In the initial three years of operation, surveys of Hamilton-Wentworth staff and a comparison health unit (Niagara) revealed that staff most frequently sought information from managers and support staff, as well as from personal books, articles and journals. Over half (57%) of the Hamilton-Wentworth staff reported use of the DPHS library, whereas 28% of Niagara Regional Health Unit staff reported use of their library. Other information services, for example, bibliographic indexes on population health, were less frequently used. Plans to increase their use are discussed.

Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross.

Chloroquine is thought to act against falciparum malaria by accumulating in the acid vesicles of the parasite and interfering with their function. Parasites resistant to chloroquine expel the drug rapidly in an unaltered form, thereby reducing levels of accumulation in the vesicles. The discovery that verapamil partially reverses chloroquine resistance in vitro led to the proposal that efflux may involve an ATP-driven P-glycoprotein pump similar to that in mammalian multidrug-resistant (mdr) tumor cell lines. Indeed, Plasmodium falciparum contains at least two mdr-like genes, one of which has been suggested to confer the chloroquine resistant (CQR) phenotype. To determine if either of these genes is linked to chloroquine resistance, we performed a genetic cross between CQR and chloroquine-susceptible (CQS) clones of P. falciparum. Examination of 16 independent recombinant progeny indicated that the rapid efflux phenotype is controlled by a single gene or a closely linked group of genes. But, there was no linkage between the rapid efflux, CQR phenotype and either of the mdr-like P. falciparum genes or amplification of those genes. These data indicate that the genetic locus governing chloroquine efflux and resistance is independent of the known mdr-like genes.

Effect of cyclosporin A on rat kidney catecholamines.

The immunosuppressive agent, Cyclosporin A, (CsA) has been associated with nephrotoxicity and hypertension. The mechanism for these effects are not known. We therefore determined the levels of the catecholamines; epinephrine (EPI), norepinephrine (NE) and dopamine (DA) and some of their metabolites; epinine, dihydroxyphenyl-acetic acid (DOPAC), homovanillic acid (HVA), metanephrine (ME) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the kidneys of rats treated intraperitoneally with either CsA (120 micrograms/kg/body wt/day) or control vehicle (1 ml olive oil/kg body wt/day). Six control or CsA treated rats were sacrificed at 1 hour or 24 hours after a single treatment or after 7 days of daily treatment. Renal catecholamine levels were determined using HPLC-amperometric detector. Treatment with CsA increased renal NE and EPI levels by 59% and 70% respectively within 1 hour. In the rats sacrificed 24 hours after treatment, renal NE, EPI and DA levels were similar to or less than the control levels. Treatment with CsA for 7 days resulted in marginal increases in renal NE (22%) and EPI (30%). These changes were associated with a significant decrease in the levels of catecholamine metabolites in the CsA treated kidneys as compared to the controls. The above findings suggest that increases in renal catecholamines may be involved in the CsA-induced hypertension and nephrotoxicity, perhaps by increasing renovascular resistance.

Effect of aerobic and resistance training on fractionated reaction time and speed of movement.

To evaluate the effect of aerobic and variable resistance exercise training on fractionated reaction time (RT) and speed of movement (SM) in elderly individuals, premotor time (PMT), motor time (MT), total RT, and SM were measured in 49 healthy, untrained men and women, 70 to 79 years of age, before and after 6 months of training. Subjects were randomized into either a walk/jog (n = 17), a strength training (n = 20), or a control group (n = 12). Improvements in aerobic capacity were only weakly related to reduced total RT (r = 0.30, p less than .05). Analysis of covariance revealed that there were no differences (p greater than .05) among the three groups after training with respect to PMT, MT, total RT, and SM. These findings indicate that 6 months of aerobic and strength training did not induce significant changes in RT or SM in this group.

Purification and partial characterization of an unusual protein of Plasmodium falciparum: histidine-rich protein II.

The human malarial parasite Plasmodium falciparum secretes a histidine-rich protein (HRP-II) from infected erythrocytes. HRP-II has a very high content of histidine (H) (34%), alanine (A) (37%) and aspartic acid (D) (10%) and many contiguous repeats of the sequences AHH and AHHAAD. The histidine content of the protein suggested the potential to bind metal ions. We have demonstrated by metal chelate chromatography an extraordinary capacity of HRP-II to bind zinc ions (Zn2+) and employed this characteristic to isolate the extracellular protein. The HRP-II was further purified by antibody affinity chromatography. The identity of the purified protein was verified by relative molecular weight on denaturing polyacrylamide gels, by reactivity with monoclonal antibodies and monospecific rabbit antiserum, and by comparison of the amino-acid analysis with that derived from the cloned gene sequence. Analysis of the sequence for periodicities using the hydrophobic moment method indicated that HRP-II may potentially form a 3/10 helix. Immunoprecipitation of HRP-II from culture supernatants of parasites metabolically labeled with tritiated sugars showed that the extracellular form of HRP-II is a glycoprotein containing galactose.

In vitro and in vivo studies of the effects of halogenated histidine analogs on Plasmodium falciparum.

The effects of four halogenated analogs of histidine on in vitro growth of Plasmodium falciparum malaria parasites were monitored by measurement of the incorporation of 3H-labeled amino acids into parasite proteins and by light and electron microscopy. The uptake of [3H]isoleucine was reduced to 50% of the control value by addition of 70 microM 2-fluoro-L-histidine (2-F-HIS) or 420 microM 2-iodo-L-histidine (2-I-HIS). [3H]histidine uptake into acid-insoluble material was affected equally by these two compounds, 50% inhibition resulting at 200 microM concentration. Morphological analysis of parasite development proved a sensitive assay, since development of mature trophozoites was inhibited 50% by 25 microM 2-F-HIS or 100 2-I-HIS. Electron microscopy studies suggested different mechanisms of action of 2-F-HIS and 2-I-HIS on P. falciparum. 2-F-HIS produced a decrease in knob number at the erythrocyte surface and accumulation of electron-dense material under the parasite membrane. 2-I-HIS had no obvious effect on knobs or electron-dense material but affected parasite morphology. Surprisingly, 2-chloro-L-histidine and 2-bromo-L-histidine did not inhibit P. falciparum in vitro, even though their halogen atom substituents are intermediate in size between F and I atoms. 2-F-HIS and 2-I-HIS were tested in vivo against P. falciparum in owl monkeys (Aotus sp.) but were ineffective at doses that were nontoxic.