A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults.

BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. METHODS: A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had âˆ¼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. CONCLUSION: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. CLINICALTRIALS: gov identifier: NCT01556945.

How have patients reacted to the implications of the DCCT?

OBJECTIVES: To assess the reactions of people with insulin-treated diabetes (ITD) to the results of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: A leaflet documenting the purpose and results of the DCCT was circulated to all 771 patients ages 15-60 years with ITD attending our clinic. Patients were invited to complete and return a questionnaire on their responses. RESULTS: Of 550 respondents, 330 felt encouraged to improve glycemic control. Female respondents (P = 0.003) and younger age-groups (15-25 years, P = 0.001) were most likely to want to improve control. Patients with long duration of diabetes (> 20 years, P = 0.00001), hypoglycemia unawareness (P = 0.0001), or previous severe hypoglycemia (P = 0.001) were less likely to want to improve their control. Fear of hypoglycemia concerned all age-groups, whereas female respondents were most likely to be worried about the potential for weight gain (P = 0.00006). CONCLUSIONS: Knowledge of the results of the DCCT encourages significant numbers of patients to want to improve glycemic control. Fear of hypoglycemia and, in women, weight gain may prove significant impediments to the clinical implementation of the results of the DCCT.

New World monkey efficacy trials for malaria vaccine development: critical path or detour?

Neither GMP malaria antigens nor GMP vaccines have been compared for efficacy in monkeys and humans. It is too risky to base categorical (go/no go) development decisions on results obtained using partially characterized (non-GMP) antigens, adjuvants that are too toxic for human use or unvalidated primate models. Such practices will lead to serious errors (e.g. failure to identify and stop flawed efforts, rejection of effective vaccine strategies) and unjustifiable delays. Successful malaria vaccine development will emphasize definitive field trials in populations at risk of malaria to define and improve vaccine efficacy.

Equine motor neuron disease is not linked to Cu/Zn superoxide dismutase mutations: sequence analysis of the equine Cu/Zn superoxide dismutase cDNA.

The cDNA encoding the equine copper/zinc superoxide dismutase (SOD1) was cloned from leukocyte total RNA from healthy horses and its nucleotide (nt) sequence was determined. We further sequenced the SOD1 gene from 16 horses diagnosed with equine motor neuron disease (EMND) and eight unrelated, clinically normal horses to determine if this disease, similar to amyotrophic lateral sclerosis (ALS) in humans, is linked to SOD1 mutations. The 465-bp SOD1 coding region in the horse encodes 153 amino acid (aa) residues. Equine SOD1 exhibited 81.8 and 79.9% sequence identity to the human homolog at the nt and aa levels, respectively, with only five distinct aa in the two loops that constitute the active site of the enzyme. None of the human SOD1 mutations found in the familial form of ALS were detected in SOD1 of the 16 affected horses. Although DNA sequence analysis identified three potential polymorphisms in equine SOD1, these were silent and were found in both normal and EMND-afflicted horses. At this time, there is no conclusive evidence for EMND linkage to SOD1 mutations.

An enzyme tracer study of the organization of the somatic motor center for the innervation of different muscles of the tongue: evidence for two sources.

The hypoglossal nucleus has been described as the sole ipsilateral source of somatic motor innervation of the lingual and geniohyoideus muscles (Streeter, '40; Barnard, '40; Crosby et al., '62; Watkins, '78; Jenkins, '78). In this study microliter amounts of 30% solution of horseradish peroxidase (HRP) were injected into intact but surgically isolated canine genioglossus, hyoglossus, styloglossus, geniohyoideus, and intrinsic lingual muscles. All injections were confined to the left half of the tongue, and the right half served as control. The HRP injections resulted in ipsilateral labeling of hypoglossal neurons with the exception of the injections into the genioglossus muscle, which labeled this nucleus bilaterally. Surprisingly, a few neurons associated with the ventromedial aspect of the caudal pole of the ipsilateral facial motor nucleus also labeled after injections of lingual muscles. The somatotopic representation of the geniohyoideus and lingual muscles within the hypoglossal nucleus suggested that those muscles known to originate from the same or related primodia labeled in the same or closely related hypoglossal subnuclei. The presence of labeled neurons associated with facial motor nucleus supported the hypothesis (Langman, '75) of a possible dual origin of lingual muscles.

Experimental coonhound paralysis: animal model of Guillain-Barré syndrome.

Coonhound paralysis (CHP), a polyradiculoneuritis of dogs that resembles the human Guillain-Barré syndrome, was experimentally reproduced by inoculating a dog with raccoon saliva. The test animal was a coonhound that had previously sustained two naturally occurring attacks of CHP. Success in inducing the disease strengthened the notion that raccoon saliva contains the etiologic factor for CHP and that only specifically susceptible dogs are at risk of developing CHP when exposed to this factor.

Risk factors associated with equine motor neuron disease: a possible model for human MND.

Equine motor neuron disease (EMND), a newly described neurodegenerative disease, bears a striking resemblance to progressive muscular atrophy (PMA) in humans. We present a comparison of the equine and human diseases and the results of a case-control study conducted to identify intrinsic factors associated with EMND. Cases included all horses with a confirmed diagnosis of EMND diagnosed in the United States since 1985 (32 cases). Controls included horses diagnosed with either cervical stenotic myelopathy, equine degenerative myeloencephalopathy, or protozoan myelitis at the Veterinary Teaching Hospital at the College of Veterinary Medicine, Cornell University (153 controls). Logistic regression analysis identified factors associated with the risk of EMND. Risk factors considered were age, sex, and breed of the horse. Most cases of EMND (30 of 32) have been sporadic. There was a breed association with the risk of EMND. Quarter horses were at a high risk for developing EMND (odds ratio [OR] = 12.7; 95% confidence interval, 3.3 to 49.6); thoroughbred horses were at increased risk (OR = 2.9, 0.8 to 10.4). There was also an age association with the risk of EMND. The risk increased with age, peaked at 16 years, and then declined, a pattern similar to that for amyotrophic lateral sclerosis in humans. There was no sex association with the disease. Despite the breed association, equine lymphocyte antigen studies have not revealed a systematic pattern, suggesting that genetic factors influencing susceptibility to EMND may be outside the major histocompatibility complex.

Tibetan terrier model of canine ceroid lipofuscinosis.

Over a 10-year period, we have studied the Tibetan terrier's visual electrophysiology, light and electron microscopic (EM) retinal characteristics of a slowly evolving inherited ceroid lipofuscinosis (CL). The retinal degeneration with CL inclusions (rdi) in the inner nuclear layer (bipolar cells) and nerve fiber layer (ganglion cells) has been called "rdi" to differentiate the visual abnormality from typical early retinal degeneration (erd) reported also in the Tibetan terrier. The unique "rdi" electroretinogram (ERG) gives a predominant P III wave at age 7 weeks but becomes more characteristically depressed in all phases over several years. Nyctalopia is the only functional abnormality for the first 5 to 6 year of life. Signs are remarkably few considering the pathology. Microscopic studies of the retina show accumulations, increasing with age, of autofluorescent dense inclusion particles which stain intensely by Luxol fast blue, PAS, and acid-fast procedures. Ultrastructural studies of the retina show the dense particles to be lamellar membranes repeating every 2 to 4 nm, consistent with ceroid lipofuscin. The inner retinal layers were always the target layer to be affected first and most severely. The ganglion cells were most frequently involved. The photoreceptors eventually degenerated but relatively few particles were found in this layer. The cytosomes in the cerebral cortex and brainstem neurons resemble lipofuscin, containing granular, lamellar, and globular components. Different pigment bodies were present in the cerebellar Purkinje cells. Neuronal loss which was moderate in the cerebellum and mild in the cerebrum was accompanied by astrogliosis and a striking presence of macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Motor and sensory centers for the innervation of mandibular and sublingual salivary glands: a horseradish peroxidase study in the dog.

Horeradish peroxidase was injected at multiple sites in the mandibular and sublingual salivary glands in order to label the preganglionic salivatory neurons in the brain stem. The same injections resulted in retrograde labeling of the sympathetic and sensory neurons that project to these glands. Labeled fusiform and multipolar salivatory neurons were found ipsilaterally in the lateral reticular formation of the medulla where they extended over the rostral four-fifths of the facial nucleus and the caudal one-third of the dorsal nucleus of the trapezoid body. The vast majority of the small and medium-sized, labeled neurons appeared in thally at the ventral and lateral aspects of the facial nucleus. Enzyme injections into these glands labeled sympathetic neurons that were concentrated in the caudal one-third of the ipsilateral cranial cervical ganglion. Labeled sensory neurons were distributed randomly in the ipsilateral proximal vagal and geniculate ganglia. Large numbers of sensory neurons were concentrated ventromedially within the mandibular zone of the trigeminal ganglion.

The origins of innervation of the esophagus of the dog.

This study defined the origins of extrinsic efferent and afferent innervation of the normal canine esophagus. When all the layers of the wall of the 3 esophageal regions (cervical, thoracic and abdominal) were injected with horseradish peroxidase (HRP), labeled nerve cells were found in the nucleus ambiguus (NA) and parasympathetic nucleus of X (PX) of the brainstem. Most labeled cells in the NA were located in the compact column (retrofacial nucleus) while labeled cells in the PX were located in separate rostral and caudal areas. There was no somatotopic organization in either the NA or PX. Labeled sympathetic postganglionic neurons were found in the cranial cervical, middle cervical, cervicothoracic, thoracic sympathetic trunk and celiacomesenteric ganglia. The HRP injection of the esophageal wall labeled sensory cell bodies in the glossopharyngeal, proximal and distal vagal, and C2-T6 spinal ganglia. There was no discernible pattern of distribution of labeled cells in the autonomic or sensory ganglia. When the HRP injections were confined to the mucosa-submucosa layers of the thoracic esophagus, a small number of labeled cells were identified in the NA; however, no labeled cells were found in the NA when injections were confined to the mucosa-submucosa of either the cervical or abdominal esophageal regions. With these confined injections, the labeled nerve cells appeared in the rostral part of the PX. Thus, it appeared that the internal tunics of the esophagus (i.e., the mucosa and submucosa) were innervated by neurons in the rostral PX while the muscular tunic was innervated by neurons in the caudal PX and the rostral NA. After mucosa-submucosa injections, labeled sympathetic neurons appeared in the same ganglia that were identified after whole wall injections and these had a similar random distribution. These injections also labeled neurons in the glossopharyngeal, proximal vagal, and distal vagal ganglia, but unlike the whole wall injections there was no labeling in the spinal ganglia. This suggested that the labeled cells of the spinal ganglia seen after whole wall injections conveyed impulses from the tunica muscularis and serosa.

The progression of anterior translation after anterior cruciate ligament reconstruction in a caprine model.

Large post-operative anterior-posterior translations are frequently reported after quadruped anterior cruciate ligament (ACL) reconstructions. To determine when the translation increases occur and the mechanism responsible, we followed the anterior and posterior translation limits in 18 goat knees for six months. Reconstructions were performed using grafts 4 or 7 mm wide placed in initially tight or lax positions. The anterior and posterior translation limits at 50 N were monitored using Roentgen stereophotogrammetric analysis. Graft bone block stability and soft tissue segment lengths were also assessed. Large (> 2 mm) increases in anterior translation were noted in 71% of the subjects at two weeks, and in 88% at eight weeks. The translations in the lax and tight groups were indistinguishable after two weeks. Joints with wide grafts had less anterior translation compared to narrow grafts at all time periods, but were significant different only at 26 weeks. The posterior translation limit moved anteriorly over the 26 weeks. Eight of nine joints had stable graft bone markers and/or increases in graft soft tissue lengths. In conclusion, increased anterior translation occurred soon after ACL reconstruction, was associated with graft soft tissue changes, and appeared to be reduced by larger grafts. A post-surgical decrease in posterior translation limit was also observed.

Subject variation in caprine anterior cruciate ligament reconstruction.

We studied the subject and treatment contributions to anterior cruciate ligament (ACL) reconstruction biomechanics by reexaming the results of two bilateral reconstruction studies. Bilateral reconstruction allows a comparison between treatments exposed to the same subject related healing factors. The studies examined the effects of gamma irradiation and the effects of initial graft size and initial graft laxity. In both studies different treatments were applied to contralateral limbs. We found that the subject was the best predictor of outcome, while the surgical treatments had little influence on outcome. There was a large variation between subjects despite similar treatments, and little difference between contralateral limbs despite different surgical treatments. At 26 weeks, the graft cross sectional area and modulus were most strongly influenced (p < 0.002) by the subject. We interpret this as a subject related factor is regulating the quantity and quality of the healing tissue. Potential sources of subject related factors include the subject's pre-operative condition, the activity during the post-operative period, and an intrinsic biologic response. By better understanding the source of subject variation, more successful and consistent ACL reconstructions might be achieved.

The effects of graft width and graft laxity on the outcome of caprine anterior cruciate ligament reconstruction.

We studied how initial graft size and initial graft laxity affected the biomechanics of anterior cruciate ligament (ACL) reconstruction at six months. Sixteen goats had bilateral reconstructions staged eight weeks apart. Autografts 4 and 7 mm wide were taken from the central patellar tendon (PT). Lax grafts were created by adding 4 mm slack to the graft before fixing. We reconstructed each joint using a combination of width and laxity treatments. Both factors were changed for the contralateral joint and all combinations appeared with equal frequency. At six months we measured the joint extension limit, anterior-posterior (AP) translation, and osteoarthritic changes. The grafts were then tested to failure to determine their mechanical properties. After six months the difference in initial treatments had disappeared: there was no difference in graft cross-section due to the different initial widths and there was no difference in joint AP translation due to the initial graft laxity. We did observe that wide grafts were associated with a block to extension, decreased joint AP translation, and increased articular cartilage damage and osteophyte formation. While AP translation was reduced, it was correlated with decreased extension, possibly indicating an increase in scar tissue formation rather than a more functional graft. Neither graft width nor graft laxity produced differences in any graft mechanical properties. This suggests that the use of larger grafts to prevent increased AP translation has undesirable complications. Ultimately, we conclude that neither of these surgical treatments strongly affects the biomechanical result of caprine ACL reconstruction.

Effect of tibial attachment location on the healing of the anterior cruciate ligament freeze model.

We studied the healing response of a devitalized anterior cruciate ligament to a treatment of initial anterior-posterior joint translation in goats. Devitalization and devascularization were achieved by five successive freeze-thaw cycles. Anterior-posterior translation was surgically altered by an osteotomy of the tibial attachment of the devitalized ligament and its reattachment either in the anatomical position or in a position 5 mm posterior. Six weeks after the first surgery, the same procedure was performed on the contralateral limb, except that the ligament was reattached in the alternate position. Six months after the initial surgery, femur-anterior cruciate ligament-tibia specimens were tested to determine their structural and mechanical material properties. Anatomic ligament placement resulted in reduced anterior-posterior translation (p < 0.05) and greater anterior joint stiffness (p < 0.05). Maximum load (p < 0.05) and ligament stiffness (p < 0.01) also were greater for the anatomically placed anterior cruciate ligaments. The maximum load for anatomically placed ligaments averaged 1.625 +/- 211 N (SEM). The strength of the posteriorly placed anterior cruciate ligament, 895 +/- 164 N was similar to results of historical anterior cruciate autograft reconstructions. Ligament failure occurred near the tibial insertion in the posteriorly placed ligaments more often than in the anatomically placed ligaments (four of five times compared with one of five times). Ligament failure near the tibial insertion occurred with lower mean maximum load than failure at the midsubstance or by bone avulsion (796 compared with 1.592 N: p < 0.05). These data support the hypothesis that ligament laxity is important to the healing and remodeling of anterior cruciate ligament grafts.

Canine X-linked muscular dystrophy: morphologic lesions.

Gross pathologic lesions and light microscopic and ultrastructural features of skeletal muscle lesions in canine X-linked muscular dystrophy (CXMD) were studied in dogs from 3 months to 6 years of age. Necrosis and regeneration were present at all ages, but were most prominent in the youngest dogs studied. Increased intracytoplasmic calcium, as evidenced by positive alizarin red S staining, was associated with fiber necrosis, but was also seen in small numbers of otherwise normal fibers. Progressive changes included development of severe fiber size variation, endomysial and perimysial fibrosis, prominent cytoplasmic disorganization, internalization of myonuclei, mitochondrial proliferation, mild fat infiltration, and alterations in the fiber-type pattern. The most consistent early ultrastructural changes were dilatation of the sarcoplasmic reticulum and focal subsarcolemmal areas of degeneration. Convincing sarcolemmal defects were not found. Z-band streaming was present at all ages, and Z-band duplication and nemaline rods were seen in older dogs. Evidence for abnormal regeneration was found in the oldest dog, and was associated with extensive fibrosis. These findings document the progression of lesions in CXMD, and illustrate the profound alterations in fiber organization and fiber type that may occur in late stages of dystrophin-deficient muscular dystrophy.

The effects of in situ freezing on the anterior cruciate ligament. An experimental study in goats.

We developed an in situ freeze-thaw model designed to simulate an ideally placed and oriented autogenous graft of the anterior cruciate ligament. In this model, the anterior cruciate ligament was exposed, and the femoral insertion, tibial insertion, and body of the anterior cruciate ligament were frozen in situ with specially designed freezing probes. Freeze-thaw cycles were repeated five times. We used the technique in thirty-three mature goats to study the biological and biomechanical outcomes of the devitalized and devascularized anterior cruciate ligament at zero, six, and twenty-six weeks after treatment. Thus, the collagen fibers of the simulated autogenous graft remain in normal anatomical position and the simulated graft is fixed under physiological tension. At twenty-six weeks, no statistically significant differences were noted between treated and contralateral control (untreated) ligaments relative to anterior-posterior translation, maximum force to rupture, stiffness in the linear region of the force-length curve, modulus of elasticity in the linear region, strain to maximum stress, or maximum stress. The only statistically significant difference was an increase in cross-sectional area of the ligament. This increase was 22 and 42 per cent greater than that in the control ligaments at six weeks and six months. At six months, the ligaments in the control group had an average mid-cross-sectional area of 17.7 +/- 1.2 square millimeters and the ligaments in the experimental group, 25.2 +/- 3.1 square millimeters. Changes in the size and density of the collagen fibrils also were demonstrated at six months. These observations are in sharp contrast to our previous studies of replacement of the anterior cruciate ligament, in which an allograft of the ligament or an allograft supplemented with a 3M ligament augmentation device (LAD; 3M, St. Paul, Minnesota) was used. In those studies, an average reduction in maximum strength of 75 per cent for the allografts and 50 per cent for the allografts that had a ligament-augmentation device was found at one year. We concluded that devitalized, devascularized anterior cruciate ligaments do not lose strength if the anatomical position and the orientation of the collagen fibers are not altered.

Factors affecting sensitivity of a transducer for measuring anterior cruciate ligament force.

In order to determine the measurements and calibration methods necessary to accurately measure in vivo forces in the anterior cruciate ligament (ACL) of the goat, an in vitro study was conducted to evaluate the effect of several factors that could influence the sensitivity of a transducer implanted within the ligament. Four factors were studied in six specimens: flexion angle [0 degrees, 10 degrees, 30 degrees, 50 degrees, and 70 degrees from full extension (FFE)]; tibial rotation (0 degrees and 10 degrees of internal rotation at 30 degrees, 50 degrees, and 70 degrees flexion FFE); loading rate (cycling frequencies of 0.2, 0.5, 1.0, and 2.0 Hz); and temperature (22 degrees C and 37 degrees C). Anteroposterior tibial displacements were applied to the specimens following tissue resection to isolate the ACL. The resultant ACL force magnitude was measured with a multi-component load cell, and transducer sensitivity was calculated as the slope of the output vs force curve in the linear response region. Transducer sensitivity varied with joint position in each specimen, but there was no consistent trend from specimen to specimen in how the sensitivity changed. As a result, there were no statistically significant mean differences (p > 0.05). There were no significant differences and little variation in sensitivity due to changes in either loading rate or tissue temperature, although the latter produced a voltage offset. The results show that the transducer output with zero force on the ligament must be determined in vivo, after which in vitro calibrations may be conducted at room temperature.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo forces in the anterior cruciate ligament: direct measurements during walking and trotting in a quadruped.

In vivo forces in the anterior cruciate ligament (ACL) were measured in three adult goats during quiet standing and during gait (walking or trotting). A modified pressure transducer (MPT) was implanted within the anteromedial band of the ligament to make direct measurements of ACL force. One or two days following implantation, measurements were made of ACL force, knee joint flexion angle, ground reaction forces, and speed of locomotion. MPT calibration was performed in vitro using anteroposterior displacement tests at six flexion angles. The ACL was loaded during quiet standing (30-61 N) and during the stance phase of gait. Peak ACL forces were achieved within the first 40% of stance, with magnitudes ranging from 63 to 124 N during walking and from 102 to 150 N during trotting. The average ACL force during the stance phase ranged from 34 to 68 N while walking and from 46 to 69 N while trotting. The partial correlations between peak ACL force and speed, and between average ACL force and speed, were both statistically different from zero (p < 0.01). ACL forces dropped to zero during the swing phase in all trials. ACL forces were less than 15 N throughout swing in two of the animals, both of which did not extend their knees during gait beyond 20 degrees from full extension. In the animal which did show knee extension beyond 40 degrees (20 degrees from full extension), ACL loading occurred during late swing. The magnitude of the peak ACL force during late swing was significantly correlated with the extent of knee extension in this animal.

The use of an implantable force transducer to measure patellar tendon forces in goats.

Patellar tendon (PT) force was measured during activity with an implantable force transducer (IFT) in adult goats. PT force, vertical ground reaction force (VGRF) and the animal's speed were recorded for standing, walking and trotting. Following data collection, animals were euthanized and the IFT calibrated in vitro. Standing PT force averaged 207 N. Maximum PT force was approximately 800 N for walking and 1000 N for trotting and occurred at mid-stance. PT force dropped from 200 N at toe-off to 0 N by mid-swing. For each activity, the PT force increased with increases in VGRF. Maximum in vivo PT stress occurred during trotting and measured 29 MPa. This study demonstrates the IFT's usefulness in measuring tendon force directly.

Location-dependent variations in the material properties of the anterior cruciate ligament.

Our recent anterior drawer studies in human cadaveric knees [Guan and Butler, Adv. Bioengng 17, 5 (1990); Guan et al., Trans. orthop. Res. Soc. 16, 589 (1991)] have suggested that anterior bundles of the anterior cruciate ligament (ACL) develop higher load-related material properties than posterior bundles. This was confirmed when we reevaluated the axial failure data for these bundle-bone specimens from an earlier study [Butler et al., J. Biomechanics 19, 425-432 (1986)]. The purpose of this study was to determine, in a larger data set, if anteromedial and anterolateral bundles of the anterior cruciate ligament exhibit significantly larger load-related material properties than the posterior ligament bundles. Seven ACL-bone units from seven donors (the three tissues from the original study plus four new ones) were subdivided into three subunits, preserving the bone insertions. The subunits were failed in tension at a constant strain rate (100% s-1) and four material properties were compared within and between donors. The anterior bundles developed significantly larger moduli, maximum stresses, and strain energy densities to maximum stress than the posterior subunits. Moduli for the anterior vs posterior subunits averaged 284 MPa vs 155 MPa, maximum stresses averaged 38 MPa vs 15 MPa, and strain energy densities averaged 2.7 N m cc-1 vs 1.1 N m cc-1, respectively. No significant differences were found, however, among strains to maximum stress or between any of the other properties for the two anterior subunits. These results are important to the design of ligament replacements and suggest new experiments designed to distinguish in vivo force levels in these ACL bands, a possible reason for the material differences.