Lost in translation: taking neuroprotection from animal models to clinical trials.

Caffeinol has been proposed as a neuroprotectant for human trials. This review covers a variety of animal models used and various attempts to take animal protocols to human trials. The accompanying paper discusses the rabbit model that was used to identify the efficacy of tissue plasminogen activator (tPA) treatment. To date, this is the only model that was able to achieve laboratory to clinical translational success. Use of caffeinol as a cytoprotective agent in rat models yielded exciting results, which led to clinical trials. However, caffeinol given with tPA in rabbits leads to increased hemorrhage. Caffeinol alone does not prove to be neuroprotective, as vasodilation by itself is not efficacious. However, vasodilation combined with thrombolysis (caffeinol with tPA) poses an increased risk of hemorrhage. For a more translational approach to study neuroprotection and neuroprotective agents in human trials, it is necessary to demonstrate the efficacy of the procedure and purported agents in several animal models.

The rise and fall of NMDA antagonists for ischemic stroke.

It has long been accepted that high concentrations of glutamate can destroy neurons, and this is the basis of the theory of excitotoxicity during brain injury such as stroke. Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists such as Selfotel, Aptiganel, Gavestinel and others failed to show neuroprotective efficacy in human clinical trials or produced intolerable central nervous system adverse effects. The failure of these agents has been attributed to poor studies in animal models and to poorly designed clinical trials. We also speculate that NMDA receptor antagonism may have hindered endogenous mechanisms for neuronal survival and neuroregeneration. It remains to be proven in human stroke whether NMDA receptor antagonism can be neuroprotective.

Double cervix and vagina with septate uterus: an uncommon müllerian malformation.

BACKGROUND: The case of an unusual müllerian anomaly is described. CASE: A nulligravida was found to have a septate uterus with double cervix and a vagina with partial longitudinal vaginal septum. The anomaly presented symptomatically, was suggested by clinical examination, and confirmed by magnetic resonance imaging and intraoperative visualization. Visualization of the anomaly was enhanced by magnetic resonance-based three-dimensional reconstruction techniques. CONCLUSION: Description of double cervix and vagina in the setting of an anatomically normal or simple septate uterus is uncommon. This anomaly is inconsistent with the generally accepted understanding of müllerian development but fits with an alternative hypothesis. Magnetic resonance imaging and magnetic resonance-based three-dimensional reconstruction was useful in aiding visualization of the anomaly.

Linear measurements in 2-dimensional pelvic floor imaging: the impact of slice tilt angles on measurement reproducibility.

OBJECTIVE: Magnetic resonance imaging techniques have improved the study of female pelvic dysfunction. However, disagreements between magnetic resonance measurements and their derived 3-dimensional reconstructions were noted. We tested the hypothesis that these discrepancies stemmed from variations in magnetic resonance acquisition angle. STUDY DESIGN: Images from the pelvis of the Visible Human Female (a thinly sliced cadaveric image data set) were obtained. Slices in the axial plane were rotated around pivot points in the pelvis to yield a set of similar-appearing para-axial images. A parameter that described the maximum anterior-posterior dimension of the levator hiatus was defined. This levator hiatus parameter was measured on all of the rotated images and compared with an expected value that was calculated from trigonometry. The levator hiatus was also measured on a group of similar-appearing slices rotated slightly around a defined point. RESULTS: In 1 group of slices, expected levator hiatus variation was 1.5 to 6.1%, whereas measured variation was 4% to 15%. Among the similar-appearing rotated slices, 4.8% to 16.0% variations were seen in the levator hiatus. CONCLUSION: Identical measurements made on radiologic images can vary widely. Slice acquisition must be standardized to avoid errors in data comparison.

Variations in levator ani volume and geometry in women: the application of MR based 3D reconstruction in evaluating pelvic floor dysfunction.

OBJECTIVE: We report on the comparative 3-dimensional (3D) living female pelvic floor geometry in five women, comparing the volume, morphology, and integrity of the levator sling, and pelvic anatomic relationships among study subjects. METHODS: Five women of varying ages, parity, continence, and prolapse status were studied. Two-dimensional (2D) imaging of the pelvic floor organs was performed on each subject in the supine position. Manual segmentation techniques and solid modeling software was used to build 3D models of each patient's pelvic floor structures, which could then be viewed and measured on the computer screen. We measured levator muscle volume, posterior urethro-vesical angle, distance from the urethra to pubo-coccygeal line, and the levator plate angle. The integrity of pubo-coccygeal attachments was also recorded. RESULTS: Levator muscle volume ranged from 68 ml in the nulliparous female, to 26 ml in the grand multipara with severe prolapse and mild genuine stress incontinence (GSI). The second lowest volume (30 ml) was in the multipara with GSI. Volumes in the parous subjects without stress urinary incontinence or pelvic organ prolapse were 36 and 39 ml. Pubo-coccygeal attachments were found to be torn in the 2 symptomatic subjects, and were intact in all 3 asymptomatic subjects. CONCLUSION: MR based 3D modeling is feasible and can be used in a research setting to evaluate complex anatomic relationships which may accompany pelvic floor dysfunction. The technique can also be used to evaluate levator muscle morphology and volume, as well as pelvic floor support integrity and its possible role in GSI and prolapse. We are currently conducting a larger study to validate our technique, and to better define the relationship between pelvic floor geometry and pelvic floor dysfunction.

Two- and 3-dimensional MRI comparison of levator ani structure, volume, and integrity in women with stress incontinence and prolapse.

OBJECTIVE: The aim of this study was to identify imaging markers for genuine stress incontinence and pelvic organ prolapse by using magnetic resonance imaging and reconstructed 3-dimensional models. STUDY DESIGN: Thirty women were studied, 10 with prolapse, 10 with genuine stress incontinence, and 10 asymptomatic volunteers. Axial and sagittal T1 and T2 weighted pelvic magnetic resonance scans were obtained with the patient in the supine position. Source images were measured to determine levator hiatus height, bladder neck to pubococcygeal line, levator plate angle, and perineal descent at rest and maximum Valsalva. Manual segmentation and surface modeling was applied to build 3-dimensional models of the organs. The 3-dimensional models were measured to determine levator muscle volume, shape and hiatus width, distance between symphysis and levator sling muscle, posterior urethrovesical angle, bladder neck descent, and levator plate angle. RESULTS: The 3 groups of subjects were comparable in age, parity, and body mass index. In the control, genuine stress incontinence, and prolapse groups, the menopausal rate was 40%, 60%, and 55% (P =.7). In the same order, significant mean 2-dimensional measures were: resting bladder neck descent of 24, 17, and 3 mm (P <.005), straining levator plate angle of -4.3, -11.5, and -31 degrees (P =.01), straining levator hiatus height of 48.5, 51.1, and 65.3 mm (P <.005), and straining perineal descent of 17.2, 22.5, 27.2 mm (P =.02). Similarly ordered mean 3-dimensional parameters showed levator volumes of 32.2, 23.3, and 18.4 cm(3) (P <.005); hiatus widths of 25.7, 34.7, and 40.3 mm (P <.005); left levator sling muscle gaps of 15.6, 20.3, and 23.8 mm (P =.03), right levator sling muscle gaps of 15.6, 22.5, and 30.8 mm, (P = 0.003), and levator shape (90%, 40%, and 20% dome shaped; P <.005). CONCLUSION: Both 2-dimensional magnetic resonance images and 3-dimensional models yield findings that differ among asymptomatic subjects compared with those with genuine stress incontinence and prolapse. Our 3-dimensional data demonstrate a statistically significant continuum in levator volume, shape, and integrity across groups of asymptomatic, genuine stress incontinence, and prolapse subjects.