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PubMed1996

Evaluation of a novel nimodipine delivery system in conscious rats that allows sustained release for 24 h.

Methodologies that allow prolonged drug administration in animal models, while minimizing surgery and anesthesia, are an important contribution towards studies in awake conditions. Commercially available drug delivery systems like pellets can be customized for the evaluation of experimental therapies with minimal or no discomfort to animals. Our objective was to evaluate pharmacokinetic and physiologic parameters after subcutaneous implantation of rapid 24 h release nimodipine pellets in rats for their potential use as a delivery system for stroke therapeutics. A day prior to the study Sprague-Dawley rats were anesthetized (halothane, N2O, O2) for femoral vessel cannulation and later returned to their cages. On the day of the study the rats were briefly anesthetized (identical regimen as before), and assigned to two groups: nimodipine (NP) and placebo (PL). NP rats received either 0.5 (n = 4), 1 (n = 3), 2 (n = 2), 4 (n = 2), or 15 (n = 5) mg pellets (Innovative Research of America Inc., Sarasota, FL, USA) and PL, rats (n = 5) received placebo pellets. Nimodipine plasma levels were measured at 1, 3, and 6 h. In addition, the 15 mg NP group was followed at 18 and 24 h. Immediately following decapitation the brain was removed for later determination of nimodipine tissue concentration. The NP 15 mg group showed a significant decline of 10% in MABP from base line to 24 h post implantation (p < 0.001). All NP animals achieved at least 83% of their highest plasma concentration at 1 h and 94% at 3 h. A high degree of correspondence (r2 = 0.95, y = 0.36 + 0.28x, n = 16) between the plasma and brain concentrations of nimodipine was present. Although a significant drop in MABP was observed the drop was no greater than 10% in 24 h. Plasma nimodipine levels for the 15 mg animals were within the cerebrovascular effective range. This is the first report to show that 24 h release nimodipine pellets subcutaneously implanted in rats are a reliable delivery system that allows rapid rise and constant nimodipine plasma levels. Therefore, 24 h release pellets are a suitable alternative to other delivery systems like osmotic pumps.

Animals↗
PubMed1993

BASIC-language software for simultaneous monitoring of blood glucose level and neuronal firing frequency.

We have designed software for an Apple II GS microcomputer allowing simultaneous on-line monitoring of blood glucose level and neuronal firing frequency in experimental rats. Blood glucose level in the carotid blood was continuously measured by a glucose analyzer and digitized through an A/D board. The firing rate of a brain neuron, recorded by a classical technique, was counted by a versatile interface adapter. Both parameters are graphically displayed on the screen. They can also be exported to another computer for off-line analysis. This software is adaptable to other experimental applications in electrophysiology, involving the monitoring of glycemia or other biological parameters.

Animals↗
PubMed2006

[Neurological aspects of stuttering].

Stuttering is characterised by repetitions, prolongations and pausing while speaking. Researchers have looked for many explanations. However, the cause of stuttering remains unknown. In recent years, structural abnormalities in the speech-related structures of the central nervous system have been brought into focus as a cause of stuttering. Research has shown signs of a lateral hemisphere asymmetry, abnormalities in the basal ganglia, dysfunction in the supplementary motor area and/or a dysfunction in the coordination of the cerebellum. This article is a review of this part of the literature.

Brain↗
PubMed1981

An experimental study of the feasibility of substituting Chemical Abstracts on-line for the printed copy in a medium-sized medical library.

The reference staff of the Washington University School of Medicine Library, in an attempt to consider an alternative way of providing the information contained in the printed Chemical Abstracts, designed a study to examine whether the on-line version of Chemical Abstracts could be substituted for the hard copy. For a thirteen-week period, all patrons using the printed index were offered a free computer search of Chemical Abstracts in exchange for evaluating the searches. Only 39.6% of those offered a free search chose to do so. Of these patrons, 62% still planned to refer to the abstracts later, which are only available in the printed index. The hypothesis that the on-line version could be substituted for the printed index was not confirmed.

Abstracting and Indexing↗
PubMed1989

Compartmental and intracompartmental regulation of aging.

Individual differences of aging occur in systems of regulation and communication. Different types of suppressor capacity can change in opposite directions as an individual ages. The progression of these changes in suppressor capacity can be changed to different extents by hormones or diets differing in fatty acid composition. It seems reasonable to conclude that these two activities depend on different precursors which age under the control of two different genes, although the two precursors are almost certainly derived from a common stem cell line. A variety of molecules and activities undergo age-related reductions, which are completed by middle age; the resulting levels of a given gene product are remarkably similar in different individuals, while the levels at a young age show very great individual differences. This correlation between the youthful quantity of a given gene product and the rate of change in later life has been designated as "economic correction." The study of multicentricity of different controlling and of functional competencies of different alleles is an important component in the development of preventive geriatric medicine.

Aging↗
PubMed1978

Uptake of horseradish peroxidase from CSF into the choroid plexus of the rat, with special reference to transepithelial transport.

Protein uptake from cerebral ventricles into the epithelium of the choroid plexus, and transport across the epithelium were studied ultrastructurally in rats. Horseradish peroxidase (HRP, MW 40,000) was used as protein tracer. Steady-state ventriculo-cisternal perfusion with subatmospheric pressure (-10cm of water) in the ventricular system was applied. HRP dissolved in artificial CSF was perfused from the lateral ventricles to cisterna magna for various times, and ventriculo-cisternal perfusion, vascular perfusion or immersion fixation with a formaldehyde-glutaraldehyde solution was performed. Coated micropinocytic vesicles containing HRP were seen both connected with the apical, lateral and basal epithelial surface and within the cells. Heavily HRP-labeled vesicles were often fused with the lining membrane of slightly labeled or unlabeled intercellular spaces. Since the apical tight junctions of the epithelium never appeared open or never contained HRP in the spaces between the fusion points, and since the intercellular spaces between adjacent epithelial cells below the junctions only infrequently contained tracer after 5 min, by increasing amounts after 15-60 min of HRP perfusion, a vesicular transport of HRP from the apical epithelial surface to the intercellular spaces, bypassing the tight junctions, is suggested. In addition to the transepithelial transport, micropinocytic vesicles also transported HRP to the lysosomal apparatus of the epithelial cells. With increasing length of exposure to HRP, a sequence of HRP-labeled structures could be evaluated, from slightly labeled apical vacuoles and multivesicular bodies to very heavily labeled dense bodies.

Animals↗
PubMed2004

Flexion gap configuration in total knee arthroplasty following high tibial osteotomy.

Previous reports have described the potentially compromising effect of a high tibial osteotomy (HTO) on the results of a subsequent total knee arthroplasty (TKA). Although the reasons are not clear, some authors reported problems in soft-tissue balancing. In a prospective study, 22 patients with an average interval of 5.8 years after closed-wedge HTO were operated for TKA. All operations were performed with a CT-free navigation system, and measurements of the extension and flexion gap were assessed. The intraoperative data were compared to a control group of 100 consecutive computer-assisted TKA without previous osteotomy. In the study group, a highly significant shift towards a medial opening of the flexion gap between the posterior condylar line and the tibial resection (study group 0.4+/-4.7 degrees medial opening versus control group 3.4+/-3.3 degrees lateral opening, p<0.001) was observed. In the study group, 10/22 showed a medial opening of the flexion gap compared to 11/100 in the control group. Surgeons should be aware of difficulties in soft-tissue balance in TKA following HTO, especially for the flexion gap configuration and the axial rotation of the femoral component.

Aged↗
PubMed2002

Location and morphology of chloride cells during the post-embryonic development of the european sea bass, Dicentrarchus labrax.

Location and morphology of chloride cells were studied in the sea bass ( Dicentrarchus labrax) from hatching to the juvenile stage to determine the development of the adult osmoregulatory function as seen in adult fish. During the studied developmental sequence changes were observed in the location, number, size and structure of these cells, that were studied by microscopy (light, scanning electron, transmission electron and confocal) and immunocytochemistry. Chloride cells were found on the tegument and on the gills. They were present on the tegument already at hatching, before the development of the gills. Their density as well as their association in multicellular complexes decreased during the postembryonic development. In old larvae and in juveniles, cutaneous chloride cells were associated with the fins, the developing scales and the lateral line. Gills developed gradually during the prelarval stage and the gill arches were present at mouth opening. At that time chloride cells were already numerous on the gill arches. In older larvae, during the progressive development of the gill filaments, chloride cells were numerous on these structures and formed multicellular complexes. Several stages in the differentiation of these cells were studied, including the development of the tubulovesicular system at the end of the prelarval stage, as well as the stratification appearance of the cytoplasm that was concomitant with the considerable development of the tubular system and its association with the endoplasmic reticulum during the larval period. The involvement of different epithelia in the osmoregulatory process during the postembryonic development of this species, as well as the role of chloride cells during successive developmental stages, is discussed.

Adaptation, Physiological↗
PubMed1992

Auditory and visual verbal short-term memory in aphasia.

Phonological short-term memory was investigated in 24 aphasic left brain-damaged patients and in 12 matched controls. Aphasic patients have a reduced auditory and visual immediate memory span and show the standard detrimental effect of phonological similarity on immediate retention only when the stimuli are auditorily presented, while in the control group the effect is present with both auditory and visual input. Most patients have phonological processing deficits, but two patients have an impaired immediate verbal memory in the absence of analysis disorders. These results, in line with most individual case studies of patients with selective deficits of verbal short-term memory, are interpreted with reference to a model distinguishing a phonological short-term store component of memory, to which auditory input has direct and automatic access, and a rehearsal component, that, after phonological recoding, conveys visually presented stimuli to the phonological store. This latter system, that appears to become fully operational later in development, is less resistive to brain damage.

Adult↗
PubMedDate not supplied

[The lumbar ligamentum flavum. Anatomic characteristics with reference to microdiscotomy].

One important step in lumbar discotomy is the safe penetration and exact partial removal of the Lig. flavum. This is a crucial prerequisite for the selective and gentle removal of prolapsed and sequestrated intervertebral disc tissue. Extensive lancing of the Lig. flavum should be avoided, to minimize intraoperative and postoperative complications, such as injuries to the nerves and the Dura mater, instabilities, bleeding and scarring. As there has up to now been insufficient information on the anatomy of the Lig. flavum especially regarding microdiscotomy, an analysis of the Ligg. flava L2/L3 to L5/S1, guided by this aim, was carried out on 36 corpses kept in formaline (16 f, 20 m; 52-78 y). Preparations showed the lumbar Ligg. flava to be embodied in the Foramina interarcualia in a characteristic configuration. There also proved to be defined insertion areas on the laminae of the vertebral arches, which must be taken into consideration during the operative exposure. The Lig. flavum rises from the cranial vertebral arch from the ventral surface of the lamina (6.8 mm) whilst the insertion area on the caudal lamina covers the dorsal and the ventral surface. The extent at the ventral surface is 2.2 mm in average. Taking the insertion proportions into account we would suggest the Lig. flavum to be divided as follows: Pars interspinalis, which clearly differs from the Lig. interspinale (and from the M. interspinalis), and which houses venous anastomoses in its dorsal, ridge-shaped extension. Pars interlaminaris, which starts at the laminae and constitutes the target area for flavotomy in its lateral section, and Pars capsularis, which merges into the capsular structures of the facets. In all levels examined, there proved to be dorso-ventrally a typical change in the direction of the course of the fibres in the Pars interlaminaris. Whilst the direction of the fibres dorsally is oriented cranio-medially to caudo-laterally at an angle between 15 degrees and 30 degrees to the median line, the ventral fibres of the Lig. flavum are strictly aligned cranio-caudally. The changes in the directions of the fibres are continuous with the fibres being very closely intertwined, without there being any spatium at all. The texture of the Lig. flavum is, therefore, a mirror image of that of the autochthonuous muscular system of the back, even if the overlapping angle area is considerably smaller. The different segment levels show a segment-specific thickness profile. The analysis has provided anatomic information about the Ligg. flava L2/L3 to L5/S1. These data represent important prerequisites for a selective, gentle and safe intraoperative procedure for discotomy.

Aged↗
PubMed2003

Anchored flaps in post-Mohs reconstruction of the lower eyelid, cheek, and lateral canthus: avoiding eyelid distortion.

PURPOSE: To describe a system of post-Mohs reconstruction that addresses lower eyelid susceptibility to unopposed tractional, cicatricial, and gravitational forces. Large flaps are anchored to fixed tissue to avoid transmitting flap tension to the eyelids. METHODS: This is a retrospective, cohort study drawn from approximately 40 patients with post-Mohs defects of the nonmarginal lower eyelid, cheek, and lateral canthus. Surgical intervention involved horizontally oriented, relaxed skin tension line-designed advancement flaps, usually with eyelid margin stabilization. The use of anchoring sutures and any requirement for flap-graft combinations were based on defect size and the elasticity of adjacent tissues. RESULTS: Anchoring eyelid and cheek flaps to underlying periosteum permitted broad flap dissection and advancement without distortion, as the semimobile eyelid and canthi were protected from the resulting flap tension. Anticipated defect size limits for flap reconstruction often were exceeded. Defects too broad for flap reconstruction alone could be downsized, leaving a relatively small area for graft resurfacing. CONCLUSIONS: Anchored cheek flaps extend recognition of the continuity of the lower eyelid and midface to the primary reconstruction of tumor-free defects, and they address the relation by restoring deep attachments that minimize eyelid and canthal dystopia.

Basal Cell Carcinoma↗
PubMed2003

Spatial navigation after surgical resection of an acoustic neuroma: pilot study.

OBJECTIVE: To characterize navigation errors made by patients with the absence of vestibular function on one side owing to surgical resection of an acoustic neuroma. METHODS: Seventeen young (18-38 years) and 9 older healthy individuals (67-83 years), as well as 5 patients 2 to 20 months following surgery (37-61 years), were studied. They sidestepped laterally with eyes closed toward memorized targets located 1.25 m to their right or left. They stopped when they judged that they were in front of the target. The position of head and body markers was recorded in three dimensions with a six-camera Vicon 512 system (Oxford Metrics Ltd., Oxford, UK). Navigation errors were (1) distance error, the distance between the end target and a perpendicular line drawn from the sternum to the plane of targets, and (2) deviation, the angle formed between the line joining the initial and end targets and the line joining the subject's shoulders. RESULTS: Mean distance error was 20.9 +/- 22.0 degrees cm in patients, 29.6 +/- 30.3 cm in young healthy subjects, and -1.7 +/- 18.4 cm in older subjects (p < .01 compared with young subjects). Mean deviation was symmetric and 8 degrees and -3 degrees in healthy young and older subjects, respectively. In contrast, patients had a significantly larger deviation when navigating toward the side of their lesion than the intact side (13 degrees +/- 9 degrees versus 3 degrees +/- 9 degrees; p < .01). CONCLUSIONS: Our results suggest that patients with vestibular deficits have impaired ability to control body rotations when walking sideways without vision toward the side of their vestibular lesion.

Adolescent↗
PubMed1996

[Studies on the mechanism of embryo implantation].

Implantation is a complex process accomplished by synchronization and interactions between embryo and endometrium by local exchange of signals including a number of cytokines and growth factors and direct cell-cell and cell-matrix contact. However, the research in early events of human implantation is still in its infancy. This presentation comprises the results of our attempts to investigate the mechanisms of human implantation process in its early stage by cell-biological method, including establishment of experimental implantation model in vitro. 1. Human trophoblast of early stage of gestation showed active cell locomotion, active endocytosis, and invasion of endometrial cell monolayer in mixed cultures. Trophoblast invasion was later arrested by transformed endometrial cells similar to decidual cells in vivo. These results appeared to indicate the interactions between trophoblast and endometrial cells in implantation. 2. Coculture system of rabbit preimplantation blastocyst and endometrial epithelium reformed from isolated endometrial epithelial cells on basement membrane matrix (Matrigel) simulated the in vivo rabbit implantation processes. This coculture system may provide a useful experimental implantation model. 3. A human trophoblast cell line was established from chorionic tissues of normal early pregnancy. These cells were cytotrophoblast-like morphology and endocrine functions. They formed the villous structures similar to those in vivo in culture on Matrigel and invasion of Matrigel was observed. These indicated the extracellular matrix may affect the morphology and function of invading trophoblast in implantation site. 4. Human endometrial epithelial single cells were cultured on Matrigel. Reconstruction of gland followed by epithelium formation quite similar to in vivo structures by migration and proliferation of isolated cells was demonstrated. Height of gland was promoted by estrogen and initiation of epithelization was upregulated by platelet-derived growth factors. This system revealed the extracellular matrix regulated morphogenesis of endometrial epithelium in vivo and is an essential substrate in experimental implantation model of endometrial epithelium. 5. Parallel cultures of endometrial epithelial cells on Matrigel were carried out with the IVF. ET patients to evaluate the endometrial morphology at time of ET. Endometrial cultures were initiated in previous cycles on Matrigel and the sera of patients were added to her own cultures from 1st day of IVF treatment cycle. Evaluation of reformed epithelium revealed the apparently unsuitable morphology for implantation in group of patients who eventually failed in pregnancy. This system may provide a useful measures in evaluation of endometrial receptivity and modality of treatment for endometrial aberrations. 6. Cyclic changes of extracellular matrix components in endometrium were investigated. Collagen I, III, IV, V were immunohistochemically estimated. Relative levels of all types of collagen except for collagen V declined at early secretory phase. In rodents, not only collagen but also laminin and fibronectin levels declined at early secretory phase. These changes may facilitate trophoblast invasion of endometrium. Collagen V distributed in myometrial surface was found to consist of subunit (alpha 1)2 alpha 2 and trophoblast growth was inhibited on substrate of alpha 1 subunit. Collagen V in myometrial surface may have a role in blocking trophoblast invasion. 7. HGF (hepatocyte growth factor) mRNA was demonstrated to be expressed during menstruation and secretory phase in endometrium distinctly and its receptor in endometrial epithelial cells and decidual cells. Positive correlation between plasma HGF levels and ultrasonographic thickness of endometrium was observed at late secretory phase. Recombinant HGF promoted proliferation of endometrial epithelial cells and decidual cells and upregulated initiation of endometrial epithelization of Matrigel.

Animals↗
PubMed2003

Formation of the digestive system in zebrafish. II. Pancreas morphogenesis.

Recent studies have suggested that the zebrafish pancreas develops from a single pancreatic anlage, located on the dorsal aspect of the developing gut. However, using a transgenic zebrafish line that expresses GFP throughout the endoderm, we report that, in fact, two pancreatic anlagen join to form the pancreas. One anlage is located on the dorsal aspect of the developing gut and is present by 24 h postfertilization (hpf), the second anlage is located on the ventral aspect of the developing gut in a position anterior to the dorsal anlage and is present by 40 hpf. These two buds merge by 52 hpf to form the pancreas. Using heart and soul mutant embryos, in which the pancreatic anlagen most often do not fuse, we show that the posterior bud generates only endocrine tissue, while the anterior bud gives rise to the pancreatic duct and exocrine cells. Interestingly, at later stages, the anterior bud also gives rise to a small number of endocrine cells usually present near the pancreatic duct. Altogether, these studies show that in zebrafish, as in the other model systems analyzed to date, the pancreas arises from multiple buds. To analyze whether other features of pancreas development are conserved and investigate the influence of surrounding tissues on pancreas development, we examined the role of the vasculature in this process. Contrary to reports in other model systems, we find that, although vascular endothelium is in contact with the posterior bud throughout pancreas development, its absence in cloche mutant embryos does not appear to affect the early morphogenesis or differentiation of the pancreas.

Animals↗
PubMed1993

Rat placental lactogen-I binds to the choroid plexus and hypothalamus of the pregnant rat.

Recent findings suggest that placental lactogen has a role in the regulation of hypothalamic function during pregnancy. To explore the mechanisms by which placental hormones may exert effects in the maternal central nervous system, we have examined the binding of rat placental lactogen-I (rPL-I) to brain slices from pregnant rats at mid- and late gestation. The binding of rPL-I to maternal rat brain was compared with that of human GH (hGH). Radiolabelled rPL-I bound specifically to ependymal cells of the choroid plexus in the lateral ventricles and in the roof of the third ventricle. The binding of 125I-labelled rPL-I was inhibited by unlabelled rPL-I, hGH or rat prolactin but not by rat GH, indicating that rPL-I and rat prolactin interact with a common binding site in maternal rat brain. Radiolabelled hGH bound to the choroid plexus and to ependymal cells lining the third ventricle in the region of the arcuate nucleus. In addition, hGH bound specifically to the ventromedial nuclei and to the medial preoptic area of the hypothalamus. The binding of radiolabelled hGH to all brain regions was inhibited by unlabelled rPL-I as well as hGH, indicating that rPL-I competes for lactogenic binding sites in the hypothalamus as well as the choroid plexus of the pregnant rat. These findings suggest potential mechanisms by which placental hormones may exert direct effects on the maternal central nervous system during pregnancy. The precise functions and roles of the PL-I binding sites in maternal choroid plexus and hypothalamus remain to be explored.

Animals↗
PubMed2002

From the discovery of neuropilin to the determination of its adhesion sites.

Neuropilin (NRP) and plexin (Plex) that are now known to be semaphorin receptors were initially identified as antigens for monoclonal antibodies (MAbs) that bound to particular neuropiles and plexiform layers of the Xenopus tadpole optic tectum, several years before the discovery of semaphorin. The extracellular segment of the NRP protein is a mosaic of 3 functionally different protein motifs that are thought to be involved in molecular and/or cellular interactions, suggesting that NRP serves in a various cell-cell interaction by binding a variety of molecules. The first identified function of NRP was the cell adhesion activity; Cell reaggregation study using NRP-expressing cell lines revealed that NRP can mediate cell adhesion via heterophilic molecular interaction. Later, NRP was shown to bind semaphorins and vascular endothelial growth factor (VEGF). It was also shown that NRP makes receptor complexes with Plex to propagate semaphorin signals.

Adhesiveness↗
PubMed1986

Ultrastructural investigation of fetal rat brain hemisphere tissue in nonadherent stationary organ culture.

Fetal rat brain fragments grown in nonadherent stationary organ culture for 50 days have been investigated ultrastructurally. Synaptogenesis and myelin formation occurred at the same time as the corresponding time-dependent events in the developing brain in vivo. Intermediate junctions were observed between cellular processes lining a central cavity in the fragments and later associated with astrocytes at the surface. Gap junctions and tight junctions were also present. In some fragments cilia were observed in the central cavity. Subependymal basement membrane labyrinths were observed in all fragments after 10 days in culture. The ultrastructural characteristics and the tissue-like structure in general were preserved for at least 50 days in this tissue culture system. The brain fragments may therefore be a valuable supplement to existing culture methods for nervous tissue.

Animals↗
PubMed1979

Analgesia produced by microinjection of baclofen and morphine at brain stem sites.

Microinjection of either baclofen (1.5 microgram) or morphine (2.5 microgram), in equimolar doses (14 mM), at sites located in the caudal periaqueductal gray (PAG) resulted in a delay in tail flick latency (analgesia). The relative analgesic potency of baclofen among caudal PAG sites, however, did not correlate with that of morphine. Application of either drug into the caudal aspect of the cerebral aqueduct also produced analgesia, but neither agent caused analgesia when applied at PAG sites rostral to the interaural line. Baclofen also produced analgesia when microinjected in the lower brain stem at sites lateral to the midline in or near the nucleus gigantocellularis, but did not produce analgesia when applied on the midline at sites located within or near the raphe magnus. Conversely, morphine produced analgesia when applied locally at midline sites but not at sites located lateral to the midline. These data suggest that the analgesia produced by systemic administration of baclofen and morphine involves activation of different neuronal substrates.

Analgesics↗