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PubMed1994

The relationship between the design, position, and articular wear of acetabular components inserted without cement and the development of pelvic osteolysis.

Between 1983 and 1987, an acetabular component with a unique chamfered-cylinder design was inserted without cement in 134 hips. With use of this design, initial stability is achieved through a cylindrical interference fit with the peripheral rim of the acetabulum, without the need for pegs, spikes, or screws. At an average of sixty-four months (range, forty to ninety-six months) after implantation, follow-up data were available for 113 hips (ninety-three patients). No component had been revised for loosening or was radiographically loose. However, the prevalence of balloon-like osteolysis of the pelvis was 17 per cent (nineteen hips). This bone loss was generally not associated with pain or other symptoms. Ten of the nineteen hips that were associated with pelvic osteolysis (including six of the nine that were associated with osteolysis of the ilium) had been reconstructed with use of an acetabular component that had no holes in the shell (that is, the shell was completely solid). This finding indicates that, while elimination of holes through the acetabular shell may have advantages, it will not prevent pelvic osteolysis. The osteolysis of the ilium was associated with a lateral opening of the acetabular component of more than 50 degrees (p < 0.0001). All of the hips in this series had insertion of a porous-ingrowth femoral resurfacing component made of titanium alloy. These components are no longer used. Revision of the femoral side due to osteolysis provided a unique opportunity to inspect directly forty-two clinically well functioning acetabular components. All of the polyethylene liners and acetabular shells were found to be rigidly fixed. Inflammatory tissue at the periphery of the implant-bone interface resulted in circumferential resorption of periacetabular bone despite rigid fixation of the component. This is direct evidence that a process of bone resorption similar to that reported at the cement-bone interface of cemented acetabular components can occur at the implant-bone interface of components inserted without cement. At the reoperation, a communication that had led to the pelvic osteolysis was found through areas of bone resorption at the periphery of the implant-bone interface. These areas were essentially cystic and were filled with a mixture of fluid and friable, yellow-tan tissue. It appeared that the osteolytic process had expanded into the soft cancellous bone and marrow while being contained by the denser cortical shell of the pelvic bones.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetabulum↗

PubMedDate not supplied

PACS sans RIS.

Sutter Gould Medical Foundation (SGMF) is a multi-specialty physician practice located in Modesto, CA, and is an affiliate of Sutter Health. In May 2003, SGMF embarked on the journey to install a picture archiving and communication system (PACS) in the main facility. Unique to the project was bringing the PACS live sans (from the French "without") a radiology information system (RIS) and having the PACS driven by an electronic medical record (EMR). Other challenges were present in terms of interfaces for the dictation system, delivering images to the providers on their desktop, and mimicking the referring providers workflow as much as possible in the digital environment to which they were accustomed in the "paper and film" environment.

California↗

PubMed1995

Description and advantages of an index-driven medical knowledge base.

In the FRAMEMED system design, the inherent attributes of its concepts are expressed in the hierarchical lists of its 26 Elements (e.g., Agents, Clinical Manifestations, Diseases, Tests, etc.). These concepts, contained in regular structures, are then alphabetized by phrase (and synonym), forming a combined index in which the user may quickly find a concept either alphabetically or hierarchically. Stored in the structures of the index are pointers to four types of knowledge records: 1) Descriptive (definition); 2) Relational (incidental attributes); 3) Conditional (rules); and 4) Procedural (how to). In contrast to the index which is stored in regular structures for rapid access (like relational databases), the knowledge records are stored in free text (variable length) and may include pointers to imaging and audio records. A particular feature of the FRAMEMED system is careful attention to modifiers, an aspect usually not emphasized in other systems. In trying to structure the free text describing a patient encounter, for example, the major concepts such as cough, fever, stiff neck, etc., are relatively easy to code (although a common system has not yet been agreed upon). The devil lies in the modifiers such as 'history of', 'severe,' 'constant,' 'absent,' 'left,' 'abnormal,' etc., particularly when there is concatenation of modifiers modifying modifiers. Our Relational records (in our knowledge base) and our Chronological Medical Records (CMR) in our patient record have the same format, namely, a title, several related items, and a date/author. For example, our disease profile (Relational record) for 'Influenza' might include 'cough,' 'fever,' and 'stiff neck.' The CMR of a particular patient encounter might include the same items. The only differences would be the title (disease name for the disease profile, date for the CMR, and the omission of the redundant date in the date/author line of the CMR). Each related item in either of these records is expressed in a four-part string, namely: 1) Relation; 2) Code; 3) Phrase; and 4) Comment. Modifiers (common ASCII symbols) are structured into each of these parts. For example, if the patient did not have 'cough,' the default '+' in the Relation would be edited to a '-', while 'history of' cough would be '>'. Each Relation can be graded (on a 5-level scale) for both importance and frequency. The Code for a test can carry the result suffix, '+ positive/high,' '-negative/low,' '# abnormal (qualitatively)', or '1 unremarkable/normal.' Topological information, such as '/left,' can be appended to a Code. If the cough is getting worse, its code can have the suffix, '<'. The standardized Phrases associated with the Codes come from the hierarchical lists of the index section described earlier. Phrases are not stored, being rematched to the codes as needed for user display. This practice not only saves memory space but allows a CMR encounter recorded in one language to be displayed in another second language subsequently, requiring only the existence of the hierarchical code/phrase in the second language. A free-text Comment is allowed for any related item in a Relational record or CMR, to allow the doctor to add important nuances such as 'worse on arising' or for a numeric result such as a test result or a thermometer reading. Some structuring can be accommodated in the Comment by introducing symbols such as '> relieved by,' followed by a list containing entries such as 'antacids.' Time can be sturctured through symbol lists such as '@-2 mo' representing '2 months previously.' Because Relational records in the knowledge ase and patient encoutner records in the CMR both display findings in hierarchical order; all similar items (e.g., Agents, Clinical Manifestations, Tests, Procedures, etc.) occur together and in an unique order. (abstract truncated)

Abstracting and Indexing↗

PubMed1999

The membrane association domain of RGS16 contains unique amphipathic features that are conserved in RGS4 and RGS5.

Regulators of G protein signaling (RGS proteins) modulate G protein-mediated signaling pathways by acting as GTPase-activating proteins for Gi, Gq, and G12 alpha-subunits of heterotrimeric G proteins. Although it is known that membrane association is critical for the biological activities of many RGS proteins, the mechanism underlying this requirement remains unclear. We reported recently that the NH2 terminus of RGS16 is required for its function in vivo. In this study, we show that RGS16 lacking the NH2 terminus is no longer localized to the plasma membrane as is the wild type protein, suggesting that membrane association is important for biological function. The region of amino acids 7-32 is sufficient to confer the membrane-targeting activity, of which amino acids 12-30 are predicted to adopt an amphipathic alpha-helix. Site-directed mutagenesis experiments showed that the hydrophobic residues of the nonpolar face of the helix and the strips of positively charged side chains positioned along the polar/nonpolar interface of the helix are crucial for membrane association. Subcellular fractionation by differential centrifugation followed by conditions that distinguish peripheral membrane proteins from integral ones indicate that RGS16 is a peripheral membrane protein. We show further that RGS16 membrane association does not require palmitoylation. Our results, together with other recent findings, have defined a unique membrane association domain with amphipathic features. We believe that these structural features and the mechanism of membrane association of RGS16 are likely to apply to the homologous domains in RGS4 and RGS5.

Amino Acid Sequence↗

PubMed2006

The conformations of the manganese transport regulator of Bacillus subtilis in its metal-free state.

The manganese transport regulator (MntR) from Bacillus subtilis binds cognate DNA sequences in response to elevated manganese concentrations. MntR functions as a homodimer that binds two manganese ions per subunit. Metal binding takes place at the interface of the two domains that comprise each MntR subunit: an N-terminal DNA-binding domain and a C-terminal dimerization domain. In order to elucidate the link between metal binding and activation, a crystallographic study of MntR in its metal-free state has been undertaken. Here we describe the structures of the native protein and a selenomethionine-containing variant, solved to 2.8 A. The two structures contain five crystallographically unique subunits of MntR, providing diverse views of the metal-free protein. In apo-MntR, as in the manganese complex, the dimer is formed by dyad-related C-terminal domains that provide a conserved structural core. Similarly, each DNA-binding domain largely retains the folded conformation found in metal bound forms of MntR. However, compared to metal-activated MntR, the DNA-binding domains move substantially with respect to the dimer interface in apo-MntR. Overlays of multiple apo-MntR structures indicate that there is a greater range of positioning allowed between N and C-terminal domains in the metal-free state and that the DNA-binding domains of the dimer are farther apart than in the activated complex. To further investigate the conformation of the DNA-binding domain of apo-MntR, a site-directed spin labeling experiment was performed on a mutant of MntR containing cysteine at residue 6. Consistent with the crystallographic results, EPR spectra of the spin-labeled mutant indicate that tertiary structure is conserved in the presence or absence of bound metals, though slightly greater flexibility is present in inactive forms of MntR.

Apoproteins↗

PubMed1991

Rearrangement of the metaphyseal vasculature of the rat growth plate in rickets and rachitic reversal: a model of vascular arrest and angiogenesis renewed.

The morphology of the metaphyseal microvasculature at the epiphysis was examined at both the light and electron microscopic level in rickets and rachitic reversal. The animals studied were normal, rachitic, and rachitic reversed at 8, 24, and 96 hours post-vitamin D administration. The overall architecture of the metaphyseal vessels was significantly altered throughout the intervals examined. In the rachitic animal, arterioles, venules, and capillaries were found adjacent to the growth plate, either directly apposed to the hypertrophic chondrocytes or separated from them by bone-forming cells. These vessels are in many ways similar to the larger arterioles and venules that normally supply the metaphyseal capillary sprouts, but in the normal growing animal are usually located 350-500 microns from the epiphyseal cartilage. The rachitic capillaries appear relatively well differentiated with a partial basement membrane and a perivascular cell lining. In early rachitic reversal, small vascular projections are induced to grow from the large diameter venules that border upon the hypertrophic chondrocytes. These vascular sprouts that invade the epiphyseal cartilage are quite undifferentiated, with no basement membrane or pericyte lining at the sprout apex and occasional abluminal endothelial cell projections. Within 96 hours, the metaphyseal microvasculature has returned to an apparently normal state with only capillaries at the cartilage-vascular interface and larger vessels (arterioles and venules) located several hundred microns deeper into the metaphysis. The sequential processes of differentiation and cessation of capillary growth followed by dedifferentiation and reinitiation of microvascular growth make the rachitic system a unique one in which to study angiogenesis.

Animals↗

PubMed1995

Dictyocaulus viviparus: surface antigens of the L3 cuticle and sheath.

The bovine lungworm Dictyocaulus viviparus induces a highly protective immune response in the bovine host. It is consequently a particularly useful host-parasite system for the study of those antigens and immune responses which can induce protective immunity against a parasitic nematode. We have generated monoclonal antibodies to the L3 cuticle and sheath surfaces in order to define antigens present at the host-parasite interface of infective larvae. Three monoclonal antibodies generated against the surface of the infective L3 cuticle bind to a PC-like hapten, and the presence of such an epitope exposed on the cuticular surface appears to be unique to the D. viviparus L3. Six monoclonal antibodies which bind to the surface of the L3 sheath all detect an antigen which is immunodominant in immunised cattle. The possible basis and implications of such marked antigenicity of a molecule on the L3 sheath surface are discussed.

Animals↗

PubMed2004

Crystal structure of the actin binding domain of the cyclase-associated protein.

Cyclase-associated protein (CAP or Srv2p) is a modular actin monomer binding protein that directly regulates filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localization and the establishment of cell polarity. The crystal structure of the C-terminal dimerization and actin monomer binding domain (C-CAP) reveals a highly unusual dimer, composed of monomers possessing six coils of right-handed beta-helix flanked by antiparallel beta-strands. Domain swapping, involving the last two strands of each monomer, results in the formation of an extended dimer with an extensive interface. This structural and biochemical characterization provides new insights into the organization and potential mechanistic properties of the multiprotein assemblies that integrate dynamic actin processes into the overall physiology of the cell. An unanticipated finding is that the unique tertiary structure of the C-CAP monomer provides a structural model for a wide range of molecules, including RP2 and cofactor C, proteins involved in X-linked retinitis pigmentosa and tubulin maturation, respectively, as well as several uncharacterized proteins that exhibit very diverse domain organizations. Thus, the unusual right-handed beta-helical fold present in C-CAP appears to support a wide range of biological functions.

Actins↗

PubMed2004

The anti-Müllerian hormone type II receptor: insights into the binding domains recognized by a monoclonal antibody and the natural ligand.

Anti-Müllerian hormone (AMH) [also called Müllerian inhibiting substance (MIS)] is a member of the transforming growth factor-beta family. AMH and its type II receptor (AMHR-II) are involved in the regression of the Müllerian ducts in the male embryo, and in gonadal functions in the adult. AMH is also known to be a marker of granulosa and Sertoli cell tumours. We selected a high-affinity monoclonal antibody, mAb 12G4, specific for human AMHR-II (hAMHR-II), by FACS analysis, Western blotting and immunohistochemical staining of a hAMHR-II-transfected CHO (Chinese hamster ovary) cell line, normal adult testicular tissue and granulosa cell tumours. Using peptide array screening, we identified the binding sequences of mAb 12G4 and AMH on the receptor. Identification of Asp53 and Ala55 as critical residues in the DRAQVEM minimal epitopic sequence of mAb 12G4 definitively accounted for the lack of cross-reactivity with the murine receptor, in which there is a glycine residue in place of an aspartic acid residue. In a structural model, the AMH-binding interface was mapped to the concave side of hAMHR-II, whereas the mAb 12G4-binding site was located on the convex side. mAb 12G4, the first mAb to be raised against hAMHR-II, therefore has unique properties that could make it a valuable tool for the immunotargeting of tumours expressing this receptor.

Alanine↗

PubMed2002

Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure.

Brca1 C-terminal (BRCT) domains are a common protein-protein interaction motif in proteins involved in the DNA damage response and DNA repair. The DNA-damage response protein 53BP1 has two BRCT domains that bind to the DNA-binding domain of p53. The 53BP1 tandem-BRCT region is homologous to the tandem-BRCT region of Brca1, which is involved in double-strand break repair and homologous recombination and which binds BACH1, a member of the DEAH helicase family. Here we report the structures of a human 53BP1-p53 complex and of the rat Brca1 BRCT repeats. The 53BP1-p53 structure shows that the two BRCT repeats are arranged tandemly and pack extensively through an interface that also involves the inter-repeat linker. The first BRCT repeat and the linker together bind p53 on a region that overlaps with the DNA-binding surface of p53 and involves p53 residues that are mutated in cancer and are important for DNA binding. Comparison with the structure of the tandem-BRCT region of Brca1 shows a remarkable conservation of the repeat arrangement and of the inter-BRCT repeat interface. Analysis of human BRCA1 tumor-derived mutations and conservation identifies a potential protein-binding site that we show through mutagenesis is involved in BACH1 binding. The BACH1-binding region of Brca1 consists of a unique insertion in the first BRCT repeat and the inter-repeat linker and is analogous to the region of 53BP1 that binds p53.

Amino Acid Sequence↗

PubMed1998

[Computer-assisted evaluation of aortic aneurysm morphology for choosing the method of therapy].

Computer aided surgery planning software for AAA is a industry-standard software development for viewing patient-specific data on a personal computer through a unique approach, which improve visualization, navigation, and decision support capabilities for both open and endovascular surgery. Raw scan data is extracted from CT scans, and rendered into a three-dimensional format. This 3D modeling technology and user interface provides a patient-specific model with a rapid visual access to the full range of information, including accurate 3D assessment of AAA morphology and pathology, interactive multiplanar reconstructions, measurements, and views to assist the surgeon in understanding of complex 3D relationships. It provides an optimal system for patient evaluation and selection for endovascular repair of AAA and in the post-operative evaluation of stent deployment and/or complications, such as endoleaks.

Aortic Aneurysm↗

PubMed1996

Crystal structure of macrophage migration inhibitory factor (MIF), a glucocorticoid-induced regulator of cytokine production, reveals a unique architecture.

The mediator originally described as a macrophage migration inhibitory factor (MIF) has been identified recently to be a novel anterior pituitary hormone and the first protein to be released from immune cells upon stimulation with glucocorticoids. Once released, MIF acts to override or counter-regulate the immunosuppressive effects of glucocorticoids on cytokine production in vitro and on LPS lethality in vivo. MIF also has been described to catalyze a tautomerization reaction, suggesting that an enzymatic activity may underlie certain of its biological properties. The three-dimensional crystal structure of human MIF has been solved at 2.6A resolution. The X-ray crystal structure reveals MIF to be a trimer of identical subunits. Each monomer contains two antiparallel alpha-helices that pack against a four-stranded beta-sheet. The monomer has an additional two beta-strands that interact with the beta-sheets of adjacent subunits to form the interface between monomers. The three beta-sheets are arranged to form a barrel containing a solvent-accessible channel that runs through the center of the protein along a molecular three-fold axis. Electrostatic potential maps reveal that the channel has a positive potential, suggesting that it binds negatively charged molecules. The elucidated structure for MIF is unique among cytokines or hormones and suggests that this glucocorticoid-induced counter-regulatory hormone has a novel mechanism of action.

Animals↗

PubMed2001

Hydration state of single cytochrome c monolayers on soft interfaces via neutron interferometry.

Yeast cytochrome c (YCC) can be covalently tethered to, and thereby vectorially oriented on, the soft surface of a mixed endgroup (e.g., -CH3/-SH = 6:1, or -OH/-SH = 6:1) organic self-assembled monolayer (SAM) chemisorbed on the surface of a silicon substrate utilizing a disulfide linkage between its unique surface cysteine residue and a thiol endgroup. Neutron reflectivities from such monolayers of YCC on Fe/Si or Fe/Au/Si multilayer substrates with H2O versus D2O hydrating the protein monolayer at 88% relative humidity for the nonpolar SAM (-CH3/-SH = 6:1 mixed endgroups) surface and 81% for the uncharged-polar SAM (-OH/-SH = 6:1mixed endgroups) surface were collected on the NG1 reflectometer at NIST. These data were analyzed using a new interferometric phasing method employing the neutron scattering contrast between the Si and Fe layers in a single reference multilayer structure and a constrained refinement approach utilizing the finite extent of the gradient of the profile structures for the systems. This provided the water distribution profiles for the two tethered protein monolayers consistent with their electron density profile determined previously via x-ray interferometry (Chupa et al., 1994).

Biophysical Phenomena↗

PubMed2005

Novel two-dimensional "ring and chain" morphologies in Langmuir-Blodgett monolayers of PS-b-PEO block copolymers: effect of spreading solution concentration on self-assembly at the air-water interface.

A polystyrene-b-poly(ethylene oxide) (PS-b-PEO) (MW = 141k, 11.4 wt% PEO) diblock copolymer in the hydrophobic regime was spread from chloroform solutions of various concentrations at the air-water interface, and the resultant monolayers were transferred to glass substrates and imaged using atomic force microscopy. Monolayers prepared under identical conditions were also characterized at the air-water interface via Langmuir compression isotherms. The effects of spreading solution concentration on surface features, compressibility, and limiting mean molecular area were determined, revealing several interesting trends that have not been reported for other systems of PS-b-PEO. Spreading solutions > or = 0.50 mg/mL resulted almost exclusively in dot and spaghetti morphologies, with no observed continent features, which have been commonly found in more hydrophobic systems. For lower spreading solutions, < or = 0.25 mg/mL, we observed a large predominance of two novel surface morphologies, nanoscale rings and chains. The surface pressure (pi)-area (A) isotherms also exhibited a unique dependence on the spreading solution concentration, with limiting mean molecular areas and isothermal compressibilities of PS-b-PEO monolayers increasing below a critical concentration of spreading solution, suggesting a greater contribution from the PEO blocks. These results suggest that PS chain entanglement prior to solvent evaporation plays an important kinetic role in the extent of PEO adsorption at the air-water interface and in the morphologies of the resulting self-assembled surface aggregates.

Journal Article↗

PubMed2005

Proteomic analysis of rhoptry organelles reveals many novel constituents for host-parasite interactions in Toxoplasma gondii.

Rhoptries are specialized secretory organelles that are uniquely present within protozoan parasites of the phylum Apicomplexa. These obligate intracellular parasites comprise some of the most important parasites of humans and animals, including the causative agents of malaria (Plasmodium spp.) and chicken coccidiosis (Eimeria spp.). The contents of the rhoptries are released into the nascent parasitophorous vacuole during invasion into the host cell, and the resulting proteins often represent the literal interface between host and pathogen. We have developed a method for highly efficient purification of rhoptries from one of the best studied Apicomplexa, Toxoplasma gondii, and we carried out a detailed proteomic analysis using mass spectrometry that has identified 38 novel proteins. To confirm their rhoptry origin, antibodies were raised to synthetic peptides and/or recombinant protein. Eleven of 12 of these yielded antibody that showed strong rhoptry staining by immunofluorescence within the rhoptry necks and/or their bulbous base. Hemagglutinin epitope tagging confirmed one additional novel protein as from the rhoptry bulb. Previously identified rhoptry proteins from Toxoplasma and Plasmodium were unique to one or the other organism, but our elucidation of the Toxoplasma rhoptry proteome revealed homologues that are common to both. This study also identified the first Toxoplasma genes encoding rhoptry neck proteins, which we named RONs, demonstrated that toxofilin and Rab11 are rhoptry proteins, and identified novel kinases, phosphatases, and proteases that are likely to play a key role in the ability of the parasite to invade and co-opt the host cell for its own survival and growth.

Animals↗

PubMed2004

Three-dimensional structure of the vacuolar ATPase. Localization of subunit H by difference imaging and chemical cross-linking.

The structure of the proton-pumping vacuolar ATPase (V-ATPase) from bovine brain clathrin coated vesicles was analyzed by electron microscopy and single molecule image analysis. A three-dimensional structural model of the complex was calculated by the angular reconstitution method at a resolution of 27 A. Overall, the appearance of the V(0) and V(1) domains in the three-dimensional model of the intact bovine V-ATPase resembles the models of the isolated bovine V(0) and yeast V(1) domains determined previously. To determine the binding position of subunit H in the V-ATPase, electron microscopy and cysteine-mediated photochemical cross-linking were used. Difference maps calculated from projection images of intact bovine V-ATPase and a V-ATPase preparation in which the two H subunit isoforms were removed by treatment with cystine revealed less protein density at the bottom of the V(1) in the subunit H-depleted enzyme, suggesting that subunit H isoforms bind at the interface of the V(1) and V(0) domains. A comparison of three-dimensional models calculated for intact and subunit H-depleted enzyme indicated that at least one of the subunit H isoforms, although poorly resolved in the three-dimensional electron density, binds near the putative N-terminal domain of the a subunit of the V(0). For photochemical cross-linking, unique cysteine residues were introduced into the yeast V-ATPase B subunit at sites that were localized based on molecular modeling using the crystal structure of the mitochondrial F(1) domain. Cross-linking was performed using the photoactivatable sulfhydryl reagent 4-(N-maleimido)benzophenone. Cross-linking to subunit H was observed from two sites on subunit B (E494 and T501) predicted to be located on the outer surface of the subunit closest to the membrane. Results from both electron microscopy and cross-linking analysis thus place subunit H near the interface of the V(1) and V(0) domains and suggest a close structural similarity between the V-ATPases of yeast and mammals.

Animals↗

PubMed2007

Analysis of coating structures and interfaces in solid oral dosage forms by three dimensional terahertz pulsed imaging.

Three dimensional terahertz pulsed imaging (TPI) was evaluated as a novel tool for the nondestructive characterization of different solid oral dosage forms. The time-domain reflection signal of coherent pulsed light in the far infrared was used to investigate film-coated tablets, sugar-coated tablets, multilayered controlled release tablets, and soft gelatin capsules. It is possible to determine the spatial and statistical distribution of coating thickness in single and multiple coated products using 3D TPI. The measurements are nondestructive even for layers buried underneath other coating structures. The internal structure of coating materials can be analyzed. As the terahertz signal penetrates up to 3 mm into the dosage form interfaces between layers in multilayered tablets can be investigated. In soft gelatin capsules it is possible to measure the thickness of the gelatin layer and to characterize the seal between the gelatin layers for quality control. TPI is a unique approach for the nondestructive characterization and quality control of solid dosage forms. The measurements are fast and fully automated with the potential for much wider application of the technique in the process analytical technology scheme.

Capsules↗

PubMed1999

What is the blood-brain barrier? A molecular perspective. Cerebral vascular biology.

The term "blood-brain barrier" was coined over one hundred years ago as a result of the observation that vital dyes introduced into the circulation quickly penetrated and stained nearly all organs and tissues of the mammalian body except the brain which retained its pale creamy appearance. Advances in microscopy revealed that, in contrast to other vascular beds, the brain endothelial cells lining the vascular wall are tightly linked with junctional complexes that eliminate gaps or spaces between cells and prevent any free diffusion of blood-borne substances into the brain parenchymal space. The endothelial cells, situated at the interface between blood and brain, therefore, play a critical role in performing essential biological functions including transport of micro- and macronutrients, receptor-mediated signaling, leukocyte trafficking, and osmoregulation. A number of molecular components responsible for some of these unique properties have now been identified and are being characterized under physiological and disease conditions. These include the proteins involved in formation and assembly of tight junctions; the plasma membrane-embedded proteins that are responsible for transport of brain energy substrates and nutrients (glucose, monocarboxylic acids, nucleosides, amino acids, others); the multi-drug transporter protein, p-glycoprotein, and other drug-rejecting proteins that protect the brain from foreign, potentially disruptive chemicals. These and other recent findings, taken as a whole, reveal the brain endothelium as a complex and dynamic biological system, in contrast to the simple, inert and rigid barrier initially perceived.

Animals↗