Resolution of intractable retching following mobilization of a dolichoectatic vertebral artery: case report of a unique brainstem-cranial nerve compression syndrome.

The authors present the case of a 53-year-old man who was referred with disabling retching provoked by left arm abduction. At the time of his initial evaluation, a cervical MRI study was available for review and revealed an anatomical variation of the ipsilateral juxtamedullary vertebrobasilar junction. After brain imaging revealed contact of the medulla by a dolichoectatic vertebral artery at the dorsal root entry zone of the glossopharyngeal and vagus nerves, the patient was successfully treated by microvascular decompression of the brainstem and cranial nerves. This case demonstrates how a dolichoectatic vertebral artery-a common anatomical variation that typically has no clinical consequence-should be considered in cases of cranial nerve dysfunction.

New Concept to Restore Normal Cell Responses in Osteoarthritic Knee Joint Cartilage.

Prediction of osteoarthritis progression does not exist. Cartilage "health" and degeneration during osteoarthritis depend on the signals perceived by chondrocytes. We hypothesize that biomechanical responses of chondrocytes in osteoarthritic cartilage can be restored close to their normal state. We propose an approach to evaluate quantitatively these responses in human joints and demonstrate how they can return close to normal levels.

Topographical investigation of changes in depth-wise proteoglycan distribution in rabbit femoral articular cartilage at 4 weeks after transection of the anterior cruciate ligament.

In this study, we explore topographical changes in proteoglycan distribution from femoral condylar cartilage in early osteoarthritis, acquired from both the lateral and medial condyles of anterior cruciate ligament transected (ACLT) and contralateral (CNTRL) rabbit knee joints, at 4 weeks post operation. Four sites across the cartilage surface in a parasagittal plane were defined across tissue sections taken from femoral condyles, and proteoglycan (PG) content was quantified using digital densitometry. The greatest depth-wise change in PG content due to an ACLT (compared to the CNTRL group) was observed anteriorly (site C) from the most weight-bearing location within the lateral compartment. In the medial compartment, the greatest change was observed in the most weight-bearing location (site B). The depth-wise changes in PG content were observed up to 48% and 28% depth from the tissue surface at these aforementioned sites, respectively (p < 0.05). The smallest depth-wise change in PG content was observed posteriorly (site A) from the most weight-bearing location within both femoral condyles (up to 20% and up to 5% depth from the tissue surface at lateral and medial compartments, respectively). This study gives further insight into how early cartilage deterioration progresses across the parasagittal plane of the femoral condyle.

Controlling cell-cell interactions using surface acoustic waves.

The interactions between pairs of cells and within multicellular assemblies are critical to many biological processes such as intercellular communication, tissue and organ formation, immunological reactions, and cancer metastasis. The ability to precisely control the position of cells relative to one another and within larger cellular assemblies will enable the investigation and characterization of phenomena not currently accessible by conventional in vitro methods. We present a versatile surface acoustic wave technique that is capable of controlling the intercellular distance and spatial arrangement of cells with micrometer level resolution. This technique is, to our knowledge, among the first of its kind to marry high precision and high throughput into a single extremely versatile and wholly biocompatible technology. We demonstrated the capabilities of the system to precisely control intercellular distance, assemble cells with defined geometries, maintain cellular assemblies in suspension, and translate these suspended assemblies to adherent states, all in a contactless, biocompatible manner. As an example of the power of this system, this technology was used to quantitatively investigate the gap junctional intercellular communication in several homotypic and heterotypic populations by visualizing the transfer of fluorescent dye between cells.

Probing cell-cell communication with microfluidic devices.

Intercellular communication is a mechanism that regulates critical events during embryogenesis and coordinates signalling within differentiated tissues, such as the nervous and cardiovascular systems. To perform specialized activities, these tissues utilize the rapid exchange of signals among networks that, while are composed of different cell types, are nevertheless functionally coupled. Errors in cellular communication can lead to varied deleterious effects such as degenerative and autoimmune diseases. However, the intercellular communication network is extremely complex in multicellular organisms making isolation of the functional unit and study of basic mechanisms technically challenging. New experimental methods to examine mechanisms of intercellular communication among cultured cells could provide insight into physiological and pathological processes alike. Recent developments in microfluidic technology allow miniaturized and integrated devices to perform intercellular communication experiments on-chip. Microfluidics have many advantages, including the ability to replicate in vitro the chemical, mechanical, and physical cellular microenvironment of tissues with precise spatial and temporal control combined with dynamic characterization, high throughput, scalability and reproducibility. In this Focus article, we highlight some of the recent work and advances in the application of microfluidics to the study of mammalian intercellular communication with particular emphasis on cell contact and soluble factor mediated communication. In addition, we provide some insights into likely direction of the future developments in this field.

How the structural integrity of the matrix can influence the microstructural response of articular cartilage to compression.

This study investigated how the structural integrity of healthy, surface-removed (healthy), and degenerate matrices can modify the response of cartilage to compression. Six groups of specimens were loaded up to the onset of consolidation or at full consolidation (N = 30, 5 per group, respectively) and then subsequently chemically fixed to capture the deformed state of the tissues. Creep compression was applied through an 8 mm flat-ended indenter containing a 450 µm diameter central pore, providing a region of high stress that also allowed the tissue samples to deform freely around the indenter pore during compression. Differential interference contrast microscopy was used in order to explore the microstructural responses of the tissues. The results demonstrated that superficial layer removal or tissue degeneration can reduce the observed deformation within the tissue region corresponding to the central pore of the loading indenter. Fibril crimping within the central pore matrix and matrix shear at the indenter edge regions are also reduced by both superficial layer removal and by tissue degeneration. These findings suggest that surface removal or tissue degeneration renders the matrix more susceptible to deformation and can also reduce the tissue's ability to transfer forces over a greater surface area and induce stress within the matrix.

Articular cartilage surface failure: an investigation of the rupture rate and morphology in relation to tissue health and hydration.

This study investigates the rupture rate and morphology of articular cartilage by altering the bathing environments of healthy and degenerate bovine cartilage. Soaking tissues in either distilled water or 1.5 M NaCI saline was performed in order to render the tissues into a swollen or dehydrated state, respectively. Creep compression was applied using an 8 mm flat-ended polished indenter that contained a central pore of 450 microm in diameter, providing a consistent region for rupture to occur across all 105 tested specimens. Rupture rates were determined by varying the nominal compressive stress and the loading time. Similar rupture rates were observed with the swollen healthy and degenerate specimens, loaded with either 6 or 7MPa of nominal compressive stress over 11 and 13 min. The observed rupture rates for the dehydrated specimens loaded with 7 MPa over 60 and 90s were 20% versus 40% and 20% versus 60% for healthy and degenerate tissues, respectively. At 8 MPa of nominal compressive stress over 60 and 90s the observed rupture rates were 20% versus 60% and 40% versus 80% for healthy and degenerate tissues, respectively; with all dehydrated degenerate tissues exhibiting a greater tendency to rupture (Barnard's exact test, p < 0.05). Rupture morphologies were only different in the swollen degenerate tissues (p < 0.05). The mechanisms by which dehydration and swelling induce initial surface rupture of mildly degenerate articular cartilage differ. Dehydration increases the likelihood that the surface will rupture, however, swelling alters the observed rupture morphology.

Articular cartilage surface rupture during compression: investigating the effects of tissue hydration in relation to matrix health.

This study aimed at investigating articular cartilage rupture by investigating the response of healthy and degenerate cartilage through altering the osmotic swelling environment of surface-intact, cartilage-on-bone specimens. The osmotic environment in healthy and degenerate bovine cartilage was varied by soaking tissues in either distilled water or 1.5 M NaCl saline to render the tissues into a swollen or dehydrated state (respectively). Creep compression was applied using an 8 mm flat-ended polished indenter that contained a central pore of 450 µm diameter, providing a consistent region for rupture to occur across all specimens. In the first set of experiments, surface rupture of healthy and degenerate specimens required similar levels of nominal compressive stress (8 MPa) when dehydrated than when swollen (7 MPa). In the second set of experiments, the time required for surface rupture to occur (for healthy and degenerate specimens) occurred over similar loading times (p>0.05). However, the time required for surface rupture for the swollen specimens occurred over a significantly longer time (approximately one order of magnitude) than that required for the dehydrated specimens (p<0.05). The compressive strains that were measured at rupture in the dehydrated degenerate specimens were significantly lower than those measured in the dehydrated healthy tissues (p<0.05). Rupture in dehydrated degenerate cartilage suggested a weakened articular surface, and it also suggested that dehydrated cartilage may undergo failure due to stress concentrations as it is unable to redistribute stress away from the site of loading.

Articular cartilage compression: how microstructural response influences pore pressure in relation to matrix health.

Our research investigated the influence of degeneration on both the pore-pressure development and microstructural response of cartilage during indentation with a flat-porous-indenter. Experiments were conducted to link the mechanical and structural responses of normal and degenerate articular cartilage. We found that from the instant of loading the degenerate matrix generated a higher peak hydrostatic excess pore pressure in a shorter period of time than the normal matrix. Following the attainment of this peak value the pore pressure in both tissue groups then gradually decayed toward zero over time, thus demonstrating a classical consolidation response. The microstructural analysis provided a unique insight into the influence of degeneration on the mechanisms of internal stress-sharing within the loaded matrix. Both disruption of the articular surface and general matrix destructuring results in an altered deformation field in both the directly loaded and nondirectly loaded regions. It is argued that the higher levels of matrix shear combined with less of the applied load being redirected into the wider cartilage continuum accounts for the elevated levels of peak hydrostatic pore pressure generated in the degenerate matrix.

Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial.

To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.

Caveolin-1 expression is maintained in rat and human astroglioma cell lines.

Caveolin-1 is the principal structural and functional component of caveolae, a plasmalemmal compartment that has been proposed to sequester lipid and protein components that participate in transmembrane signal transduction processes. Multiple studies reveal a reduction in the expression level of caveolin-1 mRNA and protein in many carcinomas as well as transformed cells. The human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). Collectively, these data have been taken to imply that caveolin-1 may function in a tumor suppressor capacity. To determine if a reduction in the expression level of caveolin-1 mRNA and protein accompanied the transformation of astrocytes, we undertook studies of two transformed rat astroglial cell lines, C6 and DI TNC(1), as well as several cell lines derived from human glioblastoma tumors: T98G, U87MG, U118MG, U138MG, and U373MG. Ultrastructural, immunolocalization, immunoblot, and Northern blot analyses demonstrated that caveolin-1 message and protein were expressed in all rat and human glioma cells. The localization pattern, buoyant density, and detergent-insolubility property of caveolin-1 protein were indistinguishable from that determined for nontransformed type 1 astrocytes in culture. Nucleotide sequence analyses of caveolin-1 cDNAs indicate that mutations are not present in the caveolin-1 sequence in any of the glioma cell types. Taken together with previous analyses, these data indicate that, at least for astrocytes, the process of transformation in and of itself is not solely sufficient to reduce the level of caveolin-1 expression, and that caveolin-1 expression in and of itself is not solely sufficient to prevent the acquisition of a transformed phenotype.