Pathogenesis of non-traumatic atlanto-axial subluxation (Grisel''s syndrome)

Ten years ago' endothelium derived relaxing factor' was identified as nitric oxide (NO.). This highly significant discovery revealed the importance of NO. in normal physiology and pathophysiology. Research over the past decade into the potential therapeutic use of inhaled NO. in the management of ARDS is reviewed. In critical care, inhaled NO. seems to produce selective pulmonary vasodilation and this is already beginning to have an impact on the management of lung injuries including ARDS. The effect of NO. in multi-system failure is not yet established. Formal evaluation in the form of clinical trials has yet to be undertaken, and further study of all the potential side effects and toxicity are required for conclusive evidence of the value of inhaled NO. in the treatment of ARDS.     

Enhanced radioresponse of paclitaxel-sensitive and -resistant tumours in vivo

Functional assembly of the plasminogen-dependent proteolytic system on the cell surface requires multiple interactions involving urokinase (uPA), urokinase receptor (uPAR), plasminogen activator inhibitors, and other molecules that mediate cell migration and adhesion. We analyzed the in vitro interaction of uPAR-containing particulate cell fractions with the amino-terminal fragment (ATF) of human urokinase and the matrix-like form of vitronectin. Binding and cross-linking of 125I-labeled ATF to crude membrane extracts from LB6-19 mouse cells overexpressing human uPARs in the presence of 25 nM urea-denatured vitronectin led to the formation of Mr 137,000, 92, 000, and 82,000 covalent complexes. Immunoprecipitation of the preformed cross-linked 125I-labeled complexes with anti-vitronectin, anti-uPA, or anti-uPAR antibodies revealed that the Mr 82,000 and 92, 000 species do contain ATF and vitronectin and identified the Mr 137, 000 species as a ternary complex formed by ATF, uPAR, and vitronectin. A similar electrophoretic pattern was displayed by acid-pretreated membranes extracted from MCF-7 breast carcinoma or HT1080 fibrosarcoma cell lines, as well as a ductal breast carcinoma specimen; the latter exhibited complex formation at concentrations of vitronectin lower than 10 nM. Finally, uPAR-vitronectin interaction was further documented by the decreased reactivity of an anti-uPAR polyclonal antibody to acid-pretreated sections of 10 breast carcinomas that had been preincubated with vitronectin. Our findings highlight the ability of uPAR to interact simultaneously with vitronectin and uPA in breast cancer, supporting a dynamic coupling of the molecular mechanisms underlying plasminogen-dependent matrix degradation and cell adhesion.     

ATP- and gap junction-dependent intercellular calcium signaling in osteoblastic cells

Many cells coordinate their activities by transmitting rises in intracellular calcium from cell to cell. In nonexcitable cells, there are currently two models for intercellular calcium wave propagation, both of which involve release of inositol trisphosphate (IP3)- sensitive intracellular calcium stores. In one model, IP3 traverses gap junctions and initiates the release of intracellular calcium stores in neighboring cells. Alternatively, calcium waves may be mediated not by gap junctional communication, but rather by autocrine activity of secreted ATP on P2 purinergic receptors. We studied mechanically induced calcium waves in two rat osteosarcoma cell lines that differ in the gap junction proteins they express, in their ability to pass microinjected dye from cell to cell, and in their expression of P2Y2 (P2U) purinergic receptors. ROS 17/2.8 cells, which express the gap junction protein connexin43 (Cx43), are well dye coupled, and lack P2U receptors, transmitted slow gap junction-dependent calcium waves that did not require release of intracellular calcium stores. UMR 106-01 cells predominantly express the gap junction protein connexin 45 (Cx45), are poorly dye coupled, and express P2U receptors; they propagated fast calcium waves that required release of intracellular calcium stores and activation of P2U purinergic receptors, but not gap junctional communication. ROS/P2U transfectants and UMR/Cx43 transfectants expressed both types of calcium waves. Gap junction-independent, ATP-dependent intercellular calcium waves were also seen in hamster tracheal epithelia cells. These studies demonstrate that activation of P2U purinergic receptors can propagate intercellular calcium, and describe a novel Cx43-dependent mechanism for calcium wave propagation that does not require release of intracellular calcium stores by IP3. These studies suggest that gap junction communication mediated by either Cx43 or Cx45 does not allow passage of IP3 well enough to elicit release of intracellular calcium stores in neighboring cells.     

Posttraumatic amnesia: its relation to functional outcome

OBJECTIVE: To investigate the relation between duration of posttraumatic amnesia (PTA) and functional outcome in a traumatically brain injured population. PATIENTS: Two hundred seventy-six patients with traumatic brain injury (TBI) who were admitted to a Level I university trauma center and required inpatient rehabilitation. MEASURES: Duration of PTA was assessed by serial administrations of the Galveston Orientation Amnesia Test (GOAT). Functional Independence Measure (FIM) total scores, FIM cognitive and motor subscores, and Disability Rating Scale (DRS) scores were obtained at admission and discharge from inpatient rehabilitation. RESULTS: Duration of PTA was a significant predictor of all admission and discharge DRS and FIM scores. Duration of PTA and age at the time of injury, in combination, contributed significantly to the prediction of the DRS score and FIM total, cognitive, and motor scores at discharge. CONCLUSION: Duration of PTA appears to be a useful variable in predicting specific functional outcome in the TBI population receiving inpatient rehabilitation services. The use of age as a factor in addition to duration of PTA enhances the prediction of functional outcome.     

Left ventricular geometry in presenting untreated hypertension

In order to investigate the spectrum of geometry in our patient population, 63 untreated hypertensives underwent two-dimensional echocardiography. Left ventricular (LV) mass index and relative wall thickness, a measure of wall thickness in relation to cavity size, were calculated from the M-mode strip. In addition, to assess the sphericity of the left ventricle the ratio of LV minor to major hemiaxis was calculated. The subjects comprised 41 men (17 Caucasian, 22 Afro-Caribbean and two Oriental), and 21 women (five Caucasian, 12 Afro-Caribbean and two Oriental). Concentric hypertrophy was present in 46% of subjects, concentric remodelling in 32% of subjects, eccentric hypertrophy in only 6% of subjects and a normal left ventricular shape in 16% of subjects. The degree of sphericity of the left ventricle was similar among the four groups, suggesting that it does not change in uncomplicated hypertension. In contrast to the previously published combined series from Sassari and New York we had a low proportion of patients with either eccentric hypertrophy or normal left ventricular geometry. This is probably due to the high proportion of Afro-Caribbean subjects in our clinic population who are more likely to have left ventricular hypertrophy.     

Thermodynamics of dT--dT base pair mismatching in linear DNA duplexes and three-arm DNA junctions

We have used a combination of magnetic-suspension densimetry and calorimetry to derive complete thermodynamic profiles, including volume changes, for the formation of linear DNA duplexes and three-arm branched DNA junctions, from their component strands, with and without dT-dT mismatches. The formation of each type of complex at 20 degrees C is accompanied by a favorable free energy, with a favorable enthalpy term partially compensated by an unfavorable entropy. Formation is associated also with net uptake of water molecules. Using the formation of the fully-paired linear duplex or three-arm junction as reference states, we can establish a thermodynamic cycle in which the contribution of the single-strand species cancels. From this cycle, we determine that substitution of dA for dT has a differential free energy of deltadeltaG degrees of +2.4 kcal mol(-1) for mismatched duplex and +2.0 kcal mol(-1) (on the average) for the mismatched junction. These unfavorable differential free energies result from an unfavorable enthalpy, partially compensated by a favorable entropy, and a negative deltadeltaV. The free energies in the two cases have signs opposed to those of deltadeltaV, a situation that implicates hydration changes in creating the mismatch. When the deltadeltaV terms are normalized by the total number of base pairs involved, the immobilization of structural water molecules (and/or substitution of electrostricted for hydrophobic water molecules) is about 7 times greater for junctions than duplexes. This is consistent with more extensive hydrophobic hydration of branched DNA structures than of duplexes.