Anaesthetic potency of inhalation agents is independent of membrane microviscosity

The decrease in membrane microviscosity of erythrocyte ghosts in the presence of clinically relevant concentrations of seven inhalation anaesthetic agents was studied using fluorescence polarization anisotropy of the membrane incorporated fluorescent probes 1,6-diphenyl- 1,3,5-hexatriene and 1-[4-trimethylammoniumphenyl]-6-phenyl-1,3,5- hexatriene. All anaesthetic agents produced a dose-dependent decrease in anisotropy of both probes, indicating decreased membrane microviscosity. The reduction in anisotropy measured at the minimum alveolar concentration (ED50) for anaesthesia was related inversely to the anaesthetic potency of the agent and was directly proportional to the hypothetical concentration of agent in the membrane calculated from lipid-water partition coefficients. These findings do not support the hypothesis that volatile anaesthetic agents act by increasing membrane microviscosity of the bulk lipid bilayer to produce anaesthesia.      

Structure of autonomic neuromuscular junctions in the sinus venosus of the toad.

The structure of cholinergic and adrenergic neuromuscular junctions in the sinus venosus of the toad, Bufo marinus, was determined by electron microscopy. From random sections of sinus venosus tissue it appeared that there were variable separations between cholinergic or adrenergic varicosities and the nearest sinus venosus muscle cell. However, when the structure of complete cholinergic and adrenergic varicosities was determined by examining serial electron micrographs, virtually all varicosities that lost their covering of Schwann cell were found to form an area of close apposition with an adjacent muscle cell. At the region of close apposition, the neuromuscular cleft was filled with a single layer of basal lamina to give a neuromuscular separation of about 70 nm. Synaptic vesicles within a varicosity were usually found to be concentrated towards the region of close apposition. These observations are discussed in relationship to the idea that when transmission occurs at these neuromuscular junctions the transmitters act on discrete pools of specialized subsynaptic receptors.     

The fragile X syndrome.

An amplification of a highly unstable DNA element has been identified at the fragile X locus in Xq27.3. This sequence appears to be both the source of the primary mutation causing the fragile X syndrome, apparently having its causative effect through the methylation of the FMR-1 HTF island and the region of cytogenetic fragility. The direct analysis of the genotype of carrier and affected individuals can be used as a direct diagnosis tool which will improve both the accuracy and speed of diagnosis. The identification of hereditary unstable DNA in a disease with such a wide level of non-penetrance and variable phenotype may give clues as to the basis of non-penetrance in other human genetic disorders.     

New approaches to QSAR: Neural networks and machine learning

Summary Neural networks and machine learning are two methods that are increasingly being used to model QSARs. They make few statistical assumptions and are nonlinear and nonparametric. We describe back-propagation from the field of neural networks, and GOLEM from machine learning, and illustrate their learning mechanisms using a simple expository problem. Back-propagation and GOLEM are then compared with multiple linear regression (using the parameters and their squares) on two real drug design problems: the inhibition ofEscherichia coli dihydrofolate reductase (DHFR) by pyrimidines and the inhibition of rat/mouse tumour DHFR by triazines.     

Results of revision total knee arthroplasty performed for aseptic loosening

One hundred thirty-seven revision total knee arthroplasties (TKA) performed in 117 patients with failed aseptic metal-to-plastic knees over ten years (1974-1984) were studied to determine the long-term clinical and roentgenographic results and were compared to primary TKA. The mean age was 65 years (range, 32-90 years). Fifty-three percent had rheumatoid arthritis, and 47% had osteoarthritis. The mean interval from initial to revision TKA (129 knees) was four years (range, three months to 11 years) and from the first to second revision (seven knees) was 2.4 years (range, seven months to 5.5 years). The most common reasons for failure were loosening (73%), patellar complications (13%), and instability (10%). The mean follow-up time was 5.2 years (range, two to 12 years). Function, instability, motion, and pain all improved after revision TKA, but these improvements were significantly less than those seen after primary TKA. One-third of the patients still ambulated with crutches, a walker, or not at all. While mean postoperative flexion was 100 degrees, 24% could not flex to 90 degrees. Most patients (90%) were malaligned at the time of failure and remained so after revision (78%). The increased incidence of radiolucent lines (tibial, 61%; femoral, 24%) was not related to increased failure. Complications were not increased over primary TKA. The failure rate was 5.8% at 5.2 years, or approximately 1% per year. A successful clinical result was defined as a knee with mild or no pain, mild or no instability, and flexion to at least 90 degrees.(ABSTRACT TRUNCATED AT 250 WORDS)