A phase II trial of murine monoclonal antibody 17-1A and interferon-γ: Clinical and immunological data

Summary A group of 15 patients with metastatic colorectal adenocarcinoma received a combination of interferon (0.1 mg/m², days 1–15) and the murine monoclonal antibody 17-1A (400 mg, days 5, 7, 9 and 12). The treatment was tolerated with minimal toxicity. Of the 14 evaluable patients, 13 developed human antibody to murine 17-1A, with 11 patients demonstrating antibody to the variable region of 17-1A (anti-idiotype). Antibody to the variable region was inhibited by 17-1A but not by mouse immunoglobulin. Sera from patients with substantial anti-idiotype reactivity were capable of inhibiting the binding of murine 17-1A to antigen expressing LS174-T cells thus indicating the presence of antibody directed against the 17-1A combining site (mirror-image anti-idiotype). The median survival of the whole group was 56 weeks and there was no correlation between clinical response/survival and the development of anti-idiotype antibody.Supported by the Veterans Administration Medical Center and by Public Health Services grant CA 45 232 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services     

Control of respiratory motor pattern by sensory neurons in spinal cord of lamprey

Summary Extracellular stimulation over the dorsal funiculus in the spinal cord of lampreys was found to selectively activate prolonged episodes of fictive arousal respiration (Figs. 1, 3). The induced episodes showed comparable increases in cycle frequency and motoneuron burst duration to the spontaneous arousal pattern observed in isolated brain preparations (Fig. 2). Intracellular stimulation of primary sensory neurons with axons in the dorsal funiculus, called dorsal cells, also elicited the arousal pattern (Fig. 4). Mechanoreceptive dorsal cells respond to cutaneous stimulation. When mechanical stimuli were applied to the skin of intact lampreys (Fig. 6) or to lampreys with ipsilateral vagotomy, arousal respiration was induced (Figs. 7, 8). Bilateral, but not unilateral, trigeminal lesion blocked dorsal cell induction of the arousal response (Fig. 5). Spontaneous arousal respiration was recorded from intact, unrestrained lampreys (Fig. 9). These results suggest that fictive arousal respiration is the in vitro correlate of natural arousal respiration in lampreys, and that one mechanism leading to arousal respiration may be the activity of sensory dorsal cells. A model for respiratory motor pattern switching in lamprey is proposed. The model suggests that the normal and arousal patterns are produced by separately engaging rostral or caudal pattern generators in the medulla, rather than by modifying one pattern generator (Fig. 10).     

The Alzheimer amyloid precursor-related transcript lacking the beta/A4 sequence is specifically increased in Alzheimer's disease brain

The deposition of cerebrovascular and plaque amyloid in the CNS is a primary feature of Alzheimer's disease and aged Down's syndrome pathology. The localization of the Alzheimer amyloid protein precursor (APP) gene on chromosome 21, along with its overexpression in Down's syndrome brain compared with normal brain, suggests that alterations in APP gene expression may play a role in the development of the neuropathology common to the two diseases. In the present report, we demonstrate that a specific spliced form of mRNA that is transcribed from the APP gene and that lacks the beta/A4 sequence is elevated in the nucleus basalis, occipitotemporal cortex, and parahippocampal gyrus in Alzheimer's disease brain relative to controls. These results are based on combined data from RNA slot blot analysis, in situ hybridization, and polymerase chain reaction quantification of specific mRNAs taken directly from tissue sections.     

Medical problems of adults who were sexually abused in childhood.

The aim of the study was to see whether adults who had been sexually abused in childhood were vulnerable to physical symptoms and therefore investigation and intervention. The case histories of seven patients who were aged 22-39, were under the care of three consultant psychiatrists, had experienced childhood sexual abuse, and had a history of medical or surgical intervention were surveyed. The patients had had a mean of 18 contacts with non-psychiatric consultant teams and a mean of eight operations, with a high rate (66-70%) of normal findings. They had experienced many somatic symptoms, which led to investigations and interventions in the specialties of gynaecology, obstetrics, gastroenterology, urology, rheumatology, haematology, orthopaedics, neurology, and neuropsychiatry. The history of childhood sexual abuse was recognised only in the later stages of this medical and surgical intervention. The possibility of childhood sexual abuse should be considered earlier in such cases to prevent further unnecessary intervention.     

Canine alpha-L-fucosidase in relation to the enzymic defect and storage products in canine fucosidosis.

Canine liver alpha-L-fucosidase was purified to apparent homogeneity by affinity chromatography on agarose-epsilon-aminohexanoyl-fucopyranosylamine. It is composed of multiple forms of a common active subunit of 45-50 kDa, which can aggregate in different combinations to form polymers, predominantly dimers. Antiserum was raised against the purified enzyme. There is negligible residual alpha-L-fucosidase in the tissues of English springer spaniels with the lysosomal storage disease fucosidosis. Although no alpha-L-fucosidase protein was detected by Western blotting or by the purification procedure in the affected tissues, some enzymically inactive cross-reacting material was detected in both normal and affected tissues. This suggests that another protein without alpha-L-fucosidase activity was co-purified with the enzyme. Dog liver alpha-L-fucosidase was precipitated by goat anti-(human liver alpha-L-fucosidase) IgG, indicating homology between the enzymes in the two species. Two purified storage products isolated from the brain of a dog with fucosidosis were used as natural substrates for various preparations of canine liver alpha-L-fucosidase. Analysis of the digestion mixtures by t.l.c. and fast-atom-bombardment mass spectrometry suggests that canine alpha-L-fucosidase acts preferentially on the alpha-(1-3)-linked fucose at the non-reducing end and that removal of alpha-(1-6)-linked asparagine-linked N-acetylglucosamine is rate-limiting in the lysosomal catabolism of fucosylated N-linked glycans.     

Segmentation and moral status in vivo and in vitro: a scientific perspective

A basic consideration in research on human embryos is the controversy about when the embryo acquires moral status. The author refutes the contention that segmentation is the determinant of moral status. She notes that segmentation, as a stage in embryonic development, does not coincide with the development of "irreversible individuality" upon which the segmentation argument depends. Dawson also finds a lack of clarity in the meaning of "individuality." These problems, she maintains, prevent segmentation from being morally important and render the proposed 14-day limit on embryo research unnecessary. Dawson concludes that to introduce a time restriction on embryo research is premature because it is based on an inadequate philosophical argument.     

Site-directed mutagenesis to fine-tune enzyme specificity

We have used a combination of a genetic selection and oligonucleotide-directed mutagenesis to introduce a series of amino acid replacements for a single residue into Escherichia coli glutaminyl-tRNA synthetase. The mutant enzymes mischarge supF tRNA(Tyr), with glutamine, to varying degrees depending on the polarity of the side chain introduced but apparently not depending on the size or shape of the side chain. These results indicate that repulsive charge-charge interactions may be important for specific recognition of nucleic acids by proteins and illustrate how a mutant, derived from genetic selection, may be further modified in activity by oligonucleotide-directed mutagenesis.     

Variation in adhesion and cell surface hydrophobicity in Candida albicans white and opaque phenotypes

A previous study had established that a select group of pathogenic isolates of Candida albicans was capable of switching heritably, reversibly and at a high frequency (10^–2 to 10^–3) between two phenotypes (white or opaque) readily distinguishable by the size, shape, and color of colonies formed on agar at 25°C. This paper describes experiments designed to determine the ability of these two phenotypes to attach to buccal epithelial cells (BECs) and plastic, and to compare the cell surface hydrophobicities of white and opaque phenotypes from three clinical isolates. White cells were found to be significantly more adhesive to BECs, and a strong correlation was also found between phenotype adhesiveness and the percentage of BECs to which C. albicans had attached. The percentage of BECs with one or more attached C. albicans was approximately 90% for the white phenotype and approximately 50% for the opaque phenotype. Opaque cells, in contrast, were twice as hydrophobic as white cells, and the percentage of opaque cells bound to BECs by coadhesion was also double that of white cells. The differences in adhesion to plastic between the two phenotypes were not statistically significant and there was no distinct trend to suggest which phenotype might be more adhesive to plastic. These results indicate that several factors are involved in the adhesion of C. albicans to plastic, and confirm the hypothesis that cell surface hydrophobicity is of minor importance in direct adhesion to epithelial cells but that it may contribute to indirect attachment to epithelial cells by promoting yeast coadhesion. Moreover, the data presented in this paper also revealed that under identical growth conditions, adhesion of C. albicans was significantly altered depending on the phenotypic state of the organism tested. Therefore, because C. albicans can switch at a high frequency to various phenotypes in vitro, it may be that in future adhesion studies involving Candida the phenotypic state of the organism at the time of testing will have to be determined. Otherwise, the results, even within the same laboratory, may be difficult to interpret.