Cholinergic side-effects of tetrahydroaminoacridine.
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Biomedical subjects
Publications and source records attributed to R Morgan.
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A site-specific endonuclease was isolated from a eukaryotic Chlorella-like green alga infected with the dsDNA-containing virus NYs-1. The enzyme recognizes the sequence 5'-CC-3' and cleaves 5' to the first C. It cleaves 5'-CmC-3' sequences but not 5'-mCC-3' sequences. The enzyme creates breaks in dsDNA whenever two 5'-CC-3' sequences on opposite strands are close enough for the two strands to separate; when the 5'-CC-3' sequences on opposite strands are further apart only a portion of the strands separate. Consequently, NYs-1 endonuclease does not produce a completely stable DNA digestion pattern. The enzyme probably does not cleave ssDNA and definitely does not cleave ssRNA or dsRNA.
Whole-arm Robertsonian rearrangements are common constitutional changes of chromosomes that possess unusual properties. They occur spontaneously, are not inducible by ionizing radiation or clastogenic chemicals, show an exceptionally high meiotic mutation rate and nonrandom chromosome composition. A sample of 30 Robertsonian rearrangements in cancer patients revealed only three to have been acquired, none as a primary or significant secondary cancer chromosome change. The frequency of Robertsonian rearrangements is in the range of one per 1,100 at birth versus one acquired per 10,000 in cancer. Consistent with the prediction that Robertsonian rearrangements are recombinants, a subfamily of alpha satellite DNA displays selective homology between the centromeric regions of acrocentric autosomes proportional to their preferential entry into Robertsonian chromosomes. Recombination leading to Robertsonian rearrangements is common in meiosis, but is rare in mitosis. Hence, Robertsonian rearrangements are rare in cancer.
The Philadelphia (Ph) chromosome translocation which is classically observed in chronic myeloid leukemia (CML) is sporadically found in acute lymphoblastic leukemia (ALL). In CML the translocation breakpoint on chromosome 22 is within the breakpoint cluster region, while in childhood ALL, no detectable change in breakpoint cluster region is routinely observed. In order to investigate the nature of this difference, we have established and characterized two cell lines from a child with Ph positive ALL. The cell lines have retained the cytochemical staining pattern, enzyme activity, monoclonal antibody profile, and immunoglobulin gene rearrangements of the child's malignant cells. The cell lines had the same Ph translocation t(9;22) (q34;q11) as the child's malignant cells along with additional chromosome changes. Southern blot analysis showed that the Ph translocation did not involve the 5.8-kilobase breakpoint cluster region segment characteristically seen in CML. The cell lines reported here will be a valuable resource in ascertaining the biological significance of the Ph translocation seen in ALL.
The mechanism of cyanide intoxication has been attributed to the inhibition of cytochrome oxidase, thereby decreasing the tissue utilization of oxygen. One mechanism of cyanide antagonism is by sequestering cyanide with methaemoglobin to form cyanmethaemoglobin and another mechanism is detoxifying with a sulphur donor to thiocyanate. Questions have been raised with regard to these classical mechanisms. Oxygen with nitrite-thiosulphate antagonizes the lethal effects of cyanide. Theoretically, increased oxygen should serve no useful purpose, as it is the tissue utilization of oxygen which is inhibited. In the nitrite-thiosulphate antidotal combination, the proposal is made that the predominate antidotal action of nitrite is a vasogenic action, rather than methaemoglobin formation, because when methaemoglobin formation is inhibited by methylene blue the protective action of sodium nitrite persists. This suggests that methaemoglobin formation plays only a small part, if any, in the therapeutic antagonism of the lethal effects of cyanide. The roles and implications of sodium thiosulphate and non-rhodanese substrates in the detoxification mechanism are compared. Lastly, a new approach to cyanide antagonism has been initiated which involves the erythrocyte encapsulation of thiosulphate and sulphurtransferase as an antidote and prophylaxis against cyanide.
Fragile sites in chromosome bands 4q23 and 7q11.23 were discovered in bone marrow cells. Expression of these fragile sites was induced by treatment of the cells sequentially with 10(-7) M methotrexate and then 10(-5) M thymidine. No expression was observed in bone marrow cells without treatment. The fragile sites at 4q23 and 7q11.23 were seen individually, together, and in the homozygous state in a total of 20 bone marrow samples. The bone marrow karyotypes were normal in all cases. Expression of these common fragile sites at 4q23 and 7q11.23 could not be induced in blood lymphocytes from two subjects using methotrexate and thymidine, or by any other means including the addition of bromodeoxyuridine and fluoro-deoxyuridine or growth in folate-deficient medium. Because the fragile sites at 4q23 and 7q11.23 have never been observed in lymphocytes treated with methotrexate and thymidine for high-resolution chromosome analysis, it appears that these fragile sites are not expressed under these conditions in T lymphocytes. We propose that the differential expression of these fragile sites in bone marrow cells reflects genes active in bone marrow cells but not in blood lymphocytes.
We present a case of B-cell acute lymphoblastic leukemia (ALL) in whose leukemic cells trisomy 5 (+5) was the only cytogenetic anomaly observed. This is the first report of +5 as the sole cytogenetic abnormality in ALL; two cases (one questionable) of acute nonlymphocytic leukemia with such a change have been reported. The findings are presented in relation to other cases with +5 as part of a more complicated cytogenetic picture in hematologic disorders.
A case of pancytopenia with dysplastic changes in the bone marrow with trisomy 11 (+11) as the sole karyotypic anomaly in an adult male is described. The literature on +11, both as a primary (14 cases) and secondary (55 cases) cytogenetic event in hematologic disorders, is summarized and the findings are discussed. There is the possibility that +11 is a nonrandom chromosomal anomaly in some myelodysplastic disorders.
Inversions of the long (q) arm of chromosome #5 are reported in five cases with hematologic disorders. Inversion of 5q with breakpoints in bands 5q13 and 5q33 was found in two cases with lymphoid malignancy and in two cases of myeloid hematologic malignancy. Because an inversion of 5q with breakpoints in 5q22 and 5q33 was also found in a case with myeloproliferative syndrome, the common denominator in these five cases was band 5q33. An extraordinary cluster of genes affecting cell growth and differentiation is present on 5q and may be altered by the chromosome rearrangement of 5q in hematologic disorders.
In T cell malignancy, rearrangements of chromosome 14 have been observed with a break in the band that contains the alpha chain gene for the T cell receptor (TCR). Because the beta chain TCR gene is in chromosome band 7q34, we searched for and report finding specific rearrangements of 7q34 exclusively in T cell malignancies. The rearrangements were reciprocal translocations between 7q34 and other points: 1p34, 9q32, 9q34, 15q22, and 19p13. The malignancies containing a 7q34 translocation were either T cell acute lymphoblastic leukemias or T cell lymphoblastic lymphomas that had similarities in clinical, enzyme, immunologic, and cellular characteristics. Hybridization using a probe to the beta-TCR gene disclosed unique rearrangements consistent with clonality in every case. A common pattern with chromosome breakpoints involving TCR genes may be emerging in T cell neoplasia.
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This paper describes the establishment and characterization of a new cell line (SUP-B7) which was established from a child with "common" acute lymphoblastic leukemia. The SUP-B7 cells (and the patient's tumor) have been characterized by cytochemical staining, monoclonal antibodies, enzyme analyses, gene rearrangement studies, and karyotype analysis. The SUP-B7 cells are periodic acid-Schiff positive, common acute lymphoblastic leukemia antigen positive, and terminal deoxynucleotidyl transferase positive, and they lack the Epstein-Barr virus genome. In addition, the SUP-B7 cells lack cytoplasmic and surface immunoglobulins, and the immunoglobulin gene rearrangement studies showed rearranged heavy chain genes with germ line light chain genes. Concordance between the cell line and the patient's tumor was established by the immunoglobulin gene rearrangement studies. Using Southern blot analysis of the DNA from the patient's tumor and the SUP-B7 cells, there was comigration of the bands representing the rearranged immunoglobulin heavy chain gene. In addition, the SUP-B7 cells possess a single chromosome abnormality: del(3)(q26q28), with the chromosome breakpoint at or near the transferrin receptor gene. Since the SUP-B7 cell line is concordant with the patient's malignancy and since these cells possess a single chromosomal abnormality, the SUP-B7 cell line may be a useful tool in determining the biological significance of the chromosome deletion: del(3)(q26q28).
The definition of resectability has changed in the management of advanced pelvic malignancy. Most tumors previously considered unresectable can be removed by a function-preserving composite resection of the pelvis. We have performed resection in 55 such patients. Most had posterior pelvic tumors (47 patients), had previously undergone irradiation, and required a combined sacral resection. Included were patients with recurrent or locally advanced rectal cancer (32 patients), epidermoid cancer of the anorectum (seven patients), and primary pelvic malignancies (eight patients). Most had good functional recovery. The five-year actuarial survival rate was 23% (five of 25 patients survived longer than 51 months) in the patients with resected rectal cancer and 14% (one of seven patients) in the patients with resected anorectal carcinoma. Five of eight patients with primary tumors survived longer than 48 months. Lateral pelvic resections were done for five tumors that involved the ileum or ischium, and anterior resection was done in three patients for malignancy that involved the symphysis and rami. Four of these patients were living three to six years after surgery. The overall mortality rate was 7% (four of 55 patients). Composite pelvic resections can provide good local control with preservation of limb function in most patients with primary or secondary tumors of the bony pelvis.
The maintenance of human equilibrium is a complex process. Several physiological systems provide afferent information for postural stabilization. This study describes a noninvasive methodology to estimate the relative roles of interacting afferent inputs relevant for postural control. A multiaxis force platform in conjunction with specially designed test procedure provided semi-quantitative insight into the roles of vision, proprioceptors and vestibular apparatus in controlling postural sway when it was perturbed by a central nervous system perturbator such as alcohol. Experiments were conducted on 10 male and 10 female subjects. The males did not show statistically significant increases in body sway at these low levels of alcohol. For the females, the present methodology could detect subtle changes in postural sway at low blood alcohol levels ranging between 0.015% and 0.03%. At these low levels of alcohol, the results from females show that when the vision was excluded and the proprioception was modified, the postural sway was most affected. The postural instability experienced in this condition is probably due to inappropriate responses to proprioceptive inputs and lack of vision. Both male and female subjects showed a strong "eyes by standing surface" interaction. The proprioceptor manipulation alone did not affect the postural stability.
Trisomy 4 is a newly recognized primary chromosome change in leukemia. Five cases of acute nonlymphocytic leukemia (ANLL) are described from the United States and France. As in cases from Belgium, the only chromosome abnormality detected in the leukemic cells was trisomy 4. This was associated preferentially with ANLL of the M4 type (by FAB classification): acute myelomonocytic leukemia.
Robertsonian translocations between the acrocentric autosomes are the most common type of constitutional chromosome rearrangement in humans. However, Robertsonian translocations are very rarely acquired in cancer cells. We report a patient with prolymphocytic leukemia and an acquired Robertsonian translocation in the leukemic cells. The translocation was between chromosomes #13 and #15; t(13;15)(q11;p12). Two other cases of malignancy with an acquired Robertsonian translocation have been found, one being of the t(13;15) type, which accounts for only 1% of constitutional Robertsonian translocations. We propose, therefore, that although Robertsonian translocations are occasionally observed in cancer cells, they are very rarely acquired.
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