Health economics and economists in the NHS.
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Biomedical subjects
Publications and source records attributed to R Robinson.
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In this report we demonstrate the novel finding that aldolase A interacts with DNA sequences in mouse SEWA sarcoma cells. This interaction was initially observed through the identification of a 40 kDa protein which was eluted from a DNA affinity chromatography column consisting of the long terminal repeat (LTR) of the endogenous intracisternal A-type particle (IAP). Microsequencing analysis identified this 40 kDa protein as the glycolytic enzyme, aldolase A. The use of specific anti-aldolase antibodies enabled the identification and subsequent purification of aldolase from the nuclear protein fraction of two SEWA sublines, one that is adherent and one that grows in suspension. In order to confirm our initial finding that aldolase is capable of interacting with DNA, proteins from each subline were immunopurified with anti-aldolase antibodies, eluted and then tested for their ability to interact with IAP-LTR DNA sequences. Interestingly, only aldolase derived from the anchorage dependent SEWA cells was capable of interacting with the IAP-LTR, however, several cell lines derived from human tumors also exhibited this activity. Subsequent studies revealed the ability of aldolase to interact with some but not every DNA sequence tested, implying that there may be a minimal DNA conformation and/or sequence requirement for this activity. The presence of aldolase A in the nuclei and its ability to interact with certain DNA sequences suggest a novel role for this metabolic enzyme.
Intracisternal A-type particle (IAP) transcripts are endogenous retrovirus-like sequences expressed during specific stages of normal development and in a variety of murine tumors. In this study, we have analyzed two cell lines derived originally from the SEWA murine osteosarcoma and grown either as ascites or as solid tumors, for proteins that might regulate IAP expression. We found that subline AA7-NA, originally derived from the ascites tumor, expressed about five times more IAP RNA than the AS12-AD subline, which was derived from a solid tumor. In view of this finding, we examined the binding of cellular proteins from the two cell lines to the 5' end of an IAP long terminal repeat sequence. Gel retardation assays of DNA-protein complexes and DNase I footprinting assays identified several DNA sequences within the long terminal repeat fragment that were protected by protein extracts from both SEWA sublines. Gel retardation assays using specific synthetic oligonucleotide sequences that correspond to two of these protected regions revealed different patterns of DNA-protein complexes with extracts from the two SEWA sublines. These data suggest that expression of IAP sequences is regulated by complex mechanisms involving several proteins that appear to differ between the two sublines.
We have recently shown that a peptide (residues 35-47) from a functional region of the ras p21 protein, thought to be involved in the binding of p21 to GTPase activating protein, the antibiotic azatyrosine, known to induce the ras-recision gene, and the selective protein kinase C inhibitor, CGP 41,251, all inhibit oncogenic p21 protein-induced maturation of oocytes in a dose-dependent manner. We now show that these three agents only partially inhibit insulin-induced oocyte maturation, known to be dependent on activation of cellular p21 protein. On the other hand, the anti-p21 protein antibody Y13-259 completely inhibits both insulin- and oncogenic p21 protein-induced maturation as does a tetrapeptide, CVIM, known to block the enzyme farnesyl transferase which covalently attaches the farnesyl moiety to the p21 protein allowing it to attach to the cell membrane. Our results suggest that while the oncogenic and insulin-activated normal p21 proteins share certain elements of their signal transduction pathways in common, these pathways diverge and allow for selective inhibition of the oncogenic pathway.
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We studied the in vivo antifungal activity of azoles in humans and in a murine model of disseminated trichosporonosis. Eight patients infected with Trichosporon species were treated with fluconazole, SCH 39304, or miconazole for 2-26 weeks. Four patients had fungemia, two patients had disseminated trichosporonosis, and one patient each had soft-tissue infection and cystitis. Response of trichosporonosis to azoles was seen in all eight patients, although one patient died with disseminated aspergillosis while still receiving SCH 39304. A literature review indicated that responses to ketoconazole or miconazole were noted in four patients with trichosporonosis. In the experimental infection, amphotericin B, SCH 39304, and fluconazole were effective in prolonging survival and reducing fungal counts in the kidneys of mice infected with a clinical strain of Trichosporon beigelii. Fluconazole but not amphotericin B prolonged survival of mice infected with a clinical strain of Trichosporon capitatum. We conclude that azoles represent effective therapy for infection with Trichosporon species.
Cryotherapy has been shown to reduce the unfavourable outcome in retinopathy of prematurity with stage 3 threshold disease by 50%. In a prospective study cryotherapy had a favourable outcome in 13 of 24 eyes with stage 3 threshold disease. The visual outcome, refraction, and complications of cryotherapy are discussed.
Cigarette smoking is known to affect many haematological parameters but little is known of their rate of return to normal on withdrawal of cigarettes. Two groups of chronic smokers were studied whilst smoking and in the 2 weeks after cessation. A rapid return towards normal was found in the elevated haemoglobin concentration, packed cell volume, red cell count, white cell count, neutrophil count, lymphocyte count and platelet count, indicating that at least some of the abnormalities in these parameters are an acute, reversible effect of cigarette smoking rather than being a response to tissue damage.
Salivary glands synthesize and secrete an unusual family of proline-rich proteins (PRPs) that can be broadly divided into acidic and basic PRPs. We studied the tissue-specific expression of these proteins in rabbits, using antibodies to rabbit acidic and basic PRPs as well as antibodies and cDNA probes to human PRPs. By immunoblotting, in vitro translation, and Northern blotting, basic PRPs could be readily detected in the parotid gland but were absent in other salivary glands. In contrast, synthesis in vitro of acidic PRPs was detected in parotid, sublingual, and submandibular glands. Ultrastructural localization with immunogold showed heavy labeling with antibodies to acidic PRPs of secretory granules of parotid acinar cells and sublingual serous demilune cells. Less intense labeling occurred in the seromucous acinar cells of the submandibular gland. With antibodies to basic PRPs, the labeling of the parotid gland was similar to that observed with antibodies to acidic PRPs, but there was only weak labeling of granules of a few sublingual demilune cells, and no labeling of the submandibular gland. These results demonstrate a variable pattern of distribution of acidic and basic PRPs in rabbit salivary glands. These animals are therefore well suited for study of differential tissue expression of PRPs.
The purposes of this study were to assess the career development needs of entering medical students as measured by the Medical Career Development Inventory and to examine gender differences in responses to the inventory. A total of 115 entering medical students (representing two entering classes) took the inventory two months prior to matriculation. Analysis suggested that this sample of entering students had formed a vocational identity and that they had evaluated the suitability and viability of a commitment to a physician's career. However, the participants had not formed a clear picture of their specialty interest and goals. No significant gender differences were indicated. A recommended career assistance workshop is presented as appropriate for these students' needs.
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Cystic lesions involving the peritoneum and/or mesentery are uncommon. We present a case of metastatic mucinous adenocarcinoma of the breast to the peritoneum, a new entity to be added to the list of diagnoses that may present with this appearance.
The incidence of urinary tract infection is higher in the geriatric population than in younger adults despite the exclusion of patients with known risk factors. Tamm-Horsfall protein, a renal glycoprotein excreted in urine, may constitute a natural defense mechanism against ascending urinary tract infection by binding mannose-sensitive fimbriated microorganisms. We hypothesized that the quantity of Tamm-Horsfall protein excreted is decreased in the elderly. Native aggregated Tamm-Horsfall protein was measured in urine samples from 24 young women (group 1, mean age 33 years) and 47 female nursing home patients (group 2, mean age 84 years) using enzyme-linked immunosorbent assay techniques. Another 16 elderly women (group 3, mean age 85 years) had active urinary tract infection. The aggregated Tamm-Horsfall protein was then disaggregated by dilution and quantified. Significant differences in mean urinary disaggregated Tamm-Horsfall protein concentrations were found between groups 1 (64.22 mg./l.) and 2 (35.07 mg./l.), and between groups 1 and 3 (34.71 mg./l.), respectively. In contrast, mean aggregated Tamm-Horsfall protein levels were significantly higher in group 2 (1.56 mg./l.) than in group 1 (0.92 mg./l.) or group 3 (0.97 mg./l.). Our studies show that urinary disaggregated Tamm-Horsfall protein concentration is decreased in the elderly, and that aggregated Tamm-Horsfall protein is increased compared to younger adults. The aggregated Tamm-Horsfall protein concentration is decreased in the elderly during episodes of urinary tract infection.
Changes in the fibrinolytic system may lead to coagulation disorders in acute trauma patients. This study examined fibrin degradation by measuring D-dimer crosslinked fibrin degradation products (indicates hypercoagulability), plasminogen activators (fibrinolysis), and antithrombin III in 42 adult trauma patients and correlated these data with injury severity, types of injury, complications, and clinical tests of coagulation. Hypercoagulability and suppression of fibrinolysis were seen in most patients and were not correlated with severity of injury. These changes appeared most severe in patients with nervous system injury. Several patients with less severe injuries but evidence of hypercoagulability developed clinical evidence of pathologic thrombosis. Latex agglutination of D-dimer provides a rapid test of fibrinolysis that may be clinically useful in the management of trauma patients who cannot be easily studied for thrombosis.
Synovial tissues from inflamed and noninflamed knee joints of 13 patients with untreated rheumatoid arthritis were examined for vascular proliferation and morphological alteration of endothelial cells. Perivascular mononuclear cell infiltration and increased thickness of the synovial lining layer were noted in tissues from inflamed and noninflamed joints of patients with rheumatoid arthritis; vascular proliferation and morphological alteration of endothelial cells to resemble high endothelial venules were seen only in tissues from inflamed joints of patients with rheumatoid arthritis. These observations suggest that the migration of mononuclear cells from the peripheral blood to the perivascular areas and lining layer occurs before vascular proliferation and morphological alteration of endothelial cells.
Pulsatile ocular blood flow, intraocular pressure, systemic blood pressure, and heart rate was measured in two groups of 15 patients. One received lignocaine 1.5 mg/kg intravenously prior to induction. There was a significant increase in intraocular pressure after suxamethonium, which was not associated with any rise in ocular blood flow. Both the IOP and ocular blood flow increased significantly after tracheal intubation. A rise in ocular blood flow reflects the stress response associated with intubation. Lignocaine failed to attenuate either response.