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P Prior

Publications and source records attributed to P Prior.

At least 55 records · Page 3Linked to original sources
PubMed1990

Neuraxin corresponds to a C-terminal fragment of microtubule-associated protein 5 (MAP5).

From cloned DNA, neuraxin has been identified as a tubulin binding protein of predicted molecular weight of 94 kDa. The deduced sequence of the rat protein exhibits high homology to the C-terminal region of mouse microtubule-associated protein 5 (MAP5). Here, we show that different neuraxin antibodies recognize MAP5, but fail to detect a protein of 94 kDa, in subcellular and microtubular fractions of the rat central nervous system. Furthermore, tubulin binding by neuraxin was found to be dependent on taxol. These data are consistent with neuraxin corresponding to a C-terminal fragment of MAP5 that contains a low-affinity tubulin binding site.

Alkaloids↗
PubMed1990

Leukemia following chemotherapy for ovarian cancer.

An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case-control study design, with three controls matched to each case of leukemia. Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known.

Antineoplastic Agents↗
PubMed1990

Cloning and expression of the 58 kd beta subunit of the inhibitory glycine receptor.

The inhibitory glycine receptor (GlyR) mediates post-synaptic inhibition in spinal cord and other regions of the CNS. Purified mammalian GlyR contains two membrane-spanning subunits 48 kd (alpha) and 58 kd (beta) plus a 93 kd receptor-associated cytoplasmic protein. Here, the primary structure of the beta subunit was deduced from cDNAs isolated from rat spinal cord and brain cDNA libraries. The predicted amino acid sequence exhibits 47% identity to the previously characterized rat alpha 1 polypeptide. Northern blot analysis revealed high levels of beta subunit transcripts in postnatal spinal cord, cerebellum, and cortex. Nuclear injection into Xenopus oocytes of a beta subunit cDNA engineered for efficient expression generated weak glycine-activated chloride currents that were insensitive to the classic GlyR antagonist, strychnine. Our data indicate a differential expression of GlyR alpha and beta subunits in the rat nervous system and support a structural role of the beta polypeptide in the native receptor complex.

Amino Acid Sequence↗
PubMed1990

Steady-state pharmacokinetics of tacrine in patients with Alzheimer's disease.

Neurochemical studies of Alzheimer's disease (AD) suggest deficiencies in the cholinergic system. We evaluated the steady-state pharmacokinetics of tacrine (Cognex), an oral cholinesterase inhibitor, in 12 patients with AD. Patients sequentially received nine doses of 10 mg, 20 mg, and 30 mg of tacrine every 6 hours. Blood samples were collected until 24 hours after the final dose. Plasma tacrine concentrations were measured using a validated high-performance liquid chromatographic method. Mean maximum plasma concentrations (Cmax) were 5.1 ng/ml, 20.7 ng/ml, and 33.9 ng/ml following administration of 10 mg, 20 mg, and 30 mg doses, respectively. Corresponding mean values for steady-state area under the curve (AUC) were 19.7 ng/ml, 82.9 ng/ml, and 139 ng/ml.hr. Dose-normalized Cmax and AUC values after administration of the 20 mg and 30 mg doses of tacrine were comparable to each other but were significantly greater (p less than .05) than those after the 10 mg doses. The apparent elimination half-life was approximately 3.4 hours for all dosing regimens. Dose-dependent increases in Cmax and AUC values in patients with AD were similar to those previously reported in normal volunteers. The mechanism of the nonlinearity in tacrine pharmacokinetics is unknown.

Aged↗
PubMed1989

Radiation dose and breast cancer risk in patients treated for cancer of the cervix.

The relationship between breast cancer and radiation treatment for cervical cancer was evaluated in an international study of 953 women who subsequently developed breast cancer and 1,806 matched controls. Radiation doses to the breast (average 0.31 Gy) and ovaries (average 32 Gy) were reconstructed for exposed subjects on the basis of their original radiotherapy records. Overall, 88% of the breast cancer cases and 89% of the controls received radiation treatment [relative risk (RR) = 0.88; 95% confidence interval (CI) = 0.7-1.2]. Among women with intact ovaries (561 cases, 1,037 controls), radiotherapy was linked to a significant 35% reduction in breast cancer risk, attributable in all likelihood to the cessation of ovarian function. Ovarian doses of 6 Gy were sufficient to reduce breast cancer risk but larger doses did not reduce risk further. This saturation-type response is probably due to the killing of a critical number of ovarian cells. Cervical cancer patients without ovaries (145 cases, 284 controls) were analyzed separately because such women are at especially low natural risk for breast cancer development. In theory, any effect of low-dose breast exposure, received incidentally during treatment for cervical cancer, should be more readily detectable. Among women without ovaries, there was a slight increase in breast cancer risk (RR = 1.07; 95% CI = 0.6-2.0), and a suggestion of a dose response with the RR being 1.0, 0.7, 1.5 and 3.1 for breast doses of 0, 0.01-0.24, 0.25-0.49 and 0.50+ Gy, respectively. However, this trend of increasing RR was not statistically significant. If low-dose radiation increases the risk of breast cancer among women over age 40 years, it appears that the risk is much lower than would be predicted from studies of younger women exposed to higher doses.

Adult↗
PubMed1989

Neuraxin, a novel putative structural protein of the rat central nervous system that is immunologically related to microtubule-associated protein 5.

During screening of a rat spinal cord lambda gt11 cDNA library with poly- and monoclonal antibodies against the postsynaptic glycine receptor a cDNA was isolated which covers an open reading frame encoding a protein of calculated mol. wt 94 kd. Sequence analysis identified a novel type of neuron-specific protein (named neuraxin) which is characterized by an unusual amino acid composition, 12 central heptadecarepeats and putative protein and/or membrane interaction sites. The gene encoding neuraxin appears to be unique in the haploid rat genome and conserved in higher vertebrates. Northern blot and in situ hybridization revealed neuraxin mRNA to be expressed throughout the rodent central nervous system (CNS). In spinal cord, neuraxin transcripts were abundant in motoneurons which also expressed glycine receptor subunit mRNA. A bacterial fusion protein containing approximately 90% of the neuraxin sequence was found to specifically bind tubulin. Polyclonal neuraxin antibodies cross-reacted with microtubule-associated protein 5 (MAP5), and a monoclonal antibody against MAP5 recognized the neuraxin fusion construct. Based on these data we suggest that neuraxin is related to MAP5 and may be implicated in neuronal membrane-microtubule interactions.

Amino Acid Sequence↗
PubMed1989

Subsequent primary cancers in relation to treatment of ovarian cancer.

The incidence of subsequent primary cancers was assessed in relation to treatment for a cohort of 7,203 patients from the Birmingham and West Midlands Cancer Registry diagnosed between 1957 and 1976. The total of 213 cancers observed one or more years after treatment for ovarian cancer (mean follow-up = 6.5 person-years) represented a significant excess (observed (O) = 213, expected (E) = 140.07, relative risk (RR) = 1.5, 95% CI 1.3-1.7, P less than 0.001). Among patients whose treatment included chemotherapy (CT), with or without radiotherapy (RT), the risk of acute and non-lymphocytic leukaemia (A + NLL) was significantly increased (O = 5, E = 0.18, RR = 27.8, 95% CI 9.0-64.8, P less than 0.001). The relative risks of A + NLL following RT without CT (RR = 4.5) and after other treatments (RR = 2.9) were not significantly in excess of 1.0. Significant excesses of subsequent cancers were observed at several sites: breast (RR = 1.7, 95% CI 1.3-2.2), lung (RR = 2.0, 95% CI 1.3-3.4), colon and rectum (RR = 1.6, 95% CI 1.1-2.3), urinary system (RR = 1.9, 95% CI 0.9-3.7), nervous system (RR = 3.3, 95% CI 1.2-7.3) and connective tissue (RR = 6.7, 95% CI 1.8-17.1) but the relationship with type of treatment was not so clearly defined as that for leukaemia. Although the treatment groups were broad and based on routinely collected data, they can enhance the use of cohort analyses for exploratory and monitoring purposes.

Adult↗
PubMed1989

Malignancy in coeliac disease--effect of a gluten free diet.

Two hundred and ten patients with coeliac disease previously reported from this unit were reviewed at the end of 1985 after a further 11 years of follow up. The initial review at the end of 1974 could not demonstrate that a gluten free diet (GFD) prevented these complications, probably because the time on diet was relatively short. The same series has therefore been kept under surveillance with the particular aim of assessing the effects of diet on malignancy after a further prolonged follow up period. Twelve new cancers have occurred: of which one was a carcinoma of the oesophagus and two lymphomas. Thirty nine cancers developed in 38 patients and of 69 deaths, 33 were the result of malignancy. A two-fold relative risk (RR) of cancer was found and was because of an increased risk of cancer of the mouth and pharynx (RR = 9.7, p less than 0.01, 95% confidence interval (CI) = 2.0-28.3), oesophagus (RR = 12.3, p less than 0.01, CI = 2.5-36.5), and of non-Hodgkin's lymphoma (RR = 42.7, p less than 0.001, CI = 19.6-81.4). The results indicate that for coeliac patients who have taken a GFD for five years or more the risk of developing cancer over all sites is not increased when compared with the general population. The risk is increased, however, in those taking a reduced gluten, or a normal diet, with an excess of cancers of the mouth, pharynx and oesophagus (RR = 22.7, p < 0.001), and also of lymphoma (RR = 77.8, p < 0.001). A significant decreasing trend in the excess morbidity rate over increasing use of a GFD was found. The results are suggestive of a protective role for a GFD against malignancy in coeliac disease and give further support for advising all patients to adhere to a strict GFD for life.

Celiac Disease↗
PubMed1988

Hodgkin's disease: subsequent primary cancers in relation to treatment.

A consecutive series of 2,999 patients, diagnosed with Hodgkin's disease (HD) between 1950 and 1979, was assembled from the records of the Birmingham and West Midlands Cancer Registry and followed to the end of 1984. Cohort analyses of subsequent primary cancers among 1,976 patients, surviving one or more years (mean follow-up 6.7 person-years), were carried out in relation to overall treatment by radiotherapy (RT), chemotherapy (CT) or both modalities (CT + RT). Over all sites a 50% increase in risk, relative to the West Midlands population, was found [observed (O) = 65; relative risk (RR) = 1.5; P less than 0.01]. Among patients treated by CT (with or without RT) a significant increase in acute and non-lymphocytic leukaemias was found (O = 6; RR = 30.0; P less than 0.001). The excess risk was of the order of 1 per 1000 patient-years and the cumulative risk was 1.2%. Among solid tumours increased risks, which might be attributable to RT, occurred in the lung (O = 15; RR = 1.6; P less than 0.05), breast (O = 9; RR = 2.2; P less than 0.05) and bone (O = 2; RR = 20.0; P less than 0.01). The excess of skin cancers (O = 13; RR = 2.9; P less than 0.01) occurred mainly within 10 years of treatment with CT. The follow-up period is still insufficient to determine the long-term effect on the incidence of solid tumours with long latent periods from multiple-agent CT which became more frequently used in the early 1970s. A sub-set of these data was analysed over all treatments and the results were contributed to an international study co-ordinated by the International Agency for Research on Cancer, Lyon.

Adolescent↗
PubMed1988

Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres.

A retrospective cohort of 823 patients with ulcerative colitis who resided at the time of diagnosis in one of three defined geographical areas (West Midlands region, Oxford region, England and Stockholm County, Sweden) was assembled. The patients were first seen at named hospitals in these areas and the diagnosis of ulcerative colitis established within five years of onset of symptoms between 1945-1965. All patients were 15 years of age or more at onset of disease and were followed for a minimum of 17 years and a maximum of 38 years. Ninety seven per cent completeness of follow up was achieved. Examining the colorectal cancer risk in the series relative to the risk in the general population by standardised morbidity ratios, there was an eight fold increased risk of cancer in the series as a whole. Dividing the series by extent of colitis, extensive colitis patients showed a 19 fold increase in risk. A four fold increased risk was shown in the remainder of the series (left sided colitis, proctitis and extent unknown). Life table analyses in extensive colitis gave cumulative risks of 7.2% (CI 3.6-10.8) at 20 years from onset of disease and 16.5% (CI 9.0-24.0) at 30 years from onset. No significant effect of age at onset, sex or referral centre could be detected. Examination of the data by interval from onset to cancer and by actual age at development of cancer suggests that patients who develop colorectal cancer will do so in a distribution around 50 years of age independent of duration of disease in adult onset ulcerative colitis (greater than 15 years at onset of disease). An inverse relationship was shown between age at onset of disease and interval from onset of disease to cancer. Further age specific rates for cancer increased up to 50 years and decreased thereafter. These results suggest that extensive colitis patients have a genetic predisposition to colorectal cancer and that longstanding inflammation is not of primary importance in the initiation/promotion of cancer in this disease.

Actuarial Analysis↗
PubMed1988

A preliminary study of excess mortality using a psychiatric case register.

Systematic screening of death certificates referable to residents of two health districts covered by a psychiatric case register allows the study of excess mortality in unselected psychiatric patients from a defined area of known population. Deaths among the case register patients exceeded those expected by 80%; the relative risk was maximal during the first year after registration and was significantly raised in both sexes and in patients of all age-groups. Patients may be selected by service use and by diagnostic group: the excess mortality of "inpatients" both in relative and absolute terms exceeded that of "outpatients". For dementia patients both the relative risk and more notably the absolute risk was high, and the excess mortality was significantly raised in both sexes and all age-groups. It was again greatest during the first year after registration. Deaths of patients with schizophrenia and paranoid psychosis exceeded those expected by 40 per cent and the excess was limited to the first year after registration and occurred predominantly among men.

Adolescent↗
PubMed1988

Radiation dose and second cancer risk in patients treated for cancer of the cervix.

The risk of cancer associated with a broad range of organ doses was estimated in an international study of women with cervical cancer. Among 150,000 patients reported to one of 19 population-based cancer registries or treated in any of 20 oncology clinics, 4188 women with second cancers and 6880 matched controls were selected for detailed study. Radiation doses for selected organs were reconstructed for each patient on the basis of her original radiotherapy records. Very high doses, on the order of several hundred gray, were found to increase the risk of cancers of the bladder [relative risk (RR) = 4.0], rectum (RR = 1.8), vagina (RR = 2.7), and possibly bone (RR = 1.3), uterine corpus (RR = 1.3), cecum (RR = 1.5), and non-Hodgkin's lymphoma (RR = 2.5). For all female genital cancers taken together, a sharp dose-response gradient was observed, reaching fivefold for doses more than 150 Gy. Several gray increased the risk of stomach cancer (RR = 2.1) and leukemia (RR = 2.0). Although cancer of the pancreas was elevated, there was no evidence of a dose-dependent risk. Cancer of the kidney was significantly increased among 15-year survivors. A nonsignificant twofold risk of radiogenic thyroid cancer was observed following an average dose of only 0.11 Gy. Breast cancer was not increased overall, despite an average dose of 0.31 Gy and 953 cases available for evaluation (RR = 0.9); there was, however, a weak suggestion of a dose response among women whose ovaries had been surgically removed. Doses greater than 6 Gy to the ovaries reduced breast cancer risk by 44%. A significant deficit of ovarian cancer was observed within 5 years of radiotherapy; in contrast, a dose response was suggested among 10-year survivors. Radiation was not found to increase the overall risk of cancers of the small intestine, colon, ovary, vulva, connective tissue, breast, Hodgkin's disease, multiple myeloma, or chronic lymphocytic leukemia. For most cancers associated with radiation, risks were highest among long-term survivors and appeared concentrated among women irradiated at relatively younger ages.

Female↗
PubMed1988

Long-term cancer risk in alcoholism.

A series of 1110 patients seen at hospitals in the Birmingham Region between 1948 and 1971 for alcohol related conditions were followed to 1981. By means of cohort analysis, the incidence of cancer in the series was compared with that in the West Midlands Region. In men the cancer risk was increased 1.7-fold: individual sites at risk were liver (8-fold), buccal cavity and throat (27-fold), respiratory system (2.4-fold), and oesophagus (4-fold). No excess of colo-rectal cancers was observed. Although in women there was no overall excess of cancers, the risk was high in the biliary system (15-fold) and was moderately increased for cervix uteri (4-fold).

Adult↗
PubMed1987

Synaptophysin: molecular organization and mRNA expression as determined from cloned cDNA.

Synaptophysin is a major glycoprotein of Mr approximately 38,000 (in deglycosylated form: Mr approximately 34,000) characteristic of a certain class of small (30-80 nm diameter) neurosecretory vesicles, including presynaptic vesicles, but also vesicles of various neuroendocrine cells of both neuronal and epithelial phenotype. Using synaptophysin-specific antibodies we have isolated cDNA clones from rat nervous tissue libraries, which identify an approximately 2.5-kb mRNA in rat and human cells, including neuroendocrine tumours, that contains a reading frame for a polypeptide of 307 amino acids with a total mol. wt of 33 312. The deduced amino acid sequence, which was partly confirmed by comparison with sequences of two tryptic peptides obtained from purified synaptophysin, revealed four hydrophobic regions of 24 amino acids each, which are characterized, according to conformation prediction analyses, by marked alpha-helicity. The sequence shows a single potential N-glycosylation site, which is assigned to the vesicle interior, and a carboxy-terminal tail of 89 amino acids which contains glycine-rich tetrapeptide repeats, the epitope of monoclonal antibody SY38, and a number of collagenase-sensitive sites accessible on the surface of the intact vesicles. These features suggest that the polypeptide spans the vesicle membrane four times, with both N and C termini located on the outer, i.e. cytoplasmic, surface of the vesicles.

Amino Acid Sequence↗
PubMed1987

Radiation dose and leukemia risk in patients treated for cancer of the cervix.

To quantify the risk of radiation-induced leukemia and provide further information on the nature of the relationship between dose and response, a case-control study was undertaken in a cohort of over 150,000 women with invasive cancer of the uterine cervix. The cases either were reported to one of 17 population-based cancer registries or were treated in any of 16 oncologic clinics in Canada, Europe, and the United States. Four controls were individually matched to each of 195 cases of leukemia on the basis of age and calendar year when diagnosed with cervical cancer and survival time. Leukemia diagnoses were verified by one hematologist. Radiation dose to active bone marrow was estimated by medical physicists on the basis of the original radiotherapy records of study subjects. The risk of chronic lymphocytic leukemia, one of the few malignancies without evidence for an association with ionizing radiation, was not increased [relative risk (RR) = 1.03; n = 52]. However, for all other forms of leukemia taken together (n = 143), a twofold risk was evident (RR = 2.0; 90% confidence interval = 1.0-4.2). Risk increased with increasing radiation dose until average doses of about 400 rad (4 Gy) were reached and then decreased at higher doses. This pattern is consistent with experimental data for which the down-turn in risk at high doses has been interpreted as due to killing of potentially leukemic cells. The dose-response information was modeled with various RR functions, accounting for the nonhomogeneous distribution of radiation dose during radiotherapy. The local radiation doses to each of 14 bone marrow compartments for each patient were incorporated in the models, and the corresponding risks were summed. A good fit to the observed data was obtained with a linear-exponential function, which included a positive linear induction term and a negative exponential term. The estimate of the excess RR per rad was 0.9%, and the estimated RR at 100 rad (1 Gy) was 1.7. The model proposed in this study of risk proportional to mass exposed and of risk to an individual given by the sum of incremental risks to anatomic sites appears to be applicable to a wide range of dose distributions. Furthermore, the pattern of leukemia incidence associated with different levels of radiation dose is consistent with a model postulating increasing risk with increasing exposure, modified at high doses by increased frequency of cell death, which reduces risk.

Adult↗
PubMed1986

Current-distance relations of axons mediating circling elicited by midbrain stimulation.

Stimulation of mediocaudal midbrain in rats produces ipsiversive circling due to the stimulation of longitudinal axons. The refractory periods of these axons were measured by delivering trains of conditioning and testing pulses via a single electrode at various conditioning-testing (C-T) intervals. As C-T interval increased from 0.3 to 2.0 ms, the frequency required to produce a constant amount of circling halved. The current-distance relations of these axons were measured by placing two electrodes lateral to one another, and delivering conditioning pulses via one electrode and testing pulses via the second electrode. The required frequency decreased less at C-T intervals in the refractory period range using two electrodes rather than using a single electrode. This partial refractoriness suggests that only part of the axons were stimulated by both electrodes. The refractoriness increased as current increased or as interelectrode distance decreased. The overlap in the fields of stimulation at each current was calculated from the refractoriness observed in single and double electrode experiments. The results suggest that the axons mediating circling have a wide range of thresholds rather than a single threshold. The current required to activate an axon is roughly equal to K X r2, were K is a constant and r is the radial distance from electrode to axon. K must range from 400 to at least 3000 microA/mm2, to account for the circling data. For axons mediating medial forebrain bundle self-stimulation3, K must range from 1000 to at least 6400 microA/mm2. Estimation of the K distribution allows calculation of the effects of electrode size, placement and current on the recruitment of axons with different thresholds.

Animals↗
PubMed1986

Factors influencing mortality in rheumatoid arthritis.

The prognosis in rheumatoid arthritis respecting mortality was studied in a consecutive series of 489 hospital patients over a period of 18 years. The relative risk of mortality was raised in both men (2.6; p less than 0.001) and women (3.4; p less than 0.001). In the women the relative risk was also influenced by prior duration of RA and was characterised by a diminution in risk 5-9 years after first presentation. Relative risks for men were more uniformly distributed over time. Annual excess mortality rates were strongly associated with age at first presentation in women, the rate increasing with increasing age in both the group seen within 5 years of onset of disease (chi 2(1) for trend = 30.4; p less than 0.001) and in the later referral group (chi 2(1) = 34.0; p less than 0.001). A similar but much less marked effect was observed in men in the early referral group (chi 2(1) = 13.7; p less than 0.001) only. These results suggest that initially women may have a milder form of disease and that hormonal status may affect prognosis. Future long-term therapeutic studies in RA should take into account the prognostic factors of age, sex and duration of disease.

Adolescent↗