Clinical utility of long latency 'cognitive' event-related potentials (P3): the cons.
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Cognition↗
Biomedical subjects
J M Ford
Publications and source records attributed to J M Ford.
Cancer incidence in migrants to New South Wales from England, Wales, Scotland and Ireland.
Cancer incidence in migrants to New South Wales (NSW) from individual countries within the British Isles has been compared with that in the Australian-born population using data from the NSW Central Cancer Registry for the period 1972-84. Indirectly age-standardised incidence ratios (SIR) showed that, for cancer at all sites combined, Scottish migrants had a significantly higher, and English migrants a lower, incidence than the native-born Australians. Melanoma of skin was less common in migrants from all four countries while lung cancer was more common. In all except the Irish migrants, stomach cancer was more frequent than in the Australian-born. Raised SIRs for bladder cancer were found in men from all the countries and for breast cancer in all except the Irish women but only in the English migrants were these ratios significant. English migrants differed from those from Wales, Scotland and Ireland in that, compared with the Australian-born, they had significantly lower SIRs for cancer of the colon (both sexes), head and neck, larynx and prostate (men), gallbladder and kidney (women), and a higher SIR for ovarian cancer. Bone cancer was relatively more common in men born in Wales. 'Other genital' cancers (penis and scrotum; vulva and vagina) tended to be more frequent in migrants from each country than in the Australian-born.
England↗
Cancer incidence in European migrants to New South Wales.
The incidence of cancer in migrants to New South Wales (NSW) from Italy, Greece, Yugoslavia, Germany, the Netherlands, Poland and USSR has been compared with that in the Australian-born population using data from the NSW Central Cancer Registry for 1972-84. The indirectly age-standardized incidence ratios (SIR) in all seven countries were low for melanoma of skin and high for gastric cancer. Cancers of the colon, oesophagus and lip also tended to have low SIRs. Migrants from Italy, Greece and Yugoslavia had significantly less cancer at all sites than the native-born Australians mainly due to low SIRs for cancers of colon, lung (except Yugoslavian-born men), prostate and, in men, 'head and neck' (excluding nasopharynx). Cancers of breast and testis were relatively less common in migrants from Italy and Yugoslavia. SIRs were high for cancers of bladder (in Italian-born men), liver (in Greek- and Yugoslavian-born men) and nasopharynx (in Greek-born men and Italian-born men and women). Amongst migrants from the four more northerly European countries, ovarian cancer was relatively more common in women from Germany and Poland as was bladder cancer in men, but not women, from Germany and the Netherlands. Cancers which had significantly increased SIRs in one migrant group only were lung (Dutch-born men), cervix uteri and body of uterus (German-born women), gallbladder and bile ducts (Polish-born women), thyroid (Italian-born women), connective and other soft tissue (Russian-born men) and brain (Greek-born men and women computed together). Lymphomas were relatively less common in men born in Yugoslavia.
Emigration and Immigration↗
The effect of propranolol on paracetamol metabolism in man.
Ten healthy volunteers were treated for 4 days with 160 mg propranolol HCl and placebo in random order. At the end of each treatment salivary antipyrine kinetics and the plasma kinetics and urinary excretion of paracetamol and its major metabolites were measured following a 1500 mg oral dose. Propranolol prolonged the half-life of antipyrine by 11 +/- 5% (mean +/- s.e. mean) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol increased the half-life of paracetamol by 25 +/- 12% (P less than 0.05) and lowered its clearance by 14 +/- 3% (P less than 0.05). Propranolol decreased the partial clearance of paracetamol to its cysteine and mercapturate derivatives by 16 +/- 3% (P less than 0.05) and 32 +/- 7% (P less than 0.05), respectively. The partial clearance to the glucuronide conjugate was decreased by 27 +/- 6% (P less than 0.05), whereas that to sulphate was not changed significantly. Propranolol inhibits paracetamol metabolism predominantly through inhibition of the oxidation and glucuronidation pathways.
Acetaminophen↗
Geographical distribution of cancers of the kidney and urinary tract and analgesic nephropathy in Australia and New Zealand.
Age-standardised incidence rates for cancers of the renal parenchyma, renal pelvis and bladder and for end-stage renal failure due to analgesic nephropathy for the years 1982-83 were compared between the Australian states and New Zealand, and within New South Wales (NSW), to determine whether these rates paralleled the previous prevalence of consumption of phenacetin-containing analgesics. Whereas little variation was seen within Australasia in respect of the incidence of cancer of the renal parenchyma and bladder, both cancer of the renal pelvis and end-stage renal failure due to analgesic nephropathy had higher incidence rates amongst women in NSW and Queensland than in the other states or New Zealand. Within NSW, the average annual incidence rates during 1973-82 for renal pelvic cancer in the Hunter region of 1.3 (m) and 1.6 (f) per 100,000 were the highest in the state. These high incidence rates coincided with areas known to have had a high prevalence of consumption of compound analgesics containing phenacetin. In an international comparison with populations which had published incidence rates for each of the periods 1973-77 and 1978-82, the rate for cancer of the renal pelvis in women was highest in both time periods in NSW and had increased absolutely at a faster rate.
Adolescent↗
Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers.
Racemic gossypol has been shown to have antitumor properties that may be due to its ability to uncouple tumor mitochondria or to its inhibitory effects on a variety of nonmitochondrial enzymes. We have studied the antimitochondrial and enzyme-inhibiting properties of gossypol in human carcinoma cell lines of breast (MCF-7, T47-D), ovarian (OVCAR-3) colon (HCT-8), and pancreatic (MiaPaCa) origin by comparing the effects of its purified (+)- and (-)-enantiomers. (-)-Gossypol shows up to 10-fold greater antiproliferative activity than (+)-gossypol in the cancer cell lines and in normal hematopoietic stem cells grown in vitro, with IC50 values ranging from 1.5 to 4.0 microM for the cancer cells and from 10 to 20 microM for the human marrow stem cells. As well, multidrug-resistant MCF/Adr cells appear more resistant to (-)-gossypol than their parental cell line. Electron microscopy indicates that the earliest ultrastructural change in tumor cells exposed to a cytotoxic (10 microM) concentration of (-)-gossypol is the selective destruction of their mitochondria. Consistent with this observation, 31P magnetic resonance spectroscopy detects pronounced changes in tumor cell high energy phosphate metabolism within 24 hr of (-)-gossypol treatment, manifest by 1.6- to greater than 50-fold differential reductions in the intracellular ratios of ATP/Pi, relative to (+)-gossypol-treated cell lines; the magnitude of these antimitochondrial effects correlates with the antiproliferative activity of (-)-gossypol. Northern blot RNA analyses suggest that treatment with a 5-10 microM dose of (-)-gossypol induces a transient increase in the expression of heat shock gene products, particularly hsp-70 transcripts. The mean 5-fold increase in (-)-gossypol-induced hsp-70 mRNA appears coincident with a comparable heat-stimulated increase in transcript levels, as compared with control or (+)-gossypol-treated cells. The enzyme-inhibiting properties of gossypol enantiomers were compared in cell-free assays measuring glutathione-S-transferase-alpha, -mu, and pi activities, calmodulin stimulation of cyclic nucleotide phosphodiesterase, and protein kinase C activity. Both enantiomers are near equivalent antagonists of calmodulin stimulation and protein kinase C activity, exceeding the potency of known inhibitors such as phenothiazines by as much as 50-fold. In contrast, (-)-gossypol is a 3-fold more potent inhibitor of glutathione-S-transferase-alpha and -pi isozyme activity, resulting in IC50 values of 1.6 and 7.0 microM, respectively, for these two isozymes.(ABSTRACT TRUNCATED AT 400 WORDS)
Antineoplastic Agents↗
Pharmacology of drugs that alter multidrug resistance in cancer.
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Animals↗
Epidemiology of alimentary cancers in New South Wales, 1973-82.
Incidence and mortality data from New South Wales (NSW) for 1973-82 were examined using log-linear regression to determine the temporal trends of cancers of the alimentary tract. There were significant increases in incidence of cancers of the colon (1.7%/year), rectum (2.6%/year), and liver (4.0%/year) and decreases for cancers of the oesophagus (-2.2%/year) and stomach (-1.4%/year). By contrast, the mortality decreased significantly for cancers of the colon (-1.0%/year) and pancreas (-1.4%/year) as well as for cancers of the oesophagus (-3.4%/year) and stomach (-4.1%/year). Cancers of the colon, rectum and oesophagus were generally less frequent, and cancer of the stomach was more frequent, among migrants to NSW than among the native-born Australians in NSW. This pattern was most evident in migrants from Greece, Italy, Yugoslavia and England and was absent in migrants from Scotland and New Zealand. When compared with the state as a whole, rural NSW had significantly lower incidences of cancers of the oesophagus, stomach, colon and rectum.
Age Factors↗
The incidence of malignant mesothelioma in Australia, 1947-1980.
Details of patients with malignant mesothelioma that was diagnosed in Australia before 1981 were obtained by searching all possible sources throughout Australia as far into the past as possible and up to and including 1980. The earliest patient with mesothelioma who was identified was diagnosed in Victoria in 1947. By 1980, 535 (81%) men and 123 (19%) women had been diagnosed with the disease; only 14 persons were aged less than 35 years at the time of diagnosis (the youngest person was 15 years of age). The incidence rate in subjects who were 35 years or older at diagnosis was less than 1.0 cases per million person-years until 1964-1968, and then it rose progressively to 15.5 cases per million person-years in 1979-1980. The highest rate (69.7 cases per million person-years) was observed in 65- to 74-year-old men in 1979-1980. The incidence rate in Western Australia was greater than were the rates in other states of Australia after the mid 1960s. Pleural mesotheliomas accounted for 88% of cases in which the site of the tumour was known; peritoneal mesotheliomas accounted for 10% of such cases and "other" sites for 2% of such cases. In 6% of cases the site was not specified. The exposure to asbestos was stated as "definite" in 59% of the cases with a recorded history of exposure: 8% of all the cases in the study had been exposed to crocidolite (blue asbestos) from Wittenoom Gorge in Western Australia. The age at diagnosis of patients with known exposure to asbestos was similar to that in those without known exposure. The increases in the incidence of malignant mesothelioma in Australia follow the published trends in the production and use of the amphibole varieties of asbestos in this country after a lag period of between 20 and 30 years.
Adolescent↗
P3 in schizophrenia is affected by stimulus modality, response requirements, medication status, and negative symptoms.
Eighteen schizophrenics who were not taking medication, 13 schizophrenics who were taking medication, and 37 age-matched controls were tested with event-related potential paradigms designed to elicit P3 response automatically or effortfully (ie, with a choice reaction time task). Electroencephalograms were recorded from the 19 standard 10-20 electrode sites. Compared with controls, both groups of schizophrenics had reduced P3 amplitudes for both effortful and automatic paradigms. P3 latencies were delayed relative to controls for the medication-taking schizophrenics in the effortful paradigms. Negative symptoms derived from the Brief Psychiatric Rating Scale within 1 week of event-related potential testing correlated negatively with both auditory and visual P3 amplitude in the subjects who were not taking medication. There was no evidence that P3 is smaller over left temporal electrode sites in schizophrenics, as has been reported by others. P3 amplitude reduction in schizophrenia is a robust psychobiological phenomenon that is present regardless of medication status or task demands.
Adult↗
Pharmacokinetics of tacrine hydrochloride in Alzheimer's disease.
The clinical pharmacokinetics of tacrine hydrochloride have been characterized in patients who have Alzheimer's disease. Serum concentrations of the drug and of its probable metabolite were monitored in eight patients after a 25 mg oral dose, in six patients after a 50 mg oral dose, in four patients after repeated administration of 50 mg, and in two patients after a small intravenous dose. Urinary excretion of drug and metabolite for 24 hours was measured in one of the patients who received a small intravenous dose. The serum half-life was 1.59 +/- 0.15 hours (mean +/- SEM) after the 25 mg dose, 2.14 +/- 0.24 hours after the 50 mg dose, and 2.91 +/- 0.39 hours after continuous treatment. After intravenous administration, clearance was above 600 ml/min in both patients, and oral bioavailability was calculated at below 5%. Urine recovery was less than 3% of the dose. The low bioavailability of tacrine hydrochloride is partly explained by presystemic metabolism.
Administration, Oral↗
Trends in invasive cancer of the cervix uteri in New South Wales, 1973-1982.
Data from the New South Wales (NSW) Central Cancer Registry comprising all new cases of, and deaths from, invasive cancer of the cervix uteri registered in persons aged 15 years and over for the 10-year period 1973 to 1982 were examined using log-linear regression to determine whether incidence and mortality had been changing in NSW. Allowing for the estimated fraction of women who had undergone hysterectomy, this cancer had decreased significantly in incidence (-1.3% per year) as well as mortality (-3.6%). There were no significant trends in relation to age at diagnosis, stage at diagnosis or histological type. Overall, younger age at diagnosis was associated with an earlier stage at presentation and there was no evidence for a trend towards more severe disease in young women during the 10-year period. No evidence was found for an increasing incidence of adenocarcinoma. By 1982 the age-standardized incidence rate was 10.4 per 100,000 (12.5 per 100,000 after adjustment for the hysterectomy fraction). Cancer of the cervix uteri was more common in Inner and Western Sydney and less common in the Northern Metropolitan region of Sydney and rural New South Wales.
Adenocarcinoma↗
Toremifene: pharmacologic and pharmacokinetic basis of reversing multidrug resistance.
Triphenylethylene compounds, such as tamoxifen, have shown chemosensitizing activity independent of estrogen receptor status in doxorubicin-resistant cells. We examined the chemosensitizing activity of a new triphenylethylene, toremifene, and its major metabolites in a doxorubicin-resistant human breast cell line, MCF-7/DOX. In addition, we examined the chemosensitizing activity of unbound plasma toremifene and its metabolites isolated from patients treated with toremifene doses of 20 to 400 mg/d. MCF-7/DOX cells were exposed to ultrafiltrate plasma specimens in the absence and presence of doxorubicin. These latter studies were single-blinded. Toremifene and its major metabolites were capable of sensitizing multidrug-resistant cells to doxorubicin. The degree of chemosensitizing activity in vitro correlated with the plasma concentrations of toremifene and its metabolites (P less than .05). Plasma samples isolated from patients receiving high-dose toremifene (400 mg/d) had the greatest chemosensitizing activity. We present evidence that toremifene and its metabolites can sensitize resistant MCF-7/DOX cells to doxorubicin, that this effect is concentration-dependent, and that sensitizing activity can be detected at clinically achieved concentrations.
Blood↗
Structural features determining activity of phenothiazines and related drugs for inhibition of cell growth and reversal of multidrug resistance.
Phenothiazines and structurally related compounds inhibit cellular proliferation and sensitize multidrug-resistant (MDR) cells to chemotherapeutic agents. To identify more potent pharmaceuticals, we studied the structure-activity relationships of 30 phenothiazines and related compounds on cellular proliferation and MDR in sensitive MCF-7 and resistant MCF-7/DOX human breast cancer cells. Substitutions on the phenothiazine ring that increased hydrophobicity increased antiproliferative and anti-MDR activities. For example, -Cl and -CF3 groups increased whereas -OH groups decreased potency. Modifying the length of the alkyl bridge and the type of amino side chain also influenced potency. Compounds with increased activity against cellular proliferation and MDR possessed a four-carbon bridge rather than a three- or two-carbon bridge and a piperazinyl amine rather than a noncyclic amino group. Compounds with tertiary amines were better anti-MDR agents than those with secondary or primary amines but were equipotent antiproliferative agents. The effects of these substituents were unrelated to hydrophobicity. The structure-activity relationships suggest that an ideal phenothiazine structure for reversing MDR has a hydrophobic nucleus with a -CF3 ring substitution at position 2, connected by a four-carbon alkyl bridge to a para-methyl-substituted piperazinyl amine. We subsequently studied related compounds having certain of these properties. Substitution of a carbon for a nitrogen at position 10 of the tricyclic ring, with a double bond to the side chain (thioxanthene), further increased activity against MDR. For example, (trans)-flupenthixol, the most potent of these compounds, increased the potency of doxorubicin against MDR cells by 15-fold, as compared with its stereoisomer (cis)-flupenthixol (5-fold) or its phenothiazine homolog fluphenazine (3-fold). (cis)- and (trans)-flupenthixol were equipotent antiproliferative agents. (trans)-flupenthixol was not accumulated more than (cis)-flupenthixol in MDR cells, implying that their stereospecific anti-MDR effects were not the result of selective differences in the access of the drugs to intracellular targets. Both drugs increased the accumulation of doxorubicin in MDR cells, but not in sensitive cells, suggesting that they modulate MDR by interacting with a uniquely overexpressed cellular target in these resistant cells. The apparent lack of clinical toxicity of (trans)-flupenthixol makes it an attractive drug for further investigation.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
The effect of withdrawal of phenacetin-containing analgesics on the incidence of kidney and urothelial cancer and renal failure.
Incidence data for cancers of the kidney and urinary tract (1973-83) and for end stage renal failure (ESRF) due to analgesic nephropathy (1973-86) were examined by loglinear regression to determine the effect of the withdrawal of phenacetin from analgesic preparations in New South Wales and the Australian Capital Territory. Allowing for the altered age and sex structure of the population, the incidence rate between 1973-83 for ESRF due to analgesic nephropathy, in persons aged between 5 and 54 years, decreased by 4.2% per year while that for ESRF excluding patients with analgesic nephropathy or diabetes increased annually by 1.3%. The incidence rates in persons over 14 years of age for cancer of the renal parenchyma (3.4% per year), renal pelvis (5.5%) and bladder (2.1%) increased significantly more than that for cancer at all sites (1.2%). Thus the decrease in ESRF due to analgesic nephropathy had not, by 1983, been paralleled by a decrease in renal parenchymal or urothelial cancer.
Analgesics↗
Determination of tacrine hydrochloride in human serum by chloroform extraction, reversed-phase high-performance liquid chromatography and fluorimetric detection.
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Aminoacridines↗
The changing incidence of cancer in adults in New South Wales.
Data from the New South Wales (NSW) Central Cancer Registry comprising all new cases of cancer registered in persons aged 15 years and over for the 10-year period 1973 to 1982 were examined using log-linear regression to determine whether the incidence of cancer had been changing in NSW. Allowing for the altered age and sex structure of the population over this period, the annual incidence rate for all sites combined increased significantly by 1.7% in men and 1.0% in women. Cancers which had increased at a rate significantly greater than that for all sites combined were those of unknown primary site (8.7% per year), lung (in women only, 5.6%), kidney (4.5%), bladder (2.7%) and rectum (2.6%) and lymphomas (2.6%). Other cancers which showed a significantly increased incidence rate per se were testis (3.5%), larynx (3.2%), prostate (2.1%), colon (1.7%), brain (1.6%), leukaemias (1.3%) and lung (in men only, 0.7%). Cancers which had decreased significantly in incidence were those of oesophagus (-2.2%), cervix uteri (-2.0%) and stomach (-1.4%). No significant change in incidence over the 10 years had occurred for cancers of the corpus uteri, breast, ovary or pancreas.
Adolescent↗
Risk factors for cancer of the renal parenchyma.
A case-control study of cancer of the renal parenchyma (360 cases and 985 controls) investigated lifestyle and dietary risk factors by means of a questionnaire survey. A lifetime history concerning urological disease and consumption of analgesics, tobacco, and prescribed medicines, was obtained together with current dietary and demographic information. Estimates of relative risk were calculated using logistic regression. Statistically significant associations were found with phenacetin-containing analgesics, urological disease and increasing consumption of milk. No association was found with consumption of aspirin, paracetamol, prescribed medicines, tea, coffee or animal proteins other than milk, or with the type of fat or oil used for cooking or spreading. The association with tobacco just failed to reach significance.
Australia↗