Colin Taylor

PREVENTION OF RECURRENT ABORTION WITH LEUCOCYTE TRANSFUSIONS

Abstract Three women, each with a history of three spontaneous abortions, were typed for A, B, C, and DR histocompatibility (HLA) antigens and found to share antigens with their husbands. The women were repeatedly transfused throughout pregnancy with leucocyte-enriched plasma from at least sixteen different erythrocyte-compatible donors. The pregnancies were normal and each mother produced a healthy baby. The presence of trophoblast/lymphocyte cross-reactive (TLX) antigens, which stimulate the mother to mount a response with blastocyst protective factors and which prevent maternal rejection of the antigenically unique embryo, might explain these results.

Substance misuse and psychiatric comorbidity: an overview of the OPCS National Psychiatric Morbidity Survey

There have been a number of national surveys of psychiatric morbidity, which have included questions on drugs, alcohol, and tobacco. These surveys have helped delineate the overlap between substance use and dependence and other psychological morbidity. There is a strong association reported between high substance consumption and other measures of psychological problems. This article provides an overview of a national household survey, a survey of institutional residents with psychiatric disorders, and a national survey of a homeless population. All three surveys used comprehensive and complex sampling strategies and lay interviewers to conduct structured diagnostic interviews. The household survey included over 10,000 households, the institutional survey interviewed 755 individuals, and the homeless survey of hostels, night shelters, day centres, and private sector leased accommodation interviewed 1,061 individuals. This overview looks at patterns of nicotine, alcohol, and other drug use in the different samples and examines interactions with other psychiatric morbidity. The survey reports that substance-related disorders are some of the commonest disorders in the community, with 5% of the household sample alcohol dependent, 7% alcohol dependent in the institutional sample and over 21% in the homeless sample recorded as alcohol dependent. Tobacco, alcohol and other drug use and dependence were dramatically higher in the homeless sample than in either of the other two samples. Substance use was significantly associated with higher rates of psychological morbidity as measured by the Clinical Interview Schedule Revised. Future service planning needs to take account of the striking disparity of prevalence of psychiatric disorders in different subsections of the population.

A feasibility study of the MTT assay for chemosensitivity testing in ovarian malignancy

We assess the feasibility of using the MTT assay as a measure of cell viability in chemosensitivity testing in ovarian malignancy. The assay utilises the conversion of the tetrazolium salt MTT to formazan by dehydrogenase enzymes in living cells. We show that the optical density of the formazan produced from MTT is directly proportional to the number of live cells tested. Optimum MTT conversion occurred after 4 h incubation and dimethyl sulphoxide was found to be the most suitable solvent for the formazan. Seventy-five samples of ascitic fluid and/or solid tumour were collected from 56 patients with FIGO stage III-IV ovarian adenocarcinoma. Malignant cell suspensions with a viability greater than 75% were prepared from 95% of ascitic fluid and 75% of biopsy samples by simple techniques. The effect of cytotoxic drugs was assessed in 91% of patients included in the study. Variation in drug effect between patients was evident following a 48 h incubation period and was reproducible. Overall platinum and anthraquinone analogues produced the greater effect but resistance did occur. Our results mirrored reported clinical response rates. Only one sample tested against chlorambucil showed any drug effect. As this assay produces results in a high percentage of tests and is rapid and simple it appears suitable for prospective clinical trials to correlate the in vitro results with in vivo response.

Breast cancer resistance protein expression and resistance to daunorubicin in blast cells from patients with acute myeloid leukaemia

Breast cancer resistance protein (BCRP) is a recently described member of the ATP binding cassette transporter superfamily. It has been shown to confer resistance to mitoxantrone, topotecan, doxorubicin and daunorubicin in human tumour cell lines. We describe a study of BCRP expression in blast cells derived from 20 patients with acute myeloid leukaemia (AML). Twelve samples were from patients who had received previous cytotoxic therapy. BCRP expression was measured by immunocytochemistry using the BXP‐34 monoclonal antibody. In vitro drug sensitivity was assessed using the methyl thiazol tetrazoliumbromide assay. BCRP expression varied between patients, and six out of 22 (27%) samples had > 10% cells staining positively (median 37%, range 13–95%). BCRP positivity was seen in both de novo samples and those from previously treated patients. There was a marked variation in the effect of all drugs tested between patients. Although there was no correlation between BCRP positivity and the effect of mitoxantrone, topotecan or doxorubicin, the median daunorubicin LC50 value of BCRP+ cells was fourfold higher than that of BCRP− cells (0·89 µmol/l compared with 0·21 µmol/l, P < 0·05). These results suggest that BCRP may be involved in resistance to the agents commonly used in AML and may explain some of the anomalous results found when studying other membrane transporters, such as P‐gp or MRP.

Methadone treatment for opiate addiction: Benefits in the first month

Data are presented on benefits observed in the immediate post-recruitment phase of outpatient treatment of opiate addicts with oral methadone. On re-interview by independent researchers at one-month, levels of drug use had reduced, with weekly intake of heroin reducing to a fifth, and of cocaine to a quarter (with significant reductions in both frequency of use and in amounts used per occasion). Significantly fewer opiate addicts were still injecting at follow-up, and those who were injecting were doing so less often. Measures of both physical and psychological health showed significant improvements over the first month of methadone treatment. A trend of reduction in involvement in acquisitive crime was also found. The finding of such wide-spread benefits so early within methadone treatment is encouraging in view of the recent increased provision of methadone programmes in the UK. However, the early acquisition of such benefits should prompt more rigorous study of the extent to which these changes are ass...

Nicotine, alcohol and drug dependence, and psychiatric comorbidity--results of a national household survey

There is a well-recognized relationship between substance use disorders and other psychiatric disorders. This relationship has been well documented in a range of population-based studies. This study aims to report on consumption patterns of and dependence on nicotine, alcohol, and non-prescribed drugs and to report on the levels of psychiatric morbidity in these groups. A national household study of psychiatric morbidity was conducted in England and Wales. Psychiatric assessment was based on the Clinical Interview Schedule-Revised (CIS-R). Measures of nicotine, alcohol and drug use and dependence were obtained. This paper compares the levels of psychiatric morbidity in the non-dependent and the nicotine-, alcohol- and drug-dependent cases. Twelve per cent of the non-dependent population were assessed as having any psychiatric disorder compared with 22% of the nicotine-dependent, 30% of the alcohol-dependent, and 45% of the drug-dependent population. There is a clear relationship between dependence on nicotine, alcohol, and drugs and other psychiatric morbidity.

Heparin and Pregnancy in Women with a History of Repeated Miscarriages

Many patients who experience recurrent spontaneous abortions (RSA) have high titered antibodies to trophoblast antigens and/or negatively charged phospholipids. Pregnancy success has been documented in some of these patients subsequent to heparin treatment. The effect of heparin on in vitro assays used to detect antibodies to phospholipids and trophoblast antigens has been investigated. We have found that complement-mediated detection of antibodies to trophoblast and lymphocyte antigens is inhibited by absorption of sera with solid-phase heparin. The data show that such inhibition involves an inhibitor and a heparin-sensitive regulator of the inhibitor. Heparin inhibits binding of antiphospholipid antibodies to phospholipids in solid-phase ELISA. The mechanism for this inhibition appears to involve an interaction between heparin and antibody to phospholipid. These findings reveal novel heparin-mediated reactions that bridge immunological and hematological interactions. The extent of heparin modulation of these antibody reactivities should be clarified in future clinical trials involving heparin treatment for RSA.

Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562.

Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide – the FAC regime) leads to a significant decrease in doxorubicin cardiotoxicity and a significant increase in median survival time for patients with advanced breast cancer responsive to FAC. The reason for this increase in survival may be due to interference with the mechanism involved in the emergence of multidrug resistance (MDR). In order to test this hypothesis, we induced resistance to doxorubicin in the K562 cell line by growing cells in increasing concentrations of doxorubicin (10–30 nM) in the presence and absence of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sublines was measured using the MTT assay. Flow cytometry was used to assess the MDR1 phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functional P-glycoprotein. Long-term growth in doxorubicin increased the cellular resistance (IC50) of K562 cells in a concentration-dependent manner (r2 = 0.908). Doxorubicin resistance was not induced in the presence of dexrazoxane (P< 0.0001) for several months. In parallel, the expression of functional P-glycoprotein was delayed after concomitant addition of dexrazoxane to the selecting medium (P< 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may delay the development of MDR1, thus allowing responders to the FAC regime to continue to respond.

How do general practitioners manage alcohol-misusing patients? Results from a national survey of GPs in England and Wales.

The appropriateness of the primary care setting to undertake health promotional activities has been emphasized, but little is known about the clinical work of GPs with patients misusing alcohol. This study examines how GPs managed alcohol-misusing patients. A 20% random sample of all general practitioners in England and Wales were surveyed using a postal questionnaire. A 44% response rate was achieved. GPs reported managing different levels of severity of drinking problems differently. Basic interventions, such as reporting the alcohol misuse diagnosis and the provision of advice and information, were routine. Health promotion leaflets were not used uniformly, even with the less severe problem drinkers. Detoxification, prescribing of drugs and the management of medical complications were undertaken mainly with dependent patients. Dependent drinkers were the most likely group to be referred to specialist services, while internal practice referrals occurred with all drinking status categories. Anti-depressants were the drugs most usually prescribed to alcohol-misusing patients. The data point to a need for basic guidelines, not only on how to manage and refer dependent drinkers, but also on how to detect and manage those who are not yet manifesting problems but are drinking above recommended guidelines. One of the most evident areas in which there appears to be a need for guidelines is that of prescribing within primary care.

The Modelling of Injecting Behaviour and Initiation into Injecting

The modelling of injecting by injecting drug users (IDUs) around non-injecting drug users (NIDUs) is examined as a precursor to NIDUs initiation into injecting. Structured self-report interviews were conducted with 86 IDUs. 86% of the sample had been initiated into injecting by an IDU: 78% of their initiators being either a friend, partner, or sibling. Only 7% of respondents reported being pressured into injecting. 70% of respondents assessed that modelled injecting had been an important influence on their decision to inject by making them curious about injecting. In turn 98% of the respondents had modelled injecting around NIDUs, but 59% reported being unsure, or thought it unlikely, that they had made someone want to try injecting. Of these respondents 90% had talked to an NIDU about injecting, and 77% had injected around an NIDU. The findings suggest the need for interventions that raise awareness about the socially transmitted nature of injecting drug use.