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Biomedical subjects

J K Morris

Publications and source records attributed to J K Morris.

At least 19 recordsLinked to original sources
PubMed2000

Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice.

Receptor tyrosine kinase erbB2, which is activated by neuregulin, is expressed in Schwann and muscle cells in the developing neuromuscular junction (NMJ). In vitro studies have shown that neuregulin promotes the survival and migration of Schwann cells and stimulates acetylcholine receptor gene transcription in cultured muscle cells. These findings suggest an important role for erbB2 in the development of the NMJ. Here we examine erbB2-deficient mice to determine whether erbB2 is required for NMJ development in vivo. Our analysis shows that there are pre- and postsynaptic defects of developing NMJ in erbB2-deficient embryos. The presynaptic defects include defasciculation and degeneration of the motor nerves, and an absence of Schwann cells. The postsynaptic defect features an impairment of junctional folds at the neuromuscular synapse in the mutants. These results demonstrate that erbB2 is essential for in vivo development of the NMJ.

Animals↗
PubMed1999

Rescue of the cardiac defect in ErbB2 mutant mice reveals essential roles of ErbB2 in peripheral nervous system development.

ErbB2 receptor tyrosine kinase plays a role in neuregulin signaling and is expressed in the developing nervous system. We genetically rescued the cardiac defect of erbB2 null mutant embryos, which otherwise died at E11. These rescued erbB2 mutant mice die at birth and display a severe loss of both motor and sensory neurons. Motor and sensory axons are severely defasciculated and aberrantly projected within their final target tissues. Schwann cells are completely absent in the peripheral nerves. Schwann cell precursors are present within the DRG and proliferate normally, but their ability to migrate is decreased. Acetylcholine receptors cluster within the central band of the mutant diaphragm muscle. However, these clusters are dispersed and morphologically different from those in control muscle. Our results reveal an important role for erbB2 during normal peripheral nervous system development.

Animals↗
PubMed1999

Serum markers for Down's syndrome in women who have had in vitro fertilisation: implications for antenatal screening.

To examine the Down's syndrome screening positive rate among in vitro fertilisation (IVF) pregnancies, we measured second trimester serum marker levels in singleton IVF pregnancies (cases) and in five non-IVF pregnancies (controls) matched to each case for gestational age, age of mother, and duration of storage of the serum sample. There were 151 IVF pregnancies in which alpha fetoprotein, unconjugated oestriol (uE3), free beta-human chorionic gonadotrophin (hCG) and total hCG were measured, 104 IVF pregnancies in which free alpha-hCG was measured, and 39 IVF pregnancies in which inhibin A was measured. Median uE3 levels were 6% lower (P = 0.003), median free beta-hCG 9% higher (P = 0.024), and median total hCG 14% higher (P = 0.026) in IVF pregnancies compared with controls. The screen positive rate in the IVF pregnancies (28%) was about twice as high as that in controls (17%). High hCG levels may be explained by progesterone remaining high in IVF pregnancies. The low uE3 levels remain unexplained. In Down's syndrome screening in IVF pregnancies hCG and uE3 values should be adjusted to avoid the high screen positive rate.

Biomarkers↗
PubMed1999

The importance of age in screening for cancer.

OBJECTIVE: To derive a rational method of selecting the age range over which screening tests for cancer should be offered (that is, over which they would be most effective in saving life). MAIN OUTCOME MEASURE: The number of person-years of life that are lost through deaths occurring at each year of age from each of six cancers. RESULTS: For each cancer the number of years of life lost to age 80, plotted against age at death, showed a rise followed by a fall. The peak indicates the age at which deaths from the cancer result in most years of life lost. Special screening tests, such as mammography for breast cancer, will be most effective in saving life shortly before that age. The peak (as a five year age span) occurs at age 55-59 for breast cancer (189 years of life lost per 10,000 women per year), 70-74 for prostate cancer (114), 65-69 for colorectal cancer (96), 55-59 for ovarian cancer (61), 50-54 for cervical cancer (47), and 45-50 for melanoma (8). The precise interval by which special screening tests should precede the peak age is not critical; five years would be appropriate. Given current evidence on the efficacy of cancer screening, if it were stipulated that screening could only be performed when at least 50 years of life were to be gained per 10,000 persons screened, only mammography for breast cancer would be conducted, between the ages of 50 and 59. If the stipulation was 25 or more years of life gained mammography would be offered to women aged 40-69 and cervical smears to women aged 35-59. With only 10 or more years of life gained (unlikely to be worthwhile) mammography would be extended to women aged 30-74, cervical smears to 25-69, and faecal occult blood testing for colorectal cancer offered to those aged 45-74. Extending cervical cancer screening to age 69 would save more years of life than the present policy of screening women aged 20-29. Extending breast cancer screening to the age of 74 would be more effective than cervical screening at any age. CONCLUSIONS: Determining the number of years of life lost through deaths from a particular cancer at each age is useful in public health screening policy, both in selecting the age range over which special screening tests of proven efficacy should be offered and in quantitatively comparing the value of screening for different cancers.

Adolescent↗
PubMed1999

Fetal loss in Down syndrome pregnancies.

It is recognized that pregnancies with Down syndrome are liable to end in spontaneous fetal loss. It is important to determine the magnitude of this effect so that it can be taken into account when assessing the results of antenatal screening programmes for Down syndrome. Failure to do so will tend to overestimate the detection rate in intervention studies in which the screening results are used to identify women for a diagnostic test and the offer of a termination of pregnancy if indicated. We present new data on the spontaneous fetal loss in Down syndrome pregnancies from the National Down Syndrome Cytogenetic Register (1989-1996). We compare our results with published results of other studies on the subject to obtain a summary estimate. We exclude one study from the meta analysis due to incorrect methodology resulting in an overestimate of fetal loss. Based on the combined data (i) between the time of chorionic villus sampling and term an estimated 43 per cent (95 per cent CI: 31-54 per cent) of pregnancies ended in a miscarriage or still birth, (ii) between the time of amniocentesis and term an estimated 23 per cent (95 per cent CI: 19 28 per cent) of pregnancies ended in a miscarriage or still birth, and (iii) 12 per cent (95 per cent CI: 2-23 per cent) of births were stillborn or resulted in a neonatal death.

Abortion, Spontaneous↗
PubMed1998

Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization.

BACKGROUND: In vitro fertilization is associated with a high risk of multiple births, which is a direct consequence of the number of embryos transferred. However, other factors that contribute to the risk are not well defined. METHODS: Using the data base established by the Human Fertilization and Embryology Authority in the United Kingdom, we studied the factors associated with an increased risk of multiple births in 44,236 cycles in 25,240 women. The factors included the woman's age, the cause and duration of infertility, previous attempts at in vitro fertilization, previous live births, number of eggs fertilized, and number of embryos transferred. RESULTS: Older age, tubal infertility, longer duration of infertility, and a higher number of previous attempts at in vitro fertilization were all associated with a significantly decreased chance of a birth and of multiple births. Previous live birth was associated with an increased chance of a birth but not of multiple births. The higher the number of eggs fertilized, the higher the likelihood of a live birth. When more than four eggs were fertilized, there was no increase in the birth rate for women receiving three transferred embryos as compared with those receiving two, but there was a considerable increase in the rate of multiple births when three were transferred (odds ratio, 1.6; 95 percent confidence interval, 1.5 to 1.8). CONCLUSIONS: Among women undergoing in vitro fertilization, the chances of a live birth are related to the number of eggs fertilized, presumably because of the greater selection of embryos for transfer. When more than four eggs are fertilized and available for transfer, the woman's chance of a birth is not diminished by transferring only two embryos. Transferring more embryos increases the risk of multiple births.

Adult↗
PubMed1998

By how much does fruit and vegetable consumption reduce the risk of ischaemic heart disease?

OBJECTIVE: To quantify the relationship between fruit and vegetable consumption and the incidence of ischaemic heart disease. DESIGN: A meta-analysis of cohort studies of the relationship between ischaemic heart disease and markers of fruit and vegetable consumption, namely dietary intake of fruit, vegetables, carotenoids, vitamin C, fruit fibre and vegetable fibre, and serum concentration of carotenoids and vitamin C, adjusted for other risk factors. MAIN OUTCOME MEASURES: Risk of ischaemic heart disease at the 90th centile of consumption relative to that at the 10th, equivalent to about a four-fold difference in fruit consumption and a doubling of vegetable consumption. RESULTS: The association with ischaemic heart disease was of similar magnitude for all six dietary markers of fruit and vegetable consumption. The median of the six estimates was that risk was 15% (range 12-19%) lower at the 90th centile of consumption than at the 10th. The estimates were generally adjusted for the possible confounding effect of other heart disease risk factors. The serum studies of vitamin C were consistent with this; those of carotenoids suggested a larger difference (43%) but were not adjusted for the important confounding effect of smoking. The substances in fruit and vegetables responsible for the protective effect on heart disease are uncertain but the effect is commensurate with the estimated protective effects of the potassium and folate in fruit and vegetables. Beta-carotene or vitamin E are not likely to be important because randomised trials of these vitamins in large doses have shown no reduction in heart disease mortality. CONCLUSIONS: The risk of ischaemic heart disease is about 15% lower at the 90th than the 1Oth centile of fruit and vegetable consumption.

Adult↗
PubMed1998

Is there evidence of clustering in Down syndrome?

BACKGROUND: Associations between environmental hazards and the occurrence of congenital anomalies may be detectable by seeking evidence of non-random occurrence of cases (clusters). There have been a number of anecdotal reports of occurrences of clusters of Down syndrome (DS). METHODS: Data from a national register of cytogenetic diagnoses of Down syndrome births and legal terminations occurring between 1989 and 1995 were used to examine the possibility of clustering. Space-time clustering at Regional Health Authority (RHA) level was examined by comparing the expected monthly number of DS pregnancies given the maternal age distribution, with the observed numbers. Knox's method was used to determine if any clustering of RHA of unexpectedly high prevalence had occurred. Seasonality was also investigated by comparing monthly expected and observed numbers of DS pregnancies. Time clustering was examined by using the scan statistic to determine whether a statistically significant excess of pregnancies in any 3-month period occurred in any individual or adjacent groups of District Health Authority (DHA). RESULTS: The numbers of DS pregnancies were no higher than expected (P < 0.05) in the same RHA over consecutive months. There was no evidence of any seasonality of DS pregnancies (P > 0.5). Only two individual DHA and three pairs of adjacent DHA had significantly high scan statistics (P < 0.03), but as over 400 statistical tests had been completed 12 clusters would be expected to have occurred due to chance alone. CONCLUSION: There was no evidence of any space-time clustering in DS at DHA level.

Causality↗
PubMed1998

Why is mortality higher in poorer areas and in more northern areas of England and Wales?

STUDY OBJECTIVE: To identify and quantify the factors responsible for the differences in mortality between affluent and deprived areas, the north and the south, and urban and rural areas in England and Wales. DESIGN: A multiple Poisson regression analysis of cause specific mortality in the 403 local authority districts, each classified by deprivation (using the Jarman Index), latitude (from 50 degrees to 55 degrees north) and urbanisation, adjusting for age, sex, and proportion of ethnic minorities. SETTING: England and Wales 1992. MAIN RESULTS: All cause mortality was 15% higher in the districts comprising the most compared with the least deprived tenth of the population, 23% higher in the most northern (55 degrees) than in the most southern (50 degrees) districts, and 4% higher in metropolitan (within large cities) than rural districts. Nationally these differences were associated with 40,000, 65,000, and 15,000 excess deaths respectively. More than two thirds of the overall excess mortality with deprivation, latitude, and urbanisation was from three diseases--ischaemic heart disease, lung cancer, and chronic bronchitis and emphysema. The excess mortality from these and other diseases closely matched that predicted from differences according to deprivation and latitude in smoking, heavy alcohol consumption, Helicobacter pylori infection, and temperature, and thus could be attributed to these causes. About 85% of the overall excess mortality with deprivation was attributable to heavier smoking and 6% to heavier alcohol consumption, but diet varied little. Deaths more directly related to deprivation (such as those caused by H pylori infection, drug misuse, psychoses) accounted for an estimated 12% of the excess deaths, but variation in provision and uptake of healthcare services only 1%. The direct effects of deprivation are more strongly related to morbidity than mortality. Of the difference in mortality with latitude, about 45% was attributable to differences in smoking, and 25% to climate (mainly the association of cardiovascular and respiratory disease with cold). The differences with urbanisation were mainly because of smoking. CONCLUSIONS: Differences in the prevalence of smoking account for much of the variation in mortality between areas. Alcohol accounts for some, diet little. The more direct material effect of deprivation contributes to the variation in mortality but is particularly important with respect to differences in morbidity.

Age Factors↗
PubMed1997

Helicobacter pylori infection and mortality from ischaemic heart disease: negative result from a large, prospective study.

OBJECTIVE: To determine whether there is an independent association between Helicobacter pylori infection of the stomach and ischaemic heart disease. DESIGN: Prospective study with measurement of IgG antibody titres specific to H pylori on stored serum samples from 648 men who died from ischaemic heart disease and 1296 age matched controls who did not (nested case-control design). SUBJECTS: 21,520 professional men aged 35-64 who attended the British United Provident Association (BUPA) medical centre in London between 1975 and 1982 for routine medical examination. MAIN OUTCOME MEASURE: Death from ischaemic heart disease. RESULTS: The odds of death from ischaemic heart disease in men with H pylori infection relative to that in men without infection was 1.06 (95% confidence interval 0.86 to 1.31). In a separate group of 206 people attending the centre, plasma fibrinogen was virtually the same in those who were positive for H pylori (2.62 g/l) and those who were negative (2.64 g/l). CONCLUSIONS: A study that by its size and design minimised both random error and socioeconomic bias found no relation between H pylori infection and ischaemic heart disease. The validity of the study was shown by its confirmation of the recognised association between H pylori infection and stomach cancer (odds ratio 4.0 (1.9 to 8.2); P < 0.001). Eradication of H pylori infection may greatly reduce the incidence of stomach cancer, one of the most common causes of death from cancer worldwide, but it cannot be expected to have any effect in preventing ischaemic heart disease.

Adult↗
PubMed1997

Environmental tobacco smoke exposure and ischaemic heart disease: an evaluation of the evidence.

OBJECTIVES: To estimate the risk of ischaemic heart disease caused by exposure to environmental tobacco smoke and to explain why the associated excess risk is almost half that of smoking 20 cigarettes per day when the exposure is only about 1% that of smoking. DESIGN: Meta-analysis of all 19 acceptable published studies of risk of ischaemic heart disease in lifelong non-smokers who live with a smoker and in those who live with a non-smoker, five large prospective studies of smoking and ischaemic heart disease, and studies of platelet aggregation and studies of diet according to exposure to tobacco smoke. RESULTS: The relative risk of ischaemic heart disease associated with exposure to environmental tobacco smoke was 1.30 (95% confidence interval 1.22 to 1.38) at age 65. At the same age the estimated relative risk associated with smoking one cigarette per day was similar (1.39 (1.18 to 1.64)), while for 20 per day it was 1.78 (1.31 to 2.44). Two separate analyses indicated that non-smokers who live with smokers eat a diet that places them at a 6% higher risk of ischaemic heart disease, so the direct effect of environmental tobacco smoke is to increase risk by 23% (14% to 33%), since 1.30/1.06 = 1.23. Platelet aggregation provides a plausible and quantitatively consistent mechanism for the low dose effect. The increase in platelet aggregation produced experimentally by exposure to environmental tobacco smoke would be expected to have acute effects increasing the risk of ischaemic heart disease by 34%. CONCLUSION: Breathing other people's smoke is an important and avoidable cause of ischaemic heart disease, increasing a person's risk by a quarter.

Aged↗
PubMed1997

Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones.

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.

Animals↗
PubMed1997

The dose-response relationship between cigarette consumption, biochemical markers and risk of lung cancer.

The relationship between the number of cigarettes smoked per day and the incidence of lung cancer is linear but, from the multistage model of carcinogenesis, it should be quadratic (upwards curving). We investigated this anomaly in a study of 11,403 male never smokers and current smokers in whom carboxyhaemoglobin (COHb) was measured in all and serum cotinine in 1175. The relationship between the biochemical markers and the reported number of cigarettes per day was approximately linear up to 20 cigarettes per day as expected. But above 20 cigarettes per day the marker levels increased less steeply and were 35% lower than expected in men who smoked more than 40 cigarettes per day. Less smoke is inhaled from each cigarette by men with high daily cigarette consumption than by men with lower consumption. Allowance for this transforms the observed linear dose-response relationship into one consistent with the expected quadratic relationship. The anomaly is explained by the observation that heavier smokers inhale less smoke from each cigarette.

Adult↗
PubMed1997

Reliability of statistics on Down's syndrome notifications.

OBJECTIVES: To evaluate the completeness of notifications of Down's syndrome live births and terminations to the Office for National Statistics (ONS) using data from the National Down Syndrome Cytogenetic Register (NDSCR). To examine the agreement of observed birth prevalence of Down's syndrome with the expected birth prevalence derived from published maternal age specific rates. METHODS: The number of live births (adjusted to allow for the estimated underascertainment) and the number of terminations due to fetal Down's syndrome from NDSCR were compared with those figures reported to the ONS. Subsequently, using the NDSCR figures, the live birth prevalence of Down's syndrome that would have occurred in the absence of antenatal diagnosis and selective termination was calculated in England and Wales in the years 1990-1993. These figures were compared with those derived by applying published age specific prevalences to the maternal age distribution in England and Wales. RESULTS: It is estimated that only 48% and 46% respectively of Down's syndrome live births and terminations of pregnancy were notified to ONS between 1990 and 1993. The annual expected birth prevalences of Down's syndrome obtained by applying maternal age specific prevalences to the maternal age distribution were in close agreement with observed rates from NDSCR. CONCLUSIONS: There is considerable underreporting of Down's syndrome births and terminations to ONS. The NDSCR data are more complete and therefore the effects of screening should be monitored using data from this source, or using estimates derived from the age specific rates of Down's syndrome.

Abortion, Induced↗
PubMed1996

Factors that affect outcome of in-vitro fertilisation treatment.

BACKGROUND: The effectiveness of in-vitro fertilisation (IVF) treatment depends both on the overall success rate in the treating clinic and on the characteristics of the couple seeking treatment. Since 1991, the Human Fertilisation and Embryology Authority (HFEA) has been collecting information on all IVF cycles carried out in the UK. This database has been analysed to identify the factors that affect the outcome of treatment. METHODS: All IVF treatment cycles and outcomes registered between August, 1991, and April, 1994, were identified (52507). Cycles that involved gamete or embryo donation, frozen embryo transfer, or micromanipulation and unstimulated cycles were excluded. Thus, 36961 cycles (70% of those registered) were included in the analysis. The main outcome measure was liverbirth rate per cycle started. The relation between age and outcome was investigated by fitting of different fractional polynomials of age with logistic regression models. All other factors were analysed by logistic regression with age included in the model. FINDINGS: The overall livebirth rate per cycle of treatment was 13.9%. The highest livebirth rates were in the age-group 25-30 years; younger women had lower rates and there was a sharp decline in older women. At all ages over 30, use of donor eggs was associated with a significantly higher livebirth rate than use of the woman's own eggs, but there was also a downward trend in success rate with age (p = 0.04). After adjustment for age, there was a significant decrease in livebirth rate with increasing duration of infertility from 1 to 12 years (p < 0.001). The medical indication for treatment had no significant effect on the outcome. Previous pregnancy and livebirth significantly increased treatment success. The possibility of success decreased with each IVF treatment cycle. INTERPRETATION: We were able to identify by logistic regression the factors that significantly affect the outcome of IVF treatment, and to measure the magnitude of that effect. These factors should be taken into account in assessment of IVF results. After allowance for background clinic success rates, these factors can be used to predict outcome in individual cases.

Adult↗