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J K Morris

Publications and source records attributed to J K Morris.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1996

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships.

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.

Anti-HIV Agents↗
PubMed1996

An E-box region within the prostaglandin endoperoxide synthase-2 (PGS-2) promoter is required for transcription in rat ovarian granulosa cells.

The prostaglandin endoperoxide synthase-2 (PGS-2) gene encodes an isoform of prostaglandin synthase that is transiently induced by protein kinase A (luteinizing hormone/cAMP) and protein kinase C (gonadotropin-releasing hormone) agonists in granulosa cells of ovulating follicles. The promoter of the rat PGS-2 gene contains a CAAT enhancer-binding protein consensus site (CAAT box) which can confer hormone inducibility to a PGS-2.CAT reporter gene, as well as a putative E-box region. To determine if the E-box region was involved in hormone induced trans-activation of the rat PGS-2 gene, constructs with the CAAT box and E-box regions (-192 PGS-2.CAT), only the putative E-box (-110 PGS-2.CAT), or neither region (-52 PGS-2.CAT) were transiently transfected into rat granulosa cell cultures. CAT activity was induced in both the -192 and -110 PGS-2*CAT vectors by luteinizing hormone (10-fold) and gonadotropin-releasing hormone (6-fold), whereas CAT activity of the -52 PGS-2.CAT construct did not differ from the promoterless vector (pCAT-Basic). Deletion of 1 base pair from the E-box within the -110 PGS-2.CAT construct, as well as point mutations within the CAAT box, E-box, or both regions of the -192 PGS-2.CAT construct, demonstrated that the E-box is critical for basal transcription, and that regions, in addition to the CAAT box, are involved in hormone induction of the PGS-2 gene. An oligonucleotide spanning the rat PGS-2 E-box bound two specific protein complexes which were supershifted in the presence of antibody specific for the upstream stimulatory factor. Thus, in rat granulosa cells, the PGS-2 E-box region appears to interact with upstream cis-acting elements other than the CAAT box to confer hormonal regulation of the gene. The E-box region of the rat PGS-2 promoter does not contain ATF/CRE activity found in the human and mouse PGS-2 promoters, but is critical for basal transcription of the PGS-2 gene in rat granulosa cells and binds the upstream stimulatory factor (as do E-box regions of other genes regulated in the ovary).

Animals↗
PubMed1995

Mortality in relation to tar yield of cigarettes: a prospective study of four cohorts.

OBJECTIVE: To investigate relation between tar yield of manufactured cigarettes and mortality from smoking related diseases. DESIGN: Prospective epidemiological study of four cohorts of men studied between 1967 and 1982. SETTING: Combined data from British United Provident Association (BUPA) study (London), Whitehall study (London), Paisley-Renfrew study (Scotland), and United Kingdom heart disease prevention project (England and Wales). SUBJECTS: Of the 56,255 men aged over 35 who were included in the studies, 2742 deaths occurred among 12,400 smokers. Average follow up was 13 years. MAIN OUTCOME MEASURES: Relative mortality from smoking related diseases according to tar yields of cigarettes smoked. RESULTS: Age adjusted mortality from smoking related diseases in smokers of filter cigarettes was 9% lower (95% confidence interval 1% to 17%) than in smokers related diseases consistently decreased with decreasing tar yield. Relative mortality in cigarette smokers for a 15 mg decrease in tar yield per cigarette was 0.75 (0.52 to 1.09) for lung cancer, 0.77 (0.61 to 0.97) for coronary heart disease, 0.86 (0.50 to 1.50) for stroke, 0.78 (0.40 to 1.48) for chronic obstructive lung diseases, 0.78 (0.65 to 0.93) for these smoking related diseases combined, and 0.77 (0.65 to 0.90) for all smoking related diseases. CONCLUSION: About a quarter of deaths from lung cancer, coronary heart disease, and possibly other smoking related diseases would have been avoided by lowering tar yield from 30 mg per cigarette to 15 mg. Reducing cigarette tar yields in Britain has had a modest effect in reducing smoking related mortality.

Adult↗
PubMed1995

Structure-based design of nonpeptidic HIV protease inhibitors from a cyclooctylpyranone lead structure.

Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was identified in our labs, and an X-ray structure of this inhibitor complexed with HIV-2 protease was obtained. This crystal structure was used to develop two strategies for creating derivatives of 1 with enhanced enzyme inhibitory activity. The first strategy, substitution on the cyclooctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cycloocytyl ring on the inhibitors. The second strategy, substitution at the meta position of the aryl ring, was far more successful and generated compounds, such as the carboxamide derivatives 41 (Ki = 3.0 +/- 0.4 nM) and 36 (Ki = 4.0 +/- 0.8 nM), which were significantly more active than the corresponding unsubstituted cycloocytlpyranone 2 (Ki = 11.7 +/- 4.7 nM). An X-ray crystal structure of 36 complexed with HIV-1 protease indicated the increase in binding affinity is most likely due to the additional interactions between the amide substituent and the S3 region of the protease.

Aspartic Acid Endopeptidases↗
PubMed1995

Use of medium-sized cycloalkyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors.

A unique strategy for the enhancement of secondary binding of an inhibitor to an enzyme has been demonstrated in the design of new human immunodeficiency virus (HIV) protease inhibitors. When the planar benzene ring of a 4-hydroxycoumarin lead compound (1a, Ki = 0.800 microM) was replaced with medium-sized (i.e., 7-9), conformationally-flexible, alkyl rings, the enzyme inhibitory activity of the resulting compounds was dramatically improved, and inhibitors with more than 50-fold better binding (e.g., 5d, Ki = 0.015 microM) were obtained. X-ray crystal structures of these inhibitors complexed with HIV protease indicated the cycloalkyl rings were able to fold into the S1' pocket of the enzyme and fill it much more effectively than the rigid benzene ring of the 4-hydroxycoumarin compound. This work has resulted in the identification of a promising lead structure for the design of potent, deliverable HIV protease inhibitors. Compound 5d, a small (MW = 324), nonpeptidic structure, has already shown several advantages over peptidic inhibitors, including high oral bioavailability (91-99%), a relatively long half-life (4.9 h), and ease of synthesis (three steps).

4-Hydroxycoumarins↗
PubMed1995

Increasing incidence of tuberculosis in England and Wales: a study of the likely causes.

OBJECTIVE: To examine factors responsible for the recent increase in tuberculosis in England and Wales. DESIGN: Study of the incidence of tuberculosis (a) in the 403 local authority districts in England and Wales, ranked according to Jarman score, and (b) in one deprived inner city district, according to ethnic origin and other factors. SETTING: (a) England and Wales 1980-92, and (b) the London borough of Hackney 1986-93. MAIN OUTCOME MEASURE: Age and sex adjusted rate of tuberculosis. RESULTS: In England and Wales notifications of tuberculosis increased by 12% between 1988 and 1992. The increase was 35% in the poorest 10th of the population and 13% in the next two; and in the remaining 70% there was no increase. In Hackney the increase affected traditionally high risk and low risk ethnic groups to a similar extent. In the "low risk" white and West Indian communities the incidence increased by 58% from 1986-8 (78 cases) to 1991-3 (123), whereas in residents of Indian subcontinent origin the increase was 41% (from 51 cases to 72). Tuberculosis in recently arrived immigrants--refugees (11% of the Hackney population) and Africans (6%)--accounted for less than half of the overall increase, and the proportion of such residents was much higher than in most socioeconomically deprived districts. The local increase was not due to an increase in the proportion of cases notified, to HIV infection, nor to an increase in homeless people. CONCLUSIONS: The national rise in tuberculosis affects only the poorest areas. Within one such area all residents (white and established ethnic minorities) were affected to a similar extent. The evidence indicates a major role for socioeconomic factors in the increase in tuberculosis and only a minor role for recent immigration from endemic areas.

Asia↗
PubMed1995

Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes.

During the development of preovulatory follicles, tonic levels of FSH (and steroid) induce expression of aromatase, the LH receptor, and RII beta in a coordinate manner. Despite the similar temporal increase in steady-state levels of mRNA encoding these proteins, the cis-acting DNA elements and trans-acting factors regulating each gene are distinct (Richards, 1993). Whereas the aromatase gene has a TATA motif and a single transcriptional initiation site (Fitzpatrick and Richards, 1993), both the LH receptor (Wang et al., 1992; Tsai-Morris et al., 1993) and RII beta (Kurten et al., 1992; Luo et al., 1992) genes have promoters that are GC rich, lack TATA motifs, and initiate transcription at multiple sites. The aromatase promoter appears to be regulated, in part, by SF-1, a CRE-like region, and possibly another or overlapping region binding an Ad3BP-like factor. The RII beta promoter has a region that binds several nuclear proteins, whose identity is not yet known. Likewise, the LH receptor promoter elements have yet to be clearly defined (Figures 2, 4, and 25; Kurten et al., 1992). FSH can also induce the expression of at least three immediate-early genes that encode novel kinases or kinase-like proteins (Figure 25). One of these is called serum-inducible kinase (snk) (Simmons et al., 1992), another is serum and glucocorticoid regulated kinase (sgk) (Webster et al., 1993), and a third is called pole kinase (Clay et al., 1993). Steady-state levels of snk and sgk mRNA are induced rapidly (within a few hours) by FSH in granulosa cells prior to the appearance of transcripts for aromatase, LH receptor, and RII beta (T. Alliston and J. S. Richards, in preparation). The functional role of these kinases in the initial response of granulosa cells to tonic (not surge) levels of FSH remains to be elucidated. The cellular signaling pathways mediating the effects of the LH surge appear equally or more complex (Fig. 25). Based on data presented herein, as well as on analyses of the cloned and expressed LH receptor (Guderman et al., 1992), it is clear that low concentrations of LH stimulate adenylyl cyclase, cAMP production, and activation of protein kinase A. Higher (surge) concentrations of LH also increase IP3 and activation of protein kinase C. GnRH has been used in several studies to examine the ability of the protein kinase C pathway to mimic effects of high LH.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Cost comparison of different methods of screening for cystic fibrosis.

OBJECTIVE: To compare the costs of several proposed methods of screening for cystic fibrosis. SETTING: England and Wales. METHODS: The costs of screening carried out at hospital antenatal clinics, general practitioner (GP) antenatal consultations, GP surgeries, and at work were estimated using data from demonstration projects. Couple screening, stepwise screening, and screening of individuals were considered. RESULTS: Couple screening at antenatal hospital clinics was the least expensive per carrier couple detected, amounting to 35,700 pounds (142,900 pounds for each potential cystic fibrosis fetus detected). The costs of the reagents (25 pounds per test) accounted for over 60% of this total. CONCLUSIONS: Antenatal screening, in addition to being the most cost effective method of screening, is also medically the screening method of choice as it provides information at the latest time when effective preventive action can be taken and at a time when all people to be screened are likely to be accessible. If the costs of the reagents could be reduced to 5 pounds (still higher than the costs of most diagnostic reagents) the cost for each pregnant carrier couple offered screening would be reduced by 50% to about 18,000 pounds, and the cost of offering screening to 684,000 pregnant couples in England and Wales would be about 9 1/2 m instead of 19 m pounds.

Costs and Cost Analysis↗
PubMed1995

Luteinizing hormone induces prostaglandin endoperoxide synthase-2 and luteinization in vitro by A-kinase and C-kinase pathways.

The LH surge induces ovulation [prostaglandin synthase-2 (PGS-2)] and luteinization (progesterone synthesis) of preovulatory follicles by cAMP-dependent mechanisms. Peptides, such as GnRH and angiotensin-II, that activate other cellular signaling pathways have been shown to mimic some of the effects of LH. Therefore, the relative functional importance of different cellular signaling pathways in mediating the induction of PGS-2 and luteinization was analyzed using the agonists (LH, GnRH, and angiotensin-II) and selective inhibitors of A-kinase (H-89), C-kinase (calphostin-C), and calmodulin kinase-II (KN93). LH or GnRH, but not angiotensin-II, markedly induced PGS-2 protein in preovulatory follicles. H-89 and calphostin-C, but not KN93 inhibited LH induction of PGS-2, whereas calphostin-C selectively blocked induction by GnRH. In contrast, the A- and C-kinase inhibitors prevented both LH and GnRH induction of granulosa cell luteinization. Taken together, these results provide biological evidence that the response of granulosa cells to the LH surge appears to involve the activation of A- and C-kinase pathways.

Animals↗
PubMed1994

Loss of employment and mortality.

OBJECTIVE: To assess effect of unemployment and early retirement on mortality in a group of middle aged British men. DESIGN: Prospective cohort study (British Regional Heart Study). Five years after initial screening, information on employment experience was obtained with a postal questionnaire. SETTING: One general practice in each of 24 towns in Britain. SUBJECTS: 6191 men aged 40-59 who had been continuously employed for at least five years before initial screening in 1978-80: 1779 experienced some unemployment or retired during the five years after screening, and 4412 remained continuously employed. MAIN OUTCOME MEASURE: Mortality during 5.5 years after postal questionnaire. RESULTS: Men who experienced unemployment in the five years after initial screening were twice as likely to die during the following 5.5 years as men who remained continuously employed (relative risk 2.13 (95% confidence interval 1.71 to 2.65). After adjustment for socioeconomic variables (town and social class), health related behaviour (smoking, alcohol consumption, and body weight), and health indicators (recall of doctor diagnoses) that had been assessed at initial screening the relative risk was slightly reduced, to 1.95 (1.57 to 2.43). Even men who retired early for reasons other than illness and who appeared to be relatively advantaged and healthy had a significantly increased risk of mortality compared with men who remained continuously employed (relative risk 1.87 (1.35 to 2.60)). The increased risk of mortality from cancer was similar to that of mortality from cardiovascular disease (adjusted relative risk 2.07 and 2.13 respectively). CONCLUSIONS: In this group of stably employed middle aged men loss of employment was associated with an increased risk of mortality even after adjustment for background variables, suggesting a causal effect. The effect was non-specific, however, with the increased mortality involving both cancer and cardiovascular disease.

Adult↗
PubMed1994

Serum albumin and mortality in the BUPA study. British United Provident Association.

In the British United Provident Association (BUPA) study, a prospective observational study of 21,520 men, the serum albumin of 877 men who died during 10 years of follow-up was compared with that of 877 controls, each matched to a case by age (within 1 year) and date of attendance (within 3 months). There was little overall difference (mean case-control difference = -0.11 milligram, P > 0.2) despite the fact that other studies have reported a long-term association between low serum albumin and increased mortality. Cause-specific mortality data showed no association of low albumin with ischaemic heart disease or other circulatory diseases. An inverse association with cancer was confined to the first few years of follow-up and so attributable to pre-clinical cancer lowering both serum albumin itself and serum cholesterol, with which albumin was associated. There was an association of chronic respiratory, neurological, renal, liver and gut diseases with low serum albumin (case-control difference = -1.19 milligram, P < 0.001) consistent with the effect of pre-clinical disease lowering serum albumin. Other causes of death showed no association with albumin. Our data do not support a cause and effect association of low serum albumin and mortality.

Accidents↗
PubMed1994

Monitoring trends in prenatal diagnosis of Down's syndrome in England and Wales, 1989-92.

The national register of chromosomal anomalies that lead to Down's syndrome has enabled the monitoring of change in prenatal diagnosis for this condition, and the factors which affect the change. The proportion of cases of cytogenetically diagnosed Down's syndrome in England and Wales detected prenatally rose to 46% in 1991-2 from 31% in 1988-9, a 1.5-fold increase (95% confidence interval 1.3 to 1.7). The increase was confined to mothers under 40 years and was due to the introduction of screening by maternal serum analysis and ultrasound. Over a quarter of affected pregnancies in women aged 25-29 were detected prenatally in 1991-2 compared with less than 10% in 1988-9. Analysis of the data showed regional differences in prenatal diagnosis rates, and in the length of time elapsing between the diagnostic test and termination of an affected pregnancy. An inexplicable finding was that this period varied with the sex of the fetus, being on average a day longer for females than for males.

Adult↗