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Biomedical subjects

J M Watson

Publications and source records attributed to J M Watson.

At least 19 recordsLinked to original sources
PubMed1998

Identification of the structural region of taxol that may be responsible for cytokine gene induction and cytotoxicity in human ovarian cancer cells.

PURPOSE: Interleukin-8 (IL-8) is a pleiotropic chemokine with both chemoattractant and angiogenic properties. In addition to its cytotoxic effects on ovarian cancer cells, taxol can transcriptionally activate genes such as IL-8 that may play a role in tumorigenesis. Utilizing IL-8 as a prototypic marker of tumor-derived modulators of growth, we undertook a systematic study of taxol and 11 structurally modified taxol analogs to identify the region of the taxane skeleton responsible for IL-8 gene induction. METHODS: The human ovarian cancer cell line OVCA-420 was exposed to taxol or taxol analogs. IL-8 gene induction was assessed by Northern blot analysis after 6 h and cytotoxicity after 72 h. RESULTS: Changes in the southern hemisphere (C-1 to C-4) of the taxane skeleton had greater effects on IL-8 induction than changes in the northern hemisphere (C-7 to C-11). Some of the taxol analogs modified at positions C-1 and/or C-2 with increased hydrophobicity induced IL-8 expression more than threefold over that induced by taxol or taxotere and more than 20-fold over control cells. Cells that failed to induce IL-8 gene expression in response to taxol were only marginally responsive to the analogs unless first primed with IL-1beta. Modifications to the northern hemisphere did not alter taxol's effect on IL-8 expression in human cells, but did influence TNFalpha expression in murine macrophage cells, suggesting species and/or gene specificity. We found a direct correlation between IL-8 induction and cytotoxicity, in that analogs that dramatically upregulated IL-8 expression proved to be the most cytotoxic, inhibiting cell survival by > 90%. CONCLUSION: Taken together our results demonstrate that changes in the southern hemisphere of the taxane skeleton influence both the gene induction and cytotoxic potential of taxol in human ovarian cancer cells.

Antineoplastic Agents, Phytogenic↗
PubMed1998

The origin and loss of the ubiquitin activating enzyme gene on the mammalian Y chromosome.

Mammalian sex chromosomes are thought to be descended from a homologous pair of autosomes: a testis-determining allele which defined the Y chromosome arose, recombination between the nascent X and Y chromosomes became restricted and the Y chromosome gradually lost its non-essential genetic functions. This model was originally inferred from the occurrence of few Y-linked genetic traits, pairing of the X and Y chromosomes during male meiosis and, more recently, the existence of X-Y homologous genes. The comparative analysis of such genes is a means by which the validity of this model can be evaluated. One well-studied example of an X-Y homologous gene is the ubiquitin activating enzyme gene ( UBE1 ), which is X-linked with a distinct Y-linked gene in many eutherian ('placental') and metatherian (marsupial) mammals. Nonetheless, no UBE1 homologue has yet been detected on the human Y chromosome. Here we describe a more extensive study of UBE1 homologues in primates and a prototherian mammal, the platypus. Our findings indicate that UBE1 lies within the X-Y pairing segment of the platypus but is absent from the human Y chromosome, having been lost from the Y chromosome during evolution of the primate lineage. Thus UBE1 illustrates the key steps of 'autosomal to X-specific' evolution of genes on the sex chromosomes.

Animals↗
PubMed1997

Influenza surveillance in England and Wales: October 1996 to June 1997.

This report summarises information collected for the surveillance of influenza in England and Wales during the winter of 1996/97. Consultations for 'influenza and influenza-like illness' with sentinel general practitioners in England and Wales began to increase towards the end of November and peaked at the start of January. In England, consultations for 'aggregated respiratory disease' (ARD) began to increase a little earlier, perhaps as a result of increased respiratory syncytial virus activity, but also peaked in early January. Influenza A (H3N2) viruses were first detected in early October, but rarely until November, and activity peaked in early January, coinciding with the peak in consultations for flu-like illness. A few influenza B viruses were detected in late November and early December, and substantial activity was recorded in mid-January. Approximately equal numbers of influenza A(H3N2) and B viruses were identified over the winter as a whole, and circulating strains were antigenically similar to those included in the vaccine for 1996/97. Although influenza activity was 'moderate' in terms of consultations and laboratory confirmed infections, a large peak in death registrations occurred at the same time as influenza A(H3N2) virus activity peaked. The number of deaths during the winter was similar to that seen in 1989/90, when the last severe influenza epidemic occurred in England and Wales.

Disease Outbreaks↗
PubMed1997

PHLS work on the surveillance and epidemiology of tuberculosis.

The re-emergence worldwide of tuberculosis as a major threat to public health and continuing and changing challenges in the control of tuberculosis in England and Wales provide the basis for the designation, by the PHLS, of tuberculosis as a priority area. In addition to the mycobacteriology reference services provided by the PHLS in England and Wales (summarised in an accompanying article) the PHLS contributes to the control of tuberculosis through its surveillance and other epidemiological work. This article summarises the range of this work, emphasising the collaborative nature of the effort required for surveillance, prevention, and control of tuberculosis.

England↗
PubMed1997

SB-216641 and BRL-15572--compounds to pharmacologically discriminate h5-HT1B and h5-HT1D receptors.

Despite only modest homology between h5-HT1B and h5-HT1D receptor amino acid sequences, these receptors display a remarkably similar pharmacology. To date there are few compounds which discriminate between these receptor subtypes and those with some degree of selectivity, such as ketanserin, have greater affinity for other 5-HT receptor subtypes. We now report on two compounds, SB-216641 (N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide) and BRL-15572 3-[4-(3-chlorophenyl) piperazin-1-yl]-1,1-diphenyl-2-propanol), which display high affinity and selectivity for h5-HT1B and h5-HT1D receptors, respectively. In receptor binding studies on human receptors expressed in CHO cells, SB-216641 has high affinity (pKi = 9.0) for h5-HT1B receptors and has 25-fold lower affinity at h5-HT1D receptors. In contrast, BRL-15572 has 60-fold higher affinity for h5-HT1D (pKi = 7.9) than 5-HT1B receptors. Similar affinities for these compounds were determined on native tissue 5-HT1B receptors in guinea-pig striatum. Functional activities of SB-216641 and BRL-15572 were measured in a [35S]GTPgammaS binding assay and in a cAMP accumulation assay on recombinant h5-HT1B and h5-HT1D receptors. Both compounds were partial agonists in these high receptor expression systems, with potencies and selectivities which correlated with their receptor binding affinities. In the cAMP accumulation assay, results from pK(B) measurements on the compounds again correlated with receptor binding affinities (SB-216641, pK(B) = 9.3 and 7.3; BRL-15572, pK(B) = <6 and 7.1, for h5-HT1B and h5-HT1D receptors respectively). These compounds will be useful pharmacological agents to characterise 5-HT1B and 5-HT1D receptor mediated responses.

Animals↗
PubMed1997

NF-kappa B as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA.

One of the most challenging issues of anti-inflammatory gene therapy is the complexity of inflammatory pathways. Transcription factor NF-kappa B plays a pivotal role in activation of multiple inflammatory molecules, and therefore represents the logical target for intervention. We evaluated the feasibility of suppressing the inflammatory responses in different cell lines through specific inhibition of NF-kappa B by gene transfer of I kappa B alpha, the naturally occurring intracellular inhibitor of NF-kappa B. The I kappa B alpha overexpressing cells were established using retroviral gene transfer or stable transfection with the wild-type (wt) I kappa B alpha cDNA. In all cell types, overexpression of wt I kappa B alpha resulted in a profound (> 100-fold) increase of the I kappa B alpha message and a moderate (two- to three-fold) increase of the I kappa B alpha protein. The effects of the I kappa B alpha overexpression on the NF-kappa B activation and the inflammatory responses varied significantly in different cell lines. In conditionally immortalized human endometrial stromal cells, overexpression of I kappa B alpha prevented both interleukin-1 (IL-1)-inducible degradation of endogenous I kappa B alpha protein and activation of NF-kappa B. Accordingly, induction of cytokines interleukin-8 (IL-8) and Gro gamma was markedly suppressed. In monocytic THP-1 cells, both lipopolysaccharide (LPS)-inducible degradation of I kappa B alpha and NF-kappa B activation were only partially inhibited by overexpression of exogenous I kappa B alpha cDNA. None the less, the LPS-induced transcription of IL-1 beta and secretion of cytokines interleukin-6 (IL-6) and IL-8 were virtually abolished. In epithelial HT-29 cells, no inflammatory responses were inhibited. These results demonstrate the range of responses in various cell lines to gene transfer of I kappa B alpha and indicate the feasibility of suppression of inflammatory responses in appropriate target cells and their progeny by suppression of NF-kappa B.

Cell Line↗
PubMed1997

Tuberculosis in England and Wales in 1993: results of a national survey. Public Health Laboratory Service/British Thoracic Society/Department of Health Collaborative Group.

BACKGROUND: A national survey of tuberculosis notifications in England and Wales was carried out in 1993 to determine the notification rate of tuberculosis and the trends in the occurrence of disease by ethnic group in comparison with the findings of similar surveys in 1978/79, 1983, and 1988. The prevalence of HIV infection in adults notified with tuberculosis in the survey period was also estimated. METHODS: Clinical, bacteriological, and sociodemographic information was obtained on all newly notified cases of tuberculosis in England and Wales during the six months from 2 January to 2 July 1993. The prevalence of HIV infection in 16-54 year old patients with tuberculosis notified throughout 1993 was assessed using "unlinked anonymous" testing supplemented by matching of the register of patients with tuberculosis with that of patients with AIDS reported to the PHLS AIDS centre. Annual notification rates were calculated using population estimates from the 1993 Labour Force Survey. RESULTS: A total of 2706 newly notified patients was eligible for inclusion in the survey of whom 2458 were previously untreated the comparable figures for 1988 were 2408 and 2163. The number of patients of white ethnic origin decreased from 1142 (53%) in 1988 to 1088 (44%) in 1993 whereas those of patients of Indian, Pakistani, or Bangladeshi (Indian subcontinent (ISC)) ethnic origin increased from 843 (39%) in 1988 to 1014 (41%) and those of "other" (non-white, non-ISC) ethnic origins increased from 178 (8%) to 356 (14%). The largest increase was seen in the black African ethnic group from 37 in 1988 to 171 in 1993. Forty nine per cent of patients had been born abroad and the highest rates were seen in those who had recently arrived in this country. The overall annual notification rate for previously untreated tuberculosis in England and Wales increased between 1988 and 1993 from 8.4 to 9.2 per 100,000 population. The rate declined in the white, Indian, and black Caribbean ethnic groups and increased in all other groups. In the white group the rate of decline has slowed since the last survey: in several age groups the rates were higher in 1993 than 1988 but the numbers in these groups were small. Thirty six (4.1%) of the 882 previously untreated respiratory cases were resistant to isoniazid and three (0.3%) to isoniazid and rifampicin. Sixty two (2.3%) adults aged 16-54 years were estimated to be HIV-infected. Evidence of under-reporting of HIV positive tuberculosis patients was found. CONCLUSIONS: The number of cases and annual notification rate for previously untreated tuberculosis increased between 1988 and 1993. Although the decline in rates in the white population has continued, the rate of decline has slowed. The high rates in the ISC ethnic group population have continued to decline since 1988 whereas rates in the black African group have increased. An increased proportion of cases were found among people born abroad, particularly those recently arrived in this country. In previously untreated cases the level of drug resistance remains low and multi-drug resistance is rare. A small proportion of adults with tuberculosis were infected with HIV but there may be selective undernotification of tuberculosis in these patients.

Adolescent↗
PubMed1996

Influenza surveillance in England and Wales: October 1995 to June 1996.

This report summarises information collected for the surveillance of influenza virus infection in England and Wales from October 1995 to June 1996 (weeks 40/95 to 25/96). Total respiratory disease' activity, as reported by the Birmingham Research Unit of the Royal College of General Practitioners, rose to peaks in weeks 48/95, 51/95, and 01/96. The first peak coincided with a peak in "influenza and flu-like illness'. The subsequent peaks were accounted for by an increase in reports of acute bronchitis, including bronchiolitis, and may have been associated with the annual rise in infections with respiratory syncytial virus. Influenza A virus was responsible for most infections, with moderate activity occurring in the early part of the winter, peaking in December (week 48/95). Influenza A subtype H3N2 predominated until week 07/96, after which subtype H1N1 accounted for most infections. Influenza activity was first seen in central and northern England, followed by the south of England, Wales, and Scotland. Circulating influenza viruses were antigenically similar to the components of the 1995/96 vaccine. International surveillance during 1995/96 has led to a different H3N2 component being included in the influenza vaccine recommended for 1996/97.

Adolescent↗
PubMed1996

GR127935 acts as a partial agonist at recombinant human 5-HT1D alpha and 5-HT1D beta receptors.

In this study we have investigated the functional activity of GR127935 (2-methyl-1,2,4 oxadiazol-3-yl)-biphenyl-[4-carboxylic acid 4-methoxy-3-(4-methyl-piperazine-1-yl]-amide) at human 5-HT1D alpha and 5-HT1D beta receptors which have been expressed in a Chinese Hamster Ovary (CHO) cell line. Using [35S] GTP gamma S binding to cell membranes as a measure of receptor-G protein coupling. GR127935 showed partial agonist activity in both 5-HT1D alpha and 5-HT1D beta receptor expressing cells (Emax: 29 and 31% above basal control; pEC50: 8.6 and 9.7, respectively). GR127935 also acted as a potent antagonist at the 5-HT1D alpha (app. pA2 8.5) and 5-HT1D beta (app. pA2 9.1) receptors. From studies measuring cAMP accumulation in cultured CHO cells GR127935 also displayed partial agonism, as well as acting as a potent antagonist at the 5-HT1D alpha receptors which stimulate cAMP levels and 5-HT1D beta receptors which inhibit cAMP levels (app. pA2 8.6 and 9.7, respectively). The 5\-HT1-like receptor antagonist methiothepin showed negative intrinsic activity at both receptors in the [35S]GTP gamma S binding assay only. From studies using the receptor alkylating agent EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline) the 5-HT1D alpha cell line displayed a lack of receptor reserve but it was evident in the 5-HT1D beta cell line. In previous studies we have also shown that agonist stimulation of 5-HT1D alpha receptors increases cAMP levels which may be due to high receptor expression. Further investigation using up to 1 microM EEDQ to reduce 5-HT1D alpha receptor number did not reveal an underlying inhibitory adenylyl cyclase response. In conclusion, GR127935 acts as a partial agonist, as well as a potent antagonist, at the human 5-HT1D alpha and 5-HT1D beta receptors when expressed in CHO cells.

Adenylyl Cyclases↗
PubMed1996

Opportunist mycobacteria in England and Wales: 1982 to 1994.

Three thousand and fifty-two infections with opportunist mycobacteria were reported to the PHLS Communicable Disease Surveillance Centre from 1982 to 1994. The commonest reported species was Mycobacterium avium-intracellulare (MAI), followed by M. kansasii and M. malmoense. The annual totals of opportunist mycobacteria increased steadily over this period, mostly, but not exclusively, due to an increase in reports of MAI associated with HIV infection. There were also increases in reports of MAI not associated with HIV infection, and in reports of M. malmoense. The increase in reports of opportunist mycobacteria was seen throughout England and Wales, but underreporting of MAI infection in the National Health Service Thames regions appears to have increased in recent years. Continued referral of isolates of opportunist mycobacteria to one of the PHLS regional centres for mycobacteriology or the Mycobacterium Reference Unit, and reporting to CDSC, is essential for the surveillance of these infections.

AIDS-Related Opportunistic Infections↗
PubMed1996

Legionnaires' disease surveillance: England and Wales, 1995.

One hundred and sixty cases of legionnaires' disease were reported to the PHLS Communicable Disease Surveillance Centre in 1995. Twenty cases (13%) were known to have died. Ninety cases (56%) were associated with travel (in the United Kingdom or abroad), four were associated with a stay in hospital, and the remaining 66 were presumed to have acquired infection in the community. One hundred and twenty-three cases (77%) occurred sporadically. Three community outbreaks and one outbreak at an industrial site were detected in England and Wales. One outbreak and five clusters were detected among visitors to Turkey, Spain, and Italy. Seven cases and one outbreak of nonpneumonic legionellosis were also reported. Cases of travel associated legionnaires' disease continue to account for the largest proportion of the total reported in 1995 and the number of hospital acquired cases continues to decline. A cause for concern in 1995 was a fall in the proportion of cases diagnosed by culture of the organism (from 16% in 1994 to only 9% in 1995). This corresponded with a small increase in the proportion of cases diagnosed solely by detection of antigen to L. pneumophila serogroup 1 in urine.

Adult↗
PubMed1996

Ordered tandem arrangement of chromosomes in the sperm heads of monotreme mammals.

A very old unanswered question in classical cytology is whether chromosomes are arranged randomly in sperm or whether they occupy specific positions. Even with modern methods of chromosome painting, it is difficult to resolve this question for the very condensed and almost spherical sperm head of most mammals. We have taken advantage of the unusual fibrillar sperm head of monotreme mammals (echidna and platypus) to examine the position of chromosome landmarks in a two-dimensional array. We used fluorescence and radioactive in situ hybridization to telomeric, rDNA, and unique sequences to show that chromosomes are arranged tandemly and in a defined order in the sperm nucleus.

Animals↗
PubMed1996

Are healthcare workers in England and Wales at increased risk of tuberculosis?

OBJECTIVE: To determine whether healthcare workers in England and Wales are at increased risk of tuberculosis and to examine the frequency of drug resistance in this population. DESIGN: Comparison of notification rates by occupation obtained from national tuberculosis notification surveys in 1988 and 1993, with denominators from the 1991 census. SUBJECTS: People with notified tuberculosis in professional and associate professional occupations from the two surveys. MAIN OUTCOME MEASURES: Rates of notified tuberculosis in health professionals (mainly doctors) and health associate professionals (mainly nurses) compared with rates in other professional and associate professional occupations, adjusted for ethnic group, sex, and age. RESULTS: 119 cases of tuberculosis were identified in healthcare workers, including 61 nurses and 42 doctors. The crude notification rate in healthcare workers was 11.8 per 100,000 per year (95% confidence interval 9.8 to 14.1) compared with 3.3 per 100,000 per year (2.9 to 3.6) in other professional and associate professional occupations; rate ratios were higher (range 1.7 to 3.2) in all ethnic groups. The relative risk adjusted for ethnic group, sex, and age was 2.4 (95% confidence interval 2.0 to 3.0), slightly higher for health professionals (2.7 (1.9 to 3.8)) than for associate professionals (2.0 (1.5 to 2.6)). No multiple drug resistant strains of tuberculosis were identified in healthcare workers. CONCLUSIONS: Better detection and notification of cases of tuberculosis in healthcare workers may account for some of the apparent increased risk, but these findings imply that tuberculosis remains a hazard for healthcare workers and highlight the importance of ensuring that occupational health monitoring and protection workers are not neglected.

Disease Notification↗
PubMed1996

Comparative mapping identifies the fusion point of an ancient mammalian X-autosomal rearrangement.

Previous comparisons of gene location in the three major groups of mammals (eutherians, marsupials, and monotremes) have suggested that the long arm of the human X represents the ancestral mammalian X chromosome, whereas the short arm represents an autosomal region(s) recently added to the eutherian X chromosome. To identify the fusion point of this ancient X-autosome rearrangement, we have mapped four genes, three of which map near the centromere of the human Xp, in marsupials and in a monotreme. We found that ARAF1, ALAS2, and GATA1 are located on the X chromosome in marsupials, and ALAS2 and GATA1 are also located on the X in the platypus. This implies that the proximal short arm of the human X chromosome, including the centromere, was part of the ancestral mammalian X chromosome. The fusion point between the conserved region and the recently added regions therefore maps to human Xp11.23, although gene order on the human X indicates that there has been some rearrangement of this region.

Animals↗