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Biomedical subjects

J Bartholomew

Publications and source records attributed to J Bartholomew.

At least 19 recordsLinked to original sources
PubMed2002

Polymerase eta and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation.

Xeroderma pigmentosum variant (XPV) cells lack the damage-specific polymerase eta and undergo a protracted arrest at the S phase checkpoint(s) following UV damage. The S phase checkpoints encompass several qualitatively different processes, and stimulate downstream events that are dependent on the functional state of p53. Primary fibroblasts with wild-type p53 arrest in S, and require a functional polymerase eta (pol eta) to carry out bypass replication, but do not recruit recombination factors for recovery. XPV cells with non-functional p53, as a result of transformation by SV40 or HPV16 (E6/E7), recruit the hMre11/hRad50/Nbs1 complex to arrested replication forks, coincident with PCNA, whereas normal transformed cells preferentially use the pol eta bypass replication pathway. The formation of hMre11 foci implies that arrested replication forks rapidly undergo a collapse involving double strand breakage and rejoining. Apoptosis occurs after UV only in cells transformed by SV40, and not in normal or XPV fibroblasts or HPV16 (E6/E7) transformed cells. Conversely, ultimate cell survival in XPV cells was much less in HPV16 (E6/E7) transformed cells than in SV40 transformed cells, indicating that apoptosis was not a reliable predictor of cell survival. Inhibition of p53 transactivation by pifithrin-alpha or inhibition of protein synthesis by cycloheximide did not induce hMre11 foci or apoptosis in UV damaged fibroblasts. Inhibition of kinase activity with wortmannin did not increase killing by UV, unlike the large increase seen with caffeine. Since HPV16 (E6/E7) transformed XPV cells were highly UV sensitive and not further sensitized by caffeine, it appears likely that caffeine sensitization proceeds through a p53 pathway. The S phase checkpoints are therefore, a complex set of different checkpoints that are coordinated by p53 with the capacity to differentially modulate cell survival, apoptosis, bypass replication and hMre11 recombination.

Acid Anhydride Hydrolases↗
PubMed2001

Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated syndrome caused by heparin. Complications range from thrombocytopenia to thrombocytopenia with thrombosis. We report a prospective, historical- controlled study evaluating the efficacy and safety of argatroban, a direct thrombin inhibitor, as anticoagulant therapy in patients with HIT or HIT with thrombosis syndrome (HITTS). METHODS AND RESULTS: Patients with HIT (isolated thrombocytopenia, n=160) or HITTS (n=144) received 2 microgram. kg(-1). min(-1) IV argatroban, adjusted to maintain the activated partial thromboplastin time 1.5 to 3.0 times baseline value. Treatment was maintained for 6 days, on average. Clinical outcomes over 37 days were compared with those of 193 historical control subjects with HIT (n=147) or HITTS (n=46). The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or new thrombosis, was reduced significantly in argatroban-treated patients versus control subjects with HIT (25.6% versus 38.8%, P=0.014). In HITTS, the composite incidence in argatroban-treated patients was 43.8% versus 56.5% in control subjects (P=0.13). Significant between-group differences by time-to-event analysis of the composite end point favored argatroban treatment in HIT (P=0.010) and HITTS (P=0.014). Argatroban therapy, relative to control subjects, also significantly reduced new thrombosis and death caused by thrombosis (P<0.05). Argatroban-treated patients achieved therapeutic activated partial thromboplastin times generally within 4 to 5 hours of starting therapy and, compared with control subjects, had a significantly more rapid rise in platelet counts (P=0.0001). Bleeding events were similar between groups. CONCLUSIONS: Argatroban anticoagulation, compared with historical control subjects, improves clinical outcomes in patients who have heparin-induced thrombocytopenia, without increasing bleeding risk.

Aged↗
PubMed1999

Antiphospholipid antibody syndrome in a patient with neurosarcoidosis.

The case of a 56-year-old woman who developed neurosarcoidosis and was discovered to have inferior vena cava and lower extremity thromboses is described. She was found to have anticardiolipin antibodies. This newly described association of antiphospholipid antibody syndrome with sarcoidosis is discussed and the relevant literature reviewed.

Antiphospholipid Syndrome↗
PubMed1998

Apoptosis, reproductive failure, and oxidative stress in Chinese hamster ovary cells with compromised genomic integrity.

Chromosomal instability and persistent reproductive cell death show a significant correlation after cells are exposed to ionizing radiation. To examine the possible role of apoptosis in persistent reproductive cell death, we analyzed subsets of chromosomally stable and unstable clones for relationships between chromosome stability, reproductive integrity, and apoptosis. All clones were generated from the GM10115 cell line and derived from single progenitor cells surviving 10 Gy of X-rays, and all measurements were made approximately 60-80 generations after irradiation. The incidence of apoptosis, as measured by both annexin V binding of phosphatidylserine residues and terminal deoxynucleotidyl transferase labeling of DNA strand breaks, was significantly higher in chromosomally unstable clones than it was in chromosomally stable clones (P < 0.05; ANOVA and Student's t test). Furthermore, statistical analyses of the biological end points of persistent reproductive cell death and apoptosis were consistent, showing R2 values of 0.78 and 0.76, respectively. These results suggest that persistent reproductive cell death can, in part, be explained by the predisposition of a fraction of the clonal population to undergo apoptosis or necrosis. Immunological blot analyses of protein levels and DNA bandshift assays confirmed the mutant status of p53 in the host cell line, implying an apoptotic pathway that is independent of p53. Induction of apoptosis by agents such as actinomycin D, etoposide, and staurosporine and induction of necrosis by sodium azide were accompanied by an increase in the level of intracellular peroxy radicals and lipid peroxidation products, two independent end points that are typically associated with oxidative stress. Similar findings were observed in several subclones showing persistent apoptosis. These results suggest that the elevated levels of free radical damage that we detected were derived from the fraction of cells dying by apoptotic or necrotic processes. Possible mechanisms whereby oxidative stress may contribute indirectly to the perpetuation of chromosomal instability are discussed.

Animals↗
PubMed1997

Patients' perceptions of changes in their blood pressure.

OBJECTIVES: (1) To investigate patients' experience of changes in their blood pressure (BP) in an every day setting and the accuracy of patients' predictions; and (2) to examine what influences patients' belief that they can tell when their BP is up. SUBJECTS: A total of 102 hypertensive patients were recruited sequentially as they presented for routine BP checks. The setting was an inner city general practice. DESIGN: Patients attended for BP checks on a weekly basis. Before each check they were asked whether they thought their BP was higher, lower or the same as usual. Subjects were classified as predictors if they thought they could tell when their BP was up. On completing their series of BP checks each subject completed symptom and Hospital Anxiety and Depression questionnaires. MAIN OUTCOME MEASURES: Accuracy of BP predictions, BP levels and variability, number of symptoms reported and anxiety level. RESULTS: One hundred and two hypertensive patients entered the study of whom 51 patients were predictors. The majority (86%) of predictors could not accurately predict their BP. There were no significant differences in either BP or variability between predictors and non-predictors. Predictors were significantly more anxious and reported more symptoms than non-predictors. CONCLUSIONS: For the majority of predictors there is no significant relationship between predictions of BP and clinical measurements. Predictor status is associated with the reporting of more symptoms and higher levels of anxiety. Doctors should counsel patients against using subjective BP assessments to guide their use of antihypertensive medication.

Adult↗
PubMed1996

Computerized assessment of common mental disorders in primary care: effect on clinical outcome.

OBJECTIVE: A randomized controlled trial was conducted to examine the clinical effectiveness of providing general practitioners (GPs) with the results of a self-administered computerized assessment of common mental disorders. METHOD: Attenders at a general practice in a deprived inner city area of South London were identified using case finding questionnaires. Six hundred and eighty-one subjects were randomly allocated to three groups which differed in the information provided to the GP: 1) no additional information was given to the GP; 2) the results of the 12 item General Health Questionnaire (GHQ) were given to the GP (the GHQ is a paper and pencil questionnaire that assesses common mental disorders); 3) the results of a self-administered computerized assessment (PROQSY) of common mental disorders were provided for the GP. RESULTS: Clinical outcome was assessed using the 12-item GHQ. Consultations with the GP, prescriptions and referrals within and outside the practice were also recorded. The group in whom the GP received the results of the computerized assessment showed a modest clinical improvement, relative to the other two groups after 6 weeks. There was no difference in clinical outcome between the groups at 6 months. There appeared to be no increase in consultations or prescriptions in the computerized assessment group. CONCLUSIONS: Self-administered computerized assessments for psychiatric disorder have potential as a means of improving the clinical outcome of patients in primary care. It is likely that the effectiveness of the approach would be greatly increased by linking the results of computerized assessments to clinical practice guidelines, tailored to the individual patient by means of computerized technology.

Adolescent↗
PubMed1996

Duplex ultrasound examination of the acutely painful and swollen leg.

OBJECTIVE: The aim of this study was to assess the value of duplex ultrasound examination in establishing diagnosis in acutely swollen and painful lower limbs, and to examine how often the diagnosis of superficial and/or deep venous thrombosis can be made in the symptomatic legs. METHODS: Venous duplex scan examination was performed on 188 extremities of 180 ambulatory outpatients. The examination included testing patency and competency of the deep and superficial veins. The ultrasound study was also extended to finding soft tissue abnormalities. RESULTS: Of the 188 lower limbs venous thrombosis was found on 82 occasions: 29 legs contained deep venous thrombosis only; 23 legs presented with superficial thrombophlebitis as a sole venous pathology; and in 30 cases superficial and deep venous thrombosis coexisted. In those 106 limbs where venous thrombosis was not present the most frequent positive ultrasound findings were incompetent leg veins or soft tissue masses (Baker's cyst and calf haematoma). CONCLUSION: The variety of pathological processes related to the lower limb veins and the extravascular tissue suggest that routine, "detailed" ultrasound scanning would be indicated in all acutely symptomatic legs with a suspected venous disorder. The important diagnostic information so gained provides guidance to the most appropriate treatment strategy.

Edema↗
PubMed1996

Breast screening: a randomised controlled trial in UK general practice of three interventions designed to increase uptake.

STUDY OBJECTIVES: To determine the relative effectiveness of three interventions designed to increase the uptake of breast screening. DESIGN: Randomised controlled trial of a nurse visit with health education (group A), nurse visit without health education (group B), and GP letter (group C). SETTING: The area of south east London served by the Butterfly Walk Breast Screening Unit in Camberwell. PARTICIPANTS: Women aged between 50 and 64 years who were registered with 27 GPs in the Lambeth, Southwark and Lewisham family health services authority and who had not attended for first round screening. MAIN RESULTS: Altogether 799 women were randomly allocated to the three groups. In general, delivering the nurse based interventions proved difficult. In group A, 11.4% (95% CI 7.9, 14.9%) of women subsequently attended for screening compared with 7.8% (95% CI 5.1, 11.4%) in group B and 13.1% (95% CI 7.9, 18.4%) in group C. The differences between the groups (95% CIs) were not statistically significant: A versus C, -1.7% (-8.0, +4.6%); B versus C, -5.3% (-11.3, +0.7%); A versus B, +3.6% (-1.0, +8.2%). CONCLUSIONS: A personal letter from the GP seems to be at least as effective at increasing the uptake of breast screening in non-attenders as a nurse making a home visit to discuss the issue of breast screening, and is not noticeably less effective than a visit at which a health education intervention is delivered. It is possible that the GP letter is considerably more effective than either of the two interview-based interventions. With regard to implementing strategies which will increase breast screening uptake and are cost effective, further trials of similar minimal interventions in primary care are required.

Breast Neoplasms↗
PubMed1995

Regulation of CYP1A1 by indolo[3,2-b]carbazole in murine hepatoma cells.

To determine the basis for unexpected differences in CYP1A1 inducing potencies and efficacies for the diet-derived indole derivative, indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we conducted a systematic analysis of events involved in the induced expression of CYP1A1 in murine hepatoma-derived cell lines (Hepa-1). In contrast to the effects of TCDD, induction kinetics and CYP1A1 mRNA half-life were dependent on ICZ concentration, and the response from low doses of inducer was transient due to rapid clearance of ICZ. TCDD and ICZ produced the same maximum response (i.e. equal efficacies) from a TCDD-responsive CAT reporter construct in Hepa-1 cells. When measured by the immediate responses associated with CYP1A1 expression, including cellular uptake of inducer, receptor transformation and binding to DRE (gel mobility shift assay), initiation of transcription (nuclear run-on assay), and short-term accumulation of mRNA (Northern blot assay), ICZ also exhibited an efficacy equal to that of TCDD and a potency that corresponds to its receptor affinity. ICZ is a potent and selective noncompetitive inhibitor of ethoxyresorufin O-deethylase activity (Ki = 1.5 nM). Taken together these results indicate that ICZ is a bifunctional modulator of CYP1A1 expression with intrinsic efficacy equal to that of TCDD.

Animals↗
PubMed1994

Arranging hospital admission for acutely ill patients: problems encountered by general practitioners.

BACKGROUND: Reports in the national press suggest that general practitioners in London are experiencing difficulties in securing hospital admission for their acutely ill patients. AIM: A study was undertaken to investigate the problems encountered by general practitioners in one family health services authority in south east London in arranging acute admissions to hospital. METHOD: A self-report questionnaire was completed by a sample of general practitioners every time an acute hospital admission was attempted. RESULTS: A total of 493 questionnaires were completed by 111 general practitioners over the 47-day study period. Problems during the hospital admission procedure were experienced in 171 (35%) of the cases reported, with 115 of the 537 telephone calls to a hospital (21%) resulting in a refusal to admit the patient to that particular hospital. The main problem reported was that of 'no beds available', an obstacle to admission that was more likely to be encountered if the patient was aged 75 years or over than if the patient was younger. CONCLUSION: In the light of the problems reported, possible changes to the current method of arranging acute admissions to hospital in London are discussed.

Adolescent↗
PubMed1993

Blockage of EGF receptor signal transduction causes reversible arrest of normal and immortal human mammary epithelial cells with synchronous reentry into the cell cycle.

We demonstrate that blockage of EGF receptor signal transduction is sufficient by itself to cause a rapid, efficient, and reversible G0-like growth arrest of normal human mammary epithelial cells (HMEC) of finite lifespan as well as two immortally transformed cell lines derived from normal HMEC following in vitro transformation with benzo[a]pyrene. For normal HMEC, the significant level of endogenous production of TGF alpha requires utilization of blocking antibodies to the EGF receptor to achieve cessation of growth in mass culture, whereas removal of EGF is sufficient to arrest the immortal cell lines. In the growth-arrested cells, protein synthesis remains depressed; reexposure to EGF leads to a rapid increase in protein synthesis. Inhibition of DNA synthesis is not detectable until approximately 12 h after removal of EGF/TGF alpha and is pronounced by 24 h. Reexposure to EGF produces high levels of synthesis of the early response genes, c-myc, c-fos, c-jun, and MGSA, within 1 h. DNA synthesis increases only after 10 h, with a sharp peak after 15-20 h. Reexposure of the growth-arrested normal HMEC for 1 h with EGF allows a majority of the cells capable of cycling to subsequently enter the S phase. Little is currently known about cell cycle control in normal human epithelial cells. The efficient and gentle method of achieving reversible G0 growth arrest reported here may facilitate studies on the cell cycle of this cell type. Additionally, results from normal HMEC can be compared with those from syngeneic immortalized cell populations to determine possible cell cycle parameters altered as a result of immortal transformation.

Antibodies, Monoclonal↗
PubMed1992

A deletion in the simian virus 40 large T antigen impairs lytic replication in monkey cells in vivo but enhances DNA replication in vitro: new complementation function of T antigen.

We describe a new complementation function within the simian virus 40 (SV40) A gene. This function is required for viral DNA replication and virus production in vivo but, surprisingly, does not affect any of the intrinsic enzymatic functions of T antigen directly required for in vitro DNA replication. Other well-characterized SV40 T-antigen mutants, whether expressed stably from integrated genomes or in cotransfection experiments, complement these mutants for in vivo DNA replication and plaque formation. These new SV40 mutants were isolated and cloned from human cells which stably carry the viral DNA. The alteration in the large-T-antigen gene was shown by marker rescue and nucleotide sequence analysis to be a deletion of 322 bp spanning the splice-donor site of the first exon, creating a 14-amino-acid deletion in the large T antigen. The mutant gene was expressed in H293 human cells from an adenovirus vector, and the protein was purified by immunoaffinity chromatography. The mutant protein directs greater levels of DNA replication in vitro than does the wild-type protein. Moreover, the mutant protein reduces the lag time for in vitro DNA synthesis and can be diluted to lower levels than wild-type T antigen and still promote good replication, which is in clear contrast to the in vivo situation. These biochemical features of the protein are independent of the source of the cellular replication factors (i.e., HeLa, H293, COS 7, or CV1 cells) and the cells from which the T antigens were purified. The mutant T antigen does not transform Rat-2 cells. Several different models which might reconcile the differences observed in vivo and in vitro are outlined. We propose that the function of T antigen affected prepares cells for SV40 replication by activation of a limiting cellular replication factor. Furthermore, a link between the induction of a cellular replication factor and transformation by SV40 is discussed.

Amino Acid Sequence↗
PubMed1991

Consultants' and patients' views about patient access to their general practice records.

Semi-structured interviews were conducted with 24 hospital consultants and 47 general practice patients, asking for their opinions about a proposed policy of partial access to records in one general practice. Eleven consultants were opposed to the policy, 10 were in favour and three were classified as ambivalent. Arguments against access were couched largely in terms of consultants' own interests whereas arguments in favour of access were couched in terms of patients' interests. Although 81% of patients interviewed said that they should in principle be allowed to see their own records, only 51% wanted access to their own records. Fears expressed by consultants on patients' behalf are not necessarily well founded.

Attitude of Health Personnel↗
PubMed1990

Understanding hospital referral rates: a user's guide.

Detailed referral information from one practice was used to investigate the effect of calculating referral rates in several different ways. Referral rates for individual general practitioners should be related to the number of consultations carried out and not to the number of registered patients; for whole practices list size may be used as the denominator. Most doctors will not need to control for age and sex of patients when comparing referral rates but may need to control for case mix when comparing referral rates to individual specialties. In addition, a method is described for distinguishing systematic variation between the referral rates of individual doctors from the random variation that may arise from data based on fairly small numbers of referrals. The method indicates whether systematic variation is greater than would be expected by chance, and it can be extended to indicate whether variability in referral rates is greater in one specialty than another. Because of random variation with time a year's data may not be sufficient to allow reliable interpretation of referral rates to individual specialties, except for the largest. At present there is no known relation between high or low referral rates and quality of care. Nevertheless, if doctors are to interpret their own rates of referral they need those rates to be reliable and valid. Use of the 10 guidelines described in this paper will help to prevent unwarranted conclusions being drawn from information on general practitioners' rates of referral to hospital.

Adolescent↗
PubMed1989

A health visitor investigation of home accidents in pre-school children.

The incidence and characteristics of home accidents in pre-school children were investigated in the northern part of Lambeth with the help of health visitors. Accidents were identified using the notification system from accident and emergency departments to health visitors. The study shows that there is not an easily identifiable group of high risk children so all must be regarded as potentially at risk. It also highlights how important it is that accidents treated at hospital are notified to health visitors and some ways for improving the system are suggested.

Accidents, Home↗
PubMed1986

Outcome of respiratory illness occurring in the first year of life.

This paper describes the outcome of respiratory illness presented by a birth cohort of infants in the first year of life who were born to mothers in two inner London group general practices in terms of the ventilatory capacity measured at their fifth birthday. A history of two or more episodes of "lower" respiratory illness in the first year of life was associated with a significant reduction in peak expiratory flow when compared with those who had no such history. Boys had significantly higher peak flow rates than girls; those whose parents were in manual occupations had significantly lower peak flow rates than those whose parents were in non-manual occupations. There was a significant interaction between sex and social class.

Humans↗