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Biomedical subjects

H Graham

Publications and source records attributed to H Graham.

At least 19 recordsLinked to original sources
PubMed2000

Structures of active and latent PAI-1: a possible stabilizing role for chloride ions.

Serpins exhibit a range of physiological roles and can contribute to certain disease states dependent on their various conformations. Understanding the mechanisms of the large-scale conformational reorganizations of serpins may lead to a better understanding of their roles in various cardiovascular diseases. We have studied the serpin, plasminogen activator inhibitor 1 (PAI-1), in both the active and the latent state and found that anionic halide ions may play a role in the active-to-latent structural transition. Crystallographic analysis of a stable mutant form of active PAI-1 identified an anion-binding site between the central beta-sheet and a small surface domain. A chloride ion was modeled in this site, and its identity was confirmed by soaking crystals in a bromide-containing solution and calculating a crystallographic difference map. The anion thus located forms a 4-fold ligated linchpin that tethers the surface domain to the central beta-sheet into which the reactive center loop must insert during the active-to-latent transition. Timecourse experiments measuring active PAI-1 stability in the presence of various halide ions showed a clear trend for stabilization of the active form with F(-) > Cl(-) > Br(-) >> I(-). We propose that the "stickiness" of this pin (i.e., the electronegativity of the anion) contributes to the energetics of the active-to-latent transition in the PAI-1 serpin.

Base Sequence↗
PubMed2000

Tip-mediated fusion involving unipolar collagen fibrils accounts for rapid fibril elongation, the occurrence of fibrillar branched networks in skin and the paucity of collagen fibril ends in vertebrates.

Collagen fibrils are the principal source of mechanical strength of connective tissues such as tendon, skin, cornea, cartilage and bone. The ability of these tissues to withstand tensile forces is directly attributable to the length and diameter of the fibrils, and to interactions between individual fibrils. Although electron microscopy studies have provided information on fibril diameters, little is known about the length of fibrils in tissue and how fibrils interact with each other. The question of fibril length has been difficult to address because fibril ends are rarely observed in cross-sections of tissue. The paucity of fibril ends, or tips, has led to controversy about how long individual fibrils might be and how the fibrils grow in length and diameter. This review describes recent discoveries that are relevant to these questions. We now know that vertebrate collagen fibrils are synthesised as short (1-3 microm) early fibrils that fuse end-to-end in young tissues to generate very long fibrils. The diameter of the final fibril is determined by the diameter of the collagen early fibrils. During a late stage of tissue assembly fibril tips fuse to fibril shafts to generate branched networks. Of direct relevance to fibril fusion is the fact that collagen fibrils can be unipolar or bipolar, depending on the orientation of collagen molecules in the fibril. Fusion relies on: (1) specific molecular interactions at the carboxyl terminal ends of unipolar collagen fibrils; and (2) the insulator function of small proteoglycans to shield the surfaces of fibrils from inappropriate fusion reactions. The fusion of tips to shafts to produce branched networks of collagen fibrils is an elegant mechanism to increase the mechanical strength of tissues and provides an explanation for the paucity of fibril tips in older tissue.

Animals↗
PubMed2000

Two weekly vinorelbine: administration in patients who have received at least two prior chemotherapy regimes for advanced breast cancer.

This study examined the response to and toxicity of two weekly vinorelbine administration in patients with at least two prior chemotherapeutic treatments for advanced breast cancer. This single centre study enrolled 20 patients, 19 of whom had received prior taxane treatment for advanced breast cancer. Taxane treatment was in the form of docetaxel for all but 1 patient who had received paclitaxel. All patients had received two or more prior chemotherapeutic regimes for advanced breast carcinoma, including anthracyclines (epirubicin) in 19 patients. Vinorelbine 25 mg/m2 two weekly was given for 6 months, until disease progression or toxicity precluded further treatment. 5 earlier studied patients started vinorelbine at 25 mg/m2/week; all changed to the two weekly schedule, limiting the incidence and severity of neutropenia. 7 partial responses (PRs) out of 20 assessable patients (35% overall response rate, 95% confidence interval 15-59%) were noted, all PRs occurring in taxane pretreated patients. The median duration of response was 4 months whilst the median time to progression was 2.75 months. Overall, there were 7 neutropenic events (35%) of 2 week median duration, spanning common toxicity criteria (CTC) grades 1-3 in severity. 5 neutropenia cases (25%) occurred in patients whilst on two weekly vinorelbine. 2 cases (10%) required granulocyte colony stimulating factor support, 1 having had febrile neutropenia (52%). One case of thrombocytopenia, neurotoxicity and nausea (each CTC grade 1) were recorded. Although this study involves a small number of cases, these preliminary results suggest that two weekly vinorelbine is effective in heavily pretreated (including taxane pretreated) advanced breast carcinoma. Response is comparable with that of traditionally used weekly regimes, with markedly less toxicity.

Adult↗
PubMed2000

Relational narratives: solving an ethical dilemma concerning an individual's insurance policy.

Decisions based on ethics confront nurses daily. In this account, a cardiac nurse struggles with the challenge of securing health care benefits for Justin, a patient within the American system of health care. An exercise therapy that is important for his well-being is denied. The patient's nurse and an interested insurance agent develop a working relationship, resulting in a relational narrative based on Justin's care. Gadow's concept of a relational narrative and Keller's concept of a relational autonomy guide this particular case. As an ethics framework influenced by feminist ethical theory, Gadow's, Keller's and Tisdale's ideas demonstrate the fluidity with which the nurse and others can work while maintaining both autonomy and engagement without being self-sacrificing.

Adult↗
PubMed2000

Response of circulating tumor cells to systemic therapy in patients with metastatic breast cancer: comparison of quantitative polymerase chain reaction and immunocytochemical techniques.

PURPOSE: We previously developed a quantitative system for the detection of cytokeratin 19 (CK-19) transcripts using reverse transcriptase polymerase chain reaction (PCR) to detect breast carcinoma cells in blood and bone marrow. The aim of this study was to determine the value of this system in monitoring patients with metastatic disease and to compare it with an established immunocytochemical method. PATIENTS AND METHODS: Patients with progressive, locally advanced, and metastatic breast cancer (all stage IV) who were due to start systemic treatment were recruited. Blood samples were analyzed for CK-19 transcripts using quantitative PCR (QPCR) and immunocytochemistry (ICC) throughout their course of treatment. RESULTS: One hundred forty-five blood samples were obtained from 22 patients over 13 months. Seventy-two (49.6%) of these samples were positive by QPCR, and 56 (42%) of 133 were positive by ICC. Of the 133 specimens analyzed by both techniques, 95 (71.4%) had the same results for each, and of the 71 samples that were positive, 40 (56%) were positive by both methods. The relationship between the number of cells detected and the QPCR values was statistically significant (P <.0001). Of the 25 courses of assessable treatment, 17 (68%) of 25 treatment outcomes (either response or disease progression) were reflected by QPCR measurements, and 12 (57%) of 21 were reflected by ICC. During the course of the study, five patients showed a response, and of these, ICC was in agreement in four cases (80%) and QPCR in three cases (60%). Eighteen courses of treatment resulted in progression of the disease; however, only 15 of these were assessable by ICC. ICC was in agreement in eight (53%) of 15 of these cases, and QPCR in 15 (83%) of 18 cases. CONCLUSION: Circulating carcinoma cells are frequently found in patients with metastatic breast cancer. In the majority of patients, cancer cell numbers as evaluated by QPCR or ICC reflected the outcome of systemic treatment.

Adult↗
PubMed1999

Patterns and predictors of tobacco consumption among women.

The study examines the patterns and predictors of cigarette consumption among 920 female smokers aged 16-49 who formed part of the British Household Panel Survey, a representative survey of households in Britain. The study assesses the influence of three key factors: socio-economic circumstances, psychological health and partner's smoking status. The study confirms that female smokers are more disadvantaged than the broader population of women, both with respect to their socio-economic circumstances and their psychological health. Within this disadvantaged group, higher cigarette consumption was linked to greater socio-economic disadvantage and poorer psychological health but not partner's smoking status. Age and pregnancy status also had an independent effect on consumption. Of these factors, being in poor psychological health was the single most powerful predictor of high rates of consumption. The implications of the findings for health promotion are discussed.

Adolescent↗
PubMed1997

Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility.

Decorin is a member of the expanding group of widely distributed small leucine-rich proteoglycans that are expected to play important functions in tissue assembly. We report that mice harboring a targeted disruption of the decorin gene are viable but have fragile skin with markedly reduced tensile strength. Ultrastructural analysis revealed abnormal collagen morphology in skin and tendon, with coarser and irregular fiber outlines. Quantitative scanning transmission EM of individual collagen fibrils showed abrupt increases and decreases in mass along their axes. thereby accounting for the irregular outlines and size variability observed in cross-sections. The data indicate uncontrolled lateral fusion of collagen fibrils in the decorindeficient mice and provide an explanation for the reduced tensile strength of the skin. These findings demonstrate a fundamental role for decorin in regulating collagen fiber formation in vivo.

Animals↗
PubMed1996

Comparison of nonrandomized trials with slow-release sodium fluoride with a randomized placebo-controlled trial in postmenopausal osteoporosis.

The results of slow-release sodium fluoride (SR-NaF) treatment in two nonrandomized trials involving 65 patients with postmenopausal osteoporosis from the primary site and 121 patients from collaborative sites were compared with those obtained from 54 treated patients and 56 patients taking placebo from a randomized controlled trial. Spinal fracture data were analyzed separately in mild to moderate bone loss of lumbar spine (baseline L2-L4 bone density [BD] > or = 65% young normal) and in severe bone loss (BD < 65%). Since demographic and fracture data were similar among fluoride-treated patients from the three trials at each stratum of bone loss, their data were combined. In mild to moderate bone loss, SR-NaF treatment in the combined group virtually eliminated new spinal fractures with 96.6% of patients remaining fracture-free. The Fluoride group had a markedly lower individual vertebral fracture rate (0.025 vs. 0.188/patient year, p = 0.0001) and group vertebral fracture rate (0.029 vs. 0.175/patient year, relative risk [RR] 0.12, p = 0.0001) than the Placebo group. In severe bone loss, the combined treated group had a significantly lower new spinal fracture rate than the Placebo group, although the differences were not as marked (group vertebral fracture rate of 0.150 vs. 0.276/patient year, RR 0.54, p = 0.03). In the combined fluoride-treated group, the L2-L4 bone mass rose by 4-6%/year for 4 years, and the femoral neck BD increased by 1-2%/year during first 2 years. The radial shaft BD did not change. The Placebo group did not show a change in bone mass at any site. The prevalence (percentage) of patients with related gastrointestinal side effects and nonvertebral fracture rates did not differ significantly between the combined SR-NaF group and the Placebo group (hip fracture rate of 0.0045/patient year in SR-NaF and 0.0053/patient year in Placebo; appendicular fracture other than hip (see text) rate of 0.0193/patient year in SR-NaF and 0.0159/patient year in Placebo). A subgroup analysis showed a low baseline L2-L4 BD, high prevalent spinal fractures, and reduced body weight to be important determinants of the development of spinal fracture during SR-NaF treatment. Concomitant medications (estrogen, vitamin D, thiazide and thyroid hormone) were not independent predictors of the spinal fracture risk. Only 17% of fluoride-treated patients were nonresponders (new spinal fractures or a fall/no change in L2-L4 bone mass). Thus, the effects of SR-NaF treatment on the spinal fracture rate from nonrandomized trials were similar to those of the treated group of the randomized trial but different from those of the Placebo group. The similarity of response of nonrandomized trials with that of the randomized controlled trial and the resultant combined analysis further validate the efficacy and safety of SR-NaF in the treatment of postmenopausal osteoporosis.

Bone Density↗
PubMed1996

Smoking prevalence among women in the European community 1950-1990.

The paper reviews trends in tobacco use among women in the European Community (EC) between 1950 and 1990. The data suggest that EC countries occupy different points on what appears to be a common prevalence curve. Southern EC countries are represented in the early phases of this curve, marked out by sharply rising prevalence. In northern EC countries, female smoking prevalence appears to have peaked. Across the EC, the commodification of tobacco use, and the production and promotion of manufactured cigarettes in particular, underlies this prevalence curve. Young women in higher socio-economic groups have led the way into cigarette smoking in both northern and southern Europe, with smoking prevalence declining first among women who are privileged in terms of their education, occupation and income. Because the decline in prevalence has yet to be repeated among women in more disadvantaged circumstances, cigarette smoking among women in the EC is likely to become a habit increasingly linked to low socio-economic status.

Adolescent↗
PubMed1996

Family systems ideas in the 10-minute consultation: using a reflecting partner or observing team in a surgery.

BACKGROUND: Family therapy and the ideas that underlie it have not had much impact on general practice, although there is good reason to think this could be a useful approach. AIM: As a group of general practitioners (and a practice nurse) with experience of family therapy, we were interested in demonstrating whether family therapy methods could usefully inform general practice consultations. METHOD: Two surgeries were observed by the general practitioner's colleagues. RESULTS: Selected cases are discussed to illustrate the impact of the use of family therapy ideas and a reflecting colleague or team. CONCLUSIONS: Family therapy ideas can be a helpful framework within which to think about both demanding and ordinary consultations. Inviting a colleague to contribute respectfully could be useful both as a method of teaching, and in resolving difficult or faltering consultations.

England↗
PubMed1994

Gender and class as dimensions of smoking behaviour in Britain: insights from a survey of mothers.

The decline in cigarette smoking in Britain over the last four decades has been associated with a profound change in its social distribution. Gender differences have narrowed to the point where smoking has all but lost its male identity. Class differences have widened, with cigarette smoking emerging as a habit sustained within working class communities. The paper reports on a study which sheds light on how being a woman and being working class connects with smoking behaviour. Focusing on women with young children, the study points to clear associations between smoking status and the social and material circumstances of mothers' lives. Specifically, it highlights how cigarette smoking is linked to additional caring responsibilities and restricted access to material resources.

Female↗
PubMed1993

Characteristics associated with smoking cessation during pregnancy among working class women.

Although smoking prevalence among pregnant women is highest among those of lower socio-economic status, the factors associated with cessation in this high risk group are poorly documented. This paper reports on data from a survey of working class women in Nottingham and Coventry, who were interviewed 6 months after having delivered a baby. It compares the characteristics of the 32 women who quit smoking during their pregnancy and were still ex-smokers at the 6 month post-natal point, with 472 women who had continued to smoke during their pregnancy or had returned to smoking in the post-partum period. A logistic regression analysis revealed three variables that were independently associated with long term cessation-having previously quit for more than 1 week, having a non-smoking partner, and believing that the children of smokers are more likely to get infections. Among the most disadvantaged, an understanding of how close social ties and economic circumstances influence smoking behaviour is crucial, if we are to develop more effective smoking cessation intervention strategies for working class women.

Adolescent↗
PubMed1993

A study of the pathogenesis of Helicobacter pylori negative chronic duodenal ulceration.

In the past five years 12 patients have been identified presenting with chronic duodenal ulcer (DU) disease and with no evidence of current or recent Helicobacter pylori (H pylori) infection. Four of them were taking regular non-steroidal anti inflammatory agents, one was subsequently found to have Crohn's disease of the duodenum, and one to have the Zollinger-Ellison syndrome. The remaining six patients with idiopathic DU disease were remarkable for their absence of the A1 blood antigen gene. Detailed studies of gastric function were performed in these six patients and compared with H pylori positive patients with DU and with healthy volunteers. The median integrated gastrin response in the patients with idiopathic DU (2810 (range 750-8750) ng/l min) was similar to that of the H pylori positive patients with DU (3355 (550-8725)) and higher than that of the H pylori negative healthy volunteers (560 (225-1125)). The median peak acid output in the patients with idiopathic DU (37 mmol/h, range 17-52) was similar to that of the H pylori positive patients with DU (40 (15-57)) and higher than that of the non-ulcer controls (22 (16-29)). The median percentage of a liquid meal retained in the stomach at 60 minutes was less in the patients with idiopathic DU (23 (15-33)) than in H pylori negative healthy volunteers (34 (30-53) p < 0.01). The median percentage of a solid meal retained at 60 minutes was less in the patients with idiopathic DU (54 (9-83)) than in either H pylori negative healthy volunteers (87 (49-95) p<0.01) or H pylori positive patients with DU (79 (51-100) p<0.01). In conclusion, three abnormalities of gastric function are prevalent in patients with H pylori negative idiopathic DU disease - hypergastrinaemia, increased acid secretion, and the one feature distinguishing them from H pylori positive patients with DU - rapid gastric emptying of both liquids and solids. Each of these abnormalities will increase the exposure of the duodenal mucosa to acid and thus explain its ulceration. The absence of the blood group A1 antigen gene is consistent with a genetic basis for the disturbed gastric function linked to the ABO blood group antigen genes.

ABO Blood-Group System↗
PubMed1993

Women's smoking: government targets and social trends.

Hilary Graham reviews the government's targets for a reduction in smoking prevalence among women in the light of the changing patterns of women's smoking. She argues that the targets can not be met unless both policy-makers and health professionals give greater attention to the links between women's smoking and the circumstances of women's lives.

Adolescent↗
PubMed1992

Informal care: problem or solution?

Government policy stresses that care in the community must mean care by the community. Government policies have increasingly recognised, too, that care by the community means care by families. Yet social support policies have reduced the benefits available to carers. Hilary Graham examines the problems facing those giving and seeking informal care.

Caregivers↗
PubMed1992

Family therapy in general practice: views of referrers and clients.

Family therapy is being used in a variety of settings, including general practice. To assess the views as to the effectiveness and acceptability of a family therapy clinic in a north London surgery, questionnaires were given to general practitioners referring patients, and to clients. Replies were received from seven doctors and 20 clients, representing 11 families. There was a high level of satisfaction among general practitioners referring patients. The clinic proved to be highly acceptable for clients, with 90% agreeing that it was easier to attend a clinic at the practice than at a hospital; and only one patient thought that knowing the general practitioner worked in the practice made it harder to talk openly. Eighty per cent of patients felt the problem had improved at the time of follow up. Where the problem had not improved, 60% felt that they were dealing with it better. Almost all of the patients felt that the family therapy clinic should become a permanent part of local services. The family therapy clinic in general practice has been shown to be effective and popular with users of the service.

Adolescent↗
PubMed1991

The informal sector of welfare: a crisis in caring?

The informal sector is the major provider of informal care for dependent people and everyday care for able-bodied people in Britain. A large and complex sector of care, it has come to occupy a central place in British government policies for health and welfare. Through the 1980s, the informal sector was increasingly identified as a solution to problems in the formal systems of care. The paper reviews the concept of informal care and the welfare philosophies which informed the development of these policies, arguing for a broader and more critical perspective which locates informal care within the context of the wider caring work that goes on in households. Seen in this context, structural features of caring that are celebrated as strengths (its base in kinship relations where carers are unpaid, for example), can be experienced as problematic by those involved in caring. As a case study, the paper focuses on the experiences of mothers caring for children on low incomes for insights into some of the contradictions of caring.

Delivery of Health Care↗