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Biomedical subjects

J Sanders

Publications and source records attributed to J Sanders.

At least 37 records · Page 2Linked to original sources
PubMed2001

Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers.

This report summarizes the experience with a conditioning regimen of cyclophosphamide and antithymocyte globulin in patients with severe aplastic anemia given HLA-matched related marrow grafts at 4 transplantation centers. Enrolled were 94 consecutive patients, of whom 87 had received multiple transfusions and 38 had failed immunosuppressive therapy. Their ages ranged from 2 to 59 years. After transplantation, 89 patients received a methotrexate/cyclosporine regimen for graft-versus-host disease (GVHD) prevention. Cyclosporine with or without prednisone was given in 4 patients, and no immunosuppression was given in 1 patient. Ninety-six percent of patients had sustained grafts, whereas 4% rejected grafts between 2 and 7 months after transplantation. Of the 4 rejecting patients, 3 are alive with successful second engraftments. Acute grade II GVHD was seen in 21% of patients, grade III in 7%, and grade IV in 1% of patients. Chronic GVHD was seen in 32% of patients, most of whom responded completely to immunosuppressive therapy. With a median follow-up of 6.0 years (range, 0.5-11.6 years), the survival rate was 88%. No unusual long-term side effects have been seen with the regimen. We conclude that the cyclophosphamide/antithymocyte globulin regimen combined with methotrexate/cyclosporine after transplantation is well tolerated and effective in heavily pretreated patients with aplastic anemia.

Adolescent↗
PubMed2001

The buck stops where? Contracting, service delivery and the challenge to provide responsive services.

This paper discusses the impact of contract-based purchasing on the delivery of social and health services to families in New Zealand. The paper arose out of research conducted by the authors into the effectiveness of certain human service interventions. It begins with an outline of the agency in which the research took place. It presents a brief overview of the development of contracting and then considers four key issues raised by this development from both the international literature and from the authors' experience of researching a social service agency. These issues are: defining what is to be purchased, accountability mechanisms, specificity/fragmentation and partial funding. The paper identifies that central components of the first two issues are informational, the third is about control and the fourth is about reducing government spending and extending state control over the activities of the not-for-profit sector.

Competitive Bidding↗
PubMed2001

X-ray crystal structure of a monoclonal antibody that binds to a major autoantigenic epitope on thyroid peroxidase.

Thyroid peroxidase (TPO) catalyzes the production of thyroid hormones and is a major autoantigen in autoimmune thyroid disease (AITD). It is believed that the majority of TPO autoantibodies bind to an immunodominant region consisting of two overlapping domains. Precise location of these domains would help our understanding of the interaction between TPO and TPO autoantibodies. 4F5 is a mouse monoclonal antibody (IgG1, kappa) that reacts with high affinity (2.6 x 10(10) mol/L(-1)) with one of the major autoantigenic regions on TPO. Heavy chain genes of 4F5 were from the VH1 germline gene family, germline genes for the D region could not be assigned and the J region was from the JH2 germline. Light chain genes were from Vkappa4/5 and Jkappa2, germline gene families. The Fab fragment of 4F5 was prepared by papain digestion, purified, crystallized, and the structure solved to 1.9 A using molecular replacement. The refined structure had an R factor of 19.5% and a free R factor of 23.9%. Deduced amino acid sequence and amino acid sequence obtained from diffraction analysis were compared and used to finalize the 4F5 Fab model. Structural analysis indicated that the structure of 4F5 is that of a standard Fab and its combining site is flat and is rich in tyrosine residues. Comparison of the structure of 4F5 with that of a TPO autoantibody Fab, TR1.9 suggests that the two antibodies are unlikely to recognise the same structures on TPO.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Reactivity of thyrotropin receptor autoantibodies with the thyrotropin receptor on western blots.

Affinity purified recombinant human thyrotropin receptor (TSHR) was run on sodium dodecyl sulfate (SDS) gels and subjected to a renaturing and blotting procedure. Twenty sera from thyrotropin receptor autoantibodies (TRAb)-positive patients with a history of hyperthyroidism and 20 sera with high levels of TSH blocking activity were analyzed. Four of 20 sera with blocking-type of TRAb (i.e., TSH antagonist activity) were able to recognize the mature, fully glycosylated 120-kd form of the receptor on blots of gels run under reducing conditions. No sera recognized the 100-kd high mannose precursor form of the TSHR. Three of the four recognized a 74-kd band and 2 of the 4 recognized a 50-kd band. These bands are probably proteolytic cleavage fragments of the mature 120-kd TSHR. In the absence of reducing agent the same 4 of 20 sera described above together with a further serum sample (i.e., 5/20 in total) reacted with the 120-kd form of the receptor. No specific reaction with the TSHR was observed on Western blots with the remaining 15 sera with TSH blocking activity, nor with 20 sera from patients with a history of hyperthyroidism, nor with sera from 10 healthy blood donors, 10 Hashimoto sera (negative for TRAb) and 10 systemic lupus erythematosus sera. No clear differences were observed in the TRAb positive sera that were reactive and nonreactive on Western blots in terms of their ability to inhibit TSH binding or to immunoprecipitate 125I-labeled TSHR. Overall, our results indicate that the mature 120-kd form of the TSHR that is principally responsible for binding TSH is also responsible for binding TRAb (when this binding can be detected). These observations together with immunoprecipitation and TSH binding inhibition studies, emphasize the close relationship between the receptor's binding sites for TSH and TRAb.

Antibody Specificity↗
PubMed2001

Interleukin-6 gene -174g>c and -572g>c promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery.

Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (-174G>C, -572G>C, and -597G>A) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (+/-95% CIs) were similar to those reported previously: -597A 0.36 (0.30 to 0.42), -572C 0.07 (0.04 to 0.10), and -174C 0.37 (0.31 to 0.43). The -174G>C and -597G>A genotypes were in strong allelic association (Delta=0.97, P<0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (P=0.03) in carriers of the -572C allele than in those of the -572GG genotype (355+/-67 versus 216+/-13 pg/mL, respectively) and in those with genotype -174CC compared with -174G allele carriers (287+/-31 versus 227+/-15 pg/mL, respectively; P=0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury.

Coronary Artery Bypass↗
PubMed2000

Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors.

BACKGROUND: Survival following metastatic or recurrent Ewing sarcoma family tumors (ESFT) remains <25%. Myeloablative therapy with hematopoietic stem cell transplantation (HSCT) may improve survival for poor-risk ESFT. We describe the toxicity and efficacy of a myeloablative chemotherapy regimen, followed by a second myeloablative radiotherapy regimen as consolidation treatment for poor-risk ESFT. PROCEDURE: Sixteen patients with poor-risk ESFT were treated with myeloablative therapy followed by HSCT. All patients received busulfan, melphalan, and thiotepa (BuMelTT) as chemotherapy conditioning. Nine patients received total marrow irradiation (TMI) as a second myeloablative therapy, also followed by HSCT. Seven patients were excluded from TMI because of inadequate peripheral blood stem cell harvest, extensive prior radiation therapy, early disease progression, orpatient refusal. The disease status prior to my eloablative therapy was first complete response (CR1) in three patients, CR2 in nine, second partial response (PR2) in one, CR3 in one, and progressive disease (PD) in two. RESULTS: One patient died of regimen-related toxicity, one from late pulmonary toxicity, and one following allogeneic transplantation for myelodysplasia. Eight developed recurrent disease (median time to progression 6.8 months). Six survive without relapse from 27 to 66 months following BuMelTT (median follow-up 42 months), all of whom received both BuMelTT and TMI patients (3-year event-free survival 36%). CONCLUSIONS: Dual myeloablative therapy with BuMelTT and TMI was a feasible and promising treatment approach for patients with poor-risk ESFT. Inability to collect sufficient PBSC and extensive previous radiation therapy limit the ability to deliver TMI as a second HSCT conditioning regimen.

Adolescent↗
PubMed2000

Concordance of the toxicity of pharmaceuticals in humans and in animals.

This report summarizes the results of a multinational pharmaceutical company survey and the outcome of an International Life Sciences Institute (ILSI) Workshop (April 1999), which served to better understand concordance of the toxicity of pharmaceuticals observed in humans with that observed in experimental animals. The Workshop included representatives from academia, the multinational pharmaceutical industry, and international regulatory scientists. The main aim of this project was to examine the strengths and weaknesses of animal studies to predict human toxicity (HT). The database was developed from a survey which covered only those compounds where HTs were identified during clinical development of new pharmaceuticals, determining whether animal toxicity studies identified concordant target organ toxicities in humans. Data collected included codified compounds, therapeutic category, the HT organ system affected, and the species and duration of studies in which the corresponding HT was either first identified or not observed. This survey includes input from 12 pharmaceutical companies with data compiled from 150 compounds with 221 HT events reported. Multiple HTs were reported in 47 cases. The results showed the true positive HT concordance rate of 71% for rodent and nonrodent species, with nonrodents alone being predictive for 63% of HTs and rodents alone for 43%. The highest incidence of overall concordance was seen in hematological, gastrointestinal, and cardiovascular HTs, and the least was seen in cutaneous HT. Where animal models, in one or more species, identified concordant HT, 94% were first observed in studies of 1 month or less in duration. These survey results support the value of in vivo toxicology studies to predict for many significant HTs associated with pharmaceuticals and have helped to identify HT categories that may benefit from improved methods.

Animals↗
PubMed2000

Distributive and procedural justice in seven nations.

The paper examines the impact of distributive justice and procedural justice variables on judgments in seven countries (Bulgaria, France, Hungary, Poland, Russia, Spain, and the United States). Subjects were presented with each of two experimental vignettes: one in which the actor unsuccessfully appeals being fired from his job and one in which the actor unsuccessfully goes to an employment agency to seek a job; they were asked to rate the justness of the outcome and how fairly the actor had been treated. The vignettes manipulated deservingness and need of the actor (distributive justice factors) and impartiality and voice in the hearing (procedural justice factors). Four hypotheses were tested: first, a distributive justice hypothesis that deservingness would be more important than need in these settings; second, a procedural justice hypothesis that the importance of voice and impartiality vary depending on the nature of the encounter and the forum in which it is resolved; third, because of their recent socialist experience, Central and Eastern European respondents make greater use of need information and less use of deservingness information than Western respondents; and fourth, that distributive justice and procedural justice factors interact. The distributive justice hypothesis is supported in both vignettes. The procedural justice hypothesis receives some support. Impartiality is more important in the first vignette and voice is more important in the second vignette. The interaction hypothesis was not supported in the first vignette, but does receive some support in the second vignette. The cultural hypothesis is not supported in either vignette. The implications for distributive and procedural justice research are discussed.

Adult↗
PubMed2000

Uptake and incorporation of docosahexaenoic acid (DHA) into neuronal cell body and neurite/nerve growth cone lipids: evidence of compartmental DHA metabolism in nerve growth factor-differentiated PC12 cells.

Docosahexaenoic acid (DHA) accumulates in nerve endings of the brain during development. It is released from the membrane during ischemia and electroconvulsive shock. DHA optimizes neurologic development, it is neuroprotective, and rat adrenopheochromocytoma (PC12) cells have decreased PLA2 activity when DHA is present. To characterize DHA metabolism in PC12 cells, media were supplemented with [3H]DHA or [3H]glycerol. Fractions of nerve growth cone particles (NGC) and cell bodies were prepared and the metabolism of the radiolabeled substrates was determined by thin-layer chromatography. [3H]glycerol incorporation into phospholipids indicated de novo lipid synthesis. [3H]DHA uptake was more rapid in the cell bodies than in the NGC. [3H]DHA first esterified in neutral lipids and later in phospholipids (phosphatidylethanolamine). [3H]glycerol primarily labeled phosphatidylcholine. DHA uptake was compartmentalized between the cell body and the NGC. With metabolism similar to that seen in vivo, PC12 cells are an appropriate model to study DHA in neurons.

Adrenal Gland Neoplasms↗
PubMed2000

Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation.

We evaluated the outcome of allogeneic bone marrow transplantation (BMT) in 21 patients with chronic myelomonocytic leukaemia (CMML) who were treated at the Fred Hutchinson Cancer Research Center between 1990 and 1998. There were 11 male and 10 female patients with a median age of 47.4 years (range 1.0-62.9). Patients were conditioned either with total body irradiation (TBI) and chemotherapy, with or without antithymocyte globulin (n = 19), or with chemotherapy alone (n = 2). The marrow donor was an HLA-identical sibling in 12 patients, an HLA-non-identical related donor in three patients and an unrelated volunteer donor in six patients. All evaluable patients achieved sustained engraftment. Fifteen patients developed grades II-IV acute graft-versus-host disease (GVHD). Nine patients (43.0%) are surviving disease free at 0.7-8.1 years (median 6.9) after transplantation. Five patients relapsed 75-660 d after transplant and all died. Five patients died with organ failure and two died with GVHD and associated infections. The Kaplan-Meier estimates of disease-free survival and relapse at 3 years were 39% and 25% respectively. The probability of survival was improved in patients with shorter disease duration compared with those with a long interval from diagnosis to BMT. Thus, as with other myeloproliferative diseases or myelodysplastic syndromes, BMT offers curative therapy for a proportion of patients with CMML. We suggest that patients with CMML who have a suitable donor should be considered for transplantation, probably early in their disease course. However, it will be important to develop new regimens with enhanced antileukaemic efficacy without further increasing regimen-related toxicity and mortality.

Adolescent↗
PubMed2000

A review of health professional attitudes and patient perceptions on 'inappropriate' accident and emergency attendances. The implications for current minor injury service provision in England and Wales.

Increasing attendances in accident and emergency (A and E) departments in the United Kingdom have been attributed to a greater number of patients presenting with minor injuries. A and E staff believe this type of patient is suitable for primary care, and is 'inappropriate' for A and E management. Thus, A and E staff find 'inappropriate' attenders time-consuming and unrewarding, and are less motivated to help them, whilst 'inappropriate' patients believe they have attended the appropriate service for their medical needs and expectations. This review examines research into health professional and patient attitudes towards 'inappropriate' attendances in accident and emergency. It identifies a discrepancy between health professional and patient perspectives regarding 'inappropriate' attendances. However, the change in accident and emergency services with the development of minor injury units and nurse practitioners within A and E to treat minor injury patients away from the mainstream A and E service, appears to be based on the professional attitude of what constitutes an appropriate A and E attendance, and not on the patients' perspective. As negative attitude formation towards 'inappropriate' A and E attendances has occurred, there is concern that such attitudes could remain or develop again in the new units. Patients are generally not medically trained and may experience difficulty in ascertaining the severity of their own condition and attending the 'appropriate' service, as defined by trained professionals. This is exacerbated by the unclear boundaries and roles of minor injury units, nurse practitioners and general practitioners in minor injury care. Therefore research is required into current attendances in minor injury units, A and E departments and general practice, in order to develop clear roles and boundaries for these services. More importantly, research is warranted into the attitudes of all minor injury care providers towards attending patients, and into patient perceptions of the services offered.

Adult↗
PubMed2000

Epitope analysis of the human thyrotropin (TSH) receptor using monoclonal antibodies.

A panel of thyrotropin (TSH) receptor (TSHR) monoclonal antibodies (mAbs), produced using highly purified Chinese hamster ovary (CHO) cell-produced TSHR, has been used to study TSHR structure. All 41 mAbs recognized full-length TSHR containing complex carbohydrate (120 kDa), and 40 mAbs recognized full-length precursor-containing high mannose sugars (100 kDa). The mAbs also recognized TSHR cleavage products with three types of reactivity: type 1 mAbs reacting with bands at 70 kDa and 58 kDa, type 2 with bands at 70 kDa and 52 kDa, and type 3 with bands at 52 kDa and 40 kDa. Deglycosylation studies showed that the 70-kDa and 58-kDa bands contained complex carbohydrate, whereas the 52-kDa and 40-kDa bands were unglycosylated. These results are consistent with TSHR cleavage occurring at two sites. Cleavage at both sites gives rise to glycosylated A subunit (58 kDa) corresponding to the extracellular domain of the receptor and nonglycosylated B subunit (40 kDa) corresponding to the C-terminal transmembrane domain. Cleavage only at site 1 gives rise to the 58-kDa A subunit and a large B subunit (52 kDa). Cleavage only at site 2 gives rise to a large A subunit (70 kDa) and the B subunit (40 kDa). Four of the mAbs inhibited 125I-labeled TSH binding to solubilized full-length TSHR. TSH binding was inhibited by (a) two type 3 mAbs reactive with the N-terminal region of the B subunit (epitopes between amino acids 381 and 385 and between 380 and 418, respectively) and (b) two type 2 mAbs reactive with epitopes on the A subunit (between amino acids 246 and 260). These results together with previous studies on the direct binding of TSH to the TSHR A subunit suggest that at least two distinct regions of the TSHR sequence, including one region on the A subunit and one region on the B subunit, fold together to form part of a complex TSH binding site.

Amino Acid Sequence↗
PubMed2000

The views and anticipated needs of women in early pregnancy.

OBJECTIVE: To assess the expectations of antenatal care of pregnant women at the outset of pregnancy. DESIGN: Questionnaire study within a randomised controlled trial, comparing traditional antenatal care with a more flexible schedule. SETTING: Eleven primary care centres providing midwifery care in Avon. POPULATION: Five hundred and ninety-three pregnant women at low risk of obstetric complications presenting for antenatal care. METHODS: A questionnaire was completed by women who agreed to participate in the trial shortly after antenatal booking. The questionnaire explored women's views on their attitudes to pregnancy and antenatal care, the locus of control related to pregnancy, the planning of the pregnancy and expectations of care. MAIN OUTCOME MEASURES: Comparisons between nulliparous and multiparous women in terms of their views of antenatal care, and their stated preference for a particular package of care. RESULTS: There was no difference in their views of pregnancy as an event entailing risk. On a locus of control scale that measured women's perceptions of factors which might affect their babies' health, nulliparous women rated antenatal care higher than multiparous women (P = 0.0001). However, this was not associated with any difference between the two groups in their stated preference for traditional or flexible care. Approximately half of the women expressed no preference, and of those who did 61% would opt for traditional care. Almost one-fifth of the whole sample welcomed the idea of flexible care. DISCUSSION: These data support the evidence of previous studies that there remains a strong desire among pregnant women to receive a 'traditional' pattern of care, even among those who have previously experienced normal pregnancy. However, a minority can be identified at the outset of pregnancy who may welcome a change to a more flexible pattern of care.

Attitude to Health↗
PubMed2000

A randomised controlled trial of flexibility in routine antenatal care.

OBJECTIVE: To assess changes in satisfaction associated with a flexible approach to antenatal care schedules offered to women at low obstetric risk. DESIGN: Randomised controlled trial. SETTING: Eleven primary care centres providing midwifery care in Avon. PARTICIPANTS: Six hundred and nine women at low risk of obstetric complications presenting for antenatal care. METHODS: A standard antenatal care schedule ('traditional care') was compared with a schedule based on a minimum number of visits and additional visits with timing agreed between women and midwives ('flexible care'). MAIN OUTCOME MEASURES: Women's attitudes to pregnancy and motherhood using a subscale of the Maternal Adjustment and Maternal Attitudes scale, satisfaction with antenatal care, and perception of the speed of recognition of antenatal complications. RESULTS: There was no difference between the two groups in terms of attitudes to pregnancy and motherhood (mean difference on Maternal Adjustment and Maternal Attitudes scale -0.64, 95% CI -1.39 to 0.11, P = 0.068) and no difference in the proportions of women reporting antenatal problems as soon as possible (traditional group 74.5%, flexible group 76.4%, difference -2%, 95% CI -12.1 to 8.2, P = 0.70). Women receiving traditional care reported higher levels of satisfaction for the care provided by community midwives (P < 0.01). Women receiving flexible care were more likely to report having a choice over the number and timing of their antenatal visits (P < 0.001), but were also more likely to report that they would like to have been seen more often (P < 0.01). There was no difference between the groups in rates of obstetric complications. CONCLUSIONS: An imposed reduction in antenatal visits has been reported to increase dissatisfaction in other studies. In this study, encouraging women to adopt a flexible approach to antenatal care resulted in a similar finding. Successful implementation of such approaches may depend on more careful selection of women who welcome such an approach, more encouragement to pregnant women to express their own needs and greater feelings of commitment on the part of the care providers.

Adaptation, Psychological↗
PubMed2000

Regulation of secretion of PTHrP by Ca(2+)-sensing receptor in human astrocytes, astrocytomas, and meningiomas.

Parathyroid hormone-related protein (PTHrP) is the major mediator of the humoral hypercalcemia of malignancy and of malignant osteolysis associated with skeletal metastases of common epithelial cancers. PTHrP secretion is regulated by the extracellular calcium concentration ([Ca(2+)](o)) in several types of normal and malignant cells. Because the [Ca(2+)](o)-sensing receptor (CaR) is a key mediator of [Ca(2+)](o)-regulated hormone secretion [e.g., of parathyroid hormone (PTH) by parathyroid chief cells], we investigated the expression of the CaR and PTHrP in normal and neoplastic glial cells and studied the effects of [Ca(2+)](o) on PTHrP secretion. Our results show that primary embryonic human astrocytes (HPA) express CaR mRNA and protein as detected by RT-PCR and Western analysis, respectively. Furthermore, astrocytomas and meningiomas also express the CaR at similar levels as assessed by RT-PCR and Northern and Western blot analyses. HPA and astrocytomas express transcripts encoding all three known isoforms of PTHrP [PTHrP(139), PTHrP(141), and PTHrP(173), comprising 139, 141, and 173 predicted amino acid residues, respectively] as assessed by RT-PCR, whereas meningiomas express only the first two of these. Finally, elevated levels of [Ca(2+)](o) and other polycationic CaR agonists dose dependently stimulate PTHrP secretion from HPA, astrocytomas, and meningiomas, although both basal and high [Ca(2+)](o)-stimulated rates of PTHrP secretion are approximately 2. 5-fold higher in HPA than in the glial tumors studied here. Therefore, our results show that HPA, astrocytomas, and meningiomas express both the CaR and PTHrP and that CaR agonists stimulate PTHrP secretion.

Astrocytes↗
PubMed2000

Getting to the heart of the matter: making meaning--three challenges for family researchers.

This article explores three of the challenges that qualitative researchers face when working in the family health and well-being field. It is based on the authors' experiences of an ongoing research program that involves research in a human services organization and a family-focused community study. The authors discuss three challenges in the context of this experience and highlight the ways in which they have resolved them within this research program. The first challenge centers on forming research questions. The second challenge concerns access and reciprocity. The final challenge involves research partnerships and teams. Partnerships can take many different forms and hold much potential in qualitative research. Participants can become research partners, or they can maintain more traditional roles as providers of information. Deciding which role participants should have and how to manage the resultant relationships become important tasks in qualitative research because of the intense levels of involvement that often characterize these sorts of research programs.

Community Health Planning↗