Desperately seeking solutions: rationing health care
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Journal Article↗
Biomedical subjects
D Price
Publications and source records attributed to D Price.
Male erectile dysfunction.
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Case Management↗
Engraftment after myeloablative doses of 131I-metaiodobenzylguanidine followed by autologous bone marrow transplantation for treatment of refractory neuroblastoma.
BACKGROUND: Metaiodobenzylguanidine (MIBG) labeled with 131I has been used for targeted radiotherapy of neural crest tumors, with bone marrow suppression being the primary dose-limiting toxicity. The purpose of this study was to examine the engraftment and toxicity of higher myeloablative doses of 131I-MIBG with autologous bone marrow support. PROCEDURE: Twelve patients with refractory neuroblastoma were given infusions of their autologous, cryopreserved bone marrow following 1-4 doses of 131I-MIBG. The median cumulative administered activity per kilogram of 131I-MIBG was 18.0 mCi/kg (range 14.1-50.2 mCi/kg), the median total activity was 594 mCi (range 195-1,353 mCi), and the median cumulative whole body irradiation from 131I-MIBG was 426 cGy (range 256-800 cGy). A median of 2.5 x 10(8) viable cells/kg (range 0.9-4.7 x 10(8) cells/kg) was given in the bone marrow infusion. RESULTS: All 12 patients achieved an absolute neutrophil count > 500/microliter with a median of 19 days, but only 5/11 evaluable patients achieved red cell transfusion independence, in a median of 44 days; and 4/11 evaluable patients achieved platelet count > 20,000/microliter without transfusion, in a median of 27 days. CONCLUSIONS: Autologous bone marrow transplantation may allow complete hematopoietic reconstitution following ablative 131I-MIBG radiotherapy in patients with neuroblastoma. Risk factors for lack of red cell or platelet recovery include extensive prior chemotherapy, progressive disease at the time of transplant, especially in the bone marrow, and a history of prior myeloablative therapy with stem cell support.
3-Iodobenzylguanidine↗
HLA-A*0201 presents TAP-dependent peptide epitopes to cytotoxic T lymphocytes in the absence of tapasin.
Tapasin is a 48-kDa endoplasmic reticulum (ER)-resident glycoprotein that binds to the transporter associated with antigen processing (TAP) and mediates an interaction between TAP and newly synthesized MHC class I molecules. It is also essential for the proper antigen presenting function of HLA-A*0101 (HLA-A1), HLA-A*0801 (HLA-B8) and HLA-B*4402 (HLA-B4402). We show here that while tapasin is required for HLA-A*0201 (HLA-A2) molecules to bind to TAP, its absence does not block the presentation of HLA-A2-restricted TAP-dependent epitopes to cytotoxic T lymphocytes indicating that, unlike HLA-A1, HLA-B8 and HLA-B4402, HLA-A2 has access to the TAP-dependent peptide pool even in the absence of tapasin. Nevertheless, the overall efficiency with which HLA-A2 was loaded with optimal, stabilizing peptides was impaired in the cell line .220, resulting in a significant increase in the fraction of HLA-A2 molecules being released from the ER in a "peptide-receptive" state.
Antigen Presentation↗
Psychological predictors of attendance at annual breast screening examinations.
This retrospective analysis of psychological predictors of attendance studied the women from the annual screening arm of the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) trial of annual screening mammography for the early detection of breast cancer. Some women attended screening at the first invitation in year 1 (attenders), others did not attend for screening at any time (non-attenders), whereas a third group delayed attending until year 2 (ambivalent attenders). A total of 147 women were recruited to the study: 80 attenders, 28 non-attenders and 39 ambivalent attenders. It proved extremely difficult to contact non-attenders to take part in the study. Non-attenders were significantly more depressed on the Hospital Anxiety and Depression Scale; had experienced more miscarriages, stillbirths or terminations of pregnancy; were less knowledgeable about mammography; and were displeased to have received an invitation to screening. Whereas non-attenders are unlikely ever to attend breast screening because of their long-standing attitudes and preferred coping styles, ambivalent attenders may become more amenable to screening with the passage of time. In this study such women were persuaded to attend in year 2 with a simple, cost-effective intervention: an additional invitation letter after a year.
Breast Neoplasms↗
Effects of estrogen replacement therapy on the lipoprotein profile in postmenopausal women with ESRD.
BACKGROUND: Patients with ESRD have excessive cardiovascular morbidity and mortality. In postmenopausal women with normal renal function, estrogen replacement therapy decreases cardiovascular mortality by 50%, in part because of their beneficial effects on the lipoprotein profile. Because of similarities in the lipoprotein profile between healthy, postmenopausal women, and women with ESRD, we examined the effects of estrogen replacement on lipoproteins in 11 postmenopausal women with ESRD. METHODS: In a randomized, placebo-controlled crossover study (8 week treatment arms) using 2 mg daily of oral, micronized estradiol, 11 postmenopausal women with ESRD were treated. Neither baseline lipid nor lipoprotein abnormalities were used as entry criteria for study participation. RESULTS: Blood estradiol levels were 19 +/- 4 with placebo and 194 +/- 67 pg/ml (P = 0.024) with estradiol treatment. Total HDL cholesterol concentrations increased from 52 +/- 19 mg/dl to 61 +/- 20 mg/dl (16%), with placebo and estradiol treatments, respectively (P = 0.002). Apolipoprotein A1 increased by 24.6% (P = 0.0002) with estradiol intervention. HDL2 concentrations were 19 +/- 13 with placebo and 24 +/- 16 with estradiol treatment (P = 0.046). There were no differences in total or LDL cholesterol, other lipoprotein fractions including Lp(a), and triglycerides with 2 mg daily estradiol treatment. No significant side effects were observed. CONCLUSIONS: Therefore, using standard dosage regimens for estrogen replacement therapy in postmenopausal women with ESRD, HDL cholesterol is increased to an extent that would be expected to improve their cardiovascular risk profile. Further studies are needed to assess whether estrogen replacement therapy decreases the incidence or severity of cardiovascular disease in ESRD patients to a similar degree compared with other women.
Cardiovascular Diseases↗
Changes in medical student attitudes as they progress through a medical course.
OBJECTIVES: To explore the way ethical principles develop during a medical education course for three groups of medical students--in their first year, at the beginning of their penultimate (fifth) year and towards the end of their final (sixth) year. DESIGN: Survey questionnaire administered to medical students in their first, fifth and final (sixth) year. SETTING: A large medical school in Queensland, Australia. SURVEY SAMPLE: Approximately half the students in each of three years (first, fifth and sixth) provided data on a voluntary basis, a total of 385 students. RESULTS: At the point of entry, minor differences were found between medical students and first year law and psychology students. More striking were differences between male and female medical students, suggesting early socialization had a substantial impact here. CONCLUSIONS: Results indicate that substantial changes in attitude have developed by the beginning of fifth year with little change thereafter. Gender difference persisted. Some difference in ethical attitudes were found when groups of different ethnic backgrounds were compared. The impact of a move to a graduate medical course, which gives high priority to ethics within a professional development domain, can now be evaluated.
Attitude of Health Personnel↗
Phase I dose escalation of 131I-metaiodobenzylguanidine with autologous bone marrow support in refractory neuroblastoma.
PURPOSE: The analogue 131I-metaiodobenzylguanidine (MIBG), which is specifically targeted to neuroblastoma cells, may provide more effective and less toxic treatment for neuroblastoma than conventional external-beam radiotherapy. We report a dose escalation study of 131I-MIBG to define dose-limiting toxicity without and with autologous bone marrow support. PATIENTS AND METHODS: Thirty patients with relapsed neuroblastoma were treated in groups of six with escalating doses of 3 to 18 mCi/kg of 131I-MIBG. After rapid escalation in the first three patients treated at 3 to 6 mCi/kg, treatment was escalated in 3-mCi/kg increments from 9 to 18 mCi/kg. Autologous tumor-free bone marrow was cryopreserved in all patients receiving 12 mCi/kg and more. Toxicity and response were assessed. RESULTS: Eighty percent of patients who received 12 mC/kg or more experienced grade 4 thrombocytopenia and/or neutropenia. Dose-limiting hematologic toxicity was reached at 15 mCi/kg, at which level two of five assessable patients required bone marrow reinfusion for absolute neutrophil count (ANC) of less than 200/microL for more than 2 weeks, and four of nine at the 18-mCi/kg level. Prolonged thrombocytopenia was common, with failure to become platelet-transfusion independent in nine patients. One patient with extensive prior treatment developed secondary leukemia and three became hypothyroid. Responses were seen in 37% of patients, with one complete response (CR), 10 partial response (PR), three mixed response, 10 stable disease, and six progressive disease. The minimum dose of 131I-MIBG for 10 of the 11 responders was 12 mCi/kg. CONCLUSION: Treatment with 131I-MIBG has mainly hematologic toxicity, which can be abrogated with bone marrow rescue. The high response rate in refractory disease suggests that this agent may be useful in combination with myeloablative chemotherapy and autologous stem-cell rescue to improve outcome in advanced neuroblastoma.
3-Iodobenzylguanidine↗
Radiology quiz. Suspected urinary calculus.
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Adult↗
Keratin modifications and solubility properties in epithelial cells and in vitro.
The gains that have been made in characterizing some of the keratin posttranslational modifications have helped answer some questions regarding these modifications and have generated an information base for asking additional refined questions in future studies. Highlights of where we believe we currently stand with regard to keratin posttranslational modifications are as follows: 1. Keratin glycosylation, via O-GlcNAc, is a dynamic modification that has been conclusively identified in K13, K8, and K18. Three serine glycosylation sites in the head domain of K18 have been identified, and it is possible that all keratins are glycosylated. The function of this modification remains to be defined, but is likely to be different from phosphorylation, since the two modifications are generally segregated on different molecules and several examples exist whereby both modifications increase simultaneously. 2. Keratin phosphorylation occurs within the tail and/or head domains of all keratins that have been examined. Several serine phosphorylation sites and some of the relevant kinases have been characterized in K8, K6, and K18, and serine/threonine sites have been identified in K1. Functions of keratin phosphorylation that have significant experimental support include a role in filament solubility and reorganization and a role in regulating keratin binding with other cytoplasmic proteins. The significance of filament reorganization and increased solubility under a variety of physiologic conditions such as mitosis and cell stress are important areas of future and ongoing investigation. Other associations with keratin phosphorylation include protection against cell stress, cell signaling, apoptosis, and cell compartment-specific roles. At this stage, however, it is not known if these associations play direct or indirect roles. 3. Keratin transglutamination occurs in epidermal and simple epithelial keratins under physiologic and pathologic states, respectively. In the physiological context, the role of this modification is clear in terms of providing a compact protective structure, while in the pathologic context of liver disease the role remains ambiguous. 4. Proteolysis of K18 and K19 by caspases occurs during apoptosis, and generates stable keratin fragments that are highly enriched within the cytoskeletal compartment. Proteolysis of the type II keratins appears to be spared for reasons that remain to be defined. It is likely that this apoptosis-associated degradation involves all type I keratins. Keratin fragments are also noted in sera of patients in association with a variety of epithelial tumors. If a signal does exist for the apoptosis-associated fragmentation, aside from caspase activation, then it appears that the overall increase in keratin phosphorylation during apoptosis does not account for this signal. 5. Keratins undergo several other posttranslational modifications including disulfide bond formation (not found in K8/18 due to lack of cystienes) and acetylation of their N-terminal serines. Modification by lipids is also possible, but this modification requires further confirmation. 6. Keratin solublility is highly dynamic and varies profoundly depending on the keratin pair and the physiologic state of the cell. Within the keratin family, simple epithelial keratins are among the most soluble (approximately 5% of K8/18 is soluble at basal conditions). Phosphorylation plays an important role in modulating keratin solubility, and distinct differences occur in site-specific phosphorylation depending on the soluble versus cytoskeletal partitioning of the keratin. Keratin solubility (at least for K8/18) also appears to be regulated by 14-3-3 proteins via K18 Ser33 phosphorylation.
Acetylation↗
Drosophila factor 2, an RNA polymerase II transcript release factor, has DNA-dependent ATPase activity.
Drosophila factor 2 has been identified as a component of negative transcription elongation factor (N-TEF) that causes the release of RNA polymerase II transcripts in an ATP-dependent manner (Xie, Z. and Price D. H. (1996) J. Biol. Chem. 271, 11043-11046). We show here that the transcript release activity of factor 2 requires ATP or dATP and that adenosine 5'-O-(thiotriphosphate) (ATPgammaS), adenosine 5'-(beta,gamma-imino)triphosphate (AMP-PNP), or other NTPs do not support the activity. Factor 2 demonstrated a strong DNA-dependent ATPase activity that correlated with its transcript release activity. At 20 microg/ml DNA, the ATPase activity of factor 2 had an apparent Km(ATP) of 28 microM and an estimated Kcat of 140 min-1. Factor 2 caused the release of nascent transcripts associated with elongation complexes generated by RNA polymerase II on a dC-tailed template. Therefore, no other protein cofactors are required for the transcript release activity of factor 2. Using the dC-tailed template assay, it was found that renaturation of the template was required for factor 2 function.
Adenosine Triphosphatases↗
Profiting from closure: the private finance initiative and the NHS.
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Financing, Organized↗
Association of glucose-regulated protein (grp78) with human keratin 8.
Keratin polypeptides 8 and 18 (K8/18) are intermediate filament proteins that are expressed in 'simple-type' epithelial cells. They associate with several proteins including the 70 kDa cytoplasmic heat shock proteins (hsp70). We identified the human 78 kDa glucose-regulated protein (grp78) as a keratin-associated protein. Keratin-grp78 association was noted after co-immunoprecipitation of K8/18 from HT29 detergent solubilized cell lysates, and appears to involve non-posttranslationally modified grp78. The grp78-K8/18 association is induced by culturing cells in the presence of tunicamycin or after glucose starvation. K8/18-bound grp78 can be dissociated by Mg-ATP and the association can be reconstituted in vitro using purified grp78, then redissociated again by Mg-ATP. Binding of grp78 occurs preferentially with K8, and when reconstituted does not depend on the posttranslational modification state of K8/18. Co-incubation of K8/18 with hsp70 and grp78 shows preferential association with hsp70. Our results demonstrate a direct association of grp78 with K8 under conditions that induce grp78 expression.
Adenosine Triphosphate↗
P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro.
To identify novel inhibitors of transcriptional activation by the HIV Tat protein, we used a combination of in vitro and in vivo Tat-dependent transcription assays to screen >100,000 compounds. All compounds identified blocked Tat-dependent stimulation of transcriptional elongation. Analysis of a panel of structurally diverse inhibitors indicated that their target is the human homolog of Drosophila positive transcription elongation factor b (P-TEFb). Loss of Tat transactivation in extracts depleted of the kinase subunit of human P-TEFb, PITALRE, was reversed by addition of partially purified human P-TEFb. Transfection experiments with wild-type or kinase knockout PITALRE demonstrated that P-TEFb is required for Tat function. Our results suggest that P-TEFb represents an attractive target for the development of novel HIV therapeutics.
Animals↗
Effect of variation in seat tube angle at different seat heights on submaximal cycling performance in man.
The effect of seat tube angle at selected seat heights (96, 100 and 104% trochanteric height) on heart rate, VO2 and lower limb kinematics was evaluated in 14 competitive male road racing cyclists during discontinuous submaximal exercise (200 W) on an air-resistance ergometer at seat tube angles of 68, 74 and 80 degrees. The tests were randomized to complete the nine combinations (three seat heights, three tube angles) in opposite directions from a starting tube angle of 74 degrees and 100% trochanteric height to avoid any time or sequence bias. Power efficiency was calculated for each combination from work done and VO2. All results were analysed using ANOVA for repeated measures. At a seat tube angle of 80 degrees, mean VO2 was significantly lower and power efficiency significantly higher compared with an angle of 74 degrees at all three seat heights, while heart rate was significantly lower only at a seat height equal to trochanteric height. At a seat tube angle of 74 degrees, mean VO2 and heart rate were significantly lower and power efficiency significantly higher compared with an angle of 68 degrees at all three seat heights. Hip range of movement and maximum and minimum hip angle were significantly less at an angle of 80 degrees compared with 68 degrees. Further biomechanical analysis suggested that the improvement in cycling efficiency observed at steeper seat tube angles was produced in part by the resultant altered ankling pattern of the cyclist.
Adult↗
Co-evolution of human immunodeficiency virus and cytotoxic T-lymphocyte responses.
After more than a decade of intensive research, the precise role of human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) in determining the course of the infection remains open to argument. It is established that HIV-specific CTL appear early in the infection and are temporally associated with the clearance of culturable virus from the blood; that CTL are generally detectable at very high levels throughout the asymptomatic phase and decline at the time of progression to AIDS; and that CTL-mediated killing is sufficiently fast to prevent production of new virions by HIV-infected cells. However, viral turnover is high throughout the course of the infection, and infected individuals progress inexorably to disease in spite of the CTL response. In order to address the question of whether CTL play an active part in influencing the course of HIV infection, one approach has been to seek evidence for CTL-mediated selection pressure on the virus. Several clear examples of CTL epitope-specific mutations selected to fixation are described. We argue that CTL escape is a common event which occurs at all stages of the infection. Detailed longitudinal studies are required to detect CTL escape and to understand the complexities contributed by factors such as a polyvalent CTL response and the presence of epitope variants which antagonise the CTL response. In conclusion, there is strong evidence of a dynamic process in which CTL impose important selection constraints upon HIV from which the virus attempts to escape; ultimately, at the time of disease progression, the tenuous control of CTL over the virus is lost.
Animals↗
Selective effects of nerve growth factor on spatial recent memory as assessed by a delayed nonmatching-to-position task in the water maze.
Nerve growth factor (NGF) ameliorates age-related deficits in certain types of memory in rats. Although the effects of NGF on reference memory are well documented, the influence of NGF on recent memory is less well understood. The issue of recent memory is of primary importance in the design of therapies for cognitive disorders, because this type of memory is impaired in elderly humans and is severely affected early in the course of Alzheimer's disease (AD). The present study was designed to evaluate the efforts of NGF on recent memory in a task that used escape from water as the motivating stimulus and used the same design as forced-choice recognition tasks given to humans. Fischer-344 rats, 4 months old (4MO) or 23 months old (23MO), were pretested in a new spatial recent memory task designed for the Morris water maze, a delayed nonmatching-to-position task, and infused intraventricularly with recombinant human NGF or vehicle. After 2 weeks of NGF infusion, no substantial changes in behavior were observed in either age group. However, NGF treatment extended over 4 weeks improved considerably the choice accuracy of 23MO rats to a level similar to the performance of 4MO rats. These results, together with our previous work (Markowska et al., 1994), indicate that the effects of NGF on spatial recent memory are more intense than on spatial reference memory. NGF suppressed the body weight gain in 4MO rats but did not affect 23MO rats. In 23MO rats, NGF mildly counteracted age-related deficits in inhibitory avoidance, but did not have an effect in young rats.
Aging↗
Lessons for health care rationing from the case of child B.
More details have emerged about the child B leukaemia case with the publication of the All England Law Report on the Appeal Court decision. At the time the view was widely held that the controversy might have been avoided if the responsible health authority had consulted the public. The law report reveals, however, that the courts adopted a moral language widely at variance with that of the patient's doctor. The courts were concerned to support a utilitarian decision procedure based on calculations of the greatest overall good; the doctor was concerned with the best interests of a sick child. The doctor-patient relationship may be damaged when public consideration transforms the issue in this way. Also, the Appeal Court supported a decision which claimed to have "weighed" opposing evaluations, but it excused the health authority from describing how that weighing took place. One of the main criticisms of the utilitarian approach, however, is that weighing of this type is extremely difficult to justify. By its ruling the court has made legal challenge on the grounds of inadequate consultation virtually impossible to substantiate.
Child↗