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Biomedical subjects

S Robinson

Publications and source records attributed to S Robinson.

At least 127 records · Page 7Linked to original sources
PubMed2000

Stereotactic conformal radiotherapy for pituitary adenomas: technique and preliminary experience.

OBJECTIVE: Stereotactic conformal radiotherapy (SCRT) is a high precision technique of fractionated radiotherapy which ensures accurate delivery of radiation with reduction in the volume of normal tissue irradiated as compared to conventional external beam radiotherapy. We describe the technique and preliminary experience of SCRT in patients with residual and recurrent pituitary adenomas. PATIENTS AND METHODS: Between February 1995 and March 1999, 22 patients (mean age: 45.3, range: 20-67 years) with residual or recurrent pituitary adenomas (13 nonfunctioning, nine secretory) were treated with SCRT. All were immobilized in a relocatable Gill-Thomas-Cosman (GTC) frame and tumour was localized on a postcontrast planning computerized tomography (CT) and MRI scan. The gross tumour volume (GTV) and the critical structures were outlined on contiguous 2-3 mm separated slices. A margin of 5 mm (12 patients) to 10 mm (10 patients) was grown around GTV in three-dimensions (3-D) to generate the planning target volume (PTV). The treatment was delivered by three (five patients) and four (17 patients) maximally separated conformal fixed fields with each field conformed to the shape of the tumour using customized lead alloy blocks (19 patients) or multileaf collimator (three patients). The patients were treated on a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions (18 patients) and 50 Gy in 30 fractions (four patients). RESULTS: The technique of SCRT has become a part of the routine work of the radiotherapy department. The treatment was well tolerated with minimal acute toxicity. One patient developed transient quadrantanopia 2 weeks after treatment with full recovery after a short course of corticosteroids. One patient had a transient visual deterioration 7 months after treatment due to cystic degeneration of the tumour which fully recovered following surgical decompression. Nine of the 15 patients presenting with visual impairment had improvement after treatment and the visual status remained stable in all others. One patient with acromegaly and one with a prolactinoma achieved normalization of elevated hormonal abnormality four and 10 months after SCRT, respectively. The remaining seven patients with a secretory adenoma had declining hormone levels at last follow-up. Newly initiated hormone replacement therapy was required in five patients. At a median follow-up of 9 months (range 1-44 months), the 1 and 2 year actuarial progression free and overall survival were 100%. CONCLUSION: Stereotactic conformal radiotherapy is a high precision technique suitable for the treatment of pituitary adenomas requiring radiotherapy. Preliminary results suggest effective tumour control and low toxicity within the range expected for conventional external beam radiotherapy. While the technique is of potential benefit in reducing the volume of normal brain irradiated, the advantages in terms of sustained tumour control and reduced toxicity over conventional radiotherapy need to be demonstrated in long-term prospective studies.

Adenoma↗
PubMed1999

Thermodynamic comparison of PNA/DNA and DNA/DNA hybridization reactions at ambient temperature.

The thermodynamics of 13 hybridization reactions between 10 base DNA sequences of design 5'-ATGCXYATGC-3' with X, Y = A, C, G, T and their complementary PNA and DNA sequences were determined from isothermal titration calorimetry (ITC) measurements at ambient temperature. For the PNA/DNA hybridization reactions, the binding constants range from 1.8 x 10(6)M(-1)for PNA(TT)/DNA to 4.15 x 10(7)M(-1)for PNA(GA)/DNA and the binding enthalpies range from -194 kJ mol(-1)for PNA(CG)/DNA to -77 kJ mol(-1)for PNA(GT)/DNA. For the corresponding DNA/DNA binding reactions, the binding constants range from 2.9 x 10(5)M(-1)for DNA(GT)/DNA to 1.9 x 10(7)M(-1)for DNA(CC)/DNA and the binding enthalpies range from -223 kJ mol(-1)for DNA(CG)/DNA to -124 kJ mol(-1)for DNA(TT)/DNA. Most of the PNA sequences exhibited tighter binding affinities than their corresponding DNA sequences resulting from smaller entropy changes in the PNA/DNA hybridization reactions. van't Hoff enthalpies and extrapolated Delta G values determined from UV melting studies on the duplexes exhibited closer agreement with the ITC binding enthalpies and Delta G values for the DNA/DNA duplexes than for the PNA/DNA duplexes.

Base Sequence↗
PubMed1999

Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation.

Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are generated during development through the proliferation and differentiation of a distinct progenitor population. Not all oligodendrocyte progenitors generated during development differentiate, however, and large numbers of oligodendrocyte progenitors are present in the adult CNS, particularly in white matter. These "adult progenitors" can be identified through expression of the NG2 proteoglycan. Adult oligodendrocyte progenitors are thought to develop from the original pool of progenitors and in vitro are capable of differentiating into oligodendrocytes. Why these cells fail to differentiate in the intact CNS is currently unclear. Here we show that contact with CNS myelin inhibits the maturation of immature oligodendrocyte progenitors. The inhibition of oligodendrocyte progenitor maturation is a characteristic of CNS myelin that is not shared by several other membrane preparations including adult and neonatal neural membrane fractions, PNS myelin, or liver. This inhibition is concentration dependent, is reversible, and appears not to be mediated by either myelin basic protein or basic fibroblast growth factor. Myelin-induced inhibition of oligodendrocyte progenitor maturation provides a mechanism to explain the generation of a residual pool of immature oligodendrocyte progenitors in the mature CNS.

Animals↗
PubMed1999

Effects of exercise training on peak performance and quality of life in congestive heart failure patients.

BACKGROUND: Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy, young patients. They also have not measured the impact of exercise performance on daily activities and quality of life. METHODS AND RESULTS: We investigated the impact of a 6-month supervised and graded exercise program in 33 elderly patients with moderate to severe heart failure randomized to usual care or an exercise program. Six of 17 patients did not tolerate the exercise program. Of those who did, peak oxygen consumption increased by 2.4 +/- 2.8 mL/kg/min (P < .05) and 6-minute walk increased by 194 ft (P < .05). However, outpatient energy expenditure did not increase, as measured by either the doubly labeled water technique or Caltrac accelerometer. Perceived quality of life also did not improve, as measured by the Medical Outcomes Study, Functional Status Assessment, or Minnesota Living With Heart Failure questionnaires. CONCLUSION: Elderly patients with severe heart failure can safely exercise, with an improvement in peak exercise tolerance. However, not all patients will benefit, and daily energy expenditure and quality of life do not improve to the same extent as peak exercise.

Activities of Daily Living↗
PubMed1999

Assessing the diet of adolescent girls in the UK.

OBJECTIVE: To assess the ability of a food frequency questionnaire (FFQ1) and a food checklist (FCL) to determine energy and macronutrient intakes of adolescent girls in the general population. DESIGN: Energy and macronutrient intakes determined by FFQ1 and the FCL were compared with those from a 7-day weighed dietary record (WDR). The reproducibility of FFQ1 was assessed by a comparison of intakes with those from a repeated questionnaire (FFQ2) completed a month later. SETTING: Southampton, UK. SUBJECTS: Forty-seven 15-year-old girls completed FFQ1 and the WDR and FCL; and 61 girls completed FFQ1 and FFQ2. RESULTS: The broad dietary patterns described by the three methods of assessment were similar, although absolute intakes differed. Energy and macronutrient intakes determined by FFQ1 were higher than those recorded in the WDR (all P < 0.001), but intakes assessed by the FCL and WDR were similar. Only FFQ1-assessed energy intakes appeared consistent with predicted energy requirements. With the exception of protein intake, there was reasonable agreement between FFQ1 and the WDR in their estimation of energy and macronutrient intake (range of correlation coefficients 0.28 for energy to 0.33 for carbohydrate). The poorer agreement between FFQ1 and the WDR in their estimates of protein intake arose principally from the misclassification of meat and fish intake, although there was no obvious explanation for this. Energy and macronutrient intakes were similar for FFQ1 and FFQ2. CONCLUSIONS: Adolescent girls give reproducible answers in response to a self-administered FFQ, which yield useful information about their broad dietary patterns. The FFQ may be a more suitable dietary assessment method than prospective records for use in general population studies of girls of this age. We discuss suggestions for its improved performance.

Adolescent↗
PubMed1999

Child protection: a survey of experience and knowledge within the dental profession of New South Wales, Australia.

AIM: To establish the experience and knowledge of dental practitioners in New South Wales, Australia in the area of child abuse and protection. DESIGN: A cross-sectional telephone questionnaire. SAMPLE: One hundred and twenty-two interviews; 67 general dental practitioners randomly selected and 55 members of the Australia and New Zealand Society of Paediatric Dentistry. RESULTS: All of the dentists interviewed could identify physical abuse and most identified emotional abuse, however, none could describe all five forms of abuse. Significantly more (58%) members of the paediatric dental society had at some time suspected abuse, compared with only 24% of the general practitioners. However, only 20 of the paediatric dentists and seven general practitioners had actually reported any cases. The main reason given for not reporting concerned confidentiality. Seventy-two per cent of general practitioners did not know their legal obligations or with whom they could discuss any concerns. While paediatric dentists achieved a better percentage, still over half of them were similarly unsure. CONCLUSIONS: Further education and training is required for both the dental profession and the child protection agencies to improve the inter-agency working relationship and thus provide better protection for children.

Attitude of Health Personnel↗
PubMed1999

Glucose production by the human placenta in vivo.

The human placenta transports glucose by facilitated diffusion down a concentration gradient from mother to fetus. It has previously been considered incapable of glucose synthesis. However, recent work has demonstrated the presence in placental tissue of glucose-6-phosphatase, which is required for the final step in the synthesis of glucose. Following continuous intravenous infusion into the maternal circulation of the stable isotope, 6,6-(2)H(2)glucose, during elective caesarean section, we have observed isotope dilution in the umbilical vein, without further dilution in the umbilical artery. Using a mathematical model containing maternal, placental and fetal compartments, the data were compatible with the release of glucose by the placenta. We conclude that the human placenta at term can produce glucose.

Adult↗
PubMed1999

Cytokine profile of human bronchoalveolar macrophages and bronchial epithelial cells in response to inhalation particles of the cyclosporine derivative IMM 125.

Administration of antiasthmatic drugs in the form of inhalation particles may alter the cytokine network in the airways, independently of their pharmacological actions. Changes induced by drugs not well tolerated may potentially contribute to the immunopathology of the disease, a strongly undesirable effect. In this study, cell viability assays and characterization of the cellular profile of cytokines and chemokines were performed in order to investigate the response of human bronchoalveolar macrophages and bronchial epithelial cells in culture to inhalation particles of the cyclosporine derivative IMM 125. Interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-8 were assayed by enzyme-linked immunosorbent assay (ELISA) in the supernatants of bronchoalveolar macrophages, and RANTES, granulocyte--macrophage colony-stimulating factor (GM-CSF), and IL-8 in those of bronchial epithelial cells. Cells were studied both under basal and stimulated conditions (lipopolysaccharide and TNFalpha were used for activating macrophages and epithelial cells, respectively). The immunosuppressant FK 506 and the glucocorticoid Budesonide served as comparison. IMM 125 did not affect cell viability (except at high concentrations and long time periods). Moreover, IMM 125 did not induce an increase in the secretion of any of the cytokines and chemokines measured with respect to nontreated cells, except for a slight increase in IL-8, an effect that was also observed for FK 506, Budesonide, and inert latex particles, and was therefore regarded as nonspecific. Furthermore, IMM 125 significantly decreased the secretion of TNFalpha, IL-1beta by macrophages, and GM-CSF by epithelial cells, suggesting an antiinflammatory potential. In conclusion, the present in vitro results point to a good tolerance of human airways to IMM 125 inhalation particles.

Administration, Inhalation↗
PubMed1999

In vitro selection of integration host factor binding sites.

Integration host factor (IHF) is a bacterial protein that binds and severely bends a specific DNA target. IHF binding sites are approximately 30 to 35 bp long and are apparently divided into two domains. While the 3' domain is conserved, the 5' domain is degenerate but is typically AT rich. As a result of physical constraints that IHF must impose on DNA in order to bind, it is believed that this 5' domain must possess structural characteristics conducive for both binding and bending with little regard for specific contacts between the protein and the DNA. We have examined the sequence requirements of the 5' binding domain of the IHF binding target. Using a SELEX procedure, we randomized and selected variants of a natural IHF site. We then analyzed these variants to determine how the 5' binding domain affects the structure, affinity, and function of an IHF-DNA complex in a native system. Despite finding individual sequences that varied over 100-fold in affinity for IHF, we found no apparent correlation between affinity and function.

Bacterial Proteins↗
PubMed1999

Degradation products of factor VIII which can lead to increased immunogenicity.

The biochemical and immunochemical aspects of the development of inhibitors with a plasma-derived, double-virus inactivated factor VIII (FVIII) concentrate (marketed as Octavi SDPlus in Germany and Bisinact in Belgium) are described. A total of 12 cases of inhibitor formation (predominantly type II) were reported in Germany, 8 in Belgium but none in Portugal. Initially, the only difference between the non-pasteurised, SD virus-inactivated product Octavi and the pasteurised product Octavi SDPlus appeared to be pasteurisation, though subsequently, the quality of source material for the product was found to differ in different countries. Separation studies revealed the presence of a 40 kDa peptide fragment in some batches. It was subsequently shown that there was a strong correlation between inhibitor development and batches containing the 40 kDa marker, and a relationship between elevated markers of coagulation activation (FPA in particular) and the occurrence of the 40 kDa marker. Further work revealed that analytical methods commonly used for quality control were not suitable to highlight batch-to-batch differences. It was concluded that inhibitor potential (neoantigenicity) in Octavi SDPlus arose due to two effects; degradation of FVIII already present in source material; and heating of unstable FVIII degradation products. In this case, inhibitors were not caused by the overall production process, nor by GMP failures. The problem of inhibitor potential can be avoided if appropriate preventive measures are taken. Further work is needed to prove non-neoantigenicity and to reinforce the scientific findings, and to characterise pilot batches.

Chromatography, High Pressure Liquid↗
PubMed1999

Implications of new diagnostic criteria for abnormal glucose homeostasis in women with previous gestational diabetes.

OBJECTIVE: To determine the consequences of applying revised American Diabetes Association (ADA) (1997) and World Health Organization (WHO) (1998) recommendations for the classification of glucose intolerance in women with previous gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: There were 192 women with previous GDM who took an oral glucose tolerance test (OGTT) 1-86 months after delivery and were classified by WHO (1985), ADA (1997, fasting glucose), and revised WHO (1998) guidelines. RESULTS: Among the 165 women without a preexisting diagnosis of diabetes, WHO-1985 and ADA-1997 provided similar estimates of diabetes prevalence (13.3% vs. 11.5%) but widely differing estimates of impaired glucose homeostasis (31.5% impaired glucose tolerance [IGT] by WHO-1985 vs. 10.9% impaired fasting glucose by ADA-1997 criteria). Overall, 56 women (34%) showed a classification discrepancy between WHO-1985 and ADA-1997 criteria, including 44 with normal fasting glucose by ADA-1997 criteria, but abnormal 2-h glucose by WHO-1985 criteria (40 IGT, 4 diabetes). The cardiovascular risk profile of these women was more favorable than that of 18 women with impaired fasting glucose. WHO-1998 recommendations reproduced ADA-1997 findings when used as a fasting screen, but behaved similarly to WHO-1985 criteria when 2-h glucose values were also analyzed. CONCLUSIONS: All criteria produced similar estimates of diabetes prevalence. However, analyses based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) failed to identify 60% of women with abnormal 2-h glucose levels. Screening women with previous GDM (and by analogy, other groups at high risk of diabetes) with a single fasting glucose has low sensitivity for the detection of abnormal glucose tolerance. Recent guidelines recommending this approach require reevaluation.

Adult↗
PubMed1999

Sudden death in right ventricular dysplasia with minimal gross abnormalities.

Arrhythmogenic right ventricular cardiomyopathy is emerging as a relatively common cause of exercise-induced sudden death in the young. The diagnostic criteria at autopsy are, however, not fully established, leading to both over- and underdiagnosis. We report a young man and a young woman dying suddenly of right ventricular dysplasia during exercise, in whom the gross autopsy findings in the right ventricle were minimal or even absent. However, the histologic features in both right and left ventricles were typical of the disease, and consisted of fibrofatty infiltrates with typical myocyte degeneration of the right ventricle and subepicardial regions of the left ventricle. These cases illustrate that microscopic findings are diagnostic and may be present in the absence of gross findings. Marked fat replacement is not essential for the diagnosis of right ventricular dysplasia, and the right ventricle should be extensively sampled histologically in all cases of sudden unexpected death, especially those that are exercise related.

Adult↗
PubMed1999

Low levels of p53 are associated with resistance to tetrachlorodibenzo-p-dioxin toxicity in DBA/2 mice.

We show here that DBA/2 strain mice have a complex mutation/polymorphism in the promoter region of the Trp53 locus (the mouse p53 locus). This region has previously been shown to be essential for p53 expression. We further show that the DBA/2 mutation is associated with approximately fourfold lower p53 levels in thymocytes treated with the DNA-damaging agent etoposide in-vitro, and with relative resistance of these thymocytes to apoptosis induced by the DNA-damaging agent etoposide compared with C57BL/6 mice. When part of the promoter containing this mutation was inserted into a plasmid containing a luciferase reporter gene but lacking eukaryote promoter sequences and transfected into MCF-7 human breast cell line cells, the mean luciferase activity was slightly less with the DBA/2 than with the C57BL/6 promoter-reporter construct (p < 0.01). We found that DBA/2xC57BL/6 F2 hybrid mice with the DBA/2 genotype at the Trp53 locus were relatively resistant to tetrachlorodibenzo-p-dioxin toxicity, and this resistance was additive with resistance associated with the Ahr locus. DBA/2 mice are long-lived and do not have particularly high levels of cancer, suggesting either that they carry other compensatory tumour resistance alleles (such as Ahr(d)), or that, while there may be a p53 protein dosage effect for acute toxicity, lower than normal levels of p53 may still be sufficient to protect against cancer. In evolutionary terms, it may be better to maintain low levels of p53 in order to avoid death from acute toxicity, even at the expense of a higher incidence of cancer in later life.

Animals↗
PubMed1999

Long-term effects of growth hormone therapy on intermediary metabolism and insulin sensitivity in hypopituitary adults.

Experience with growth hormone (GH) therapy in adult hypopituitarism has been gained for more than 10 years. Most of the data on GH therapy derive from studies with a duration of 2 years or less, but longer term information is required if patients are to be treated with GH replacement therapy for many years. We have studied patients after 4 years of treatment. At the end of this time, body mass index was unchanged but short-term benefits in body composition (decreased percentage body fat and increased fat-free mass) which had been evident at 2 years were still apparent. Fasting plasma glucose and the plasma glucose area under the curve during an oral glucose tolerance test were similar before and after 4 years of therapy, although fasting insulin levels were increased in comparison with baseline. Total cholesterol and low density lipoprotein cholesterol concentrations were lower at 4 years than at the outset but high density lipoprotein cholesterol and triglyceride levels were unchanged. The available evidence therefore suggests that concerns regarding glucose intolerance in patients receiving long-term GH therapy have not been substantiated. The beneficial effects on body composition, and on total and low density lipoprotein cholesterol levels, persisted over the 4 years of study.

Adult↗