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Biomedical subjects

N Cook

Publications and source records attributed to N Cook.

At least 73 records · Page 4Linked to original sources
PubMed1991

Estimating the effect of the run-in on the power of the Physicians' Health Study.

In the Physicians' Health Study, a randomized, placebo-controlled, double-blind trial of aspirin in the reduction of cardiovascular mortality and beta-carotene in decreasing cancer incidence, 33,223 subjects were eligible and willing to enter the trial. Instead of randomizing this group immediately, all participants received identical calendar packs that contained active aspirin and beta-carotene placebo. Following an 18-week run-in, only 22,071 subjects who remained eligible and willing and had taken at least 2/3 of their pills were randomized. We estimated the effect of the run-in as follows: pill taking compliance increased 20-41 per cent; sample size decreased 34 per cent; duration of follow-up decreased 7 per cent which resulted in a 7 per cent decrease in the expected event rate for the placebo group. To estimate these changes, we made assumptions about compliance and outcome risk for those excluded by the run-in. Our conclusion, however, about the net effect of the run-in on the power of the study remains constant across variations in a number of those assumptions. The power with the run-in, with 22,071 good compliers was typically higher, and never more than negligibly lower, than the power without the run-in, with 33,223 good and poor compliers. In addition, savings from enrolling 11,152 fewer subjects in the trial resulted from the use of the run-in.

Aspirin↗
PubMed1991

Effect of fixation on the amplification of nucleic acids from paraffin-embedded material by the polymerase chain reaction.

Amplification of nucleic acids from paraffin-embedded material by the polymerase chain reaction (PCR) is increasingly being used to detect viral genomes and oncogene mutations. To determine the effect of fixation on the preservation of the nucleic acids, we fixed two randomly chosen fresh pathology specimens in formalin, B-5, Bouin's, Zenker's, ethanol, and Omnifix for 6, 24, 48, 72, and 168 hr (1 week), and then embedded the tissue in paraffin. Oligonucleotide primers specific for the cytoplasmic-beta-actin gene were chosen to span an intron such that amplification yielded a product of 250 BP for DNA and 154 BP for RNA. A single 6-microns section was cut from each paraffin block, deparaffinized, and then subjected to 30 rounds of amplification for either DNA or RNA. On amplifying DNA, consistent product was seen in the ethanol and Omnifix specimens up to 72 hr of fixation time, whereas variable product was seen with formalin or Zenker's fixation; all specimens fixed in Bouin's or B-5 were negative. On amplifying RNA, a product could be detected even after 1 week of fixation in ethanol or Omnifix, and after 48 hr in the formalin-fixed tissue. The Zenker's-fixed tissues gave variable results, and the Bouin's and B-5 tissues gave consistent results only after 6 hr of fixation. We therefore conclude that choice of fixative and fixation time are critical factors influencing the outcome of PCR amplification of nucleic acids from paraffin-embedded material.

Base Sequence↗
PubMed1991

Development of multipotential haemopoietic stem cells to neutrophils is associated with increased expression of receptors for granulocyte macrophage colony-stimulating factor: altered biological responses to GM-CSF during development.

Interleukin-3 (IL-3) dependent multipotent haemopoietic stem cells FDCP-Mix A4 (A4) were induced to differentiate and develop into mature neutrophils in response to Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) plus granulocyte CSF (G-CSF). This resulted in an increase in cell number over seven days of culture, following which the cells lost the ability to undergo further proliferation. The effect of GM-CSF on these cells has been assessed at various stages of development. Clonogenic cells, able to respond to GM-CSF, were generated only at days 3, 4 post-induction. From day 5 onwards, mature post-mitotic neutrophils are produced and clonogenic cells are lost. Loss of proliferative potential, in response to GM-CSF, was confirmed using [3H]-thymidine incorporation. Receptors for GM-CSF, were also measured during development using [125I]-GM-CSF binding assays. Although the dissociation constant for GM-CSF binding sites did not vary considerably, the number of such sites increased dramatically from about 20 (day 0, when the cells have a primitive morphology) to about 1000 by day 6 (when the cells are predominantly mature neutrophils). GM-CSF-stimulated Na+/H+ antiport activation was also determined. Although few GM-CSF receptors are expressed at day 0, there is a significant response (63% of maximal) to GM-CSF in terms of intracellular alkalinisation: this response increased markedly until, by day 4 (700 GM-CSF binding sites/cell), there is a maximal activation of the antiport by GM-CSF. By day 7 (greater than 900 GM-CSF binding sites/cell), however, there is significant reduction in activation of the Na+/H+ antiport by GM-CSF. Nonetheless, increased viability of these mature cells is still seen in response to GM-CSF. These results suggest that not only does expression of GM-CSF receptors alter during development of multipotential cells to mature neutrophils, but that these receptors are coupled to different intracellular effector mechanisms as the cells progressively mature.

Cell Differentiation↗
PubMed1990

Comparisons of plasma and salivary cortisol determinations for the diagnostic efficacy of the dexamethasone suppression test.

The current status of the saliva dexamethasone suppression test (DST) is discussed and results from the literature reviewed. Evidence is presented that demonstrates that the efficacy of the salivary-based test is equal to that of the plasma DST provided that specifically developed radioimmunoassays are used for determination of salivary cortisol. Such evidence relied on measurement of cortisol in 300 matched samples of plasma and saliva provided by patients admitted to a routine psychiatric ward over a 2-year period. The results according to diagnosis (DSM-III categories) were in line with those generally reported. The influence of anticholinergic medication was examined: this had no significant effects on the performance of the plasma or salivary-based DST.

Depressive Disorder↗
PubMed1990

Histopathological changes in simian immunodeficiency virus infection.

The histological lesions were studied in seven rhesus and three cynomolgus monkeys infected with simian immunodeficiency virus for periods ranging from nine weeks to 18 months. Lymphoreticular changes included hyperplasia, follicular involution and depletion, and one animal had amyloidosis of the spleen. Hyperplastic changes also took place in mucosa-associated lymphoid tissue and infiltrations occurred in the vaginal mucosa of one animal, which could be significant in sexual transmission of the infection. The range of opportunistic infections was small compared with that in human AIDS patients, although two monkeys had Pneumocystis carinii pneumonia. Enterocolitis was a common finding and brown adipose tissue was transformed into a large vacuolated type. Lesions of the central nervous system were found in five of nine monkeys, and consisted of foci of glial activity and perivascular and meningeal lymphocytic infiltration. A lymphoma involving the lumbar spinal cord developed in one animal.

Adipose Tissue, Brown↗
PubMed1990

Seasonal variation and the results of the dexamethasone suppression test.

There is controversy over the presence of a circannual rhythm in cortisol values in samples provided by depressed patients after a standard dexamethasone suppression test (DST). Post-DST cortisol values from patients admitted to an acute psychiatric ward over a 2-year period have therefore been analysed by appropriate statistical tests. No evidence was found for significant seasonal variation.

Depressive Disorder↗
PubMed1990

Information needs of patients and visitors in a district general hospital.

A survey of the information needs of patients and visitors to a large District General Hospital was conducted during a one-month period in 1988 to identify sources of information used by patients and their visitors, whether these sources were perceived as adequate and what improvements were suggested. The findings indicate that of 406 respondents, 37% had wanted to know more about a particular condition within the preceding 12 months. The most frequently used sources of information were general practitioners, hospital doctors and nurses, and written material. The most frequent inquires were about disease aetiology and prevention, and the treatment and prognosis of a wide range of medical conditions. Thirty-six per cent of the inquirers had received little or none of the information that they sought. Visitors were more likely than patients to be dissatisfied with presently available sources of information, and patients over 60 years old were more likely to be satisfied than younger groups. Dissatisified persons were most often seeking improved access to doctors and nurses, more explanations from these staff, and more readily available booklets and leaflets. The results are discussed in relation to previous findings with hospital in-patients. They support a stated need in the recent Government White Paper, Working For Patients, for patient information leaflets and for clear and sensitive explanations about what is happening to them in hospital.

Adolescent↗
PubMed1989

Identification of a common signal associated with cellular proliferation stimulated by four haemopoietic growth factors in a highly enriched population of granulocyte/macrophage colony-forming cells.

We have prepared a population of bone marrow cells that is highly enriched in neutrophil/macrophage progenitor cells (GM-CFC). Four distinct haemopoietic growth factors can stimulate the formation of mature cells from this population, although the proportions of neutrophils and/or macrophages produced varied depending on the growth factor employed: interleukin 3 (IL-3) and granulocyte/macrophage colony-stimulating factor (GM-CSF) stimulated the formation of colonies containing both neutrophils and macrophages; macrophage colony-stimulating factor (M-CSF) produced predominantly macrophage colonies; and granulocyte colony-stimulating factor (G-CSF) promoted neutrophil colony formation. Combinations of these four growth factors did not lead to any additive or synergistic effect on the number of colonies produced in clonal soft agar assays, indicating the presence of a common set of cells responsive to all four haemopoietic growth factors. These enriched progenitor cells therefore represent an ideal population to study myeloid growth-factor-stimulated survival, proliferation and development. Using this population we have examined the molecular signalling mechanisms associated with progenitor cell proliferation. We have shown that modulation of cyclic AMP levels has no apparent role in GM-CFC proliferation, whereas phorbol esters and/or Ca2+ ionophore can stimulate DNA synthesis, indicating a possible role for protein kinase C activation and increased cytosolic Ca2+ levels in the proliferation of these cells. The lack of ability of all four myeloid growth factors to mobilize intracellular Ca2+ infers that these effects are not achieved via inositol lipid hydrolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1989

The pharmacokinetics of low-dose dexamethasone in congenital adrenal hyperplasia.

The pharmacokinetics of dexamethasone, given at low dose, were studied in 13 patients with congenital adrenal hyperplasia (CAH) to ascertain whether kinetics differed in this inherited disorder of cortisol metabolism from those seen in healthy individuals. Changes in plasma dexamethasone concentration after intravenous bolus, measured using a simple novel radioimmunoassay, were well described by a two-compartment open model with first-order kinetics. Values for lambda 2: 0.206 h-1, t1/2: 3.53 h, Vc: 24.41 and f: 0.64 were similar to those previously reported for normal subjects. There were considerable interindividual differences in parameter values and Cmaxp.o. (range 22-67 nmol/l). As suppression of the hypothalamo-pituitary-adrenal axis correlates with plasma dexamethasone levels, this variability may partly explain the differing dose and dose schedule requirements necessary to achieve adequate therapeutic control in the clinical management of CAH.

Administration, Oral↗
PubMed1989

The effects of TGF beta on haemopoietic cells.

Transforming growth factor beta (TGF beta) suppresses the growth of differentiation inducible, murine IL-3-dependent multipotential cell lines but has no growth inhibitory effect upon an IL-3-independent (leukaemic) cell line arising from one of them, nor on IL-3-dependent cell lines that are unable to undergo differentiation. TGF beta inhibits in vitro colony formation by normal multipotential haemopoietic progenitor cells. Bipotential progenitors recruited by GM-CSF are, however, more resistant to the inhibitory effects of TGF beta, whereas progenitors recruited by the lineage restricted factor, M-CSF, are sensitive to the inhibitory effects. These data indicate that responsiveness to TGF beta is differentiation linked and studies with the cell lines suggest that response (or lack of response is not determined solely by levels of expression of TGF beta receptors. Furthermore, the effects of TGF beta 2 on haemopoietic progenitors are very similar to those induced by TGF beta.

Animals↗
PubMed1988

Anxiety and the dexamethasone suppression test monitored with saliva.

To assess the effect of anxiety on response to the Dexamethasone Suppression Test (DST), cortisol concentrations were determined in patients who had various diagnoses, with anxiety as a secondary characteristic. Saliva was collected before and after venepuncture at 4:05 PM following completion of the Leeds Questionnaire at 3:00 PM. Matrix effects, which caused an initial artefactual decrease in cortisol levels in some saliva samples in patients with high anxiety, could be eliminated by repeated freezing/thawing. There was no significant difference between salivary cortisol concentrations before and after venepuncture, indicating that variability in response to the DST is not a correlate of anxiety and stressful venepuncture. There was no association between anxiety scores and plasma or salivary cortisol values: thus, anxiety is unlikely to be a major contributory cause of nonsuppression of hypercortisolemia in the DST.

Adult↗
PubMed1988

Is the human platelet beta 2 adrenoceptor coupled to adenylate cyclase?

The presence of beta 2 adrenoceptors on the human platelet is well established although the coupling of this receptor to adenylate cyclase is disputed. In this study of highly purified platelets isoprenaline did not stimulate whole platelet cyclic AMP alone or in the presence of forskolin. Minimal contamination of the purified platelets (approximately 0.05%) with mononuclear white blood cells may lead to the spurious appearance of isoprenaline stimulated cAMP. These results confirm our previous findings of lack of coupling of the human platelet beta 2 adrenoceptor to adenylate cyclase and indicate the importance of purity of preparation for platelet biochemical studies.

Adenylyl Cyclases↗
PubMed1988

Performance of the dexamethasone suppression test in depressive illness according to ICD and DSM-III classification systems.

The performance of the dexamethasone suppression test was assessed in 90 consecutive admissions with a diagnosis of depression, categorised according to two classification systems (DSM-III and ICD-9). Non-suppression was found in most of the diagnostic categories, but there was a highly significant association with the DSM-III classification 'major depressive episode with melancholia' (52%) in comparison with the ICD group 'manic-depressive illness-depressed' (29%).

Adolescent↗
PubMed1988

Protein binding studies of technetium-99m-labeled phosphine and isocyanide cationic complexes.

Most 99mTc/phosphine/isocyanide complexes synthesized to date show preferential uptake by the myocardium of many animal species but not in man. A new complex has been synthesized, [99mTc(DEPE)2(CNR)2], +(DEPIC), where R = t - butyl isocyanide, which in three animal species images the myocardium very well, but in humans it remains primarily in the blood pool. One reason for the difference in the behavior of these complexes in different species could be the characteristics of their binding to plasma proteins. The protein binding characteristics of DEPIC and two other well-known complexes have therefore been studied. Whereas the other complexes bind nonspecifically to many proteins both in animal and human plasma, DEPIC binds almost exclusively to prealbumin in humans but nonspecifically to other proteins in the rabbit. The binding sites in human plasma appear to be those normally occupied by thyroxine on the prealbumin tetramer and these can be blocked by sodium salicylate.

Animals↗
PubMed1987

Butryic acid analogues augment gamma globin gene expression in neonatal erythroid progenitors.

The gamma----beta globin gene switch in humans is normally on a set developmental clock but is delayed in infants of diabetic mothers. We cultured cord blood erythroid progenitors and assayed globin produced in the presence and absence of metabolites that are elevated in such infants. Analogues of butyric acid at supranormal concentrations significantly augmented gamma and inhibited beta globin expression. The uptake of alpha-amino-n-butyric acid into colony-derived erythroblasts was increased in the presence of supranormal insulin. These findings suggest that elevated levels of alpha-amino-n-butyric acid and insulin in the developing fetus delay the globin switch and may offer potential for augmenting gamma globin expression in the beta globin chain diseases.

Butyrates↗
PubMed1987

Human platelet beta 2-adrenoceptors: agonist-induced internalisation and down-regulation in intact cells.

1. The effect of isoprenaline (10 microM at 37 degrees C for 30 min) pretreatment on [125I]-(-)-pindolol ([125I]-(-)-Pin) binding to beta 2-adrenoceptors on intact human platelets has been examined. 2. By use of saturation analysis, maximal binding capacity (Bmax) of [125I]-(-)-Pin binding in control and treated cells was assessed in the presence of 1 microM (-)-propranolol or 1 microM (+/-)-CGP 12177 which were taken to represent total or cell surface beta-adrenoceptors respectively. Assay incubations were performed at 37 degrees C and 4 degrees C, the latter to prevent recycling of internalised receptors. 3. Isoprenaline treatment resulted in an identical, highly significant, loss of binding sites (approximately equal to 25%) defined by (-)-propranolol at both assay temperatures as compared to control cells. Binding sites identified in the presence of (+/-)-CGP 12177 were reduced to a much greater extent (approximately equal to 70%), but this was only seen when assays were performed at 4 degrees C. 4. Agonist-induced changes in receptor numbers were concentration-dependent with half maximal receptor loss occurring at an isoprenaline concentration of approximately 2 x 10(-8) M. These effects were inhibited by the presence of a beta-adrenoceptor antagonist and absent if agonist pretreatment was performed at 4 degrees C. 5. Recovery experiments showed that the isoprenaline-induced reduction in total receptor number defined by (-)-propranolol was irreversible whereas the reduction in cell surface receptors defined by (+/-)-CGP 12177 was rapidly reversible (less than 40 min). 6. These data suggest that isoprenaline treatment of intact human platelets causes redistribution of beta 2-adrenoceptors. A proportion are sequestered away from the cell surface (internalised), becoming inaccessible to the hydrophilic ligand (+/-)-CGP 12177. A smaller proportion defined by (-)-propranolol are apparently totally lost from the cell (down regulated).

Adrenergic beta-Agonists↗