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Biomedical subjects

C Brown

Publications and source records attributed to C Brown.

At least 163 records · Page 9Linked to original sources
PubMed1998

Altered surfactant homeostasis and alveolar type II cell morphology in mice lacking surfactant protein D.

Surfactant protein D (SP-D) is one of two collectins found in the pulmonary alveolus. On the basis of homology with other collectins, potential functions for SP-D include roles in innate immunity and surfactant metabolism. The SP-D gene was disrupted in embryonic stem cells by homologous recombination to generate mice deficient in SP-D. Mice heterozygous for the mutant SP-D allele had SP-D concentrations that were approximately 50% wild type but no other obvious phenotypic abnormality. Mice totally deficient in SP-D were healthy to 7 months but had a progressive accumulation of surfactant lipids, SP-A, and SP-B in the alveolar space. By 8 weeks the alveolar phospholipid pool was 8-fold higher than wild-type littermates. There was also a 10-fold accumulation of alveolar macrophages in the null mice, and many macrophages were both multinucleated and foamy in appearance. Type II cells in the null mice were hyperplastic and contained giant lamellar bodies. These alterations in surfactant homeostasis were not associated with detectable changes in surfactant surface activity, postnatal respiratory function, or survival. The findings in the SP-D-deficient mice suggest a role for SP-D in surfactant homeostasis.

Animals↗
PubMed1998

Prevention of allogeneic fetal rejection by tryptophan catabolism.

In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.

Animals↗
PubMed1998

Randomised controlled trial of the READER method of critical appraisal in general practice.

OBJECTIVE: To evaluate the READER model for critical reading by comparing it with a free appraisal, and to explore what factors influence different components of the model. DESIGN: A randomised controlled trial in which two groups of general practitioners assessed three papers from the general practice section of the BMJ. SETTING: Northern Ireland. SUBJECTS: 243 general practitioners. MAIN OUTCOME MEASURES: Scores given using the READER model (Relevance, Education, Applicability, Discrimination, overall Evaluation) and scores given using a free appraisal for scientific quality and an overall total. RESULTS: The hierarchical order for the three papers was different for the two groups, according to the total scores. Participants using the READER method (intervention group) gave a significantly lower total score (P < or = 0.01) and a lower score for the scientific quality (P < or = 0.0001) for all three papers. Overall more than one in five (22%), and more men than women, read more than 5 articles a month (P < or = 0.05). Those who were trainers tended to read more articles (P < or = 0.05), and no trainers admitted to reading none. Overall, 58% (135/234) (68% (76/112) of the intervention group) believed that taking part in the exercise would encourage them to be more critical of published articles in the future (P < or = 0.01). CONCLUSION: Participants using the READER model gave a consistently lower overall score and applied a more appropriate appraisal to the methodology of the studies. The method was both accurate and repeatable. No intrinsic factors influenced the scores, so the model is appropriate for use by all general practitioners regardless of their seniority, location, teaching or training experience, and the number of articles they read regularly.

Education, Medical, Continuing↗
PubMed1998

Diagnosis and treatment of depression in primary medical care practice: the application of research findings to clinical practice.

Approximately 50% of persons experiencing clinical depression seek help for this disorder from their primary care physician. This pattern of help-seeking has stimulated interest in providing appropriate treatment for depressed primary medical care patients. While the efficacy of both psychotherapy and pharmacotherapy for depression have been demonstrated in the mental health specialty sector, current research endeavors to establish the effectiveness of such treatments when provided to primary medical care patients. We review and discuss the clinical, practical, and methodological issues pertaining to the transfer of depression research to routine primary care practice. Possible directions for future research which will inform the continued applicability of research findings to routine practice are discussed.

Delivery of Health Care↗
PubMed1998

Perseverative writing errors in a patient with Alzheimer's disease.

This study reports the writing performance of a dysgraphic patient with Alzheimer's disease and moderate dementia who frequently perseverated on strokes and letters. Letter formation errors were also frequently produced. Oral spelling was superior to written spelling. The habitual style of writing (cursive writing) was significantly more prone to perseverations than writing in uppercase letters, a form of writing less frequently used by the patient. Central (linguistic) spelling processes were relatively preserved. The pattern of preserved and impaired functions is consistent with impairment of the peripheral mechanism that generates the graphic motor patterns code. We suggest that damage to the peripheral orthographic mechanism may cause deficits in some patients with Alzheimer's disease.

Aged↗
PubMed1998

A phase II trial of intraperitoneal cisplatin and etoposide as consolidation therapy in patients with Stage II-IV epithelial ovarian cancer following negative surgical assessment.

PURPOSE: To determine the efficacy of three courses of intraperitoneal (i.p.) cisplatin (CDDP) and etoposide (VP-16) as consolidation therapy following pathologically negative second-look surgical reassessment for Stage IIC-IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Between September 1988 and April 1996, 40 patients were treated with three cycles of i.p. CDDP (100 mg/m2)/VP-16 (200 mg/m2) as consolidation therapy. Survival was compared to that of a group of 46 contemporaneous patients undergoing observation only. RESULTS: Median age of the 36 eligible patients was 52 years (range 30-70 years). Stage distribution was II (3), III (31), and IV (2); histologic grade was 1 (2), 2 (7), 3 (25), and not recorded (2); and residual disease at completion of initial surgery was none/microscopic in 13/36 (36%) patients. Median age of the 46 patients who did not receive consolidation was 52 years (range, 27-80 years); stage distribution was II (18), III (26), and IV (2); histologic grade was 1 (5), 2 (12), 3 (28), and not recorded (1). With a median follow-up of 36 months in both groups, 14/36 (39%) of the protocol group have recurred compared with 25/46 (54%) of those undergoing observation alone. Median disease-free survival (DFS) for the observed patients is 28.5 months and has not been reached in the consolidation group. Disease-free survival distribution between the two groups was compared using the log-rank test and was found to be significant (P = 0.03). Multivariate analysis revealed that the only significant predictor of improved DFS was protocol treatment (P < 0.01). CONCLUSION: Intraperitoneal consolidation with CDDP/VP-16 following negative second-look reassessment in patients with advanced EOC resulted in a significant increase in DFS compared to nonprotocol patients treated concurrently who underwent observation alone.

Adult↗
PubMed1998

Neoral induction in pediatric renal transplantation.

Neoral was instituted in pediatric renal transplant patients with the hypothesis it would have more predictable kinetics than Sandimmun. However, significant questions have arisen concerning potential toxicity and dosing interval related to its rapid absorption with subsequent high initial peak. This is compounded by the fact that children appear to metabolize cyclosporine at a greater rate than adults. This combination of a rapid peak and rapid absorption may then result in lower trough levels at 12 h. We compared the trough cyclosporine levels of nine children who received Neoral with nine who received Sandimmun at the time of initial transplantation. More frequent dosing (every 8 h) was required in the Neoral population compared with the Sandimmun population for the 1st month in order to obtain comparable trough levels. Beyond the initial 4-6 weeks, trough levels were similar for Neoral and Sandimmun. Whereas 1-month creatinine levels and blood pressures were similar, the number of blood pressure medications was significantly higher in the Neoral group. At 5.5 +/- 1.1 months' followup, a single patient in the current Neoral group and in the retrospective Sandimmun group each experienced a single OKT3 allograft-treated rejection. We suggest that the area under the curve is different in Neoral than Sandimmun, and the initial dosing frequency may need to be adjusted accordingly.

Blood Pressure↗
PubMed1998

Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission.

Sexually transmitted diseases, genital ulcer disease, and progesterone therapy increase susceptibility to lentivirus transmission. Infection of cells by human immunodeficiency virus (HIV) is dependent on expression of specific chemokine receptors known to function as HIV co-receptors. Quantitative kinetic reverse transcription-polymerase chain reaction was developed to determine the in vivo expression levels of CCR5, CXCR4, CCR3, CCR2b, and the cytomegalovirus-encoded US28 in peripheral blood mononuclear cells and cervical biopsies from 12 women with and without sexually transmitted diseases, genital ulcer disease, and progesterone-predominant conditions. Our data indicate that CCR5 is the major HIV co-receptor expressed in the female genital tract, and CXCR4 is the predominantly expressed HIV co-receptor in peripheral blood. CCR5 mRNA expression in the ectocervix was 10-fold greater than CXCR4, 20-fold greater than CCR2b, and 100-fold greater than CCR3. In peripheral blood, CXCR4 expression was 1.5-fold greater than CCR5, 10-fold greater than CCR2b, and 15-fold greater than CCR3. US28 was not expressed in cervical tissue despite expression in peripheral blood mononuclear cells from five individuals. CCR5 was significantly increased (p < 0.02) in biopsies from women with sexually transmitted diseases and others who were progesterone predominant. In vitro studies demonstrate that progesterone increases CCR5, CXCR4, and CCR3 expression and decreases CCR2b expression in lymphocytes and monocytes/macrophages. Characterization of chemokine receptors at the tissue level provides important information in identifying host determinants of HIV-1 transmission.

Adult↗
PubMed1998

Thoracoscopic anterior spinal procedures in children.

METHODS: From February 1996 through July 1997, 20 patients were determined to be appropriate for a thoracoscopic approach for the anterior portion of their spinal surgery. Ages ranged from 8 to 17 years of age and weight from 20 to 70 kg. The diagnosis included severe idiopathic and neurogenic scoliosis or kyphosis (n = 20) and congenital hemivertebra (n = 4). The procedures performed included diskectomy and anterior release from two to nine vertebral levels, hemivertebrectomy, and epiphysiodesis. Four patients also had an open lumbar exposure and all had a posterior fusion. RESULTS: All procedures were completed successfully endoscopically. Surgical times for the thoracoscopic portion of the procedure averaged 106 minutes and total procedure times were comparable with the standard open technique. Three patients were extubated at the end of the procedure with the majority extubated on postoperative day 1. Average intensive care unit stay was 1.8 days, and chest tubes were removed between postoperative day 1 and 5 (average, 2.2 days). In follow-up, surgical correction was deemed to be acceptable and equivalent to open techniques in all cases. CONCLUSION: This technique has proven to be safe and effective in children and appears to be associated with less pain and morbidity as evidenced by earlier extubation and chest tube removal and shorter ICU stay.

Adolescent↗
PubMed1998

Understanding ambiguous words in sentence contexts: electrophysiological evidence for delayed contextual selection in Broca's aphasia.

This study investigates whether spoken sentence comprehension deficits in Broca's aphasics results from their inability to access the subordinate meaning of ambiguous words (e.g. bank), or alternatively, from a delay in their selection of the contextually appropriate meaning. Twelve Broca's aphasics and twelve elderly controls were presented with lexical ambiguities in three context conditions, each followed by the same target words. In the concordant condition, the sentence context biased the meaning of the sentence-final ambiguous word that was related to the target. In the discordant condition, the sentence context biased the meaning of the sentence-final ambiguous word that was incompatible with the target. In the unrelated condition, the sentence-final word was unambiguous and unrelated to the target. The task of the subjects was to listen attentively to the stimuli. The activational status of the ambiguous sentence-final words was inferred from the amplitude of the N400 to the targets at two inter-stimulus intervals (ISIs) (100 ms and 1250 ms). At the short ISI, the Broca's aphasics showed clear evidence of activation of the subordinate meaning. In contrast to elderly controls, however, the Broca's aphasics were not successful at selecting the appropriate meaning of the ambiguity in the short ISI version of the experiment. But at the long ISI, in accordance with the performance of the elderly controls, the patients were able to successfully complete the contextual selection process. These results indicate that Broca's aphasics are delayed in the process of contextual selection. It is argued that this finding of delayed selection is compatible with the idea that comprehension deficits in Broca's aphasia result from a delay in the process of integrating lexical information.

Aged↗
PubMed1998

A crystallographic and molecular modeling study of butyrophenones.

The X-ray crystal structures of four butyrophenone analogues have been completed and are reported herein. These include spiperone hydrochloride (I), N-methylspiperone hydrochloride (II), pimozide (III), and fluspirilene (IV). These structures were compared to other structurally similar molecules with similar pharmacological activity. In addition, a molecular modeling study was done in order to determine the low energy conformations of these molecules. It was found that calculations of parameters that describe the molecular conformations showed that all four molecules were structurally similar. Crystallographic data: [see text]

Butyrophenones↗
PubMed1998

The National Heart Attack Alert Program: Progress at 5 Years in Educating Providers, Patients, and the Public and Future Directions.

The National Heart Attack Alert Program (NHAAP) was launched by the National Heart, Lung, and Blood Institute in 1991 with the goal of reducing morbidity and mortality from acute myocardial infarction (AMI) through the rapid identification and treatment of individuals with symptoms and signs of an AMI. To achieve this goal, the NHAAP established objectives for each of three phases of action where treatment delays can occur: in the hospital, the prehospital setting, and the patient/bystander arena. The NHAAP initially directed its educational efforts toward emergency department professionals. Recommendations for reducing delays in emergency department identification of patients presenting with heart attack symptoms were developed by a working group convened in late 1991. These recommendations were published in February 1994 in a peer-reviewed journal reaching more than 17,000 emergency physicians. The NHAAP worked in a partnership with its coordinating committee, representing 40 health professional, voluntary, and government organizations, to extend the reach of the report's recommendations to their members. Strategies for promoting the emergency department recommendations included publication of excerpts in newsletters and journals of the medical, nursing, and prehospital provider organizations represented on the NHAAP Coordinating Committee, and through symposia at annual meetings. Industry assisted with dissemination efforts and with implementing a continuous quality improvement program based on the paper's recommendations. The NHAAP also developed, with the Joint Committee on Accreditation of Health Care Organizations, a time-to-treatment indicator for thrombolytic therapy to be incorporated into their Indicator Measurement System (IMSystem). To track achievement of the objectives related to the Hospital Action Phase, national data sources for emergency department management of patients with AMI were evaluated at the 5-year point of the NHAAP. Data from a national registry showed that the median time from presentation at the emergency department to receiving thrombolytic therapy declined by about one third between 1992 and the last half of 1995. The percentage of all Medicare patients receiving thrombolytic therapy within the recommended 30 minutes after emergency department arrival nearly doubled between 1992 and 1995. Based on these and other results presented at the 5-year juncture of the program, the NHAAP Coordinating Committee assessed progress and identified new areas of focus for the next 5 years. Improvements in emergency departments' ability to identify and treat AMI patients progressed during the first 5 years of the NHAAP, when the program was highlighting this as a priority. This model is continuing to be used to address delays in the Prehospital Action Phase. Further research from a National Heart, Lung, and Blood Institute (NHLBI) community intervention trial will guide the program in its plans for full-scale public education to address the Patient/Bystander Recognition and Action Phase.

Journal Article↗
PubMed1998

Analysis of membrane protein cluster densities and sizes in situ by image correlation spectroscopy.

Communication between cells invariably involves interactions of a signalling molecule with a receptor at the surface of the cell. Typically, the receptor is imbedded in the membrane and it is hypothesized that the binding of the signalling molecule causes a change in the state of aggregation of the receptor which, in turn, initiates a biochemical signal within the cell. Subsequently, many of the occupied receptors bind to membrane-associated structures, called coated pits, which invaginate and pinch off to form coated vesicles, thereby removing the receptors from the cell surface. The state of aggregation of membrane receptors is obviously in constant flux. Any useful approach to measuring the state of aggregation must, therefore, allow for dynamic measurements in living cells. It is possible to use fluorescently labelled signalling molecules or antibodies directed at the receptor of interest to visualize the receptor on the cell surface with a fluorescence microscope. By employing a laser confocal microscope, high resolution images can be produced in which the fluorescence intensity is quantitatively imaged as a function of position across the surface of the cell. Calculations of autocorrelation functions of these images provide direct and accurate measures of the density of fluorescent particles on the surface. Combined with the average intensity in the image, which reflects the total average number of molecules, it is possible to estimate the degree of aggregation of the receptor molecules. We refer to this analysis as image correlation spectroscopy (ICS). We show how ICS can be used to measure the density of several receptors on a variety of cells and how it can be used to measure the density of coated pits and the number of molecules per coated pit. We also show how the technique can be used to monitor fusion of virus particles to cell membranes. Further, we illustrate that, by calculating cross-correlation functions between pairs of images, we can extend the analysis to measurements of the distributions as a function of time, on the second timescale, as well as to measurements of the movement of the receptor aggregates on the surface. Finally, we illustrate that, by this approach, we can measure the extent of interaction between two different receptors as a function of time. This represents the most quantitative measurement of the extent of co-localization of receptors available and is independent of the spatial resolution of the confocal microscope. The theory of ICS and image cross-correlation spectroscopy (ICCS), focussing on the interpretation of the data in terms of the biological phenomenon being probed, is discussed.

Animals↗