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Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 325 records · Page 18Linked to original sources
PubMed1995

Mechanisms of acquired resistance to the quinazoline thymidylate synthase inhibitor ZD1694 (Tomudex) in one mouse and three human cell lines.

Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in thymidylate synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation.

Animals↗
PubMed1995

The relationship of strength to function in the older adult.

Reduced lower extremity strength has been associated with reduction in gait speed, balance, stair-climbing ability, and getting up from a seated position. The relationship of lower extremity strength and the ability to accomplish selected functional activities was examined in 16 healthy but frail older adults ranging in age from 75 to 88 years (mean = 80.9 years). The following measures were obtained for each subject: preferred gait speed under laboratory and free walking conditions, 5 timed chair stand-ups, and time to complete an obstacle course. Strength measures of the hip extensors, hip abductors, knee extensors, planter flexors, and dorsiflexor muscle groups were obtained using a hand-held dynamometer. The relationship between the time to complete the functional activities and each of the strength variables was determined using Pearson product moment correlations. In addition, performance was examined in relation to various combinations of strength measures (e.g., hip and knee extension). Weak, nonsignificant hip, knee and ankle strength/functional activity relationships were found for all of the variables examined. When hip extension, knee extension, and ankle plantar flexion strength values were combined and normalized to body weight, a significant strength-to-functional activity relationship was found for 14" chair stand-ups (r = .636, p < .01). When values for quadriceps strength and gait speed for 35 adults ranging in age from 60-72 years were compared to those for 75-88 year olds, marked differences emerged. A more significant relationship between knee extension force and gait speed was observed for the younger adults (r = .528 vs r = .353).(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Daily Living↗
PubMed1995

The effect of training on equine metacarpal bone breaking strength.

Right third metacarpal bones (n = 24) from Thoroughbreds, 24 to 48 months old and in race training, were tested to failure in 3 point bending. The neutral load axis was estimated and the distance from the axis to the outer dorsal cortical surface measured. Mid-diaphyseal dorsopalmar and lateromedial outer cortical and medullary diameters were measured. Breaking strength, cortical area and area moment of inertia were also calculated. Significant correlations were demonstrated between months in training and dorsopalmar bone diameter, cortical area and area moment of inertia. Significant linear models were illustrated between the same 3 variables and number of months in training. It was concluded that increased duration of training significantly enlarges dorsopalmar bone diameter, cortical area and area moment of inertia. Training did not affect metacarpal bone breaking strength as determined by 3 point bending.

Age Factors↗
PubMed1995

Molecular studies on kinin receptors.

We describe the results of functional studies on DNA clones encoding functional bradykinin receptors derived from human, rat, and mouse sources and including both genomic and complementary DNA clones. In both the Xenopus oocyte and the COS cell expression systems, the receptors from human and rat showed the pharmacological properties of B2 receptors, but receptors from mouse displayed both B1- and B2-like pharmacological properties. We further investigated the molecular relationship between the B1 and B2 receptor subtypes expressed by a human fibroblast cell line, and we demonstrate that these two receptor subtypes are encoded by distinct mRNA species.

Amino Acid Sequence↗
PubMed1995

On the functional equivalence of fuzzy inference systems and spline-based networks.

The conditions under which spline-based networks are functionally equivalent to the Takagi-Sugeno-model of fuzzy inference are formally established. We consider a generalized form of basis function network whose basis functions are splines. The result admits a wide range of fuzzy membership functions which are commonly encountered in fuzzy systems design. We use the theoretical background of functional equivalence to develop a hybrid fuzzy-spline net for inverse dynamic modeling of a hydraulically driven robot manipulator.

Fuzzy Logic↗
PubMed1995

A perspective and critique of adaptive neurofuzzy systems used for modelling and control applications.

This paper outlines some of the theoretical and practical developments being made in neurofuzzy systems. As the name suggests, neurofuzzy networks were developed by fusing the ideas that originated in the fields of neural and fuzzy systems. A neurofuzzy network attempts to combine the transparent, linguistic, symbolic representation associated with fuzzy logic with the architecture and learning rules commonly used in neural networks. These hybrid structures have both a qualitative and a quantitative interpretation and can overcome some of the difficulties associated with solely neural algorithms which can usually be regarded as black box mappings, and with fuzzy systems where few modelling and learning theories existed. Both B-spline and Gaussian Radial Basis Function networks can be regarded as neurofuzzy systems and soft inductive learning algorithms can be used to extract unknown, qualitative information about the relationships contained in the training data. In a similar manner, qualitative rules or information about the network's structure can be used to initialise the system. These areas, coupled with the extensive work being carried out on theoretically analysing their modelling, convergence and stability properties means that this research topic is highly applicable in "intelligent" modelling and control problems. Apart from outlining this work, the paper also discusses a wide variety of open research questions and suggests areas where new efforts may be fruitfully applied.

Algorithms↗
PubMed1995

Rat aortic vasoreactivity is altered by old age and hindlimb unloading.

Prolonged bed rest in young adults leads to a number of cardiovascular alterations, including orthostatic intolerance and decreased exercise capacity. Similar changes occur with advanced age. These modifications of cardiovascular function have been suggested to be causally related to changes in peripheral vascular reactivity. Using rat hindlimb unloading as an animal model of physical inactivity, this study was designed to determine whether prolonged decreases in weight-bearing activity induce changes in vascular reactivity that are similar to those occurring in senescent rats and whether the imposition of inactivity on old rats further modifies any age-related alterations in vasomotor responsiveness. Responses to vasoactive compounds were examined in vitro by using isolated abdominal aortic rings. Maximal isometric contractile force evoked by the vasoconstrictors KCl, norepinephrine (NE), and arginine vasopressin was lower in aortic segments from young hindlimb-unloaded (YHU), old control (OC), and old hindlimb-unloaded (OHU) rats compared with that from young control (YC) rats. Sensitivity [mean effective concentration (EC50)] to KCl was enhanced in segments from both old and unloaded animals compared with YC rats, but EC50 values for the other constrictors were not different among groups. Vasorelaxation responses induced by acetylcholine (10(-7) M NE preconstriction) were lower in vessel rings from OC (1 x 10(-7) to 3 x 10(-6) M), YHU (10(-7) to 10(-5) M), and OHU (10(-7) to 10(-5) M) rats than those from YC animals. In addition, vessel rings from OC, YHU, and OHU rats were less sensitive to sodium nitroprusside-induced relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Dietary sodium intake modulates vasodilation mediated by nitroprusside but not by methacholine in the human forearm.

Studies in animals suggest that nitric oxide production is increased under conditions of salt loading and that this increase protects against the development of salt-induced hypertension. To determine the effect of dietary sodium intake on nitric oxide-mediated vascular responses, we studied seven healthy male volunteers twice 4 weeks apart while they were receiving a diet containing 10 or 250 mmol Na+ per 24 hours. Methacholine (0.25 to 8 micrograms/min) and sodium nitroprusside (0.25 to 8 micrograms/min) were infused intra-arterially in incremental doses, and forearm blood flow was measured. The response of forearm blood flow to sodium nitroprusside was greater when subjects received a high sodium diet than when they received a low sodium diet (F = 7.11, P < .05); however, the response to methacholine was not altered by sodium intake (F = 0.57, P = NS). Plasma renin activity was significantly higher (3.99 versus 1.0 ng angiotensin I/mL per hour) when subjects received a low salt diet (P < .05). Systolic pressure, diastolic pressure, heart rate, and baseline forearm blood flow were not affected by sodium status. We conclude that under conditions of salt loading, vasodilation in response to sodium nitroprusside was enhanced, whereas the response to methacholine was not affected, suggesting a differential effect of sodium intake on endothelium-dependent and endothelium-independent responses after the administration of methacholine and sodium nitroprusside, respectively.

Adult↗
PubMed1995

Nine suicide pacts. A clinical study of a consecutive series 1974-93.

BACKGROUND: Suicide pacts are rarely discussed in the medical literature. We report here the medical and social aspects of a consecutive series of double or pact suicides. METHOD: Coroners' records were examined for 722 consecutive suicides. Data were extracted from them and from medical and psychiatric records. RESULTS: Nine pacts (2.5% of suicides) were located: 11 of the 18 people appeared to have been mentally ill at the time of death and three more had a history of mental illness. Five had a significant medical history (three cancer). CONCLUSIONS: Mental disorder is common in those who enter suicide pacts (mainly depression, with alcohol dependence rare). Motivations for suicide appear to be relief of mental disorder and pain.

Adult↗
PubMed1995

The use of patient symptoms to screen for serious back problems.

Even when a patient is referred by a physician, the physical therapist must remain alert to the possibility that the patient may require medical care outside the realm of physical therapy. Physical therapists must be able to screen low back pain patients to identify those who have serious low back problems which require additional diagnostic evaluation and treatment by a physician. It is important for physical therapists to know which symptoms and signs or combination of symptoms and signs best indicate the likelihood of a serious problem. The purpose of this study was to test the sensitivity and specificity of low back pain symptoms in distinguishing individuals with a benign low back problem from those requiring surgical or medical intervention. Demographic and clinical data were collected retrospectively from a standardized low back pain questionnaire located in the medical records of 174 low back pain patients. Patients were classified as having a benign low back problem (N = 41) or a serious low back problem (N = 133) based on surgical findings or long term follow-up. Some individual symptoms had high specificity, but none had high sensitivity. To improve sensitivity while attempting to maintain moderate specificity, a number of symptoms were considered in parallel. The highest combination of sensitivity (.87) and specificity (.50) was obtained by combining in parallel the symptoms of unable to sleep, awakened and unable to fall back to sleep, medication required to sleep, and pain worsened by walking.

Adult↗
PubMed1995

Power and new economic relationships.

We are going through a transformation of our health services from a community and patient focus fueled by fee-for-service and cost-plus reimbursement. This transformation, called managed care, is shifting power away from professionals and communities into both new and old organizations financed by Wall Street. Even traditional community organizations are driven by Wall Street-dictated financial ratios that represent scoreboards to determine who gets capital for growth and development. Times are changing, organizations are changing, and still more change is ahead.

Cost-Benefit Analysis↗
PubMed1995

Quinazoline thymidylate synthase inhibitors: methods for assessing the contribution of polyglutamation to their in vitro activity.

Many quinazoline thymidylate synthase (TS) inhibitors undergo intracellular metabolism to polyglutamate forms which can significantly alter their activity and pharmacodynamics through improved TS inhibition and drug retention. When a series of quinazolines was tested for inhibitory activity towards TS (IC50 0.001-2 microM) and the growth of L1210 cells (IC50 0.005-10 microM), no direct correlation was observed. However, a very good correlation was apparent if a L1210 variant cell line (L1210: RD1694) was used. This line is deficient in its ability to form antifolate polyglutamates. A number of other intact cell methods have also been developed which estimate the contribution that intracellular polyglutamation makes to a compound's activity. These assays were validated using a series of quinazoline-based TS inhibitors with well-defined activity for TS, folypolyglutamate synthetase (FPGS) and the reduced-folate cell membrane carrier (RFC). Short-exposure growth-inhibition assays or the measurement of TS activity in situ after various incubation times, followed by different lengths of time in drug-free medium, can indicate both the speed and extent of appearance of retentive forms (usually polyglutamates). Continuous-exposure growth-inhibition assays, in the presence of leucovorin (LV), are also useful, since only the growth-inhibitory potency of polyglutamated analogues is significantly decreased by LV. Highly polyglutamated compounds, e.g. ZD1694, are virtually inactive in the presence of a high concentration of LV. It is proposed that these methods, when considered together, provide a greater degree of information concerning the rate and extent of polyglutamation of a particular compound than isolated FPGS assays alone.

Animals↗