Biomedical subjects

M J Forster

Publications and source records attributed to M J Forster.

At least 37 records · Page 2Linked to original sources

PubMed1994

Acromegaly. Clinical and biochemical features in 500 patients.

This prospective study defines the clinical and biochemical features of acromegaly in a large cohort of patients. There was no difference in sex distribution, and for men and women the mean ages at diagnosis (40 +/- 12 and 40 +/- 14 yr, respectively) were similar. Nearly three-quarters of patients were overweight and some 12% severely overweight; the frequency and severity of obesity also was not different between the sexes. Half of patients were hypertensive or were taking anti-hypertensive drugs. Neither GH nor insulin levels were significantly different between normotensive and hypertensive patients. Acral growth and facial coarsening, soft tissue swelling, and excessive perspiration were present in the majority (98%) of patients. Mean serum GH, Sm-C, and PRL levels did not differ between the sexes. Sm-C levels correlated with mean GH concentration (r = 0.31, p < 0.001), both variables inversely related to age. With each decade of life, mean GH and Sm-C levels declined by 7.6 +/- 0.2 ng/mL and 0.5 +/- 0.2 U/mL, respectively. Impaired glucose tolerance was diagnosed in 36% and frank diabetes mellitus in 30% of patients. Hyperprolactinemia was noted in 18% of patients. Galactorrhea was noted in 43 (9%) patients, most of whom were female; the mean GH levels of patients with galactorrhea (60.1 +/- 13 ng/mL) were higher than those of patients without (35.4 +/- 2.6 ng/mL, p = 0.02). Acromegaly appears to afflict men and women equally with a preponderance of presentation in the fourth decade of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1993

N.m.r. and molecular-modelling studies of the solution conformation of heparin.

The solution conformations of heparin and de-N-sulphated, re-N-acetylated heparin have been determined by a combination of n.m.r. spectroscopic and molecular-modelling techniques. The 1H- and 13C-n.m.r. spectra of these polysaccharides have been assigned. Observed 1H-1H nuclear Overhauser enhancements (n.O.e.s) have been simulated using the program NOEMOL [Forster, Jones and Mulloy (1989) J. Mol. Graph. 7, 196-201] for molecular models derived from conformational-energy calculations; correlation times for the simulations were chosen to fit experimentally determined 13C spin-lattice relaxation times. In order to achieve good agreement between calculated and observed 1H-1H n.O.e.s it was necessary to assume that the reorientational motion of the polysaccharide molecules was not isotropic, but was that of a symmetric top. The resulting model of heparin in solution is similar to that determined in the fibrous state by X-ray-diffraction techniques [Nieduszynski, Gardner and Atkins (1977) Am. Chem. Soc. Symp. Ser. 48, 73-80].

Carbon Isotopes↗

PubMed1992

Learning and memory-enhancing effects of Ro 15-4513: a comparison with flumazenil.

Synthetic benzodiazepines produce an anterograde amnesia, which can be reversed by selective benzodiazepine antagonists or inverse agonists. It has therefore been suggested that the memory-enhancing effects of the antagonists are due to antagonism of an endogenous "benzodiazepine-like" endocoid. If the memory-enhancing effects of the benzodiazepine antagonists are determined predominantly by the antagonism of such endogenous benzodiazepine-ligands, then it could be hypothesized that administration of an inverse agonist, which produces effects functionally opposite to those of benzodiazepine agonists, may also mimic the effects of benzodiazepine antagonists but not produce effects greater than those of the pure antagonists. The purpose of the present study was therefore to investigate the memory-enhancing effects of the benzodiazepine inverse agonist, ethyl-8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5a] [1,4] benzodiazepine-3-carboxylate (Ro 15-4513) in young HSD:(ICR)BR mice and to compare these effects with those of the benzodiazepine antagonist, flumazenil. Pretraining injections of flumazenil and Ro 15-4513 (2.5 and 10.0 mg/kg) enhanced equally, both the acquisition and the retention of a task for 1 week requiring mice to discriminate the correct arm of a T-maze, to avoid a mild electric shock. Pretreatment with Ro 15-4513 also dose-dependently protected the animals from experimental amnesia, induced by the cholinergic receptor antagonist, scopolamine in a second model of memory, in which mice were required to passively avoid a dark chamber after shock. In contrast, Ro 15-4513, injected prior to daily active avoidance sessions, failed to significantly improve either the acquisition or retention performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Amnesia↗

PubMed1991

N.m.r. and conformational analysis of the capsular polysaccharide from Streptococcus pneumoniae type 4.

The 1H- and 13C-n.m.r. data on the capsular polysaccharide (1) produced by Streptococcus pneumoniae type 4, the depyruvated polysaccharide (2), and a tetrasaccharide (3a) derived by Smith degradation of 2 were used as constraints on a computer-generated model of the conformation of 1 and to assess the effects of the pyruvic acetal substituent on the conformation. The dynamics of the polysaccharide systems and the influence of the pyruvic acetal were investigated using 13C-n.m.r. relaxation measurements.

Amides↗

PubMed1991

Neurobehavioral biomarkers of aging: influence of genotype and dietary restriction.

Because of the importance of central nervous system (CNS) functions to productive capacity and quality of life, biomarkers of these functions will play a key role in evaluating the success of interventions targeting aging processes. The CNS biomarkers may also be useful for predicting aging in other systems and in the organism as a whole. Age-related behavioral changes, the products of CNS aging, have content and predictive validity with respect to human functional capacities and may, therefore, represent important "neurobehavioral" markers of functional aging. This article presents a discussion of some behavioral paradigms which are currently being considered as neurobehavioral biomarkers of aging in mice and the experimental approaches being employed in the assessment of their validity. Studies conducted in the authors' laboratory using dietary restriction and genetic comparisons to evaluate the validity of neurobehavioral biomarkers have revealed several methodological concerns, and hypothetical and empirical examples of these pitfalls are described and discussed. In spite of those concerns, it is concluded that approaches to validity using genetic comparisons and dietary restriction can be successfully implemented and should ultimately lead to identification of valid and useful neurobehavioral biomarkers of aging.

Aging↗

PubMed1990

Flumazenil improves active avoidance performance in aging NZB/BlNJ and C57BL/6NNia mice.

C57BL/6NNia and autoimmune NZB/BlNJ mice aged 12-14 months were tested for acquisition and retention of an active avoidance response following vehicle or flumazenil (40 mg/kg), a benzodiazepine antagonist. Acquisition and retention performance was improved in flumazenil-treated mice when compared with vehicle-treated mice, although the degree of improvement varied with the level of performance in vehicle-treated mice of each strain. The NZB/BlNJ mice, which generally performed more poorly than the C57BL/6NNia mice, showed the greater improvements following flumazenil. These results suggest that antagonism of benzodiazepine receptors leads to improved learning and/or memory performance in mice with spontaneous age-associated deficits.

Aging↗

PubMed1990

Animal models of age-related dementia: neurobehavioral dysfunctions in autoimmune mice.

The development of strategies for treatment of Alzheimer's disease and other age-associated dementias is an important goal of research in the neurosciences. It is suggested that advances in understanding of the etiology of those disorders would provide the most obvious avenues to development of preventative treatments. Research findings from both clinical investigations and studies of animal models are presented which suggest a neuroimmunologic component in age-associated dementia. Clinical studies suggest an association between dementia and brain-reactive autoantibodies in subsets of patients with Alzheimer's disease. Studies of mice suggest that: 1) when compared with normal genotypes, mutant mice with accelerated autoimmunity show learning and memory impairments at earlier chronological ages; 2) the learning and memory deficits of autoimmune and normal mice are qualitatively similar; 3) the behavioral deficits of normal aged and autoimmune mice are sensitive to similar pharmacologic interventions. Overall, these findings suggest that intervention strategies targeting the immune system might be useful in the treatment or prevention of aging-associated dementia. Autoimmune mice would be useful as models for the development and testing of such immune-based interventions.

Animals↗

PubMed1990

Cholinergic modulation of aged-like retention deficits in young autoimmune mice.

Separate age groups of autoimmune NZB/BINJ and non-autoimmune C57BL/BNNia mice were compared for habituation of locomotor activity and its retention over four separate testing sessions spaced at 24-hr intervals. A decline in locomotion (distance in cm) or in the time spent in the center zone as a function of sessions was taken to indicate retention for habituation to stimuli within the test apparatus. The time spent in the center zone decreased as a function of sessions in young and mature C57BL/6NNia mice but failed to show reliable between-session decreases in old (24-26-months) C57BL/6NNia mice. When compared with the old C57BL/6NNia mice, young NZB/BINJ mice showed similar impairments. Habituation of locomotion was present in all age groups of C57BL/6NNia mice, but absent in NZB/BINJ mice regardless of age. The retention impairments of 2-4 month old NZB/BINJ mice were attenuated when i.p. injections of 0.04-0.16 mg physostigmine/kg were given just following each habituation session. The effectiveness of physostigmine was substantially reduced when injections were delayed by 20 min or longer following each habituation session. The time-dependent reversal of the aged-like retention deficits by the cholinesterase inhibitor, physostigmine, suggests that cholinergic modulation of memory storage processes may be impaired in NZB/BINJ mice.

Aging↗

PubMed1989

Determination of internal dynamics of deoxyriboses in the DNA hexamer d(CGTACG)2 by 1H NMR.

The conformations and internal dynamics of the deoxyriboses of d(CGTACG)2 have been determined by NMR measurements at 15 degrees C. The conformations of the sugars were determined using coupling constants and time-dependent NOE measurements. The J-splitting patterns of the H1', H2' and H2" resonances show that the sugars exist as mixtures of conformations near C2' endo (south) and C3' endo (north). The population of the south conformation was larger for the purines than for the pyrimidines. The overall tumbling time of the molecule in 2H2O was determined from measurements of the cross relaxation rate constant for the H6-H5 vectors of the two cytosine residues. Order parameters were determined for the H1'-H2", H2'-H2" and H2'-H3' vectors from measurements of cross relaxation rate constants, making use of multi-spin analysis of the NOE build up rates. These order parameters are weakly dependent of the base sequence, and except for the terminal Cyt 1 residue, the H2'-H2" and H2'-H3' vectors are near unity, indicating the absence of rapid pseudorotation on the nanosecond time scale. However, the order parameter for the H1'-H2" vector is significantly smaller than expected for rapid pseudorotation indicating the presence of other motions of the sugars. This motion must be about an effective axis parallel to the H2'-H2" vector, and to occur with an angular fluctuation of about 30 degrees. The results show that to obtain highly refined structures for nucleic acids by NMR the effects of spin diffusion and motional averaging cannot be ignored.

Base Sequence↗

PubMed1988

CGS 8216, a benzodiazepine receptor antagonist, enhances learning and memory in mice.

Mice pretreated with the benzodiazepine antagonist, CGS 8216 (2.5, 10, or 40 mg/kg, i.p.) learned a T-maze discrimination to a fixed performance criterion more rapidly than vehicle-treated mice. In retention tests conducted one week later, the drug-treated groups had better first-trial recall and greater difficulty reversing the previously trained maze habit when compared with controls, suggesting improved memory for the previously trained maze habit. The enhanced acquisition and retention following CGS 8216 was similar to that observed previously with another benzodiazepine antagonist, flumazenil (Ro 15-1788). It is postulated that CGS 8216 and flumazenil could act at benzodiazepine receptors to antagonize a tonic inhibitory influence of endogenous, diazepam-like, benzodiazepine receptor ligands on memory processes.

Animals↗

PubMed1988

Age differences in acquisition and retention of one-way avoidance learning in C57BL/6NNia and autoimmune mice.

Acquisition and 48-h retention of a step-up active avoidance response were studied in separate age groups of C57BL/6NNia mice (aged 1.5, 3.5, 6, 12, or 26 months) and five strains of genetically autoimmune mice differing in life span. The C57BL/6NNia mice showed no change in ability to acquire the avoidance response between 1.5 and 3.5 months, but showed a steady decline in that ability thereafter. Mouse strains with early-onset autoimmune disorder (NZB/B1NJ, MRL/MpJ-lpr, and BXSB/MpJ) showed declines in acquisition capability between 1.5 and 3.5 months of age, whereas mouse strains with mild, late-onset autoimmune disorder (MRL/MpJ- + and NZBWF1/J) showed stable or improved acquisition during that period. Both the C57BL/6NNia and NZB/B1NJ mice showed age-dependent declines in 48-h retention performance by 12 months of age. These findings suggested that while 48-h retention performance deficits were most related to chronological age, avoidance acquisition deficits were related to development of autoimmunity.

Aging↗

PubMed1988

Dynamics of trimethoprim bound to dihydrofolate reductase.

The conformation of a small molecule in its binding site on a protein is a major factor in the specificity of the interaction between them. In this paper, we report the use of 1H and 13C NMR spectroscopy to study the fluctuations in conformation of the anti-bacterial drug trimethoprim when it is bound to its "target," dihydrofolate reductase. 13C relaxation measurements reveal dihedral angle changes of +/- 25 degrees to +/- 35 degrees on the subnanosecond time scale, while 13C line-shape analysis demonstrates dihedral angle changes of at least +/- 65 degrees on the millisecond time scale. 1H NMR shows that a specific hydrogen bond between the inhibitor and enzyme, which is believed to make an important contribution to binding, makes and breaks rapidly at room temperature.

Binding Sites↗

PubMed1988

Enhancement of learning and memory in mice by a benzodiazepine antagonist.

Benzodiazepines, a class of drugs widely employed as anxiolytics and anticonvulsants, can induce impairments of learning and memory. The purpose of the present investigation was to determine if a benzodiazepine receptor antagonist, flumazenil (Ro 15-1788), could enhance learning and memory. Pretraining injection of flumazenil (2.5 to 40.0 mg/kg) was found to enhance both learning and memory in a test requiring young mice to discriminate the correct arm of a T-maze to escape mild electric shock. In a second test, which required mice to passively avoid a dark chamber after shock, flumazenil pretreatment prevented the occurrence of amnesia induced by the cholinergic receptor antagonist scopolamine. It is hypothesized that flumazenil may facilitate learning or memory processes by reversing a negative modulatory influence of endogenous diazepam-like ligands for benzodiazepine receptors.

Animals↗

PubMed1987

Differences in behavioral responses to oxotremorine and physostigmine in New Zealand black (NZB/BlNJ) and C57BL/6 mice.

The NZB/BlNJ (NZB) mice are an autoimmune-prone strain, known to develop brain-reactive antibodies in serum at much earlier chronological ages than normal mice. Measurement of locomotor activity in 8-10 month old C57BL/6 (C57) mice following the administration of either oxotremorine or physostigmine, revealed a biphasic response consisting of inhibition at small doses, but increased motor activity at large doses. In contrast, age-matched NZB mice exhibited little inhibition at the smaller doses, but had much greater increases in activity after the larger doses. Similarly, when compared to C57 mice, NZB mice were less sensitive to oxotremorine-induced salivation, diarrhea and visible tremors. Moreover, oxotremorine-induced hypothermia occurred at smaller doses in C57 mice than in NZB mice and was of a greater magnitude. Thus, at an age when NZB mice possess high levels of brain-reactive antibodies, and exhibit impairment in tests of learning/memory, these mice also show diminished responses in several tests of cholinomimetic-induced behavior and physiological alterations.

Aging↗

PubMed1987

Motor responses of autoimmune NZB/B1NJ and C57BL/6Nnia mice to arecoline and nicotine.

In 11-13 month C57BL/6Nnia mice, arecoline produced a dose-dependent decrease in motor activity at doses of 0.64-2.5 mg/kg, whereas at doses of 5.0-20.0 mg/kg arecoline produced a dose-dependent increase in motor activity. In marked contrast, age-matched NZB/B1NJ (New Zealand Black) mice failed to exhibit the first phase of the response, but showed a greater dose-dependent increase in motor activity following the doses of 10 and 20 mg/kg. Nicotine, 0.64-2.5 mg/kg, produced a dose-dependent decrease in motor activity in both strains. The effects of arecoline and nicotine were antagonized by scopolamine (2.5 mg/kg) and mecamylamine (1.0 mg/kg), respectively. These findings suggest that muscarinic neurotransmission may be altered in NZB/B1NJ mice, which produce brain-reactive autoantibodies, exhibit learning/memory dysfunctions, and also exhibit a loss of neurons staining positive for choline acetyltransferase.

Animals↗

PubMed1987

Age differences in locomotor behavior of C57BL/6NNia mice: a data management approach.

Separate age groups of C57BL/6NNia mice were tested for within- and between-session habituation of locomotor behavior using a Digiscan System for simultaneous automated gathering of 23 locomotor variables. A computer program, Raw Data Input Program (RDIP) was developed for the reformatting and transfer of raw data samples to a spreadsheet/database management system, and a method for summarization, analysis and presentation of the multivariate data is described. It is concluded that large samples of multivariate locomotor activity data can be effectively managed using a single microcomputer and commercially available software packages.

Aging↗

PubMed1986

Learning deficits occur in young mice following transfer of immunity from senescent mice.

The extent to which immune processes contribute to senescence-related neurological/behavioral impairment was examined using an adoptive transfer procedure. C57BL/6 mice aged 22 to 24 months showed impaired ability for acquisition of an active avoidance response when compared with younger mice aged 3 months. An immunofluorescence assay of the sera of these mice indicated that only sera from the senescent mice reacted with brain antigen. When tested three months following irradiation and receipt of bone marrow/spleen cell suspensions from senescent mice, young mice showed senescence-like serum-brain reactivity and declines in their abilities to acquire learning. Young control mice receiving cell suspensions from age-matched donors showed no evidence of serum-brain reactivity or learning deficits, suggesting that impaired learning was related to acquisition of aged immunity and not a nonspecific effect of the transfer procedure. These findings indicate that immune processes may be involved in the etiology of senescence-related neurological/behavioral dysfunctions.

Aging↗

PubMed1986

Age-dependent enhancement of diazepam sensitivity is accelerated in New Zealand Black mice.

Separate age groups of C57BL/6 and autoimmune New Zealand Black (NZB) mice were compared for diazepam-induced ataxia and barbiturate-induced loss of righting reflex. Between 1 and 3 months of age, both strains showed a similar age-related decrease in ED50 for diazepam-induced ataxia. However, between 3 and 12 months the decrease in ED50 was markedly greater in NZB mice. In contrast, age-related increases in the durations of loss of righting reflex following hexobarbital or barbital were similar in both strains. The results suggest that NZB mice show relatively accelerated age-related increases in sensitivity to benzodiazepine, but not to barbiturates.

Aging↗