Search PubMed⌕ Search

Biomedical subjects

R Baker

Publications and source records attributed to R Baker.

At least 379 records · Page 21Linked to original sources
PubMed1990

Novel quinuclidine-based ligands for the muscarinic cholinergic receptor.

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.

Animals↗
PubMed1990

Role of hydrogen bonding in ligand interaction with the N-methyl-D-aspartate receptor ion channel.

Displacement of [3H]MK-801 (dizocilpine, 1) binding to rat brain membranes has been used to evaluate the affinities of novel dibenzocycloalkenimines related to 1 for the ion channel binding site (also known as the phencyclidine or PCP receptor) on the N-methyl-D-aspartate (NMDA) subtype of excitory amino acid receptor. In common with many other agents having actions in the central nervous system, these compounds contain a hydrophobic aromatic moiety and a basic nitrogen atom. The conformational rigidity of these ligands provides a unique opportunity to evaluate the importance of specific geometrical properties that influence active-site recognition, in particular the role of the nitrogen atom in hydrogen-bonding interactions. The relative affinities (IC50s) of hydrocarbon-substituted analogues of 1 and ring homologated cyclooctenimines illustrate the importance of size-limited hydrophobic binding of both aryl rings and of the quaternary C-5 methyl group. Analysis of the binding of a series of the 10 available structurally rigid dibenzoazabicyclo[x.y.z]alkanes, by using molecular modeling techniques, uncovered a highly significant correlation between affinity and a proposed ligand-active site hydrogen bonding vector (r = 0.950, p less than 0.001). These results are used to generate a pharmacophore of the MK-801 recognition site/PCP receptor, which accounts for the binding of all of the known ligands.

Animals↗
PubMed1990

Synthesis and muscarinic activities of 1,2,4-thiadiazoles.

A series of novel 1,2,4-thiadiazoles bearing a mono- or bicyclic amine at C5 were prepared. Quinuclidine and 1-azabicyclo[2.2.1]heptane derivatives were synthesized by reaction of the lithium enolate of the 3-methoxycarbonyl compounds followed by ester hydrolysis and decarboxylation. The receptor-binding affinity and efficacy of these compounds as muscarinic ligands was assessed by radioligand binding assays using [3H]-N-methylscopolamine and [3H]oxotremorine-M. Optimal agonist affinity was observed for 3'-methyl compounds. Smaller substituents (H) retained efficacy with reduced affinity while larger groups led to substantially lower efficacy. The observed binding affinity was influenced both by the conformational energy of rotation around the C3-C5' bond and the steric requirement of the mono- or bicyclic amine.

Animals↗
PubMed1990

Synthesis and biological activity of 1,2,4-oxadiazole derivatives: highly potent and efficacious agonists for cortical muscarinic receptors.

The synthesis and biochemical evaluation of novel 1,2,4-oxadiazole-based muscarinic agonists which can readily penetrate into the CNS is reported. Efficacy and binding of these compounds are markedly influenced by the structure and physicochemical properties of the cationic head group. In a series of azabicyclic ligands efficacy and affinity are influenced by the size of the surface area presented to the receptor, at the active site, and the degree of conformational flexibility. The exo-1-azanorbornane 16a represents the optimum arrangement, and this compound is one of the most efficacious and potent muscarinic agonists known. In a series of isoquinuclidine based muscarinic agonists efficacy and affinity are influenced by the geometry between the cationic head.group and hydrogen bond acceptor pharmacophore and steric bulk in the vicinity of the base. The anti configuration represented by 22a is optimal for muscarinic activity. Ligands with pKa below 6.5 show poor binding to the muscarinic receptor as exemplified by the diazabicyclic derivative 42.

Animals↗
PubMed1990

Quality assurance for family practice trainees in the USA and the UK: too little too late?

A postal survey about opinions of quality assurance and the methods used to teach this subject was sent to all family practice course organizers in England, Wales and Scotland, and to all family practice residency directors in the USA. Opinions of quality assurance were more positive from the American responders. A wide variety of teaching methods was employed, with review of records for the quality of care more common in the USA, but trainees in the UK were more likely to participate in quality assurance, rather than merely being exposed to it. However, the proportion of trainees in either country that undertook projects was disappointingly low. The teaching of quality assurance to trainees needs to be given a higher priority in both the USA and UK.

Attitude of Health Personnel↗
PubMed1990

A novel series of non-quaternary oxadiazoles acting as full agonists at muscarinic receptors.

1 A novel series of non-quaternary oxadiazole-based muscarinic agonists demonstrated high affinity for muscarinic receptors. 2. These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations. 3. Two amino oxadiazoles, one from a quinuclidine series (L-660,863) and one from a 1-azanorbornane series (L-670,207) possessed a high ratio of potency for displacing the binding of [3H]-N-methyl-scopolamine ([3H]-NMS) to potency for displacing the agonist [3H]-oxotremorine-M cortex. 4. The two azanorbornane derivatives L-670,548 and L-670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 microM respectively). 5. The maximum response obtained with L-670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine. 6. These oxadiazole muscarinic agonists are among the most potent and efficacious non-quaternary muscarinic agonists ever described.

Animals↗
PubMed1990

Circadian rate variation in rate-adaptive pacing systems.

By mimicking the natural rate slowdown during sleep, a pacing system can enhance patient comfort while improving device longevity. A new family of rate-adaptive pacemakers accomplishes this circadian rate variation by modeling the patient's sleep-wake cycle using a time-of-day clock inside the device. Furthermore, to account for minor variations in the patient's sleep-wake cycle, sensor data can be used to automatically adapt the starting and stopping points of this change in rate. Using the model, the device begins to gradually reduce the pacing rate beginning one-half hour before the selected bed time. Similarly, the rate begins to increase one-half hour before the selected waking time. Sensor data indicating the presence or absence of patient activity are used to adapt the selected bed and wake times, enabling the system to maintain an appropriate schedule despite changes in the patient's actual schedule. The model approximates natural human adaptation times for time zone or work shift changes. This circadian rate adaptation does not preclude the system's rate response to patient activity; even during sleep time the response to moderate or heavy exercise is essentially unchanged.

Cardiac Pacing, Artificial↗
PubMed1990

Studies of intestinal lymphoid tissue. XIV--HLA status, mucosal morphology, permeability and epithelial lymphocyte populations in first degree relatives of patients with coeliac disease.

Fifty two first degree relatives of patients with coeliac disease were investigated for HLA status, small intestinal permeability, and mucosal morphology together with the size of the intraepithelial lymphocyte pool and indices of lymphocyte activation, in an attempt to identify genetically determined markers of the disease. Thirty eight per cent of these subjects had increased intraepithelial lymphocyte populations and a highly significant association with HLA-DR3 compared with controls. Their intestinal permeability to 51chromium-labelled ethylenediamine tetraacetate was invariably normal and there was no evidence of abnormal mucosal architecture, increased crypt cell mitotic activity or lymphocyte 'activation'. Although increased intraepithelial lymphocyte counts clearly do not cause alterations in intestinal structure or function, it is likely that this parameter together with the HLA-DR3 status identifies a genetically determined predisposition to the disease which may only become clinically evident with larger doses of ingested gluten.

Adolescent↗
PubMed1990

Synaptic organization of tectal-facial pathways in cat. II. Synaptic potentials following midbrain tegmentum stimulation.

1. The organization of the synaptic pathways underlying midbrain tegmentum influence over the facial musculature was studied with the use of an acute electrophysiological approach in the cat. Under pentobarbital sodium anesthesia, synaptic potentials were recorded intracellularly in antidromically identified facial motoneurons following electrical stimulation of the paralemniscal zone. The cells of origin and the pathways responsible for the potentials evoked from the paralemniscal zone were defined with the use of retrograde transport of horseradish peroxidase (HRP). The putative role of the paralemniscal zone with regard to the production of disynaptic, tectally evoked potentials in facial motoneurons was investigated both by inactivating this nucleus with injections of lidocaine and by making acute brain stem lesions to sever the paralemniscal-facial and other afferent pathways. 2. Following paralemniscal stimulation, monosynaptic, excitatory postsynaptic potentials (EPSPs) with latencies ranging from 0.6 to 0.9 ms, steep rising phases, and amplitudes in excess of 4.0 mV were recorded in motoneurons of the temporal and auriculoposterior subdivisions, which supply the pinna muscles. Smaller amplitude EPSPs (less than 1.0 mV) with monosynaptic latencies were observed in the zygomatic subdivision. Polysynaptic EPSPs with latencies ranging from 1.0 to 1.8 ms were also observed in all three of these subdivisions. However, only long-latency EPSPs, arriving at 2.0 ms or later, were present in ventral subdivision motoneurons. 3. Inhibitory postsynaptic potentials (IPSPs) were also frequently recorded in facial motoneurons after paralemniscal stimulation. Monosynaptic IPSPs with latencies ranging from 0.8 to 1.2 ms and amplitudes in excess of 4.0 mV were recorded in facial motoneurons of the temporozygomatic and auriculoposterior subdivisions, as were polysynaptic IPSPs with latencies ranging from 1.2 to 1.8 ms. IPSPs were sometimes observed in combination with a smaller, shorter latency EPSPs. Only long-latency IPSPs of greater than 2.0 ms were recorded in ventral subdivision motoneurons. In all cases, both the EPSPs and the IPSPs were graded in character and could be augmented by multiple stimuli. 4. The contralateral paralemniscal zone and the supraoculomotor area, bilaterally, represented the two most prominent afferent sources labeled after HRP injection of the facial nucleus. The superior colliculus and numerous reticular formation regions were also identified as facial nucleus afferents by the presence of retrogradely labeled cells. The retrogradely labeled cells in the paralemniscal zone exhibited heterogeneous soma size. HRP-labeled axons of the paralemniscal-facial pathway were observed to cross the midline by traveling ventral to the brachium conjunctivum in the caudal mesencephalon.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Behavior of accessory abducens and abducens motoneurons during eye retraction and rotation in the alert cat.

1. The activity of both accessory abducens (Acc Abd) and abducens (Abd) motoneurons (Mns) was recorded in the alert cat during eye retraction and rotational eye movements. Cats were fitted with two scleral coils, one measured rotational eye movements directly and the other retraction by distinguishing the translational component. 2. Acc Abd and Abd Mns were identified following antidromic activation from electrical stimulation of the ipsilateral VIth nerve. 3. In response to corneal air puffs, bursts of spikes were produced in all (n = 30) Acc Abd Mns. The burst began 7.2 +/- 1.2 (SD) ms after onset of the air puff and 8.9 +/- 1.9 ms before eye retraction. 4. Acc Abd Mns were silent throughout all types of rotational eye movements, and tonic activity was not observed during intervals without air-puff stimulation. 5. In contrast, all (n = 50) identified Abd Mns exhibited a burst and/or pause in activity preceding and during horizontal saccades as well as a tonic activity proportional to eye position. 6. Only 10% of Abd Mns fired a weak burst of spikes in response to air-puff stimulation. 7. We conclude that Acc Abd Mns are exclusively involved in eye retraction in the cat and that only a few Abd Mns have an eye-retraction signal added to their eye position and velocity signals. Thus any rotational eye-movement response described in retractor bulbi muscle must result from innervation by Mns located in the Abd and/or the oculomotor nuclei. 8. The organization of the prenuclear circuitry and species variation are discussed in view of the nictiating membrane extension response measured in associative learning.

Abducens Nerve↗
PubMed1990

Monitoring of general practitioners' outpatient referral rates by Family Health Services Authorities: how practical?

The Government proposes that Family Health Services Authorities should monitor general practitioner referral rates, although the information available to them might be inadequate for the task. This study was undertaken to assess the difficulties Family Health Services Authorities could face when monitoring referrals using rates related to doctors' list size. This paper describes an investigation into this problem which analysed all outpatient referrals from one general practice from 1984 to 1988. Referral rates showed important variations between calendar quarter recording periods, and rates based on list size were inaccurate compared with those based on consultations. Proportions of obstetric, gynaecological and private referrals varied widely between the doctors. These findings suggest that monitoring of referral rates by Family Health Services Authorities will be relatively crude, and can only be improved by the full cooperation of general practitioners.

Data Collection↗
PubMed1990

Development of a questionnaire to assess patients' satisfaction with consultations in general practice.

The assessment of patient satisfaction has become an important concern in the evaluation of health services. Measures of satisfaction must be valid and reliable if they are to be used widely. This paper reports the development of a new questionnaire to assess patients' satisfaction with consultations together with initial tests of the questionnaire's reliability and validity. Principal components analysis of the patients' assessments of care revealed three factors of satisfaction: the professional aspects of the consultation, the depth of the patient's relationship with the doctor, and the perceived length of the consultation. The consultation satisfaction questionnaire is reliable under the conditions of this study and may have a role in research, medical education and audit.

Consumer Behavior↗
PubMed1990

Prevalence of undiagnosed eye disease in high-risk diabetic individuals.

A total of 533 diabetic individuals using the Marshall, Minn, medical care system were identified as potential subjects for a study of unrecognized eye disease. Of these, 172 (32%) stated they had never had an ophthalmologic eye examination and subsequently were defined as being at high risk for unrecognized diabetic eye disease. Ophthalmic examination was performed on 145 (84%) of these high-risk individuals and revealed that 61% had clinical characteristics consistent with diabetic retinopathy, glaucoma, cataract, or other eye abnormalities. Twenty-five (17%) of these subjects presented with eye disease that required immediate treatment, referral, or accelerated follow-up. Of those indicating they had an ophthalmologist, approximately 35% reported a time since last visit of 2 years or greater. These findings indicate a high prevalence of ocular morbidity among diabetic individuals who are not under routine ophthalmic surveillance and suggest that improvements in patient and professional compliance with recommended guidelines for eye care are warranted.

Adult↗
PubMed1989

Relationships between renin, aldosterone, blood pressure and renal function in hypertensive insulin-dependent diabetes mellitus.

A cross-sectional analysis of associations between total plasma renin (TPR) and aldosterone, blood pressure, renal haemodynamics, autonomic function and electrolyte balance was carried out in 35 hypertensive non-azotaemic insulin-dependent diabetics. Supine TPR was increased in 10 subjects and reduced in one, although erect TPR was increased in nine but reduced in 18 subjects. The supine to erect TPR gradient was greater than 40% in all cases. Supine and erect TPR correlated closely (r = 0.99, P less than 0.001). No correlation was found between TPR and age or blood pressure and multiple regression analysis failed to reveal independent predictors for TPR. Supine aldosterone was reduced in two subjects and increased in three, and erect aldosterone levels were reduced in three but increased in eight subjects. However, the postural aldosterone gradient was greater than 40% in only 20 cases. Supine and erect aldosterone correlated with each other (rs = 0.64, P = 0.001) but not with TPR. Aldosterone levels were most strongly related inversely to duration of diabetes, diabetic retinopathy, parasympathetic neuropathy and directly to diastolic blood pressure and glomerular filtration rate. Aldosterone levels correlated negatively with age. This was corrected for in multiple regression analysis which revealed an inverse relationship between supine aldosterone and serum potassium (P less than 0.05) and a direct one with renal plasma flow (P less than 0.007). Erect aldosterone was independently associated with duration of diabetes (P less than 0.005), systolic postural gradient (P less than 0.02), and the postural aldosterone gradient with the presence of parasympathetic neuropathy (P less than 0.004). The observation of elevated TPR in 10 subjects and the lack of relationship between TPR and other variables may reflect the overproduction of inactive relative to active renin in insulin-dependent hypertensive diabetics with autonomic dysfunction. The association between aldosterone and blood pressure, renal haemodynamics and electrolyte balance suggests that mineralocorticoids may be relevant to the natural history of hypertensive diabetic renal disease.

Adult↗