Evidence for the presence of a non-catecholamine, clonidine-displacing substance in crude, methanolic extracts of bovine brain and lung

In the present study we have prepared crude, methanolic extracts of bovine lung and bovine brain and, using radioligand binding assays in conjunction with a number of simple chromatographic techniques, provided evidence for the presence of a non-catecholamine ’clonidine-displacing substance‘ (CDS). The level of CDS in lung extracts (9?units/g wet weight n=11) is approximately 3 times that in the brain extracts. Furthermore, the effect of the crude, methanolic extracts are selective for non-adrenoceptor, imidazoline (labelled by [ ³H]-idazoxan) and a ₂-adrenoceptor binding sites (labelled by [ ³H]-clonidine); both extracts are 5–10-fold more potent displacers of ligand binding to a ₂-adrenoceptors compared with binding to opiate receptors (labelled by [ ³H]-etorphine) and practically inactive against a ₁-adrenoceptor and muscarinic binding sites (labelled by [ ³H]- prazosin and [ ³H]-quinuclidinyl benzilate, respectively). With the exception of the non-adrenoceptor, imidazoline binding assay, which used rat kidney membranes labelled by [ ³H]-idazoxan in the presence of the a ₂-adrenoceptor antagonist RS-15385-197, all radioreceptor assays involved bovine cerebral cortex membranes. Although the extracts contain catecholamines (brain only), histamine (lung only) and monovalent cations (both), which have the potential to interfere with the radioligand binding assays, their concentrations were too low to account for the effects observed. Preliminary attempts at purification of the extracts revealed that CDS activities from the two tissues are similar, i.e., practically insoluble in organic solvents at room temperature, not affected by either Sep-Pak C ₁₈ column or anion exchange resins but retained (along with the monovalent cations) by cation exchange resin. However, following chromatographic separation on a Biogel P2 column, the CDS-containing eluates are cation-free and exhibit qualitatively similar elution profiles. Future experiments will involve further purification of ’clonidine-displacing substance‘ to characterize its interaction with a ₂-adrenoceptor binding sites in greater detail and establish whether it has biological activity consistent with the properties implied by its effects in radioligand binding assays.     

Negative symptoms in schizophrenia: considerations for clinical trials

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.     

DNA probe technology: implications for service planning in Britain

For certain genetic conditions DNA testing identifies carriers and determines the risk status of foetuses, thus helping parents to make more informed prenatal decisions. Data, collected from three genetic centres in England and Wales from August 1986 to July 1990, are used to describe trends in demand for DNA testing, the impact of DNA tests on carrier risk assessment, and the use of DNA tests in relation to pregnancy outcome. Altogether the data include 23,388 subjects and 681 pregnancies in 8738 families divided into five cohorts by year of entry and referral. The most frequent gene disorders referred to the genetic centres are currently being tested or will soon be tested. For these disorders the initial high level of activity has declined and may have reached steady state. Demand for DNA services is high for cystic fibrosis and Duchenne muscular dystrophy, intermediate for Huntington's disease, and low for adult polycystic kidney disease, phenylketonuria and tuberous sclerosis. Based on these findings we suggest that demand for DNA tests will be high in serious, untreatable and slow progressing conditions with early onset; intermediate for conditions affecting intellect and neurological integrity with later onset; and low for treatable, late-onset conditions, or those for which there is evidence of heterogeneity, and variable penetrance. It would be helpful to assess the extent to which this view of demand is confirmed when the new disorders being DNA tested are considered and for the pattern of activity of DNA testing for some types of cancer. Since no DNA centre could offer a fully comprehensive testing service, it is recommended that a structure is created to audit overall activity, assist in policy formulation, and influence supraregional service organisation, in order that the spread of DNA services be planned as effectively as possible. This structure would facilitate monitoring of the evolution of contract specifications agreed by commissioners and providers on a regional basis.     

Clinical correlates of high signal lesions on magnetic resonance imaging in Alzheimer's disease

Summary The pathophysiology and clinical significance of high signal lesions, visualized on magnetic resonance imaging (MRI) in patients with Alzheimer's disease (AD), remain controversial. Since they are known to correlate with vascular disease and vascular risk factors, we reviewed the clinical correlates of periventricular high signal (PVH) and subcortical white matter lesions (WML) in a sample of 106 patients with probable AD, excluding persons with treated vascular risk factors or symptomatic cerebrovascular and cardiovascular disease. Grade 2 PVH were seen in 26 (25%) and scattered WML were identified in 29 (18%). PHV were associated with advancing age and gait disturbance. WML were associated with gait disturbance and incontinence. Neither radiologic finding was related to dementia severity. The findings suggest that these lesions are common in patients with AD even when those with evidence of cerebrovascular disease are excluded; their presence, therefore, should not preclude a diagnosis of AD. Additionally, the data suggest that HSL on MRI may be one of many risk factors associated with functional disability in persons with probable AD.     

NMDA agonists and antagonists alter the hypnotic response to ethanol in LS and SS mice

Involvement of glutamate neurotransmission in the differential response of long-sleep (LS) and short-sleep (SS) mice to acute ethanol was examined by measuring the effect of centrally administered glutamate receptor agonists and antagonists on blood ethanol concentration (BEC) at loss of righting response following intragastric administration of ethanol. NMDA coinjected with glycine, and quinolinic acid (QA), decreased sensitivity to ethanol in both lines of mice. SS mice were more sensitive to QA than were LS. The NMDA antagonists 2-amino-5-phosphonovaleric acid (APV), MK-801 and an inhibitor of glutamate synthesis, methionine sulfoximine, increased sensitivity to ethanol in both lines of mice. MK-801 effects were line dependent with SS being more sensitive. In addition, coinjection of APV, Mg++ or Zn++ with QA blocked the decrease in sensitivity seen with QA alone. These results demonstrate that NMDA agonists and antagonists alter the acute hypnotic response to ethanol in both LS and SS mice, and support the hypothesis that ethanol exerts its effects in part by altering glutamatergic neurotransmission.     

Rigid contact lens decentration: a risk factor for corneal warpage

Clinically significant contact lens induced corneal warpage is seen in a small proportion of soft and rigid contact lens wearers. Previous studies using the keratometer have found no correlation between the fit of the lens and the induced topographic changes. In this study, using computer-assisted topographic analysis, seven eyes (four patients) with rigid contact lens-induced corneal warpage were noted to have topographic abnormalities that correlated with the decentered resting position of the contact lens on the cornea. The warpage topography for each of these corneas was characterized by a relative flattening of the cornea underlying the resting position of the contact lens. Lenses that rode high, for example, produced flattening superiorly and resulted in a relatively steeper contour inferiorly that simulated the topography of early keratoconus patients who had not worn contact lenses. After discontinuing contact lenses the corneal topography returned to a normal pattern in five eyes. Two eyes retained asymmetry that is not characteristic of normal corneas. Up to 6 months was required for the corneas to return to a stable topography after contact lens wear was discontinued.     

The relationship between neuropsychological function and brain damage detected by neuroimaging after closed head injury

Studies relating neuropsychology and structural neuroimaging after closed head injury are reviewed. Particular attention is given to the question of the relative contribution of focal and diffuse damage to neuropsychological impairment. The evidence currently available emphasizes the importance of diffuse damage in closed head injury. Diffuse damage is not equally distributed in the brain, and the review suggests three axes that are relevant for neuropsychological function: (1) damage may be unilateral or bilateral, (2) damage is characteristically greater in anterior regions than posterior regions, and (3) damage shows a centripetal gradient. A large gap remains between the emergent generalizations concerning head injury and reliable neuropsychological interpretation of scans from individual patients.     

Serum measurements of soluble CD23 in HIV infection.

A gradual reduction in cell-mediated immunity is thought to occur with the progression of human immunodeficiency virus (HIV) infection. This suggests a selective attrition of the Th1 subset. The regulation of the soluble form of the low-affinity receptor for IgE (sCD23) by the opposing actions of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) allows the assessment of the overall balance of Th1 to Th2 activity in a given disease. In order to investigate this further we employed an enhanced chemiluminescent ELISA to analyse serum levels of sCD23 in male subjects with and without HIV infection. Serum levels of sCD23 were similar in 34 HIV seronegative homosexuals, 39 homosexuals with asymptomatic HIV infection, 27 homosexuals with acquired immune deficiency syndrome (AIDS) and 20 healthy controls. This suggests that HIV has no predilection for either the Th1 or Th2 subsets of CD4 T cells.     

The chief medical residency in Canada: comparison of opinions between physicians-in-chief and chief medical residents.

We conducted a survey of physicians-in-chief (PCs) and chief medical residents (CMRs) in training programs throughout Canada to determine their attitudes toward the need for and role of CMRs in Canada and to rate the importance of CMR duties and attributes. Forty-three hospitals with 5 to 126 house staff in all eight provinces with medical schools were surveyed; 36 PCs (84%) and 29 CMRs (67%) returned a completed questionnaire. Compared with the CMRs the PCs preferred more prior training (p less than 0.03), estimated as significantly less the time spent by CMRs in required duties (p less than 0.05) and rated as more important the responsibilities of faculty-house staff liaison, house staff leader, house staff role model and teaching house staff (p less than 0.05) and the attributes of clinical judgement, medical knowledge, clinician model and research interests (p less than 0.03). All of the PCs and 97% of the CMRs rated the position as somewhat to very necessary; 83% of the PCs and 66% of the CMRs would not alter the present CMR roles. A total of 92% of the PCs felt that the position was very or somewhat advantageous with respect to a future private practice, compared with 67% of the CMRs (p less than 0.02). Increased administrative and committee duties, decreased teaching and future reductions in house staff were identified as major but reversible threats to the unique quality of the CMR position. We conclude that the CMR has a necessary, important and highly regarded role in Canadian university hospitals that could possibly be improved by regular review by the PC and CMR at each hospital to avoid the identified problems.     

Endothelial function and aqueous humor flow rate in patients with Fuchs' dystrophy

Using a two-dimensional scanning fluorophotometer, we studied 50 subjects with symmetric ocular involvement of Fuchs' dystrophy without epithelial edema. Twenty-six subjects with confluent or nearly confluent cornea gutata with increased corneal thickness and 24 subjects with mild to moderate cornea guttata with normal corneal thickness were compared to normal control subjects. There were no statistically significant differences in endothelial permeability between the three groups. Corneal thickness was significantly increased in the subjects with confluent to nearly confluent guttae, however. These results suggest that endothelial pump function may be affected in subjects with advanced cornea guttata with stromal edema.