In two clinical samples, alcohol consumption, other drug use, and tobacco use were measured at approximately 6 months following admission of individuals into treatment. Using only the alcohol consumption variables, cluster analyses with several different solutions consistently identified abstinent, moderate, and unremitted groups. With the addition of tobacco and other drug use, analyses identified a largely abstinent group, a drug use group that did not drink, a heavy drinking group that did not use other drugs, and a group using both alcohol and other drugs, indicating the need for broad definitions of relapse. All solutions distinguished clusters of tobacco users and nonusers in remission from alcohol and other drug use, and tobacco users and nonusers tended to be differentiated among those continuing to drink or use other drugs, suggesting that the presence or absence of tobacco use marks different outcome groups. Generally speaking, clustering methods using complete and average linkage as agglomeration measures with cosine similarity as a proximity measure produced the most consistent clusters and the most clinically interpretable results.

Adult↗

PubMedDate not supplied

Modification of CD4 immunoadhesin with monomethoxypoly(ethylene glycol) aldehyde via reductive alkylation.

CD4 immunoadhesin (CD4-IgG) is a chimeric glycoprotein molecule comprised of the gp120-binding portion of human CD4 fused to the hinge and Fc portions of human IgG. As a candidate for human therapeutic use, CD4-IgG represents an important advance over soluble CD4, insofar as the systemic clearance in humans of CD4-IgG is significantly slower. In an effort to prolong its in vivo residence time even further, we have modified CD4-IgG chemically by attaching monomethoxypoly(ethylene glycol) (MePEG) moieties to lysine residues via reductive alkylation. We synthesized MePEG aldehyde and investigated reaction conditions for adding a range of MePEG moieties per protein molecule. At neutral pH in the presence of sodium cyanoborohydride, the reaction was sufficiently slow to allow for significant control over the extent of MePEGylation. Addition of 7.7 or 14.4 MePEG moieties to CD4-IgG resulted in an approximately 4- or 5-fold increase, respectively, in the persistence of the protein in rats, as compared with unmodified CD4-IgG. These results suggest that the therapeutic utility of a human receptor IgG chimera can be improved by MePEGylation technology, provided that the modified immunoadhesin retains its biological activity in vivo. Such modification can lead to a significant additional increase in the in vivo residence time of the protein.

Alkylation↗

PubMedDate not supplied

Opening of the blood-brain barrier in Anolis carolinensis. A high voltage electron microscope protein tracer study.

The tight junctions between endothelial cells of capillaries in the forebrain of Anolis carolinensis are a common component of the structural basis for the blood-brain barrier in this reptile. The complexity of these junctions, which is apparent in platinum replicas of freeze-fractured brain capillaries, is unchanged by treatments designed to render the blood-brain barrier of these lizards leaky to horseradish peroxidase. An alternative route for extravasation of horseradish peroxidase, following injection of chameleons with 2.7 mg of D-glucose to render their brain capillaries leaky, is a system of transient cytoplasmic vesicles and vesiculo-tubular channels whose lumina may be open to the luminal or abluminal surface (or both) of the capillary endothelial cell. High voltage electron microscopy (HVEM) of 0.25 and 0.5 micron thick plastic sections of experimental brain capillary endothelium confirmed the existence of vesiculo-tubular conduits. These channels display a sigmoid morphology and are situated in the cytoplasm at angles oblique to the luminal and abluminal surfaces of the endothelium. Occasionally, the channels spanned the entire endothelial wall of the capillary, and in such cases, appeared to connect the lumen with the brain extracellular compartment. HVEM images (including stereo pairs) of the vesiculo-tubular channels show them to have a scalloped, irregular profile consistent with their proposed formation by fusion of pinocytotic vesicles. Also, HVEM examinations of experimental capillaries from peroxidase-treated lizards reveal massive quantities of dense reaction product in cytoplasmic vesicles and vesiculo-tubular membrane compartments of the endothelium, and the complex pleomorphism exhibited by these structures. Observations made in the present study suggest that as a consequence of severe hyperglycaemia, transendothelial channels form in the brain capillaries by fusion of pinocytotic vesicles generated by accelerated pinocytosis at the luminal surface of the endothelium, and subsequently serve as open routes for massive floods of tracer into the central nervous system.

Animals↗

PubMedDate not supplied

Cerebral blood flow and edema following carotid occlusion in the gerbil.

A technique for measuring focal cerebral blood flow (CBF) and brain specific gravity (SG) in gerbils is described; CO2 reactivity and autoregulation were tested. The mean CBF was 29.5 +/- 4.5 ml/100 gm/min and brain SG 1.0500 +/- 0.0004. Unilateral carotid occlusion resulted in a reduction of flow to 12.8 +/- 5.8 ml/100 gm/min in the ipsilateral hemisphere with little change in the contraleteral hemisphere; there was also a decrease in brain SG. One hour after occlusion, brain edema, as judged by decreased SG, developed at CBF less than 20 ml/100 gm/min and reached maximal levels at 7 +/- 2 ml/100 gm/min. The amount of edema appeared to be related chiefly to the residual post-occlusion flow. With bilateral occlusion, CBF was close to zero and there was no change in SG, indicating that in the "no flow" situation, there is no edema.

Animals↗

PubMedDate not supplied

Modulation of the pathophysiology of primate focal cerebral ischaemia by indomethacin.

The effect of indomethacin (3mg/kg IA) preloading on the pathophysiology of a model of acute cerebral ischaemia has been tested. Primates anaesthetised with alpha-chloralose were used. Indomethacin reduced basal blood flow by 39% and reduced CO2 reactivity by 71%. Water content changes of the cerebral cortex and relationships between blood flow and extracellular potassium (Ke), and calcium (Cae) activities have been measured. Indomethacin infusion did not effect the water content of the left side but there was more water in all regions of the right hemisphere which were rendered ischaemic. There water increases were significant for blood flows greater than 5ml/100g/min in exposed areas. There was a significant increase in the flow thresholds for change in Ke and Cae. Possible mechanisms for these changes have been discussed.

Animals↗

PubMedDate not supplied

The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischaemia.

The effects of a calcium antagonist, nimodipine, were tested on the response of the cerebral circulation to arterial pCO2 and blood pressure changes. The effects of reduced blood flow upon oedema formation and extracellular ion homeostasis under nimodipine preloading were studied. Both open and closed skull primate models were used, with alpha-chloralose anaesthesia. Nimodipine infusion increased basal blood flow in the open skull, but not the closed skull animals. Autoregulation to increased blood pressure was little affected. Responses to arterial pCO2 changes and autorerulation to reduced blood pressure were severely imparied. Residual blood flow after middle cerebral artery occlusion was significantly higher with nimodipine than in controls. The threshold levels of blood flow for the development of cortical oedema and for disturbance of ion homeostasis were, however, increased, suggesting that nimodipine interferes with cellular energy metabolism and increases the susceptibility of tissue to ischaemic damage.

Animals↗

PubMedDate not supplied

An analysis of contemporary morphological concepts of synaptic remodelling in the CNS: perforated synapses revisited.

Perforated synapses refer to a synaptic type found in the central nervous system. They are characterized by their large size and by a discontinuity of the postsynaptic density when viewed in transverse sections, and by a doughnut or horseshoe shape when viewed in en face views. Of recent morphological studies, one approach has followed their characteristics throughout development and maturity, while others have concentrated on their probable roles in activities including kindling, long-term potentiation, spatial working memory, differential rearing, and the functioning of neuroleptics. An assessment is made of the hypotheses and models that have proved determinative in the emergence of perforated synapses as being significant in synaptic plasticity. Their distribution and frequency are summarized, with emphasis on the importance of unbiased stereological procedures in their analysis. Using three-dimensional approaches various subtypes are recognized. Of these, a complex or fragmented subtype appears of especial significance in synaptic plasticity. Ideas regarding the life-cycle of perforated synapses are examined. The view that they originate from conventional, non-perforated synapses, enlarge, and subsequently split to give rise to a new generation of non-perforated synapses, is critically assessed. According to an alternative model, perforated and non-perforated synapses constitute separate populations from early in their development, each representing complementary forms of synaptic plasticity. An attempt is also made to discover whether synaptic studies on the human brain in normal aging and in Alzheimer's disease throw light on the role of perforated synapses in synaptic plasticity. The loss of synapses in Alzheimer's disease may include a loss of perforated synapses - of particular relevance for an understanding of certain neuropathological conditions.

Aging↗

PubMedDate not supplied

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Evaluation Studies as Topic↗