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The present studies were undertaken to determine if viral particles can be delivered across the rat blood-brain barrier (BBB). Osmotic BBB modification with intracarotid mannitol (25%) was immediately followed by bolus intracarotid administration of 0.5 ml purified, ultraviolet-inactivated, herpes simplex virus type 1 endogenously labeled with 35S-labeled methionine (2.0 x 10(6) cpm, approximately 5 x 10(8) plaque-forming units/ml). After 60 minutes, intravascular virus was cleared by saline perfusion and the animals were sacrificed. A marked increase (fourfold, p less than or equal to 0.02) in radioactivity was observed in the ipsilateral brain hemisphere when compared to control animals without barrier modification. Administration of intravenous virus immediately after BBB modification displayed no difference in delivery when compared to intracarotid saline-infused controls (without BBB modification) suggesting the importance of a first-pass phenomenon. There were no significant differences in serum concentrations among intracarotid or intravenous groups. These preliminary studies suggest the possibility of delivering viral particles across the BBB with osmotic disruption, which may permit delivery of genetic material in replication-defective viral vectors in the feline model of GM2-gangliosidosis.

Proton and deuterium NMR relaxation methods were used to characterize water compartmentalization and hydration in work-free wheat flour doughs. Transverse (spin-spin) relaxation measurements define three motionally unique water compartments in the work-free dough preparations. The apparent occupancy fraction and relative mobility of each water domain are found to be functions of moisture content, temperature, and flour type. Additionally, the number of relaxation-resolved water compartments and their characteristic relaxation rate constants are found to depend critically on both moisture content and the interpulse-delay employed for the multi-pulse relaxation experiments. Under controlled experimental conditions, dynamics between the three water compartments can be observed to be consistent with the onset of flour hydration. The most notable observation during the initial period of hydration is a loss of "free" or "loosely bound" water to environments characterized by less mobility. Freezing studies show that hard wheat doughs have slightly less amorphous, non-freezable water than do soft wheat flour doughs prepared under similar conditions.

Osmotic modification of the blood-brain barrier (BBB) provides an experimental model of vasogenic edema, is totally reversible, and does not cause any structural damage. In the present communication, the effect of corticosteroids on drug delivery to normal rat brain was evaluated in this model. Intraperitoneal dexamethasone was administered at doses ranging from 12 to 48 mg/sq m for 3 days; gentamicin delivery to the brain was then evaluated after either intravenous or intracarotid administration in both control and BBB-modified animals. Only animals receiving the highest dose of dexamethasone and in which the gentamicin was given intravenously demonstrated a statistically significant decrease in drug delivery. The effect of dexamethasone over a wide range of dosages, therefore, exhibited only modest effects on drug delivery to normal brain after osmotic BBB disruption.

This paper reports the results of a prospective investigation of 100 women during their pregnancies to test the hypothesis that social and psychological factors influence pregnancy outcome after controlling for demographic, biomedical, and lifestyle variables. Subjects completed questionnaires that assessed family social supports, life events, and anxiety. In addition, data were collected on general biomedical and pregnancy risk, lifestyle practices including smoking and drinking, as well as demographic information. Four infant outcomes, birthweight, gestational age, and 1 and 5 min Apgar scores, were studied via hierarchical multiple regression analyses for their relationship to the social and psychological variables, after controlling for all other sets of variables. The results of these analyses showed that life events stress accounted for significant variation in birthweight, and social supports and anxiety were associated with the two pediatric Apgar scores. Gestational age bore a simple relationship to anxiety, with higher anxiety predictive of lower gestational age. Further analyses revealed that women with either low social supports or high anxiety were, on the average, younger, more often single, of lower education level, had less income, smoked more, and had higher general biomedical risk than women with adequate social supports or lower anxiety. This suggests the multiple ways in which social and psychological risk factors may be related to pregnancy outcome and emphasizes the need for well controlled studies in this area.

Plasma bicarbonate losses during acetate dialysis were prevented by using a combination of acetate and bicarbonate in the dialysate. In 21 patients who were treated with combination dialysate, the fall in mean blood pressure (MBP), and frequency of symptoms, and post-dialysis task performance were all similar to that observed during dialysis with acetate alone. Furthermore, dialysis performed with bicarbonate dialysate resulted in significantly smaller MBP drops, fewer symptoms, and an improved task performance compared to either an acetate or a combination dialysis. These findings indicate that the presence of acetate, rather than a bicarbonate loss, was responsible for the patients' intolerance to acetate dialysis. Patients symptomatic on acetate dialysis had a similar ultrafiltration rate, weight loss, MBP drops, and postdialysis serum acetate levels; they were similar in age and weight to symptom-free patients. Thus, the toxic effect of acetate was not related to serum acetate level. There was no difference in bicarbonate dialysis between patients with symptoms on acetate and the symptom-free patients in reference to MBP drops and task performance. This finding suggests that symptomatic patients were not simply less tolerant to the process of dialysis, but differed from symptom-free patients in their response to the presence of acetate.

Studies of social support networks have almost exclusively measured only their positive aspects. In this research, we investigated both the helpful or positive and the upsetting or negative aspects of social networks in a longitudinal study of spouses caring for a husband or wife with Alzheimer's disease, a progressive senile dementia. Measures of helpful and upsetting aspects of the care givers' networks, derived from interviews and daily interaction ratings, were studied for their relations with overall network satisfaction and depression at an initial interview period (n = 68) and at a follow-up period about 10 months later (n = 38). Results from hierarchical multiple regression analyses, in which care givers' age and sex and a measure of the spouses' health status were controlled, showed that the care givers' degree of upset with their networks was strongly associated with lower network satisfaction and increased depression at both time periods. Helpful aspects bore little or no direct relation to either depression or network satisfaction. Helpful aspects of the network did, however, interact with network upset in predicting network satisfaction, and depression (combined probabilities test, p less than .05). Longitudinal predictions of follow-up depression, after age, sex, care givers' health status, and initial depression levels were controlled, showed that changes in upsetting aspects of one's network were predictive of changes in depression over time. We interpreted these results within an attributional framework that emphasizes the salience of upsetting events within a social network.

We compared the predictive validities of three prominent models of attitudes and behavioral decisions: Rosenberg's instrumentality-value model, Fishbein's belief-evaluation model, and Beach's adaptation of subjective expected utility theory. Seventy female undergraduates rated each of the models' components and reported their attitudes and behavioral plans toward using three different methods of contraception. With the traditional across-subjects prediction procedure, the Rosenberg model generally accounted for 5-25% less variance in subjects' attitudes and behavioral plans than the Fishbein an Beach models, which were not different. With a within-subject prediction procedure, the Rosenberg model was again the least accurate, and the Fishbein and Beach models had similar predictive accuracy. As hypothesized, within-subject predictions were more accurate than across-subjects predictions. The relatively poor performance of the Rosenberg model was attributable to the instrumentality component. In addition, we found that the Beach model could be simplified with no appreciable loss in predictive accuracy. Finally, a subject's personal normative beliefs emerged as a strong independent predictor of behavioral plan.

Comparisons among taxa provide a powerful means for helping to understand why primate species differ from each other in morphology, behaviour and life history. Comparative tests can also mislead when not applied correctly, and correct application means taking into account the phylogenetic relationships among the species being compared. Adaptation is defined as a comparative concept. The reasons for phenotypic similarity among closely related taxa are summarized. Different models of evolutionary change dictate different methods for reconstructing ancestral character states and for performing comparative analyses on categorical and continuously varying character. All comparative methods rely either implicitly of explicitly on some model of how evolution proceeds. The choice of a particular method of analysis is, therefore, an implicit choice of a model of evolution.

We have detected a disorder in Korat cats (initially imported from Thailand) that is analogous to human Sandhoff's disease. Pedigree analysis indicates that this disease in an autosomal recessive disorder in the American Korat. Postmortem studies on one affected cat showed hepatomegaly that was not reported in the only other known feline model of GM2-gangliosidosis type II. Histologic and ultra-structural evaluation revealed typical storage vacuoles. There was a marked deficiency in the activity of hexosaminidase (HEX) A and B in affected brain and liver as compared to controls. Electrophoresis of a liver extract revealed a deficiency of normal HEX A and B in the affected animals. The blocking primary enzyme immunoassay verified the presence of antigenically reactive HEX present in affected cat livers in quantities slightly elevated with respect to the normal HEX concentration in control cats. In leukocytes, obligate heterozygotes had intermediate levels of total HEX activity with a slight increase in the percent activity due to HEX A. Indeed, 4 of 11 phenotypically normal animals in addition to four obligate heterozygotes appear to be carriers using this assay. Affected brain and liver compared with control brain and liver contained a great excess of bound N-acetylneuraminic acid in the Folch upper-phase solids; thin-layer chromatography showed a marked increase in GM2-ganglioside. In summary, we have characterized the pedigree, pathology, and biochemistry of a new feline model of GM2-gangliosidosis which is similar to but different from the only other known feline model.

The inability of most chemotherapeutic agents to adequately penetrate the blood-brain barrier (BBB), in either normal brain or tumor-infiltrated brain, is a major factor limiting the use of chemotherapy in central nervous system malignancy. This barrier, however, can be opened in a reversible manner by the intra-arterial administration of hyperosmotic agents such as mannitol. It has been suggested that the intravenous administration of dimethyl sulfoxide (DMSO) or 5-fluorouracil (5-FU) can accomplish the same thing in a less invasive manner. We have not been able to confirm these findings. DMSO was administered to 25 rats intravenously at concentrations ranging from 25 to 90% or into the internal carotid artery at a concentration of 30%. The penetration of methotrexate, Evans blue-albumin, and hexosaminidase A was then evaluated at intervals ranging from 1.5 to 3.5 hours after administration. Significant barrier opening was not observed in animals receiving intravenous DMSO. Barrier modification, albeit generally modest, was obtained in animals receiving intracarotid DMSO, but this may have been the result of grand mal seizures, inasmuch as 5 of 6 of these animals had such seizures. Several of the animals receiving i.v. DMSO also had seizures, and all animals developed varying degrees of hematuria. Similarly, 5-FU was administered at a dose of 30 mg/kg i.v. and the permeability of the BBB to either Evans blue-albumin or methotrexate was evaluated. No increased permeability of the BBB to these two markers was observed. In summary, osmotic BBB opening in our hands remains the most consistent and reliable means available to open the BBB in a reversible fashion. Neither intravenous DMSO nor 5-FU seems to increase the delivery of chemotherapy or protein tracer to the central nervous system, and the use of DMSO can result in seizures and hematuria.

Comparative methods can be used to test ideas about adaptation by identifying cases of either parallel or convergent evolutionary change across taxa. Phylogenetic relationships must be known or inferred if comparative methods are to separate the cross-taxonomic covariation among traits associated with evolutionary change from that attributable to common ancestry. Only the former can be used to test ideas linking convergent or parallel evolutionary change to some aspect of the environment. The comparative methods that are currently available differ in how they manage the effects brought about by phylogenetic relationships. One method is applicable only to discrete data, and uses cladistic techniques to identify evolutionary events that depart from phylogenetic trends. Techniques for continuous variables attempt to control for phylogenetic effects in a variety of ways. One method examines the taxonomic distribution of variance to identify the taxa within which character variation is small. The method assumes that taxa with small amounts of variation are those in which little evolutionary change has occurred, and thus variation is unlikely to be independent of ancestral trends. Analyses are then concentrated among taxa that show more variation, on the assumption that greater evolutionary change in the character has taken place. Several methods estimate directly the extent to which ancestry can predict the observed variation of a character, and subtract the ancestral effect to reveal variation of phylogeny. Yet another can remove phylogenetic effects if the true phylogeny is known. One class of comparative methods controls for phylogenetic effects by searching for comparative trends within rather than across taxa. With current knowledge of phylogenies, there is a trade-off in the choice of a comparative method: those that control phylogenetic effects with greater certainty are either less applicable to real data, or they make restrictive or untestable assumptions. Those that rely on statistical patterns to infer phylogenetic effects may not control phylogeny as efficiently but are more readily applied to existing data sets.

The effect of large-surface area dialysis (LS) using dialysate containing both acetate and bicarbonate (LS-C) on a patient's symptomatology was compared with that noted with acetate (LS-A) or bicarbonate (LS-B) in the dialysis fluid. Patients experienced significantly more symptoms and deterioration of objective performance test scores with both LS-A and LS-C than LS-B. Furthermore, a correlation was seen between plasma acetate level at the end of dialysis and decrement in the performance test scores. The results suggest that accumulation of acetate rather than acute alteration in acid-base status is primarily responsible for the morbidity.

The mechanisms by which social supports and personality variables may buffer against psychopathology are not well understood. We studied depression, depressive cognitions, social supports, and self-esteem in a sample of 68 spouse-caregivers of patients with Alzheimer's Disease in an attempt to identify possible buffering mechanisms of the latter two variables. Specifically, we hypothesized that the well-known relation of depressive cognitions to depression would vary as a function of satisfaction with social supports and with level of self-esteem. Hierarchical multiple regression analyses conducted to predict depression revealed significant and independent main effects for depressive cognitions (p less than .01), social supports (p less than .025), and self-esteem (p less than .001), with depressive cognitions associated with higher depression and the other two variables associated with reduced depression (R2 = .53 for the three main effects). In addition, the relation of depressive cognitions with depression varied substantially depending on the level of social supports (p less than .01); caregivers with high levels of depressive cognitions had high levels of depression only if social supports were low (R2 = .61 including interaction). Self-esteem and depressive cognitions showed a similar interaction, but it failed to reach significance. Analyses to determine whether self-esteem and social supports were directly associated with lower depressive cognitive activity yielded a main effect for self-esteem only (p less than .03). Thus, whereas social supports and self-esteem were directly associated with lower depression, only the social supports variable was further associated with reduced depression because it apparently buffered the impact of depressive thinking. Self-esteem was also indirectly associated with lower depression via its relation with lower depressive thinking. Implications of our results for cognitive theories of depression and for the psychosocial mechanisms of stress buffering are discussed.

The effect of reversible blood-brain barrier modification on the delivery of Adriamycin to the brain was studied in a rodent and canine model. Pharmacokinetic and physiological studies were done in these animals after a wide range of doses of Adriamycin (0.1 to 1.0 mg/kg) were administered into the carotid artery following osmotic barrier modification with mannitol. In the absence of barrier modification, no immunoreactive Adriamycin was detected in the cerebrum; whereas, following barrier modification, up to 4.5 micrograms of drug and/or metabolites per g of brain were found. Optimum tissue levels of Adriamycin and metabolites were achieved following barrier modification when the drug was administered by either bolus or slow continuous (15-min) infusion. Immunoreactive drug was identified in brain for up to 6 hr after administration. Significant functional neurotoxicity occurred at all dose levels, even at 0.1 mg/kg, a level at which Adriamycin concentration in the brain was below the level of detectability. Neuropathological examination revealed the presence of necrosis and hemorrhagic infarcts. Thus, these pharmacological and toxicity studies suggest that Adriamycin (or its metabolites) may produce significant clinical neurotoxicity when even small amounts penetrate the blood-brain barrier.

An animal model was developed to describe respiratory muscle work output, blood flow, and oxygen consumption during mechanical ventilation, resting spontaneous ventilation, and the increased unobstructed ventilatory efforts induced by CO2 rebreathing. Almost all of the work of breathing was inspiratory work at all ventilatory levels; thus, only blood flows to the diaphragm and external intercostals increased in the transition from mechanical to spontaneous ventilation, and they further increased linearly as ventilatory work was incrementally augmented ninefold by CO2 rebreathing. No other muscles of inspiration manifest increased blood flows. A small amount of expiratory work was measured at high ventilatory volumes during which two expiratory muscles (transverse abdominal and intercostals) had moderate increases in blood flow. Blood pressure did not change, but cardiac output doubled. Arterial-venous oxygen content difference across the diaphragm increased progressively, so oxygen delivery was augmented by both increased blood flow and increased oxygen extraction at all work loads. Oxygen consumption increased linearly as work of breathing increased, so efficiency did not change significantly. The mean efficiency of the respiratory muscles was 15.5%. These results differ significantly from the patterns previously observed by us during increased work of breathing induced by inspiratory resistance, suggesting a different distribution of work load among the various muscles of respiration, a different fractionation of oxygen delivery between blood flow and oxygen extraction, and a higher efficiency when shortening, not tension development, of the muscle is increased.

Antibiotics vary widely in their ability to penetrate the blood-brain barrier. In studies of 70 rats, the permeability of the normal blood-brain barrier to gentamicin was shown to be poor. In experimental brain abscesses, during the cerebritic stage of development, the penetration of intravenous antibiotics was increased compared to normal brain but was very inconsistent. Antibiotic delivery to brain abscess was not significantly altered with the administration of high-dose steroids, but the macrophage and glial response was markedly decreased with high-dose steroid therapy. Reversible osmotic blood-brain barrier modification with mannitol increased the delivery of gentamicin both to brain abscess and to the surrounding brain. It also resulted in more consistent tissue drug levels. The clinical implications of these studies suggest that, because of the inconsistent delivery of gentamicin to brain abscess, the therapeutic efficacy of medical management alone may be quite variable. This mode of therapy could possibly increase the efficacy of medical management of brain abscesses, especially in patients with multiple or surgically inaccessible brain abscesses.

A bibliography of 199 annotated references was compiled to aid the reader in determining the impact of marijuana on psychomotor, cognitive, and physiological factors considered pertinent to flight performance. The bibliography contains an index which categorizes the references into the following major areas: (1) reviews or overviews of issues, literature or research; (2) psychological effects of marijuana use; (3) physiological and pharmacological research; (4) medical comments and research critiques; and (5) additional reference sources. The basic period of coverage is 1970 to 1975, although selected studies from earlier years are also included.

Theories for the evolution of brain weight in mammals suggest that closely related species have diverged largely as a result of selection for differences in body weight, but that differences among more distantly related species have arisen due to greater net directional selection on brain weight. This pattern of changing selection causes brain weight to evolve more slowly than body weight among closely related species, such as those in the same genus, than among more distantly related species, such as those from different families or orders; a phenomenon known as the "taxon-level effect." Thus, brain weight differs more for a given difference in body weight as the species compared are more distantly related. An alternative explanation for the taxon-level effect is proposed. Distantly related species are more likely to inhabit different ecological conditions than are more closely related species. Where the taxon-level effect occurs, brain weight appears to have evolved in response to the demands of these different ecological conditions. As a consequence, brain weight differs more among distantly related species, for any given difference in body weight, than among closely related species. This effect, rather than a progressive pattern of changing selection pressures, may account for the taxon-level effect in mammals.

In a prospective double-blind study. 12 patients were dialyzed four times each with nasal oxygen (O2) and 4 times each with air throughout acetate dialysis. Fewer symptoms (p less than 0.01), improved postdialysis task performance (p less than 0.04) and a tendency for less mean blood pressure drop (p less than 0.07 two-sided) were noted on O2 dialyses than on air dialyses. The rate of acetate metabolism was increased during O2 dialyses since serum acetate levels were significantly lower at 2, 3 and 4 h. Significant hypoxemia was demonstrated in 10 of these patients on acetate dialysis without O2. These results clearly demonstrate that: (1) prevention Of hypoxemia during dialysis reduces acetate intolerance, and (2) compromised tissue O2 availability may be partly responsible for dialysis morbidity.

This paper describes a pilot study of biomedical and psychosocial risk and the outcome of pregnancy. Ninety-three pregnant women completed four instruments to identify three types of psychosocial risk: life events, family function and social support. Biomedical risk was identified through analysis of self-reported health histories and hospital records. Information on complications of pregnancy was obtained from hospital delivery records. Further complications data were obtained by a home interview at 6 weeks postpartum. In the sample studied, from an agricultural-university community in Eastern Washington, biomedical risk alone was not substantially related to complications. Psychosocial risk was related to both delivery and postpartum complications. Family function was the best single psychosocial predictor. The interaction between family function and biomedical risk also predicted complications reliability. A total of 11% of variance in postpartum complications could be explained jointly by biomedical and psychosocial risk. The results of the study suggest that psychosocial risk assessment alone and in interaction with biomedical risk assessment will offer significant improvement in the identification of women who may experience pregnancy complication.

The ability to deliver enzymatically active human hexosaminidase A across the blood-brain barrier and into brain cells of the normal rat was examined. Following osmotic blood-brain barrier modification in the rat, intraarterially administered human hexosaminidase A and B were shown to cross the barrier and enter brain cells. Subcellular fractionation studies demonstrated that most of the human enzyme delivered across the barrier was functionally active and appeared to be inside a subcellular organelle. These studies provide evidence that blood-brain barrier modification permits delivery of functionally active hexosaminidase A into subcellular organelles consistent with that known to be the appropriate site of physiologic activity.

The present studies were undertaken to evaluate the possibility that hexosaminidase A, the enzyme deficient in Tay--Sachs disease, could be effectively delivered to brain. Previous studies from our laboratory have shown that hypertonic mannitol can be used to osmotically produce reversible disruption of the blood--brain barrier in animals (rat and dog) and man without significant neurotoxicity and that such barrier modification significantly increases the delivery of cytoreductive chemotherapy agents to selected areas of brain. By using the rat model of blood--brain barrier modification and radiolabeled enzyme, increased hexosaminidase A delivery to brain has been demonstrated in more than 85 animals. The time of injection of hexosaminidase A after blood--brain barrier disruption is critical for maximum delivery. Rapid (over 30 sec) intra-arterial administration of hexosaminidase A immediately after blood--brain barrier disruption resulted in a marked increase in enzyme delivery to the brain when compared with controls without prior barrier disruption. When the enzyme was administered 15-20 min after barrier disruption, approximately 50% less hexosaminidase A was delivered; when given 60-120 min after barrier modification, the amount delivered was the same as in control animals. This critical time course is very different than that seen in trials of low molecular weight chemotherapeutic agents (methotrexate and adriamycin). These preliminary studies suggest that hexosaminidase A can be delivered to the brain by blood--brain barrier modification and may be indicative of the potential for enzyme replacement in patients who hae Tay--Sachs disease.

When bacteriophage SP02 infects a Bacillus subtilis culture during or shortly after transformation, the frequency of transformants among the resulting lysogens is greatly reduced relative to that in the uninfected culture. The effect can occur after the deoxyribonucleic acid has been taken up and covalently attached to recipient deoxyribonucleic acid.