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Transdermal delivery of chloroquine by amidated pectin hydrogel matrix patch in the rat.

The aim of the present study was to investigate the suitability of amidated pectin matrix patch for transdermal chloroquine delivery in an effort to mask the bitter taste when orally administered. Chloroquine has easily measurable outputs that are linked to increased renal Na+ excretion. We thus monitored urinary Na+ output in separate groups intravenously administered chloroquine or topically applied pectin hydrogel chloroquine matrix patch. Male groups of anesthetized Sprague-Dawley rats were placed on a continuous jugular infusion of 0.077 M NaCl at 150 microL min(-1). After 3 h equilibration period, consecutive 20 min urine collections were made over the subsequent 4 h of 1 h control, 1 h 20 min treatment, and 1 h 40 min recovery periods for measurements of urine flow and Na+ and K+ excretion rates. The effects of intravenous chloroquine infusion or topical application of pectin hydrogel chloroquine matrix patch were examined in rats in which the drug was added to the infusate or patch applied onto the shaved area during the 1 h 20 min treatment period. The animals were switched back to the infusate alone for the final 1 h 40 min recovery period. Vehicle infused animals acted as controls. Trunk blood was collected after the treatment period from parallel groups for chloroquine measurements. The plasma chloroquine concentrations following iv chloroquine or application of pectin chloroquine hydrogel matrix patch were 9.3 +/- 0.8 mg L(-1) and 7.3 +/- 1.1 mg L(-1) respectively (n = 7 in both groups). Chloroquine infusion and pectin chloroquine patch significantly (p < 0.01) increased Na+ excretion to peak values of 14.1 +/- 0.9 micromol min(-1). and 20.35 +/- 1.0 micromol min(-1), respectively by comparison with controls (9.1 +/- 0.9 micromol min(-1)), at the corresponding period. The results suggest that the pectin chloroquine patch matrix preparation has potential applications for transdermal delivery of chloroquine and perhaps in the management of malaria.

Administration, Cutaneous↗

Food reward: brain substrates of wanting and liking.

What are the neural substrates of food reward? Are reward and pleasure identical? Can taste pleasure be assessed in animals? Is reward necessarily conscious? These questions have re-emerged in recent years, and there is now sufficient evidence to prompt re-examination of many preconceptions concerning reward and its relation to brain systems. This paper reviews evidence from many sources regarding both the psychological structure of food reward and the neural systems that mediate it. Special attention is paid to recent evidence from "tasty reactivity" studies of affective reactions to food. I argue that this evidence suggests the following surprising possibilities regarding the functional components and brain substrates of food reward. (1) Reward contains distinguishable psychological or functional components--"liking" (pleasure/palatability) and "wanting" (appetite/incentive motivation). These can be manipulated and measured separately. (2) Liking and wanting have separable neural substrates. Mediation of liking related to food reward involves neurotransmitter systems such as opioid and GABA/benzodiazepine systems, and anatomical structures such as ventral pallidum and brainstem primary gustatory relays. Mediation of wanting related to food reward involves mesotelencephalic dopamine systems, and divisions of nucleus accumbens and amygdala. Both liking and wanting arise from vastly distributed neural systems, but the two systems are separable. (3) Neural processing of food reward is not confined to the limbic forebrain. Aspects of food reward begin to be processed in the brainstem. A neural manipulation can enhance reward or produce aversion but no single lesion or transection is likely abolish all properties of food reward. (4) Both wanting and liking can exist without subjective awareness. Conscious experience can distort or blur the underlying reward process that gave rise to it. Subjective reports may contain false assessments of underlying processes, or even fail at all to register important reward processes. The core processes of liking and wanting that constitute reward are distinct from the subjective report or conscious awareness of those processes.

Behavior↗

Breed effects on growth performance, carcass characteristics, fatty acid composition, and palatability attributes in finishing steers.

Crossbred steers (n = 136) were used to assess breed differences in growth performance, carcass characteristics, fatty acid composition (total lipids and phospholipids), and palatability attributes of longissimus muscle. A multiple regression model was applied to crossbreeding data to estimate genetic differences between Simmental and Red Angus at the same level of backfat finish (10 mm). Simmental spent 71 more (P < 0.001) days on feed to acquire the same degree of backfat thickness as Red Angus, had heavier (P < 0.001) slaughter weights, larger (P = 0.002) longissimus muscle area, and increased (P = 0.023) lean yield. Average daily gain did not differ (P = 0.297) between breeds. Simmental were less (P = 0.012) efficient in converting feed to gain than Red Angus. Generally, there were few breed differences in palatability attributes for longissimus and semitendinosus muscles, with the exception of increased (P < 0.05) beef flavor scores for Simmental beef vs Red Angus beef across both muscles. For total lipids, concentrations of myristoleic acid (14:1), palmitoleic acid (16:1), and vaccenic acid (18:1n-7), along with n-6 to n-3 fatty acid (n-6:n-3) ratio, were greater (P < 0.05) in Simmental than Red Angus. In contrast, concentrations of margaric acid (17:0), eicosapentaenoic acid (20:5n-3), and total n-3 polyunsaturated fatty acids (n-3 PUFA) were greater (P < 0.05) in Red Angus than Simmental. For phospholipids, Simmental had lower (P < 0.05) amounts of 20:5n-3, docosahexaenoic acid (22:6n-3), and n-3 PUFA, with a greater (P = 0.017) n-6:n-3 ratio. Activity of delta9-desaturase enzyme in the conversion of palmitic acid (16:0) to 16:1 was greater (P = 0.001) in total lipids from Simmental as compared with Red Angus. A genetic basis for fatty acid differences is suggested, although the biological and practical significance needs to be demonstrated.

Animals↗

Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine.

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.

Animals↗

Sex differences in voluntary drinking by Long Evans rats following early stress.

Models for early stress and voluntary drinking were used to determine the contribution of early stress to increased intake of alcoholic beverages during puberty and adulthood. Newborn litters of Long Evans rats were: (1) stressed by daily separation from the mother for 15 min/day on days 1 to 7 of life ["handled" (H)]; or (2) left untouched with the mother on days 1 to 7 of life ["nonhandled" (NH)]. All animals were weaned on day 22, separated by sex (M and F), and caged individually with an assignment of 10 animals per sex per treatment group (H and NH). From 25 to 85 days of age, all animals were given free access to beer containing 5% ethanol (v/v), water, and regular laboratory food. Beer, food, and water intake was measured daily at the same time each day, and animals were weighed weekly. HM had greater ethanol intake and preference for ethanol during the peripubertal period (days 32 to 45), compared with all other groups. There were no differences in ethanol intake between NHF and NHM. HM had greater ethanol preference than HF on 22 of the 60 drinking days. HF consumed the same amount of water as the males and significantly greater amounts of water than NHF on 28 of the 60 drinking days. HM had greater ethanol preference than NHM on 8 of the 60 drinking days. From day 75 to day 85, HF had greater ethanol intake than HM, and NHF had greater ethanol intake than NHM. There were no differences in body weights of HF and NHF throughout the study. Growth of HM lagged behind NHM into adulthood. Early stress of males was linked to increased ethanol intake during the peripubertal and adult periods and stunted body growth into adulthood. Early stress of females was linked to polydipsia (water) throughout development and continuing into adulthood, and to increased alcohol intake in adulthood.

Alcohol Drinking↗

Demographic and psychosocial predictors of fruit and vegetable intakes differ: implications for dietary interventions.

OBJECTIVE: The National Cancer Institute (Rockville, Md) has launched a nationwide initiative--5 A Day for Better Health--to encourage consumption of fruits and vegetables. Because the tastes and culinary uses of fruits and vegetables differ, however, it is not known whether a general 5-A-Day message is an effective intervention strategy. This study examined whether there are differences between the demographic and psychosocial correlates of fruit and vegetable intakes. DESIGN: Data are from the Washington State Cancer Risk Behavior Survey (1995-1996), a cross-sectional, random-digit-dial telephone survey representative of the adult population of Washington State. SUBJECTS/SETTING: Interviews were completed with 1,450 adults. Data were collected about demographic characteristics, health status, health-related behavior, fruit and vegetable intakes, and the following diet-related psychosocial factors: beliefs, motives, barriers, attitudes, and stages of dietary change. STATISTICAL ANALYSES: Multivariate linear regression analysis was used to test whether the associations of demographic characteristics and psychosocial factors with fruit intake differed from associations with vegetable intake. RESULTS: In general, health status, health-related behavior, and psychosocial factors were more strongly associated with fruit intakes than vegetable intakes. For example, regular exercisers consumed 0.44 more daily servings of fruits and 0.36 more servings of vegetables than nonexercisers. Compared with those in the preaction stage of dietary change, adults in the maintenance stage consumed 0.99 more daily servings of fruits and 0.68 more servings of vegetables. Intrinsic motivations for eating a healthful diet (eg, to feel better) were strongly associated with both fruit and vegetable intakes, and these associations were stronger for fruit. Extrinsic motivations were not associated with either fruit or vegetable intakes. APPLICATIONS: Dietary interventions based on a general 5-A-Day message may be more effective in increasing fruit intakes than vegetable intakes. Targeted interventions that focus specifically on vegetables are probably necessary. Intrinsic motives for eating a healthful diet should be key components of interventions to increase fruit and vegetable intakes.

Adult↗

Consumer impressions of Tender Select beef.

With the recent development of technology to classify beef for tenderness, it is now possible for packers and retailers to market brands of beef known to be consistently tender. The present experiment was conducted to determine consumer impressions of Tender Select, a model beef brand comprised of cuts from tender U.S. Select carcasses. A telephone survey was conducted in metropolitan Denver, CO, to recruit consumers (n = 1,036) for this study. Consumers who met minimal limits for household income, age, and beef consumption were invited to participate in a beef shopping and usage study in a local supermarket. Point-of-purchase material was developed that described Tender Select as "the only steak guaranteed tender and lean." When shown a copy of the Tender Select concept card, 89% of participating consumers (n = 759) indicated that they would definitely or probably buy that product. Of those consumers that said they would buy the product, 35% indicated that their purchases of Tender Select would be in addition to their current fresh meat purchases. Most consumers (54.1%) indicated that if Tender Select was available at their grocery store, 1 or 2 of their next 10 purchases of beef cuts would be Tender Select. Sixty-five percent of consumers indicated that if a grocery store carried a line of beef cuts guaranteed to be tender, they would buy all of their beef at that store. Both strip loins from 104 U.S. Select beef carcasses, representing a broad range (8.7 to 43.4 kg; CV = 42%) in slice shear force (SSF) at 14 d postmortem, were used to determine the effect of SSF classification on consumer satisfaction and the correlation among trained sensory panel descriptive attribute ratings and in-home consumer ratings of beef longissimus steaks. Both trained sensory panelists and consumers rated low-SSF steaks higher than the high-SSF steaks for all traits (P < 0.001). All consumer traits (like, tenderness, juiciness, flavor like, flavor amount, and overall satisfaction) were more highly correlated with SSF and trained sensory panel tenderness ratings than with sensory panel flavor or juiciness ratings. These data show that tenderness is the primary determinant of satisfaction among consumers of U.S. Select top loin steaks and that a segment of consumers would pay a premium to purchase guaranteed-tender U.S. Select steaks.

Adult↗

First principles predictions of the structure and function of g-protein-coupled receptors: validation for bovine rhodopsin.

G-protein-coupled receptors (GPCRs) are involved in cell communication processes and with mediating such senses as vision, smell, taste, and pain. They constitute a prominent superfamily of drug targets, but an atomic-level structure is available for only one GPCR, bovine rhodopsin, making it difficult to use structure-based methods to design receptor-specific drugs. We have developed the MembStruk first principles computational method for predicting the three-dimensional structure of GPCRs. In this article we validate the MembStruk procedure by comparing its predictions with the high-resolution crystal structure of bovine rhodopsin. The crystal structure of bovine rhodopsin has the second extracellular (EC-II) loop closed over the transmembrane regions by making a disulfide linkage between Cys-110 and Cys-187, but we speculate that opening this loop may play a role in the activation process of the receptor through the cysteine linkage with helix 3. Consequently we predicted two structures for bovine rhodopsin from the primary sequence (with no input from the crystal structure)-one with the EC-II loop closed as in the crystal structure, and the other with the EC-II loop open. The MembStruk-predicted structure of bovine rhodopsin with the closed EC-II loop deviates from the crystal by 2.84 A coordinate root mean-square (CRMS) in the transmembrane region main-chain atoms. The predicted three-dimensional structures for other GPCRs can be validated only by predicting binding sites and energies for various ligands. For such predictions we developed the HierDock first principles computational method. We validate HierDock by predicting the binding site of 11-cis-retinal in the crystal structure of bovine rhodopsin. Scanning the whole protein without using any prior knowledge of the binding site, we find that the best scoring conformation in rhodopsin is 1.1 A CRMS from the crystal structure for the ligand atoms. This predicted conformation has the carbonyl O only 2.82 A from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 0.62 A CRMS from the crystal structure. We also used HierDock to predict the binding site of 11-cis-retinal in the MembStruk-predicted structure of bovine rhodopsin (closed loop). Scanning the whole protein structure leads to a structure in which the carbonyl O is only 2.85 A from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 2.92 A CRMS from the crystal structure. The good agreement of the ab initio-predicted protein structures and ligand binding site with experiment validates the use of the MembStruk and HierDock first principles' methods. Since these methods are generic and applicable to any GPCR, they should be useful in predicting the structures of other GPCRs and the binding site of ligands to these proteins.

Algorithms↗