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PubMed2006

Multiple microarray platforms utilized for hepatic gene expression profiling of GH transgenic coho salmon with and without ration restriction.

The objectives of this study are to examine hepatic gene expression changes caused by GH transgenesis and enhanced growth. This is the first use of cDNA microarrays to study the influence of GH transgenesis on liver gene expression in a non-mammalian vertebrate, and the first such study using sexually immature animals. Three groups of coho salmon were examined: GH transgenic on full ration (T), GH transgenic on restricted ration (R), and control non-transgenic (C). Specific growth rates for weight in T were approximately eightfold higher than in C, and fourfold higher than in R. Differential gene expression in T, R, and C samples was determined using approximately 3500 and 16,000 gene microarrays, and R and C samples were compared on a different approximately 4000 gene microarray. The use of multiple microarray platforms increased the overall proportion of the hepatic transcriptome considered in these studies. Cross-platform comparisons identified genes behaving similarly between studies. For example, genes encoding a precerebellin-like protein and complement component C3 were downregulated in R relative to C (R < C) in two microarray studies, and hemoglobins alpha and beta were R > C in all three studies. Comparisons of informative gene lists within and between studies inferred causes of altered gene expression. For example, ten genes, including 78 kDa glucose-regulated protein, glycerol-3-phosphate dehydrogenase, hemoglobins alpha and beta, and a C-type lectin, were likely induced by GH transgenesis due to their presence in both T > C and R > C gene lists. Eleven genes, including hepcidin, nuclear protein p8, precerebellin-like, transketolase, and fatty acid-binding protein, were present in both T < C and R < C gene lists and were, therefore, likely suppressed by GH transgenesis. A large number of salmonid genes identified in these studies are involved in iron homeostasis, mitochondrial function, carbohydrate metabolism, cellular proliferation, and innate immunity. Pentose phosphate pathway genes phosphogluconate dehydrogenase, transaldolase, and transketolase, were dysregulated in GH transgenic samples relative to control samples. Changes in the expression of genes involved in maintaining hemoglobin levels (heme oxygenase, hemoglobins alpha and beta, Kruppel-like globin gene activator, hepcidin) in R and T fish indicate a need for additional hemoglobin in the transgenic fish, perhaps due to higher metabolic rate required for enhanced growth.

Animals↗
PubMed1989

A rational approach to anaesthetic premedication.

Rational use of premedication for anaesthesia must always be modified and updated to keep pace with the evolving fields of anaesthesiology and surgery, as well as to meet changing patient needs and preferences. It is no longer axiomatic that all patients require, and therefore should receive, premedication. Unfortunately, a variety of traditional reasons have been proposed to justify routine premedication in many institutions. Smoothing induction, decreasing reflexes and arrhythmias, decreasing nausea and vomiting, decreasing pain, decreasing secretions, and producing sedation and amnesia have all been claimed historically as beneficial results of premedication. Modern anaesthetic agents and techniques have come a long way towards eliminating the routine need for premedication. In the preoperative period, the goal of an anxiety-free patient who is physiologically uncompromised requires an individualised approach based on experience and an adequate knowledge of current pharmacology. As our knowledge of potential problems associated with anaesthesia has expanded, we have added other classes of drugs such as the H2-histamine receptor blockers and antacids to our premedicant armamentarium. Outpatient and short-stay patients have further challenged our preoperative goal of an anxiety-free patient by requiring individuals to be 'street ready' within a brief period of time after surgery. Even for in-house elective procedures, not every patient is a candidate for routine premedication. A frank preoperative discussion is all that is necessary to effectively allay anxiety in many persons. In these and other special situations, this article will hopefully guide the reader toward a more rational approach to premedicating patients.

Barbiturates↗
PubMed1996

Rational prescribing of antibacterials in ambulatory children.

The rational prescribing of oral antimicrobial agents for bacterial infections in children who can be treated in an ambulatory setting is the subject of this review. First, restrictive use of antibacterials is advocated to avoid widespread development of bacterial resistance. The use of simple methods, suitable for office use, to discern viral from bacterial infections is recommended. Second, in selecting an antimicrobial agent, the physician should consider a number of distinctive features of each agent. Besides aspects of pharmacokinetics, antibacterial spectrum and tolerability, the number of daily doses and, of particular importance for children, the palatability of suspensions plays an important role in achieving patient compliance. Agents that can be administered once or twice daily and possess an agreeable taste in addition to proven efficacy, established tolerability and a reasonable price are to be preferred. Specific paediatric aspects in choosing among penicillins, cephalosporins, macrolides and other oral antibacterials are discussed. For pharmacoeconomic reasons, the optimal duration of antibacterial treatment and the role of short course therapy for various bacterial infections should be studied in more detail. Finally, rational antimicrobial treatment of common paediatric bacterial infections, such as streptococcal tonsillopharyngitis, acute otitis media, acute sinusitis, bacterial pneumonia, pertussis, Lyme borreliosis (early stage) and lower urinary tract infection is reviewed.

Ambulatory Care↗
PubMed1996

Rational prescribing of antibacterials in hospitalised children.

The subject of this review is the rational prescribing of antimicrobial agents for the therapy of serious community-acquired infections in hospitalised infants and children. First, cost-containment strategies such as streamlining of antibacterial therapy, outpatient parenteral antibacterial therapy and sequential ('stepdown') therapy with parenteral followed by oral therapy are reviewed. In most of these areas, paediatric studies are scant or lacking. Then specific paediatric aspects of the choice of parenteral antibacterials such as penicillins, cephalosporins, aminoglycosides, macrolides and other agents are discussed. With particular reference to cost containment, rational treatment strategies for some serious bacterial infections such as meningitis, occult bacteraemia, endocarditis, osteomyelitis, arthritis, pyelonephritis, Lyme borreliosis (advanced stages) and pneumonia are proposed. In most of these disease, there is potential for cutting treatment costs and studies that compare these newer strategies with traditional treatment regimens are urgently needed.

Anti-Infective Agents↗
PubMed2005

Rational inhibitor design and iterative screening in the identification of selective plasmodial cyclin dependent kinase inhibitors.

New chemical classes of compounds must be introduced into the malaria drug development pipeline in an effort to develop new chemotherapy options for the fight against malaria. In this review we describe an iterative approach designed to identify potent inhibitors of a kinase family that collectively functions as key regulators of the cell cycle. Cyclin-dependent protein kinases (CDKs) are attractive drug targets in numerous diseases and, most recently, they have become the focus of rational drug design programs for the development of new antimalarial agents. Our approach uses experimental and virtual screening methodologies to identify and refine chemical inhibitors and increase the success rate of discovering potent and selective inhibitors. The active pockets of the plasmodial CDKs are unique in terms of size, shape and amino acid composition compared with those of the mammalian orthologues. These differences exemplified through the use of screening assays, molecular modeling, and crystallography can be exploited for inhibitor design. To date, several classes of compounds including quinolines and oxindoles have been identified as selective inhibitors of the plasmodial CDK7 homologue, Pfmrk. From these initial studies and through the iterative rational drug design process, more potent, selective, and most importantly, chemically unique compound classes have been identified as effective inhibitors of the plasmodial CDKs and the malarial parasite.

Amino Acid Sequence↗
PubMed2001

Rational drug design of DNA oligonucleotides as HIV inhibitors.

DNA oligonucleotides as anti-HIV therapeutic agents have been developed for more than a decade. Numbers of oligonucleotides have been designed as potential anti-HIV inhibitors. Here we summarized the designed anti-viral oligonucleotides in last decade and divided the designed DNA HIV inhibitors into three categories: (i) antisense inhibitors, (ii) triplex inhibitors and (iii) G-quartet inhibitors, based upon their inhibitory mechanism and structures. Also we proposed a strategy of rational drug design of anti-HIV oligonucleotides, which includes several critical steps, such as (1) structure-based rational drug design, (2) chemical synthesis/combinational chemistry, (3) the determination of structural properties, (4) assays of the inhibition of HIV-1 IN and virus replication, and (5) 3D QSAR operation. This methodology has been used by the design of G-quartet inhibitors.

Anti-HIV Agents↗
PubMed1993

Rational behavior training effectiveness for white and nonwhite incarcerated felons.

45 incarcerated male felons in a medium-security state correctional institution participated in a Rational Behavior Training treatment outcome study. 58% of the subjects were white, 18% were African-American, 17% were Hispanic, and 7% were classified as other. Subjects were selected from an institutional group-therapy waiting list and randomly assigned to one of four group facilitators. The Novaco Provocation Inventory, Buss-Durkee Hostility Inventory, and Rational Behavior Training Concepts Test were administered before and after the 10-wk. treatment period. No differences in gain scores (pretest minus posttest) were observed although the slightly greater improvement on the concepts test by subjects of ethnic minority encourages further study.

Adult↗
PubMed1999

Sex and the Barnum effect: rationality versus helpfulness.

In 1998 Piper-Terry and Downey found that women accepted friends' bogus test interpretations more readily than did men and the researchers attributed this to women's helpfulness. Layne countered that women are more open and thus rationally expected their friends' interpretations to be more accurate. Later Downey asked participants how accurately they believed their friends could describe their personalities. Although this pilot study's sensitivity to differences was low, the women's accuracy ratings still tended to exceed those of men (p < .06) as Layne predicted. This may suggest that the rationality hypothesis is better supported than the female-helpfulness hypothesis.

Adult↗
PubMed2006

Fermentation quality and nutritive value of a total mixed ration silage containing coffee grounds at ten or twenty percent of dry matter.

Six wethers were used in a replicated 3 x 3 Latin square to study the fermentation quality and nutritive value of total mixed ration (TMR) silages that included wet coffee grounds (WCG). The TMR were prepared using a commercial compound feed, timothy hay, alfalfa hay, dried beet pulp, and a vitamin-mineral supplement in a ratio of 36.5:30:20:12:1.5, respectively, on a DM basis, with timothy hay and alfalfa hay being replaced by WCG at 0, 10, or 20%. All TMR silages, irrespective of WCG addition, were well preserved, with a low pH and ammonia-N content and a high lactic acid content. Intakes by wethers of TMR silages containing 0 and 10% WCG were 96.6 and 94.8 g/kg of BW(0.75), and did not differ (P > 0.05). Intake of TMR silage containing 20% WCG was 76.8 g/kg of BW(0.75), which was equal to 80% of that of the TMR silage with no WCG (quadratic: P < 0.01). Increasing concentrations of WCG in the rations decreased the digestibility of DM, CP, ADF, NDF, and energy, and increased that of ether extract (P < 0.05). The TDN and DE contents of the TMR silages with 0 and 10% WCG were similar, but the TMR silage with 20% WCG was lower (P < 0.05). With progressive increases in WCG concentrations, N intake did not differ, but fecal and urinary N increased linearly (P < 0.001), and retained N decreased linearly (P < 0.001). This study demonstrated that the proportion of WCG to be incorporated into TMR silages should not exceed 10% of the DM.

Ammonia↗
PubMed1991

Rationality and cost-effectiveness of diagnosis and treatment of group A streptococci in primary care patients with pharyngitis.

Rationality and cost-effectiveness of several strategies for diagnosing and treating sore throat patients were evaluated in primary care. In an empirical material of 2016 patients, 3 different bacteriological methods (traditional culture, slide culture, and latex agglutination test) for the detection of group A beta-hemolytic streptococci (GAS) were compared. Sensitivity analyses were done for several variables, including GAS test performance, testing frequencies, medication rates, and accuracy of clinical evaluation. The amounts of unnecessary medication varied from 19 to 33%, and there were 2.2-8.9% of untreated GAS infections. Strategies based on bacteriology achieved more rational and economic results than treating no one, treating all patients, or using clinical evaluation without bacteriology. The cost-effectiveness of the latex agglutination test depended on the sensitivity of the test. The results were further sensitive to sick leave lengths, cost of antibacterials, and clinical accuracy, but not to GAS test cost. Rapid tests for GAS detection can be recommended, if the sensitivity of the test in the actual working conditions is acceptable.

Absenteeism↗
PubMed1993

Rational recovery: alternative to AA for addiction?

Rational Recovery (RR) is a new self-help movement for substance abusers, with a cognitive orientation. It has been suggested as an alternative to Alcoholics Anonymous. This study was designed to examine the nature of RR and its impact on those who join. A national sample of 433 substance-abusing people attending 63 established RR groups was evaluated, using codable self-report questionnaires completed at RR meetings. Members were mostly men with college experience who had previously attended AA. Among recruits who attended their first RR meeting in the last month, 38% were abstinent in the last month. Among members who had joined 3 or more months before, 73% were abstinent in the last month; they had attended an average of 4.1 RR meetings in that month, and carried out exercises at home based on Rational Emotive Therapy. Among those who joined 6 or more months before, 58% reported at least 6 months of abstinence. Among members with a history of heavy cocaine use, the portion reporting abstinence in the last month was not significantly different from those who had never used cocaine. The minority of members who were engaged for 3 months were still drinking, though, and did so on an average of 9.9 days in the last month. RR succeeded in engaging substance abusers and promoting abstinence among many of them while presenting a cognitive orientation that is different from the spiritual one of AA. Its utility in substance abuse treatment warrants further assessment.

Adult↗
PubMed1980

Rationing: how it is done with community services for the older disabled.

A number of studies have estimated the prevalence of needs for long-term community services. However, these needs inevitably exceed the services available, and little has been done to show how the supply of services is actually rationed. In 1973, allocations were studied among the patients of a well-provided rural group practice. All those aged 65 and over who had, on a fixed date, been receiving home help, home nursing, meals service, or day care in the previous two months were interviewed (N = 145), together with a comparison group composed by a 1 in 6 random sample of practice patients in the same age group (N = 149). The needs regularly considered by local agents of referral were analysed and ordered by severity. Assuming that a less severe category of cases was not normally accepted in the place of more severe categories known to be waiting, it was possible to show what categories of cases constituted a normal claim on services at this level of resources, together with the numbers of these cases per 1000. The method used is suitable for comparing the rationing process in areas with different levels of resources or needs, and for identifying the categories who suffer as a result of a given difference of resources.

Aged↗
PubMedDate not supplied

Chance favors the prepared mind--from serendipity to rational drug design.

Accidental discoveries always played an important role in science, especially in the search for new drugs. Several examples of serendipitous findings, leading to therapeutically useful drugs, are presented and discussed. Captopril, an antihypertensive Angiotensin-converting enzyme inhibitor, was the first drug that could be derived from a structural model of a protein. Dorzolamide, a Carboanhydrase inhibitor for the treatment of glaucoma, and the HIV protease inhibitors Saquinavir, Indinavir, Ritonavir, and Nelfinavir are further examples of therapeutically used drugs from structure-based design. More enzyme inhibitors, e.g. the anti-influenza drugs Zanamivir and GS 4104, are in clinical development. In the absence of a protein 3D structure, the 3D structures of certain ligands may be used for rational design. This approach is exemplified by the design of specifically acting integrin receptor antagonists. In the last years, combinatorial and computational approaches became important methods for rational drug design. SAR by NMR searches for low-affinity ligands that bind to proximal subsites of an enzyme; linkage with an appropriate tether produces nanomolar inhibitors. The de novo design program LUDI and the docking program FlexX are tools for the computer-aided design of protein ligands. Work is in progress to combine such approaches to strategies for combinatorial drug design.

Animals↗
PubMed2000

Least-cost ration formulations for Holstein dairy heifers by using linear and stochastic programming.

Four mathematical programming models were developed to formulate rations for large breed replacement dairy heifers in each of 11 different weight classes from 50 to 550 kg and daily growth rates of 600, 700, and 800 g, with the objective of achieving a final calving weight of 600 kg. First, a base linear programming model was developed; then, to account for variability in the crude protein content of ration ingredients three other methods were used: right-hand side adjustment, incorporation of a safety margin, and stochastic programming. The average daily cost to calving, given a daily gain of 600, 700, and 800 g, was $0.62, $0.64, and $0.68, respectively. The total feed cost to 600 kg was $89.87 more for a growth rate of 600 over 800 g/d. The stochastic programming model performed better, on the bases of cost and protein-feeding, than did the right-hand side adjustment or the safety margin methods. The stochastic programming model over-adjusted crude protein by 5% and cost an average of 3.5% more than the linear programming solution for a dairy heifer growing at 800 g/d with a desired probability of 80% of crude protein intake achieving the NRC minimum. The other two methods over-adjusted crude protein by 10 and 13% and cost an extra 5.5 and 7.6%, respectively, for the right-hand side adjustment and the safety margin methods.

Animal Feed↗
PubMed2001

Comparison of fatty acid content of milk from Jersey and Holstein cows consuming pasture or a total mixed ration.

Holstein (n = 19) and Jersey (n = 18) cows were used to study effects of two feeding systems on fatty acid composition of milk. Confinement cows were fed a total mixed ration with corn silage and alfalfa silage and pastured cows grazed a crabgrass (90%) and clover (10%) pasture and were allowed 5.5 kg of grain per head daily. Two milk samples were collected from each cow at morning and afternoon milkings 1 d each week for four consecutive weeks in June and July 1998. One set of milk samples was analyzed to determine fatty acid composition, and the second set was used for crude protein and total fat analyses. Data were analyzed by the general linear models procedure of SAS, using a split-plot model with breed, treatment, and breed x treatment as main effects and time of sampling and week as subplot effects along with appropriate interactions. Milk from pastured cows was higher than milk from confinement cows for the cis-9, trans-11 octadecadienoic acid isomer of conjugated linoleic acid (CLA). Also, milk from Holsteins was higher than milk from Jerseys for C16:1, C18:1, and CLA and lower than Jerseys for C6:0, C8:0, C10:0, C12:0, and C14:0. Several treatment x week interactions existed, but main effects were still important; for example, proportions of CLA in milk of grazed cows were relatively constant across weeks (0.66, 0.64, 0.64, and 0.69% +/- 0.02%, respectively), but the CLA in milk of confinement cows increased in wk 4 (0.35, 0.31, 0.31, and 0.48% +/- 0.02% for wk 1 to 4, respectively). There are potentially important differences in fatty acid composition of milk from cows consuming a warm season pasture species compared with milk from cows consuming a total mixed ration, as well as differences between Holstein and Jersey breeds.

Animal Feed↗
PubMed2002

Digestibility by dairy cows of monosaccharide constituents in total mixed rations containing citrus pulp.

Ten lactating cows were divided into two groups and individually fed ad libitum one of two experimental total mixed rations (TMR) as follows: 1) a TMR containing 20% corn grain and 10% dry citrus pulp (high corn); and 2) a TMR containing 21% citrus pulp and 9% corn grain (high citrus pulp). Both TMR also contained corn silage (28%), legume haylage (19.5%), extruded full fat soybeans (13.5 to 14%), soybean meal (6.5%), and minerals and vitamins. Voluntary dry matter intake of cows consuming the high corn ration tended to be higher than for cows in the high citrus pulp group (22.2 vs. 20.7 +/- 1.0 kg/cow per day, respectively). Digestibility of NDF was higher for the TMR with high citrus pulp compared with the TMR with higher corn. Across treatments, neutral detergent fiber (NDF) glucose was more digestible than NDF xylose and uronic acids and less digestible than NDF arabinose, galactose, and mannose. Digestibility of total neutral detergent soluble carbohydrates was also higher in the high citrus pulp group (86.8, high citrus pulp vs. 80.3 +/- 1.7%, high corn); with glucose and uronic acids accounting for most of that difference. Consequently, higher total carbohydrate digestibility was obtained in the TMR containing higher citrus pulp compared with the TMR with a higher percentage of corn (77.1 and 72.5 +/- 1.0%, respectively). Slightly lower carbohydrate intake in cows fed higher citrus pulp was compensated by higher digestibility of carbohydrates and protein. Thereby, partial replacement of corn by citrus pulp in TMR of high producing dairy cows improved feed efficiency.

Animal Feed↗
PubMed2005

Monensin for lactating dairy cows grazing mixed-alfalfa pasture and supplemented with partial mixed ration.

The effect of monensin on milk production was evaluated in 58 lactating Holstein cows (48 multiparous; 10 primiparous) grazing a mixed-alfalfa pasture and supplemented with a partial mixed ration in a completely randomized design with repeated measurements. Cows were paired by calving date, lactation number, previous lactation milk production, body weight, and body condition score and were assigned to one of 2 treatments: control or monensin. Cows on the monensin treatment received 2 monensin controlled-release capsules (335 mg/d for 90 d), one 30 d before the expecting calving date and the other 60 d after calving. Short-term (0 to 150 d in milk) and long-term (305-d adjusted lactation) effects of monensin were evaluated. Pasture (measured by difference between pre- and postgrazing pasture mass), supplements, and total dry matter intake did not differ between treatments and averaged 8.7, 14.1, and 22.9 kg/d, respectively. In the short-term, monensin increased milk production (27.7 vs. 26.6 kg/d) and milk protein yield (0.890 vs. 0.860 kg/d); milk fat yield was not affected (0.959 kg/d). Monensin decreased milk fat content (3.51 vs. 3.60%) with no changes in milk protein content (3.25%). In the long term, milk production and milk protein yield were also increased by monensin: 214 and 7 kg, respectively. Monensin reduced the loss of body condition score and increased percentage of pregnancy at first service (44.8 vs. 20.7%). Monensin improves production and reproduction performance of dairy cows grazing a mixed-alfalfa pasture and supplemented with a partial mixed ration.

Animals↗
PubMed2006

Effects of physically effective fiber on digestive processes and milk fat content in early lactating dairy cows fed total mixed rations.

Data from recent research studies were analyzed quantitatively, and the random effect of experiment was assessed to define the physiological responses of dairy cows in early lactation to intake of physically effective neutral detergent fiber (peNDF). All studies were conducted with lactating Holstein cows (84.8 +/- 3.54 days in milk) in Latin square designs, and feeds were offered ad libitum as total mixed rations (TMR). The peNDF was estimated by 2 measurement techniques, the NDF content of TMR multiplied by amount of dry matter (DM) retained on a 1.18-mm screen (peNDF(> 1.18)) and NDF content of TMR multiplied by the proportion of DM retained by 19- and 8-mm Penn State Particle Separator screens (peNDF(> 8)). Other factors, including concentrations of NDF, forage NDF, non-fiber carbohydrates, the amount of digestible organic matter of forages (FDOM), and the intake of ruminally degradable starch (RDSI) from grain in the diet were also investigated. The studied animal response variables included feed intake, ruminal fermentation, chewing activity, fiber digestibility, and milk production and composition. The ruminal pH (day mean) in this study ranged from 5.30 to 6.59. Using peNDF(> 1.18) approach, the requirements for physically effective fiber in high-yielding dairy cows fed TMR in an ad libitum intake were estimated to be about 19% of ration DM or 4.1 kg/d or 0.6 kg/100 kg of body weight to maintain a ruminal pH of about 6.0. When peNDF was measured as peNDF(> 8), ruminal pH responded in a quadratic fashion but the confidence of estimation was lower (R(2) = 0.27) compared with the peNDF(> 1.18) approach (R(2) = 0.67). Results of these data analyses showed that peNDF(> 1.18) provided a satisfactory estimation of the mean ruminal pH (R(2) = 0.67) and NDF digestibility (R(2) = 0.56). Furthermore, peNDF(> 1.18) was poorly, although positively, correlated to daily chewing (R(2) = 0.17), and rumination (R(2) = 0.24) activity. On the other hand, results from these analyses showed that milk parameters are less sensitive to the effects of dietary peNDF than other variables, such as ruminal pH, chewing activity, and fiber digestibility. Dietary FDOM correlated positively (moderately) to ruminal pH (R(2) = 0.24), daily chewing (R(2) = 0.23), and rumination (R(2) = 0.29) activity, whereas the daily RDSI from grain correlated negatively to ruminal pH (R(2) = 0.55) and positively to total volatile fatty acids (R(2) = 0.27). Inclusion of FDOM and RDSI from grain along with peNDF(> 1.18) in the models that predict rumen pH further improved the accuracy of prediction. This approach appeared to further complement the concept of peNDF that does not account for differences in ruminal fermentability of feeds.

Animal Feed↗