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PubMed2006

Digestive performance in five Mediterranean lizard species: effects of temperature and insularity.

Temperature sensitivity of digestive processes has important ramifications for digestive performance in ectothermic vertebrates. We conducted a comparative analysis of temperature effects on digestive processes [gut passage times (GPTs) and apparent digestive efficiencies (ADEs)] in five lacertid lizards occurring in insular (Podarcis erhardii, P. gaigeae), and mainland (P. muralis, P. peloponnesiaca, Lacerta graeca) Mediterranean environments. GPTs were negatively correlated to temperature with mainland taxa having 10-20% longer GPTs than island taxa. In contrast to previous studies that estimate ADEs using bomb calorimetry, we compare ADEs by analyzing discrete efficiencies for lipids, sugars and proteins at three temperature regimes (20, 25, and 30 degrees C); each of these categories produces different results. ADEs for lipids and sugars showed a monotonic increase with temperature whereas ADEs for proteins decreased with temperature. Island taxa had consistently higher ADEs than their mainland counterparts for lipids and for proteins but not for sugars. They are characterized by superior energy acquisition abilities despite significantly shorter GPTs. Their increased digestive performance relative to the mainland species appears to allow them to maximize energy acquisition in unproductive island environments where food availability is spatially and seasonally clustered.

Animals↗

PubMed1987

Phosphorolytic cleavage of 2-fluoroadenine from 9-beta-D-arabinofuranosyl-2-fluoroadenine by Escherichia coli. A pathway for 2-fluoro-ATP production.

2-Fluoroadenine (F-Ade) is a metabolite of 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) that may be involved in the development of toxic side effects from this anticancer drug. The liberation of F-Ade from F-ara-A has been examined in different biological systems. Extracts of Escherichia coli but not mammalian cells or tissues catalyzed the conversion of F-ara-A to F-Ade with apparent Km and Vmax values of 1350 microM and 7.7 nmol/min/mg protein respectively. This reaction depended on the presence of phosphate and was inhibited by purine nucleosides in a competitive manner, indicating that the enzyme responsible for the conversion is purine nucleoside phosphorylase. After incubation of intact bacteria with 100 microM [3H]F-ara-A, [3H]F-Ade was the same percentage of cellular radioactivity as in the medium, but it was only one-tenth the concentration of F-ara-A in the cells. In contrast, the cellular concentration of 2-fluoro-ATP was 20-fold greater than that of F-ara-A-5'-triphosphate. These results suggest that F-ara-A entered the bacteria intact and was phosphorolytically cleaved to liberate F-Ade, which would have been either anabolized to the toxic triphosphate or excreted. The latter pathway would provide a route by which F-Ade might be absorbed into the host circulation.

Adenine↗

PubMed1996

Effect of sequence contexts on misincorporation of nucleotides opposite 2-hydroxyadenine.

Twelve oligonucleotides containing 2-hydroxyadenine (2-OH-Ade) with different neighboring bases were used as templates in DNA polymerase reactions,and the effects of the sequence contexts were investigated. DNA polymerases alpha and beta inserted dTMP and dCMP opposite 2-OH-Ade in most of the oligonucleotides tested. The Klenow fragment of DNA polymerase I primarily incorporated dTMP and dGMP. Effects of the 5'-flanking base of 2-OH-Ade was found when the 3'-flanking base of 2-OH-Ade was A or C. Incorporation of dAMP occurred when the oxidized base was located in a 5' -TA*A- 3' (A* represents 2-OH-Ade) sequence. These results suggest that the formation of 2-OH-Ade in DNA may induce all the mutations involving A (A-->G transition, and A-->T and A-->C transversions) in cells.

Animals↗

PubMed1988

A1 and A2 adenosine receptor regulation of erythropoietin production.

The effects of adenosine (ADE) and ADE agonists on erythropoietin (Ep) production were determined using percent (%) 59Fe incorporation in red cells of exhypoxic polycythemic mice. The hemisulfate salt of ADE produced a significant increase in % 59Fe incorporation in response to hypoxia in concentrations of 400 to 1600 nmol/kg/day (i.v.). 5'-N-ethyl-carboxamideadenosine (NECA), a selective A2 receptor agonist, increased radioiron incorporation in a dose-dependent manner (10-100 nmol/kg/day, i.v.). In contrast, N6-cyclohexyladenosine (CHA), a selective A1 receptor agonist, did not affect radioiron incorporation in concentrations up to 1600 nmol/kg/day (i.v.). Albuterol, a beta 2-adrenergic agonist, enhanced % 59Fe incorporation in polycythemic mice and low doses of CHA (50 and 100 nmol/kg/day), which were not effective alone on % 59Fe incorporation in polycythemic mice exposed to hypoxia, inhibited the enhancement in radioiron induced by albuterol (25 and 100 micrograms/kg/day, i.p.) plus hypoxia. Theophylline (20 and 80 mg/kg/day, i.p.), a well-known antagonist of ADE receptors, blocked the ADE and NECA enhancement in radioiron incorporation at a dose of theophylline alone which produced only a slight enhancement of % 59Fe incorporation. These results suggest that ADE may both inhibit through A1 receptor activation and increase via A2 receptor stimulation the production of Ep.

Adenosine↗

PubMedDate not supplied

L-glutamate abolishes differential responses to alcohol deprivation in mice.

Hybrid mice produced by crossing CBA and C57BL lines were deprived of alcohol for three days after prolonged prior access. Subsequently, when access was first given to a flavored 30% alcohol solution, about half of the mice showed a greatly elevated rate of drinking during the first 1.5 h, characteristic of the alcohol-deprivation effect (ADE), but other mice showed no increase. Repeating the test three weeks later showed that having or lacking an ADE is a stable group characteristic. Behavioral differences were found on cross-maze and slip funnel tests between mice that had an ADE and those that lacked it. Topical application of L-glutamate to the frontal cortex prevented the subsequent elevation of alcohol drinking during the first 1.5 h after deprivation but did not alter drinking during the remaining 22.5 h. L-glutamate treatment also affected those cross-maze behaviors found to be related to the ADE. The results suggest that frontal cortex neurons sensitive to L-glutamate are necessary for the ADE and that comparisons between hybrid mice having and lacking an ADE might be used for determining the neuronal mechanisms responsible for the effect.

Alcohol Drinking↗

PubMed2005

Effect of artificial tears on visual acuity.

PURPOSE: To study the effect of commonly used preservative free artificial tear, carboxymethylcellulose (CMC) 0.5% (Refresh Plus, Allergan, Irvine, California) on visual acuity in symptomatic dry eye (SDE) and asymptomatic dry eye (ADE) patients. DESIGN: Nonrandomized prospective clinical trial. METHODS: Prospective study involving 20 patients (40 eyes) with SDE and 20 patients (40 eyes) with ADE, all 40 years and older, were recruited from a clinic setting over a 1-month period. Distance visual acuity was measured by the Early Treatment of Diabetic Retinopathy Study (ETDRS) vision chart and near visual acuity was measured by the Lighthouse Near Vision chart before and 30 seconds after instillation of one drop of CMC. Distance and near visual acuity was measured both with and without correction. The duration of action of CMC was measured at 1-minute intervals until the patient's visual acuity returned to pretear level. RESULTS: In both SDE and ADE groups, uncorrected and corrected near and distance vision showed a statistically significant improvement after the use of CMC (P < .05). There was no statistically significant difference in improvement between the SDE and ADE groups in all categories (P values > .05). The mean duration of improvement of vision was 2.93 minutes in the SDE group and 3.70 minutes in the ADE group (P = .036). CONCLUSIONS: CMC 0.5% provides a temporary yet significant improvement in the visual acuity of SDE and ADE patients. The effect of artificial tears on visual acuity may be of diagnostic value in detecting ocular surface abnormality in symptomatic and asymptomatic patients.

Aged↗

PubMed2001

Eulerian derivation of the fractional advection-dispersion equation.

A fractional advection-dispersion equation (ADE) is a generalization of the classical ADE in which the second-order derivative is replaced with a fractional-order derivative. In contrast to the classical ADE, the fractional ADE has solutions that resemble the highly skewed and heavy-tailed breakthrough curves observed in field and laboratory studies. These solutions, known as alpha-stable distributions, are the result of a generalized central limit theorem which describes the behavior of sums of finite or infinite-variance random variables. We use this limit theorem in a model which sums the length of particle jumps during their random walk through a heterogeneous porous medium. If the length of solute particle jumps is not constrained to a representative elementary volume (REV), dispersive flux is proportional to a fractional derivative. The nature of fractional derivatives is readily visualized and their parameters are based on physical properties that are measurable. When a fractional Fick's law replaces the classical Fick's law in an Eulerian evaluation of solute transport in a porous medium, the result is a fractional ADE. Fractional ADEs are ergodic equations since they occur when a generalized central limit theorem is employed.

Computer Simulation↗

PubMed1979

Preferential incorporation of an exogenous cytokinin, N6-benzyladenine, into 18S and 25S ribosomal RNA of tobacco cells in suspension culture.

Cytokinin-requiring tobacco cells were incubated for 10 h in the presence of a labeled cytokinin. N6-benzyl-[2-3H]Ade, and of [8-14C]Ado. After alkaline hydrolysis of total RNA and fractionation of the resulting nucleotides, 80 per cent of the 3H radioactivity of RNA were recovered as the N6-benzyl-Ado nucleotide, covalently inserted into polynucleotidic chains. The N6-benzyl-Ado nucleotide was not significantly labled by 14C: at most one part of this nucleotide per 10 000 may result from a transfer of the benzyl moiety to adenyl residues in preformed RNA. Thus, the covalent insertion of N6-benzyl-Ade into RNA involves the intact N6-substituted base. Total RNA was fractionated either by sucrose density gradient centrifugation or by polyacrylamide gel electrophoresis. All identified RNA species were shown to contain N6-benzyl-Ade. The insertion frequency, measured as the molecular proportion of N6-benzyl-Ade to the total base content, was 3 to 4 times larger in 25S and 18S rRNA than in 5S and 4S RNA. The amount of N6-benzyl-Ade inserted into cytoplasmic ribosomal RNA accounted for about 90 per cent of the amount incorporated into total RNA. Electrophoresis of denatured RNA in the presence of formamide provided additional evidence that N6-benzyl-Ade was indeed incorporated into RNA molecules.

Adenine↗

PubMed1998

2-Hydroxyadenine, a mutagenic form of oxidative DNA damage, is not repaired by a glycosylase type mechanism in rat organs.

Oxygen radicals are known to play a role in causing cellular DNA damage, which is involved in carcinogenesis. 8-Hydroxyguanine (8-OH-Gua) is a major form of oxidative DNA damage and is known as a useful marker of DNA oxidation. Recently, we found another type of oxidative DNA damage, 2-hydroxyadenine (2-OH-Ade), which has a mutation frequency comparable to that of 8-OH-Gua. We compared the repair activities for two types of oxidative DNA damage, 8-OH-Gua and 2-OH-Ade, in 7-week-old male Sprague-Dawley (SD) rat organs. The repair activities were measured by an endonuclease nicking assay using 22 mer [32P]-end-labeled double-stranded DNA substrates, which contained either 8-OH-Gua (opposite C) or 2-OH-Ade (opposite T or C). In all of the SD rat organs we studied, the nicking activity for 2-OH-Ade was not detected, while that for 8-OH-Gua was clearly detected with the same conditions. Moreover, the 2-OH-Ade nicking activity was not induced in Wistar rat kidney extracts prepared after ferric nitrilotriacetate (Fe-NTA) treatment, which is known to increase 8-OH-Gua repair activity. These results suggest that 2-OH-Ade might not be repaired by the glycosylase type mechanism in mammalian cells.

Animals↗

PubMed2000

Systematic root cause analysis of adverse drug events in a tertiary referral hospital.

BACKGROUND: Adverse drug events (ADEs) occur frequently, and serious ADEs are associated with mortality or prolonged morbidity. As many ADEs are preventable, identification and modification of systems and processes that permit ADEs has the potential to reduce the rate of ADEs. METHODS: Root cause analysis was systematically employed in a blame-free fashion to investigate the patterns of serious ADEs that occurred during a 29-month period at Hermann Hospital (Houston), and process improvements were implemented on the basis of these findings. The consistently nonpunitive responses to the results of the initial and subsequent root cause analyses was gradually seen, accepted, and ultimately embraced by the hospital staff. RESULTS: The most commonly identified root causes were environmental factors (for example, increased census, increased acuity, change of shift) and staffing issues (for example, personnel new to a unit). Policy changes that led to increased use of forcing or constraining functions (for example, removal of concentrated intravenous potassium solutions from floor stocks) and better personnel support (for example, early awareness and response to localized increases in census and acuity) were particularly effective. Although limited by our lack of active surveillance and not necessarily directly due to the process changes that we implemented, the rate of voluntarily reported serious ADEs/100,000 patient days decreased during this time from 7.2 to 4.0, a decline of 45% (p < 0.001). CONCLUSION: Systematic application of root cause analysis followed by implementation of process changes that target the underlying cause(s) of each event can be successfully implemented in a large hospital.

Adverse Drug Reaction Reporting Systems↗

PubMed1995

The incident reporting system does not detect adverse drug events: a problem for quality improvement.

OBJECTIVES: The objectives of this study were 1) to determine the frequency with which adverse drug events result in an incident report (IR) in hospitalized patients; and 2) to determine if there were differences between quality assurance administrators, nurse leaders in quality assurance, and staff nurses as to whether an incident report should or would be filed for each adverse drug event. STUDY DESIGN: All patients admitted to five patient care units (one medical intensive care unit, two surgical intensive care units, and two medical general care units) in one academic tertiary care hospital were studied between February and July 1993. The main outcome measures used were adverse drug events (ADEs) and IRs. Consensus voting was used by senior hospital administrators, nursing leaders, and staff nurses to determine whether an adverse drug event should have been reported and would have been reported. RESULTS: Of 54 adverse drug events identified by the study, only 3 patients (6%) had a corresponding incident report submitted to the hospital's quality assurance program or called into the pharmacy hotline. One additional ADE was identified by an IR, but not by the ADE study. Of the 55 ADEs, 15 were preventable, and 26 were serious or life-threatening, yet only 2 of the 26 led to an incident report. The three voting groups agreed that most ADEs justified an IR, but judged that in actual practice, an IR would infrequently have been filed. CONCLUSIONS: Voluntary reporting identified only a small fraction of ADEs. Using IRs for quality assurance/quality improvement will lead to significant bias when assessing quality of care.

Adverse Drug Reaction Reporting Systems↗

PubMed2003

What do we know about medication errors in inpatient psychiatry?

BACKGROUND: Adverse drug events (ADEs) have been implicated as a cause of substantial morbidity and mortality. Psychiatrists have successfully characterized one category of ADE--adverse drug reactions (ADRs), which have been studied from a medication-specific psychopharmacology frame of reference. The literature on ADEs, both preventable and nonpreventable, was reviewed within the broader patient safety framework. METHODS: English-language studies involving ADEs and medication errors in psychiatry for 1996 through 2003 were identified on MEDLINE and by using a hand search of bibliographies. RESULTS: Few reports on the incidence and characteristics of medication errors in psychiatric hospitals could be found. Psychiatrists may not be sufficiently aware of the harm caused by errors, methodological issues regarding error detection, the validity of reported medication error rates, and the challenge of creating a nonpunitive error-reporting culture. PREVENTION STRATEGIES: Application of a systems-oriented approach to ADE reduction and the promotion of a nonpunitive culture are essential. Clinical and pharmacy staff could monitor the literature for published reports of preventable adverse events and review those reports in multidisciplinary team meetings. CONCLUSIONS: Psychiatry would benefit from learning about the terminology used in describing medication errors and ADEs. Relatively few data are available regarding the frequency and consequences of medication errors in psychiatry; more research is needed.

Antipsychotic Agents↗

PubMed1997

Mutations induced by 2-hydroxyadenine on a shuttle vector during leading and lagging strand syntheses in mammalian cells.

An oxidatively damaged base, 2-hydroxyadenine (2-OH-Ade), was incorporated into a predetermined site of one of the strands {(+)- or (-)-strand} of the double-stranded shuttle vector, pSVK3, and the modified DNAs were transfected into simian COS-7 cells. The nucleotide sequences in which the modified base was incorporated were 5'-GTCGA*C and 5'-CTTA*AG (A* represents 2-OH-Ade). The former is the recognition site for the restriction enzyme SalI, and the latter is that for AflII. The DNAs replicated in the cells were recovered and were transfected again into Escherichia coli. The DNAs recovered from the COS-7 cells transfected with a plasmid containing 2-OH-Ade at either site of the (+)-strand (a template strand for lagging strand synthesis) formed colonies about 50%-70% as frequently as the unmodified DNA. This indicated that the base weakly blocked DNA replication during lagging strand synthesis. On the other hand, the base in the (-)-strand did not appear to affect the efficiency of leading strand synthesis in COS-7 cells. The mutation frequencies of 2-OH-Ade in COS-7 cells were 0.6%-0.1%, depending on the sequence and the strand location. Although the mutation spectra of 2-OH-Ade also differed with sequences and strands, the base elicited substitution and deletion mutations in mammalian cells, as in E. coli. These results indicate that 2-OH-Ade is mutagenic in eukaryotic cells as well as in prokaryotic cells.

Animals↗

PubMed1996

Synthesis and structure determination of the adducts formed by electrochemical oxidation of 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene in the presence of deoxyribonucleosides or adenine.

Study of DNA adducts formed with aromatic hydrocarbons is part of the strategy to elucidate the mechanisms of tumor initiation by these compounds. 1,2,3,4-Tetrahydro-7,12-dimethylbenz[a]anthracene (THDMBA) is of special interest because it allows discrimination between the pathways of bioactivation by one-electron oxidation and monooxygenation. To study and identify adducts formed biologically, synthetic adducts are needed as reference standards. THDMBA was electrochemically oxidized in the presence of deoxyadenosine (dA), adenine (Ade), deoxyguanosine (dG), or deoxycytidine (dC). In the presence of dA, four adducts were isolated: 7-methyl-1,2,3,4-tetrahydrobenz[a]anthracene-12-CH2-N7Ade (7-MTHBA-12-CH2-N7Ade, 3.6%), 12-MTHBA-7-CH2-N7Ade (4.2%), 7-MTHBA-12-CH2-N6dA (5.8%), and 12-exo-methylene-7-MTHBA-7-N6dA (22.8%); a dehydrogenated product, 7,12-di-exo-methylene-THBA (44.2%), was also obtained. In the presence of Ade, nine adducts were synthesized: 7-MTHBA-12-CH2-N7Ade (1.1%), 12-MTHBA-7-CH2-N7Ade (2.4%), 7-MTHBA-12-CH2-N1Ade (10.2%), 12-MTHBA-7-CH2-N1Ade (13.2%), 7-MTHBA-12CH2-N3Ade (1.7%), 12-MTHBA-7-CH2-N3Ade (1.7%), 7-exo-methylene-12-MTHBA-12-N3Ade (11.2%), 12-exo-methylene-7-MTHBA-7-N3Ade (27.9%), and 12-exo-methylene-7-MTHBA-7-N6Ade (12.1%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (16.7%). In the presence of dG, three adducts were produced: 7-MTHBA-12-CH2-N7Gua (24.2%), 12-MTHBA-7-CH2-N7Gua (12.2%), and 7-MTHBA-12-CH2-N2dG (3.7%), as well as the dehydrogenated product 7,12-di-exo-methylene-THBA (38.9%). Anodic oxidation in the presence of dC yielded a large amount of 7,12-di-exo-methylene-THBA (80.4%), but no adducts. The structure of the adducts was elucidated by using UV, NMR, and MS. The N-7 positions in dG, dA, and Ade, the 2-NH2 in dG, and the N-1 position in Ade form exclusively methyl-linked adducts. In contrast, the 6-NH2 group of dA and Ade and the N-3 of Ade prefer to attack the meso-anthracenic positions rather than the methyl groups. The order of reactivity of dG and dA in the formation of methyl-linked THDMBA adducts agrees well with that previously found for 7,12-dimethylbenz[a]anthracene [RamaKrishna et al. (1992) J. Am. Chem. Soc. 114, 1863-1874.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Risk factors for the development of adverse drug events in hospitalized patients.

Adverse drug events in hospitalized patients lead to increased morbidity, mortality and costs. Early detection of adverse drug events could aid in the prevention of these adverse outcomes. A cost-effective system for the early detection of adverse drug events should focus on high risk patients. A study was set up with the primary aim to identify characteristics that are associated with the development of adverse drug events (ADEs) in hospitalized patients. ADE reports were gathered from physicians and nurses (spontaneous reports) and from patients after intensive ward interviews by hospital pharmacists. All patients admitted to the internal medicine wards of two Dutch hospitals, during a two month period, were included. The following characteristics were analyzed for their potential relationship to the occurrence of ADEs: age (categorized), gender, number of drugs prescribed during hospital stay, types of drugs used and changes in drug use on admission. Age was found to be inversely associated with the development of ADEs (OR 0.36, CI 0.21-0.61 for age category > 80 years; OR 0.56; CI 0.31-1.02 for age category 75-80 years and OR 0.69; CI 0.42-1.11 for age category 60-74 years). Furthermore, statistically significant associations were found for the number of drugs prescribed per hospitalized patient (for the class of 4-6 drugs per patient OR 2.61, CI 1.32-5.18), for newly prescribed drugs (OR 6.65, CI 2.63-16.81) and for the cessation of drugs on hospital admission (OR 1.50, CI 1.02-2.20). The use of gastrointestinal drugs (OR 2.13, CI 1.32-3.45), central nervous system drugs (OR 1.66, CI 1.07-2.57) and antibiotics (OR 2.44, CI 1.65-3.60) were associated with the development of ADEs, when compared to all other drugs taken by the patients. In this study, the most important risk factors are the number of drugs used per patient and the starting of a new drug during hospitalization. As most hospitalized patients start new drug therapies while in hospital, this seems an inappropriate focus. However, careful monitoring of patients using more than 7 drugs at a time may be possible in a cost-effective system for the early detection of ADEs.

Adult↗

PubMed1998

An assessment of the use of simple methods to predict individual energy intakes for intervention studies.

OBJECTIVE: To investigate to what extent individual energy intakes can be predicted by rapid easily available low-cost estimation methods. DESIGN: Data were obtained from a controlled dietary intervention study period of nine weeks in which the subjects should be weight stable. SUBJECTS: Thirty-one male students in domestic and kitchen management aged 29 +/- 6 y. METHODS: (1) energy intake calculated from a quantitative food frequency questionnaire (FFQEI); (2) energy expenditure derived from estimates of basal metabolic rate (BMR) (FAO/WHO/UNU, 1985) based on weight, gender, age and low (1.55 x BMR), medium (1.78 x BMR) or high (2.10 x BMR) level of activity. Level of activity was determined by questions concerning habitual activities lasting more than 20 min (WHOEE); (3) energy expenditure derived from individual recording in a specially prepared activity diary (ADEE). During the intervention, the subjects were to be fed test diets which should provide them with enough energy to keep them weight stable. The energy levels were established after taking both the FFQEIs, WHOEEs and ADEEs into consideration, and 10 MJ, 13 MJ, 15 MJ and 17 MJ per day were chosen because these levels were estimated to closely match the energy requirements of most of the subjects. The levels of energy were changed during the intervention period if the weight of the subjects fluctuated. The served level of energy at the last day of the intervention was denoted the weight maintenance energy intake (WMEI). WMEI was compared to FFQEI, WHOEE and ADEE in order to evaluate if one estimation method predicted WMEI better than the two others. RESULTS: None of the three methods provided accurate estimates of WMEI of 13.3 +/- 1.8 MJ. However, WHOEE, gave the best estimate as demonstrated by the limits of agreement: -8.7 MJ to +8.9 MJ for FFQEI, -5.4 MJ to +3.9 MJ for WHOEE and -7.2 MJ to +5.2 MJ for ADEE. The coefficients of correlation between the differences and the means of WMEI and FFQEI, WHOEE and ADEE were -0.8 (P < or = 0.001), 0.1 (P = 0.6, NS) and -0.5 (P < or = 0.01), respectively. The coefficients of variation were 34.6% for FFQEI, 11.3% for WHOEE, and 21.0% for ADEE. CONCLUSIONS: Although not precise, WHOEE showed the best agreement with the WMEI. These results demonstrate that a rapid and simple low-cost method predicted WMEI closely enough to avoid major weight fluctuations among these men during the intervention period.

Adult↗

PubMed2003

Effects of repeated alcohol deprivations on operant ethanol self-administration by alcohol-preferring (P) rats.

We reported that repeated alcohol deprivations prolonged the expression of an alcohol-deprivation effect (ADE) under 24-h free-choice alcohol-drinking access and that the duration of the initial deprivation period had a positive effect of prolonging the duration of the ADE. In the present study, operant techniques (including progressive ratio measures) were used to examine the effects of initial deprivation length and number of deprivation cycles on the magnitude and duration of the ADE in alcohol-preferring (P) rats to test the hypothesis that repeated deprivations can increase the reinforcing effects of ethanol (ETOH). Adult male P rats were trained in two-lever operant chambers to self-administer 15% ETOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement in daily 1-h sessions. Following 6 weeks of daily 1-h sessions, the P rats were randomly assigned to one of four groups (n=10/group): nondeprived or deprived of alcohol for 2, 5, or 8 weeks. Following this initial period, the deprived groups were given 15% ETOH again in the operant chambers for a 2-week period, following which they were deprived again for 2 weeks (all three deprived groups). Following the fourth deprivation, the rats underwent a progressive ratio test to determine the breakpoints (FR values) for the nondeprived and the deprived groups. Repeated deprivations increased both the magnitude and duration of the ADE as indicated by increased responding on the ETOH lever. However, the length of the initial deprivation had little effect on expression of the ADE except following the first deprivation, where an ADE was not observed for the 8-week group. Breakpoint values for responding on the ETOH lever for all three deprived groups were two-fold higher than the value for the nondeprived group. The results suggest that repeated cycles of alcohol deprivation and alcohol access increased the reinforcing effects of ETOH in the P rats.

Alcohol Drinking↗

PubMed2004

Application of data mining techniques in pharmacovigilance.

AIMS: To discuss the potential use of data mining and knowledge discovery in databases for detection of adverse drug events (ADE) in pharmacovigilance. METHODS: A literature search was conducted to identify articles, which contained details of data mining, signal generation or knowledge discovery in relation to adverse drug reactions or pharmacovigilance in medical databases. RESULTS: ADEs are common and result in significant mortality, and despite existing systems drugs have been withdrawn due to ADEs many years after licensing. Knowledge discovery in databases (KDD) is a technique which may be used to detect potential ADEs more efficiently. KDD involves the selection of data variables and databases, data preprocessing, data mining and data interpretation and utilization. Data mining encompasses a number of statistical techniques including cluster analysis, link analysis, deviation detection and disproportionality assessment which can be utilized to determine the presence of and to assess the strength of ADE signals. Currently the only data mining methods to be used in pharmacovigilance are those of disproportionality, such as the Proportional Reporting Ratio and Information Component, which have been used to analyse the UK Yellow Card Scheme spontaneous reporting database and the WHO Uppsala Monitoring Centre database. The association of pericarditis with practolol but not with other beta-blockers, the association of captopril and other angiotensin-converting enzymes with cough, and the association of terfenadine with heart rate and rhythm disorders could be identified by mining the WHO database. CONCLUSION: In view of the importance of ADEs and the development of massive data storage systems and powerful computer systems, the use of data mining techniques in knowledge discovery in medical databases is likely to be of increasing importance in the process of pharmacovigilance as they are likely to be able to detect signals earlier than using current methods.

Data Collection↗