Assessment of health-related quality of life and related factors in patients with chronic liver disease

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Competition Between Novelty and Cocaine Conditioned Reward Is Sensitive to Drug Dose and Retention Interval

The conditioned rewarding effects of novelty compete with those of cocaine for control over choice behavior using a place conditioning task. The purpose of the present study was to use multiple doses of cocaine to determine the extent of this competition and to determine whether novelty’s impact on cocaine reward was maintained over an abstinence period. In Experiment 1, rats were conditioned with cocaine (7.5, 20, or 30 mg/kg ip) to prefer one side of an unbiased place conditioning apparatus relative to the other. In a subsequent phase, all rats received alternating daily confinements to the previously cocaine paired and unpaired sides of the apparatus. During this phase, half the rats had access to a novel object on their initially unpaired side; the remaining rats did not receive objects. The ability of novelty to compete with cocaine in a drug free and cocaine challenge test was sensitive to cocaine dose. In Experiment 2, a place preference was established with 10 mg/kg cocaine and testing occurred after 1, 14, or 28 day retention intervals. Findings indicate that choice behaviors mediated by cocaine conditioning are reduced with the passing of time. Taken together, competition between cocaine and novelty conditioned rewards are sensitive to drug dose and retention interval.

Two and a Half Cheers for the Midwestern Bourgeoisie: Role of the Virtues in Tempering Business Decisions

A recent book (The Bourgeois Virtues: Ethics for an Age of Commerce, D. N. McCloskey), raises the matter of the role of the virtues in business and economic choice, arguing that capitalism can indeed, be virtuous or at least better than the alternative(s). This argument is especially timely in light of the apparent excesses on Wall Street and in some banking/financial institutions. Excessive greed and often the lack of business ethics contributed in substantive ways to the financial crisis and near economic meltdown we have been experiencing. As McCloskey, (2006, pp. 1-2) argues (in setting the stage for the complex argument made in this 616-page book!): “The book … is directed toward you who are suspicious of the phrase ‘bourgeois virtues,’ pretty sure that it is a contradiction in terms. And the book is directed, with less optimism about changing their minds, toward you who think the phrase is worse: a lie. ‘Bourgeois virtues’ is neither. The claim here is that modern capitalism does not need to be offset to be good. Capitalism can on the contrary be virtuous. In a fallen world bourgeois life is not perfect. But it’s better than any available alternative. American capitalism needs to be inspirited, moralized, completed. Two and a half cheers for the Midwestern bourgeoisie (middle-class, small business owners…. yet)… Many a businessman is an ethical shell or worse. Even the virtues of the bourgeoisie, … do not lead straight to heaven.”

Community Life and Housing in Rural Nebraska: 2005 Nebraska Rural Poll Results

Many rural communities are experiencing population decline. However, rural residents have continued to show a strong attachment to their communities. How do rural Nebraskans feel about their community? Are they satisfied with the services provided? Do they own their home? What is the condition of their home? This report details 2,851 responses to the 2005 Nebraska Rural Poll, the tenth annual effort to understand rural Nebraskans’ perceptions. Respondents were asked a series of questions about their community and housing. Trends for some of these questions are examined by comparing data from the nine previous polls to this year’s results. For all questions, comparisons are made among different respondent subgroups, that is, comparisons by age, occupation, region, etc. Based on these analyses, some key findings emerged: Rural Nebraskans’ views of the change in their community are similar to those expressed last year. This year, 28 percent believe their community has changed for the better, compared to 26 percent last year. And, in 2005, only 20 percent think their community has changed for the worse, compared to 22 percent last year. The proportion of expected movers who plan to leave the state decreased this year. Last year, 56 percent of the persons planning to move from their community expected to leave the state. That proportion decreased to 47 percent this year. Rural Nebraskans living in or near the largest communities are more likely than persons living in or near the smaller communities to say their community has changed for the better. Thirty-nine percent of persons living in or near communities with populations of 10,000 or more believe their community has changed for the better during the past year, but only 15 percent of persons living in or near communities with less than 500 people share this opinion. The community services and amenities that rural Nebraskans are most dissatisfied with include: entertainment, retail shopping and restaurants. At least one-third of rural Nebraskans express dissatisfaction with these three services. They are most satisfied with parks and recreation, library services, basic medical care services, highways and bridges, and education (K - 12). At least one-half of rural Nebraskans are satisfied with the following items in their community: appearance of residential areas (66%), crime control (61%), maintenance of sidewalks and public areas (57%) and noise (54%). Rural Nebraskans generally have positive views about their community. Sixty percent agree that their community is an ideal place to live and 52 percent say their community has good business leaders. Rural Nebraskans have mixed opinions about the future of their community. Fortyfour percent agree that their community’s future looks bright, but 42 percent disagree with this statement. Fourteen percent have no opinion. Rural Nebraskans living in or near the larger communities are more likely than residents of the smaller communities to think their community’s future looks bright. Fifty-nine percent of persons living in or near communities with populations of 10,000 or more agree with this statement, compared to only 25 percent of residents living in or near communities with less than 500 people. Further, 61 percent of the residents of the smallest communities disagree with this statement, compared to only 28 percent of the residents of the largest communities. Over three-quarters of rural Nebraskans disagree that younger residents of their community tend to stay there after completing high school. Seventy-six percent disagree with this statement, 16 percent have no opinion and eight percent agree that younger residents stay after completing high school. When comparing responses by age, younger persons are more likely than older persons to agree that younger residents stay in their community after high school. Sixteen percent of persons age 19 to 29 agree with this statement, compared to only six percent of persons age 50 to 64. Younger persons are more likely than older persons to be planning to move from their community next year. Fifteen percent of persons between the ages of 19 and 29 are planning to move next year, compared to only two percent of persons age 65 and older. An additional 17 percent of the younger respondents indicate they are uncertain if they plan to move. Most rural Nebraskans own their home. Eighty-four percent of rural Nebraskans own their home. Older persons are more likely than younger persons to own their home. Eighty-eight percent of persons over the age of 50 own their home, compared to only 52 percent of persons age 19 to 29. Housing in rural Nebraska has an average age of 50 years. Twenty-four percent of residences were built before 1930. Another 24 percent were built between 1930 and 1959. Twenty-nine percent were built between 1960 and 1979 and the remaining 24 percent were built in 1980 or later. The housing stock in smaller communities is older than the housing located in larger communities. Over one-third (35%) of the residences in communities with less than 1,000 people were built before 1930. Only 12 percent of the homes in communities with populations of 10,000 or more were built in this time period. Most rural Nebraskans appear satisfied with their home. Only 24 percent say the current size of their home does not meet their needs. The same proportion (24%) say their home is in need of major repairs. Thirty-eight percent agree that their home needs a lot of routine maintenance, but 87 percent like the location (neighborhood) of their home. One-third of rural Nebraskans living in or near the smallest communities say their home is in need of major repairs. Only 19 percent of persons living in or near communities with populations of 5,000 or more are facing this problem. Home ownership is very important to most rural Nebraskans. Eighty-two percent believe it is very important to own their home. An additional 12 percent say it is somewhat important and six percent say it is not at all important. However, persons who do not currently own their home do not feel it is important for them to do so. Only 32 percent of renters say it is very important to own their home, compared to 91 percent of home owners. And, 35 percent of renters say it is not at all important to own their home.

Rediscovery and redescription of the unusual subterranean characiform Stygichthys typhlops, with notes on its life history

The rediscovery of the enigmatic subterranean characiform Stygichthys typhlops is reported almost a half-century after the collection of the holotype, the only specimen previously known. Thirty-four specimens were collected in two shallow hand-dug wells at the region of the type locality, c. 13 km south-west of the town of Jaiba, Minas Gerais, Brazil. These specimens provide new information on the morphology of this species, and for the first time on its life history. The conservation status of S. typhlops is discussed. The species is severely threatened by habitat loss caused by exploitation of the aquifer. (C) 2010 The Authors Journal compilation (C) 2010 The Fisheries Society of the British Isles

Relationship Between Oral Health-Related Quality of Life, Oral Health, Socioeconomic, and General Health Factors in Elderly Brazilians

Objectives To assess the impact of oral health on quality of life in elderly Brazilians and to evaluate its association with clinical oral health measures and socioeconomic and general health factors. Design Cross-sectional study. Setting Population-based cohort study on health, well-being, and aging. Participants Eight hundred fifty-seven participants representing 588,384 community-dwelling elderly adults from the city of Sao Paulo, Brazil. MeasurementS Self-perceived impact of oral health on quality of life was measured using the Geriatric Oral Health Assessment Index (GOHAI), with scores categorized as good, moderate, or poor, indicating low, moderate, and high degrees of negative impact on quality of life, respectively. Results Nearly half of the individuals had good GOHAI scores (44.7% of overall sample, 45.9% of dentate participants, and 43.4% of edentulous participants). In the overall sample, those with poor self-rated general health and a need for dental prostheses were more likely to have poor and moderate GOHAI scores. Individuals with depression were significantly more likely to have poor GOHAI scores. No socioeconomic variables were related to the outcome, except self-perception of sufficient income, which was a protective factor against a poor GOHAI score in dentate participants. Conclusion Moderate and high degrees of negative impact of oral health on quality of life were associated with general health and clinical oral health measures, independent of socioeconomic factors.

Interchangeability among therapeutic equivalents of lamotrigine: evaluation of quality of life

Epilepsy is the most common serious neurological disorder worldwide. Approximately 70% of patients with epilepsy have their seizures controlled by clinical and pharmacological treatment. This research evaluated the possible influence of interchangeability among therapeutic equivalents of LTG on the clinical condition and quality of life of refractory epileptic patients. The study was divided into three periods of 42 days, and an equivalent therapeutic LTG randomly dispensed for each period (two similars - formulations A and B, and the reference product - formulation C). The mean dose of LTG was 5.5 mg/kg/day. The presence of side effects tends to have a greater deleterious effect on quality of life of refractory epileptics compared to variations in number of seizures or changes in plasma concentrations. The results showed that independently of the drug prescribed, interchangeability among therapeutic equivalents can negatively impact epilepsy control.

Adverse Drug Events Leading Children to Hospital Emergency Care

To determine the incidence of adverse drug events (ADE) that resulted in the need for children's emergency care, a total of 23,286 pediatric emergency case notes were analyzed. They were selected on the basis of the ICD code indicating a possible ADE. ADEs were found in 13 case notes (0.06%), predominantly among girls and mainly in the 1 to 5 year age group. About half of the observed events occurred as a result of accidental ingestion, 27.3% were suicide attempts, and 27.3% arose due to the discontinuation of treatment. Antiepileptic drugs were those most often involved. Three (23%) were serious. The results suggest that children have easy access to medications and are involved in the majority of accidental occurrences. Using drugs involves risks, and drawing attention to such risks while prescribing and dispensing them fosters the sharing of responsibility and the empowerment of the users, measures necessary to health promotion.

Monitoring Drug Use Among HIV/AIDS Patients in Brazil: Should we Combine Self-Report and Urinalysis?

Illicit drug use in HIV-infected patients can be linked to impairment of physical and mental health, low health-related quality of life, and suboptimal adherence to HIV treatment. This study aimed to evaluate the correlation of self-report illicit drug use, urinalysis for cocaine and cannabis metabolites, and severity of dependence among HIV-infected patients on antiretroviral therapy (ART) in a treatment center in Brazil. Four hundred and thirty-eight outpatients of an HIV referral center were interviewed and assessed for drug use (lifetime, last year and last month). Urinalysis was performed to detect the presence of cocaine and cannabis metabolites in urine samples. Overall agreement between self-report and urinalysis was almost 68% for cannabis and higher than 85% for cocaine. Positive urinalysis was significantly associated with more than once a week cannabis (p < .0001) and cocaine (p <.0001) use during the last-month. Severity of Dependence Scale (SDS) properly predicted positive cocaine urinalysis results (area under the curve [AUC] = .81, p = .0001). Frequency of cannabis and cocaine use, SDS score degree and positive urinalysis for both drugs were correlated. Our findings suggest that positive self-report is a reliable predictor of positive urine sample both for cannabis and cocaine, but since the agreement was not perfect, there is a role for urine drug screening in the care of patients with HIV-related conditions.

Emergence of sensory selection mechanisms in Artificial Life simulations

Background The evolutionary advantages of selective attention are unclear. Since the study of selective attention began, it has been suggested that the nervous system only processes the most relevant stimuli because of its limited capacity [1]. An alternative proposal is that action planning requires the inhibition of irrelevant stimuli, which forces the nervous system to limit its processing [2]. An evolutionary approach might provide additional clues to clarify the role of selective attention. Methods We developed Artificial Life simulations wherein animals were repeatedly presented two objects, "left" and "right", each of which could be "food" or "non-food." The animals' neural networks (multilayer perceptrons) had two input nodes, one for each object, and two output nodes to determine if the animal ate each of the objects. The neural networks also had a variable number of hidden nodes, which determined whether or not it had enough capacity to process both stimuli (Table 1). The evolutionary relevance of the left and the right food objects could also vary depending on how much the animal's fitness was increased when ingesting them (Table 1). We compared sensory processing in animals with or without limited capacity, which evolved in simulations in which the objects had the same or different relevances. Table 1. Nine sets of simulations were performed, varying the values of food objects and the number of hidden nodes in the neural networks. The values of left and right food were swapped during the second half of the simulations. Non-food objects were always worth -3. The evolution of neural networks was simulated by a simple genetic algorithm. Fitness was a function of the number of food and non-food objects each animal ate and the chromosomes determined the node biases and synaptic weights. During each simulation, 10 populations of 20 individuals each evolved in parallel for 20,000 generations, then the relevance of food objects was swapped and the simulation was run again for another 20,000 generations. The neural networks were evaluated by their ability to identify the two objects correctly. The detectability (d') for the left and the right objects was calculated using Signal Detection Theory [3]. Results and conclusion When both stimuli were equally relevant, networks with two hidden nodes only processed one stimulus and ignored the other. With four or eight hidden nodes, they could correctly identify both stimuli. When the stimuli had different relevances, the d' for the most relevant stimulus was higher than the d' for the least relevant stimulus, even when the networks had four or eight hidden nodes. We conclude that selection mechanisms arose in our simulations depending not only on the size of the neuron networks but also on the stimuli's relevance for action.

Interchangeability among therapeutic equivalents of lamotrigine: evaluation of quality of life

Epilepsy is the most common serious neurological disorder worldwide. Approximately 70% of patients with epilepsy have their seizures controlled by clinical and pharmacological treatment. This research evaluated the possible influence of interchangeability among therapeutic equivalents of LTG on the clinical condition and quality of life of refractory epileptic patients. The study was divided into three periods of 42 days, and an equivalent therapeutic LTG randomly dispensed for each period (two similars - formulations A and B, and the reference product - formulation C). The mean dose of LTG was 5.5 mg/kg/day. The presence of side effects tends to have a greater deleterious effect on quality of life of refractory epileptics compared to variations in number of seizures or changes in plasma concentrations. The results showed that independently of the drug prescribed, interchangeability among therapeutic equivalents can negatively impact epilepsy control.

Development of original analytical methods for the therapeutic drug monitoring of CNS druges: Antipsychotics, Antidepressants and Anxiolytics-hypnotics

Great strides have been made in the last few years in the pharmacological treatment of neuropsychiatric disorders, with the introduction into the therapy of several new and more efficient agents, which have improved the quality of life of many patients. Despite these advances, a large percentage of patients is still considered “non-responder” to the therapy, not drawing any benefits from it. Moreover, these patients have a peculiar therapeutic profile, due to the very frequent application of polypharmacy, attempting to obtain satisfactory remission of the multiple aspects of psychiatric syndromes. Therapy is heavily individualised and switching from one therapeutic agent to another is quite frequent. One of the main problems of this situation is the possibility of unwanted or unexpected pharmacological interactions, which can occur both during polypharmacy and during switching. Simultaneous administration of psychiatric drugs can easily lead to interactions if one of the administered compounds influences the metabolism of the others. Impaired CYP450 function due to inhibition of the enzyme is frequent. Other metabolic pathways, such as glucuronidation, can also be influenced. The Therapeutic Drug Monitoring (TDM) of psychotropic drugs is an important tool for treatment personalisation and optimisation. It deals with the determination of parent drugs and metabolites plasma levels, in order to monitor them over time and to compare these findings with clinical data. This allows establishing chemical-clinical correlations (such as those between administered dose and therapeutic and side effects), which are essential to obtain the maximum therapeutic efficacy, while minimising side and toxic effects. It is evident the importance of developing sensitive and selective analytical methods for the determination of the administered drugs and their main metabolites, in order to obtain reliable data that can correctly support clinical decisions. During the three years of Ph.D. program, some analytical methods based on HPLC have been developed, validated and successfully applied to the TDM of psychiatric patients undergoing treatment with drugs belonging to following classes: antipsychotics, antidepressants and anxiolytic-hypnotics. The biological matrices which have been processed were: blood, plasma, serum, saliva, urine, hair and rat brain. Among antipsychotics, both atypical and classical agents have been considered, such as haloperidol, chlorpromazine, clotiapine, loxapine, risperidone (and 9-hydroxyrisperidone), clozapine (as well as N-desmethylclozapine and clozapine N-oxide) and quetiapine. While the need for an accurate TDM of schizophrenic patients is being increasingly recognized by psychiatrists, only in the last few years the same attention is being paid to the TDM of depressed patients. This is leading to the acknowledgment that depression pharmacotherapy can greatly benefit from the accurate application of TDM. For this reason, the research activity has also been focused on first and second-generation antidepressant agents, like triciclic antidepressants, trazodone and m-chlorophenylpiperazine (m-cpp), paroxetine and its three main metabolites, venlafaxine and its active metabolite, and the most recent antidepressant introduced into the market, duloxetine. Among anxiolytics-hypnotics, benzodiazepines are very often involved in the pharmacotherapy of depression for the relief of anxious components; for this reason, it is useful to monitor these drugs, especially in cases of polypharmacy. The results obtained during these three years of Ph.D. program are reliable and the developed HPLC methods are suitable for the qualitative and quantitative determination of CNS drugs in biological fluids for TDM purposes.

Bioanalytical applications of multicolour bioluminescence imaging: new tools for drug discovery and development

The subject of this thesis is multicolour bioluminescence analysis and how it can provide new tools for drug discovery and development.The mechanism of color tuning in bioluminescent reactions is not fully understood yet but it is object of intense research and several hypothesis have been generated. In the past decade key residues of the active site of the enzyme or in the surface surrounding the active site have been identified as responsible of different color emission. Anyway since bioluminescence reaction is strictly dependent from the interaction between the enzyme and its substrate D-luciferin, modification of the substrate can lead to a different emission spectrum too. In the recent years firefly luciferase and other luciferases underwent mutagenesis in order to obtain mutants with different emission characteristics. Thanks to these new discoveries in the bioluminescence field multicolour luciferases can be nowadays employed in bioanalysis for assay developments and imaging purposes. The use of multicolor bioluminescent enzymes expanded the potential of a range of application in vitro and in vivo. Multiple analysis and more information can be obtained from the same analytical session saving cost and time. This thesis focuses on several application of multicolour bioluminescence for high-throughput screening and in vivo imaging. Multicolor luciferases can be employed as new tools for drug discovery and developments and some examples are provided in the different chapters. New red codon optimized luciferase have been demonstrated to be improved tools for bioluminescence imaging in small animal and the possibility to combine red and green luciferases for BLI has been achieved even if some aspects of the methodology remain challenging and need further improvement. In vivo Bioluminescence imaging has known a rapid progress since its first application no more than 15 years ago. It is becoming an indispensable tool in pharmacological research. At the same time the development of more sensitive and implemented microscopes and low-light imager for a better visualization and quantification of multicolor signals would boost the research and the discoveries in life sciences in general and in drug discovery and development in particular.

Einfluss einer pharmazeutischen Betreuung auf den klinischen Verlauf und die Behandlungsergebnisse von Diabetikern mit Diabetischem Fußsyndrom (DFS)

Einfluss einer Pharmazeutischen Betreuung auf den klinischen Verlauf und die Behandlungsergebnisse von Diabetikern mit Diabetischem Fußsyndrom (DFS) Hintergrund/Rationale: In Deutschland gibt es etwa 6 Millionen Diabetiker und die Tendenz ist steigend. Das Diabetische Fußsyndrom (DFS) stellt eine häufige und besonders gravierende Folgeerkrankung des Diabetes mellitus dar. Jährlich werden in Deutschland ca. 45.000 Amputationen aufgrund des DFS bei Diabetikern durchgeführt. Es verursacht bei den Patienten physische und psychische Beeinträchtigungen und produziert hohe Krankheitskosten. Der Prävention, der Behandlung und der Rezidivprophylaxe des DFS kommt daher ein hoher Stellenwert zu. Ziel dieser Arbeit war es, ein klinisch-pharmazeutisches Betreuungsprogramm für Patienten mit DFS zu erarbeiten und den Einfluss der Pharmazeutischen Betreuung, speziell einer intensivierten Patientenschulung, auf klinische und soziale Behandlungsergebnisse hin zu untersuchen. Es sollte geklärt werden, ob eine zusätzliche pharmazeutische Betreuung Einfluss auf den Wundheilungsverlauf und die Abheilungsrate der Fußläsionen von Diabetikern mit DFS nehmen kann. Methoden: 52 Patienten mit DFS wurden in eine randomisierte, kontrollierte Studie eingeschlossen und im Verhältnis 1:1 einer Interventions- oder Kontrollgruppe zugeteilt. Die Interventionsgruppe wurde kontinuierlich durch einen Apotheker zusätzlich individuell betreut (Anleitung zum sachgerechten Umgang mit Arzneimitteln, Medizinprodukten und Therapiemaßnahmen), die Kontrollgruppe erhielt die übliche medizinische Betreuung. Die Auswirkungen der Intervention auf den klinischen Verlauf der beobachteten Fußläsionen, die Rezidivfreiheit und Rehospitalisierungsrate, aber auch auf die Patientenzufriedenheit, das Patientenwissen und die Lebensqualität wurden untersucht. Jeder Patient wurde über einen Zeitraum von 12 Monaten beobachtet. Ergebnisse: Die Studienergebnisse belegen einen positiven Einfluss der Pharmazeutischen Betreuung auf die klinischen Endpunkte der Diabetiker mit DFS. Die Wundheilung der Läsionen in der Interventionsgruppe, bezogen auf Abheilungsdauer und -rate, konnte klinisch positiv beeinflusst werden. Des weiteren konnte in der Interventionsgruppe die Anzahl an neu aufgetretenen Läsionen, sowie weiterer Krankenhausaufenthalte um jeweils fast 50% verringert werden. Durch die Pharmazeutische Betreuung konnte die Patientenzufriedenheit mit der Behandlung deutlich gesteigert werden. Entsprechendes fand sich für das Patientenwissen und die Lebensqualität.

Flow Field–Flow Fractionation for size analysis and characterization of nanoparticles for applications in Life Sciences

Nanotechnologies are rapidly expanding because of the opportunities that the new materials offer in many areas such as the manufacturing industry, food production, processing and preservation, and in the pharmaceutical and cosmetic industry. Size distribution of the nanoparticles determines their properties and is a fundamental parameter that needs to be monitored from the small-scale synthesis up to the bulk production and quality control of nanotech products on the market. A consequence of the increasing number of applications of nanomaterial is that the EU regulatory authorities are introducing the obligation for companies that make use of nanomaterials to acquire analytical platforms for the assessment of the size parameters of the nanomaterials. In this work, Asymmetrical Flow Field-Flow Fractionation (AF4) and Hollow Fiber F4 (HF5), hyphenated with Multiangle Light Scattering (MALS) are presented as tools for a deep functional characterization of nanoparticles. In particular, it is demonstrated the applicability of AF4-MALS for the characterization of liposomes in a wide series of mediums. Afterwards the technique is used to explore the functional features of a liposomal drug vector in terms of its biological and physical interaction with blood serum components: a comprehensive approach to understand the behavior of lipid vesicles in terms of drug release and fusion/interaction with other biological species is described, together with weaknesses and strength of the method. Afterwards the size characterization, size stability, and conjugation of azidothymidine drug molecules with a new generation of metastable drug vectors, the Metal Organic Frameworks, is discussed. Lastly, it is shown the applicability of HF5-ICP-MS for the rapid screening of samples of relevant nanorisk: rather than a deep and comprehensive characterization it this time shown a quick and smart methodology that within few steps provides qualitative information on the content of metallic nanoparticles in tattoo ink samples.