This study examined the effect of preweanling methyphenidate exposure on later drug reward. We examined the induction, extinction, and reinstatement of morphine induced conditioned place preference (CPP) in rats that received methylphenidate pretreatment during the preweanling period.

Sammanfattning Bakgrund: Att leva med bipolär sjukdom är besvärligt för många. Sjukdomen ger upphov till allvarliga förändringar i känsloläget. Medicinering är en viktig del i behandlingen av bipolär sjukdom men när detta ger upphov till allvarliga biverkningar som viktökning kan det leda till lidande hos denna patientgrupp. Syftet med studien var att beskriva hur patienter med bipolär sjukdom upplever mediciners biverkningar i samband med viktuppgång och deras erfarenheter av att hantera det samt upplevelser av stödet och deras förväntningar på sjukvården inom aktuellt området. Metod: En kvalitativ och deskriptiv design användes.  Undersökningsgruppen bestod av fem kvinnliga och en manlig patient från ett sjukhus i Mellansverige. Huvudresultatet visade att deltagarna upplevde en stark påverkan på välbefinnande och hälsa av medicinbiverkningar i form av viktökning. Genomgående led deltagarna av biverkningar som påverkade både det fysiska och psykiska måendet. Samtliga deltagare hade gått igenom svåra kamper för att hantera viktökning och det krävdes mycket av deras egna krafter. Vidare betonade de att de inte blivit sedda av sjukvården och deras viktproblem inte tagits på allvar. Deltagarna upplevde starka känslor och lidanden av medicinbiverkningar och viktökning och det framkom förväntningar på att få stöd och information samt kontinuerlig vård för att kunna känna sig trygg i behandlingen och få uppleva en bättre livskvalitet. Slutsatsen visar att personer med bipolär sjukdom lider mycket av viktökning i samband med medicinbiverkningar. Det belyser att viktproblem är svårhanterbart och förbisett av sjukvården, vilket gör att livskvalitén blir svår att bevara. Att problem tas på allvar och att få information samt stöd inom det aktuella området ansågs vara nödvändigt för att kunna lindra vårdlidande Nyckelord: Bipolär sjukdom, Medicin biverkningar, Patientupplevelse, Stöd, Viktökning. / Abstract. Background: Living with bipolar disorder is difficult for many. The disease causes severe changes in emotional state. Medication is an important component in the treatment of bipolar disorder, but when this gives rise to serious side effects such as weight gain, it can lead to suffering of this population. The purpose of the study was to describe how bipolar patients experienced the medication's side effects associated with weight gain and their experience of dealing with it and the experiences of support as well as their expectations of health care within the current range. Method: A qualitative and descriptive design was used. The study group consisted of five women and one male patient from a hospital in central Sweden. The main result showed that participants experienced a great impact on the wellbeing and health of medication side effects such as weight gain. Through the participants suffered from the side effects that affected both the physical and mental health. All participants had gone through difficult struggles to manage weight gain and it took a lot of their own powers. Furthermore, they stressed that they had not been seen by the healthcare and their weight problems were not taken seriously. The participants experienced strong feelings and suffering from the medication side effects and weight gain, and there were expectations of getting support and information as well as continuous care to be able to feel safe in the treatment and experience and to have a better quality of life. The conclusion shows that people with bipolar disorder suffer a lot of the weight gain associated with medication side effects. It highlights that weight problems are difficult to manage and overlooked by the healthcare, making the quality of life of the patient difficult to maintain. That the problems are taken seriously and to get information and support in the area concerned was considered necessary in order to alleviate the suffering of care. Keywords: Bipolar disorder, Medicine side effects, Patient experience, Support, Weight gain.

Syfte: Syftet var att utvärdera effekten av sjuksköterskans föreslagna omvårdnadsåtgärder på cytostatikarelaterade biverkningar hos cancerpatienter som genomgår cytostatikabehandling. Metod: Examensarbetet utfördes som en litteraturöversikt. Resultatet grundar sig på 13 stycken kvantitativa artiklar. För datainsamlingen användes databaserna PubMed och Cinahl. Resultat: Resultatet visade att sjuksköterskan kan utföra omvårdnadsåtgärder som minskar patienters upplevelse av cytostatikarelaterade biverkningar. Effekterna som framkom av sjuksköterskans omvårdnadsåtgärder presenteras under rubrikerna; oral kryoterapi vid oral mukosit, personcentrerad patientutbildning med underrubriken utbildning utifrån ett teoretiskt perspektiv, automatiserad och sjuksköterske- assisterad symtombehandling samt musikterapi, bildspråk och avslappning. Slutsats: Sjuksköterskan kan genom olika omvårdnadsåtgärder hjälpa patienter att lindra symtom från cytostatikarelaterade biverkningar. / Aim: To evaluate the impact of the nurse's suggested nursing interventions on chemotherapy-related side effects in cancer patients undergoing chemotherapy treatment. Method: The work was conducted as a literature review. The results are based on 13 quantitative articles. For data collection the databases PubMed and Cinahl was used. Results: The results showed that nurses can perform nursing interventions that reduce patients' experience of chemotherapy-related side effects. The effects that emerged from the nursing interventions are presented under the headings; oral cryotherapy for oral mucositis, person-centered patient education with the subtitle education from a theoretical perspective, self-care, automated and nurses assisted symptom management, music therapy, imagery and relaxation. Conclusion: Nurses can through various nursing interventions help patients to relieve symptoms from chemotherapy-related side effects.

Vendula Dvořáčková Attitudes of patients toward antidepressant medication Master's thesis Charles University in Prague, the Faculty of Pharmacy in Hradec Králové Department of Biological and Medical Sciences Pharmacy Background: The master's thesis deals with evaluation of attitudes of inpatients in the psychiatric clinic of Military University Hospital Prague. The main task was to clarify the relation between therapy attitude and the prescribed medication, diagnosis and sociodemographic characteristics. Methods: The data were collected using the Drug Attitude Inventory questionnaire (Czech version by Masopust) where sum of negative and positive answers was used to determine the patient's general attitude. Patients' characteristics were acquired from a data-entry form, specific medication from the medical records. Results: In the observed group women seemed to have a more positive attitude toward the treatment compared to men, similarly to people with a higher level of education and patients between 31 - 40 years of age in comparison with other age groups. The most positive responses were observed in patients who were prescribed agomelatine, trazodone and paroxetine. People diagnosed with personal disorders or affective bipolar disorder inclined to positive answers as well, on the other hand most negative...

Introdução - Os recém-nascidos são considerados vulneráveis a eventos adversos a medicamentos pela imaturidade fisiológica, pela necessidade de se considerar as proporções corporais ao determinar dosagens de fármacos, pelas limitações práticas durante a administração medicamentosa e pela alta proporção de medicamentos utilizados para o seu tratamento quando em cuidados hospitalares. Além disso, a população de recém-nascidos geralmente não é incluída nos estudos clínicos de utilização de medicamentos. Neste contexto, a terapêutica farmacológica em recémnascidos termina na extrapolação das informações que levam à aprovação do registro de medicamentos para uso em adultos ou em crianças mais velhas. Apesar da relevância do tema, a identificação dos eventos adversos relacionados a medicamentos em hospitais ainda é realizada por meio da notificação voluntária. Estima-se que este método detecte apenas de 5 a 10 por cento dos eventos adversos por medicamentos ocorridos em uma instituição de cuidado à saúde. Uma ferramenta conhecida como trigger foi demonstrada como uma técnica mais efetiva em relação ao convencional sistema de notificação voluntária em pacientes hospitalizados. Um trigger é definido como um rastreador encontrado a partir da revisão de prontuários de pacientes, permitindo selecionar os registros nos prontuários os quais existe maior probabilidade de ter ocorrido um evento adverso a medicamento. Objetivo - Utilizar rastreadores para a identificação de eventos adversos a medicamentos (EAM) em recém-nascidos hospitalizados. Métodos Trata-se de um estudo de coorte prospectivo observacional. A pesquisa foi realizada no Hospital Universitário da Universidade de São Paulo, nas unidades de cuidados intermediários neonatal convencional e terapia intensiva neonatal, durante o período de março a setembro de 2015. Foram incluídos os recém-nascidos hospitalizados que utilizaram medicamentos durante a internação. Uma lista de rastreadores foi desenvolvida para ser utilizada na identificação de EAM nesta população. Os prontuários dos recémnascidos eram avaliados, a fim de detectar primeiramente a existência de um rastreador. Se o rastreador fosse encontrado, era registrado e seguia-se com uma revisão mais detalhada à procura de possíveis EAM relacionados. Os recém-nascidos foram acompanhados até a sua alta ou até completarem 29 dias de vida. O desempenho de cada um dos rastreadores para identificar EAM foi calculado. As frequências dos EAM foram determinadas. As características dos eventos adversos e dos medicamentos relacionados foram descritas. Resultados O estudo incluiu 125 recém-nascidos. Foram encontrados 925 rastreadores, que foram positivos 208 vezes para identificar suspeitas de eventos adversos a medicamentos e que corresponderam ao número final de 115 EAM. A taxa de rendimento geral dos rastreadores foi 22,5 por cento. A incidência geral de EAM foi 46,4 por cento (IC 37,6; 55,1). A taxa geral de EAM por 1000 pacientes-dia foi 81,6 (IC 67,4; 98,0). Os EAM mais frequentes foram: diarreia (29,6 por cento), vômito (23,5 por cento), hipersedação (7,0 por cento) e hiperglicemia (5,2 por cento). Os medicamentos mais frequentes associados aos EAM foram: antibióticos (39,4 por cento), analgésicos (13 por cento), vitaminas (12,5 por cento), cafeína (11,1 por cento) e psicolépticos (8,7 por cento). Entre os rastreadores de alto desempenho destacam-se: hipersedação, prescrição de metadona/lorazepam e prescrição de flumazenil. Estes rastreadores identificaram EAM relacionados aos analgésicos e psicolépticos, duas das classes terapêuticas mais implicadas em EAM neste estudo. Conclusões - Os EAM mais frequentes identificados pelos rastreadores foram: diarreia, vômito, hipersedação e hiperglicemia. Os medicamentos mais frequentes associados a EAM foram: antibióticos, analgésicos, vitaminas, cafeína e psicolépticos. A incidência geral de EAM de 46,4 por cento e a taxa de incidência foi 81,6 EAM por 1000 pacientes-dia. A busca ativa de EAM por rastreadores permite uma análise focada de elementos específicos nos prontuários de pacientes. Este tipo de pesquisa permite a identificação de um maior número de EAM que podem passar despercebidos em simples revisão de prontuários. / Introduction - Newborns are considered vulnerable to adverse drug events because of their physiological immaturity, to consider the body proportions to determine dosages of drugs, the practical limitations during drug administration and the high proportion of drugs used for their treatment while in hospital care. Furthermore, the population of newborns is usually not included in clinical trials for the approval of new drugs. In this context, drug therapy in children is based on extrapolation of information that lead to the approval of the drug for use in adults or in older children. Despite the relevance of the subject, the identification of adverse drug events in hospitals is still carried out through voluntary reporting. It is estimated that this method detects only 5 to 10 per cent of the adverse events occurred by medications in a health care institution. A tool known as \"trigger\" is shown as a superior method compared to the conventional voluntary reporting system in hospitalized patients. A \"trigger\" is defined as a \"flag\" found from the patient chart review, allowing to select the records in the charts that are most likely to have experienced an adverse drug event. Aim - Use triggers to identify adverse drug events (ADE) in hospitalized newborns. Methodology - This is an observational prospective cohort study. The study was conducted at the University Hospital of the University of São Paulo, in the neonatal conventional intermediate care unit and in the neonatal intensive care unit, from March to September 2015. Hospitalized newborns were included using medications during hospitalization. A trigger list was made to identify ADE in this population. The triggers on this list were actively sought in medical charts of newborns. If a trigger was found, it was registered and followed up with a more detailed search for potential ADEs that occurred. Newborns were followed until their discharge or until completing 29 days of life. The performance of each trigger to identify ADE was calculated. The frequencies of ADE were determined. The characteristics of adverse events and related drugs have been described. Results - The study included 125 newborns. 925 triggers were found, which were positive 208 times to identify suspected ADE. That corresponded to the final number of 115 ADE. The overall triggers rate was 22.5 per cent . The overall incidence of ADE was 46.4 per cent (CI 37.6; 55.1). The overall frequency of ADEs per 1,000 patient-days was 81.6 (CI 67.4; 98.0). The most common ADE were diarrhea (29.6 per cent), vomiting (23.5 per cent), oversedation (7.0 per cent) and hyperglycemia (5.2 per cent). The most common medications associated with ADEs were antibiotics (39.4 per cent), analgesics (13 per cent), vitamins (12.5 per cent), caffeine (11.1 per cent) and psycholeptics (8.7 per cent). Among the highperformance trigger, it stand out: \"oversedation,\" \"prescription of methadone / lorazepam\" and \"prescription of flumazenil.\" These triggers identified ADE related to analgesics and psycholeptics, two of the therapeutic classes more involved in ADE in this study. Conclusions Frequent EAM identified by triggers were diarrhea , vomiting, hyperglycemia and oversedation . The most common medications associated with ADE were antibiotics, analgesics, vitamins, caffeine and psycholeptics. The overall incidence of EAM 46.4 per cent and the incidence rate was 81.6 EAM per 1000 patient-days. The active search for ADE by triggers allows a focused review of specific elements in the patient records. This kind of search allows the identification of a greater number of ADE that could go unnoticed in simple review of medical records.

一氧化二氮，俗稱笑氣，是現代臨床麻醉最為常用的一種麻醉劑。然而，關於一氧化二氮效能及安全性的研究至今仍存在爭議。近來，一個稱為ENIGMA的臨床研究項目對2,050個施行大手術的病人接受麻醉情況及術後併發癥進行了研究。研究發現手術中施行一氧化二氮麻醉的病人術後傷口感染率較之對照組上升了35%。另一方面，對423個ENIGMA病人的長期隨訪研究發現，在術中接受一氧化二氮麻醉的病人中慢性術後痛的發病率相對對照組降低了56%。 對於這些臨床發現的分子機制，目前知之甚少。 因此我們進行了一系列實驗來研究一氧化二氮導致術後感染以及預防慢性痛的分子機制。 / 一氧化二氮對基因穩定性的影響 / 在對93個接受直腸結腸大型外科手術的病人進行的隨機對照試驗中，我們比較了接受一氧化二氮麻醉及其對照組病人的外周白細胞脫氧核糖核酸（DNA）損傷情況和術後傷口感染率。通過單細胞凝膠電泳（彗星實驗），我們發現術中一氧化二氮麻醉顯著增加了手術24小時后病人的DNA損傷情況 （p < 0.001）。且這種變化是劑量依賴的，r = 0.33; p = 0.03。並且，在DNA損傷程度及術後傷口感染率間存在顯著相關。術後DNA損傷程度每增加十個單位，傷口感染率則隨之增加17%。 / 一氧化二氮對DNA損傷應答及修復的影響 / 利用大鼠模型，我們對一氧化二氮導致基因不穩定的機制進行了研究。Sprague Dawley大鼠暴露於一氧化二氮中2小時後，我們對其DNA損傷應答及修復基因的轉錄情況進行了檢測。脂多糖（LPS）注射大鼠模擬了圍手術期的炎癥反應。我們發現LPS刺激的白細胞經一氧化二氮處理后，其編碼DNA連接酶IV的LIG4基因的轉錄量顯著降低（p < 0.05）。LIG4基因的下調導致了一氧化二氮麻醉後圍手術期的免疫抑制效應。 / NMDA受體抑制在一氧化二氮預防性鎮痛中的作用 / 在大鼠慢性神經痛模型中，我們檢測了一氧化二氮鎮痛作用的機制。我們發現一氧化二氮處理組的機械痛覺過敏相較對照組顯著降低（p = 0.001）。一氧化二氮處理后，神經痛大鼠脊髓背角中的c-Fos表達量也顯著降低，這表明了一氧化二氮對神經元活性的影響。該影響可能是NMDA受體抑制的結果。另外，我們還觀察到一氧化二氮的鎮痛特徵與NMDA受體非競爭性拮抗劑MK-801的鎮痛效果相似。 / 基因表達改變在一氧化二氮預防性鎮痛中的作用 / 一氧化二氮鎮痛效果的遲發性和延續性提示了除受體拮抗之外的其他作用機制的存在。我們發現在大鼠坐骨神經壓迫損傷模型中，一氧化二氮處理顯著降低了同側脊髓背角組織中LIG4基因的轉錄及表達（p = 0.006）。同時一氧化二氮處理降低了星形膠質細胞在同側脊髓背角中的活化。我們的研究表示一氧化二氮影響DNA修復， 抑制脊髓背角基因的表達，從而起到預防性鎮痛的作用。 / 總而言之，一氧化二氮通過抑制鉀硫氨酸合成酶，削弱DNA修復和基因組穩定性，從而成為導致術后傷口感染的危險因素。另一方面，這一機制也阻止了脊髓背角中異常突觸的建立，從而預防了神經損傷導致的慢性神經痛的建立。另外，一氧化二氮的鎮痛機制也和NMDA受體抑制作用有關。 / Nitrous oxide is a commonly administered anesthetic and analgesic agent in contemporary clinical anesthesia. However, the efficacy and safety of nitrous oxide delivery remains a subject of debate. The recent Evaluation of Nitrous oxide In a Gas Mixture for Anaesthesia (ENIGMA) Trial found that nitrous oxide administration, in 2,050 patients undergoing major surgery, increased the incidence of wound infection by 35%. On the other hand, in a long term follow-up study of 423 ENIGMA patients in Hong Kong, the risk of chronic postsurgical pain was reduced by 56% in patients who received nitrous oxide in the index surgery. Little is known about the mechanisms associated with these clinical observations; we therefore conducted a series of experiments to determine the molecular changes after nitrous oxide administration leading to postoperative wound infection and preventive analgesia. / Genomic Instability after Nitrous Oxide Administration / In a randomized controlled trial of 93 patients undergoing major colorectal surgery, we compared the changes of deoxyribonucleic acid (DNA) damage in circulating leukocytes and rates of wound infection in patients who were exposed to nitrous oxide or not. Using single cell gel electrophoresis (CometAssay), we found that intraoperative nitrous oxide administration produced significant DNA damage, 24 hours after surgery, compared with controls, p < 0.001. The changes were dose-dependent, r = 0.33; p = 0.03. In addition, there was a significant correlation between DNA damage and postoperative wound infection. For every 10 units increase in the percentage of DNA in tail after surgery compared with baseline, there was 17% increase in the risk of wound infection. / DNA Damage Response and Repair / In a rat model, we explored the mechanism of genomic instability after nitrous oxide administration. In Sprague Dawley rats exposed to nitrous oxide anesthesia for 2 hours, we tested the transcription of an array of DNA damage response and repair genes. Lipopolysaccharide (LPS) was added to mimic postoperative inflammation. In the mRNA that were extracted and analyzed by real-time polymerase chain reaction (RT-PCR), we found the transcription of gene encoding for DNA Ligase IV (LIG4 gene) was significantly reduced after nitrous oxide administration in LPS-stimulated leukocytes (p < 0.05). The down regulation of LIG4 gene contributed to perioperative immunosuppression following nitrous oxide exposure. / Role of N-methyl-D-aspartate receptor (NMDAR) Blockade for Preventive Analgesia with Nitrous Oxide / Using a rat model of chronic neuropathic pain, we tested the mechanisms underlying nitrous oxide analgesia. In Sprague Dawley rats undergoing unilateral constrictive injury to the sciatic nerve, we found that mechanical hyperalgesia was significantly reduced with nitrous oxide compared with controls (p = 0.01). In addition, c-Fos expression was decreased in spinal dorsal horn suggesting that neuron excitability was reduced after nitrous oxide administration which could be caused by blockade of the NMDA receptor. Interestingly, the characteristics of analgesia were similar to that provided by MK-801, a noncompetitive antagonist of NMDA receptors. / Transcriptional Changes for Nitrous Oxide Analgesia / The onset of nitrous oxide analgesia was delayed and outlasted actual receptor antagonism. We therefore explored mechanisms, other than NMDA receptor blockade, for nitrous oxide analgesia. Specifically, in rats undergoing sciatic nerve constrictive injury, we found that transcription of LIG4 gene was down-regulated in the ipsilateral spinal dorsal horn after nitrous oxide administration (p = 0.006). There was a decrease in DNA ligase IV expression and a reduction in the activation of astrocytes. Our data suggested that regulation of DNA repair and suppression spinal dorsal horn gene transcription is one of the alternative mechanisms for nitrous oxide analgesia. / In summary, nitrous oxide administration is a risk factor for postoperative wound infection. This is related to irreversible inhibition of the enzyme methionine synthase, impaired DNA repair and genomic instability. The same mechanism however prevented aberrations of synaptic regeneration in the spinal dorsal horn and could therefore prevent the development of chronic neuropathic pain after direct nerve injury. Nitrous oxide analgesia was also related to NMDA receptor blockade. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chen, Yan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 126-157). / Abstract also in Chinese. / Declaration of origination --- p.I / Abstract: --- p.II / Acknowledgements --- p.VIII / Table of Contents --- p.X / List of Tables --- p.XV / List of Figures --- p.XVI / List of Abbreviations --- p.XVIII / Chapter Part I: --- Literature Review --- p.1 / Chapter Chapter 1 --- A review of nitrous oxide: Historical, clinical and mechanistic Perspectives --- p.2 / Chapter 1.1 --- History of Nitrous Oxide --- p.2 / Chapter 1.2 --- Clinical Pharmacology of Nitrous Oxide --- p.4 / Chapter 1.3 --- Evaluation of Nitrous oxide In the Gas Mixture for Anesthesia (ENIGMA) Trial --- p.9 / Chapter 1.4 --- Efficacy and Toxicity of Nitrous Oxide: Biochemical and Molecular Mechanisms --- p.14 / Chapter 1.4.1 --- Immunosuppression Following Nitrous Oxide Administration --- p.14 / Chapter 1.4.2 --- Analgesia with Nitrous Oxide - Molecular Mechanisms --- p.17 / Chapter 1.4.2.1 --- Direct molecular target --- p.17 / Chapter 1.4.2.2 --- Interaction with γ aminobutyric acid type A (GABAA) receptors --- p.19 / Chapter 1.4.2.3 --- Regulation of opioid system --- p.20 / Chapter 1.4.2.4 --- Regulation of noradrenergic neurons --- p.21 / Chapter 1.4.2.5 --- N-methyl-d-aspartate (NMDA) receptor inhibition --- p.22 / Chapter 1.4.2.6 --- Long-term Preventive Analgesia with Nitrous Oxide --- p.23 / Chapter 1.4.3 --- Summary --- p.24 / Chapter Part II: --- Experiments --- p.26 / Chapter Chapter 2 --- Study Hypothesis and Objectives --- p.27 / Chapter 2.1 --- Genomic Instability after Nitrous Oxide Administration --- p.27 / Chapter 2.2 --- DNA Damage Response and Repair --- p.28 / Chapter 2.3 --- NMDA Receptor Blockade for Preventive Analgesia with Nitrous Oxide --- p.28 / Chapter 2.4 --- Transcriptional Changes for Nitrous Oxide Analgesia --- p.28 / Chapter Chapter 3 --- Genomic Instability After Nitrous Oxide Administration: A Randomized Controlled Trial --- p.32 / Chapter 3.1 --- Introduction --- p.32 / Chapter 3.2 --- Methods and Materials --- p.36 / Chapter 3.2.1 --- Study Participants --- p.36 / Chapter 3.2.2 --- Study Procedures --- p.36 / Chapter 3.2.3 --- Randomization --- p.37 / Chapter 3.2.4 --- Anesthetic Care --- p.37 / Chapter 3.2.5 --- Postoperative Care --- p.38 / Chapter 3.2.6 --- Measurement of Genomic Instability --- p.44 / Chapter 3.2.7 --- Statistical Analysis --- p.47 / Chapter 3.2.8 --- Sample Size Calculation --- p.47 / Chapter 3.3 --- Results --- p.48 / Chapter 3.4 --- Discussion --- p.61 / Chapter 3.4.1 --- Principal Findings --- p.61 / Chapter 3.4.2 --- Comparison to Other Studies --- p.61 / Chapter 3.4.3 --- Strengths and Limitations --- p.63 / Chapter 3.4.4 --- Implications --- p.64 / Chapter 3.4.5 --- Conclusions --- p.64 / Chapter Chapter 4 --- DNA Damage Response and Repair After Nitrous Oxide Administration / Chapter 4.1 --- Introduction --- p.65 / Chapter 4.1.1 --- DNA Damage Response and Repair Pathways --- p.65 / Chapter 4.1.2 --- Nitrous oxide and DNA Damage Response and Repair --- p.69 / Chapter 4.2 --- Materials and Methods --- p.70 / Chapter 4.2.1 --- Animals --- p.70 / Chapter 4.2.2 --- Nitrous Oxide Administration --- p.70 / Chapter 4.2.3 --- Lipopolysaccharide-Induced Infection Model --- p.72 / Chapter 4.2.4 --- Sample Collection and Preparation --- p.72 / Chapter 4.2.5 --- Single Cell Gel Electrophoresis (CometAssay) --- p.72 / Chapter 4.2.6 --- RNA Extraction for Gene Transcription Study --- p.72 / Chapter 4.2.7 --- Reverse Transcription Polymerase Chain Reaction (RT PCR) --- p.73 / Chapter 4.2.8 --- Quantitative RT PCR --- p.74 / Chapter 4.2.9 --- Statistical Analysis --- p.76 / Chapter 4.3 --- Results --- p.76 / Chapter 4.3.1. --- Genome Instability in Rat Leukocytes after Nitrous Oxide Administration --- p.76 / Chapter 4.3.2. --- Effect of Nitrous Oxide on the Transcription of DNA Damage Response Genes --- p.78 / Chapter 4.3.3. --- Effects of Nitrous Oxide on DNA Damage Response Genes in Animals Treated with Lipopolysaccharide --- p.80 / Chapter 4.4 --- Discussion --- p.84 / Chapter 4.4.1 --- Principal Findings --- p.84 / Chapter 4.4.2 --- Implications --- p.84 / Chapter 4.4.3 --- Limitation of our Study --- p.85 / Chapter 4.4.4 --- Conclusions --- p.87 / Chapter Chapter 5 --- Preventive Analgesia with Nitrous Oxide: Role of NMDA Receptor Blockade / Chapter 5.1. --- Introduction --- p.88 / Chapter 5.1.1. --- The ENIGMA Trial: Long Term Follow-up --- p.89 / Chapter 5.1.2. --- Nitrous oxide prevents chronic postsurgical pain: putative mechanisms --- p.89 / Chapter 5.1.3. --- Hypothesis --- p.90 / Chapter 5.2. --- Materials and methods --- p.91 / Chapter 5.2.1. --- Animals --- p.91 / Chapter 5.2.2. --- Chronic constriction injury (CCI) to induce neuropathic pain --- p.91 / Chapter 5.2.3. --- Behavioral test --- p.93 / Chapter 5.2.4. --- Nitrous oxide administration --- p.93 / Chapter 5.2.5. --- Dizocilpine (MK-801) pretreatment --- p.94 / Chapter 5.2.6. --- Tissue Collection, Preparation and Western Blot --- p.94 / Chapter 5.2.7. --- Statistical Analysis --- p.96 / Chapter 5.3. --- Results --- p.96 / Chapter 5.3.1. --- Preventive Analgesia with Nitrous oxide --- p.96 / Chapter 5.3.2. --- Nitrous oxide analgesia via NMDA receptors block --- p.99 / Chapter 5.3.3. --- Preventive analgesia with NMDA receptors Blockade --- p.101 / Chapter 5.4. --- Discussion --- p.103 / Chapter 5.4.1 --- Principal Findings --- p.103 / Chapter 5.4.2 --- Our Findings compared with Other Studies --- p.103 / Chapter 5.4.3 --- Limitations of the Study --- p.104 / Chapter 5.4.4 --- Conclusions --- p.105 / Chapter Chapter 6 --- Transcriptional Changes for Nitrous Oxide Analgesia --- p.106 / Chapter 6.1 --- Introduction --- p.106 / Chapter 6.1.1 --- Neuro-immune Interactions in the Development of Chronic Neuropathic Pain --- p.106 / Chapter 6.1.2 --- Nitrous Oxide Interferes Astrocytes and Glial Responses --- p.107 / Chapter 6.2 --- Materials and methods --- p.109 / Chapter 6.2.1 --- Chronic Constriction Injury Pain Model and Nitrous Oxide Administration --- p.109 / Chapter 6.2.2 --- Lumbar Dorsal Horn Tissue Collection, Preparation and Immunoflurescence --- p.109 / Chapter 6.2.3 --- RNA Extraction and Quantitative RT PCR for Gene Transcription Study --- p.110 / Chapter 6.2.4 --- Protein Extraction and Western Blot for protein Expression Study --- p.110 / Chapter 6.2.5 --- Statistical Analysis --- p.111 / Chapter 6.3 --- Results --- p.112 / Chapter 6.3.1 --- Time Course of LIG4 Gene Transcription after Constrictive Nerve Injury --- p.112 / Chapter 6.3.2 --- Nitrous oxide reduced DNA ligase IV expression in spinal dorsal horn --- p.114 / Chapter 6.3.3 --- Nitrous oxide Reduced Astrocytes Activation in Spinal Dorsal Horn --- p.116 / Chapter 6.4 --- Discussions --- p.119 / Chapter 6.4.1 --- Principal Findings --- p.119 / Chapter 6.4.2 --- Our Findings in Relation to Other Studies --- p.119 / Chapter 6.4.3 --- Limitations of Our Study --- p.120 / Chapter 6.4.4 --- Conclusions --- p.120 / Chapter Part III: --- Conclusions --- p.122 / Chapter Chapter 7 --- Conclusions and Future Perspectives --- p.123 / Chapter 7.1 --- Conclusions --- p.123 / Chapter 7.2 --- Future Perspectives --- p.124 / Chapter Part IV --- References --- p.126

Made available in DSpace on 2015-04-22T22:14:14Z (GMT). No. of bitstreams: 1 Marina Valente Maia.pdf: 5078341 bytes, checksum: 01644b70bc08b473565219d3cfbca193 (MD5) Previous issue date: 2012-04-30 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / After introduction of multi-drug therapy (MDT/OMS) there were decline in prevalence coefficients and new cases detections, however, the records of drug resistance and relapse cases are threatening factors against lepra control, therefore, the importance of new alternative schemes and monitoring adverse effects, avoiding abandonment or irregularity to treatment. Objectives: Describe side-effects of multi-drug regimen containing minocycline, ofloxacin and clofazimine in multibacillary (MB) leprosy patients and analyse the clinicalbacteriologic indices. Materials and Methods: A prospective, descriptive and observational study, in multibacillary patients, including intolerance cases of standard MDT and relapse cases, carried out in Alfredo da Matta Foundation, Manaus, Amazonas, Brazil, during april 2010 and january 2012. The side-effects were recorded of every individual patient, filled during the course of alternative treatment. The patients received alternative therapy with daily self-administered doses of 100mg of minocycline, 400 mg of ofloxacin and 50mg of clofazimine and a month supervised dose of 300mg of clofazimine for 06 months, thereafter 18 months of daily self-administered doses of ofloxacin 400mg, clofazimine 50mg and month supervised dose of clofazimine 300mg. Results and Discussions: During research 26 patients were treated, however, of these, only 21 cases were included in this study. The mild and not persistent side-effects occurred in 33,3% of patients. From the 37 side-effects, 45,9% episodes was attributed to ofloxacin, such as abdominal pain, nausea, vomiting, headache and insomnia; 21,6% due to clofazimine, 100% of patients with skin pigmentation; however, no side-effets due to minocycline. Mean duration for the development of adverse effects from the start of therapy was 15,2 days. The media interval of follow-up was 13,7 months and 23,8% of patients completed the 24 months trerapy. All the patients tolerated the drugs well and the adhesion was satisfactory, among 15 patients that completed the first treatment year, 14 took 12 doses at 12 months from alternative regimen. Conclusion: The alternative therapy had a similar feasibility and operational mode from MB/MDT, with safe, well tolerated and good adhesion with no serious events. The side-effects attributed to alternative regimen were comparable to previous studies, however this new three drugs combination indicates the importance of these research results. No drug was stopped unlike others standard MDT studies which had treatment interruption by side-effects. There was significant correlation (p<0,001) between clinical classification and histopatologic diagnosis. At the end of first year, there was clinical improvement and bacteriologic index reduction. Nevertheless, it s necessary a follow-up and new inclusions to guarantee the efficacy and safe for the alternative regimen. / Após introdução do esquema poliquimioterápico padrão (PQT/OMS), houve declínio nos coeficientes de prevalência e detecção de casos novos, entretanto, os registros de resistência medicamentosa e casos de recidiva representam ameaça para o controle da hanseníase, por isso a importância da proposição de novos esquemas alternativos e a necessidade de monitorar seus efeitos adversos, evitando-se casos de abandono ou irregularidade ao tratamento. Objetivos: Descrever os efeitos adversos do esquema terapêutico alternativo, contendo a associação clofazimina, ofloxacina e minociclina, em pacientes com hanseníase multibacilar e análise da evolução clínico-baciloscópica dos pacientes. Materiais e Métodos: Estudo prospectivo, descritivo e observacional, de casos multibacilares, incluindo casos de recidiva da doença ou intolerância à poliquimioterapia padrão, realizado na Fundação Alfredo da Matta, Manaus, Amazonas, Brasil, no período de abril de 2010 e janeiro de 2012. Os efeitos adversos foram registrados em formulários individuais para cada paciente, preenchidos ao longo do tratamento. Os indivíduos receberam o esquema alternativo, composto de doses diárias auto-administradas de 100mg de minociclina, 400mg de ofloxacina e 50mg de clofazimina e dose mensal supervisionada de 300mg de clofazimina por seis meses, seguida de 18 meses de doses diárias autoadministradas de ofloxacina 400mg, clofazimina 50 mg e dose supervisionada mensal de clofazimina 300mg. Resultados: Durante o período foram selecionados 26 pacientes, dos quais 21 foram incluídos no estudo. Efeitos adversos leves e transitórios foram observados em 33,3% dos pacientes. Do total de 37 efeitos secundários, 45,9% foram atribuídos à ofloxacina, como dor abdominal, náuseas, vômitos, cefaléia e insônia; 21,6% associados à clofazimina, com relatos e observação em 100% dos pacientes de hiperpigmentação cutânea; entretanto, nenhum efeito foi relacionado à minociclina, especificamente. O tempo médio de desenvolvimento das reações adversas a partir do início do esquema foi de 15,2 dias. A duração média do acompanhamento dos pacientes foi de 13,7 meses, sendo que 23,8% dos pacientes já concluíram o tratamento em 24 meses. A adesão e regularidade ao esquema foram satisfatórias, dos 15 pacientes que já completaram o primeiro ano de tratamento, 14 indivíduos realizaram 12 doses do esquema proposto em 12 meses. Discussão/Conclusão: O esquema alternativo demonstrou viabilidade e operacionalização semelhantes ao esquema PQT/MB, com segurança, boa tolerabilidade e adesão dos pacientes. A porcentagem de efeitos adversos às drogas foi compatível a de outros trabalhos, contudo, a inovação na combinação das três drogas acima, demonstra a importância dos resultados desta pesquisa. Não houve registros de casos graves que indicassem à suspensão ou interrupção do tratamento. Houve correlação significativa (p<0,001) entre a classificação clínica e o diagnóstico histopatológico. Ao fim do primeiro ano do esquema alternativo, os pacientes apresentaram melhora clínica e redução do índice baciloscópico médio. Todavia, há necessidade de acompanhamento dos indivíduos e aumento do número amostral para garantir a eficácia e segurança ao tratamento em longo prazo.

Introdução - Os recém-nascidos são considerados vulneráveis a eventos adversos a medicamentos pela imaturidade fisiológica, pela necessidade de se considerar as proporções corporais ao determinar dosagens de fármacos, pelas limitações práticas durante a administração medicamentosa e pela alta proporção de medicamentos utilizados para o seu tratamento quando em cuidados hospitalares. Além disso, a população de recém-nascidos geralmente não é incluída nos estudos clínicos de utilização de medicamentos. Neste contexto, a terapêutica farmacológica em recémnascidos termina na extrapolação das informações que levam à aprovação do registro de medicamentos para uso em adultos ou em crianças mais velhas. Apesar da relevância do tema, a identificação dos eventos adversos relacionados a medicamentos em hospitais ainda é realizada por meio da notificação voluntária. Estima-se que este método detecte apenas de 5 a 10 por cento dos eventos adversos por medicamentos ocorridos em uma instituição de cuidado à saúde. Uma ferramenta conhecida como trigger foi demonstrada como uma técnica mais efetiva em relação ao convencional sistema de notificação voluntária em pacientes hospitalizados. Um trigger é definido como um rastreador encontrado a partir da revisão de prontuários de pacientes, permitindo selecionar os registros nos prontuários os quais existe maior probabilidade de ter ocorrido um evento adverso a medicamento. Objetivo - Utilizar rastreadores para a identificação de eventos adversos a medicamentos (EAM) em recém-nascidos hospitalizados. Métodos Trata-se de um estudo de coorte prospectivo observacional. A pesquisa foi realizada no Hospital Universitário da Universidade de São Paulo, nas unidades de cuidados intermediários neonatal convencional e terapia intensiva neonatal, durante o período de março a setembro de 2015. Foram incluídos os recém-nascidos hospitalizados que utilizaram medicamentos durante a internação. Uma lista de rastreadores foi desenvolvida para ser utilizada na identificação de EAM nesta população. Os prontuários dos recémnascidos eram avaliados, a fim de detectar primeiramente a existência de um rastreador. Se o rastreador fosse encontrado, era registrado e seguia-se com uma revisão mais detalhada à procura de possíveis EAM relacionados. Os recém-nascidos foram acompanhados até a sua alta ou até completarem 29 dias de vida. O desempenho de cada um dos rastreadores para identificar EAM foi calculado. As frequências dos EAM foram determinadas. As características dos eventos adversos e dos medicamentos relacionados foram descritas. Resultados O estudo incluiu 125 recém-nascidos. Foram encontrados 925 rastreadores, que foram positivos 208 vezes para identificar suspeitas de eventos adversos a medicamentos e que corresponderam ao número final de 115 EAM. A taxa de rendimento geral dos rastreadores foi 22,5 por cento. A incidência geral de EAM foi 46,4 por cento (IC 37,6; 55,1). A taxa geral de EAM por 1000 pacientes-dia foi 81,6 (IC 67,4; 98,0). Os EAM mais frequentes foram: diarreia (29,6 por cento), vômito (23,5 por cento), hipersedação (7,0 por cento) e hiperglicemia (5,2 por cento). Os medicamentos mais frequentes associados aos EAM foram: antibióticos (39,4 por cento), analgésicos (13 por cento), vitaminas (12,5 por cento), cafeína (11,1 por cento) e psicolépticos (8,7 por cento). Entre os rastreadores de alto desempenho destacam-se: hipersedação, prescrição de metadona/lorazepam e prescrição de flumazenil. Estes rastreadores identificaram EAM relacionados aos analgésicos e psicolépticos, duas das classes terapêuticas mais implicadas em EAM neste estudo. Conclusões - Os EAM mais frequentes identificados pelos rastreadores foram: diarreia, vômito, hipersedação e hiperglicemia. Os medicamentos mais frequentes associados a EAM foram: antibióticos, analgésicos, vitaminas, cafeína e psicolépticos. A incidência geral de EAM de 46,4 por cento e a taxa de incidência foi 81,6 EAM por 1000 pacientes-dia. A busca ativa de EAM por rastreadores permite uma análise focada de elementos específicos nos prontuários de pacientes. Este tipo de pesquisa permite a identificação de um maior número de EAM que podem passar despercebidos em simples revisão de prontuários. / Introduction - Newborns are considered vulnerable to adverse drug events because of their physiological immaturity, to consider the body proportions to determine dosages of drugs, the practical limitations during drug administration and the high proportion of drugs used for their treatment while in hospital care. Furthermore, the population of newborns is usually not included in clinical trials for the approval of new drugs. In this context, drug therapy in children is based on extrapolation of information that lead to the approval of the drug for use in adults or in older children. Despite the relevance of the subject, the identification of adverse drug events in hospitals is still carried out through voluntary reporting. It is estimated that this method detects only 5 to 10 per cent of the adverse events occurred by medications in a health care institution. A tool known as \"trigger\" is shown as a superior method compared to the conventional voluntary reporting system in hospitalized patients. A \"trigger\" is defined as a \"flag\" found from the patient chart review, allowing to select the records in the charts that are most likely to have experienced an adverse drug event. Aim - Use triggers to identify adverse drug events (ADE) in hospitalized newborns. Methodology - This is an observational prospective cohort study. The study was conducted at the University Hospital of the University of São Paulo, in the neonatal conventional intermediate care unit and in the neonatal intensive care unit, from March to September 2015. Hospitalized newborns were included using medications during hospitalization. A trigger list was made to identify ADE in this population. The triggers on this list were actively sought in medical charts of newborns. If a trigger was found, it was registered and followed up with a more detailed search for potential ADEs that occurred. Newborns were followed until their discharge or until completing 29 days of life. The performance of each trigger to identify ADE was calculated. The frequencies of ADE were determined. The characteristics of adverse events and related drugs have been described. Results - The study included 125 newborns. 925 triggers were found, which were positive 208 times to identify suspected ADE. That corresponded to the final number of 115 ADE. The overall triggers rate was 22.5 per cent . The overall incidence of ADE was 46.4 per cent (CI 37.6; 55.1). The overall frequency of ADEs per 1,000 patient-days was 81.6 (CI 67.4; 98.0). The most common ADE were diarrhea (29.6 per cent), vomiting (23.5 per cent), oversedation (7.0 per cent) and hyperglycemia (5.2 per cent). The most common medications associated with ADEs were antibiotics (39.4 per cent), analgesics (13 per cent), vitamins (12.5 per cent), caffeine (11.1 per cent) and psycholeptics (8.7 per cent). Among the highperformance trigger, it stand out: \"oversedation,\" \"prescription of methadone / lorazepam\" and \"prescription of flumazenil.\" These triggers identified ADE related to analgesics and psycholeptics, two of the therapeutic classes more involved in ADE in this study. Conclusions Frequent EAM identified by triggers were diarrhea , vomiting, hyperglycemia and oversedation . The most common medications associated with ADE were antibiotics, analgesics, vitamins, caffeine and psycholeptics. The overall incidence of EAM 46.4 per cent and the incidence rate was 81.6 EAM per 1000 patient-days. The active search for ADE by triggers allows a focused review of specific elements in the patient records. This kind of search allows the identification of a greater number of ADE that could go unnoticed in simple review of medical records.

Children of Hispanic origin have the highest prevalence of asthma of all ethnic groups in the United States, especially Puerto Rican children, who have a prevalence of 12.9%. Treatment nonadherence has been identified as one contributing factor. The purpose of this qualitative study was to explore the reasons for nonadherence to the asthma treatment regimen among Puerto Rican children. Parents and health care providers of asthmatic children were interviewed regarding their beliefs about asthma as a disease, its effect on the child's life, and their experience with asthma treatment. Two models served as the theoretical framework: the health belief model and the Institute of Medicine model framework for asthma disparities. Interview data were collected from 8 parents using a questionnaire, and a focus group was conducted with 3 health care professionals. Data were manually coded to identify emerging themes. Even though parents reported fear of asthma medications and medication side effects, none of the parents stopped the asthma treatment. Results also indicated that lack of education about asthma, asthma treatment, and asthma action plan was evident in 75% of the parents. None of the parents who migrated to the United States from Puerto Rico received education about asthma while living in Puerto Rico. Health care professionals reported that although parents are familiar with asthma, they do not understand that it is a chronic disease that requires daily treatment. Findings may be used to create an asthma education plan tailored to the needs of the Hispanic population.

Chemotherapy in childhood cancer patients is associated with reduced bone density that can result in osteoporotic fracture in survivors. A significant proportion of paediatric patients experience a reduction in plasma 25 - hydroxyvitamin D3 [ 25 ( OH ) D3 ] and 1,25 - dihydroxyvitamin D3 [ 1,25 ( OH ) 2D3 ] levels during treatment, the basis of which is unknown. A balance between the bioactivation and degradation of 1,25 ( OH ) 2D3 is responsible for maintaining homoeostatic levels of 1,25 ( OH ) 2D3 at the correct set - point. Whereas the cytochrome P450 enzyme, CYP27B1 ( 25 - hydroxyvitamin D3 1 α - hydroxylase ), catalyses the hydroxylation of the precursor 25 ( OH ) D3 to generate 1,25 ( OH ) 2D3, catabolic inactivation and cleavage of 1,25 ( OH ) 2D3 is achieved by the mitochondrial cytochrome P450 enzyme, 25 - hydroxyvitamin D3 24 - hydroxylase ( CYP24 ), which is highly expressed in bone and kidney cells. Since many of the signalling pathways which regulate the expression of CYP24 are also activated by chemotherapeutic drugs, we hypothesised that the drugs could cause the degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 by increasing CYP24 expression, the principal means of facilitating the bio - inactivation and degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3. Using the kidney cell - lines, COS - 1 and HEK293T cells, we now report that chemotherapeutic drugs, represented by daunorubicin hydrochloride ( an anthracycline antibiotics ), etoposide and vincristine sulphate ( vinca alkaloids and related compounds ) and cisplatin ( an alkylating agent ), were able to enhance CYP24 promoter activity in kidney cell lines transfected with a CYP24 promoter - luciferase construct, either by themselves or in the presencedaunorubicin hydrochloride and etoposide, two of the strongest inducers of CYP24 promoter activation under our experimental conditions, demonstrate that these drugs acted in a concentration - dependent manner. In addition to stimulating promoter activity on their own, the drugs also amplified the induction of the CYP24 promoter by 1,25 ( OH ) 2D3. Synergistic increases were generally observed when the cells were treated simultaneously with 1,25 ( OH ) 2D3 and a drug. The two kidney cell lines generally responded in a similar manner when challenged with the drugs, either in the presence or absence of 1,25 ( OH ) 2D3. Interestingly, the hydroxylated derivative of daunorubicin hydrochloride, doxorubicin hydrochloride which is also a commonly used chemotherapeutic drug, had no effect of promoter activity. Further studies with daunorubicin hydrochloride demonstrated that the effects of the drug per se were not mediated by oxidative stress and the vitamin D receptor was not required for daunorubicin hydrochloride per se to stimulate CYP24 promoter activity. However, daunorubicin hydrochloride caused a modest increase in the expression of the vitamin D receptor and this could contribute to its synergistic activity with 1,25 ( OH ) 2D3. In the presence of etoposide, there was also a tendency for the kidney cells to express higher levels of the vitamin D receptor. A key role for the extracellular signal - regulated protein kinase ( ERK ) 1, ERK2 and ERK5 mitogen - activated protein ( MAP ) kinases was demonstrated for the inductive action of daunorubicin hydrochloride and etoposide, with CYP24 promoter - specific transcription factors located in the first - 298bp being likely targets of the ERK activity. Studies with a dominant negative mutant of MKK4, one of the two immediate upstream activators of the c - jun N - terminal kinase isoforms, demonstrated that this MAP kinase also played a crucial role in inductive actions of the of 1,25 ( OH ) 2D3. Dose - response studies with drugs. Consistent with their use in anti - cancer therapy, all of the above drugs killed the human promyelocytic HL60 leukaemic cells at very low concentrations but had no effect on the viability of kidney or liver cells, either at concentrations used in our experiments or at higher levels. Our data provide novel biochemical evidence that some of the commonly used chemotherapeutic drugs could cause an increase in the transcriptional activation of the promoter, most likely via the MAP kinases activating the transcription factors which bind to the CYP24 promoter. Such an effect could contribute to the reduction in plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 in some of the patients undergoing chemotherapy. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2005.