In der vorliegenden Arbeit wurde das Outcome von 112 Patienten mit intrakranieller Blutung analysiert, um das Blutungsvolumen und die unterschiedliche Dynamik der Blutungen als Einfluss- und prädiktive Faktoren zu korrelieren. 21.4% der 112 eingeschlossenen Patienten hatten ein EDH, 38.4 % ein SDH- bzw. 40.2% ein Intrazerebralhämatom. Die Sub- und Epiduralhämatome waren mehrheitlich traumatische Läsionen, die intrazerebralen Blutungen vorwiegend spontane. Im Gesamtkollektiv hatten 28.6% ein funktionelles, respektive 71.4% ein nicht funktionelles Outcome. Das Ergebnis der 71 traumatischen Blutungen war signifikant besser (38.0% funktionell) als das der 41 spontanen (12.2% funktionell, p=0.004). Bei gleichem Hämatomvolumen haben operativ versorgte spontane Blutungen eine 88% geringere Chance für ein funktionelles Ergebnis als operierte traumatische Blutungen. Im Untersuchungskollektiv wurde der reziproke Zusammenhang von Volumen und GOS sowohl für spontane und traumatische, als auch für akute und subakute Blutungen demonstriert. Nicht signifikant verschieden waren akut und subakut verlaufende Blutungen bezüglich ihres Outcomes (32.8% vs. 23.5% funktionelles Outcome, p= 0.302), und der Volumina (47.5ml vs. 52.8ml, p=0.102)). Der vermutete Zusammenhang zwischen Hämatomgröße und zeitlichem Verlauf konnte damit nicht gezeigt werden. Wir fanden auch keinen signifikanten Unterschied des klinischen Ergebnisses in Bezug auf den chirurgischen Interventionszeitpunkt (< 6h vs. > 6h). Bei den traumatischen Hämorrhagien wurde ein Modell mit 3 unabhängigen Faktoren (Alter, initaler GCS und Volumen) zur Prädiktion des Outcomes entwickelt. Kleine Volumina, ein niedriges Alter und ein initial hoher GCS lassen ein funktionelles Outcome vorhersagen. Weitere Faktoren, die jedoch nicht unabhängig mit dem Outcome assoziiert waren, sind Mittellinienverlagerung, initiale Blutglukose, Vorliegen eines Hirnödems und arterielle Hypertonie. Die initiale Glukosekonzentration kann zur Vorhersage des Outcomes nach traumatischen Blutungen beitragen, Als einziger unabhängiger Prädiktor wurde bei den spontanen Raumforderungen die Mittellinienverlagerung ermittelt. Volumen und initiale GCS waren nicht unabhängige Prädiktoren. Das schlechte Outcome nach spontaner Blutung, unabhängig vom Versorgungszeitpunkt, unterstreicht die kontroverse Datenlage bezüglich operativer Therapie dieser Raumforderungen. Traumatische Hämorrhagien in temporaler Lokalisation zeigen ein besseres Ergebnis als vergleichbare lokalisierte spontane Blutungen.

This thesis explores physiological changes occurring after acute brain injury. The first two chapters focus on traumatic brain injury (TBI), a significant cause of disability and death worldwide. I discuss the evidence behind current management of secondary brain injury with emphasis on partial brain oxygen tension (PbtO2) and intracranial pressure (ICP). The second chapter describes a subgroup analysis of the effect of hypothermia on ICP and PbtO2 in 17 patients enrolled to the Eurotherm3235 trial. There was a mean decrease in ICP of 4.1 mmHg (n=9, p < 0.02) and a mean decrease in PbtO2 (7.8 ± 3.1 mmHg (p < 0.05)) in the hypothermia group that was not present in controls. The findings support previous studies in demonstrating a decrease in ICP with hypothermia. Decreased PbtO2 could partially explain worse outcomes seen in the hypothermia group in the Eurotherm3235 trial. Further analysis of PbtO2 and ICP guided treatment is needed. The third chapter focuses on delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH), another form of acute brain injury that causes significant morbidity and mortality. I include a background of alpha-calcitonin gene-related peptide (αCGRP), a potential treatment of DCI, along with results from a systematic review and meta-analysis of nine experimental models investigating αCGRP. The meta-analysis demonstrates a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated with αCGRP compared with controls (p < 0.0005, 95% CI 23.7 to 57.9). Neurobehavioural scores were reported in four publications and showed a Physiological responses to brain tissue hypoxia and blood flow after acute brain injury standardised mean difference of 1.31 in favour of αCGRP (CI -0.49 to 3.12). I conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in animal studies but note that there is insufficient evidence to determine its effect on functional outcomes. A review of previous trials of αCGRP administration in humans is included, in addition to an original retrospective analysis of CSF concentrations of αCGRP in humans. Enzyme-linked immunosorbent assay of CSF (n = 22) was unable to detect αCGRP in any sample, which contrasts with previous studies and was likely secondary to study methodology. Finally, I summarise by discussing a protocol I designed for a dose-toxicity study involving the intraventricular administration of αCGRP to patients with aSAH and provide some recommendations for future research. This protocol was based upon the systematic review and was submitted to the Medical Research Council's DPFS funding stream during the PhD.

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency. The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation. Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%. Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%. Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels. Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group. Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up. Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.

En France, 73.3% des décès maternels liés à une hémorragie du post partum (HPP) ont été jugés comme « évitables » par le comité national d’experts en 2006. Le premier objectif de cette recherche a été l’observation des événements indésirables graves (EIG) en obstétrique et l’analyse des facteurs contributifs. Trois études ont été réalisées et ont montré une proportion de cas potentiellement évitables de 22% pour les embarrures, 72% pour les asphyxies néonatales et 73% pour les transferts maternels en service de réanimation. Le second objectif a été l’amélioration de la qualité de la prise en charge de l’HPP, première cause de mortalité maternelle. Deux études ont été réalisées. La première étude a montré que le protocole de prise en charge de l’HPP était appliqué partiellement après sa diffusion passive dans un réseau périnatal en Rhône Alpes. La seconde étude, PITHAGORE 6, un essai randomisé initié dans six réseaux de périnatalité en France pour mesurer l’impact d’un programme d’intervention multifacettes, a permis de réduire le taux d’HPP graves. De nouvelles méthodes doivent être développées en intégrant l’apport des sciences humaines pour optimiser la sécurité des soins en périnatalité. / In France, 73,3% of maternal deaths from post partum haemorrhage (PPH) were considered as «avoidable» by national experts committee in 2006. The first goal of this research was to observe adverse events (AEs) in obstetrics and to analyse latent and active conditions. The three observational studies highlighted that 22% of depressed skull fractures, 72% of birth asphyxia and 73% of maternal transfers to intensive care unit care might have been avoidedThe second aim was to improve PPH management, which is a leading cause of maternal mortality. Two studies were realized. The first has shown that regional guideline of PPH management was partly applied after passive dissemination in a regional perinatal network. The second study, PITHAGORE 6, a randomised trial conducted in six perinatal networks to assess impact of multi-faceted intervention program, reduced the rate of severe PPH. New methods have to be developed and might take into account human sciences to improve safety in perinatal care.

This study was conducted to investigate two important causes of reduced performance in sport horses. In the first study, clinical records of 201 Criollo horses, 5.59±2.11 years of age, that underwent physical examination due to lameness or reduced performance in order to document the frequency of lameness problems in these horses. A total of 223 problems were diagnosed. In the forelimbs (47.08%; n=105) and in the hindlimbs (52.9%; n=118). In the forelimbs the pain was located above the fetlock joint in 17.14% (18/105), 14.30% (15/105) in the fetlock and 68.60% (72/105) distal to the fetlock. In the hindlimbs the source of lameness was frequently located in the hock (78.80%; 93/118). Lameness above the tarsus occurred in 17.80% (21/118) and below the tarsus in 3.4% (4/118) of the cases. This study showed that Criollo horses present similar lameness problems as seen in other breeds competing in rodeo disciplines. In the second study, 38 Criollo horses, 6.63±1.53 years of age, underwent endoscopic examination of the upper and lower airways, during competitions, aiming to document the frequency of respiratory problems and evaluate its impact on the Criollo horse s performance by their competition scores. Lymphoid hyperplasia was found in 57.89% (22/38) and left laryngeal hemiplegia (grade II) in 7.89% (3/38). Exercise induced pulmonary haemorrhage was diagnosed in 21.05% (8/38). Lower respiratory inflammation indicated by the presence of mucous or purulent secretion in the trachea was seen in 78.94% (30/38). There was no difference in the performance scores between horses diagnosed with EIPH and the ones considered normal (p>0.05). However, horses with mucous/purulent secretion in the trachea showed lower performance scores compared to the EIPH group (p=0.01). The high frequency of Criollo horses in this study showing inflammation in the lower respiratory tract indicates that endoscopic examination would help to identify horses with problems before the competitions. / No primeiro estudo, foram avaliados os registros clínicos de 201cavalos Crioulos em treinamento com idade média de 5,59±2,11 anos, com o objetivo de identificar as principais causas de claudicação entre os anos de 2002 e 2009. Nestes cavalos, foram diagnosticadas 223 alterações no aparelho locomotor sendo que a claudicação foi localizada nos membros anteriores e posteriores em 47,08% (n=105) e 52,90% (n=118) respectivamente. Nos membros anteriores, 17,14% (18/105) das alterações foram diagnosticadas acima do boleto, 14,30% (15/105) no boleto e 68,60% (72/105) estavam localizadas distais ao boleto. No membro posterior 78,80% (93/118) apresentaram a origem da dor na região do tarso, 17,80% (21/118) acima do tarso e 3,40% (4/118) abaixo do tarso. Muitos dos problemas relacionados à parte distal dos membros anteriores provavelmente sejam em decorrência de descuidos com o ferrageamento e treinamento sobre superfícies duras. As articulações interfalangeanas distais são importantes fontes de dor e inflamação e mais frequentemente envolvidas em claudicações de membro anterior. Claudicações em membro posterior foram mais frequentes do que em membro anterior sendo que o tarso foi a região que mais apresentou problemas. Os cavalos Crioulos apresentam problemas semelhantes aos citados em outras raças que participam de provas de rodeio. No segundo estudo, com o objetivo de determinar a frequência de patologias respiratórias e avaliar seu possível impacto no desempenho atlético de cavalos da raça Crioula, 38 cavalos com idade média de 6,63±1,53 anos foram submetidos ao exame endoscópico das vias aéreas superiores e inferiores em etapas classificatórias ao Freio de Ouro. As notas atribuídas aos cavalos nas provas foram utilizadas como referência na avaliação do desempenho. Hiperplasia linfóide foi observada em 57,89% (22/38) e hemiplegia laríngea esquerda grau II em 7,89% (3/38). Hemorragia pulmonar induzida pelo exercício (HPIE) foi observada em 21,05% (8/38). A presença de secreção em diversos graus na traquéia, indicativo de inflamação, foi observada em 78,94% (30/38). Não se observou diferença significativa (p>0,05) no desempenho de animais que sofreram HPIE em relação aos animais sadios (sem HPIE e sem muco/catarro). Entretanto, animais com muco/catarro na traquéia apresentaram desempenho inferior (p=0,0132) aos animais que sofreram HPIE. A frequência de cavalos com presença de muco/catarro na traquéia sugere que os cavalos Crioulos podem se beneficiar do uso da endoscopia antes das competições para o diagnóstico de sinais de doença inflamatória das vias aéreas.

Adverse drug reactions (ADRs) constitute a significant health problem with consequences for the patient as well as for society. Suspected ADRs have been reported to occur in about 2-14% of hospitalised patients. In about 5% of deceased hospitalised patients suspected ADRs may have caused or contributed to the fatal outcome. When a pharmaceutical drug is approved for marketing, the drug has been tested only on a limited number of patients (often &lt;6000) for a limited time period in a controlled environment. Hence mostly common ADRs are detected in these trials. Moreover, certain patient groups, for example patients with co-morbidities, elderly patients, children and pregnant women are often not included in these studies. Thus, it is important to closely monitor the use of drugs after marketing to observe new effects and detect new ADRs. The aim of this thesis is to describe the pattern of pharmaceutical substance use related to morbidity and mortality and to investigate two serious ADRs. We have studied the incidence of fatal ADRs, fatal intoxications, cerebral haemorrhage related to warfarin treatment and venous thromboembolism (VTE) related to treatment with antipsychotic drugs. Observational studies form the basis for this thesis. Data from the Swedish Cause of Death Register, medical case records, the Swedish database on ADRs, the forensic pathology and forensic toxicology databases, and Swedish and Danish hospital discharge registers, Danish prescription registers, and civil registry systems were used. In Paper I we found that 3% of all fatalities in a Swedish population were related to a suspected ADR. Of the deceased hospitalised patients, 6% were related to a suspected ADR. Haemorrhage was the most commonly observed fatal suspected ADR, accounting for almost two-thirds of the events and anticoagulantia was the most common drug group associated with fatal suspected ADRs (almost 50%). A suspected intoxication could have contributed to the fatal outcome in 0.6% of the deceased. Among the fatal intoxications in Swedish medico-legal autopsies studied in Paper II, on average four substances were detected per case. The five most commonly detected substances in individuals with a fatal intoxication were ethanol, propoxyphene, paracetamol, diazepam and flunitrazepam. Among patients diagnosed with cerebral haemorrhage, 10% (59 cases) were treated with warfarin at onset of symptoms (Paper III). Of these, 7 cases (12%) were considered to have been possibly avoidable since the patients were treated with concomitant drugs that have the potential to enhance warfarin effects. The results from Paper IV and Paper V in combination with the published literature suggest that patients treated with antipsychotic drugs have an increased risk for VTE. Compared with non-users, an adjusted odds ratio for VTE of 2.0 was found for users of any antipsychotic drugs in a Danish population. In a medico-legal autopsy series, an adjusted odds ratio for fatal pulmonary embolism of 2.4 and 6.9 was found for users of first-generation low-potency antipsychotics and second-generation antipsychotics, respectively. In summary, drug-related morbidity and mortality is a significant problem and suspected ADRs contribute to a substantial number of deaths. Fatal intoxications are relatively common and it is important to observe changes in patterns of substances associated with fatal intoxications to be able to discover new trends and monitor effects of preventive work. A significant proportion of warfarin-related cerebral haemorrhage was caused by drug-drug interactions and was considered possible to avoid. Users of antipsychotic drugs may increase the risk of VTE. / Idag finns det säkra och effektiva behandlingar mot många sjukdomar. Läkemedel är den vanligaste behandlingsformen i sjukvården och under 2006 hämtade sex miljoner svenskar (68%) ut ett eller fler recept på ett apotek i Sverige. Även om läkemedelsbehandling har många positiva effekter kan även oönskade och skadliga effekter vid läkemedelsbehandling uppkomma, dvs. läkemedelsbiverkningar. Innan ett läkemedel kommer ut för försäljning har man studerat effekter och biverkningar på ett begränsat antal individer (ofta &lt;6000) under en begränsad tidsperiod där patienterna övervakas noga. Dessutom är det i regel enbart patienter med få andra sjukdomar och läkemedel som ingår i dessa studier. Därför är oftast enbart de vanligaste biverkningarna kända när ett läkemedel börjar säljas till allmänheten. När ett läkemedel blir tillgängligt för ett stort antal patienter är det därför viktigt att man med olika metoder fortsätter att följa läkemedlets effekter och biverkningar. Tidigare har man visat att ungefär 2-14% av inläggningar på sjukhus beror på läkemedelsbiverkningar. Dessutom kan biverkningar ha bidragit eller orsakat dödsfallet i ungefär 5% av de som avlider på sjukhus. Biverkningar orsakar mycket lidande för patienten och kostar samhället både tid och pengar. Om det skulle vara möjligt att förhindra några av dessa sjukhusinläggningar eller dödsfall skulle man vinna mycket. Det är svårt att uppskatta hur många biverkningar som kan förhindras. Genom att studera faktorer som kan öka risken för en oönskad effekt kan man bättre anpassa behandlingen till den enskilde patienten och därmed förhindra biverkningar. Syftet med den här avhandlingen är att beskriva mönster av läkemedelsrelaterade sjukdomar och dödsfall, och att undersöka risken för två allvarliga läkemedelsbiverkningar. Förekomsten av misstänkta läkemedelsbiverkningar, vilka faktorer som kan öka risken för att få en läkemedelsbiverkan, samt vilka läkemedel och biverkningar som förekommer har studerats. Detta gjordes utifrån uppgifter hämtade från dödsorsaksregistret, svenska biverkningsregistret, journaler, rättsmedicinska register, slutenvårdsregister och receptregister. Genom att utnyttja sådan information har vi i närmare detalj studerat förekomsten av dödsfall där ett eller flera läkemedel kan ha haft betydelse för dödsfallet, förgiftningsdödsfall, blödningar i samband med blodförtunnande medicinering och blodproppar i samband med antipsykotisk medicinering. I de arbeten som ingår i avhandlingen har vi funnit att en läkemedelsbiverkan misstänks ha bidragit eller orsakat dödsfallet i ungefär 3% av de som avlidit i en svensk population (Arbete I). Blödningar står för nästan två tredjedelar av dessa biverkningar och blodförtunnande medel misstänks vara inblandade i nästan hälften av de misstänkta läkemedelsbiverkningarna. I den här svenska populationen avled 0,6% till följd av misstänkt läkemedelsförgiftning. Bland rättsmedicinskt undersökta förgiftningsdödsfall påvisades i genomsnitt fyra substanser per fall (Arbete II). De fem vanligaste påvisade substanserna i studien var alkohol, dextropropoxifen, paracetamol, diazepam och flunitrazepam. Bland patienter som får hjärnblödning behandlades 10% vid blödningstillfället med ett blodförtunnande medel, warfarin (Arbete III). I 7 fall (12%) skulle hjärnblödningen möjligen kunna ha förhindrats då patienterna samtidigt behandlades med andra läkemedel som kan ha ökat blödningsrisken. Den sammantagna bilden av den litteratur som finns publicerad och resultatet av Arbete IV och Arbete V, tyder på att patienter som behandlas med antipsykotiska preparat har en ökad risk för att få blodpropp. Flera faktorer har föreslagits som kan förklara den ökade risken för blodpropp bland patienter som behandlas med antipsykotika som har med sjukdomen att göra och/eller behandlingen med antipsykotiska läkemedel. Sammanfattningsvis visar detta avhandlingsprojekt att läkemedelsbiverkningar är ett väsentligt sjukvårdsproblem som bidrar till ett betydande antal dödsfall. Förgiftningsdödsfall med läkemedel är också relativt vanliga och det är viktigt att bevaka effekter av preventiva åtgärder och se om de substanser som används ändras över tid. En del läkemedelsrelaterade biverkningar skulle kunna förhindras då t.ex. en betydande andel av warfarinrelaterade hjärnblödningar beror på läkemedelsinteraktioner. Förekomsten av venösa blodproppar verkar vara förhöjd bland patienter som behandlas med antipsykotiska läkemedel, men fler studier behövs för att avgöra detta och vad det i så fall beror på.

Loss or partial loss of eye sight can have major effect on quality of person's life. One of the most common diseases, which causes loss or partial loss of eye sight are diabetic retinopathy and age releated macular degeneration. Both of these diseases can be prevented or mediated by early detection and proper treatment. The fundus camera, which is used to capture eye retina, has had major effect on increasing quality and speed of early detection. Images captured by fundus camera can be automatically analyzed in order to detect any possible signs of retina damage. This thesis proposes one possible way of automating this process. First part of this thesis describes eye, its diseases and capturing technology. Second part then proposes way of automating detection process and its implementation. Lastly, the results are evaluated.

Univerzita Karlova v Praze 1. lékařská fakulta Autoreferát disertační práce Optimalizace indikací chirurgického a endovaskulárního ošetření intrakraniálních aneurysmat Anna Štekláčová 2018 2 Doktorské studijní programy v biomedicíně Univerzita Karlova v Praze a Akademie věd České republiky Obor: Neurovědy Předseda oborové rady: Prof. MUDr. Karel Šonka, DrSc. Školicí pracoviště: Neurochirurgická a neuroonkologická klinika 1. LF UK a ÚVN, Praha Školitel: Prof. MUDr. Vladimír Beneš, DrSc. Disertační práce bude nejméně pět pracovních dnů před konáním obhajoby zveřejněna k nahlížení veřejnosti v tištěné podobě na Oddělení pro vědeckou činnost a zahraniční styky Děkanátu 1. lékařské fakulty. 3 Obsah Abstrakt - Česky ..................................................................................... 4 Abstract - English ................................................................................... 5 Úvod........................................................................................................ 6 Hypotézy a cíle studie............................................................................. 6 Materiál a metody ................................................................................... 7 Výsledky...

Much of the impetus for this research can be attributed to Kenneth W. Hinchcliff, who has studied exercise-induced pulmonary haemorrhage (EIPH) extensively. This thesis focused on EIPH in Thoroughbred racehorses competing in South Africa. Using tracheobronchoscopy, the prevalence and severity of EIPH and the association with racing performance was determined. Thereafter, the prevalence of other respiratory tract disorders and their association with racing performance is reported. This is followed by a study assessing interobserver variability using grading systems in the detection of respiratory tract disorders. Finally, there is a report on the immunopathogenesis of EIPH. Using tracheobronchoscopy after racing, the prevalence and severity of EIPH was assessed in 1,005 racehorses competing at high altitude (> 1,400 meters above sea level) and at sea level in a racing jurisdiction that does not allow the use of furosemide and nasal dilator strips. The prevalence and severity of EIPH was affected by altitude as racing at sea level was associated with a higher prevalence and greater severity of EIPH. Results also suggested that EIPH was associated with superior performance in South African Thoroughbred racehorses. Upper and lower respiratory tract disorders identified following tracheobronchoscopic examination included left arytenoid asymmetry, left laryngeal hemiplegia, epiglottic deformity, epiglottic entrapment, subepiglottic cysts, dorsal displacement of the soft palate, pharyngeal lymphoid hyperplasia (PLH), laryngeal and tracheal dirt, tracheal mucous (TM), tracheal stenosis and tracheal cartilage ring spikes in Thoroughbred racehorses after racing. Overall, there was a low prevalence of grade 2 and 3 arytenoid cartilage asymmetry, left laryngeal hemiplegia, epiglottic entrapment, subepiglottic cysts and epiglottic deformity, while more severe grades of PLH, laryngeal debris, tracheal debris, TM and tracheal cartilage ring spikes had a higher prevalence. An association with sex was identified as tracheal cartilage ring spikes occurred more often in male racehorses. Superior racing performance was identified in racehorses with grade 3 tracheal mucous and tracheal cartilage ring spikes. Endoscopic grading of EIPH, PLH, arytenoid cartilage movement (ACM), and TM was performed by 3 observers that were blinded to each racehorse’s identity and race day performance using previously established grading criteria. Excellent interobserver reliability was seen using the EIPH grading system, while the weighted kappa for PLH, ACM and TM was lower. The study demonstrated sufficient reliability for the use of the EIPH, PLH, ACM and TM grading systems in racehorses competing in South Africa. The study concluded that tracheobronchoscopy seemed to be a practical screening technique that may have prognosticative validity and clinical dependability and that would allow safe and quick assessment of the respiratory tract of a large number of racehorses in field conditions. Venous blood was collected from 10 horses in each EIPH grade classification (grade 0 to 4) following tracheobronchoscopic examinations for the determination of the presence and severity of EIPH. Following RNA isolation and cDNA synthesis, real-time PCR was used to detect equine cytokine-specific mRNA for interleukin (IL) -1, -6, -10, interferon (INF) -ã, and tumor necrosis factor (TNF) -á. Results of this study indicated that increased IL-6, and -10 mRNA production was associated with more severe forms of EIPH. Also, there was greater expression of IL-6 mRNA at sea level and TNF-á mRNA at high altitude. This study concluded that although it was unclear whether the inflammatory response observed in the study was due to pre-existing pulmonary inflammation or as a direct consequence of pulmonary bleeding, the study demonstrated a systemic correlation to pulmonary inflammation. The research reported in this thesis has contributed substantially to the determination of the prevalence, severity and affect on racing performance of respiratory tract disorders in Thoroughbred racehorses competing in South Africa. Also, determination of an association between EIPH and inflammation at a molecular level may assist future researchers in anti-cytokine therapies which may help reduce the prevalence and severity of EIPH. / Thesis (PHD)--University of Pretoria, 2007. / Companion Animal Clinical Studies / unrestricted

[ES] Durante la gestación, la mujer experimenta cambios fisiológicos, metabólicos y morfológicos que podrían conllevar importantes riesgos materno-fetales. En primer lugar, el parto prematuro es la principal causa de mortalidad infantil, con una prevalencia del 10% en gestaciones únicas (SG) y del 50% en gestaciones múltiples (MG). Por tanto, la caracterización de la actividad uterina, así como la comparación entre SG y MG, puede ayudar a comprender y manejar mejor esta patología. En segundo lugar, la inducción del parto (IOL) se asocia a un mayor riesgo de mortalidad y morbilidad materna cuando la fase latente del parto se prolonga excesivamente, especialmente en mujeres nulíparas. Sin embargo, la literatura es escasa y no se ha observado claramente la respuesta electrofisiológica uterina al fármaco de IOL. En este sentido, el estudio de biomarcadores basados en la electrohisterografía (EHG) podría ayudar a detectar precozmente el riesgo de fracaso de la IOL y orientar las decisiones clínicas en consecuencia. En tercer lugar, la hemorragia posparto (PPH) constituye una de las principales causas de mortalidad materna en el mundo. Su prevalencia es del 2-6%, y causa la muerte de 75.000 mujeres cada año. La principal causa es la atonía uterina, por lo que la EHG se convierte en la herramienta ideal para valorar el estado del útero e indicar el riesgo de PPH en función de la ausencia o no de actividad. Por ello, el objetivo de la presente tesis doctoral es la identificación de EHG-biomarcadores para la detección precoz de situaciones obstétricas de alto riesgo. Para ello, se generaron las bases de datos de señal EHG y de datos obstétricos para cada escenario en el Hospital Universitario y Politécnico La Fe. La mayor impulsividad y predictibilidad en MG respecto a SG durante el tercer trimestre, así como la correlación significativa entre los EHG-biomarcadores y el peso fetal, sugirió un acoplamiento electromecánico entre la sobredistensión y la actividad mioeléctrica registrada en superficie. En cuanto a la IOL, el grupo de éxito mostró un aumento significativo del número de contracciones y de la excitabilidad celular, junto con una menor complejidad, a partir de 2-3 horas tras la administración del fármaco de IOL. No se observaron cambios significativos con respecto a la actividad basal en el grupo de fracaso. La comparación basada en la paridad reportó una mayor ratio de progresión de la amplitud de la señal en el grupo de parosas. La actividad mioeléctrica en el postparto vaginal resultó ser más frecuente e intensa, además de exhibir una mayor excitabilidad celular que en los partos por cesárea. La capacidad discriminatoria de los biomarcadores de EHG para la detección precoz del riesgo en diversos contextos obstétricos ha hecho avanzar el conocimiento electrofisiológico actual del útero in vivo. La traslación del EHG a la práctica clínica requerirá la automatización del procesamiento de señales, para culminar en la creación de modelos predictivos generalizados y robustos que apoyen la toma de decisiones clínicas, mejoren la planificación y gestión del parto, prevengan complicaciones maternas y fetales y optimicen la asignación de recursos hospitalarios. / [CA] Durant la gestació, la dona experimenta canvis fisiològics, metabòlics i morfològics que podrien comportar importants riscos matern-fetals. En primer lloc, el part prematur és la principal causa de mortalitat infantil, amb una prevalença del 10% en gestacions úniques (SG) i del 50% en gestacions múltiples (MG). Per tant, la caracterització de l'activitat uterina, així com la comparació entre SG i MG, ajuda a millorar la comprensió i gestió d'esta patologia. En segon lloc, la inducció del part (IOL) s'associa a un major risc de mortalitat i morbiditat materna quan la fase latent del part es prolonga excessivament, especialment en dones nul·lípares. No obstant això, la literatura és escassa i no s'ha observat clarament la resposta electrofisiològica uterina al fàrmac d'IOL. En este sentit, l'estudi de biomarcadors basats en la electrohisterografia (EHG) pot ajudar a detectar precoçment el risc de fracàs de la IOL i orientar les decisions clíniques en conseqüència. En tercer lloc, l'hemorràgia postpart (PPH) constituïx una de les principals causes de mortalitat materna en el món. La seua prevalença és del 2-6%, i causa la mort de 75.000 dones cada any. La principal causa és l'atonia uterina, per la qual cosa l'EHG es convertix en la ferramenta ideal per a valorar l'estat de l'úter i indicar el risc de PPH en funció de l'absència o no d'activitat. Per tant, l'objectiu de la present tesi doctoral és la identificació de biomarcadors d'EHG per a la detecció precoç de situacions d'alt risc obstètric. En este propòsit, s'han generat les bases de dades de senyals d'EHG i informació obstètrica de cada escenari en estudi a l'Hospital Universitari i Politècnic La Fe. La major impulsivitat i predictibilitat en MG respecte a SG durant el tercer trimestre, així com la correlació significativa entre els biomarcadors d'EHG i el pes fetal, va suggerir un acoblament electromecànic entre la sobredistensió i l'activitat mioelèctrica registrada en superfície. Pel que fa a l'IOL, el grup exitós va mostrar un augment significatiu del nombre de contraccions i de l'excitabilitat cel·lular, així com una menor complexitat, a partir de 2-3 hores tras l'administració del fàrmac de IOL. No es van observar canvis significatius respecte a l'activitat basal en el grup de fracàs. La comparació basada en la paritat va reportar una major ràtio de progressió de l'amplitud del senyal en el grup de paroses. L'activitat mioelèctrica en el postpart vaginal va ser més freqüent i intensa, a més d'exhibir una major excitabilitat cel·lular en els parts per cesària. La capacitat discriminatòria dels biomarcadors d'EHG per a la detecció precoç del risc en diversos contextos obstètrics ha fet avançar el coneixement electrofisiològic actual de l'úter in vivo. La translació de l'EHG a la pràctica clínica requerirá l'automatització del processament de senyals, per a culminar en la creació de models predictius generalitzats i robustos que donen suport a la presa de decisions clíniques, milloren la planificació i gestió del part, previnguen complicacions matern-fetals i optimitzen l'assignació de recursos hospitalaris. / [EN] During pregnancy, women undergo physiological, metabolic, and morphological changes that could lead to significant maternal-foetal risks. Firstly, preterm birth is the leading cause of infant mortality, with a prevalence 10% in single (SG) and 50% in multiple gestations (MG). The characterisation of uterine activity, as well as the comparison between SG and MG, may thus help to better understand and manage this pathology. Secondly, induction of labour (IOL) is associated with an increased risk of maternal mortality and morbidity when the latent phase of labour is excessively prolonged, especially in nulliparous women. However, the literature is sparse and the uterine electrophysiological response to the IOL drug has not been clearly observed. In this sense, the study of biomarkers based on electrohysterography (EHG) could help to early detect the risk of IOL failure and guide clinical decisions accordingly. Thirdly, postpartum haemorrhage (PPH) constitutes one of the main causes of maternal mortality in the world. Its prevalence is 2-6%, causing the death of 75,000 women each year. The main cause is uterine atony, so EHG becomes the ideal tool to assess the state of the uterus and indicate the PPH risk based on the absence or not of activity. Therefore, the aim of the present doctoral thesis is the identification of EHG-biomarkers for the early detection of high-risk obstetrical situations. For this purpose, the EHG signal and obstetric databases were generated for each scenario at University and Polytechnic Hospital La Fe. The greater impulsivity and predictability in MG compared to SG during the third trimester, in addition to the significant correlation between EHGbiomarkers and foetal weight, suggested an electromechanical coupling between overdistension and surface recorded myoelectric activity. As for IOL, the successful group showed a significant increase in the number of contractions and cellular excitability, along with reduced complexity, from 2-3 hours after the IOL drug administration. No significant changes from baseline activity were observed in the failed group. Parity-based comparison reported a higher progression ratio of signal amplitude for the parous group. Myoelectric activity in vaginal postpartum was found to be more frequent and intense, in addition to exhibit a greater cellular excitability than in caesarean deliveries. Discriminatory capacity of EHGbiomarkers for early risk detection in various obstetric contexts has advanced current electrophysiological knowledge of the uterus in vivo. The translation of the EHG to clinical practice will entail the signal processing automation, culminating in the creation of generalised and robust predictive models that support clinical decision-making, improve birth planning and management, prevent maternal and foetal complications and optimise the allocation of hospital resources. / This work was supported by the Spanish Ministry of Economy and Competitiveness, the European Regional Development Fund (MCIU/AEI/FEDER, UE RTI2018-094449-A-I00-AR and PID2021-124038OB-I00 and the Generalitat Valenciana (AICO/2019/220) / Díaz Martínez, MDA. (2024). Biomarker Identification Based on Human Electrohysterography for the Early Detection of Risk in Different Obstetric Scenarios: Preterm Birth, Induction of Labour and Postpartum [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/206155