Medications that treat diseases such as Parkinson???s disease work by regulating dopamine transmission at synapses. Surprisingly, little is known about the mechanisms regulating dopamine release at synapses. In this thesis, we study mechanisms that regulate vesicle recycling in axons and dendrites of dopamine neurons. Key questions we addressed were: (1) Are vesicles in axons and dendrites associated with the same regulatory proteins, and thus by implication the same regulatory mechanisms, as in excitatory neurons; (2) Do vesicles undergo recycling, and (3) if so, are they characterised by a distinct pool size and rate of recycling. To study this, we cultured dopamine neurons and used immunocytochemistry to detect vesicular monoamine transporter 2 (VMAT2) and identify axons, dendrites and synaptic proteins, combined with labelling of recycling vesicles using FM 1-43. Vesicles in axons, but not in dendrites, were associated with presynaptic proteins such as Synaptophysin and Bassoon. We identified two kinds of presynaptic sites in axons: ???synaptic??? (located close to soma and dendrites??? and ???orphan???. The recycling vesicle pool size was smaller at orphan sites than at synaptic sites, and the initial rate of vesicle pool release was also lower at orphan sites. Both synaptic and orphan sites exhibited lower rates of vesicle pool release compared to hippocampal synapses, suggesting functional differences in presynaptic physiology between dopamine neurons and hippocampal neurons. In somatodendritic regions, VMAT2 was localised to the endoplasmic reticulum, Golgi, endosome, and large dense-core vesicles, suggesting that these vesicles might function as a part of the regulated secretory pathway in mediating dopamine release. None of the synaptic vesicle proteins we studied were detected in these regions, although some preliminary evidence of vesicle turnover was detected using FM 1-43 labelling. This thesis provides a detailed analysis of neurotransmitter release mechanisms in dopamine neurons. Our data suggests that presynaptic release of dopamine is mediated by mechanisms similar to those observed in excitatory neurons. In somatodendritic regions, our data suggests that VMAT2 is localised to organelles in secretory pathways, and that distinct mechanisms of release might be present at somatodendritic sites to those present in presynaptic sites. This thesis provides novel methods for analysing vesicle recycling in dopamine neurons, which provides the basis for further studies examining presynaptic function of dopamine neurons in normal brain function, disease, and therapeutic approaches.

Recently, the zebrafish has been considered an important animal model that can be used to investigate human diseases and drug development. Parkinson¡¦s disease (PD), an important neurodegenerative disorder, is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra and movement defects, including bradykinesia, tremor, and postural imbalance. However, current treatments for PD are limited and mainly improve only the clinical symptoms of the disease. Thus, a neurodegenerative rat model has been widely used for a long while to search for a new treatment for PD. However, the use of rats as an animal model has certain limitations such as breeding, efficiency, and high dosage. Recently, researchers indicated that neurotoxins such as rotenone, 6-hydroxydopamine (6-OHDA), and paraquat can induce Parkinson¡¦s-like symptoms in zebrafish, and this may be a useful PD model because of the complete development of the zebrafish nervous system, low costs, and low dosage. In this study, we treated zebrafish with 6-OHDA and analyzed their locomotor activity to establish an in vivo animal model of PD. Then, we analyzed the mRNA expression of parkin and PINK1 by reverse transcription¡Vpolymerase chain reaction (RT-PCR).Moreover, we observed tyrosine hydroxylase (TH) expression by immunohistochemical (IHC) staining to confirm if this can be used as a PD model. Finally, we found that treatment with 6-OHDA significantly reduced TH expression. We observed a similar declining trend in the case of mammals. Likewise, parkin and PINK1 mRNA expressions were also decreased after treatment with 6-OHDA. In summary, our study provides a feasible in vivo Parkinson¡¦s model, and a small volume of drugs or compounds can be screened using this model.

The role of the cardiovascular system is is to deliver oxygen and nutrients via arteries to the tissues of the body and to remove their waste products through the venous system. Due to certain pathological processes, arteries can be damaged resulting in a reduction of well oxygenated nutrient rich blood delivered to the tissues. Chronic hypoperfusion to the brain has been related to Alzeimer„s disease (AD). AD primarily affects people over 55 years of age, with an average duration of 7-10 years, resulting in death. Currently there are 600 million people in the world aged 60 years and over. This figure is expected to double by 2025 and to reach 2 billions by 2050. Finding a cure for a neurodegenerative disease such as AD would herald a major breakthrough in medical care. Currently AD is being widely investigated, but in order to find a cure, the complete pathophysiology of AD needs to be understood. Physilogical modelling could play a significant role to further develop that understanding. The underlying cause for AD is debated although several genetic loci have been identified for AD. Scientists have also demonstrated a strong connection with cerebral hypoperfusion. This results in tissue oxygen and nutrition deprivation which is a possible causative factor in the development of AD. In this thesis a Simulation model (SM) has been built to produce an arterial tree which resembles a natureal arterial tree. The SM model is based on Schreiner et al´s Constrained Constructive Optimization (CCO) method. The SM model produces a binary tree by choosing a random point in a defined area, and connects it to an exising tree structure, each time forming a new bifurcation. This bifurcation is optimized using the target function total minimum volume of the tree. The main difference between the CCO and SM method is the handling of the constrained areas in which the binary trees are grown within. The CCO method inceases the constrained area each time a segment is added to the tree structure, resulting in rescaling of the total tree each time. The SM tree utilizes a unit circle for the tree to grow in and uses a scaling factor to retrieve the real values of the tree segments as needed. Two trees were produced using the SM method, containing 250 (T250) and 2000 (T2000) terminals respectively. The segment Radii and length of the T2000 terminal tree was extracted and reorganized to fit the data structure of a zero-dimensional model developed by Alzaidi. This model was used to produce pressure and flow rate results for the T2000 tree. The relative perfusion of the infiltrated area in the T2000 tree was also calculated. This thesis shows a close resemblance between the SM tree and a true arterial tree, both visually and geometrically. The morphometric distribution of radii and length showed a good correlation between the SM tree and previous experimental research. The real values of radii and length found in the T2000 SM tree were found to be of larger radii and shorter length compared to previously reported values in the literature. However the results from the T250 SM tree showed excellent correlation with previous experimental results. The physiological parameters of pressure changes in the SM T2000 tree strongly mimic known in vivo physiological parameters from the human circulation. The flow rate in the tree was larger than expected, but can easily be rectified by changing the initial parameters of the SM program. The perfusion distribution diagram demonstrates a well known in vivo occurrence known as watershed zones which has recently been shown to be strongly associated with pathophysiological changes found on autopsies of brains from Alzheimer‟s patients.

Medications that treat diseases such as Parkinson???s disease work by regulating dopamine transmission at synapses. Surprisingly, little is known about the mechanisms regulating dopamine release at synapses. In this thesis, we study mechanisms that regulate vesicle recycling in axons and dendrites of dopamine neurons. Key questions we addressed were: (1) Are vesicles in axons and dendrites associated with the same regulatory proteins, and thus by implication the same regulatory mechanisms, as in excitatory neurons; (2) Do vesicles undergo recycling, and (3) if so, are they characterised by a distinct pool size and rate of recycling. To study this, we cultured dopamine neurons and used immunocytochemistry to detect vesicular monoamine transporter 2 (VMAT2) and identify axons, dendrites and synaptic proteins, combined with labelling of recycling vesicles using FM 1-43. Vesicles in axons, but not in dendrites, were associated with presynaptic proteins such as Synaptophysin and Bassoon. We identified two kinds of presynaptic sites in axons: ???synaptic??? (located close to soma and dendrites??? and ???orphan???. The recycling vesicle pool size was smaller at orphan sites than at synaptic sites, and the initial rate of vesicle pool release was also lower at orphan sites. Both synaptic and orphan sites exhibited lower rates of vesicle pool release compared to hippocampal synapses, suggesting functional differences in presynaptic physiology between dopamine neurons and hippocampal neurons. In somatodendritic regions, VMAT2 was localised to the endoplasmic reticulum, Golgi, endosome, and large dense-core vesicles, suggesting that these vesicles might function as a part of the regulated secretory pathway in mediating dopamine release. None of the synaptic vesicle proteins we studied were detected in these regions, although some preliminary evidence of vesicle turnover was detected using FM 1-43 labelling. This thesis provides a detailed analysis of neurotransmitter release mechanisms in dopamine neurons. Our data suggests that presynaptic release of dopamine is mediated by mechanisms similar to those observed in excitatory neurons. In somatodendritic regions, our data suggests that VMAT2 is localised to organelles in secretory pathways, and that distinct mechanisms of release might be present at somatodendritic sites to those present in presynaptic sites. This thesis provides novel methods for analysing vesicle recycling in dopamine neurons, which provides the basis for further studies examining presynaptic function of dopamine neurons in normal brain function, disease, and therapeutic approaches.

No description available.

No description available.

No description available.

La enfermedad de Crohn es una enfermedad inflamatoria intestinal muy rara en nuestro medio y con una distribución muy variable en diferentes partes del mundo, la incidencia media es de 6,7 (rango de 1,6 a 14,6) casos por 100 000 habitantes anualmente y la prevalencia de 140 (rango de 10 a 199) casos por 100 000 habitantes en occidente. Presentamos el caso de un varon de 52 años natural y procedente del Callao con una imagen por colonoscopia compatible con una Ulcera Cecal y sin otras alteraciones en el tracto gastrointestinal, el cual presento un diagnostico anatomopatológico compatible con una Enfermedad de Crohn que es confirmada por serología. / Crohn s Disease, is a rare inflammatory bowel disease in Perú. Incidence rates vary from 1,6 – 14,6 / 100 000 and prevalence rate is 140 / 100000 in the western hemisphere. We report a case of 52 y.o male patient from Callao Peru, with a colonoscopy image of a solitary cecal ulcer and without other gastrointestinal findings and a histology suggestive of Crohn s Disease with a ASCA positive and p –ANCA negative.

Background The conventional ileostomy can be avoided. Many attempts have been performed. The first successful solution was the continent ileostomy- Kock pouch. The high rate of complications and revisions some experienced forced surgeon to try to restore the continence by the mechanism of the anus involving an ileal pouch. Both procedures afterwards documented excellent functional outcome, but the complication rates were not negligible and the long-term failure rate were increasing. Different surgical refinements were done and the risk factors for complications and failures were investigated as experience and materials increased. Restoring of the integrity of anal function and the succsess of the ileal pouch-anal anastomosis shadowed the practise of the forerunner: the continent ileostomy reservoir. This latter procedure was more demanding and seemed in the first year of ileal pouchanal anastomosis era to have significant more complications and revisional surgery. The worldwide adoption of the pelvic pouch decreased the need for the continent ileostomy and a vicious circle evolved. Today only few centres perform the procedure. Patients who are not suitable for ileal anal-pouch anastomosis are seldom offered the possibility of having a continent ileostomy. Aims The aims of the study was to investigate surgical load, complications and long-term functional outcome and to define factors which affect these subjects in patients operated with ileal pouch-anal anastomosis, continent ileostomy or both in one single surgical department during the same period and without any institutional learning curve, and furthermore, to compare and contrast the two options. Material and methods From 1984 to 2005(7) 304 (315) patients were operated with IPAA at St. Olavs Hospital (earlier: Regional Hospital of Trondheim). From 1983 to 2002(7) 50 (65) patients had a continent ileostomy constructed. This was an observational study in the scope of surveillance and quality assurance. All patients were offered a planed regularly annual outpatient clinic follow up programme including a prospective standardised interview on clinical outcome. This was a supplement to clinical investigation with endoscopy and consecutive documentation of complications and other factors affecting the patients’ health. Data were recorded in the medical chart. In this system, all patients had recorded dataset. However, the intervals between data recordings differ and the intervals increased by time. All inpatients data were included. Standard descriptive statistical analysis and simple associations were undertaken. Handling longitudinal data with limited cases, varying time intervals was done in a Times Series Cross Sectional data model, analysed, and adjusted for several factors affecting functional outcome. Multivariable analysis was done. Results The estimated failure rate at 20 years was 11.4% for ileal pouch-anal anastomosis and 11.6% for continent ileostomy. Salvage procedures rates were 31% vs. 38%, respectively (p=0.06). The salvage procedures in IPAA included local procedures and redoes with laparotomy. Salvage procedures in CI were related to the function of the nipple valve, mainly nipple valve sliding and less frequent stenosis or fistulas. Complications rates were high. In pelvic pouch surgery, half of the patients would need re-operations in 20 years. Ten percentages had early anastomotic separation without septic complications. Four percentages had early pelvic septic complications. Fistulas and sepsis at the anastomotic site were the main severe complications, often leading to pouch failure. Closing of the loop ileostomy was accompanied with complications in six percentages. In the patients (48) who did not have a covering stoma the overall complications rate did not differ from those with a loop ileostomy, although nine needed a secondary stoma. Covering stoma seems to postpone anastomotic complications. Handsewn anastomosis had more strictures, but otherwise the complications rates were similar to stapled anastomosis. Patients having the diagnosis changed to Crohn`s diseases had more complications and higher failure rate. Early anastomotic complications were associated with long-term complications. In patients with continent ileostomy the nipple valve sliding is the main cause of revision. One third needed revision once or several times. At 20 years follow-up, half of the patients would need surgery due to complications. Although many patients with CI need several revisions, all patients were continent at the last follow up with a stable intubation frequency of 3 – 5 per 24 hour. The failure of the pelvic pouch is the end of severe complications. Two third of the failures had the pouch excision or permanent ileostomy with the pouch in situ. One third underwent a conversion to CI, with equal surgical and functional outcome as other patients with CI. In IPAA, bowel movements at day were between 5-6 at day and 0-1 at night. The rates of more or less frequent incontinence were about 10%, and 41% and 55% had reported soling at day and night respectively. The long-term functional outcome did not deteriorate with time: ie. observational time, as an independent factor did not influence outcome. Factors influencing the outcome were found but the impact of gender, age, protective stoma, hand-sewn anastomosis and early complications were negligible. Pouchitis did significantly influence functional outcome negatively, but did not create deterioration over time. Estimated pouchitis rate in IPAA was 43% for more than 20 years. The onset of the first pouchitis appears mostly in the 5-6 first years after surgery. The crude rate was 35% and 6% of the patients had chronic pouchitis. Severe/chronic pouchitis was associated with primary sclerosing cholangitis, but not with pyoderma gangrenousum or diagnosed joint affections. Idiopathic pouchitis were absent among patients with familial adenomatous polyposis. In continent ileostomy the rate of pouchitis was 26%. Conclusion The complications in both the pelvic pouch surgery and the surgery of continent ileostomy are considerable. Although not similar the surgical load are in the same order of magnitude. For the continent ileostomy revisional surgery are to be expected. The failure rate of both procedures are high and in long-term similar. The long-term functional outcome are however stabile and excellent. The failed pelvic pouch can be converted to a continent ileostomy in selected and motivated patients. The entity of pouchitis is conflicting and has to be divided into several different entities both on clinical, constitutional and other differentiating features. Patients with PSC should be informed of a possible higher risk of severe and chronic pouchitis after IPAA.

Alzheimer’s disease has increasing effects on the Swedish population. Now, about 90 000 swedes have been diagnosed with the disease. Many of these persons are cared for by someone close to them. The aim of this study is to increase understanding for the situation and experiences of the persons caring for their affected partner and to examine which support they are given by the public sector. It is a qualitative case study where four persons have been interviewed. Previous research concerning experiences, coping strategies and the need for aid is used for reference. The theories chosen for the aim of the study is coping strategies, role theory, social interaction, informal care and informal aid. The results show that the participants have had different experiences of caring for their partners of which stress, anxiety and seeing it as a burden was common. The participants had different coping abilities to master their different situations and over all had good coping strategies. Their need for aid was different but all participants stressed that there is need for support and that this need to be developed. The following conclusions can be drawn from the study. The experiences are different depending on the individual case. It is important for those active within the line of social care to have knowledge about coping strategies in order to give support to those providing care for their kin. All participants experienced a lack of cooperation and information. / Alzheimers sjukdom drabbar Sveriges befolkning i allt större utsträckning. Ungefär 90 000 personer i Sverige har diagnosen. Många av dessa personer vårdas av någon i sin omgivning. Syftet med studien är att få en ökad förståelse för partners som vårdar sin respektive som har Alzheimers sjukdom och vilka upplevelser som förekommer samt att undersöka hur stödet från samhället ser ut. Det är en kvalitativ fallstudie där intervjuer har gjorts med fyra personer. Tidigare forskning har tagits fram som berör upplevelser, olika copingstrategier och behov av stöd. De teorier som valdes för studiens ändamål är copingstrategier, rollteori, social integration, informell omsorg och informell hjälp. Resultatet visar att deltagarna hade olika upplevelser av att vårda varav stress, oro och börda var vanligt. Deltagarna hade olika copingförmågor för att bemästra de olika situationerna och det förekom överlag goda copingstrategier. Behovet av stöd såg olika ut, men deltagarna belyste att det fanns ett behov av stöd samt att stödet behöver utvecklas. Följande slutsatser kan dras av studien. Alla individer har olika upplevelser. Det är viktigt att få kunskap om olika copingstrategier, vilket medför att socialt arbete kan hjälpa dem att hantera olika situationer. Samtliga deltagare upplevde att det saknades samarbete och information.