Studies on PCSK9 in the regulation of cholesterol metabolism

Elevated levels of plasma cholesterol, mainly in low density lipoproteins (LDL), are a major risk factor for coronary heart disease. The level of plasma LDL cholesterol (LDL-C) is largely dependent on the number of hepatic LDL receptors (LDLRs). Increased number of LDLRs leads to higher uptake of LDL particles and lower concentration of plasma LDL-C. Proprotein convertase subtilisin Kexin Type 9 (PCSK9) is a novel key regulator in cholesterol metabolism. PCSK9 reduces the number of available hepatic LDLRs leading to increased plasma levels of LDL-C. Inhibition of PCSK9 has a great potential as a cholesterol-lowering agent. However, the physiological role of PCSK9 is largely unknown. In this study we investigated the regulation of PCSK9 in rats and humans, by hormones and diets and during the diurnal phases. We can show that: I) Reduced bile acid synthesis, but not changes in PCSK9, likely contributes to the agedependent hypercholesterolemia in rats. Treatment with growth hormone (GH) restores bile acid synthesis to juvenile levels and upregulates the gene transcription of PCSK9. II) Hormonal and dietary regulation of hepatic LDLRs in the rat is frequently mediated by PCSK9. Treatment with estrogen, glucagon and a cholesterol-enriched diet reduces PCSK9 expression, while it is increased by insulin. The transcription factor SREBP-2 is partly involved in the hormonal and dietary regulation of PCSK9, although our results suggest that the glucagon-mediated suppression of PCSK9 may involve other mechanisms. III) Circulating PCSK9 has a pronounced diurnal variation and is strongly reduced during fasting in humans. These changes are presumably related to oscillations in hepatic intracellular cholesterol levels mediated by SREBP-2. GH treatment reduces circulating PCSK9 in men, whereas a ketogenic diet does not alter circulating PCSK9 levels. IV) Endogenous estrogen exerts rapid and distinct effects on cholesterol metabolism in females, with reduced levels of circulating PCSK9, plasma total and LDL-C, whereas the levels of HDL- and LDL- triglycerides (TGs) and apoAI increase. Some of the effects of estrogen on cholesterol metabolism may be mediated by a rapid induction of GH secretion. The hormonal regulation of PCSK9 can partly explain the cholesterol-lowering effects of GH, estrogen, glucagon and thyroid hormone. Our results further indicate that such hormonal regulation may involve SREBP-2 independent mechanisms. The regulation of PCSK9 during the diurnal phases and fasting may explain why plasma LDL-C levels remain stable during these situations. We have also shown that PCSK9 can be dietary regulated, partly explaining the pronounced resistance to development of hypercholesterolemia following a cholesterol-enriched diet in the rat. Neither a ketogenic nor a vegan diet alters circulating PCSK9 in humans. Hormonal, dietary and diurnal regulation of PCSK9 may influence serum LDL-C levels, a fact that should be considered in the use of current and novel anti-PCSK9 agents

Studies on Venous Function after Deep Venous Thrombosis

Background The incidence of deep venous thrombosis (DVT) is estimated to be about 1-2/1000 per year of which approximately 4 % are located in the arm veins. Some of the most important late effects of a DVT are chronic venous dysfunction and the development of post-thrombotic syndrome (PTS). Objective diagnosis with detailed information on disease extent and location and global venous function is often important for clinical management of the patient. Color duplex ultrasonography (CDU) and computerized strain-gauge plethysmography (CSGP) are currently available non-invasive methods to study venous function after earlier DVT. Aims The aim of this thesis was to study venous function after earlier deep venous thrombosis assessed by CDU and CSGP; to study how findings with those methods are related to long-term sequelae, and development of postthrombotic diseases after different types of DVT. Study I and II These studies were performed to assess the efficiency of CSGP for evaluation of venous outflow capacity of the upper extremities, to receive reference values and to describe venous function using CSGP and CDU in patients with earlier primary upper extremity deep venous thrombosis (UEDVT). Thirty-four healthy controls and 32 patients with earlier UEDVT were included. The results showed that CSGP is easy to handle and can be used in a reproducible way to study venous function in the upper extremities. CSGP reference values were established for upper extremities. Patients with earlier UEDVT had reduced venous outflow, residual thrombus was a common finding, and one third had a moderate grade of PTS. CSGP and CDU are useful methods that can provide objective information regarding venous function after UEDVT. Study III This study was performed to determine whether asymptomatic deep venous thrombosis (ADVT) following minor surgery affects venous function and contributes to development of PTS. Eighty-three patients operated for Achilles tendon rupture were included; 38 patients with postoperative ADVT and 45 patients without (control group). The follow-up examinations five years after the operation consisted of CSGP, CDU and clinical scoring. More than 50 % of patients with ADVT developed post-thrombotic changes according to CDU, but these changes did not affect global venous function. Eight percent of ADVT patients and 4 % of control group patients developed PTS. Therefore, PTS is not a common sequel to ADVT after minor orthopaedic surgery. Study IV This follow-up study included 83 patients with postoperative DVT examined after a mean of 7 years. There was two series of patients, 45 with symptomatic deep venous thrombosis (SDVT) and 38 with ADVT. The objective was to describe long-term effect of SDVT and ADVT on venous function and subsequent incidence of PTS in patients operated for Achilles tendon rupture. Examinations comprised CSGP, CDU and clinical scoring. The results showed that post-operative DVT after minor surgery consists mainly of distal DVTs and is associated with a low risk for PTS, found in approximately 10 % of the patients. Deep venous reflux was more common in SDVT than in ADVT patients (84 % vs. 55 %). Abnormal plethysmographic results were seen in only a few patients without difference between the two groups. This indicates that DVT provoked by minor orthopaedic surgery represents a transient risk factor with minor long-term sequelae. In summary This thesis concerns studies of venous function and evaluation of clinical sequelae and frequency of PTS in patients with previous primary upper extremity DVT and in patients with postoperative DVT following minor orthopaedic surgery. In general, these studies show that the clinical signs as well as symptoms stated by the patients in these types of DVT are rather non-specific and often consist of pain, paresthesias, cramps, swelling and functional impairment. Therefore, in addition to the clinical examination, objective assessment of venous function and evaluation of the extent of disease are of value. Ultrasonograhy and plethysmograpy are non-invasive tests that can be used for this purpose

Konsumenter om klimat, mat och klimatmärkning

Intresset för hur maten framställs, vilka miljöeffekter den orsakar och varifrån den kommer är ett stort hos konsumenterna. Inte minst klimatfrågen är en miljöfråga som engagerar. En mängd olika märkningar och varumärken på marknaden försöker underlätta konsumentens val. I denna studie specialstuderas konsumenternas inställning till klimat, mat och klimatmärkning. Genom undersökningen ville vi få en bild av hur man ser på klimatfrågan och hur konsumenter försöker lösa frågan genom sina val av livsmedel. Som konsument tycker man att en klimatmärkning av livsmedel vore bra. Svenskt Sigill och KRAV är kända men har mycket att arbeta för när det gäller att kommunicera vad märkningarna står för och Carbon Footprint är tämligen okänd. Tre av fyra av de 184 konsumenterna ansåg att man bör ändra på sina matvanor för att bromsa klimatförändringen; framförallt genom att köpa mer närproducerad mat, köpa mat efter säsong och undvika att slänga mat

Building knowledge repositories with enterprise modelling and patterns – from theory to practice

An approach to building knowledge repositories, Enterprise Knowledge Patterns (EKP), has been developed and applied throughout a number of research projects, most recently in the ELEKTRA, HyperKnowledge1 and EKLär projects. The EKP approach combines Enterprise Modelling with organisational patterns. Systematic evaluations of applying the approach have been carried out in two of the projects, while the third project is currently running. The aim of this paper is to provide an overview of the evaluation results and to share practical experiences from building knowledge repositories with Enterprise Modelling and organisational patterns. We discuss issues concerning the knowledge content of pattern based knowledge repositories, the language used to express knowledge in organisational patterns and technology support for storing and retrieving knowledge components.

Sediment transport and coastal evolution at Thuan An Inlet, Vietnam

The Tam Giang-Cau Hai lagoon is located outside of Hue in central Vietnam. Southeast of Thuan An inlet, one of the two inlets of the lagoon, a groin was constructed in 2008 as a measure to reduce the sediment transport to prevent the inlet from closing. This groin has caused erosion of the eastern sand spit of the inlet and accretion of sediment on the coastline south east of the groin. The objectives of this study was to make a model of the sediment transport on the southeast side of the groin to be able to analyse how different measures to reduce the erosion of the inlet would affect the sediment transport past the groin. The field measurements and parts of the data collection took place in Vietnam during nine weeks in the beginning of 2013. The position of the coastline at Thuan An inlet was measured and the rest of the data, such as e.g. wave data, bathymetry data, previously measured coastlines and sediment transport was obtained from Institute of Mechanics in Hanoi. Other data used in this thesis was also obtained from The University of Agriculture and Forestry in Hue and from The Oceanographic Institute in Nha Trang. The study area has a tropical monsoon climate with two monsoon season per year – the southeast monsoon and the northwest monsoon. The micro tidal climate in the area is fully semi-diurnal and gives that the main sediment transport is wave induced. The modelling software GENESIS was used to model the sediment transport past the groin. The model was calibrated and validated using measured data and then the sediment transport on the southeast side of the groin was modelled during the years 2013 to 2017. First, the case where no measures were taken was modelled, to see what will happen if no changes of the groin were made. After that, three different measures to decrease the accretion of sediment on the southeast side of the groin (i.e. increase the sediment transport past the groin in order to reduce the erosion of the Thuan An inlet) were modelled and analyzed. These three measures were making the groin shorter, increasing the permeability of the groin and dredging sand from southeast side of the groin. The result of the model and the different measures to reduce erosion were discussed. The conclusion was that interventions to reduce the erosion are needed to protect the lagoon and the people living around it and making their livelihood from it. Many people work with e.g. fishery, aquaculture and agriculture and these occupations could be severely affected of the results of continuous erosion, such as changed water environment in the lagoon and flooding

Utfodring av rapsfoderråvara i fodersystem till mjölkkor

The feed is a major cost in the dairy production and there is a constant interest in finding alternative cost-effective feedstuffs. Competitive dairy producers have to seek ways to decrease their production costs and the pursuit of cost-effective feed rations contributes to lower costs of production. An interesting group of protein concentrates are rapeseed products like ExPro (heat treated rapeseed) which have during the autumn 2008 and spring 2009 been very favourable compared to other protein feeds. This study focuses on the feedstuff products ExPro and Raps-Drank 60/40 (rapeseeddistillers grain). The potential use of ExPro in dairy cow feed rations are also explored. ExPro is a well known feedstuff but Raps-Drank 60/40 is a relatively new product and not known for many farmers. A field study on the use of rapeseed products was made on a limited number of dairy farms. The main purpose was to study the management of the feedstuffs on the farms. The Farms were selected in cooperation with two local extension services. Selection criteria were geographic location in southern Sweden, herd size of 80-200 dairy cows and that they used ExPro in the feed ration. Of the 10 farms which were selected, 2 of them actually used Raps-Drank 60/40 as their rapeseed feed, but they were included in the study despite not fulfilling the original criteria. The farms were visited and the farmers were interviewed by using a preprepared question form. An overview of the farms use of the feed products was done. The detailed results of each interview are shown in the results section. Detailed feed ration calculations were made on four selected farms and how each feed was managed. No technical or hygienic problems with usage ExPro and Raps-Drank in mix feed were reported. Feed ration optimization revealed different outcomes. The outcome from the interview shows that ExPro was favour compared to soyabean meal. The hope of this study was to increase the interest for Swedish feed products in the feed rations on the dairy farms. Even if the study was relatively small, with only a few farms included the results show that it can be economical to feed dairy cows with ExPro compared to soybean meal

Environmental Assessment of Brine Discharge Including Wastewater Collection in the Arabian Gulf

The environmental effects of brine discharge in the Arabian/Persian Gulf have been assessed. The Arabic Gulf is a wide and shallow system having a horizontal shear dominance. The management choice of mixing brine with wastewater to reduce the salt content in the discharge has also been considered. Approximately 90% of the area around the Arabian Gulf has been compared with the world data for desalination and population growth rate. The Arabian Gulf region is occupying about 3.3% of the world area and 1.0, 2.0 and 2.2% of the total world population in the years 1950, 2008 and 2050 respectively. The annual population growth rate during the whole period is approximately 1.30 in the world and 2.07 in the area studied. The results for the study area were obtained from desalination capacities that are about 50, 40 and 45% of total world capacity for the end of 1996, 2008 and 2050 respectively.The increased recovery ratio in desalination plants over the years was considered as one important environmental factor. At the end of 1996 it was about 30 to 35% and 2008 about 40 to 45%. In some countries it can reach 50%. This development will significantly increase the brine salt concentration from 1.5 to more than 2 times seawater and negatively affect the receiving water. Water and salt mass balance were used to calculate residual flow, exchange flow and exchange time of the Arabian Gulf. For example at zero wastewater discharge and from 1996 to 2008, the net volume has decreased by the amount of 7.4 millions m3/day, exchange volume increased by 69 millions m3/day and the mixing time decreased with 22.5 days. For the next 42 years from 2008 until the year 2050 the calculation shows a decrease in the net volume by 48.7 millions m3/day, an exchange volume increase by 424 millions m3/day and a mixing time decrease of about 126 days. The more desalted water that is collected from the Gulf, the higher remaining salinity is found in the Gulf.With higher salinity in the Gulf, the exchange between the Gulf and the Indian Ocean will increase. Mixing brine with wastewater dampens the water and salt exchange between the Gulf and the Indian Ocean. This method will however also minimize the water that is coming from ocean to the Gulf. The content of nutrients in wastewater is positive for irrigation but with only secondary treatment problems like eutrophication in the Gulf may be increased if the exchange of water is low

Daily life and life quality 3 years following prostate cancer treatment.

Knowledge of experiences from prostate cancer is sparse in a longitudinal perspective. From a nursing perspective, results from combined qualitative and quantitative studies are lacking however would present the broadest knowledge base for best practice. Present descriptions of medical-physical symptoms such as urinary, bowel and sexual dysfunction from quantitative inquiries need be complemented with qualitative results. Such knowledge is essential in relation to treatment and communication with patients over the years and not only shortly after surgery

A study of lung lesions in asymptomatic rabbits naturally infected with B. bronchiseptica

A histological study of lungs performed in 40 rabbits carrying a naturally acquired subclinical B. bronchiseptica infection revealed chronic inflammatory pulmonary lesions in 38 rabbits, B. bronchiseptica was the only agent consistently isolated from lungs. Pasteurella spp. was not isolated from any animal. B. bronchiseptica infected rabbits frequently displayed changes characterized by a simultaneous occurrence of focal chronic interstitial pneumonia, vascular and perivascular infiltration of monocytes and lymphoid cells, and inflammation ofbronchi and bronchioli