Bakgrund: Humant immunbristvirus är ett obotligt virus som angriper och försvagar kroppens immunförsvar. Uppskattningsvis lever idag 36,7 miljoner människor med HIV i världen varav Sydafrika anses vara det värst drabbade landet. Stora framsteg gällande utveckling av effektiva bromsmediciner har gjorts men för att uppnå ett lyckat behandlingsresultat krävs det att patienten upprätthåller god följsamhet till den antiretrovirala behandlingen. Syfte: Avsikten med examensarbetet är att undersöka förskrivarnas och patienternas följsamhet till de nationella rekommendationerna för antiretroviral behandling av HIV/AIDS i Sverige respektive Sydafrika. Resultat: Tenofovir uppvisade bäst effektivitet samt lägst risk för läkemedelssubstitution med 5,1 % i jämförelse med zidovudin 11,3% och stavudin 30 mg 10,5 % respektive 40 mg 14,4 %. Justerad hazard ratio för mortalitet var högre för zidovudine och stavudin med 1,5 respektive 1,2 i jämförelse med tenofovir. En större risk för virologisk svikt observerades hos patienter som behandlades med TDF-3TC-NVP (16,2 %) till skillnad från de som var insatta på TDF-3TC-EFV (6,1 %) i sydafrikanska studier. En studie genomförd i Sverige uppvisade att valet av ett tredje preparat hade en avgörande betydelse för behandlingsdurationen, där patienter insatta på lopinavir var mest benägna att avbryta sin behandling medan rilpivirin uppvisade lägst risk för behandlingsavbrott. Efavirenz användes mest bland behandlingsnaiva patienter medan darunavir var vanligast bland behandlingserfarna. I Sverige var god följsamhet till antiretroviral behandling associerad med god vårdkontakt, högre ålder, inga drog- eller alkoholproblem och kortare duration på nuvarande behandling. Stigma, diskriminering, arbetslöshet, otillräckligt med pengar till mat och för transport till klinikerna var de större bidragande faktorerna till sämre följsamhet hos patienter i en sydafrikansk studie. Slutsats: Effektivaste antiretrovirala kombinationsterapin bestod av tenofovir tillsammans med lamivudin och efavirenz, vilket stödjer Sveriges och Sydafrikas riktlinjer för förstahandsrekommendation. God följsamhet uppnåddes hos patienter med god vårdkontakt, högre ålder, inga drog-alkoholrelaterade problem medan i Sydafrika ansågs finansiella begräsningar, substansmissbruk, bristningar i hälsosjukvården vara barriärer till god följsamhet.

The presence and spread of clinically important antibiotic-resistant bacteria in reservoirs from natural environments are not well studied compared to the clinical environments. The overall aim of this project was to study the presence of clinically important antibiotic-resistant bacteria in a reservoir from natural environments. Wild birds were chosen not only as indicators of the level of antibiotic resistance in surrounding natural bacterial populations, but also since birds can act as vectors of several potential pathogens including enteropathogens and because they by migration have an ability to spread these pathogens across geographical regions. The studies in this thesis showed that wild birds carry antibiotic-resistant enterobacteriaceae. The levels and spectrum of antibiotic resistance varies between different bird populations and geographical regions. In bird populations without interaction with human activities throughout the year, antibiotic resistance is lacking. Antibiotic-resistant bacteria could however probably be dispersed to remote regions by bird migration. Extended-spectrum beta-lactamases (ESBLs) and especially CTX-M types are found in comparable high levels in gull populations considering the recent emergence of these resistance genes in clinical settings. The CTX-M types found in wild birds are the same types that are found in clinical settings and in food producing animals from the same regions. ESBL-producing E. coli isolated from Yellow-legged Gulls are genetically heterogenous, reflecting that these resistance genes are present across the full E. coli genetic diversity. In wild birds CTX-M are found both in E. coli strains with previously known “human signature” as well as “novel” strains. This indicates that these genes are indeed very mobile and rapidly dispersing both through horizontal gene transfer and through successful clones. The findings in this thesis indicate that bird colonies could act as melting pots and reservoirs for new resistance types and that wild birds could act as important indicators of the level of antibiotic resistance dispersal in natural environments.

Inledning: I Sverige såväl som i många andra länder konsumerar kvinnor mer sjukvård och läkemedel än män. Till viss del kan skillnaden förklaras av sjukdomspanoramat och förskrivningen av p-piller. För depressioner och GAD kan biologiska och sociologiska faktorer påverka. Även genusbias, det vill säga snedvridning eller fördomar i förhållande till genus eller kön, förmodas spela en viss roll. Prevalensen av depression hos vuxna är ca 5–8 % och ökar bland äldre till ca13 %. Livstidsrisken att drabbas av GAD är ca 8 % och ettårsprevalensen är 1,6–3,1 %. Syftet med detta examensarbete är att ur ett genusperspektiv undersöka försäljning och förskrivning av antidepressiva läkemedel. Vem förskriver dem? Finns det preferenser mellan preparaten, eller geografiska, åldersmässiga eller ekonomiska skillnader i förskrivning mellan könen. Material och metod: Uppgifter har erhållits från Socialstyrelsens statistikdatabas och Läkemedelsenheten inom Region Kronoberg. Resultat: År 2015 köpte drygt 900 000 personer antidepressiva läkemedel i Sverige. I Kronobergs län var det 18 700 fördelat på 12,9 % till kvinnor och 6,8 % till män. Försäljningen till kvinnor ökar relativt sett mer än männens fram till klimakteriet för att sedan jämnas ut. Närmare 40 % av kvinnorna och var fjärde man köper ut antidepressiva läkemedel i de högsta åldrarna. Räknat i DDD förskrivs till kvinnor i Kronobergs län 1,87 gånger större volymer antidepressiva än till män. 70 % förskrevs från vårdcentraler, 14 % inom psykiatrin och resten från fr.a. sjukhusläkare. En mindre geografisk skillnad ses mellan länen (+/- 5 %). Sertralin (29 %) och citalopram (19 %) står för ca hälften av volymen. Inom primärvården behandlas relativt sett (65 %) mer kvinnor än inom den psykiatriska vården (59 %). Det ses ingen skillnad i kostnad (AUP) per DDD mellan könen.  Slutsats: Ca 10 % av Sveriges befolkning köpte år 2015 ett antidepressivt läkemedel. Till kvinnor försäljs/förskrivs dubbelt så mycket antidepressiva läkemedel än till män. Det finns inget entydigt svar på varför denna skillnad ses. Det kan vara en överbehandling hos kvinnor eller en underbehandling av män. / In Sweden as well as in other countries women are consuming more health care and medicinal drugs than men. Partly, this difference can be explained by disease panorama and prescription of contraceptive pills. Biological and sociological factors may have an influence in cases of depression and GAD. Also, gender bias, a twisted view and prejudice concerning gender or sex, is thought to play a part. Among adults the depression prevalence rate ranges from 5% to 8%, and it increases to around 13% among elderly people. The lifetime risk of being effected by GAD is around 8% and the one-year prevalence rate ranges from 1.6% to 3.1%. The purpose of this study is to examine the sale/prescription of antidepressants from a gender perspective. Who prescribes the drugs? Are some drugs preferred to others, and are there geographical, age-related or economical differences between the sexes regarding prescriptions of antidepressants? Information about the type and the extent of the sale of antidepressants has been obtained from The National Board of Health and Welfare and The Medicine Unit (Läkemedelsenheten) in Kronoberg County. In 2015 more then 900.000 people bought antidepressants in Sweden. In Kronoberg (G County) 18.700 people bought antidepressants, 12.9% of them were women and 6.8% men. The sale in G County is slightly higher than in the rest of the country. The purchase among women increases relatively more than among men until menopause, after which the difference in purchase is stabilized. Almost 40% of the women and one of every four men purchase antidepressants in the highest ages. Counting in terms of DDD, women in G County are buying 1.87 times bigger volumes of antidepressants than men, of which 70% are prescribed at health centers, 14% in the mental health care area and the rest mainly by doctors working at hospitals. A small geographical difference can be seen between the counties in Sweden (+/- 5%). Within each county the prescription difference between men and women is small. Two drugs, sertraline (29%) and citalopram (19%), make up about half the volume. In the mental health care area slightly larger volumes of venlafaxine and duloxetine are prescribed to women compared to men. Men are prescribed somewhat more of fluoxetin. Relatively more women (65%) are treated for depression in primary care than in psychiatric care (59%). In primary care, women are prescribed relatively more Duloxetine. No difference in cost (pharmacy sales price (PSP)) per DDD can be observed between the sexes. Conclusion: Approx. 10% of the Swedish population bought antidepressants in 2015. Two times more women than men are purchase antidepressants. There is no definite answer to what is causing this difference. Can it be caused by overconsumption among women, or inadequate treatment among men? The greater part of antidepressants is prescribed in out-patient care, which indicates that antidepressants are used mainly in cases of less noticeable anxiety symptoms and mild to moderate depression. According to The Swedish Board of Health and Welfare these cases should foremost be treated with CBT.

Background: Breathing is necessary for all human life, in order to give oxygen to muscles and to release energy by oxidation of nutrients. Breathing becomes even more important during physical activities, and especially during high intensity training. One training method that has grown in popularity during the 21st century is Crossfit. This training method puts high demands on the muscles, and a good ability to provide oxygen to the muscles is necessary for a good performance. Throughout the years, studies have been made to investigate how different breathing methods could affect the performance during physical activity. Though, there are not any studies that focus on breathing methods impact on performance during high intensity physical activity. Purpose: The purpose was to investigate if the performance, measured in time, number of repetitions, and perceived exertion was affected by conscious controlled nostril breathing during high intensity power training, as well as, compared to self-chosen breathing, for individuals training Crossfit. Method: This study was an experimental crossover study. The study was carried out in order to see which impact nostril breathing have on the performance, compared to self-chosen breathing. Participants were randomized selected into two groups, where each group did a test with nostril breathing and one test with self-chose breathing. Each participant did a max-test during one minute in each movement: double unders, push ups, box jumps, burpees and air squat, as well as a WOD of 500m row, 30 kettlebellswing and 20 pullups. Each participant also stated his or her perceived exertion after each test, using the Borgscale. Results: There were a significant difference between the interventions for performance measured in number of repetitions for the movements’ box jump and burpees, where nostril breathing had a significant negative impact on the performance compared to self-chose breathing. The performance for the rest of the movements, double unders, push ups, air squat, WOD and perceived exertion was not significant effected by the two breathing methods in this study. Conclusion: There was a significant impairment for the movements’ box jumps and burpees. There were no significant differences in air squat, push ups, double unders, WOD or perceived exertion. The future recommendation is to avoid nostril breathing during similar movements that involves multiple muscles and requires significant agility movements.

No description available.

Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin system, converting angiotensin I to the vasoactive peptide angiotensin II, and degrading bradykinin. Angiotensin II is a multifunctional peptide, acting on a number of different tissues. A common genetic variation in the gene encoding ACE; ACE I/D polymorphism influences the level of ACE in the circulation, and has been linked to increased risk for cardiovascular disease. This thesis aimed to explore the connection between ACE and cardiovascular function and dysfunction. The impact of nicotine and nicotine metabolites on ACE in cultured human endothelial cells was studied. Nicotine as well as nicotine metabolites induced increased ACE activity in cultured human endothelial cells. In elderly men a higher ACE level was seen in smokers compared to non-smokers. Furthermore, diabetes was associated with higher circulating ACE. Increased ACE level may represent a cellular mechanism which contributes to vascular damage. Elderly men carrying the ACE D allele had higher abdominal aortic stiffness compared to men carrying the I/I genotype. Our data suggest that the mechanism by which the ACE D allele modulates aortic wall mechanics is independent of circulating ACE levels. Previous studies have indicated a link between the D allele and abdominal aortic aneurysm. Increased aortic stiffness suggests impaired vessel wall integrity, which combined with local hemodynamic and/or inflammatory factors may have a role in aneurysm formation. Subjects with left ventricular dysfunction had higher levels of circulating ACE compared to those with normal left ventricular function, while there was no association between ACE and central hemodynamics. ACE might play a role in the pathogenesis of left ventricular dysfunction and our findings suggest a direct effect on the heart rather than affecting central blood pressure.

Background: Type 2 diabetes is a common disease with increased mortality and morbidity due to cardiovascular disease (CVD). This thesis is based on three studies that evaluated traditionally used and emerging risk markers to identify individuals with high-risk of developing CVD in middle-aged men and women with type 2 diabetes. One study was conducted to compare the equivalence between two different ultrasound techniques to measure intima-media thickness since IMT was used to evaluate subclinical atherosclerosis as a surrogate endpoint. Methods: Data from the cohort study, cardiovascular risk in type 2 diabetes – a prospective study in primary care (CARDIPP) was used in paper I, III and IV. In paper I, baseline data from the first 247 subjects was analysed. Associations between traditionally measured lipids, apolipoproteins, glycaemic control and low-grade inflammation and IMT were analysed. In paper III, the full baseline cohort, with data from 761 subjects from the CARDIPP study was cross-sectionally analysed regarding correlations between abdominal obesity measured as waist circumference (WC) and sagittal abdominal diameter (SAD), inflammatory markers and IMT and pulse wave velocity (PWV). In paper IV, the associations reported in paper I and III were prospectively investigated with data from the first year of follow-up four years after the baseline investigations in CARDIPP-revisited. In paper II a study was performed on 24 young healthy subjects, both men and women. IMT was measured in the common carotid artery (CCA) and in the abdominal aorta (AA), by two skilled ultrasonographers, with 2 different ultrasound techniques in a randomised order. Results: ApoB/apoA-I ratio (r=0.207, p=0.001), apoB (r=0.166, p=0.009) and non HDLcholesterol (nHDL-c) (0.129, p=0.046) correlated with IMT. In CCA IMT was equivalent using B-mode- and M-mode respectively. However in AA, IMT was 11.5% thicker using B-mode. Abdominal obesity were significantly correlated with; IL-6 and CRP (both p<0.001, WC and SAD respectively), IMT (WC p=0.012, SAD p=0.003) and PWV (p<0.001 WC and SAD respectively). Adjusting for age, sex, treatment with statins, systolic blood pressure (SBP), Body Mass Index (BMI), CRP and HbA1c, SAD (p=0.047) but not WC, remained associated with IMT. There were significant correlations between apoB (r=0.144, p=0.03) and CRP (r=0.172, p=0.009) measured at baseline and IMT measured at follow-up. After adjustment for sex, age, treatment with statins and Hba1c, the associations remained statistically significant. HbA1c, total cholesterol or LDL-cholesterol did not correlate to IMT at follow-up. Baseline body mass index (BMI) (r=0.130, p=0.049), WC (r=0.147, p=0.027) and SAD (r=0.184, p=0.007) correlated to PWV at follow-up. Challenged with sex, SBP and HbA1c, the association between SAD, not WC nor BMI, and PWV remained statistically significant (p=0.036). Conclusions: There was a significant association between apoB/apoA-I ratio and IMT. The association was independent of conventional lipids, CRP, glycaemic control and use of statins. Both SAD and WC were associated with inflammation, atherosclerosis and arterial stiffness. However, SAD was slightly more robustly associated to subclinical organ damage, compared with WC. Prospectively; apoB and CRP, but not LDL-cholesterol predicted increased subclinical atherosclerosis. Furthermore, SAD was more independent in predicting arterial stiffness over time, compared with WC, in middle-aged men and women with type 2 diabetes. The two different ultrasound techniques, B-mode and M-mode, measured different IMT thickness in the aorta, emphasizing the importance of using similar technique when comparing the impact of absolute values of IMT on cardiovascular disease.

No description available.

Periodontitis and coronary artery disease (CAD) are highly prevalent in Sweden’s population; both diseases have complicated pathogeneses and clinical manifestations due to immune-system triggered inflammation. Research in recent years reported that inflammation is a significant active participant in many chronic diseases. The literature described a CAD-periodontitis association, but underlying mechanisms are not fully understood. It is important to acquire knowledge about how periodontitis might influence CAD, which is one of the major causes of illness and death in western countries. Because periodontitis can be treated, this knowledge, when complemented with more knowledge about the CAD-periodontitis association, could lead to CAD prevention. The overall aim of studies reported in this thesis were to investigate the CAD-periodontitis association, and specifically, to: (i) compare periodontal conditions in patients with CAD and subjects without a history of CAD; (ii) study whether or not periodontal status influences outcomes in known CAD over an 8-year period; (iii) study whether or not concentrations and biological activity of hepatocyte growth factor (HGF) in serum from patients with severe CAD are different – depending on whether or not the subjects had periodontitis; and (iv) study concentrations and biological activity of hepatocyte growth factor in serum, saliva, and gingival crevicular fluid in healthy subjects with or without periodontitis. Here is a brief summary: In study I, 161 patients with CAD and 162 controls were compared regarding periodontal disease prevalence and severity. CAD patients had significant coronary stenosis and underwent percutaneous coronary intervention (PCI) or coronary artery by-pass grafts (CABG). Healthy controls were recruited from Sweden’s population database. Twenty-five per cent of the CAD patients had severe periodontitis, compared to 8% of the controls. In a multiple logistic regression analysis (controlled for age and smoking), severe periodontitis indicated an odds ratio of 5.74 (2.07–15.90) for CAD. Study II: Periodontal status was re-examined in 126 CAD patients and 121 controls from the initial sample after 8 years. Periodontal status at baseline was analysed and related to CAD endpoints (i.e., myocardial infarction, new PCI or CABG or death due to CAD) recorded from patients’ medical records and from the death index maintained by the National Board of Health and Welfare. The difference in periodontitis prevalence and severity between the two groups remained unchanged during the 8-year follow up. No significant differences were found regarding CAD endpoints during follow-up in relation to baseline periodontal status in the CAD-patient group. In study III, higher HGF serum concentrations (p&lt;0.001) were found in CAD patients, compared to healthy blood donors, which reflects chronic inflammation. In CAD patients without periodontitis, HGF concentrations increased significantly 24 hours after PCI – in parallel with increased HGF biological activity. In CAD patients with periodontitis, only small fluctuations were seen in HGF values, i.e., concentration and biological activity. HGF biological activity was temporarily elevated after PCI but only in patients without periodontitis. Thus chronic inflammation related to periodontitis might reduce HGF biological activity. In study IV, HGF concentration and biological activity in saliva, in gingival crevicular fluid (GCF), and serum were compared between 30 generally healthy subjects with severe untreated periodontitis and 30 healthy subjects without periodontitis. Compared to periodontally healthy controls, periodontal patients showed higher HGF concentrations in saliva p&lt;0.001, gingival crevicular fluid p&lt;0.0001, and in serum p&lt;0.001. HGF biological activity (measured as the binding affinity to its HSPG and c-MET receptors) was significantly reduced in saliva (p&lt;0.0001) and GCF samples (p&lt;0.0001 for HSPG and p&lt;0.01 for c-MET) from periodontitis patients. The only significant difference in serum samples was an increases in c-MET binding three minutes after subgingival debridement in periodontitis patients (p&lt;0.05), which might reflect that patients had active bursts of periodontitis. In conclusion, CAD patients more often showed severe periodontitis but there were no differences in CAD endpoints during the eight-year follow-up in relation to baseline periodontal status. Periodontitis seems to influence HGF concentration and biological activity in CAD patients, but studies on factors that cause lower HGF biological activity are necessary – to find out if periodontal treatment influences HGF biological activity. Healthy periodontitis patients had higher HGF concentrations locally and systemically, but biological activity was reduced. This might indicate that periodontitis can influence wound healing and tissue repair in other body parts. / <p>The ISBN 987‐91‐7519‐748‐7 is incorrect. Correct ISBN is 978‐91‐7519‐748‐7.</p>

Parkinson’s disease (PD) is a neurodegenerative disease affecting approximately 25000 people in Sweden. The main cause of the disease is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) projecting to the striatum. The motor symptoms of PD, due to decreased levels of dopamine, includes bradykinesia, rigidity and tremor. During the 1960ies oral L-dopa treatment was introduced increasing quality of life for PD patients. In recent decades, enzyme inhibitors have been introduced, increasing bioavailability of L-dopa in plasma. After 5-10 years of L-dopa treatment, 50% of PD patients develop disabling dyskinesias. This can be due to rapid changes in L-dopa conentrations with non physiological stimulation of the dopamine receptor. For over 20 years deep brain stimulation (DBS) has grown to be a good neurosurgical procedure for improving quality of life in advanced PD with disabling dyskinesias. With stereotactic technique, electrodes are implanted in the brain and connected to a pacemaker sending electrical impulses. The most common target in PD is the subthalamic nucleus (STN). The knowledge about DBS mechanism(s) and its interaction with L-dopa is unsatisfactory. The aims of this thesis were; to study the effect of the enzyme inhibitor entacapone on the L-dopa concentration over the blood brain barrier (BBB); to study possible interactions between L-dopa and DBS; to study alterations in neurotransmitters during DBS; to visualize microdialysis catheters in anatomical targets and to estimate sampling area of the catheters. In all four papers the microdialysis technique was used. It is a well-established technique for continuous sampling of small water-soluble molecules within the extracellular fluid space in vivo, allowing studies of pharmaceutical drugs and neurotransmitters. We showed that entacapone increases the bioavailability of L-dopa in blood with a subsequent increase of L-dopa peak levels in the cerebrospinal fluid. This in turn may cause a larger burden on the dopaminergic neurons causing an increased degeneration rate and worsening of the dyskinesias; we showed that 18% of L-dopa crosses the BBB and that there is a possible interaction between L-dopa and DBS, L-dopa concentrations increase during concomitant STN DBS, which can clarify why its possible to decrease L-dopa medication after DBS surgery. The research has also shown that STN DBS has an effect on various neurotransmitter systems, mainly L-dopa, dopamine and GABA. We showed that STN DBS may have an effect on the SNc, resulting in putaminal dopamine release. We have shown that with stereotactic technique, it is safe to do microdialysis sampling in specific areas in the human brain. Simulations with the finite element method combined with patient specific preoperative MRI and postoperative CT images gave us exact knowledge about the positions of the catheters and that the studied structures were the intended. The research has given an assumption of the maximum tissue volume that can be sampled around the microdialysis catheters.