Blood pressure lowering effects of Lactobacillus helveticus fermented milk containing bioactive peptides Ile-Pro-Pro and Val-Pro-Pro; mechanistic, kinetic and clinical studies

The purpose of the present study was to evaluate the effects of Lactobacillus helveticus fermented milk (peptide milk) containing the casein-derived tripeptides Isoleucyl-prolyl-proline (Ile-Pro-Pro) and Valyl-prolyl-proline (Val-Pro-Pro) on blood pressure and vascular function in hypertensive subjects. The peptide milk lowered systolic and diastolic blood pressure in long-term use in hypertensive subjects when blood pressure was measured by using 24-hour ambulatory blood pressure measurement (ABPM). The blood pressure lowering effect was seen with the dose of 50 mg of tripeptides, and a tendency for lowering blood pressure was also observed when the dose was 5 mg. No adverse effects compared to the placebo group were reported or detected in laboratory analysis. The effect of the peptide milk on arterial stiffness was shown using two different methods, the ambulatory arterial stiffness index (AASI) and pulse wave analysis (PWA). According to the AASI, arterial stiffness was significantly reduced in the peptide milk group compared to the baseline level, but the difference was not significant compared to the placebo group. PWA showed that the peptide milk reduced arterial stiffness significantly compared to the placebo group. Endothelium-independent relaxation (nitroglycerin) and endothelium-dependent relaxation (salbutamol) did not differ between the groups. The blood pressure lowering mechanisms of the tripeptides and the kinetics of Ile-Pro-Pro were investigated using spontaneously hypertensive rats (SHR) and Sprague-Dawley rats. Previous studies have suggested that the blood pressure lowering effect of the tripeptides Ile-Pro-Pro and Val-Pro-Pro is based on angiotensin-converting enzyme inhibition, but the present findings did not agree with these previous studies. It was shown in SHR that calcium, potassium and magnesium may also have an important role in attenuating the development of hypertension as part of the peptide milk effect. In addition, the present study suggests indirectly that improved endothelial nitric oxide release capacity is not the mechanism by which peptide milk mediates its favourable circulatory effects. The kinetics of Ile-Pro-Pro were studied using adult Sprague-Dawley rats. The results showed that orally administered Ile-Pro-Pro is absorbed at least partly intact from the gastrointestinal tract. Radiolabelled Ile-Pro-Pro was distributed in different tissues and considerable radioactivity levels were found in tissues related to the renin-angiotensin system (RAS), adrenals, aorta and kidneys. Ile-Pro-Pro does not bind to plasma proteins, and therefore it is possible that its blood pressure lowering effect is mediated by free Ile-Pro-Pro. In conclusion, consumption of the peptide milk lowers blood pressure and reduces arterial stiffness in hypertensive subjects. Ile-Pro-Pro can be absorbed partly intact from the gastrointestinal tract and might accumulate in tissues related to the RAS. The precise blood pressure lowering mechanism of peptide milk remains to be studied.

Milk casein-derived tripeptides : A special focus on blood pressure and vascular function

Increased consumption of low-fat milk products is inversely associated with the risk of hypertension. The beneficial effect of milk on blood pressure is attributed to high calcium and potassium content but also to specific peptide sequences, which are cleaved from milk protein during gastrointestinal digestion, fermentation of milk with proteolytic starter cultures or enzymatic hydrolysis. Milk products fermented with Lactobacillus helveticus contain casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro), which have been shown to possess antihypertensive effects in humans and in experimental animals. The aim of the present series of studies was to investigate the effects of tripeptides Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them on vascular function and blood pressure and to elucidate the mechanisms behind them by using different experimental models of hypertension. Another aim was to characterize the acute effects of tripeptides on blood pressure and arterial stiffness in mildly hypertensive humans. Ile-Pro-Pro and Val-Pro-Pro or fermented milk products containing them attenuated the development of hypertension in two experimental models of hypertension, spontaneously hypertensive rat (SHR) and type 2 diabetic Goto-Kakizaki (GK) rat fed with high-salt diet. Significant differences in systolic blood pressure (SBP) were seen after 8 weeks treatment with tripeptide-containing products compared to control product. Plant sterols did not enhance this effect. Two differently produced tripeptide powders produced a similar attenuating effect on SBP in SHR. In mildly hypertensive subjects, a single administration of tripeptide- and plant sterol-containing fermented milk product decreased both SBP and diastolic blood pressure (DBP) over a period of 8 hours. Protective effect of tripeptides Ile-Pro-Pro and Val-Pro-Pro and fermented milk products containing them on vascular function was demonstrated in in vitro studies and long-term experimental studies. The effect was shown to be endothelium-dependent and possibly involving endothelium-derived hyperpolarizing factor (EDHF). In the clinical study, single administration of tripeptide-containing fermented milk product did not affect measures of arterial stiffness. Long-term treatment with fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro inhibited angiotensin-converting enzyme (ACE) and decreased aldosterone levels thus showing beneficial effects on the renin-angiotensin system (RAS) in SHR and GK. No changes in the components of RAS were observed by the single administration of the same product in mildly hypertensive subjects. Increased levels of cGMP, NOx and citrulline suggest increased nitric oxide (NO) production by the tripeptides. Taken together, Ile-Pro-Pro and Val-Pro-Pro -containing products attenuate the development of hypertension after long-term treatment in experimental models of hypertension and possess an acute antihypertensive effect in mildly hypertensive subjects. In addition, these tripeptides show endothelium-mediated beneficial effects on vascular function. Attenuation of blood pressure increase by the tripeptides in experimental animals involves RAS, but its role in the antihypertensive effect in humans remains to be elucidated.

Early growth and adult health: focus on blood pressure, glucose tolerance status and body composition

Theory of developmental origins of adult health and disease proposes that experiences during critical periods of early development may have consequences on health throughout a lifespan. Thesis studies aimed to characterize associations between early growth and some components of the metabolic syndrome cluster. Participants belong to two epidemiological cohorts with data on birth measurements and, for the younger cohort, on serial recordings of weight and height during childhood. They were born as singletons between 1924-33 and 1934-44 in the Helsinki University Central Hospital, and 500 and 2003 of them, respectively, attended clinical studies at the age of 65-75 and 56-70 years, respectively. In the 65-75 year old men and women, the well-known inverse relationship between birth weight and systolic blood pressure (SBP) was confined to people who had established hypertension. Among them a 1-kg increase in birth weight was associated with a 6.4-mmHg (95% CI: 1.0 to 11.9) decrease in SBP. This relationship was further confined to people with the prevailing Pro12Pro polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPARγ2) gene. People with low birth weight were more likely to receive angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB, p=0.03), and, again, this relationship was confined to the carriers of the Pro12Pro (p=0.01 for interaction). These results suggest that the inverse association between birth weight and systolic BP becomes focused in hypertensive people because pathological features of BP regulation, associated with slow fetal growth, become self-perpetuating in adult life. Insulin resistance of the Pro12Pro carriers with low birth weight may interact with the renin-angiotensin system leading to raised BP levels. Habitual physical activity protected men and women who were small at birth, and thus at increased risk for the development of type 2 diabetes, against glucose intolerance more strongly. Among subjects with birth weight ≤3000 g, the odds ratio (OR) for glucose intolerance was 5.2 (95% CI: 2.1 to 13) in those who exercised less than 3 times per week compared to regular exercisers; in those who scored their exercise light compared with moderate exercisers (defined as comparable to brisk walking) the OR was 3.5 (1.5 to 8.2). In the 56-70 year old men a 1 kg increase in birth weight corresponded to a 4.1 kg (95% CI: 3.1 to 5.1) and in women to a 2.9 kg (2.1 to 3.6) increase in adult lean mass. Rapid gain in body mass index (BMI), i.e. crossing from an original BMI percentile to a higher one, before the age of 2 years increased adult lean mass index (LMI, lean mass/height squared) without excess fat accumulation whereas rapid gain in BMI during later childhood, despite the concurrent rise in LMI, resulted in a relatively higher increase in adult body fat mass. These findings illustrate how genes, the environment and their interactions, early growth patterns, and adult lifestyle modify adult health risks which originate from early life.

Prevention of type 2 diabetes with lifestyle intervention - emphasis on dietary composition and identification of high-risk individuals

Type 2 diabetes is an increasing, serious, and costly public health problem. The increase in the prevalence of the disease can mainly be attributed to changing lifestyles leading to physical inactivity, overweight, and obesity. These lifestyle-related risk factors offer also a possibility for preventive interventions. Until recently, proper evidence regarding the prevention of type 2 diabetes has been virtually missing. To be cost-effective, intensive interventions to prevent type 2 diabetes should be directed to people at an increased risk of the disease. The aim of this series of studies was to investigate whether type 2 diabetes can be prevented by lifestyle intervention in high-risk individuals, and to develop a practical method to identify individuals who are at high risk of type 2 diabetes and would benefit from such an intervention. To study the effect of lifestyle intervention on diabetes risk, we recruited 522 volunteer, middle-aged (aged 40 - 64 at baseline), overweight (body mass index > 25 kg/m2) men (n = 172) and women (n = 350) with impaired glucose tolerance to the Diabetes Prevention Study (DPS). The participants were randomly allocated either to the intensive lifestyle intervention group or the control group. The control group received general dietary and exercise advice at baseline, and had annual physician's examination. The participants in the intervention group received, in addition, individualised dietary counselling by a nutritionist. They were also offered circuit-type resistance training sessions and were advised to increase overall physical activity. The intervention goals were to reduce body weight (5% or more reduction from baseline weight), limit dietary fat (< 30% of total energy consumed) and saturated fat (< 10% of total energy consumed), and to increase dietary fibre intake (15 g / 1000 kcal or more) and physical activity (≥ 30 minutes/day). Diabetes status was assessed annually by a repeated 75 g oral glucose tolerance testing. First analysis on end-points was completed after a mean follow-up of 3.2 years, and the intervention phase was terminated after a mean duration of 3.9 years. After that, the study participants continued to visit the study clinics for the annual examinations, for a mean of 3 years. The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, mean weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 kg and 0.9 kg in the control group. Cardiovascular risk factors improved more in the intervention group. After a mean follow-up of 3.2 years, the risk of diabetes was reduced by 58% in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with achieved lifestyle goals. Furthermore, those who consumed moderate-fat, high-fibre diet achieved the largest weight reduction and, even after adjustment for weight reduction, the lowest diabetes risk during the intervention period. After discontinuation of the counselling, the differences in lifestyle variables between the groups still remained favourable for the intervention group. During the post-intervention follow-up period of 3 years, the risk of diabetes was still 36% lower among the former intervention group participants, compared with the former control group participants. To develop a simple screening tool to identify individuals who are at high risk of type 2 diabetes, follow-up data of two population-based cohorts of 35-64 year old men and women was used. The National FINRISK Study 1987 cohort (model development data) included 4435 subjects, with 182 new drug-treated cases of diabetes identified during ten years, and the FINRISK Study 1992 cohort (model validation data) included 4615 subjects, with 67 new cases of drug-treated diabetes during five years, ascertained using the Social Insurance Institution's Drug register. Baseline age, body mass index, waist circumference, history of antihypertensive drug treatment and high blood glucose, physical activity and daily consumption of fruits, berries or vegetables were selected into the risk score as categorical variables. In the 1987 cohort the optimal cut-off point of the risk score identified 78% of those who got diabetes during the follow-up (= sensitivity of the test) and 77% of those who remained free of diabetes (= specificity of the test). In the 1992 cohort the risk score performed equally well. The final Finnish Diabetes Risk Score (FINDRISC) form includes, in addition to the predictors of the model, a question about family history of diabetes and the age category of over 64 years. When applied to the DPS population, the baseline FINDRISC value was associated with diabetes risk among the control group participants only, indicating that the intensive lifestyle intervention given to the intervention group participants abolished the diabetes risk associated with baseline risk factors. In conclusion, the intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, body weight, and cardiovascular risk factors, and reduced diabetes risk. Furthermore, the effects of the intervention were sustained after the intervention was discontinued. The FINDRISC proved to be a simple, fast, inexpensive, non-invasive, and reliable tool to identify individuals at high risk of type 2 diabetes. The use of FINDRISC to identify high-risk subjects, followed by lifestyle intervention, provides a feasible scheme in preventing type 2 diabetes, which could be implemented in the primary health care system.

Technical efficiency of blood component preparation in blood centres of 10 European countries

Various reasons, such as ethical issues in maintaining blood resources, growing costs, and strict requirements for safe blood, have increased the pressure for efficient use of resources in blood banking. The competence of blood establishments can be characterized by their ability to predict the volume of blood collection to be able to provide cellular blood components in a timely manner as dictated by hospital demand. The stochastically varying clinical need for platelets (PLTs) sets a specific challenge for balancing supply with requests. Labour has been proven a primary cost-driver and should be managed efficiently. International comparisons of blood banking could recognize inefficiencies and allow reallocation of resources. Seventeen blood centres from 10 countries in continental Europe, Great Britain, and Scandinavia participated in this study. The centres were national institutes (5), parts of the local Red Cross organisation (5), or integrated into university hospitals (7). This study focused on the departments of blood component preparation of the centres. The data were obtained retrospectively by computerized questionnaires completed via Internet for the years 2000-2002. The data were used in four original articles (numbered I through IV) that form the basis of this thesis. Non-parametric data envelopment analysis (DEA, II-IV) was applied to evaluate and compare the relative efficiency of blood component preparation. Several models were created using different input and output combinations. The focus of comparisons was on the technical efficiency (II-III) and the labour efficiency (I, IV). An empirical cost model was tested to evaluate the cost efficiency (IV). Purchasing power parities (PPP, IV) were used to adjust the costs of the working hours and to make the costs comparable among countries. The total annual number of whole blood (WB) collections varied from 8,880 to 290,352 in the centres (I). Significant variation was also observed in the annual volume of produced red blood cells (RBCs) and PLTs. The annual number of PLTs produced by any method varied from 2,788 to 104,622 units. In 2002, 73% of all PLTs were produced by the buffy coat (BC) method, 23% by aphaeresis and 4% by the platelet-rich plasma (PRP) method. The annual discard rate of PLTs varied from 3.9% to 31%. The mean discard rate (13%) remained in the same range throughout the study period and demonstrated similar levels and variation in 2003-2004 according to a specific follow-up question (14%, range 3.8%-24%). The annual PLT discard rates were, to some extent, associated with production volumes. The mean RBC discard rate was 4.5% (range 0.2%-7.7%). Technical efficiency showed marked variation (median 60%, range 41%-100%) among the centres (II). Compared to the efficient departments, the inefficient departments used excess labour resources (and probably) production equipment to produce RBCs and PLTs. Technical efficiency tended to be higher when the (theoretical) proportion of lost WB collections (total RBC+PLT loss) from all collections was low (III). The labour efficiency varied remarkably, from 25% to 100% (median 47%) when working hours were the only input (IV). Using the estimated total costs as the input (cost efficiency) revealed an even greater variation (13%-100%) and overall lower efficiency level compared to labour only as the input. In cost efficiency only, the savings potential (observed inefficiency) was more than 50% in 10 departments, whereas labour and cost savings potentials were both more than 50% in six departments. The association between department size and efficiency (scale efficiency) could not be verified statistically in the small sample. In conclusion, international evaluation of the technical efficiency in component preparation departments revealed remarkable variation. A suboptimal combination of manpower and production output levels was the major cause of inefficiency, and the efficiency did not directly relate to production volume. Evaluation of the reasons for discarding components may offer a novel approach to study efficiency. DEA was proven applicable in analyses including various factors as inputs and outputs. This study suggests that analytical models can be developed to serve as indicators of technical efficiency and promote improvements in the management of limited resources. The work also demonstrates the importance of integrating efficiency analysis into international comparisons of blood banking.

Examination of Genetic Components Affecting Human Obesity-Related Quantitative Traits

Obesity increases the risk for several conditions, including type 2 diabetes mellitus, cardiovascular disease, hypertension, osteoarthirits and certain types of cancer. Twin- and family studies have shown that there is a major genetic component in the determination of body mass. In recent years several technological and scientific advance have been made in obesity research. For instance, novel replicated loci have been revealed by a number of genome wide association studies. This thesis aimed to investigate the association of genetic factors and obesity-related quantitative traits. The first study investigated the role of the lactase gene in anthropometric traits. We genetically defined lactose persistence by genotyping 31 720 individuals of European descent. We found that lactase persistence was significantly correlated with weight and body mass index but not with height. In the second study we performed the largest whole genome linkage scan for body mass index to date. The sample consisted of 4401 twin families and 10 535 individuals from six European countries. We found supporting evidence for two loci (3q29 and 7q36). We observed that the heritability estimate increased substantially when additional family members were removed from the analyses, which suggests reduced environmental variance in the twin sample. In the third study we assessed metabonomic, transcriptomic and genomic variation in a Finnish population cohort of 518 individuals. We formed gene expression networks to portray pathways and showed that a set of highly correlated genes of an inflammatory pathway associated with 80 serum metabolites (of 134 quantified measures). Strong association was found, for example, with several lipoprotein subclasses. We inferred causality by using genetic variation as anchors. The expression of the network genes was found to be dependent on the circulatory metabolite concentrations.

Insights into the molecular genetics of celiac disease : Applying family- and population-based strategies

Celiac disease, or gluten intolerance, is triggered by dietary glutens in genetically susceptible individuals and it affects approximately 1% of the Caucasian population. The best known genetic risk factors for celiac disease are HLA DQ2 and DQ8 heterodimers, which are necessary for the development of the disease. However, they alone are not sufficient for disease induction, other risk factors are required. This thesis investigated genetic factors for celiac disease, concentrating on susceptibility loci on chromosomes 5q31-q33, 19p13 and 2q12 previously reported in genome-wide linkage and association studies. In addition, a novel genotyping method for the detection of HLA DQ2 and DQ8 coding haplotypes was validated. This study was conducted using Finnish and Hungarian family materials, and Finnish, Hungarian and Italian case-control materials. Genetic linkage and association were analysed in these materials using candidate gene and fine-mapping approaches. The results confirmed linkage to celiac disease on the chromosomal regions 5q31-q33 and 19p13. Fine-mapping on chromosome 5q31-q33 revealed several modest associations in the region, and highlighted the need for further investigations to locate the causal risk variants. The MYO9B gene on chromosome 19p13 showed evidence for linkage and association particularly with dermatitis herpetiformis, the skin manifestation of celiac disease. This implies a potential difference in the genetic background of the intestinal and skin forms of the disease, although studies on larger samplesets are required. The IL18RAP locus on chromosome 2q12, shown to be associated with celiac disease in a previous genome-wide association study and a subsequent follow-up, showed association in the Hungarian population in this study. The expression of IL18RAP was further investigated in small intestinal tissue and in peripheral blood mononuclear cells. The results showed that IL18RAP is expressed in the relevant tissues. Two putative isoforms of IL18RAP were detected by Western blot analysis, and the results suggested that the ratios and total levels of these isoforms may contribute to the aetiology of celiac disease. A novel genotyping method for celiac disease-associated HLA haplotypes was also validated in this thesis. The method utilises single-nucleotide polymorphisms tagging these HLA haplotypes with high sensitivity and specificity. Our results suggest that this method is transferable between populations, and it is suitable for large-scale analysis. In conclusion, this doctorate study provides an insight into the roles of the 5q31-q33, MYO9B, IL18RAP and HLA loci in the susceptibility to celiac disease in the Finnish, Hungarian and Italian populations, highlighting the need for further studies at these genetic loci and examination of the function of the candidate genes.

Sindbis virus and Pogosta disease in Finland

Sindbis virus (SINV) (genus Alphavirus, family Togaviridae) is an enveloped virus with a genome of single-stranded, positive-polarity RNA of 11.7 kilobases. SINV is widespread in Eurasia, Africa, and Australia, but clinical infection only occurs in a few geographically restricted areas, mainly in Northern Europe. In Europe, antibodies to SINV were detected from patients with fever, rash, and arthritis for the first time in the early 1980s in Finland. It became evident that the causative agent of this syndrome, named Pogosta disease, was closely related to SINV. The disease is also found in Sweden (Ockelbo disease) and in Russia (Karelian fever). Since 1974, for unknown reason, the disease has occurred as large outbreaks every seven years in Finland. This study is to a large degree based on the material collected during the 2002 Pogosta disease outbreak in Finland. We first developed SINV IgM and IgG enzyme immunoassays (EIA), based on highly purified SINV, to be used in serodiagnostics. The EIAs correlated well with the hemagglutination inhibition (HI) test, and all individuals showed neutralizing antibodies. The sensitivities of the IgM and IgG EIAs were 97.6% and 100%, and specificities 95.2% and 97.6%, respectively. E1 and E2 envelope glycoproteins of SINV were shown to be recognized by IgM and IgG in the immunoblot early in infection. We isolated SINV from five patients with acute Pogosta disease; one virus strain was recovered from whole blood, and four other strains from skin lesions. The etiology of Pogosta disease was confirmed by these first Finnish SINV strains, also representing the first human SINV isolates from Europe. Phylogenetic analysis indicated that the Finnish SINV strains clustered with the strains previously isolated from mosquitoes in Sweden and Russia, and seemed to have a common ancestor with South-African strains. Northern European SINV strains could be maintained locally in disease-endemic regions, but the phylogenetic analysis also suggests that redistribution of SINV tends to occur in a longitudinal direction, possibly with migratory birds. We searched for SINV antibodies in resident grouse (N=621), whose population crashes have previously coincided with human SINV outbreaks, and in migratory birds (N=836). SINV HI antibodies were found for the first time in birds during their spring migration to Northern Europe, from three individuals: red-backed shrike, robin, and song thrush. Of the grouse, 27.4% were seropositive in 2003, one year after a human outbreak, but only 1.4% of the grouse were seropositive in 2004. Thus, grouse might contribute to the human epidemiology of SINV. A total of 86 patients with verified SINV infection were recruited to the study in 2002. SINV RNA detection or virus isolation from blood and/or skin lesions was successful in eight patients. IgM antibodies became detectable within the first eight days of illness, and IgG within 11 days. The acute phase of Pogosta disease was characterized by arthritis, itching rash, fatigue, mild fever, headache, and muscle pain. Half of the patients reported in self-administered questionnaires joint symptoms to last > 12 months. Physical examination in 49 of these patients three years after infection revealed persistent joint manifestations. Arthritis (swelling and tenderness in physical examination) was diagnosed in 4.1% (2/49) of the patients. Tenderness in palpation or in movement of a joint was found in 14.3% of the patients in the rheumatologic examination, and additional 10.2% complained persisting arthralgia at the interview. Thus, 24.5% of the patients had joint manifestations attributable to the infection three years earlier. A positive IgM antibody response persisted in 3/49 of the patients; both two patients with arthritis were in this group. Persistent symptoms of SINV infection might have considerable public health implications in areas with high seroprevalence. The age-standardized seroprevalence of SINV (1999-2003, N=2529) in the human population in Finland was 5.2%. The seroprevalence was high in North Karelia, Kainuu, and Central Ostrobothnia. The incidence was highest in North Karelia. Seroprevalence in men (6.0%) was significantly higher than in women (4.1%), however, the average annualized incidence in the non-epidemic years was higher in women than in men, possibly indicating that infected men are more frequently asymptomatic. The seroprevalence increased with age, reaching 15.4% in persons aged 60-69 years. The incidence was highest in persons aged 50-59 years.

The Road to Hell Is Paved with Good Interventions : A Pragmatic Examination of Humanitarian Intervention with Special Reference to Kosovo

Kansainvälisen oikeuden alaan kuuluvassa tutkielmassa käsitellään humanitaarisen intervention oikeutusta ja laillisuutta. Tutkimuskysymyksenä on, missä määrin humanitaarisilla näkökohdilla perusteltuja sotilaallisia toimia tai niillä uhkaamista voi pitää kansainvälisoikeudellisesti hyväksyttävänä ja millainen painoarvo ennakkotapauksena olisi annettava NATO-maiden Kosovossa toteuttamalle väliintulolle. Tutkielmassa perehdytään ihmisoikeusajattelun tiettyjen taustaoletusten kritiikkiin. Tarkastelun kohteena ovat erityisesti kannanotot, joiden mukaan ihmisoikeuksia ei voi pitää luonteeltaan universaaleina, sekä kyseiseen kritiikkiin liittyvät väitteet siitä, että ns. hegemonisessa asemassa olevat valtiot hyödyntävät ihmisoikeusargumentteja oikeuttaakseen voimankäyttönsä. Universaalisuuskritiikkiä voidaan pitää pitkälti perusteltuna, mutta nykyinen kansainvälinen yhteisö tarvitsee kuitenkin tietynlaisia yleismaailmallisia normeja voidakseen toimia tehokkaasti. Kritiikin ei voikaan katsoa pätevän humanitaarisen intervention kannalta keskeisiin ihmisoikeusnormeihin kuten kansanmurhan kieltoon, sillä kyseiset velvoitteet suojaavat kansainvälisen yhteisön toimivuutta ja uskottavuutta. Humanitaarisiin argumentteihin liittyy kuitenkin muita ongelmia: niillä on esimerkiksi aika ajoin pyritty oikeuttamaan sotilaallisia toimia, joissa ihmisoikeusnäkökohdat eivät välttämättä ole olleet etusijalla. Ihmisoikeuksille ei ole syytä antaa kansainvälisessä oikeudessa asemaa universaaleina "superargumentteina", jotka eivät olisi kyseenalaistettavissa. YK:n peruskirjan ja kansainvälisen tapaoikeuden näkökulmasta humanitaarisen intervention kaltaiseen voimankäyttöön vaaditaan turvallisuusneuvoston hyväksyntä, jota ei Kosovo-operaatioon saatu. Interventiota voi tässä suhteessa pitää yksiselitteisesti laittomana, sillä sen tueksi esitetyt oikeudelliset argumentit eivät ole vakuuttavia. Tapaukseen liittyvät ihmisoikeusnäkökohdat ovat kuitenkin siinä määrin merkittäviä, että ongelmaan ei ole perusteltua suhtautua tiukan legalistisesti. Operaation hyväksyminen moraaliargumenttien nojalla voisi kuitenkin johtaa nykyisten voimankäyttörajoitusten marginalisoitumiseen, mikä olisi yllä käsitellyn kritiikin valossa ongelmallista. Tutkielmassa nostetaan suositeltavaksi ratkaisuksi lähestymistapa, jossa Kosovon tapaus ymmärretään yksittäisenä oikeudenvastaisena mutta samalla oikeudenulkoisena poikkeustapauksena. Tällöin peruskirjan mukainen voimankäytön sääntely säilyy entisellään ilman että humanitaariset näkökohdat jäisivät tyystin huomiotta. Ratkaisu ei sulje pois mahdollisuutta suhtautua positiivisesti Kosovo-operaation mahdollisesti luomaan "poliittiseen normiin": suuren mittakaavan ihmisoikeusloukkaukset eivät jää Euroopassa seurauksitta. Ilman turvallisuusneuvoston suostumusta toteutettaviin humanitaarisiin interventioihin liittyvien käytännöllisten ja kansainvälisoikeudellisten riskien vuoksi niihin on kuitenkin aihetta suhtautua suurella varauksella.

Agreeable Agreement : An Examination into the Quest for a Solid Consensus in Light of Bilateral Doctrinal Dialogues among Anglicans, Lutherans and Roman Catholics

The purpose of this study is to analyse the development and understanding of the idea of consensus in bilateral dialogues among Anglicans, Lutherans and Roman Catholics. The source material consists of representative dialogue documents from the international, regional and national dialogues from the 1960s until 2006. In general, the dialogue documents argue for agreement/consensus based on commonality or compatibility. Each of the three dialogue processes has specific characteristics and formulates its argument in a unique way. The Lutheran-Roman Catholic dialogue has a particular interest in hermeneutical questions. In the early phases, the documents endeavoured to describe the interpretative principles that would allow the churches to together proclaim the Gospel and to identify the foundation on which the agreement in the church is based. This investigation ended up proposing a notion of basic consensus , which later developed into a form of consensus that seeks to embrace, not to dismiss differences (so-called differentiated consensus ). The Lutheran-Roman Catholic agreement is based on a perspectival understanding of doctrine. The Anglican-Roman Catholic dialogue emphasises the correctness of interpretations. The documents consciously look towards a common future , not the separated past. The dialogue s primary interpretative concept is koinonia. The texts develop a hermeneutics of authoritative teaching that has been described as the rule of communion . The Anglican-Lutheran dialogue is characterised by an instrumental understanding of doctrine. Doctrinal agreement is facilitated by the ideas of coherence, continuity and substantial emphasis in doctrine. The Anglican-Lutheran dialogue proposes a form of sufficient consensus that considers a wide set of doctrinal statements and liturgical practices to determine whether an agreement has been reached to the degree that, although not complete , is sufficient for concrete steps towards unity. Chapter V discusses the current challenges of consensus as an ecumenically viable concept. In this part, I argue that the acceptability of consensus as an ecumenical goal is based not only the understanding of the church but more importantly on the understanding of the nature and function of the doctrine. The understanding of doctrine has undergone significant changes during the time of the ecumenical dialogues. The major shift has been from a modern paradigm towards a postmodern paradigm. I conclude with proposals towards a way to construct a form of consensus that would survive philosophical criticism, would be theologically valid and ecumenically acceptable.

Towards a Critique of the Concept of the Right to Self-Determination in Africa : A Conceptual Examination and the Cases of Western Sahara, Southern Sudan and Eritrea

This thesis examines the right to self-determination which is a norm used for numerous purposes by multiple actors in the field of international relations, with relatively little clarity or agreement on the actual and potential meaning of the right. In international practice, however, the main focus in applying the right has been in the context of decolonization as set by the United Nations in its early decades. Thus, in Africa the right to self-determination has traditionally implied that the colonial territories, and particularly the populations within these territories, were to constitute the people who were entitled to the right. That is, self-determination by decolonization provided a framework for the construction of independent nation-states in Africa whilst other dimensions of the right remained largely or totally neglected. With the objective of assessing the scope, content, developments and interpretations of the right to self-determination in Africa, particularly with regard to the relevance of the right today, the thesis proceeds on two fundamental hypotheses. The first is that Mervyn Frost s theory of settled norms, among which he lists the right to self-determination, assumes too much. Even if the right to self-determination is a human right belonging to all peoples stipulated, inter alia, in the first Article of the 1966 International Human Rights Covenants, it is a highly politicized and context-bound right instead of being settled and observed in a way that its denial would need special justification. Still, the suggested inconsistency or non-compliance with the norm of self-determination is not intended to prove the uselessness or inappropriateness of the norm, but, on the contrary, to invite and encourage debate on the potential use and coverage of the right to self-determination. The second hypothesis is that within the concept of self-determination there are two normative dimensions. One is to do with the idea and practice of statehood, the nation and collectivity that may decide to conduct itself as an independent state. The other one is to do with self-determination as a human right, as a normative condition, to be enjoyed by people and peoples within states that supersedes state authority. These external and internal dimensions need to be seen as complementary and co-terminous, not as mutually exclusive alternatives. The thesis proceeds on the assumption that the internal dimension of the right, with human rights and democracy at its core, has not been considered as important as the external. In turn, this unbalanced and selective interpretation has managed to put the true normative purpose of the right making the world better and bringing more just polity models into a somewhat peculiar light. The right to self-determination in the African context is assessed through case studies of Western Sahara, Southern Sudan and Eritrea. The study asks what these cases say about the right to self-determination in Africa and what their lessons learnt could contribute to the understanding and relevance of the right in today s Africa. The study demonstrates that even in the context of decolonization, the application of the right to self-determination has been far from the consistent approach supposedly followed by the international community: in many respects similar colonial histories have easily led to rather different destinies. While Eritrea secured internationally recognized right to self-determination in the form of retroactive independence in 1993, international recognition of distinct Western Sahara and Southern Sudan entities is contingent on complex and problematic conditions being satisfied. Overall, it is a considerable challenge for international legality to meet empirical political reality in a meaningful way, so that the universal values attached to the norm of self-determination are not overlooked or compromised but rather reinforced in the process of implementing the right. Consequently, this thesis seeks a more comprehensive understanding of the right to self-determination with particular reference to post-colonial Africa and with an emphasis on the internal, human rights and democracy dimensions of the norm. It is considered that the right to self-determination cannot be perceived only as an inter-state issue as it is also very much an intra-state issue, including the possibility of different sub-state arrangements exercised under the right, for example, in the form of autonomy. At the same time, the option of independent statehood achieved through secession remains a mode of exercising and part of the right to self-determination. But in whatever form or way applied, the right to self-determination, as a normative instrument, should constitute and work as a norm that comprehensively brings more added value in terms of the objectives of human rights and democracy. From a normative perspective, a peoples right should not be allowed to transform and convert itself into a right of states. Finally, in light of the case studies of Western Sahara, Southern Sudan and Eritrea, the thesis suggests that our understanding of the right to self-determination should now reach beyond the post-colonial context in Africa. It appears that both the questions and answers to the most pertinent issues of self-determination in the cases studied must be increasingly sought within the postcolonial African state rather than solely in colonial history. In this vein, the right to self-determination can be seen not only as a tool for creating states but also as a way to transform the state itself from within. Any such genuinely post-colonial approach may imply a judicious reconsideration, adaptation or up-dating of the right and our understanding of it in order to render it meaningful in Africa today.