Causes of death in patients with rheumatoid arthritis over a 40-year period : with special emphasis on autopsy

Rheumatoid arthritis (RA) patients have premature mortality. Contrary to the general population, mortality in RA has not declined over time. This study aimed to evaluate determinants of mortality in RA by examining causes of death (CoDs) over time, accuracy of CoD diagnoses, and contribution of RA medication to CoDs. This study further evaluated detection rate of reactive systemic amyloid A amyloidosis, which is an important contributor to RA mortality. CoDs were examined in 960 RA patients between 1971 and 1991 (Study population A) and in 369 RA patients autopsied from 1952 to 1991, with non-RA patients serving as the reference cases (Study population B). In Study population B, CoDs by the clinician before autopsy were compared to those by the pathologist at autopsy to study accuracy of CoD diagnoses. In Study population B, autopsy tissue samples were re-examined systematically for amyloidosis (90% of patients) and clinical data for RA patients was studied from 1973. RA patients died most frequently of cardiovascular diseases (CVDs), infections, and RA. RA deaths declined over time. Coronary deaths showed no major change in Study population A, but, in Study population B, coronary deaths in RA patients increased from 1952 to 1991, while non-RA cases had a decrease in coronary deaths starting in the 1970s. Between CoD diagnoses by the clinician and those by the pathologist, RA patients had lower agreement than non-RA cases regarding cardiovascular (Kappa reliability measure: 0.31 vs. 0.51) and coronary deaths (0.33 vs. 0.46). Use of disease modifying anti-rheumatic drugs was not associated with any CoD. In RA patients, re-examination of autopsy tissue samples doubled the prevalence of amyloid compared with the original autopsy: from 18% to 30%. In the amyloid-positive RA patients, amyloidosis was diagnosed before autopsy in only 37%; and they had higher inflammatory levels and longer duration of RA than amyloid-negative RA patients. Of the RA patients with amyloid, only half had renal failure or proteinuria during lifetime. In RA, most important determinants of mortality were CVDs, RA, and infections. In RA patients, RA deaths decreased over time, but this was not true for coronary deaths. Coronary death being less accurately diagnosed in RA may indicate that coronary heart disease (CHD) often goes unrecognized during lifetime. Thus, active search for CHD and its effective treatment is important to reduce cardiovascular mortality. Reactive amyloidosis may often go undetected. In RA patients with proteinuria or renal failure, as well as with active and long-lasting RA, a systematic search for amyloid is important to enable early diagnosis and early enhancement of therapy. This is essential to prevent clinical manifestations of amyloidosis such as renal failure, which has a poor prognosis.

IgA nephropathy and Henoch-Schönlein nephritis in adults : with special reference to factors affecting outcome

IgA nephropathy (IgAN) is the most common primary glomerulonephritis. In one third of the patients the disease progresses, and they eventually need renal replacement therapy. IgAN is in most cases a slowly progressing disease, and the prediction of progression has been difficult, and the results of studies have been conflicting. Henoch-Schönlein nephritis (HSN) is rare in adults, and prediction of the outcome is even more difficult than in IgAN. This study was conducted to evaluate the clinical and histopathological features and predictors of the outcome of IgAN and HSN diagnosed in one centre (313 IgAN patients and 38 HSN patients), and especially in patients with normal renal function at the time of renal biopsy. The study also aimed to evaluate whether there is a difference in the progression rates in four countries (259 patients from Finland, 112 from UK, 121 from Australia and 274 from Canada), and if so, can this be explained by differences in renal biopsy policy. The third aim was to measure urinary excretions of cytokines interleukin 1ß (IL-1ß) and interleukin 1 receptor antagonist (IL-1ra) in patients with IgAN and HSN and the correlations of excretion of these substances with histopathological damage and clinical factors. A large proportion of the patients diagnosed in Helsinki as having IgAN had normal renal function (161/313 patients). Four factors, (hypertension, higher amounts of urinary erythrocytes, severe arteriolosclerosis and a higher glomerular score) which independently predicted progression (logistic regression analysis), were identified in mild disease. There was geographic variability in renal survival in patients with IgAN. When age, levels of renal function, proteinuria and blood pressure were taken into account, it showed that the variability related mostly to lead-time bias and renal biopsy indications. Amount of proteinuria more than 0.4g/24h was the only factor that was significantly related to the progression of HSN. the Hypertension and the level of renal function were found to be factors predicting outcome in patients with normal renal function at the time of diagnosis. In IgAN patients, IL-1ra excretion into urine was found to be decreased as compared with HSN patients and healthy controls. Patients with a high IL-1ra/IL-1ß ratio had milder histopathological changes in renal biopsy than patients with a low/normal IL-1ra/IL-1ß ratio. It was also found that the excretion of IL-1ß and especially IL-1ra were significantly higher in women. In conclusion, it was shown that factors associated with outcome can reliably be identified even in mild cases of IgAN. Predicting outcome in adult HSN, however, remains difficult.

Inhibition of CYP1A2-mediated drug metabolism in vitro and in humans : With special emphasis on rofecoxib and other NSAIDs

The cytochrome P450 1A2 (CYP1A2) is one of the major metabolizing enzymes. The muscle relaxant tizanidine is a selective substrate of CYP1A2, and the non-steroidal anti-inflammatory drug (NSAID) rofecoxib was thought to modestly in-hibit it. Cases suggesting an interaction between tizanidine and rofecoxib had been reported, but the mechanism was unknown. Also other NSAIDs are often used in combination with muscle relaxants. The aims of this study were to investigate the effect of rofecoxib, several other NSAIDs and female sex steroids on CYP1A2 ac-tivity in vitro and in vivo, and to evaluate the predictability of in vivo inhibition based on in vitro data. In vitro, the effect of several NSAIDs, female sex steroids and model inhibitors on CYP1A2 activity was studied in human liver microsomes, without and with preincubation. In placebo controlled, cross-over studies healthy volunteers ingested a single dose of tizanidine after a pretreament with the inhibitor (rofecoxib, tolfenamic acid or celecoxib) or placebo. Plasma (and urine) concentrations of tizanidine and its metabolites were measured, and the pharmacodynamic effects were recorded. A caffeine test was also performed. In vitro, fluvoxamine, tolfenamic acid, mefenamic acid and rofecoxib potently in-hibited CYP1A2. Ethinylestradiol, celecoxib, desogestrel and zolmitriptan were moderate, and etodolac, ciprofloxacin, etoricoxib and gestodene were weak inhibi-tors of CYP1A2. At 100 µM, other tested NSAIDs and steroids inhibited CYP1A2 less than 35%. Rofecoxib was found to be a mechanism-based inhibitor of CYP1A2. In vivo, rofecoxib greatly increased the plasma concentrations (over ten-fold) and the pharmacodynamic effects of tizanidine. Also the metabolism of caf-feine was impaired by rofecoxib. Despite the relatively strong in vitro CYP1A2 inhibitory effects, tolfenamic acid and celecoxib did not have a significant effect on tizanidine and caffeine concentrations in humans. Competitive inhibition model and the free plasma concentration of the inhibitor predicted well the effect of fluvoxam-ine and the lack of effect of tolfenamic acid and celecoxib on tizanidine concentra-tions in humans, and mechanism-based inhibition model explained the effects of rofecoxib. However, the effects of ciprofloxacin and oral contraceptives were un-derestimated from the in vitro data. Rofecoxib is a potent mechanism-based inhibitor of CYP1A2 in vitro and in vivo. This mechanism may be involved in the adverse cardiovascular effects of rofecoxib. Tolfenamic acid and celecoxib seem to be safe in combination with tizanidine, but mefenamic acid might have some effect on tizanidine concentrations in vivo. Con-sidering the mechanism of inhibition, and using the free plasma concentration of the inhibitor, many but not all CYP1A2 interactions can be predicted from in vitro data.

On a Special Co-cycle Basis of Graphs

In this paper we consider the problems of computing a minimum co-cycle basis and a minimum weakly fundamental co-cycle basis of a directed graph G. A co-cycle in G corresponds to a vertex partition (S,V ∖ S) and a { − 1,0,1} edge incidence vector is associated with each co-cycle. The vector space over ℚ generated by these vectors is the co-cycle space of G. Alternately, the co-cycle space is the orthogonal complement of the cycle space of G. The minimum co-cycle basis problem asks for a set of co-cycles that span the co-cycle space of G and whose sum of weights is minimum. Weakly fundamental co-cycle bases are a special class of co-cycle bases, these form a natural superclass of strictly fundamental co-cycle bases and it is known that computing a minimum weight strictly fundamental co-cycle basis is NP-hard. We show that the co-cycle basis corresponding to the cuts of a Gomory-Hu tree of the underlying undirected graph of G is a minimum co-cycle basis of G and it is also weakly fundamental.

Imaging of knee injuries with special focus on tibial plateau fractures

Acute knee injury is a common event throughout life, and it is usually the result of a traffic accident, simple fall, or twisting injury. Over 90% of patients with acute knee injury undergo radiography. An overlooked fracture or delayed diagnosis can lead to poor patient outcome. The major aim of this thesis was retrospectively to study imaging of knee injury with a special focus on tibial plateau fractures in patients referred to a level-one trauma center. Multi-detector computed tomography (MDCT) findings of acute knee trauma were studied and compared to radiography, as well as whether non-contrast MDCT can detect cruciate ligaments with reasonable accuracy. The prevalence, type, and location of meniscal injuries in magnetic resonance imaging (MRI) were evaluated, particularly in order to assess the prevalence of unstable meniscal tears in acute knee trauma with tibial plateau fractures. The possibility to analyze with conventional MRI the signal appearance of menisci repaired with bioabsorbable arrows was also studied. The postoperative use of MDCT was studied in surgically treated tibial plateau fractures: to establish the frequency and indications of MDCT and to assess the common findings and their clinical impact in a level-one trauma hospital. This thesis focused on MDCT and MRI of knee injuries, and radiographs were analyzed when applica-ble. Radiography constitutes the basis for imaging acute knee injury, but MDCT can yield information beyond the capabilities of radiography. Especially in severely injured patients , sufficient radiographs are often difficult to obtain, and in those patients, radiography is unreliable to rule out fractures. MDCT detected intact cruciate ligaments with good specificity, accuracy, and negative predictive value, but the assessment of torn ligaments was unreliable. A total of 36% (14/39) patients with tibial plateau fracture had an unstable meniscal tear in MRI. When a meniscal tear is properly detected preoperatively, treatment can be combined with primary fracture fixation, thus avoiding another operation. The number of meniscal contusions was high. Awareness of the imaging features of this meniscal abnormality can help radiologists increase specificity by avoiding false-positive findings in meniscal tears. Postoperative menisci treated with bioabsorbable arrows showed no difference, among different signal intensities in MRI, among menisci between patients with operated or intact ACL. The highest incidence of menisci with an increased signal intensity extending to the meniscal surface was in patients whose surgery was within the previous 18 months. The results may indicate that a rather long time is necessary for menisci to heal completely after arrow repair. Whether the menisci with an increased signal intensity extending to the meniscal surface represent improper healing or re-tear, or whether this is just the earlier healing feature in the natural process remains unclear, and further prospective studies are needed to clarify this. Postoperative use of MDCT in tibial plateau fractures was rather infrequent even in this large trauma center, but when performed, it revealed clinically significant information, thus benefitting patients in regard to treatment.

Global and EU governance for sustainable forest management with special reference to capacity building in Ethiopia and Southern Sudan

The purpose of this study was to produce information on and practical recommendations for informed decision-making on and capacity building for sustainable forest management (SFM) and good forest governance. This was done within the overall global framework for sustainable development with special emphasis on the EU and African frameworks and on Southern Sudan and Ethiopia in particular. The case studies on Southern Sudan and Ethiopia focused on local, national and regional issues. Moreover, this study attempted to provide both theoretical and practical new insight. The aim was to build an overall theoretical framework and to study its key contents and main implications for SFM and good forest governance at all administration levels, for providing new tools for capacity building in natural resources management. The theoretical framework and research approach were based on the original research problem and the general and specific aims of the study. The key elements of the framework encompass sustainable development, global and EU governance, sustainable forest management (SFM), good forest governance, as well as international and EU law. The selected research approach comprised matrix-based assessment of international, regional (EU and Africa) and national (Southern Sudan and Ethiopia) policy and legal documents. The specific case study on Southern Sudan also involved interviews and group discussions with local community members and government officials. As a whole, this study attempted to link the global, regional, national and local levels in forest-sector development and especially to analyse how the international policy development in environmental and forestry issues is reflected in field-level progress towards SFM and good forest governance, for the specific cases of Southern Sudan and Ethiopia. The results on Southern Sudan focused on the existing situation and perceived needs in capacity building for SFM and good forest governance at all administration levels. Specifically, the results of the case study on Southern Sudan presented the current situation in selected villages in the northern parts of Renk County in Upper Nile State, and the implications of Multilateral Environmental Agreements (MEAs) and of the new forest policy framework for capacity building actions. The results on Ethiopia focused on training, extension, research, education and new curriculum development within higher education institutions and particularly at the Wondo Genet College of Forestry and Natural Resources (WGCF-NR), which administratively lies under Hawassa University. The results suggest that, for both cases studies, informed decision-making on and capacity building for SFM and good forest governance require comprehensive, long-term, cross-sectoral, coherent and consistent approaches within the dynamic and evolving overall global framework, including its multiple inter-linked levels. The specific priority development and focus areas comprised the establishment of SFM and good forest governance in accordance with the overall sustainable development priorities and with more focus on the international trade in forest products that are derived from sustainable and legal sources with an emphasis on effective forest law enforcement and governance at all levels. In Upper Nile State in Southern Sudan there were positive development signals such as the will of the local people to plant more multipurpose trees on farmlands and range lands as well as the recognition of the importance of forests and trees for sustainable rural development where food security is a key element. In addition, it was evident that the local communities studied in Southern Sudan also wanted to establish good governance systems through partnerships with all actors and through increased local responsibilities. The results also suggest that the implementation of MEAs at the local level in Southern Sudan requires mutually supportive and coherent approaches within the agreements as well as significantly more resources and financial and technical assistance for capacity building, training and extension. Finally, the findings confirm the importance of full utilization of the existing local governance and management systems and their traditional and customary knowledge and practices, and of new development partnerships with full participation of all stakeholders. The planned new forest law for Southern Sudan, based on an already existing new forest policy, is expected to recognize the roles of local-level actors, and it would thus obviously facilitate the achieving of sustainable forest management.

Soft condensed matter -A special issue of solid state communications -Foreword

It is a policy of Solid State Communications’ Executive Editorial Board to organize special issues from time to time on topics of current interests. The present issue focuses on soft condensed matter, a rapidly developing and diverse area of importance not only for the basic science, but also for its potential applications. The ten articles in this issue are intended to give the readers a snapshot of some latest developments in soft condensed matter, mainly from the point of view of basic science. As the special issues are intended for a broad audience, most articles are short reviews that introduce the readers to the relevant topics. Hence this special issue can be especially helpful to readers who might not be specialists in this area but would like to have a quick grasp on some of the interesting research directions.