Dans ce document, nous étudions deux problèmes de sectorisation et proposons plusieurs méthodes de résolution exactes basées sur la décomposition de Dantzig-Wolfe et la génération de colonnes. Nous proposons deux modélisations en fonction de la manière d’appréhender l’objectif du problème qui consiste à obtenir des secteurs compacts. Pour chacune des modélisations, nous comparons des approches de résolution exactes basées sur des formulations compactes ou sur des formulations étendues obtenues par la décomposition de Dantzig-Wolfe. Le premier type de modèles proposé définit la fonction objectif à la manière d’un problème de p-median. Concernant les méthodes de résolution pour ce type de modèle, l’accent est mis sur l’accélération de la convergence de l’algorithme de génération de colonnes en mettant en place des techniques d’agrégation de contraintes afin de réduire la dégénérescence de l’algorithme du simplexe. Les expérimentations numériques montrent que la méthode d’agrégation de contraintes proposée permet effectivement de réduire le nombre d’itérations dégénérées. Cependant, elle ne suffit pas à accélérer l’algorithme de branch-and-price. Le choix d’utilisation de la formulation compacte ou de la formulation étendue dépend du type d’instances résolu. Le second type de modèles formule l’objectif d’une manière assez proche de celui des problèmes de p-centre. L’utilisation d’un tel objectif complexifie la résolution des sous-problèmes de génération de colonnes. L’accent est donc mis sur la conception d’algorithmes de branch-and-bound et de programmation dynamique pour les résoudre efficacement. Les expériences montrent que l’algorithme de branch-and-price surpasse les approches de résolution utilisant une formulation compacte du problème. / In this document, we study two districting problems and propose several exact methods, based on Dantzig-Wolfe decomposition and column generation, to solve them. For each model, we compare exact approaches based either on compact formulations or on extended formulations obtained using Dantzig-Wolfe decomposition. The first type of model that we propose defines the objective function in a p-median problem fashion. Regarding the methods used to solve that kind of model, we emphasize accelerating the convergence of the column generation algorithm by designing constraint aggregation techniques in order to reduce the degeneracy in the simplex algorithm. Numerical experiments show that this constraint aggregation method indeed reduces the proportion of degenerated iterations. However, it is not enough to speed up the branch-and-price algorithm. Choosing to tackle the problem through either a compact formulation or an extended formulation depends on the structure of the instances to solve. The second type of model formulates the objective function in a way quite similar to that of p-centre problems. Using such an objective function induces complex column generation subproblems. We focus on designing branch-and-bound and dynamic programming algorithms in order to solve them efficiently. Experiments show that the branch-and-price approach surpasses any proposed method based on compact formulations of the problem.

The pre-synaptic protein α-Synuclein (αS) is often linked to the pathology of Parkinson’s disease (PD), an age-related neurodegenerative disorder. Lewy bodies, the cytopathological hallmarks of PD, are found to be rich in aggregates of misfolded αS protein. Metal dyshomeostasis has also been linked to PD due to the accumulation of iron in the substantia nigra pars compacta, and diminished copper levels reported in this same region. Metal dyshomeostasis in the brain coupled with oxidative stress can enhance the aggregation of αS. Recently, it was confirmed that mammalian αS is universally acetylated at the N-terminus, a common post-translational modification in humans. The consequences of this modification have been understudied, and it is believed to impart a functional role under physiological conditions with respect to membrane-interactions and protein folding. In an attempt to elucidate the pathological mechanism behind PD with respect to the structural dynamics of the protein, our investigations were focused on physiologically prevalent, N-terminally acetylated αS (NAcαS) and its interaction with the most prevalent redox-active metal ions in the brain (iron and copper) under both aerobic and/or anaerobic conditions. The structural features associated with metal-bound NAcαS differed depending on the iron oxidation states, where under aerobic conditions Feᴵᴵ stabilized an oligomer-locked, anti-parallel right-twisted β-sheet conformation that could potentially impart toxicity to neurons. In contrast, Feᴵᴵᴵ promoted a fibrillar structure rich in parallel β-sheets. N-terminal capping also altered the Cuᴵᴵ coordination sphere and had a dramatic effect on protein aggregation. Parallel studies on NAcαS variants with different site mutations near the putative copper binding sites (ex: H50Q and F4W) indicated that preferential binding shifts upon changes in the side chain residues. In depth analysis of the electron structure of Cuᴵᴵ-bound NAcαS using electron paramagnetic resonance spectroscopy (EPR) revealed a coordination sphere of N3O1 that includes the H50 residue in the wild-type protein that shifts to an O4 coordination sphere at the C-terminus upon Cuᴵᴵ binding to the disease-relevant H50Q variant. Immunoblotting analyses revealed that copper-induced redox chemistry promoted O2-activation and the subsequent formation of dityrosine crosslinks, a post-translational modification identified as a biomarker of PD. EPR-detection of tyrosyl radical formation in the presence of Cuᴵ-bound NAcαS further supported this radical coupling mechanism. Intermolecular crosslinks within the fibrillar core of NAcαS as well as intramolecular crosslinks within the C-terminal region underpin the role of metal-dioxygen chemistry in PD-related pathology. The unique structural features resulting from iron vs copper coordination to NAcαS inspired studies directed at the synergistic effect of each individual metal species as revealed by photo-initiated crosslinking of NAcαS. C-terminal intramolecular tyrosine interactions were mainly impacted by the presence of both metals, which each have binding sites around the same region. These findings emphasize that protein dynamics, metal binding site conformational changes, as well as aggregation pathways can deviate drastically upon N-terminal acetylation of αS and that protein-metal interactions may play a vital role in PD etiology.

Wrapper在資訊整合系統中擔任各類異質資訊來源的轉譯器，它將某特定資訊來源資訊的結構與格式轉譯為資訊整合系統能統一識別處理的共通資料型態。 　本研究在以Web為資訊資源的資訊整合系統架構之下，根據XML開放、簡易、易於擴充並適合Web應用的特性，提出了一種以XML基礎的HTML Wrapper建置方法，此方法主要是應用XML語言定義HTML Wrapping描述語言（Descriptive HTML-Wrapping Language，DHWL），Wrapper根據DHWL Script的指示，自動執行網頁瀏覽、資料定位與讀取、資料格式轉換之作業。它擷取結構鬆散、語意不明HTML格式的網頁資訊，將其轉換成結構嚴整、具自我描述性質的XML格式輸出。 　此Wrapper建置方法的特點是當網站的結構或網頁的內容更動時，HTML Wrapper開發者只須變更DHML的設計，而不須重新更動與編譯Wrapper程式碼。這種設計將資料來源的位置、內容、關聯（以DHML描述）與資料來源的資料收集處理邏輯（HTML Wrapper所負責的部分）分開，使Wrapper具通用性質，並降低開發與維護的時間和成本。 　本研究根據此建置方法實作一Wrapper系統，應用在網路銀行個人帳戶的資訊彙整上，以檢驗此方法的可行性與效果。網路銀行個人帳戶的資訊彙整（Account Aggregation），即是指匯集消費者在各家網路銀行所開設各種帳戶的往來金融資訊，使消費者能統籌管理、規劃自己各種帳戶的金錢收支，應用此系統建置帳戶彙整服務，不須花費龐大資源整合各家銀行網站後端資訊系統與作業程序，而能藉由Wrapper整合消費者在各家銀行帳戶往來資訊。

<p>Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils. </p><p>One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.</p><p>In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR. </p><p>We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis. </p><p>We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation. </p>

Aggregation of the Amyloid β (Aβ) peptide to amyloid fibrils is associated with the outbreak of Alzheimer’s disease. Early aggregation intermediates in form of soluble oligomers are of special interest as they are believed to be the major toxic components in the process. These oligomers are of disordered and transient nature. Therefore, their detailed molecular structure is difficult to access experimentally and often remains unknown. In the present work extensive, fully atomistic replica exchange molecular dynamics simulations were performed to study the preaggregated, monomer states and early aggregation intermediates (dimers, trimers) of Aβ(25-35) and Aβ(10-35)-NH2 in aqueous solution. The folding and aggregation of Aβ(25-35) were studied at neutral pH and 293 K. Aβ(25-35) monomers mainly adopt β-hairpin conformations characterized by a β-turn formed by residues G29 and A30, and a β-sheet between residues N27–K28 and I31–I32 in equilibrium with coiled conformations. The β-hairpin conformations served as initial configurations to model spontaneous aggregation of Aβ(25-35). As expected, within the Aβ(25-35) dimer and trimer ensembles many different poorly populated conformations appear. Nevertheless, we were able to distinguish between disordered and fibril-like oligomers. Whereas disordered oligomers are rather compact with few intermolecular hydrogen bonds (HBs), fibril-like oligomers are characterized by the formation of large intermolecular β-sheets. In most of the fibril-like dimers and trimers individual peptides are fully extended forming in- or out-of-register antiparallel β-sheets. A small amount of fibril-like trimers contained V-shaped peptides forming parallel β-sheets. The dimensions of extended and V-shaped oligomers correspond well to the diameters of two distinct morphologies found for Aβ(25-35) fibrils. The transition from disordered to fibril-like Aβ(25-35) dimers is unfavorable but driven by energy. The lower energy of fibril-like dimers arises from favorable intermolecular HBs and other electrostatic interactions which compete with a loss in entropy. Approximately 25 % of the entropic cost correspond to configurational entropy. The rest relates to solvent entropy, presumably caused by hydrophobic and electrostatic effects. In contrast to the transition towards fibril-like dimers the first step of aggregation is driven by entropy. Here, we compared structural and thermodynamic properties of the individual monomer, dimer and trimer ensembles to gain qualitative information about the aggregation process. The β-hairpin conformation observed for monomers is successively dissolved in dimer and trimer ensembles while instead intermolecular β-sheets are formed. As expected upon aggregation the configurational entropy decreases. Additionally, the solvent accessible surface area (SASA), especially the hydrophobic SASA, decreases yielding a favorable solvation free energy which overcompensates the loss in configurational entropy. In summary, the hydrophobic effect, possibly combined with electrostatic effects, yields an increase in solvent entropy which is believed to be one major driving force towards aggregation. Spontaneous folding of the Aβ(10-35)-NH2 monomer was modeled using two force fields, GROMOS96 43a1 and OPLS/AA, and compared to primary NMR data collected at pH 5.6 and 283 K taken from the literature. Unexpectedly, the two force fields yielded significantly different main conformations. Comparison between experimental and calculated nuclear Overhauser effect (NOE) distances is not sufficient to distinguish between the different force fields. Additionally, the comparison with scalar coupling constants suggest that the chosen protonation in both simulations corresponds to a pH lower than in the experiment. Based on this analysis we were unable to determine which force field yields a better description of this system. Dimerization of Aβ(10-35)-NH2 was studied at neutral pH and 300 K. Dimer conformations arrange in many distinct, poorly populated and rather complex alignments or interlocking patterns which are rather stabilized by side chain interactions than by specific intermolecular hydrogen bonds. Similar to Aβ(25-35) dimers, transition towards β-sheet-rich, fibril-like Aβ(10-35) dimers is driven by energy competing with a loss in entropy. Here, transition is mediated by favorable peptide-solvent and solvent-solvent interactions mainly arising from electrostatic interactions. / Die Aggregation des Amyloid β (Aβ) Peptids zu Amyloidfibrillen wird mit dem Ausbruch der Alzheimer Krankheit in Verbindung gebracht. Die toxische Wirkung auf Zellen wird vor allem den zeitigen Intermediaten in Form von löslichen Oligomeren zugeschrieben. Aufgrund deren ungeordneter und flüchtiger Natur kann die molekulare Struktur solcher zeitigen Oligomere oft experimentell nicht aufgelöst werden. In der vorliegenden Arbeit wurden aufwendige atomistische Replica-Exchange-Molekulardynamik-Simulationen durchgeführt, um die molekulare Struktur von Monomeren und Oligomeren der Fragmente Aβ(25-35) und Aβ(10-35)-NH2 in Wasser zu untersuchen. Die Faltung und Aggregation von Aβ(25-35) wurde bei neutralem pH und 293 K untersucht. Monomere dieses Fragments bilden hauptsächlich β-Haarnadelkonformationen im Gleichgewicht mit Knäulstrukturen. Innerhalb der β-Haarnadelkonformationen bilden die Residuen G29 und A30 einen β-turn, während N27–K28 and I31–I32 ein β-Faltblatt bilden. Diese β-Haarnadelkonformationen bildeten den Ausgangspunkt zur Modellierung spontaner Aggregation. Wie zu erwarten, bilden sich eine Vielzahl verschiedener, gering besetzter Dimer- und Trimerkonformationen. Mit Hilfe einer gröberen Einteilung können diese in ungeordnete und fibrillähnliche Oligomere unterteilt werden. Ungeordnete Oligomere bilden kompakte Strukturen, die nur durch wenige intermolekulare Wasserstoffbrückenbindungen (HBB) stabilisiert sind. Typisch für fibrillähnliche Oligomere ist hingegen die Ausbildung großer intermolekularer β-Faltblätter. In vielen dieser Oligomere finden wir antiparallele, in- oder out-of-register β-Faltblätter gebildet durch vollständig ausgestreckte Peptide. Ein kleiner Teil der fibrillähnlichen Trimere bildet parallele, V-förmige β-Faltblätter. Die Ausdehnungen ausgestreckter und V-förmiger Oligomere entspricht in etwa den Durchmessern von zwei verschiedenen, experimentell gefundenen Fibrillmorphologien für Aβ(25-35). Die Umwandlung von ungeordneten zu fibrillähnlichen Aβ(25-35) Dimeren ist energetisch begünstigt, läuft aber nicht freiwillig ab. Fibrillähnliche Dimere haben eine geringere Energie aufgrund günstiger Peptidwechselwirkungen (HBB, Salzbrücken), welche durch den Verlust an Entropie kompensiert wird. Etwa 25 % entsprechen dem Verlust an Konfigurationsentropie. Der restliche Anteil wird einem Verlust an Lösungsmittelentropie aufgrund von hydrophoben und elektrostatischen Effekten zugesprochen. Im Gegensatz zur Umwandlung in fibrillähnliche Dimere, ist die Assoziation von Monomeren oder Oligomeren entropisch begünstigt. Beim Vergleich thermodynamischer Eigenschaften der Monomer-, Dimer- und Trimersysteme zeigt sich im Verlauf der Aggregation, wie erwartet, eine Abnahme der Konfigurationsentropie. Zusätzlich nimmt die dem Lösungsmittel zugängliche Oberfläche (SASA), insbesondere die hydrophobe SASA, ab. In Verbindung damit beobachten wir eine Abnahme der freien Solvatisierungsenergie, welche den Verlust an Konfigurationsentropie kompensiert. Mit anderen Worten, der hydrophobe Effekt in Kombination mit elektrostatischen Wechselwirkungen führt zu einem Ansteigen der Lösungsmittelentropie und begünstigt damit die Aggegation. Die spontane Faltung des Aβ(10-35)-NH2 Monomers wurde für zwei verschiedene Proteinkraftfelder, GROMOS96 43a1 und OPLS/AA, untersucht und mit primären NMR-Daten aus der Literatur, gemessen bei pH 5.6 und 283 K, verglichen. Beide Kraftfelder generieren unterschiedliche Hauptkonformationen. Der Vergleich zwischen experimentellen und berechneten Kern-Overhauser-Effekt (NOE) Abständen ist nicht ausreichend, um zwischen beiden Kraftfeldern zu unterscheiden. Der Vergleich mit Kopplungskonstanten aus Experiment und Simulation zeigt, dass beide Simulationen einem pH-Wert geringer als 5.6 ensprechen. Basierend auf den bisherigen Ergebnissen können wir nicht entscheiden, welches Kraftfeld eine bessere Beschreibung für dieses System liefert. Die Dimerisierung von Aβ(10-35)-NH2 wurde bei neutralem pH und 300 K untersucht. Wir finden eine Vielzahl verschiedener, gering besetzter Dimerstrukturen, welche eher durch Seitenkettenkontakte als durch spezifische HBB stabilisiert sind. Wie bei den Aβ(25-35) Dimeren, ist die Umwandlung zu β-Faltblattreichen, fibrillähnlichen Aβ(10-35) Dimeren energetisch begünstigt, konkurriert aber mit einem Entropieverlust. Die Umwandlung wird in diesem Fall durch elektrostatische Wechselwirkungen zwischen Peptid und Lösungsmittel und innerhalb des Lösungsmittels bestimmt.

Background In the event of an acute coronary syndrome (ACS), the risk of death and complications such as stroke and re-infarction is high during the first month. Diabetes, impaired kidney function, elevated markers of systemic inflammation and high level of platelet reactivity have all been associated with worsened prognosis in ACS patients. Impaired kidney function is a condition with high cardiovascular morbidity and there is an established association between level of kidney function and outcome in the event of an ACS. Aims We sought to investigate the level of platelet reactivity during the first days of an ACS and specifically the level of platelet reactivity in patients with different conditions associated with worsened prognosis in the event of an ACS. We also wanted to investigate the prognostic impact of baseline levels of cystatin C as well as the importance of decreasing kidney function during the first days of an ACS. Methods We included 1028 unselected patients with ACS or suspected ACS during the years 2002 and 2003, of which 534 were diagnosed with an acute myocardial infarction (AMI). Blood samples for measuring platelet aggregation, cystatin C levels and other clinically important biomarkers were collected day 1, 2, 3 and 5 following admission. Platelet reactivity was measured using 2 different methods. Platelet aggregation was measured using Pa-200, a particle count method, based on scattering of laser light. PFA 100 is a method of measuring primary hemostasis in whole blood. Results Platelet aggregation and comorbidities. We found an increase in platelet aggregation when an ACS was complicated by an infection and there was an increased frequency of aspirin non-responsiveness in patients suffering from pneumonia during the first days of an ACS. Furthermore, we found an independent association between levels of C-reactive protein and platelet aggregation. During the first 3 days following an acute myocardial infarction, platelet aggregation increased despite treatment with anti-platelet agents. Platelet aggregation was found to be more pronounced in patients with diabetes. Patients with impaired kidney function, showed increased platelet aggregation compared to patients with normal renal function, however, this difference was explained by older age, higher prevalence of DM and levels of inflammatory biomarkers. We found no independent association between chronic kidney disease (CKD) and levels of platelet aggregation. Kidney function and outcome Serum levels of cystatin C on admission had an independent association with outcome following an acute myocardial infarction. With a mean follow-up time of 2.9 years, the adjusted HR for death was 1.62 (95% CI 1.28-2.03; p&lt;0.001) for each unit of increase in cystatin C on admission. The level of dynamic changes in cystatin C during admission for an acute myocardial infarction was independently associated with prognosis in patients with normal or mild impairment of renal function. The adjusted HR for death was 10.1 (95% CI 3.4-29.9; p&lt;0.001). Conclusion In patients suffering from an AMI platelet aggregation increases during the first days, despite anti-platelet treatment. Diabetes, age and biomarkers of inflammation are independently associated with platelet aggregation. Admission levels of cystatin C as well as changes in cystatin C levels during hospitalisation are independently associated with outcome.

There are many applications of small organic compounds, e.g. as drugs or as tools to study biological systems. Once a compound with interesting biological activity has been found, medicinal chemists typically synthesize small libraries of compounds with systematic differences to the initial “hit” compound. By screening the new ensemble of compounds for their ability to perturb the biological system, insights about the system can be gained. In the work presented here, various ways to synthesize small libraries of ring-fused 2‑pyridones have been developed. Members of this class of peptidomimetic compounds have previously been found to have a variety of biological activities, e.g. as antibacterial agents targeting virulence, and as inhibitors of the aggregation of Alzheimer b‑peptides. The focus in this work has been to alter the core skeleton, the central fragment, of the previously discovered biologically active 2‑pyridones and evaluate the biological effects of these changes. Several new classes of compounds have been constructed and their preparations have included the development of multi-component reactions and a method inspired by diversity-oriented synthesis. Some of the new compounds have been evaluated for their effect on the fibrillation of different amyloid proteins. Both the Parkinson-associated amyloid protein a-synuclein and the bacterial protein CsgA that is involved in bacterial biofilm formation are affected by subtle changes of the compounds’ central fragments. This is an example of the usefulness of central-fragment alterations as a strategy to probe structure-activity relationships, and the derived compounds may be used as tools in further study of the aggregation of amyloid proteins.

Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils. One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits. In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR. We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis. We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.

Amyloid is a form of abnormal protein aggregation within the living body. Massive deposits can lead to organ failure. There is also increasing evidence that smaller pre-amyloid aggregates exert direct toxic effects to cells. To date 25 different proteins are known to occur as amyloid deposition in human tissues, although not all of these conditions are known to be associated with clinical diseases. This thesis deals with the very common form of amyloid localized to the arterial media. The fibril protein called ‘medin’ was identified in 1999. Medin is a 50 amino acid residue internal fragment of the precursor protein lactadherin. Lactadherin, first found in human milk, is expressed in various tissues such as breast epithelium (including carcinomas), macrophages and aorta. The function of the protein is not known but it has several functional domains. There is an EFG like domain, including an RGD-sequence, in the N-terminal part of the molecule. The C-terminal part consists of C1 and C2 coagulation factor V and VIII like domains. Medin is from within the C2 domain. This region is suggested to be involved in phosphatidyl serine binding, important in phagocytosis of apoptotic cells. Medin amyloid was originally described from studies of the aorta. It is shown here that deposits are more widely spread and can be found in many large arteries, particularly within the upper part of the body. The prevalence of medin amyloid increases with age and deposits are found, to a certain degree, in virtually everyone above the age of 60 years. The amyloid is not only found extracellularly but intracellular deposits may also occur. Amyloid is usually associated with elastic lamina or lamellae which often show signs of fragmentation. Given the localization of amyloid to elastic structures of the arterial media, three different vascular diseases were studied: temporal (giant cell) arteritis, thoracic aortic aneurysm and thoracic aortic dissection. Medin amyloid was found in temporal arteries with and without inflammation. In inflamed arteries, amyloid was mainly located along the broken internal elastic lamina. Medin was also demonstrated within giant cells. It is suggested that medin may be an antigen triggering autoimmune giant cell arteritis. In the study of thoracic aortic aneurysms and dissections, we found significant less medin amyloid in diseased aortic tissues compared with a control material. On the other hand, immunoreactive medin, probably in the state of oligomeric aggregates, was regularly found in association with aneurysms and dissections but not in the control material. It is suggested that medin oligomers exert toxic effects on smooth muscle cells which may lead to weakening of the arterial wall with aneurysm or dissection as a consequence.

The familial aggregation of Major Depressive Disorder (MDD) has been repeatedly demonstrated. Several studies have investigated associations between various clinical characteristics of MDD in probands and overall rates of MDD in relatives. Few studies, however, have considered the familial aggregation of clinical characteristics of MDD. The aim of the present report is to examine mother–offspring associations of a variety of clinical characteristics of MDD in a general population sample. Data were derived from baseline and 4-year-follow-up data of 933 adolescents and their biological mothers of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study. MDD and its characteristics were assessed with the Munich-Composite International Diagnostic Interview. We found that children of mothers who had a lifetime history of severe MDD and high number of symptoms, high impairment and/or melancholia, revealed elevated odds of MDD regarding the same characteristics as their mothers (ORs between 5.2 and 13.9). The observed associations did not differ by the children’s sex. DSM-IV melancholia and severity as well as impairment were found to aggregate within families. This finding can be interpreted as a validation of the DSM-IV MDD severity subtypes as well as of the melancholic specifier. Severe and melancholic MDD reveal a considerable high degree of familiar aggregation making the search for mechanisms involved in the familiar transmission of these forms of MDD particularly promising.