Pubblici poteri e signorie di castello nella romagna nord-occidentale (secoli XI-XIII)

La presente ricerca di dottorato consiste in un’analisi di carattere politico ed istituzionale dei poteri signorili e territoriali, collegati a distretti castrensi, documentati nella Romagna nord-occidentale durante il pieno medioevo. L’indagine mira a ricostruire, principalmente attraverso fonti documentarie, alcune delle quali inedite, la geografia dei poteri in un’area sub-regionale, con particolare attenzione al fenomeno della signoria rurale, dei poteri comitali e dell’incastellamento. Partendo dallo studio di una realtà locale, la ricerca arriva a sviluppare argomentazioni di carattere generale, ricollegandosi al dibattito storiografico sui poteri signorili e l’incastellamento. La ricerca risulta incentrata sui soggetti politici, laici ed ecclesiastici, detentori dei castelli e dei poteri pubblici nella Bassa Romagna, in primo luogo gli arcivescovi di Ravenna, i vescovi e i conti di Imola, le famiglie comitali di Cunio, Bagnacavallo e Donigallia nei secoli XI-XIII. L'attenzione si concentra, in particolare, sulla fase del cosiddetto “secondo incastellamento” e sui decenni a cavaliere tra XII e XIII secolo, con il tentativo di espansione dei comuni nel contado e la formalizzazione dei poteri dei signori rurali da parte dei sovrani svevi. Proprio alla complessa interazione con il mondo cittadino e allo stretto rapporto dei Cunio e dei Malvicini con la corte di Federico II viene dato ampio spazio nei capitoli conclusivi del presente lavoro.

La creazione del distretto comunale: Il caso di Reggio Emilia (XII-prima metà XIII secolo)

L’oggetto della ricerca è stato il processo di creazione del distretto del Comune di Reggio Emilia tra il XII e l’inizio del XIII secolo, di cui sono stati analizzati diversi aspetti salienti, così come emergono in primo luogo dall’analisi del liber iurium reggiano, il Liber grossus antiquus. L’elaborato è suddiviso in due parti. Nella prima parte si è cercato di ricostruire le vicende, i legami e il patrimonio delle famiglie rurali reggiane nel corso del XII secolo in particolare e gli aspetti caratteristici del Comune cittadino nella sua fase iniziale. Nella seconda parte ci si è concentrati sull’analisi dei caratteri più rilevanti del processo di creazione del distretto comunale reggiano: il rapporto tra i signori del contado, i Comuni rurali e il Comune urbano; la difesa e l’incremento dei Communia cittadini; la fondazione di borghi franchi e nuovi. Il Comune di Reggio Emilia tentò di annettere l’intero territorio diocesano al distretto cittadino, non riuscendoci completamente e adottando una politica territoriale diversificata a seconda dei caratteri delle zone controllate.

Tipologia e diffusione delle produzioni ceramiche in Romagna tra XIII e XV secolo

In questo lavoro si è avuta la possibilità di studiare e confrontare i reperti ceramici provenienti da tre recenti scavi condotti nella zona della Romagna dall’Università di Bologna: il monastero di San Severo a Classe (RA), il castello di Rontana (Brisighella-RA) e la pieve di S. Reparata a Terra del Sole (FC). Si tratta di scavi ancora inediti differenti tra loro sia per connotazione distrettuale di appartenenza che per tipologia insediativa La cesura cronologica che si è preso in esame va dal XIII a XV secolo. Il XIII secolo corrisponde a un periodo in cui si assiste ad una riapertura dei trasporti a lunga distanza e si diffonde la tendenza al trasferimento dei saperi tecnici da Oriente verso Occidente, fenomeno che include l’introduzione di nuove tecnologie produttive in campo ceramico come l’ingobbio e la maiolica in diversi centri urbani. Si passa poi attraverso il XIV secolo, momento in cui alcune produzioni, come quella della maiolica, raggiungono la loro massima diffusione, con una diversificazione qualitativa dei prodotti, raggiungendo anche l’ambito rurale, e si assiste alla moltiplicazione dei centri di produzione. Si arriva così al XV secolo periodo in cui iniziano ad affermarsi dei veri e propri centri produttivi “industriali”, rappresentativi anche di una specializzazione regionale dei prodotti di qualità medio-alta. La possibilità di confrontare materiali di siti così differenti tra loro ha dato modo di sottolineare analogie e differenze anche tra città e campagna, in un territorio come quello romagnolo che ancora risente del peso della lunga tradizione antiquaria che ha caratterizzato gli studi fino al secolo scorso.

Coagulation factor XIII activation peptide and subunit levels in patients with acute ischaemic stroke: a pilot study

We have recently shown that FXIII activation peptide (AP-FXIII) can be measured in plasma. The objective of this pilot study was to investigate for the first time if AP-FXIII can be detected in plasma from patients with acute ischaemic stroke.

Mutations affecting disulphide bonds contribute to a fairly common prevalence of F13B gene defects: results of a genetic study in 14 families with factor XIII B deficiency

Severe factor XIII (FXIII) deficiency is a rare autosomal recessive coagulation disorder affecting one in two million individuals. The aim of the present study was to screen for and analyse F13B gene defects in the German population. A total of 150 patients presenting with suspected FXIII deficiency and one patient with severe (homozygous) FXIII deficiency were screened for mutations in F13A and F13B genes. Twenty-five individuals presented with detectable heterozygous mutations, 12 of them in the F13A gene and 13 of them in the F13B gene. We report on the genotype-phenotype correlations of the individuals showing defects in the F13B gene. Direct sequencing revealed 12 unique mutations including seven missense mutations (Cys5Arg, Ile81Asn, Leu116Phe, Val217Ile, Cys316Phe, Val401Glu, Pro428Ser), two splice site mutations (IVS2-1G>C, IVS3-1G>C), two insertions (c.1155_1158dupACTT, c.1959insT) and one in-frame deletion (c.471-473delATT). Two of the missense mutations (Cys5Arg, Cys316Phe) eliminated disulphide bonds (Cys5-Cys56, Cys316-Cys358). Another three missense mutations, (Leu116Phe, Val401Glu, Pro428Ser) were located proximal to other cysteine disulphide bonds, therefore indicating that the region in and around these disulphide bonds is prone to functionally relevant mutations in the FXIII-B subunit. The present study reports on a fairly common prevalence of F13B gene defects in the German population. The regions in and around the cysteine disulphide bonds in the FXIII-B protein may be regions prone to frequent mutations.

Identification of eight novel coagulation factor XIII subunit A mutations: implied consequences for structure and function

Severe hereditary coagulation factor XIII deficiency is a rare homozygous bleeding disorder affecting one person in every two million individuals. In contrast, heterozygous factor XIII deficiency is more common, but usually not associated with severe hemorrhage such as intracranial bleeding or hemarthrosis. In most cases, the disease is caused by F13A gene mutations. Causative mutations associated with the F13B gene are rarer.

Acquired factor XIII deficiency: a therapeutic challenge

Less than 60 cases of acquired factor (F)XIII deficiencies have been reported, most having distinct clinical features. To illustrate the therapeutic challenges of acquired FXIII inhibitors, we report a case of a 65-year-old patient with no previous bleeding history who suddenly developed massive haemorrhages associated to a strong and isolated FXIII inhibitor. No underlying disorder has been detected till now after three years of follow-up. Despite aggressive treatment with prednisone, rituximab, cyclophosphamide, immunoglobulin, immunoadsorption and immune tolerance his inhibitor is still present, although at low titre and with a clinical benefit since the patient has no more bleed since more than one year. Moreover the patient had a venous thromboembolic complication. After a review of the management of acquired FXIII deficiency patients and based on the management of acquired haemophilia we discuss a possible strategy for such difficult cases.

New developments in the area of factor XIII

To cite this article: Schroeder V, Kohler HP. New developments in the area of factor XIII. J Thromb Haemost 2013; 11: 234-44. Summary.  Coagulation factor (F)XIII is best known for its role in fibrin stabilization and cross-linking of antifibrinolytic proteins to the fibrin clot. From patients with congenital FXIII deficiency, it is known that FXIII also has important functions in wound healing and maintaining pregnancy. Over the last decade more and more research groups with different backgrounds have studied FXIII and have unveiled putative novel functions for FXIII. FXIII, with its unique role as a transglutaminase among the other serine protease coagulation factors, is now recognized as a multifunctional protein involved in regulatory mechanisms and construction and repair processes beyond hemostasis with possible implications in many areas of medicine. The aim of this review was to give an overview of exciting novel findings and to highlight the remarkable diversity of functions attributed to FXIII. Of course, more research into the underlying mechanisms and (patho-)physiological relevance of the many described functions of FXIII is needed. It will be exciting to observe future developments in this area and to see if and how these interesting findings may be translated into clinical practice in the future.

Characterisation of six novel A-subunit mutations leading to congenital factor XIII deficiency and molecular analysis of the first diagnosed patient with this rare bleeding disorder

In 1960, the first case report on factor XIII deficiency was published describing a seven-year-old Swiss boy with a so far unknown bleeding disorder. Today, more than 60 mutations in the factor XIIIA- and B-subunit genes are known leading to congenital factor XIII deficiency. In the present study, we describe six novel mutations in the factor XIII A-subunit gene. Additionally, we present the molecular characterisation of the first described patient with congenital factor XIII deficiency. The six novel mutations include a small deletion, Glu202 delG, leading to a premature stop codon and truncation of the protein, and a splice site mutation at the exon 10/intron 10 boundary, +1G/A, giving rise to an incorrect spliced mRNA lacking exons 10 and 11. The remaining four mutations are characterised by the single amino acid changes Met159Arg, Gly215Arg, Trp375Cys, and His716Arg, and were expressed in COS-1 cells. Antigen levels and activity of the mutants were significantly reduced compared to the wild-type. The patient described in 1960 also shows a single amino acid change, Arg77Cys. Structural analysis of all mutant enzymes suggests several mechanisms leading to destabilisation of the protein.

Factor XIII in severe sepsis and septic shock

OBJECTIVE: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. Thus, clot stability might be a critical issue in the development of multiple organ dysfunction syndrome. Activated FXIII (FXIIIa) forms stable fibrin clots by covalently cross-linking fibrin monomers. Therefore, we investigated the impact of FXIII antigen and activity levels on disease severity and fatality in sepsis patients. PATIENTS AND METHODS: FXIII subunit A (FXIIIA) and FXIII cross-linking activity (FXIIICA) were measured in 151 controls, in 32 patients with severe sepsis and 8 with septic shock. In addition, FXIII subunit B (FXIIIB) was measured in the sepsis patients. Moreover, clotting parameters were determined. RESULTS: Patients suffering from sepsis (n=40) had significantly (p<0.005) lower FXIIIA levels (median [range]: 36.5% [8.8-127.4%]) and FXIIICA levels (76.5% [9.4-266%]) as compared to healthy controls (n=151, 119% [31.3-283.2] and 122.4% [40.6-485.3], respectively). No difference in FXIIIA, FXIIIB and FXIIICA levels between survivors and non-survivors, nor between patients with severe sepsis and septic shock was found. The specific activity of FXIII (FXIIICA/FXIIIA, SA(FXIII)) was significantly (p<0.001) higher in sepsis patients (2.0 [0.8-5.3]) as compared to healthy controls (1.0 [0.4-5.1]). SA(FXIII) significantly (p<0.05) increased with fatality (non-survivors [n=13] vs. survivors [n=27]: 3.3 [1.2-5.0] vs. 1.9 [0.8-5.3]) and disease severity (septic shock vs. severe sepsis: 3.4 [1.8-4.3] vs. 1.9 [0.8-5.3]). CONCLUSION: We show decreased FXIIICA and FXIIIA levels, but higher SA(FXIII) in sepsis as compared to controls. Increased SA(FXIII) correlates with disease severity and fatality in sepsis patients.

Phenotype-genotype correlation in eight Polish patients with inherited Factor XIII deficiency: identification of three novel mutations

Inherited factor XIII (FXIII) deficiency is known as one of the most rare blood coagulation disorder in humans. In the present study, phenotype and genotype of eight FXIII deficient Polish patients from five unrelated families were compared. The patients presented with a severe phenotype demonstrated by a high incidence of intracerebral haemorrhages (seven of eight patients), haemarthrosis (six patients) and bleeding due to trauma (five patients). Introduction of regular substitution with FXIII concentrate prevented spontaneous bleeding in seven patients. In all patients, mutations within the F13A gene have been identified revealing four missense mutations (Arg77Cys, Arg260Cys, Ala378Pro, Gly420Ser), one nonsense mutation (Arg661X), one splice site mutation (IVS5-1 G>A) and one small deletion (c.499-512del). One homozygous large deletion involving exon 15 was detected by failure of PCR product. The corresponding mutations resulted in severely reduced FXIII activity and FXIII A-subunit antigen concentration, while FXIII B-subunit antigen remained normal or mildly decreased. Structural analysis demonstrated that the novel Ala378Pro mutation may cause a disruption of the FXIII catalytic triad leading to a non-functional protein which presumably undergoes premature degradation. In conclusion, the severe phenotype with high incidence of intracranial bleeding and haemarthrosis was in accordance with laboratory findings on FXIII and with severe molecular defects of the F13A gene.