Constitutional Disorder Research Articles

Stromal cell-derived factor 1 alpha (SDF-1alfa) and cartilage oligomeric matrix protein (COMP): Two potential signature biomarkers of radiological detectable hemophilic arthropathy.

Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed. The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score. Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy.

Stromal Cell-Derived Factor 1 Alpha (SDF-1α), Cartilage Oligomeric Matrix Protein (COMP) and Circulating microRNAs 208a-3p and 221-3p: Potential Signature Biomarkers of Hemophilic Arthropathy

Introduction. Hemophilia A is a rare constitutional bleeding disorder due to a deficiency in Factor VIII. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition difficult to diagnose with current strategies (ultrasound and magnetic resonance imaging [MRI]), with possible delayed diagnosis. MRI, the gold standard, is not of easy access nor cheap and requires sedation in young children. Ultrasound is liable to inter-operator variability and difficult to apply to such joints as ankles, especially in children for whom this is the most frequently involved location of hemophilic arthropathy. Circulating MicroRNAs are a group of endogenous, small, non-coding RNA molecules that regulate gene expression ; and knowledge on the potential roles of miRNAs in haemophilia is very limited. Aim. The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease. We also investigated microRNA expression in patients with haemophilia A with and without inhibitors, compared to healthy controls. Methods In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson radiologic score. For miRNAs analysis, all RNAs were extracted from plasma samples. We synthesised complementary DNA from the RNA samples, and used to quantitative PCR and microarray analysis to allow us to look at changes in expression levels. Results Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis. We also identified two microRNAs of interest, the microRNA 208a-3p was significantly downregulated in hemophilia patients with arthropathy but not in patients without arthropathy and the microRNA 221-3p had a clear tendency for statistically significant down regulation in hemophiliacs with arthropathy. Interestingly, miRNA 221-3p has been shown to be involved in rheumatoid arthritis. Dysregulation of this microRNA leads to a reduced anti-inflammatory response and drives macrophages into a pro-inflammatory state. Conclusion Two plasma proteins SDF-1 alfa and COMP and two circulating micro-RNAs have been identified as potential biomarkers that could help physicians to assess the presence and severity of hemophilic arthropathy.

Von Willebrand disease in a neonate: A case report

Von Willebrand disease (VWD) is a constitutional bleeding disorder of autosomal inheritance characterized by a quantitative or functional abnormality of the factor Willebrand. We report the observation of a neonate with a confirmed diagnosis of von Willebrand disease in the neonatal period. This disease is a very heterogeneous clinically, phenotypically and genetically, and poses a diagnostic difficulty. The biological diagnosis is based on first-line tests (prothrombin level and activated partial thromboplastin time) completed by the measurement of the coagulant activity of factors VIII, IX and XI, as well as the activity and antigen of Von Willebrand factor (VWF). The treatment strategy for VWD should be considered in collaboration with a hematologist aiming to correcting VWF and factor VIII levels. Therefore, a recombinant VWF concentrate has recently been introduced and has proven to be effective.

POSTER ABSTRACTS

POSTER ABSTRACTS

The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia.

Updating the classification of hematologic neoplasia with germline predisposition, pediatric myelodysplastic syndrome (MDS), and juvenile myelomonocytic leukemia (JMML) is critical for diagnosis, therapy, research, and clinical trials. Advances in next-generation sequencing technology have led to the identification of an expanding group of genes that predispose to the development of hematolymphoid neoplasia when mutated in germline configuration and inherited. This review encompasses recent advances in the classification of myeloid and lymphoblastic neoplasia with germline predisposition summarizing important genetic and phenotypic information, relevant laboratory testing, and pathologic bone marrow features. Genes are organized into three major categories including (1) those that are not associated with constitutional disorder and include CEBPA, DDX41, and TP53; (2) those associated with thrombocytopenia or platelet dysfunction including RUNX1, ANKRD26, and ETV6; and (3) those associated with constitutional disorders affecting multiple organ systems including GATA2, SAMD9, and SAMD9L, inherited genetic mutations associated with classic bone marrow failure syndromes and JMML, and Down syndrome. A provisional category of germline predisposition genes is created to recognize genes with growing evidence that may be formally included in future revised classifications as substantial supporting data emerges. We also detail advances in the classification of pediatric myelodysplastic syndrome (MDS), expanding the definition of refractory cytopenia of childhood (RCC) to include early manifestation of MDS in patients with germline predisposition. Finally, updates in the classification of juvenile myelomonocytic leukemia are presented which genetically define JMML as a myeloproliferative/myelodysplastic disease harboring canonical RAS pathway mutations. Diseases with features overlapping with JMML that do not carry RAS pathway mutations are classified as JMML-like. The review is based on the International Consensus Classification (ICC) of Myeloid and Lymphoid Neoplasms as reported by Arber et al. (Blood 140(11):1200-1228, 2022).

Hemophilia in the south of Tunisia.

Hemophilia is a rare constitutional hemorrhagic disorder. There is insufficient epidemiological data on hemophilia in Tunisia. To describe the epidemiological, clinical, therapeutic, and outcome of a cohort of patients with hemophilia in southern Tunisia. A retrospective study was conducted on patients with hemophilia at the Hemophilia Treatment Center of Southern Tunisia in Sfax over 38 years (from January 1982 to December 2020). Data were collected in a regional hemophilia registry of the South Tunisian center. We collected 141 cases of hemophilia, 85% of whom had hemophilia A and 15% had hemophilia B. The severe form represented 65%, followed by the moderate form at 25%. The prevalence of hemophilia was 4.4 in 100 000 population. Family history of hemophilia was found in 70%. The mean age of patients at diagnosis was 28 months. Hemophilia was detected in 87% of cases after hemorrhagic syndrome. Bleeding occurred mainly in hemarthrosis (73%), hematoma (70%), and visceral bleeding (28%). Intracranial bleeding occurred in 6% of cases. Thirty-six percent of patients were on prophylactic therapy. Hemophilic arthropathy was the most important orthopedic complication in our patients (38%). Inhibitory antibodies occurred in 16% of PWH. Transfusion-transmitted infections with HIV and hepatitis C were in 2 and 31% of cases, respectively. The prevalence of hemophilia is still underestimated in our center. The severe form of hemophilia is the most frequent. Hemophilic arthropathy was the most important complication in our patients. This showed that hemophilia is still a disabling disease in our country.

EP334: Optical genome mapping workflow for constitutional genomic structural and copy number variation and analysis

The ability to detect a breadth of variants and prioritize the most interesting is desirable for constitutional disorder workflows. In contrast to methods like karyotyping, chromosomal microarray (CMA), fluorescence in situ hybridization (FISH), or sequencing, optical genome mapping (OGM) is sufficiently versatile to resolve classes of structural variants from large-scale fusions to intragenic deletions/insertions. OGM also identifies copy number variants (CNV), absence of heterozygosity (AOH), aneuploidy, and triploidy in an easy-to-master technical and analytical workflow.

Political constitutionalism in the age of populism

This article examines the relationship between populism and political constitutionalism. It claims that while political constitutionalism is at odds with, and better than, the wide range of experiences labelled under the term ‘populism’, political constitutionalists would do well to distance themselves from the claim that the constitution is political “all the way down”. First, the article argues that the normative ambiguity of the term ‘populism’ makes it ill-fated for the purposes of constitutional theory and a call for clearer language for constitutional discussion is defended. Second, it argues that political constitutionalism should abandon, or significantly adjust, its commitment to what the article calls constitutional lawlessness and is defined as the idea that the constitution is and ought to be entirely malleable. The reasons offered for this proposal differ from those advanced by legal constitutionalism and instead hang on the democratic authority that political constitutionalists vindicate for majoritarian institutions. Political constitutionalism, the article concludes, should grant some of the normative advantages of the law to the outcomes of constitutional decision-making processes. The move makes political constitutionalism more consistent in its own right and, importantly, safer from the charge that it feeds different sorts of constitutional disorder.

Dysmenorrhea as a constitutional disorder

Completely denying mechanical dysmenorrhea and recognizing the previous ideas about the so-called. nervous dysmeporrhea imprecise and unsatisfactory, Hirsch (Zentr. f. Gyn., 1923, no. 39) considers dysmenorrhea of one and the other kind of constitutional disorder.

Class and classification: the London Word Blind Centre for Dyslexic children, 1962–1972

ABSTRACT The Word Blind Centre for Dyslexic Children opened in London in 1963. It was not only the first clinic established in Britain specifically to cater for children diagnosed with dyslexia. It was also intended to provide compelling evidence that a condition called dyslexia actually existed. The results of this work were published in Sandhaya Naidoo’s path-breaking study, Specific Dyslexia, which did exactly what its promoters had hoped it would, drawing on in-depth studies of 196 children to argue that dyslexia was indeed a distinct ‘constitutional disorder’. Using the archives produced by Naidoo and other sources, my article offers the first-ever account of this pioneering enterprise, exploring the reasons the Centre was set up, the way it worked, and the consequences of its work. In particular, it focuses on the rationale for Naidoo’s report, which only dealt with the experiences of middle-class boys. This choice is highly revealing, illuminating attitudes to reading, to class and gender, and to the competition for authority amongst the professionals who sought to explore all these issues. An intriguing case study in its own right, this also sets the scene for many of the themes that follow in this Special Issue.

Applications of Genome Editing Technology in Research on Chromosome Aneuploidy Disorders.

Chromosomal segregation errors in germ cells and early embryonic development underlie aneuploidies, which are numerical chromosomal abnormalities causing fetal absorption, developmental anomalies, and carcinogenesis. It has been considered that human aneuploidy disorders cannot be resolved by radical treatment. However, recent studies have demonstrated that aneuploidies can be rescued to a normal diploid state using genetic engineering in cultured cells. Here, we summarize a series of studies mainly applying genome editing to eliminate an extra copy of human chromosome 21, the cause of the most common constitutional aneuploidy disorder Down syndrome. We also present findings on induced pluripotent stem cell reprogramming, which has been shown to be one of the most promising technologies for converting aneuploidies into normal diploidy without the risk of genetic alterations such as genome editing-mediated off-target effects.

Intracutaneous Delivery of Gelatins Reduces Fat Accumulation in Subcutaneous Adipose Tissue

Subcutaneous adipose tissue (SAT) accumulation is a constitutional disorder resulting from metabolic syndrome. Although surgical and non-surgical methods for reducing SAT exist, patients remain non-compliant because of potential adverse effects and cost. In this study, we developed a new minimally-invasive approach to achieve SAT reduction, using a microneedle (MN) patch prepared from gelatin, which is capable of regulating fat metabolism. Four gelatin types were used: three derived from fish (SA-FG, GT-FG 220, and GT-FG 250), and one from swine (SM-PG 280). We applied gelatin-based MN patches five times over 4 weeks to rats with high-fat diet (HD)-induced obesity, and determined the resulting amount of SAT. We also investigated the histological features and determined the expression levels of fat metabolism-associated genes in SAT using hematoxylin and eosin staining and western blotting, respectively. SAT decreased following treatment with all four gelatin MN patches. Smaller adipocytes were observed in the regions treated with SA-FG, GT-FG 250, and SM-PG 280 MNs, demonstrating a decline in fat accumulation. The expression levels of fat metabolism-associated genes in the MN-treated SAT revealed that GT-FG 220 regulates fatty acid synthase (FASN) protein levels. These findings suggest that gelatin MN patches aid in decreasing the quantity of unwanted SAT by altering lipid metabolism and fat deposition.

Rosenthal's Disease (Hemophilia C or factor XI Deficiency) Revealed by Chronic Epistaxis: The First Observation in Sub-Saharan Africa.

Objective Rosenthal's disease (RD) is a rare constitutional hemorrhagic disorder defined by factor XI deficiency. It is clinically characterized by the presence of minimal haemorrhage. We report the first observation of RD in Togo. Observation Mrs. G. A., 45 years old with no particular pathological antecedents, was referred for anemia in a context of chronic epistaxis. It was a spontaneous anterior exteriorization epistaxis often of great abundance, rocking and which evolved episodically. The patient received several transfusions for anemia. The ear-nose-throat examination was normal and a sinus CT scan found only an inflammatory process of the right maxillary sinus. The blood count showed microcytic severe anemia (2,2g/dl). Hemostasis tests showed a prolonged aPTT (57,9 seconds). Clinical examination documented an anemic syndrome with dry skin. Iron deficiency was found. The hemostasis balance confirmed aPTT elongation. Coagulation factors activity showed normal VIII and IX level, but moderate decrease of factor XI (32%). The family survey was not possible (orphan patient). It is recommended the setting under fresh frozen plasma (FFP) in case of a new episode. Follow-up is in progress. Conclusion In the event of any hemorrhagic syndrome, the isolated elongation of the aPTT must lead to a systematic analysis of intrinsic pathway factors

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.

Periodontal disease as a potential factor of migraine chronification

Migraine is a hereditary constitutional base disorder, which is characterized by recurrent episodes of headache pulsatile characteristics associated with photophobia/phonophobia, nausea and/or vomiting. The main complication in migraine is the chronicity of the process, now recognized as a chronic migraine. Although pathogenic mechanisms that may influence the pathophysiology of migraine and its possible chronicity are not fully understood, previous studies have shown in patients with migraine molecular alterations of systemic inflammation, neurogenic inflammation, endothelial dysfunction, innate immunity, dysfunction of matrix proteases and blood-brain barrier. Periodontal disease is an inflammatory lesion caused by bacteria. After the bacterial infection begins, an immune response that will be responsible for individual susceptibility appears. More advanced forms of periodontitis have demonstrated molecular alterations of inflammation, endothelial dysfunction, dysfunction of matrix proteases and innate immunity, similar to those observed in migraine. Furthermore, the main molecular mediators of neurogenic inflammation related to activation of the trigeminovascular system, which are characteristic of migraine, are overexpressed in gingival crevicular fluid and mucosa in patients with periodontal disease. Hypertension, hypercholesterolemia, insulin resistance, stroke or coronary artery disease are comorbidities that periodontal disease and migraine could share. Therefore, several mechanisms and hypotheses could explain the possible association between both diseases. However, epidemiological and molecular studies will be necessary to provide a better understanding of this potential association, which could be implicated in the chronification of migraine.

四君子湯이 免疫機能에 미치는 影響

Objectives : The extract of Sagunja-tang has been traditionally used for restorative treatment of constitutional weakness, vascular and immune disorder, and nervous disease in Oriental country. This study investigated the regulatory effects of Sagunja-tang on the expression, production, and activity of immune mediators.Methods : In this study, the extract of Sagunja-tang was prepared by extracting with distilled water at 100<TEX>$^{\circ}C$</TEX> for 2.5h. The extract was freeze-dried following filtration through 0.45<TEX>${{\mu}m}$</TEX> filter. The extract was dissolved in Hank's balanced salt solution (HBSS) and filtered again through 0.45<TEX>${{\mu}m}$</TEX> filter before use. The level of nitrite, an oxidative product of nitric oxide(NO) was measured in the culture medium by the Griess reaction. The levels of prostaglandin E₂(PGE₂), Th1 cytokines (IFN-<TEX>${\gamma}$</TEX>, IL-2) and Th2 cytokines(IL-4, IL-5, IL-13) were measured by enzyme-linked immunosorbent assay and the protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression were determined by Western blot analysis. Also examined the effects of the extract on T-cell proliferation and cytotoxic activity of natural killer cells.Results : In this investigation, Production levels of Th2 cytokines (IL-4, IL-5, IL-13) was inhibited in a dose dependent manner by treatment with the extract. I also found that the extract increased T-cell proliferation and cytotoxic activity of natural killer cells in a dose-dependent manner.Conculsions : These results suggest that the water extract of Sagunja-tang may be useful for a therapeutic drug against a sickly constitution and immune diseases, probably by regulating the production of immune mediators.

Maternal serum copeptin concentrations in early- and late-onset pre-eclampsia

ObjectiveEarly-onset pre-eclampsia is primarily associated with placental dysfunction, whereas late-onset pre-eclampsia is defined as a maternal constitutional disorder. As a protein cosynthesized with vasopressin, copeptin is a potential marker of metabolic syndrome and insulin resistance, which shares similar risk factors with pre-eclampsia. The aim of this study was to investigate the copeptin levels in patients with early-onset and late-onset pre-eclampsia. Materials and methodsA total of 80 pregnant women receiving antenatal and obstetric care were recruited. The patients were subdivided into four groups: Early-onset pre-eclampsia (n = 20), late-onset pre-eclampsia (n = 20), and two control groups of similar gestational ages for both pre-eclamptic groups (n = 20 in each group). The maternal serum copeptin levels were measured using an enzyme-linked immunosorbent assay. ResultsThe mean copeptin levels were 0.92 ± 0.57 ng/mL and 1.65 ± 0.95 ng/mL in the early-onset and late-onset pre-eclampsia groups, respectively. These values were higher compared with the control groups (0.54 ± 0.25 ng/mL and 1.15 ± 0.94 ng/mL, respectively). However, the difference was only statistically significant in the early-onset pre-eclampsia group (p = 0.011). Copeptin levels were associated only with gestational age and systolic–diastolic blood pressure. ConclusionOur results suggest that copeptin levels might be useful in the evaluation of the severity of pre-eclampsia. However, copeptin might be involved in early- rather than late-onset pre-eclampsia.

Acquired Von Willebrand Syndrome Associated with B Cell Chronic Lymphoproliferative Disorders. Results from a Prospective Observational Study

▪Introduction. Whereas von Willebrand disease is the most common constitutional bleeding disorder, acquired von Willebrand syndrome (AVWS) is rare with an estimated prevalence between 0.04 to 0.5%(1). AVWS has been related in various pathophysiological conditions including cardiovascular diseases such as aortic stenosis, autoimmune and lymphoproliferative disorders. To our knowledge, the prevalence of AVWS in lymphoproliferative disorders has never been investigated.Methods. We conducted an observational monocentric prospective study in Caen university hospital to evaluate the incidence of AVWS in B cell chronic lymphoproliferative disorders (B-CLPD) and characterize its phenotype. Inclusion criteria were the presence of a BCLPD in patients with no personal or family history of bleeding. Every enrolled patients was tested for Biological parameters were measured including closure time, von Willebrand Antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo) and factor VIII procoagulant activity (FVIII:C). The bleeding phenotype was evaluated using Tossetto bleeding score(2). AVWS was suspected when patients presented a decrease of VWF:Ag and VWF:RCo and/or a VWF:RCo/VWF:Ag below 0.7.Results. A total of 147 patients were included with the following diagnosis: fifty five patients (37%) with chronic lymphocytic leukemia, 48 patients (33%) with monoclonal gammopathies of undetermined significance (MGUS), 22 patients (15 %) with non hodgkin B cell lymphoma, 9 patients (6 %) with multiple myeloma, 4 patients (3 %) with Waldenstrom macroglobulinemia and 9 patients with other B-CLPD. Closure times, with epinephrine and ADP, were prolonged for six patients (6/147, 4.1%) with median levels of VWF:Ag, VWF:RCo, FVIII:C and VWF:RCo/VWF:Ag ratio at 29.5 IU/dL [9-284], 11.4 IU/dL [1-140] , 42.5 [6-204] and 0.3 [0.04-0.84], respectively. Five of these 6 patients had MGUS and 1 patient presented a follicular lymphoma. Serum protein electrophoresis revealed a monoclonal component in 5 patients with a median concentration at 8.45 g/L [4.4-9.1]. Four out of these 6 patients presented mucocutaneous bleedings including menorragia, ecchymoses, epistaxis, gingival bleedings, post-operative bleedings and gastro intestinal bleedings. The median bleeding score of these six patients was 4.5 [-1 – 12]. In four patients, the biological phenotype was a type 2 von Willebrand disease, with decreased VWF:RCo/VWF:Ag ratio (<0.7), loss of high and intermediate molecular weight multimers and a decrease of von Willebrand binding to collagen (VWF:CB) (VWF:CB/VWF:Ag<0.6). Anti-von Willebrand factor inhibitor screening was negative for the six patients. Four of these 6 patients presented an accelerated clearance of VWF with increased von willebrand factor propeptide/VWF:Ag ratios.Table 1Different proposed cutoffs with their prospective sensitivity, specificity, and likelihood ratios (LR).Cutoff >Sensitivity %95% CISpecificity %95% CILR +LR -503.50100.0066.37% to 100.0%0.300.007557% to 1.652%1.000.002514.0088.8951.75% to 99.72%75.2270.24% to 79.76%3.590.155020.0077.7839.99% to 97.19%85.6781.46% to 89.24%5.430.26Conclusion: In this original prospective study, we observed AVWS for 4.1% of patients with B-CLPD. Monoclonal gammopathies of undetermined significance (MGUS) were associated with AVWS in 5 of 6 patients with AVWS. For patients with type 2 phenotypes, an increased clearance of VWF was the main mechanism of AVWS. The annual follow-up of these patients will give informations regarding the time of appearance and clinical informations for AVWS.Tiede A et al. Blood 2011.Tosetto A et al. Blood Rev 2007. DisclosuresNo relevant conflicts of interest to declare.

HLXB9 gene expression, and nuclear location during in vitro neuronal differentiation in the SK-N-BE neuroblastoma cell line.

Different parts of the genome occupy specific compartments of the cell nucleus based on the gene content and the transcriptional activity. An example of this is the altered nuclear positioning of the HLXB9 gene in leukaemia cells observed in association with its over-expression. This phenomenon was attributed to the presence of a chromosomal translocation with breakpoint proximal to the HLXB9 gene. Before becoming an interesting gene in cancer biology, HLXB9 was studied as a developmental gene. This homeobox gene is also known as MNX1 (motor neuron and pancreas homeobox 1) and it is relevant for both motor neuronal and pancreatic beta cells development. A spectrum of mutations in this gene are causative of sacral agenesis and more broadly, of what is known as the Currarino Syndrome, a constitutional autosomal dominant disorder. Experimental work on animal models has shown that HLXB9 has an essential role in motor neuronal differentiation. Here we present data to show that, upon treatment with retinoic acid, the HLXB9 gene becomes over-expressed during the early stages of neuronal differentiation and that this corresponds to a reposition of the gene in the nucleus. More precisely, we used the SK-N-BE human neuroblastoma cell line as an in vitro model and we demonstrated a transient transcription of HLXB9 at the 4th and 5th days of differentiation that corresponded to the presence, predominantly in the cell nuclei, of the encoded protein HB9. The nuclear positioning of the HLXB9 gene was monitored at different stages: a peripheral location was noted in the proliferating cells whereas a more internal position was noted during differentiation, that is while HLXB9 was transcriptionally active. Our findings suggest that HLXB9 can be considered a marker of early neuronal differentiation, possibly involving chromatin remodeling pathways.

The Euro Crisis and the Constitutional Disorder of the European Union

The Lisbon Treaty is the outcome of several constitutional compromises. The compromise between the supranational and the intergovernmental views of the European Union (EU), the compromise between the member states engaged in building a European Monetary Union (EMU) and those allowed to opt-out from it and the compromise, within the EMU, between a centralized approach to monetary policy and decentralized economic, fiscal and budgetary policies, constrained however within the formalized rules of the Stability and Growth Pact (SGP). The euro crisis has called into question this multiple constitutional setting. The balance between supranational and intergovernmental views has been upset in favour of the former. The approval of new intergovernmental treaties has made crystal clear the separation of interests between the EMU and the opt-out member states (the United Kingdom in specific). The inefficacy of the voluntary coordination between national governments in dealing with the euro crisis has brought to an unprecedented centralization and judicialization in the governance of the common currency. In the constitutional disorder induced by the euro crisis the EU has assumed specific institutional, legal and ideological configurations.