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Introduction Unfractionated heparin (UFH) therapy is monitored by using the anti-activated factor X (anti-Xa) activity, or the activated partial thromboplastin time (APTT), which remains the most widely used assay. One of the main advantages of anti-Xa relies on its hypothesized standardization, with a unique therapeutic range (0.30-0.70 IU/ml) for all reagents, whereas APTT is influenced by numerous preanalytical and analytical parameters not related to the anticoagulant activity of UFH. Methods The aim of this study was to compare the anti-Xa-correlated APTT therapeutic ranges calculated using different combinations of APTT (n = 4) and anti-Xa reagents (n = 4) in frozen citrated plasmas from 87 inpatients on UFH. Results The median APTT ratio ranged from 2.19 for the less sensitive to 3.23 for the most sensitive reagent, whereas the median anti-Xa activity was between 0.37 IU/ml and 0.57 IU/ml. The APTT therapeutic ranges calculated to correlate with anti-Xa activities between 0.30 and 0.70 IU/ml were found to be highly different from one combination of APTT reagent and analyzer to another. The same applied to the therapeutic range of a single APTT reagent calculated using different anti-Xa assays performed on the same analyzer, leading to a lack of agreement as to whether a sample was classified as subtherapeutic, therapeutic or supratherapeutic in 8.0% to 23.0% of the patients, with kappa coefficients between 0.908 and 0.753. Conclusions These results suggest that the APTT therapeutic range calculated to correlate with anti-Xa activities between 0.30 and 0.70 IU/ml is influenced not only by the APTT reagent, but also by the anti-Xa reagent used for calculation.

Autoinflammatory diseases related to RIPK1 mutations have been recently described. Two distinct clinical phenotypes have been reported and depend on the type and location of the mutation. When the mutation is recessive with loss of function, patients develop a combined phenotype of immune deficiency with recurrent bacterial and fungal infections and signs of early inflammatory bowel disease, non-erosive polyarthritis and growth retardation. On the other hand, when the mutation is dominant, gain of function, the manifestations are only auto-inflammatory with extensive lymphoproliferation, oral lesions such as aphthosis or ulcers, abdominal pain and hepatosplenomegaly. The mutations described for the dominant form affect only the cleavage site of caspase 8 and the clinical phenotype is called CRIA for Cleavage-Resistant RIPK1-Induced Autoinflammatory syndrome. The recessive form is severe and life-threatening requiring hematopoietic stem cell transplantation while the dominant form responds well to interleukin-6 receptor antagonists. Thus, RIPK1 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because of their recent description, these diseases can be suspected by an internist, in front of recurrent digestive features and will be increasingly diagnosed in the future through the integration of this gene in the diagnostic chips dedicated to autoinflammatory diseases and early inflammatory bowel diseases, using next generation sequencing.

Background D-dimer levels below a well-defined cut-off level enable to safely rule out VTE in patients with a low or intermediate pre-test probability (PTP), as the test negative predictive value (NPV) was high. As ageing is associated with increased D-dimer levels, the question was raised of the usefulness of their measurement to rule out VTE in elderly patients. Various attempts were made in the recent years to address that issue, particularly the use of age-adjusted cut-off values calculated by multiplying the patient's age by 10, in patients aged over 50. Aim of that study The aim of the study was to validate such a strategy, and to evaluate its economic impact in unselected outpatients referred to the emergency departments of 5 French centres (2 university hospitals, and 3 general hospitals). Patients, Materials and Methods After exclusion of those on anticoagulant treatment at the time of the diagnosis (n=23), a total of 1255 consecutive patients with a non-high PTP of VTE were included in the study. The same standardized procedure was used in the 5 centres, i.e. D-dimer measurement in patients with a non-high PTP, and imaging techniques (usually computed pulmonary angiography in case of suspected PE and Doppler ultrasonography in case of suspected DVT) only when D-dimer was above the cut-off level. D-dimer was evaluated using the same latex-based fully automated assay (HemosIL D-dimer HS500 assay, Instrumentation Laboratory). Test results were expressed in ng/mL fibrinogen equivalent units (FEU), and the traditional cut-off level for VTE exclusion was 500 ng/mL. Results VTE was diagnosed in 105 patients of the 1255 included patients (8.4%): 88 patients were diagnosed out of the 1082 patients referred for suspected PE and 27 out the 173 referred for suspected DVT. D-dimer levels were above 500 ng/mL in all patients with VTE and in 521 of the 1150 patients without VTE (45.3%). The test NPV was 100% as well as its sensitivity. If the overall test specificity was 54.7%, it significantly decreased in an age-dependent manner over 70 years, related to a high percentage of increased D-dimer levels in elderly patients, particularly in those above 80 years. Using age-adjusted cut-off levels, calculated by multiplying the patient's age by 10, induced a significantly improvement in test specificity, particularly in very old patients with an overall NPV=60.2% vs. 54.7% using the fixed cut-off value. The overall NPV remained high (99.9%), even if a 78 y-old female with a low PTP of PE would have been misdiagnosed as her D-dimer level (540 ng/mL) was above 500 ng/mL but below the age-adjusted cut-off value. Such an improvement in test performance was found both in patients with suspected PE and DVT (Table). As this increase in test specificity would have led to exclude VTE in a higher percentage of patients in the studied population, we evaluated the cost-effectiveness of that strategy, taking into account the local cost of D-dimer testing, angiography and Doppler US (16.20, 58.72, and 75.60 Euros respectively). In the case of suspected PE, the economic impact of the proposed diagnosis strategy was a decreased of 6.9% of total costs (45,023.4 vs. 48,356.4 Euros). In the case of DVT, the overall saving was 5.1% (9,909 vs. 10,438.2 Euros). If such an analysis was used in the US, where angiography and Doppler US were more expensive (648 and 226 US$ respectively), and D-dimer less costly (14 US$), the cost savings would have been even higher (-11.0% for PE, and -6.3% for DVT). Conclusions The use age-adjusted cut-off levels for D-dimer, in patients aged over 50 years old, leaded to a significant increase in the test specificity, but correlatively to slightly decreased NPV and sensitivity, as some patients with D-dimer levels above 500 ng/mL but below the age-adjusted cut-off value could be misdiagnosed. However such a strategy was found to be safe in our studied populations, as the NPV remained high (99.9%), and cost-effective. Table Table. Disclosures No relevant conflicts of interest to declare.

Objective Our prospective study aims to define the correlation of EGFR(epidermal growth factor receptor) mutations with major histological subtypes of lung adenocarcinoma from resected and non-resected specimens, according to the WHO 2015 classification, in Moroccan North East Population. Methods Epidermal growth factor receptor mutations of 150 primary lung adenocarcinoma were performed using Real-Time PCR or SANGER sequencing. SPSS 21 was used to assess the relationship between histological subtypes of lung adenocarcinoma and EGFR mutation status. Results 25 mutations were detected in the series of 150 lung adenocarcinomas, most of which were found in cases with papillary, acinar, patterns than without these patterns and more frequently occurred in the cases without solid pattern than with this pattern. A significant correlation was observed between EGFR mutation and acinar (P = 0,024), papillary pattern (P = 0,003) and, negative association with a solid pattern (P < 0,001). In females, EGFR mutations were significantly correlated with the acinar pattern (P = 0,02), whereas in males with the papillary pattern (P = 0,01). Association between the histologic component and exon 19 deletions and exon 21 mutations were also evaluated and, we found a significant correlation between the papillary major pattern with exon 19 mutations (P = 0,004) and, ex21 with the acinar component (P = 0,03). Conclusion An analysis of resected and non-resected lung ADC specimens in 150 Moroccan Northeast patients, revealed that acinar and papillary patterns may predict the presence of a mutation in the EGFR gene. While the solid major pattern may indicate a low mutation rate of the EGFR gene.

Introduction One of the main advantages of using anti-Xa instead of activated partial thromboplastin time in monitoring of unfractionated heparin (UFH) therapy relies on its hypothesized standardization, with a unique therapeutic range defined to be 0.30 to 0.70 IU/mL. The aim of the present study was to compare the inter-reagent agreement of anti-Xa activity. Methods Citrate tubes were obtained from 104 inpatients on UFH. Plasma samples were stored frozen in aliquots at -70°C before being shipped to three accredited coagulation laboratories to be evaluated for anti-Xa activity using their routine assay(s). Pooled normal plasmas spiked with dilutions of the 6th International Standard of UFH to achieve anti-Xa activities up to 1.0 IU/mL were evaluated using the same techniques. Results In the plasmas from patients on UFH, the median anti-Xa activity ranged from 0.37 IU/mL with one reagent to 0.57 IU/mL with another; results were in between (0.45 IU/mL) using two other reagents. Comparisons of results obtained using the different reagents demonstrated unacceptable bias up to 0.24 IU/mL between some reagents (41% difference). The concordance as whether anti-Xa activities measured using different reagents were within or outside the therapeutic range was between 0.411 and 0.939 (kappa). Similar discrepancy was demonstrated for anti-Xa activities when evaluating normal plasma spiked with the International Standard. A discrepancy of the same order of magnitude was demonstrated in the 2017 External Quality Assessment Program provided by the External Quality Control in Assays and Tests exercises. Conclusions The reported discrepancy between test results obtained using different anti-Xa assays clearly suggests a lack of standardization of that assay with potentially significant impact on the patients' anticoagulation.

Replacement therapy with plasma-derived or recombinant FVIII and FIX (pdFVIII/pdFIX or rFVIII/rFIX) concentrates is the standard of treatment in patients with haemophilia A and B, respectively. Measurement of factor VIII (FVIII:C) or factor IX (FIX:C) levels can be done by one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). The French study group on the Biology of Hemorrhagic Diseases (a collaborative group of the GFHT and MHEMO network) presents a literature review and proposals for the monitoring of FVIII:C and FIX:C levels in treated haemophilia A and B patients, respectively. The use of CSA is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. Except for rFVIII-Fc, great caution is required when measuring FVIII:C levels by OSA in patients substituted by EHL-rFVIII. The OSA is recommended for the monitoring of patients treated with pdFIX or rFIX. Large discordances in the FIX:C levels measured for extended half-life rFIX (EHL-rFIX), depending on the method and reagents used, must lead to great attention when OSA is used for measuring FIX:C levels in patients substituted by EHL-rFIX. Data of most of recent studies, obtained with spiked plasmas, deserve to be confirmed in plasma samples of treated patients.

Pulmonary aspergilloma is a form of aspergillosis characterized by the colonization of a preexisting pulmonary cavity, most often of tuberculosis origin. Clinical symptoms are predominately hemoptysis that can be life-threatening, and thoracic computed tomography can distinguish simple from complex pulmonary aspergilloma. The best therapeutic option remains surgery which allows surgical resection of the mycetoma and the underlying cavity. Nonsurgical treatment is performed in inoperable patients because of severe respiratory failure or a poor general condition.

Hydatidosis disease is commonly localized in the lungs and liver and the radical treatment remains surgery. Cardiac hydatid cyst is a rare and particular location disease that can be associated with serious complications. The most common site in the heart according to the is the left ventricle. We describe a case of cardiac hydatid cyst localized between the right atrium and right ventricle on the tricuspid valve in a 15-year-old patient.

Introduction Pneumonectomy is a surgical procedure associated with high rates of morbidity and mortality. Chronic inflammatory pathologies increase these rates, depending on the degree of pleural symphysis and the underlying pulmonary pathology. The occurrence of a bronchopleural fistula after pneumonectomy remains of great concern to the thoracic surgeon, because it leads to empyema in the pneumonectomy cavity, which requires protracted and difficult management. Methods A retrospective single-center study was carried out on 38 patients who underwent pneumonectomy for non-tumoral pathologies between 2010 and 2017. Of the 38 patients, 22 (57.8%) men and 16 (42.2%) women, the average age was 40.3 years, and 30 (79%) patients were treated for tuberculosis. Results The symptoms were predominantly hemoptysis with bronchorrhea in 22 (57.9%) cases. Chest computed tomography showed right-sided involvement in 15 (39.5%) patients, with destroyed lung in 31 (81.5%). Early postoperative complications included bleeding in 11 (28.9%) patients, postpneumonectomy empyema in 4 (10.5%), and death in 2 (5.2%). The average duration of follow-up was 2 years, without any recurrence. Conclusion The endemicity of tuberculosis in our context, and the absence of screening for lung cancer, explain the frequency of pneumonectomy for chronic inflammatory diseases, and the rate of complications after this surgical procedure.

Hypohidrotic or anhidrotic ectodermal dysplasia (HED/EDA) is characterized by impaired development of the hair, teeth, or sweat glands. HED/EDA is inherited in an X-linked, autosomal dominant, or autosomal recessive pattern and caused by the pathogenic variants in 4 genes: EDA, EDAR, EDARADD, and WNT10A. The aim of the present study was to perform molecular screening of these 4 genes in a cohort of Turkish individuals diagnosed with HED/EDA. We screened for pathogenic variants of WNT10A, EDA, EDAR, and EDARADD through Sanger sequencing. We further assessed the clinical profiles of the affected individuals in order to establish phenotype-genotype correlation. In 17 (63%) out of 27 families, 17 pathogenic variants, 8 being novel, were detected in the 4 well-known ectodermal dysplasia genes. EDAR and EDA variants were identified in 6 families each, WNT10A variants in 4, and an EDARADD variant in 1, accounting for 35.3, 35.3, 23.5, and 5.9% of mutation-positive families, respectively. The low mutation detection rate of the cohort and the number of the EDAR pathogenic variants being as high as the EDA ones were the most noteworthy findings which could be attributed to the high consanguinity rate., Scientific and Technological Research Council of Turkey (TÜBİTAK); Programme Hospitalier de Recherches Cliniques (PHRC); CRANIRARE of the European Research Area Network projects (E-RARE); CRANIRARE-2 of the European Research Area Network projects (E-RARE); European Union (European Union); Horizon 2020

Background Vitamin C (ascorbic acid, AscH2) has been shown to enhance immunity. Here, we studied its immunomodulatory effect on human endothelial cells (ECs) during S. aureus infection. Materials and methods The ex vivo effects of AscH2 were performed on primary human umbilical vein endothelial cells (HUVECs) infected or not with S. aureus. Results AscH2 treatment induced a marked downregulation of nitric oxide (NO) production and a moderate upregulation of arginase activity in S. aureus-infected HUVECs (respectively, p 0.05). Although the upregulated release levels of soluble intercellular adhesion molecular 1 (sICAM-1/sCD54) and sE-selectin (sCD62E) molecules were not significantly different between treated and untreated S. aureus-infected HUVECs, AscH2 treatment induced reversing effect on sICAM-1 release when comparing to uninfected control HUVECs. Moreover, AscH2 treatment appears to have a significant effect on preventing HUVEC necrosis induced by S. aureus infection (p 0.05). Additionally, S. aureus infection markedly downregulated total bound calcium ions (bCa2+) levels as compared to control HUVECs, whereas, AscH2 treatment induced a slight upregulation of bCa2+ levels in infected HUVECs as compared to infected and untreated HUVECs (p > 0.05). On the other hand, AscH2 treatment downregulated increased total cellular cholesterol content (tccCHOL) levels in HUVECs induced by S. aureus infection (p 0.05, and p Conclusions Our outcomes demonstrated that, during S. aureus infection, AscH2 treatment promotes human ECs survival and function, as well as prevents inflammatory response exacerbation, while inducing bactericidal activity.

International audience

Actin-Related Protein-Testis1 (ARP-T1)/ACTRT1 gene mutations cause the Bazex-Dupré-Christol Syndrome (BDCS) characterized by follicular atrophoderma, hypotrichosis, and basal cell cancer. Here, we report an ARP-T1 interactome (PXD016557) that includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. In agreement, ARP-T1 localizes to the midbody during cytokinesis and the basal body of primary cilia in interphase. Tissue samples from ARP-T1-associated BDCS patients have reduced ciliary length. The severity of the shortened cilia significantly correlates with the ARP-T1 levels, which was further validated by ACTRT1 knockdown in culture cells. Thus, we propose that ARP-T1 participates in the regulation of cilia length and that ARP-T1-associated BDCS is a case of skin cancer with ciliopathy characteristics., Park et al. characterise the interactome, localisation and function of Actin-Related Protein-Testis1 protein (ARP-T1), encoded by the ACTRT1 gene, associated with inherited basal cell cancer. They find that ARP-T1 is localised to the primary cilia basal body in epidermal cells, interacts with the cilia machinery, and is needed for proper ciliogenesis.

Postpneumonectomy empyema is a collection of pus in the pleural space after removal of the underlying lung. Postpneumonectomy empyema is a serious complication responsible for high rates of morbidity and mortality. Several risk factors for the development of postpneumonectomy empyema have been highlighted in the literature. The association of postpneumonectomy empyema with a bronchopleural fistula increases the rate of mortality by flooding the remaining lung. The management of postpneumonectomy empyema depends on the timing of presentation and the presence or absence of a bronchopleural fistula. The goals of care in the acute period are mainly preservation of the contralateral lung and sterilization of the pleural space, which may take a considerable time. The aims in the late period are closure of the bronchopleural fistula, obliteration of the pleural space, and closure of the chest wall.

Introduction Our purpose is to report our experience in the management of pulmonary hydatid cysts ruptured in the pleura. Materiel and methods: We collected all records of patients with a ruptured hydatid cyst of the lung in the pleura who underwent surgery for this in the department of thoracic surgery of the CHU Hassan II of Fes during the 6-year period that started in 2010. Results The study included 20 men and 14 women with an average age of 30.44 ± 18.4 years. Radiological findings showed a hydropneumothorax in 21 cases, hydrothorax in 10, pachypleuritis in 29, and a floating membrane in 13 cases. In all cases, pleuropulmonary decortication was associated with pericystectomy in 20 cases and parenchymal resection in 3 cases. A hydatid membrane bathing in the pleural cavity was found in 32 cases. The postoperative course was uneventful in 28 cases. Conclusion Long-term follow-up should be established to detect possible recurrences or pleural dissemination, which appear to be prevented by long-term use of anthelmintic agents.

Aspergillus is a mycelial fungus formed of filaments that penetrate the airways when its spores are inhaled. It is rarely located in the pleura. We report two cases of patients, one aged 67 years and the other 37 years, with pleural aspergillosis. The first underwent a thoracostomy, followed later by a myoplasty for closure. Pleuropulmonary decortication was performed in the second patient. The pathology examination confirmed an intrapleural aspergilloma in both patients. Antifungal treatment was not performed. The postoperative course was simple and no recurrence was noted. Based on these two cases over a 7-year period and a review of the literature, we detail the issues in this management and emphasize the interest of surgery.

Homozygous or compound heterozygous IL36RN gene mutations underlie the pathogenesis of psoriasis-related pustular eruptions including generalized pustular psoriasis, palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau, and acute generalized exanthematous pustular eruption. We identified two unreported IL36RN homozygous mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) in patients with familial generalized pustular psoriasis. We analyzed the impact of a spectrum of IL36RN mutations on IL-36 receptor antagonist protein by using site-directed mutagenesis and expression in HEK293T cells. This enabled us to differentiate null mutations with complete absence of IL-36 receptor antagonist (the two previously unreported mutations, c.80T>C/p.Leu27Pro, c.28C>T/p.Arg10X, c.280G>T/p.Glu94X, c.368C>G/p.Thr123Arg, c.368C>T/p.Thr123Met, and c.227C>T/p.Pro76Leu) from mutations with decreased (c.95A>G/p.His32Arg, c.142C>T/p.Arg48Trp, and c.308C>T/p.Ser113Leu) or unchanged (c.304C>T/p.Arg102Trp and c.104A>G/p.Lys35Arg) protein expression. Functional assays measuring the impact of mutations on the capacity to repress IL-36–dependent activation of the NF-κB pathway showed complete functional impairment for null mutations, whereas partial or no impairment was observed for other mutations considered as hypomorphic. Finally, null mutations were associated with severe clinical phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), whereas hypomorphic mutations were identified in both localized (palmoplantar pustular psoriasis, acrodermatitis continua of Hallopeau) and generalized variants. These results provide a preliminary basis for genotype-phenotype correlation in patients with deficiency of the IL-36Ra (DITRA), and suggest the involvement of other factors in the modulation of clinical expression.

In the industrialized countries, most of Bilio-bronchial fistula are secondary to hepatobiliary trauma, hepatic resection surgery or in the case of congenital malformation of the biliary tract, Bilio-bronchial fistula is recognized as the complication of a number of infectious pathologies such as hydatidosis and hepatic amoebiasis. Among the causes, the Bilio-bronchial fistula of hydatic origin is by far the most frequent especially in the zones of hydatid endemic as Morocco. It is a serious complication of liver hydatid cysts. The surgical management has long been believed to be difficult, and often associated with a very pejorative prognosis due to the simultaneous attack of the thoracic and abdominal stage through the diaphragm. This tripartite involvement reflects the difficulty of choosing the first approach between the thoracic, abdominal or a combination of both approaches. However, progress, especially in the possibility of carrying out adequate preoperative preparation with the increasing introduction of retrograde endoscopic cholangiography with sphincterotomy, has made possible this exclusive thoracotomy surgery with acceptable outcomes.

Background Pulmonary aspergilloma presents in two clinical and radiological forms: simple and complex aspergilloma. Surgery is the best therapeutic option, most often by anatomic lung resection. Our aim was to report the surgical outcomes according to our experience. Methods A retrospective study was conducted on data of 79 patients operated on for pulmonary aspergilloma over a period of 10 years. There were 57 (72.15%) men and 22 women (27.84%), with a mean age of 40.45 years. Results Tuberculosis, all-form combined, was the predominant pathological antecedent in 57 (72.15%) patients, and hemoptysis was the most frequent functional sign in 43 (54.43%). The right side was involved in 39 (49.36%) patients. All patients were operated on via a posterolateral thoracotomy, and an extrapleural plane was necessary in 40 (50.63%). The surgical procedure was a lobectomy in 38 (48.10%) patients and a pneumonectomy in 14 (17.72%). Transfusion of red blood cells was carried out in 10 (12.65%) patients, with one (1.26%) requiring a rethoracotomy for postoperative clotted hemothorax. Two (2.53%) patients presented with empyema after pneumonectomy. The mortality rate was 2.53% (2 patients), and the mean follow-up was 2.5 years. Conclusion Surgery for pulmonary aspergilloma is associated with a high rate of morbidity and mortality. This surgery has been performed in our department with a very acceptable rate of mortality, especially considering that all patients were operated on by open surgery.

Posttraumatic diaphragmatic hernias have long been known, but the variety of their clinical expression can lead to diagnostic delay and difficulties in treatment. An intrathoracic hernia of hollow abdominal viscera with subsequent necrosis and perforation is an uncommon late complication with poor prognosis. Surgical treatment is mandatory. Laparotomy is an excellent approach, making it possible to achieve therapeutic objectives for the abdomen and thorax with a short operative time and minimal complications in these patients whose hemodynamic status is often precarious. We report 2 cases of posttraumatic left diaphragmatic hernias with intrathoracic necrosis of the digestive tract, treated by laparotomy.

Cervicothoracic cellulitis is a very serious, potentially life-threatening infection of the cervical and thoracic soft tissue. It is a genuine medical and surgical emergency with substantial mortality, and its surgical therapy has not yet been standardized. It spreads through the layers of the cervical fascia and can then disseminate to the mediastinum and the pleural cavities, requiring specific management that includes the thoracic surgeon. We present reports of 3 patients with cervicothoracic cellulitis, all complicated by mediastinitis, with pericardial effusion in 1 case and unilateral or bilateral pyothorax in 2 cases. Combining these cases with a review of the literature enables us to describe the management of these complicated cases as seen by a thoracic surgeon.

International audience; Replacement therapy with plasma-derived or recombinant FIX (pdFIX or rFIX) concentrates is the standard of treatment in patients with hemophilia B. The method predominantly used for measuring factor IX (FIX:C) levels is the one-stage clotting assay (OSA) but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FIX recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network), presents a review of the literature and proposals for the monitoring of FIX:C levels in treated hemophilia B patients. The use of OSA calibrated with a plasma reference tested against the current FIX WHO International Standard is recommended for the monitoring of patients treated with pdFIX or rFIX. Chromogenic substrate assays (CSA) are adequate for the monitoring of patients treated with Rixubis®, but data available for Benefix® are currently too limited. For extended half-life rFIX (EHL-rFIX), large discordances in the FIX:C levels measured were evidenced, depending on the method and reagents used. Great attention is therefore required for measuring FIX:C levels by OSA in patients substituted by EHL-rFIX. Commercial kits for CSA are not equivalent, and although potentially useful, they are not validated for all EHL-rFIX. Most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients.

International audience; Replacement therapy with plasma-derived or recombinant FVIII (pdFVIII or rFVIII) concentrates is the standard of treatment in patients with hemophilia A. The reference method used for measuring factor VIII (FVIII:C) levels in patients treated by FVIII concentrates is the chromogenic substrate assay (CSA). However, the one-stage clotting assay (OSA) is predominantly used in current clinical practice, but this method depends on the activated partial thromboplastin time (APTT) reagent and the coagulation analyzer used, and wide variations in the measurements of FVIII recovery have been reported with some factor concentrates. The French study group on the biology of hemorrhagic diseases (a collaborative group of the GFHT and MHEMO network) presents a review of the literature and proposals for the monitoring of FVIII:C levels in treated hemophilia A patients. The use of CSA calibrated with a plasma reference tested against the current FVIII WHO (World Health Organization) International Standard is recommended for the monitoring of patients treated with pdFVIII or rFVIII including extended half-life (EHL) rFVIII. OSA are adequate for the monitoring of patients treated with pdFVIII or with most of rFVIII concentrates. However, preliminary comparison with CSA is mandatory before measuring FVIII:C by OSA in patients treated by Refacto AF®. For rFVIII-EHL, OSA are only acceptable for Elocta®. Great caution is therefore required when measuring FVIII:C levels by OSA in patients substituted by other EHL-rFVIII. Indeed, most of recent studies reported data obtained with spiked plasmas, which deserve to be confirmed on plasma samples collected in treated patients.

Neonatal sepsis remains an important cause of morbidity and mortality. The ability to quickly and accurately diagnose neonatal sepsis based on clinical assessments and laboratory blood tests remains difficult, where haemoculture is the gold standard for detecting bacterial sepsis in blood culture. It is also very difficult to study because neonatal samples are lacking.Forty-eight newborns suspected of sepsis admitted to the Neonatology Department of the Mother-Child Specialized Hospital of Tlemcen. From each newborn, a minimum of 1-2 ml of blood was drawn by standard sterile procedures for blood culture. The miRNA-23b level in haemoculture was evaluated by RT-qPCR.miR-23b levels increased in premature and full-term newborns in early onset sepsis (p 0.001 and p 0.005 respectively), but lowered in late onset sepsis in full-term neonates (p 0.05) compared to the respective negative controls. miR-23b levels also increased in late sepsis in the negative versus early sepsis negative controls (p 0.05). miR-23b levels significantly lowered in the newborns who died from both sepsis types (p 0.0001 and p 0.05 respectively). In early sepsis, miR-23b and death strongly and negatively correlated (correlation coefficient = - 0.96, p = 0.0019). In late sepsis, miRNA-23b and number of survivors (correlation coefficient = 0.70, p = 0.506) positively correlated.Lowering miR-23b levels is an important factor that favours sepsis development, which would confirm their vital protective role, and strongly suggest that they act as a good marker in molecular diagnosis and patient monitoring.

Incontinentia pigmenti (IP) is an X-linked-dominant Mendelian disorder caused by mutation in the IKBKG/NEMO gene, encoding for NEMO/IKKgamma, a regulatory protein of nuclear factor kappaB (NF-kB) signaling. In more than 80% of cases, IP is due to recurrent or nonrecurrent deletions causing loss-of-function (LoF) of NEMO/IKKgamma. We review how the local architecture of the IKBKG/NEMO locus with segmental duplication and a high frequency of repetitive elements favor de novo aberrant recombination through different mechanisms producing genomic microdeletion. We report here a new microindel (c.436_471delinsT, p.Val146X) arising through a DNA-replication-repair fork-stalling-and-template-switching and microhomology-mediated-end-joining mechanism in a sporadic IP case. The LoF mutations of IKBKG/NEMO leading to IP include small insertions/deletions (indel) causing frameshift and premature stop codons, which account for 10% of cases. We here present 21 point mutations previously unreported, which further extend the spectrum of pathologic variants: 14/21 predict LoF because of premature stop codon (6/14) or frameshift (8/14), whereas 7/21 predict a partial loss of NEMO/IKKgamma activity (two splicing and five missense). We review how the analysis of IP-associated IKBKG/NEMO hypomorphic mutants has contributed to the understanding of the pathophysiological mechanism of IP disease and has provided important information on affected NF-kB signaling. We built a locus-specific database listing all IKBKG/NEMO variants, accessible at http://IKBKG.lovd.nl.

Our purpose is to evaluate our results of surgery for tracheobronchial carcinoid tumour as well as the long-term survival.This is a retrospective and descriptive study performed in the department of thoracic surgery of CHU Hassan II (Marocco) over a period of 9 years. It concerns all patients with a tracheal or bronchial carcinoid tumour who underwent surgery.Twenty-three patients with a mean age of 39 years were operated on for 24 carcinoid tumours. The sex ratio was 0.29. The diagnostic delay ranged from 3 months to 8 years and the main symptom was haemoptysis in 74% of cases (n=17). The tumour was localized in the right bronchial tree in 70% of cases (n=16). The procedures performed were tracheal resection and end-to-end anastomosis in 1 case, lobectomy in 12 cases including 3 sleeve lobectomies, bilobectomy of middle and lower lobes in 7 cases and pneumonectomy in 4 cases. The prognosis was favourable in 91% after an average follow-up of 29 months.Surgery remains the only curative therapeutic option for tracheobronchial carcinoid tumours with acceptable morbidity and mortality.

Primary tumours of the trachea are very rare and may develop from the tracheal salivary glands.We describe four patients operated on in our service between 2010 and 2017 of whom two had an adenocystic carcinoma, one a mucoepidermoid carcinoma and one a pleomorphic adenoma of the trachea. All were treated by resection and tracheal anastomosis with clear margins in three cases. The malignant cases received adjuvant treatment consisting of radiotherapy in one case and radiochemotherapy in the second. Immediate postoperative recovery was uncomplicated in all patients. One death followed the developement of post irradiation tracheal stenosis two years after surgery in a patient with an adenocystic carcinoma where the resection margins were invaded by tumour.Resection and anastomosis of the trachea remains the best therapeutic option with a better prognosis when the resection is complete.

Background The occurrence of lung metastasis from benign uterine leiomyomas is rarely reported especially in post menopausal women. The pathogenesis of these metastatic benign tumors still remains a subject of various speculations. Case presentation A 57-year-old woman presented with a chronic cough and dyspnea. She had undergone 8 years previously, hysterectomy for benign leiomyomas. A chest computed tomography scan showed a 4 cm solitary nodular parenchymal tumor that increased in size after 12 months. The histological analysis of the biopsy from this nodule showed a benign tumor with regular spindle cells disposed in intersected fascicles. At immunohistochemical analysis, the tumor cells were positive for smooth muscle markers and oestrogen-progesterone receptors with a low mitotic index assessed by Ki-67. These features were consistent with a benign metastasizing uterine leiomyoma. At the multidisciplinary meeting, prescription of an aromatase inhibitor has been decided for the patient. Conclusions Benign metastasizing uterine leiomyomas of the lung are very rare tumors. Although extremely rare in post menopausal women, their diagnosis should be considered in symptomatic patients with a history of hysterectomy for leiomyomas.

Hypohidrotic ectodermal dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.

Pulmonary arteriovenous malformations (AVM) lung is defined by an abnormal communication between pulmonary artery(ies) and vein(s) responsible for a right-left shunt. Congenital forms are most common and usually associated with Rendu-Osler disease (ROD). Inversely, 15–45% of patients with ROD present lung AVM.[1] Nowadays, embolization is preferred to surgical resection in the majority of cases. Except for certain cases where surgery is indicated. This paper shows the role of surgery in AVMs.

Background Neuroendocrine tumors are a large group of tumors with a wide spectrum of behavior, affecting mainly the digestive system and the lung. The thymus is very rarely affected. Case presentation A 28-year-old Arab woman presented with chronic chest pain and dyspnea. A computed tomography scan showed a huge anterior mediastinal mass invading neighboring structures. A mediastinotomy was performed with biopsies of the mass. Pathological findings were consistent with a thymic large cell neuroendocrine carcinoma. Conclusions The occurrence of a large cell neuroendocrine carcinoma in the thymus, especially in young people, is extremely rare. In this current report, we discuss the clinicopathological issues of this rare tumor according to recent literature data.

Incontinentia Pigmenti (IP) is a skin disorder with neurological impairment in 30% of cases. The most common disease causing mutation is a deletion of exons 4-10 of the IKBKG gene, located on chromosome Xq28, with skewed X-chromosome inactivation in females, but few cases of random X-inactivation have been reported. We have correlated brain anomalies with X-chromosome inactivation status determined on leucocytes circulating DNA. We reviewed MRI of 18 girls with genetically proven IP. We found three patterns of MRI, normal MRI ( n = 5), mild white matter abnormalities with cortical and corpus callosum atrophy ( n = 6), and severe cortical abnormalities suggesting a vascular disease ( n = 7). Most patients with severe abnormalities had random X-inactivation (6/7,86%), while 80% (4/5) of patients with normal MRI and 100% (6/6) of patients with mild white matter abnormalities had skewed inactivation. These results suggest that skewed chromosome X-inactivation may protect brain from damage, while in case of random inactivation, expression of the mutated IKBKG gene may lead to severe brain lesions.

Carcinoid tumors are well differentiated neuroendocrine tumors of low grade malignancy or attenuated malignancy. Atypical bilateral bronchial forms are rarely reported. They pose a real problem of therapeutic strategy. We report a case of a 36-year-old woman with two large bilateral atypical carcinoid tumors. She received delayed bilateral parenchymal resection with postoperative uneventful course. Through a review of the literature, we discuss the therapeutic strategy. This observation remains special for several reasons. Not only by the rarity of the bilateral and atypical forms but also for the bilateral tumor sizes which led to a difficult intraoperative anesthetic management.

Primary or secondary diaphragmatic echinococcosis is rare, accounting for 1% of the thoracic locations. They may be operative discovery or by their complication, hence a variable symptomatology making this localization a particular entity. The thoracic and abdominal CT allows a complete assessment. Surgery remains the only therapeutic approach. In complicated forms an additional surgery is required for complete care. The prognosis is generally good apart from the risk of recurrence. Through a series of 4 operated patients, we focus on the clinical and therapeutic features of this pathology and its complications.

Lipin-1 deficiency is associated with massive rhabdomyolysis episodes in humans, precipitated by febrile illnesses. Despite well-known roles of lipin-1 in lipid biosynthesis and transcriptional regulation, the pathogenic mechanisms leading to rhabdomyolysis remain unknown. Here we show that primary myoblasts from lipin-1-deficient patients exhibit a dramatic decrease in LPIN1 expression and phosphatidic acid phosphatase 1 activity, and a significant accumulation of lipid droplets (LD). The expression levels of LPIN1-target genes [peroxisome proliferator-activated receptors delta and alpha (PPARδ, PPARα), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), acyl-coenzyme A dehydrogenase, very long (ACADVL), carnitine palmitoyltransferase IB and 2 (CPT1B and CPT2)] were not affected while lipin-2 protein level, a closely related member of the family, was increased. Microarray analysis of patients' myotubes identified 19 down-regulated and 51 up-regulated genes, indicating pleiotropic effects of lipin-1 deficiency. Special attention was paid to the up-regulated ACACB (acetyl-CoA carboxylase beta), a key enzyme in the fatty acid synthesis/oxidation balance. We demonstrated that overexpression of ACACB was associated with free fatty acid accumulation in patients' myoblasts whereas malonyl-carnitine (as a measure of malonyl-CoA) and CPT1 activity were in the normal range in basal conditions accordingly to the normal daily activity reported by the patients. Remarkably ACACB invalidation in patients' myoblasts decreased LD number and size while LPIN1 invalidation in controls induced LD accumulation. Further, pro-inflammatory treatments tumor necrosis factor alpha+Interleukin-1beta(TNF1α+IL-1ß) designed to mimic febrile illness, resulted in increased malonyl-carnitine levels, reduced CPT1 activity and enhanced LD accumulation, a phenomenon reversed by dexamethasone and TNFα or IL-1ß inhibitors. Our data suggest that the pathogenic mechanism of rhabdomyolysis in lipin-1-deficient patients combines the predisposing constitutive impairment of lipid metabolism and its exacerbation by pro-inflammatory cytokines.

YM is the first son of Tunisian consanguineous parents who developed, at 2 weeks of life, an erythematous and scaly eruption, with subsequent rapid evolution toward generalized pustular psoriasis. Afterward, cutaneous flares of diffuse erythematous rash and pustules involving the whole body appeared, with a once weekly periodicity. Intense irritability was present during flares without fever. Moreover, since 1 month of age the infant presented with diarrhea, dysphagia, and reduced feeding rate, with failure to thrive. Laboratory tests during acute flares showed marked leukocytosis, thrombocytosis, and anemia without C-reactive protein elevation. Skin biopsy and clinical presentation were consistent with pustular psoriasis; nevertheless, the patient did not respond to high-potency topical corticosteroids and retinoid acid. As the patient presented with repeated skin flares early after birth, as well as serious constitutional distress with failure to thrive, an autoinflammatory syndrome like interleukine-1-receptor antagonist deficiency or interleukin-36-receptor antagonist deficiency (DITRA) was considered. The hypothesis was reinforced by parental consanguinity, and absence of skin lesion improvement under standard topical treatment. Genetic analyses showed a homozygous mutation in the IL36RN gene (L27P), which represents the same mutation recently described in DITRA patients. At age 6 months we started treatment with the recombinant interleukin-1 receptor antagonist anakinra with efficacy both on constitutional symptoms and skin involvement. DITRA is a recently described autoinflammatory disease characterized by repeated flares of generalized pustular psoriasis, high fever, asthenia, and systemic inflammation. We report herein the first exhaustive clinical description of an infant with DITRA who was successfully treated with anakinra.

Objective Bronchoalveolar lavage (BAL) is a diagnostic tool often used during the management of interstitial lung diseases (ILD). However, its diagnostic value in discrimination between entities comprising the very heterogenous group of ILD, is still a controversial issue. The objective of our study is to assess the diagnostic value of BAL in the management of ILD, by comparing the cytological findings in BAL fluid among the different diseases of this group. Methods It was a retrospective, observational study of 151 patients between January 2012 and December 2015. BAL fluid cytology was performed to analyse the distribution of leucocytes population subsets in patients with ILD. Results The mean age was 52.78 years; 74.83% were women. The analysis of the following main groups of diseases was performed : sarcoïdosis (n = 30), idiopathic pulmonary fibrosis (IPF; n = 22), other idiopathic interstitial pneumonia (non specific interstitial pneumonia, cryptogenic organising pneumonia and respiratory bronchiolitis interstitial lung disease; n = 20) and connective tissue disease (n = 14). Overall, out of 141 patients, 22% had sarcoïdosis, 15.6% had idiopathic pulmonary fibrosis (IPF), 14.18% had other idiopathic interstitial pneumonia (IIP) and 9.9% had connective tissue disease (CTD). Mixed alveolitis was common in the 4 groups, sarcoïdosis had higher proportion of lymphocytes and IPF had higher neutrophils count. However, there was no significant statistical difference of BAL cellular count among these diseases (p > 0.05). Also, the prevalence of studied diseases did not change with variation of BAL cellular count (p > 0.05). Conclusion Alone, the BAL cytological analysis has a limited value to provide substantial information that could lead to discriminate between diseases that form ILD. Thus, it must be always associated with other diagnostic methods.

Tumors of the mediastinum are a heterogeneous group of dysembryoplatic and neoplastic diseases essentially with different prognoses and therapeutic. These tumors develop slowly and remain long asymptomatic in 40-50% of cases. The purpose of our work is to bring the result of surgical management in diagnostic and therapeutic of principal mediastinum tumors framework.We reviewed retrospectively the records of 68 patients in our training, between January 2009 and December 2013, for tumor of the mediastinum in the diagnostic framework and or therapy.There were 37 men and 31 women with a mean age of 37 years with extremes ranging from 11 to 73 years and 77.94% had an age between 11 and 50. In 39 patients, surgery had a diagnostic purpose (2 benign tumors and 37 malignancies including 27 cases of lymphomas). Curative surgery was performed in 34 patients, dominated by the tumors of thymic origin in 15 cases. Conventional surgery had involved 32 patients. The surgical approach was a total vertical sternotomy in 14 patients, in 17 patients was posterolateral thoracotomy and a left anterior thoracotomy in 1 patient. Video assisted thoracic surgery had been done in 3 patients under resection of a pleuropericardique cyst. Overall mortality was 4.41 percent. It is a death at D17 of the postoperative (thymoma with myasthenia) following a myasthenic crisis requiring a tracheotomy. A patient operated on for invasive thymoma developed myopathy and died at D44 of the postoperative following a difficulty of weaning. Another patient had a thymoma B3 benefited from 6 courses of neoadjuvant chemotherapy and then a thymectomy had presented a respiratory distress with bilateral pleural effusion, death at D10 of the postoperative by septic shock following a nosocomial infection.Tumors of the mediastinum are infrequent, discovered more often by chance. The main prognostic factor is the completeness of tumor resection without taking the break. Conventional surgery always keeps a place in our context, despite the advent of minimally invasive surgery.

Bronchiectasis is a serious and disabling disease. Surgical treatment is an interesting alternative to be proposed early to patients in case of complications or deterioration of quality of life, despite an optimal medical treatment. Through this retrospective study and literature review, we analyze surgical results for bronchiectasis.We conducted a monocentric, retrospective, descriptive and analytical study in the Department of thoracic surgery of CHU Hassan II Fès, about 64 patients operated for bronchiectasis during the period from January 2009 to December 2016.There were 30 men and 34 women with an average age of 32years. Twenty six percent (26 %) had a history of recurrent lung infection, and 17.18 % would have been treated for pulmonary tuberculosis and declared cured. Productive cough (93 %), morning chronic bronchorrhea (92 %) and repeatedly hemoptysis (62.5 %) were the main symptoms. On CT scanning, the bronchiectasis was unilateral and localized in 49 cases. The right lung was involved in 27 cases and the location was bilateral in 15 cases. It was 38 cystic bronchiectasis, 16 cylindrical bronchiectasis, and 10 mixed lesions predominantly cylindrical. The flexible bronchoscopy carried out in 34 cases, had shown a carcinoid tumor in 1 case, a bronchiolithiasis in 1 case and a intrabronchial foreign body in 1 case. The incision was a conservative posterolateral thoracotomy in all cases. The performed surgical procedure was lobectomy in 53 % of patients. The morbidity rate was 32.80 % and dominated by septic complications. After a mean follow-up of 20.52months, 2 cases of recurrence minimal hemoptysis and 1 case of renewed bronchorrhea are noted. For all other patients the outcome was favorable and no deaths have been noted to date.The surgery of bronchiectasis requires a perfect collaboration between the pulmonologist, the thoracic surgeon, the anesthesiologist, the biologist and particularly the physiotherapist for an optimal care of patients.

The bronchial biliary fistula surgery is a major one, always going with a higher rate of complication especially in case of bile duct obstruction. The aim of this study is to find out the contribution of endoscopic sphincterotomy while reporting the results of surgical treatment of bronchial biliary fistulae by exclusive thoracotomy.This was a retrospective study, which took place in the Department of Thoracic Surgery, University Hospital Hassan II, from January 2009 to March 2016. The parameters studied in connection with the bronchial biliary fistula of hydatid origin were: age, sex, origin, history of surgery especially for hepatic hydatid cyst, term of bilyptysie, imaging results, preoperative cholangiography indications, surgical treatment modalities and patients trends.A sample of 12 patients was included (6 men and 6 women) with an average age of 44 years old, with a gap spanning between 17 and 81 years. Seven patients had at least a history of hepatic hydatid surgery. The biliptysie was the main symptom in 8 patients. A biological cholestasis syndrome was found in 6 patients. The thoracoabdominal CT scan performed on all patients comes out with results in 100% of cases. Four patients received endoscopic retrograde cholangiography that allowed them to release the bile duct completely by sphincterotomy with extraction of hydatid membrane in one patient and with development of a biliary stent in another patient. The incision was a low posterolateral thoracotomy in 10 patients that went under surgery. It has allowed to deal in one-time liver and lung injuries combined with diaphragmatic breach repair. Inside the group of patients that went under surgery, the postoperative results were simple in 8 cases. We have noted an overall mortality rate of 18.2%.Bronchial biliary fistula surgery complications remains considerable despite the progress of diagnostic imaging. Preoperative endoscopic sphincterotomy is a milestone in the handling of this surgery. It may even be suggested as exclusive therapy in inoperable patients with significant biliptisy.

The aim of our study is to report our surgery results in bilateral sequelae bronchiectasis and to assess its impact on the life quality of our patients.This is a retrospective descriptive study in thoracic surgery department of Teaching Hospital Hassan II of Fez in Morocco. It involved all patients with bilateral bronchiectasis which is predominant on a few lobes or segments (localized) and who underwent surgery during the period 2010-2015. The epidemiological, clinical and paraclinical data, the surgery results, the evolution and the impact on life quality were assessed.From a total of 47 patients with bilateral bronchiectasis, 13 were operated, thus a frequency of 27.6%. The average age was 32years, ranging from 15 to 54years. Women were in majority (61.5%) representing a sex ratio of 1.6. The association of chronic bronchorrhea and hemoptysis was the main reason of medical consultation in 46.16%, followed by isolated chronic bronchorrhea in 38.46%. Surgical resection involved the left side in 61.5% of cases. The left lower lobectomy was the most accomplished gesture. An improvement in symptoms was found in 11 patients (84.6%) as a decrease in bronchorrhea, hemoptysis episodes and decreasing use of antibiotics.Bilateral bronchiectasis surgery can be performed with acceptable morbidity and mortality in well-selected patients with an improvement in symptoms.

The occurrence of empyema after pneumonectomy or in suites with chronic pleural pocket is a dreaded complication. The management is long and difficult. The authors report their experience before this complication including infection control by an emptying of the pleural pocket percutaneous drainage or thoracostomy which will be complemented by a thoracomyoplasty the aim to erase the pleural pocket.This is a retrospective study conducted between 2009 and 2015 concerning the records of 9 patients treated for empyema or in the aftermath of a lung resection or as part of a chronic pleural pocket and calcific.We had identified all 9 male patients aged 30 to 67 years. This was pyothorax complicating pneumonectomy in 4 patients and 1 pyothorax after a left upper lobectomy in 1 case. For the other 4 patients, there was a post-tuberculous pleural pocket, calcified chronic and whose attempts to decortication seemed impossible. We observed 3 cases of bronchopleural fistula. All patients had received evacuation of the contents of the pleural drainage bag is either thoracostomy laying the bed of a possible filling thoracomyoplasty. The evolution of pleural cavities after thoracostomy was favorable on septic map leading to a retraction of the pleural cavity and its spontaneous closure in 1 patient. In 6 patients, filling the cavity with thoracomyoplasty was necessary. The evolution immediate postoperative was favorable in all patients and no deaths were noted in connection with this technique.Pyothorax on pneumonectomy cavity and chronic pleural calcified pockets are serious complications whose management is long and delicate. The thoracomyoplastie is a real alternative to the filling of the cavity in fragile patients with significant operational risk. The results are satisfactory in the hands of a broken team this technique.

IKBKG/NEMO gene mutations cause an X-linked, dominant neuroectodermal disorder named Incontinentia Pigmenti (IP). Located at Xq28, IKBKG/NEMO has a unique genomic organization, as it is part of a segmental duplication or low copy repeat (LCR1LCR2, 99 identical) containing the gene and its pseudogene copy (IKBKGP). In the opposite direction and outside LCR1, IKBKG/NEMO partially overlaps G6PD, whose mutations cause a common X-linked human enzymopathy. The two LCRs in the IKBKG/NEMO locus are able to recombine through non-allelic homologous recombination producing either a pathological recurrent exon 410 IKBKG/NEMO deletion (IKBKGdel) or benign small copy number variations. We here report that the local high frequency of micro/macro-homologies, tandem repeats and repeat/repetitive sequences make the IKBKG/NEMO locus susceptible to novel pathological IP alterations. Indeed, we describe the first two independent instances of inter-locus gene conversion, occurring between the two LCRs, that copies the IKBKGP pseudogene variants into the functional IKBKG/NEMO, causing the de novo occurrence of p.Glu390ArgfsX61 and the IKBKGdel mutations, respectively. Subsequently, by investigating a group of 20 molecularly unsolved IP subjects using a high-density quantitative polymerase chain reaction assay, we have identified seven unique de novo deletions varying from 4.8 to approximate to 115 kb in length. Each deletion removes partially or completely both IKBKG/NEMO and the overlapping G6PD, thereby uncovering the first deletions disrupting the G6PD gene which were found in patients with IP. Interestingly, the 4.8 kb deletion removes the conserved bidirectional promoterB, shared by the two overlapping IKBKG/NEMO and G6PD genes, leaving intact the alternative IKBKG/NEMO unidirectional promoterA. This promoter, although active in the keratinocytes of the basal dermal layer, is down-regulated during late differentiation. Genomic analysis at the breakpoint sites indicated that other mutational forces, such as non-homologous end joining, Alu-Alu-mediated recombination and replication-based events, might enhance the vulnerability of the IP locus to produce de novo pathological IP alleles.

This study aimed to investigate whether the anomalies affecting the antioxidant and humoral immune defenses could start at birth and to check whether the decrease in antioxidant defenses may precede the immune abnormalities in macrosomic newborns. Thirty macrosomic and 30 sex-matched control newborns were recruited for a retrospective case-control study at the Maghnia Maternity Hospital of Tlemcen Department (Algeria). The serum IgG levels were similar in both groups. However, plasma ORAC, albumin, vitamin E, SOD, CAT and GSH-Px levels were significantly decreased in macrosomic as compared to control newborns, yet no difference was observed after adjustment for weight. Additionally, serum concentrations of complement C3, MDA and XO were significantly higher in macrosomic as compared to controls before adjustment for weight. Moreover, macrosomia was significantly associated with high levels of complement C3 (OR=8, p=0.002) ; whereas no association with those of IgG was observed (OR0.05). Furthermore, macrosomia was significantly associated with low levels of ORAC (OR=4.96, p=0.027), vitamin E (OR=4.5, p=0.018), SOD (OR=6.88, p=0.020) and CAT (OR=5.67, p=0.017), and with high levels of MDA (OR=10.29, p=0.005). Abnormalities of the humoral defense system in excessive weight could be preceded by alterations of the anti-oxidative defense and by inflammatory response and activation of innate immunity at birth. Additionally, excessive weight could be a potential factor contributing to decreased anti-oxidative capacity and increased oxidative stress. MEDICAL SCIENCE MONITOR, ISSN : 1234-1010, Issue : 11, Volume : 17, pp. CR650-CR656, NOV 2011.

Sampling small volumes of blood may be necessary, particularly in pediatric patients, or in case of difficult or recurrent venipunctures.Routine hemostasis test results evaluated in partial- and full-draw evacuated polymer tubes obtained in 4 centers were compared.No relevant discrepancy (Bland-Altman) was found between test results measured in partial- and full-draw tubes obtained from untreated patients and from patients on vitamin K-antagonist or low molecular weight heparin. In patients on unfractionated heparin (UFH), significantly lower anti-FXa activity [median=0.29IU/mL (range:0.04-1.15) vs. 0.39 (0.05-1.25), n=89, p0.0001] and shorter aPTT were measured in partial-draw tubes. This discrepancy was likely to be related to the release of higher amounts of PF4 after increased platelet activation in partial-draw tubes. As CTAD is known to counteract platelet activation, we then collected blood into partial-draw CTAD tube and full-draw citrate tube. Both in patients on UFH and in untreated patients, no relevant difference could be demonstrated for all studied parameters (Bland-Altman), including aPTT and anti-FXa activity, even if analytical comparison showed significantly higher anti-FXa activity in partial-draw CTAD than in full-draw citrated tubes with a mean bias of 0.02 IU/mL, identical throughout the measuring range.These results suggest that samples collected into partial-draw citrate tubes allow accurate routine coagulation testingin all patients but those requiring UFH assessment,in which their use led to a significant underestimation ofanticoagulation. In such cases, partial-draw tubes containing CTAD could be validly used to monitor heparin therapy as well as to perform routine coagulation testing.

Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of ectodermal structures and its molecular etiology corresponds to mutations of EDA-EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4-20) to 22.5 (10-28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub-domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA-EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA-EDAR genes during odontogenesis. The present genotypic-phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA-NF-kB in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.