Factor VIII products and inhibitor development in severe hemophilia A.

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations.

MYH9-related disease (MYH9-RD) is a rare autosomal-dominant disorder caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9-RD is characterized by a considerable variability in clinical evolution: patients present at birth with only thrombocytopenia, but some of them subsequently develop sensorineural deafness, cataract, and/or nephropathy often leading to end-stage renal disease (ESRD). We searched for genotype-phenotype correlations in the largest series of consecutive MYH9-RD patients collected so far (255 cases from 121 families). Association of genotypes with noncongenital features was assessed by a generalized linear regression model. The analysis defined disease evolution associated to seven different MYH9 genotypes that are responsible for 85% of MYH9-RD cases. Mutations hitting residue R702 demonstrated a complete penetrance for early-onset ESRD and deafness. The p.D1424H substitution associated with high risk of developing all the noncongenital manifestations of disease. Mutations hitting a distinct hydrophobic seam in the NMMHC-IIA head domain or substitutions at R1165 associated with high risk of deafness but low risk of nephropathy or cataract. Patients with p.E1841K, p.D1424N, and C-terminal deletions had low risk of noncongenital defects. These findings are essential to patients' clinical management and genetic counseling and are discussed in view of molecular pathogenesis of MYH9-RD.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) impairs the regulation of apoptosis in megakaryocytes by activating NF-κB: a proteomic study.

We previously showed that the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and its receptor VPAC1 are negative regulators of megakaryopoiesis and platelet function, but their downstream signaling pathway that inhibits this process still remained unknown. A combined proteomic, transcriptomic, and bioinformatic approach was here used to elucidate the molecular mechanisms underlying PACAP signaling via VPAC1 in megakaryocytes. Two-dimensional difference gel electrophoresis and tandem MS were applied to detect differentially expressed proteins in megakaryocytic CHRF cells stimulated with PACAP. The majority of the 120 proteins modulated by PACAP belong to the class of "cell cycle and apoptosis" proteins. The up- or down-regulated expression of some proteins was confirmed by immunoblot and immunohistochemical analysis. A meta-analysis of our data and 12 other published studies was performed to evaluate signaling pathways involved in different cellular models of PACAP response. From 2384 differentially expressed genes/proteins, 83 were modulated by PACAP in at least three independent studies and Ingenuity Pathway Analysis further identified apoptosis as the highest scored network with NF-κB as a key-player. PACAP inhibited serum depletion-induced apoptosis of CHRF cells via VPAC1 stimulation. In addition, PACAP switched on NF-κB dependent gene expression since higher nuclear levels of the active NF-κB p50/p65 heterodimer were found in CHRF cells treated with PACAP. Finally, a quantitative real time PCR apoptosis array was used to study RNA from in vitro differentiated megakaryocytes from a PACAP overexpressing patient, leading to the identification of 15 apoptotic genes with a 4-fold change in expression and Ingenuity Pathway Analysis again revealed NF-κB as the central player. In conclusion, our findings suggest that PACAP interferes with the regulation of apoptosis in megakaryocytes, probably via stimulation of the NF-κB pathway.

Obsessive-compulsive behavior as presenting symptom of primary antiphospholipid syndrome.

OBJECTIVE: This study aimed to improve understanding and treatment of psychiatric symptoms in antiphospholipid syndrome (APS) and to present an approach to the medical management of patients presenting with obsessive-compulsive disorder (OCD) with suspected neurovascular pathology. METHOD: A 15-year-old boy presented with severe OCD of recent onset. An infarct of the caudate nucleus was identified as the initial presentation of primary APS. This case report includes a selective literature review of the neuropsychiatric correlates of APS. RESULTS: The patient had OCD for 3 months with increasing symptoms resulting in admission for psychiatric reasons. After referral to the emergency department 3 weeks later, an infarct of the caudate nucleus was documented using magnetic resonance images of the brain, and APS was diagnosed based on additional laboratory findings. Anticoagulant treatment (enoxaparin and phenprocoumon) in this patient was effective in reducing obsessive-compulsive symptom severity. CONCLUSION: OCD may present as a neuropsychiatric manifestation of APS. The present observations are consistent with a thrombotic mechanism for neurologic or psychiatric symptoms in APS. In general, routine medical workup for childhood OCD is not indicated, but a comprehensive psychiatric, medical, and family history taking and physical examination are essential, particularly if OCD is of recent onset. The role of anticoagulant therapy in neuropsychiatric manifestations of APS without the presence of a cerebral infarct requires further research.

3D Multi-segment foot kinematics in children: A developmental study in typically developing boys.

BACKGROUND: The relationship between age and 3D rotations objectivized with multisegment foot models has not been quantified until now. The purpose of this study was therefore to investigate the relationship between age and multi-segment foot kinematics in a cross-sectional database. METHODS: Barefoot multi-segment foot kinematics of thirty two typically developing boys, aged 6-20 years, were captured with the Rizzoli Multi-segment Foot Model. One-dimensional statistical parametric mapping linear regression was used to examine the relationship between age and 3D inter-segment rotations of the dominant leg during the full gait cycle. RESULTS: Age was significantly correlated with sagittal plane kinematics of the midfoot and the calcaneus-metatarsus inter-segment angle (p<0.0125). Age was also correlated with the transverse plane kinematics of the calcaneus-metatarsus angle (p<0.0001). CONCLUSION: Gait labs should consider age related differences and variability if optimal decision making is pursued. It remains unclear if this is of interest for all foot models, however, the current study highlights that this is of particular relevance for foot models which incorporate a separate midfoot segment.

Venous thrombosis in a child with ulcerative colitis in remission: a case report.

Over the past 70 years, an association between venous thromboembolism and inflammatory bowel disease has been described. We report on a thirteen year old boy with ulcerative colitis and venous thrombosis. Literature on incidence of venous thromboembolism in inflammatory bowel disease (IBD) is reviewed as well as the possible pathogenetic mechanisms of this 'hypercoagulable state': role of acquired risk factors, inflammation, coagulation abnormalities and platelets. Finally, treatment of IBD and thrombosis is discussed.

Rotavirus surveillance in Kisangani, the Democratic Republic of the Congo, reveals a high number of unusual genotypes and gene segments of animal origin in non-vaccinated symptomatic children.

Group A rotavirus (RVA) infections form a major public health problem, especially in low-income countries like the Democratic Republic of the Congo (COD). However, limited data on RVA diversity is available from sub-Saharan Africa in general and the COD in particular. Therefore, the first aim of this study was to determine the genetic diversity of 99 RVAs detected during 2007-2010 in Kisangani, COD. The predominant G-type was G1 (39%) and the most predominant P-type was P[6] (53%). A total of eight different G/P-combinations were found: G1P[8] (28%), G8P[6] (26%), G2P[4] (14%), G12P[6] (13%), G1P[6] (11%), G9P[8] (4%), G4P[6] (2%) and G8P[4] (1%). The second aim of this study was to gain insight into the diversity of P[6] RVA strains in the COD. Therefore, we selected five P[6] RVA strains in combination with the G1, G4, G8 (2x) or G12 genotype for complete genome analysis. Complete genome analysis showed that the genetic background of the G1P[6] and G12P[6] strains was entirely composed of genotype 1 (Wa-like), while the segments of the two G8P[6] strains were identified as genotype 2 (DS-1-like). Interestingly, all four strains possessed a NSP4 gene of animal origin. The analyzed G4P[6] RVA strain was found to possess the unusual G4-P[6]-I1-R1-C1-M1-A1-N1-T7-E1-H1 constellation. Although the majority of its genes (if not all), were presumably of porcine origin, this strain was able to cause gastro-enteritis in humans. The high prevalence of unusual RVA strains in the COD highlights the need for continued surveillance of RVA diversity in the COD. These results also underline the importance of complete genetic characterization of RVA strains and indicate that reassortments and interspecies transmission among human and animal RVAs strains occur regularly. Based on these data, RVA vaccines will be challenged with a wide variety of different RVA strain types in the COD.

Antibiotic prescribing in DR Congo: a knowledge, attitude and practice survey among medical doctors and students.

OBJECTIVES: Antibiotic resistance (ABR) particularly hits resource poor countries, and is fuelled by irrational antibiotic (AB) prescribing. We surveyed knowledge, attitudes and practices of AB prescribing among medical students and doctors in Kisangani, DR Congo. METHODS: Self-administered questionnaires. RESULTS: A total of 184 questionnaires were completed (response rate 94.4%). Knowledge about AB was low (mean score 4.9/8 points), as was the estimation of local resistance rates of S. Typhi and Klebsiella spp.(correct by 42.5% and 6.9% of respondents respectively). ABR was recognized as a problem though less in their own practice (67.4%) than nation- or worldwide (92.9% and 85.5%, p<.0001). Confidence in AB prescribing was high (88.6%) and students consulted more frequently colleagues than medical doctors when prescribing (25.4% versus 11.6%, p= 0.19). Sources of AB prescribing included pharmaceutical companies (73.9%), antibiotic guidelines (66.3%), university courses (63.6%), internet-sites (45.7%) and WHO guidelines (26.6%). Only 30.4% and 16.3% respondents perceived AB procured through the central procurement and local pharmacies as of good quality. Local AB guidelines and courses about AB prescribing are welcomed (73.4% and 98.8% respectively). CONCLUSIONS: This data shows the need for interventions that support rational AB prescribing.

Olmsted syndrome: exploration of the immunological phenotype.

BACKGROUND: Olmsted syndrome is a rare congenital skin disorder presenting with periorifical hyperkeratotic lesions and mutilating palmoplantar keratoderma, which is often associated with infections of the keratotic area. A recent study identified de novo mutations causing constitutive activation of TRPV3 as a cause of the keratotic manifestations of Olmsted syndrome. METHODS: Genetic, clinical and immunological profiling was performed on a case study patient with the clinical diagnosis of Olmsted syndrome. RESULTS: The patient was found to harbour a previously undescribed 1718G-C transversion in TRPV3, causing a G573A point mutation. In depth clinical and immunological analysis found multiple indicators of immune dysregulation, including frequent dermal infections, inflammatory infiltrate in the affected skin, hyper IgE production and elevated follicular T cells and eosinophils in the peripheral blood. CONCLUSIONS: These results provide the first comprehensive assessment of the immunological features of Olmsted syndrome. The systemic phenotype of hyper IgE and persistent eosinophilia suggest a primary or secondary role of immunological processes in the pathogenesis of Olmsted syndrome, and have important clinical consequences with regard to the treatment of Olmsted syndrome patients.

Novel findings in the Marden-Walker syndrome.

Reports about the Marden-Walker syndrome mainly consist of sporadic cases. We describe a 14-year-old girl with the Marden-Walker syndrome who presented with a huge scalp hematoma. The case and the corresponding images demonstrate an association with a defective hemostasis, skin hyperlaxity, and impaired wound healing.

Propranolol as a novel treatment for congenital visceral haemangioma.

Haemangiomas are the most common soft tissue tumours in infancy, occurring in approximately 5-10% of 1-year-old children. Current drug-based therapeutic options for large haemangiomas include corticosteroids, α-interferon and vincristin, all of which can result in harmful side effects. Recently, promising results have been reported using the non-cardio-selective ß-blocker propranolol for the treatment of cutaneous capillary haemangiomas, in which a spectacular size reduction was observed during the first 7 days of treatment. We here report a similar significant and rapid inhibitory effect of propranolol on the growth of a viscerally located congenital haemangioma.