The Challenging Evaluation of Patients with Severe Psoriasis for Latent Tuberculosis: An Important Indication for IGRA

It is well-established that tumour necrosis factor (TNF)-α-antagonist regimens are advisable for the control of moderate to severe psoriasis; however the application of these agents is associated with increased risk of TB reactivation. Screening for latent tuberculosis infection (LTBI) is indispensable prior to treatment inception in order to diminish the risk of active TB. Although tuberculin skin test (TST) still represents a useful tool for LTBI detection, it is difficult to be performed and read in patients with extensive psoriatic lesions. In this paper, we report the case of a 65-year-old male with severe psoriasis, who was evaluated by an interferon-gamma release assay (IGRA) for LTBI diagnosis prior to anti-TNF-α therapy. Furthermore, the physiological aspects of interferon-gamma release assays are discussed emphasizing the value of these novel immunodiagnostic tests (IGRAs) for presumable LTBI in all patients with extensive skin disorders

Membranous Glomerulonephritis With Crescents.

INTRODUCTION: Membranous glomerulonephritis (MGN) is rarely associated with necrotizing and crescentic glomerulonephritis (NCGN). METHODS: We report the clinical and pathologic findings in 15 patients with MGN and NCGN associated with anti-neutrophil cytoplasm antibodies (ANCAs), anti-glomerular basement membrane (GBM), or anti-phospholipase A2 receptor (PLA2R) antibodies. RESULTS: The cohort consisted of 15 patients: 7 males and 8 females with a median age of 63 years (range: 18-79). In 12 of 15 patients, MGN and NCGN were diagnosed at the time of the biopsy, and in 3 cases, MGN predated the NCGN. ANCA was positive in 7 cases (6 MPO myeloperoxidase (MPO)-ANCA and 1 PR3-ANCA), anti-GBM antibodies were detected in 5 cases, and anti-PLA2R antibodies were found in 2 cases. One case was negative for all antibodies. Microscopic hematuria was present in all but one patient who was anuric, and median urinary protein-to-creatinine ratio was 819.5 mg/mmol (range: 88-5600). Pathologic evaluation revealed MGN and NCGN with crescents involving 28% of glomeruli (median; range: 5%-100%). Follow-up was available for all 15 patients; all were treated with steroids; 10 with cyclophosphamide, and 6 also received rituximab. At a median follow-up of 72 months, 9 had stabilization or improvement of renal function, 6 had progressed to end-stage renal disease, and 4 died during the follow-up period. CONCLUSION: MGN with crescents associated with ANCAs or anti-GBM antibodies is a rare dual glomerulopathy. Patients present with heavy proteinuria, microscopic hematuria, and acute kidney injury and should be treated for a rapidly progressive glomerulonephritis. Prognosis is variable, and 40% of patients progress to end-stage renal disease

Deliverable 9.1 - Report on mixtures and implementation strategy in Europe – Assessment of chemical mixtures under consideration of current and future regulatory requirements and scientific approaches

This report gives an overview on the regulatory processes and requirements for risk assessment of chemical mixtures, identifies gaps in the European legislation and summarises potential approaches for the health risk assessment of chemical mixtures

Vangl2 disruption alters the biomechanics of late spinal neurulation leading to spina bifida in mouse embryos

peer-reviewedHuman mutations in the planar cell polarity component VANGL2 are associated with the neural tube defect spina bifida. Homozygous Vangl2 mutation in mice prevents initiation of neural tube closure, precluding analysis of its subsequent roles in neurulation. Spinal neurulation involves rostral-to-caudal ‘zippering’ until completion of closure is imminent, when a caudal-to-rostral closure point, ‘Closure 5’, arises at the caudal-most extremity of the posterior neuropore (PNP). Here, we used Grhl3Cre to delete Vangl2 in the surface ectoderm (SE) throughout neurulation and in an increasing proportion of PNP neuroepithelial cells at late neurulation stages. This deletion impaired PNP closure after the ∼25-somite stage and resulted in caudal spina bifida in 67% of Grhl3Cre/+Vangl2Fl/Fl embryos. In the dorsal SE, Vangl2 deletion diminished rostrocaudal cell body orientation, but not directional polarisation of cell divisions. In the PNP, Vangl2 disruption diminished mediolateral polarisation of apical neuroepithelial F-actin profiles and resulted in eversion of the caudal PNP. This eversion prevented elevation of the caudal PNP neural folds, which in control embryos is associated with formation of Closure 5 around the 25-somite stage. Closure 5 formation in control embryos is associated with a reduction in mechanical stress withstood at the main zippering point, as inferred from the magnitude of neural fold separation following zippering point laser ablation. This stress accommodation did not happen in Vangl2-disrupted embryos. Thus, disruption of Vangl2-dependent planar-polarised processes in the PNP neuroepithelium and SE preclude zippering point biomechanical accommodation associated with Closure 5 formation at the completion of PNP closure

Pterional variable topography and morphology. An anatomical study and its clinical significance

Background: Pterion is the junction of the frontal, parietal, greater wing of the sphenoid and the squamous part of the temporal bone. The sphenoparietal, frontotemporal, stellate and epipteric pteria were described. The current study determines pterion topography, morphology (variant types’ frequency) and morphometry, as well as epipteric bones presence in dried skulls. Gender impact is underlined as well. Material and methods: Ninety Greek adult dried skulls were observed. The distances in between pterion and the zygomatic arch midpoint and in between pterion and the frontozygomatic suture were measured. Results: The sphenoparietal pterion was the commonest (58.3%), following by the stellate (25%), epipteric (15.5%) and by the frontotemporal pterion (1.1%). Twenty-eight skulls (15.5%) had epipteric bones, further categorized as quadrisutural (35.7%), trisutural (57.1%), bisutural and multiple (3.57%). The mean distances between pterion and the midpoint of zygomatic arch were 4.13+0.45cm on the right and 4.09 + 0.47cm on the left side and between pterion and the frontozygomatic suture were 3.47 + 0.61 cm on the right and 3.52 + 0.65 cm on the left. Both distances were symmetrical. Male skulls showed slightly higher values on the left side for the distance pterion and midpoint of zygomatic arch. Conclusions: Pterion is a commonly used neurosurgical landmark and thus in depth knowledge of the pteric area and its variants could be valuable. Recognition of the possible variability in pterion location, morphology and morphometry, as well as possible occurrence of epipteric bones may render pterional craniotomy safer among different population groups

Biomechanical coupling facilitates spinal neural tube closure in mouse embryos

Neural tube (NT) formation in the spinal region of the mammalian embryo involves a wave of “zippering” that passes down the elongating spinal axis, uniting the neural fold tips in the dorsal midline. Failure of this closure process leads to open spina bifida, a common cause of severe neurologic disability in humans. Here, we combined a tissue-level strain-mapping workflow with laser ablation of live-imaged mouse embryos to investigate the biomechanics of mammalian spinal closure. Ablation of the zippering point at the embryonic dorsal midline causes far-reaching, rapid separation of the elevating neural folds. Strain analysis revealed tissue expansion around the zippering point after ablation, but predominant tissue constriction in the caudal and ventral neural plate zone. This zone is biomechanically coupled to the zippering point by a supracellular F-actin network, which includes an actin cable running along the neural fold tips. Pharmacologic inhibition of F-actin or laser ablation of the cable causes neural fold separation. At the most advanced somite stages, when completion of spinal closure is imminent, the cable forms a continuous ring around the neuropore, and simultaneously, a new caudal-to-rostral zippering point arises. Laser ablation of this new closure initiation point causes neural fold separation, demonstrating its biomechanical activity. Failure of spinal closure in pre-spina bifida Zic2Ku mutant embryos is associated with altered tissue biomechanics, as indicated by greater neuropore widening after ablation. Thus, this study identifies biomechanical coupling of the entire region of active spinal neurulation in the mouse embryo as a prerequisite for successful NT closure

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

Spinal neural tube closure depends on regulation of surface ectoderm identity and biomechanics by Grhl2

Lack or excess expression of the surface ectoderm-expressed transcription factor Grainyhead-like2 (Grhl2), each prevent spinal neural tube closure. Here we investigate the causative mechanisms and find reciprocal dysregulation of epithelial genes, cell junction components and actomyosin properties in Grhl2 null and over-expressing embryos. Grhl2 null surface ectoderm shows a shift from epithelial to neuroepithelial identity (with ectopic expression of N-cadherin and Sox2), actomyosin disorganisation, cell shape changes and diminished resistance to neural fold recoil upon ablation of the closure point. In contrast, excessive abundance of Grhl2 generates a super-epithelial surface ectoderm, in which up-regulation of cell-cell junction proteins is associated with an actomyosin-dependent increase in local mechanical stress. This is compatible with apposition of the neural folds but not with progression of closure, unless myosin activity is inhibited. Overall, our findings suggest that Grhl2 plays a crucial role in regulating biomechanical properties of the surface ectoderm that are essential for spinal neurulation

Over-expression of Grainyhead-like 3 causes spina bifida and interacts genetically with mutant alleles of Grhl2 and Vangl2 in mice.

The genetic basis of human neural tube defects (NTDs), such as anencephaly and spina bifida, is complex and heterogeneous. Grainyhead-like genes represent candidates for involvement in NTDs based on the presence of spina bifida and exencephaly in mice carrying loss-of-function alleles of Grhl2 or Grhl3. We found that reinstatement of Grhl3 expression, by BAC-mediated transgenesis, prevents spina bifida in Grhl3 null embryos, as in the Grhl3 hypomorphic curly tail strain. Notably however, further increase in expression of Grhl3 causes highly penetrant spina bifida. Grhl3 over-expression recapitulates the spinal NTD phenotype of loss-of-function embryos, although the underlying mechanism differs. However, it does not phenocopy other defects of Grhl3 null embryos such as abnormal axial curvature, cranial NTDs (exencephaly) or skin barrier defects, the latter being rescued by the Grhl3-transgene. Grhl2 and Grhl3 can form homo- and heterodimers, suggesting a possible model in which defects arising from over-expression of Grhl3 result from sequestration of Grhl2 in heterodimers, mimicking Grhl2 loss of function. This hypothesis predicts that increased abundance of Grhl2 would have an ameliorating effect in Grhl3 over-expressing embryo. Instead we observed a striking additive genetic interaction between Grhl2 and Grhl3 gain-of-function alleles. Severe spina bifida arose in embryos in which both genes were expressed at moderately elevated levels that individually do not cause NTDs. Furthermore, moderate Grhl3 over-expression also interacted with the Vangl2Lp allele to cause spina bifida, demonstrating genetic interaction with the planar cell polarity signalling pathway that is implicated in mouse and human NTDs