A blast of mistakes: undiagnosed cervical ppondylolisthesis following a bomb explosion

Background: A case of spinal trauma had an unusual clinical course due to medical mistakes, from which we can learn some important lessons. Case Report: We report a case of spondylolisthesis following a bomb explosion, which went undiagnosed for a long time because of a series of mistakes that are highlighted in this article. What makes this case unique is that the spondylolisthesis developed during hospital stay, but the patient had no loss of mobility, strength, or sensitivity. Conclusions: This case shows that establishing the conditions of an organ or a body part upon admission to hospital may not be enough when a patient has suffered extensive and serious trauma, and that it is necessary to carry out more checkups over time, especially if there are new clues and symptoms

UVA-1 phototherapy as adjuvant treatment for eosinophilic fasciitis: in vitro and in vivo functional characterization

Introduction: Eosinophilic fasciitis (EF) is a rare autoimmune disease causing progressive induration of dermal, hypodermal, and muscularis fascia. The exact pathogenesis is yet to be fully understood, and a validated therapy protocol still lacks. We here aimed to realize a clinical–functional characterization of these patients. Materials and methods: A total of eight patients (five males, 45 years average) were treated with adjuvant high-dose UVA-1 phototherapy (90 J/cm), after having received the standard systemic immunosuppressive protocol (oral methylprednisolone switched to methotrexate). Body lesion mapping, Localized Scleroderma Assessment Tool (LoSCAT), Dermatology Life Quality Index (DLQI), High-Resolution Ultrasound (HRUS) (13-17MHz), and ultra HRUS (55–70 MHz) were performed at each examination time taking specific anatomical points. Gene expression analysis at a molecular level and in vitro UVA-1 irradiation was realized on lesional fibroblasts primary cultures. Results: The LoSCAT and the DLQI showed to decrease significantly starting from the last UVA-1 session. A significant reduction in muscularis fascia thickness (−50% on average) was estimated starting from 3 months after the last UVA-1 session and maintained up to 12 months follow-up. Tissues was detected by HRUS. The UVA-1 in vitro irradiation of lesional skin sites cells appeared not to affect their viability. Molecular genes analysis revealed a significant reduction of IL-1ß and of TGF-ß genes after phototherapy, while MMPs 1,2,9 gene expression was enhanced. Comment: These preliminary in vivo and in vitro findings suggest that UVA-1 phototherapy is a safe and useful adjuvant therapy able to elicit anti-inflammatory effects and stimulate tissue matrix digestion and remodeling at lesional sites

Inclusion of a degron reduces levelsof undesired inteins after AAV-mediated proteintrans-splicing in the retina

Split intein-mediated protein trans-splicing expands AAV transfer capacity, thus overcoming the limited AAV cargo. However, non-mammalian inteins persist as trans-splicing by-products, and this could raise safety concerns for AAV intein clinical applications. In this study, we tested the ability of several degrons to selectively decrease levels of inteins after protein trans-splicing and found that a version of E. coli dihydrofolate reductase, which we have shortened to better fit into the AAV vector, is the most effective. We show that subretinal administration of AAV intein armed with this short degron is both safe and effective in a mouse model of Stargardt disease (STGD1), which is the most common form of inherited macular degeneration in humans. This supports the use of optimized AAV intein for gene therapy of both STGD1 and other conditions that require transfer of large genes

Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model

Retinitis pigmentosa (RP) is a group of progressive retinal degenerations of mostly monogenic inheritance, which cause blindness in about 1:3,500 individuals worldwide. Heterozygous variants in the rhodopsin (RHO) gene are the most common cause of autosomal dominant RP (adRP). Among these, missense variants at C-terminal proline 347, such as p.Pro347Ser, cause severe adRP recurrently in European affected individuals. Here, for the first time, we use CRISPR/Cas9 to selectively target the p.Pro347Ser variant while preserving the wild-type RHO allele in vitro and in a mouse model of adRP. Detailed in vitro, genomic, and biochemical characterization of the rhodopsin C-terminal editing demonstrates a safe downregulation of p.Pro347Ser expression leading to partial recovery of photoreceptor function in a transgenic mouse model treated with adeno-associated viral vectors. This study supports the safety and efficacy of CRISPR/Cas9-mediated allele-specific editing and paves the way for a permanent and precise correction of heterozygous variants in dominantly inherited retinal diseases

Gauge theories as a geometrical issue of a Kaluza-Klein framework

We present a geometrical unification theory in a Kaluza-Klein approach that achieve the geometrization of a generic gauge theory bosonic component. We show how it is possible to derive the gauge charge conservation from the invariance of the model under extra-dimensional translations and to geometrize gauge connections for spinors, thus we can introduce the matter just by free spinorial fields. Then, we present the applications to i)a pentadimensional manifold $V^{4}\otimes S^{1}$, so reproducing the original Kaluza-Klein theory, unless some extensions related to the rule of the scalar field contained in the metric and the introduction of matter by spinors with a phase dependence from the fifth coordinate, ii)a seven-dimensional manifold $V^{4}\otimes S^{1}\otimes S^{2}$, in which we geometrize the electro-weak model by introducing two spinors for any leptonic family and quark generation and a scalar field with two components with opposite hypercharge, responsible of spontaneous symmetry breaking.Comment: 37 pages, no figure

Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism

Biological roles of obscurin and its close homolog Obsl1 (obscurin-like 1) have been enigmatic. While obscurin is highly expressed in striated muscles, Obsl1 is found ubiquitously. Accordingly, obscurin mutations have been linked to myopathies, whereas mutations in Obsl1 result in 3M-growth syndrome. To further study unique and redundant functions of these closely related proteins, we generated and characterized Obsl1 knockouts. Global Obsl1 knockouts are embryonically lethal. In contrast, skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only deletion of both proteins and removal of their functional redundancy revealed their roles for sarcolemmal stability and sarcoplasmic reticulum organization. To gain unbiased insights into changes to the muscle proteome, we analyzed tibialis anterior and soleus muscles by mass spectrometry, uncovering additional changes to the muscle metabolism. Our analyses suggest that all obscurin protein family members play functions for muscle membrane systems

Effective delivery of large genes to the retina by dual AAV vectors.

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, AAV's limited cargo capacity prevents its application to therapies of inherited retinal diseases due to mutations of genes over 5 kb, like Stargardt's disease (STGD) and Usher syndrome type IB (USH1B). Previous methods based on "forced" packaging of large genes into AAV capsids may not be easily translated to the clinic due to the generation of genomes of heterogeneous size which raise safety concerns. Taking advantage of AAV's ability to concatemerize, we generated dual AAV vectors which reconstitute a large gene by either splicing (trans-splicing), homologous recombination (overlapping), or a combination of the two (hybrid). We found that dual trans-splicing and hybrid vectors transduce efficiently mouse and pig photoreceptors to levels that, albeit lower than those achieved with a single AAV, resulted in significant improvement of the retinal phenotype of mouse models of STGD and USH1B. Thus, dual AAV trans-splicing or hybrid vectors are an attractive strategy for gene therapy of retinal diseases that require delivery of large gene

Vitamin D deficiency isassociated with increased osteocalcin levels in acute aortic dissection : a pilot study on elderly patients

An imbalance between degradation and reconstruction of the aortic wall is one of the leading causes of acute aortic dissection (AAD). Vitamin D seems an intriguing molecule to explore in the field of AAD since it improves endothelial function and protects smooth muscle cells from inflammation-induced remodeling, calcification, and loss of function, all events which are strongly related to the aging process. We quantified 25-hydroxy vitamin D, calcium, parathormone, bone alkaline phosphatase, and osteocalcin levels in 24 elderly AAD patients to identify a potential pathological implication of these molecules in AAD. Median 25-hydroxy vitamin D (10.75\u2009ng/mL, 25th\u201375th percentiles: 6.86\u201319.23\u2009ng/mL) and calcium levels (8.70\u2009mg/dL, 25th\u201375th percentiles: 7.30\u20138.80\u2009mg/dL) suggested hypovitaminosis D and a moderate hypocalcemia. Thirty-eight percent of AAD patients had severe (<10\u2009ng/mL), 38% moderate (10\u201320\u2009ng/mL), and 24% mild 25-hydroxy vitamin D deficiency (20\u201330\u2009ng/mL). A significant inverse correlation was observed between 25OHD and osteocalcin levels. All the other molecules were unchanged. A condition of hypovitaminosis D associated to an increase in osteocalcin levels is present in AAD patients. The identification of these molecules as new factors involved in AAD may be helpful to identify individuals at high risk as well to study preventing strategies

Anisotropic Vacuum Induced Interference in Decay Channels

We demonstrate how the anisotropy of the vacuum of the electromagnetic field can lead to quantum interferences among the decay channels of close lying states. Our key result is that interferences are given by the {\em scalar} formed from the antinormally ordered electric field correlation tensor for the anisotropic vacuum and the dipole matirx elements for the two transitions. We present results for emission between two conducting plates as well as for a two photon process involving fluorescence produced under coherent cw excitationComment: 6 pages with 2 figures, to appear in Phys. Rev. Lett. (tentative june 2000