Self-perceived attention difficulties are associated with sensory hypersensitivity in migraine.

BACKGROUND: Attention is the process which enables to preferentially select salient or relevant stimuli and to attenuate the response to irrelevant incoming stimuli. Migraine is characterized by both attentional alterations and an abnormal sensory processing to external stimulations. The aim of the study was to investigate potential interactions between self-perceived attentional difficulties and sensory hypersensitivity in migraine patients. METHODS: Forty-six episodic migraineurs without aura and 46 healthy controls filled out questionnaires on self-perceived attention difficulties and self-reported sensitivity to visual, auditory and olfactory stimulations. RESULTS: Compared to controls, migraineurs reported significantly higher levels of attention difficulty and sensory sensitivity. Sensory hypersensitivity correlated significantly with self-perceived attentional difficulties in migraineurs (P=0.002), but not with migraine disability or levels of anxiety or depression. Ictal and interictal sensory sensitivities were significantly correlated in migraineurs within visual (P<0.001), auditory (P<0.001) and olfactory (P=0.001) modalities. CONCLUSION: This study shows for the first time an association between self-reported attentional difficulties and multimodal sensory hypersensitivity. Studies combining behavioral and physiological measures of sensory processing and attention processes are necessary to further understand the peculiar vulnerability of migraineurs to sensory stimuli.

[Cutaneous loxoscelism, about an exceptional observation of 9 consecutive cases]. / Le loxoscelisme cutané, à propos d'une observation exceptionnelle de 9 cas consécutifs.

INTRODUCTION: Loxosceles spiders are ubiquitous and responsible for many cases of envenomation in the world. The kind rufescens is present in the Provence and Occitan regions in France. During the summer 2015, we faced many Loxosceles rufescens cases of bites having led to extensive integumental necrosis whose features and singular evolution seems important to report. MATERIAL AND METHODS: We report the cases of nine patients who experienced a spider bite in the summer of 2015 in the Languedoc Roussillon. RESULTS: Of nine patients, eight patients had skin necrosis and five required surgical care. Five patients had a fever and had five other general signs such as important asthenia, joint pain, nausea and dizziness. CRP was very low normal in all patients. Finally, five of the nine patients reported a residual pain. DISCUSSION: L. rufescens is a small spider (7 to 15mm in diameter) having a cytotoxic venom. Loxoscelism diagnosis is usually made by removing a front necrotic skin lesion. Of systemic loxoscelism that have been described, some American species had fatal outcomes. The treatment remains controversial with various options: surgery, antibiotics, antihistaminics, antivenom. CONCLUSION: The diagnosis must be made in endemic areas when confronted to a necrosic integumentary infectious rapidly progressive, unresponsive to antibiotic treatment associated with atypical general signs.

Preliminary insights into RNA in CSF of pediatric SMA patients after 6 months of nusinersen.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre-mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery. METHODS: By RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0). RESULTS: We observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into "homogeneous" and "heterogeneous" according to their gene expression pattern. The "heterogeneous" group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern. CONCLUSIONS: This study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.

In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.

Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.

Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein.

To determine the function of the pS2 trefoil protein, which is normally expressed in the gastric mucosa, the mouse pS2 (mpS2) gene was inactivated. The antral and pyloric gastric mucosa of mpS2-null mice was dysfunctional and exhibited severe hyperplasia and dysplasia. All homozygous mutant mice developed antropyloric adenoma, and 30 percent developed multifocal intraepithelial or intramucosal carcinomas. The small intestine was characterized by enlarged villi and an abnormal infiltrate of lymphoid cells. These results indicate that mpS2 is essential for normal differentiation of the antral and pyloric gastric mucosa and may function as a gastric-specific tumor suppressor gene.

Receptor activated C kinase is down-regulated in the male gonad of the marine bivalve mollusc Mya arenaria exposed to tributyltin (TBT).

This study was aimed at investigating the molecular mechanisms by which tributyltin (TBT) impairs the reproductive processes in the marine bivalve Mya arenaria. The suppression polymerase chain reaction subtractive hybridization (SSH) method was used to identify differentially expressed transcripts in the gonads of adult M. arenaria 72 h after a single injection of 160 ng TBT in the adductor muscle. Subtractive cDNA libraries comprising 322 clones were obtained. These clones were sequenced and corresponded to 55 female and 26 single male non-redundant cDNAs. Following similarity searches in genome databases, some of the transcripts could be assigned to cellular functions including mitochondrial respiration, structural proteins, structure of cytoskeleton, nucleic acid regulation, general metabolism and signal transduction. Among the potentially differentially regulated transcripts, Receptor for activated C kinase 1 (RACK1) represented 6% of the total down-regulated clones in males and the corresponding protein exhibited a high degree of similarity (80%) with the human polypeptide. The RACK1 cDNA from M. arenaria consists of 1085 bp, encoding a 318 deduced polypeptide which contains five internal tryptophan-aspartate (WD) repeats, six putative PKC phosphorylation sites, one tyrosine kinase site, four putative N-myristoylation sites as well as a transmembrane segment spanning amino acid 228-251. A significant down-regulation (by approximately 30% (p<0.05)) of RACK1 expression in male gonads exposed to TBT was confirmed by quantitative real-time RT-PCR. Transcript levels of RACK1 were higher in the female gonads than in the mantle, gills and male gonads. Gene expression as detected by in situ hybridization was strong in mature oocytes comparatively to primary germ cells. RACK1 may be a useful biomarker for TBT exposure in the reproductive system of bivalve molluscs.

[Pediatric cases in preclinical emergency medicine: critical aspects in the range of missions covered by ground ambulance and air rescue services]. / Pädiatrische Notfälle in der präklinischen Notfallmedizin: Schwerpunkte des Einsatzspektrums im bodengebundenen Rettungsdienst und in der Luftrettung.

BACKGROUND: The aim of this study was to demonstrate differences in structure and severity of pediatric emergencies treated by aeromedical (air rescue) or ground ambulances services. Conclusions for the training of emergency physicians are discussed. PATIENTS AND METHODS: In a 3-year study period, a total of 9,274 pediatric emergencies covered by the ADAC air rescue service are compared to 4,344 pediatric patients of ground ambulance services in Saarland. RESULTS: In aeromedical services pediatric emergencies are more frequent (12.9% vs. 6.4%), trauma predominates (59.9% vs. 35.6%) and severe injuries or diseases occur more frequently (30.5% vs. 15.0%). In both groups pediatric emergency cases are concentrated into very few diagnostic groups: more than one third of the cases involving pre-school children is due to convulsions. Respiratory diseases and intoxication are the next most frequent causes and are more common in ground ambulance patients. Head trauma is the most common diagnosis in cases of pediatric trauma, followed by musculoskeletal and thoracoabdominal trauma. All types of severe trauma are more frequent in pediatric patients of the aeromedical services. CONCLUSIONS: Training of emergency physicians should include pediatric life support and specific information about frequent pediatric emergency situations. For emergency physicians in aeromedical services, an intensive training in pediatric trauma life support is also necessary.

High cancer cell death in syngeneic tumors developed in host mice deficient for the stromelysin-3 matrix metalloproteinase.

Matrix metalloproteinases (MMPs) are extracellular enzymes. Some of them are known to be involved in tumor development and/or progression. Several cellular functions have been proposed for MMPs during malignant processes. Notably, they may be involved in tissue-remodeling processes through their ability to digest matrix components or to participate in tumor neoangiogenesis and, subsequently, in cancer cell proliferation. One of these MMPs, stromelysin-3 (ST3/MMP11), although devoid of enzymatic activity against the matrix components, is associated with human tumor progression and poor patient clinical outcome. Using several in vivo experimental models, it has been demonstrated that ST3 expression by the fibroblastic cells surrounding malignant epithelial cells promotes tumorigenesis in a paracrine manner. The present study was devoted to the identification of the cellular function underlying this ST3-induced tumor promotion using a syngeneic tumorigenesis model in mice. Our results show that ST3 exhibits a new and unexpected role for a MMP, because ST3-increased tumorigenesis does not result from increased neoangiogenesis or cancer cell proliferation but from decreased cancer cell death through apoptosis and necrosis. Thus, during malignancy, the cellular function of ST3 is to favor cancer cell survival in the stromal environment.

Early white matter involvement in an infant carrying a novel mutation in ACOX1.

We describe the clinical findings and MRI features observed in a child who presented a two-step disease course: he was hypotonic at birth and soon afterwards developed seizures, which were partially responsive to treatment; he subsequently showed developmental delay and a progressive neurological deterioration with the onset of severe seizures at around three years of age. Head MRI at age 20 days was unremarkable, whereas at 25 months it showed bilateral hyperintensity of the deep cerebellar nuclei; five months later, the signal hyperintensity was also present in the cerebellar white matter and ventral pontine fibre tracts. Molecular analysis revealed a novel ACOX1 mutation, predicting a largely truncated protein. The white matter involvement, which followed an ascending trajectory from cerebellar and brainstem structures to the cerebral hemispheres, seemed to originate from the perinuclear white matter of the deep cerebellar nuclei.

Diagnosing pelvic osteomyelitis beneath pressure ulcers in spinal cord injured patients: a prospective study.

There is no consensus on a diagnostic strategy for osteomyelitis underlying pressure ulcers. We conducted a prospective study to assess the accuracy of multiple bone biopsies and imaging to diagnose pelvic osteomyelitis. Patients with clinically suspected osteomyelitis beneath pelvic pressure ulcers were enrolled. Bone magnetic resonance imaging (MRI) and surgical bone biopsies (three or more for microbiology and one for histology per ulcer) were performed. Bacterial osteomyelitis diagnosis relied upon the association of positive histology and microbiology (at least one positive culture for non-commensal microorganisms or three or more for commensal microorganisms of the skin). From 2011 to 2014, 34 patients with 44 pressure ulcers were included. Bacterial osteomyelitis was diagnosed for 28 (82.3%) patients and 35 (79.5%) ulcers according to the composite criterion. Discrepancy was observed between histology and microbiology for 5 (11.4%) ulcers. Most common isolates were Staphylococcus aureus (77.1%), Peptostreptococcus (48.6%) and Bacteroides (40%), cultured in three or more samples in 42.9% of ulcers for S. aureus and ≥20% for anaerobes. Only 2.8% of ulcers had three or more positive specimens with coagulase-negative staphylococci, group B Streptococcus, and nil with enterococci and Pseudomonas aeruginosa. Staphylococcus aureus, Proteus and group milleri Streptococcus were recovered from one sample in 22.8%, 11.4% and 11.4% of ulcers, respectively. Agreement was poor between biopsies and MRI (κ 0.2). Sensitivity of MRI was 94.3% and specificity was 22.2%. The diagnosis of pelvic osteomyelitis relies on multiple surgical bone biopsies with microbiological and histological analyses. At least three bone samples allows the detection of pathogens and exclusion of contaminants. MRI is not routinely useful for diagnosis.

Tumor necrosis factor receptor associated factor 4 (TRAF4) expression pattern during mouse development.

This is the first in situ hybridization analysis of expression of a tumor necrosis factor (TNF) receptor associated factor (TRAF) during development. TRAF4 is observed throughout mouse embryogenesis, most notably during ontogenesis of the central (CNS) and peripheral (PNS) nervous system, and of nervous tissues of sensory organs. TRAF4 is preferentially expressed by post-mitotic undifferentiated neurons. Interestingly, TRAF4 remains expressed in the adult hippocampus and olfactory bulb, known to contain multipotential cells responsible for neoneurogenesis.

Chromosomal assignment and expression pattern of the murine Lasp-1 gene.

The human Lasp-1 (LIM and SH3 protein) gene was previously identified by differential screening of a breast cancer-derived metastatic lymph node cDNA library. It was located on the q12-q21 region of human chromosome 17 and was shown to be amplified and overexpressed in 12% of breast tumors. Lasp-1 defines a new LIM-protein subfamily, as it associates a C-terminal Src homology 3 (SH3) domain to a N-terminal LIM motif. In this study, the isolation and characterization of the cDNA encoding the mouse Lasp-1 protein are described, and it is shown to be highly conserved with its human counterpart. In addition to the LIM and SH3 domains, both human and mouse Lasp-1 contain an actin-binding domain. The mouse gene was mapped by in situ hybridization to the 11C-11D region of chromosome 11. Northern blot analysis shows that this gene is expressed from 7.5 to 17.5 days post-coitum of mouse embryogenesis and in almost all adult tissues.

Descending projections to the rat sacrocaudal spinal cord.

Descending supraspinal and propriospinal neurons projecting to the female rat sacrocaudal spinal cord, the portion of the spinal cord that innervates the tail, were identified following injection of Fluoro-Gold into the S1-Ca2 spinal cord segments. This study attempted to determine anatomical substrates for propriospinal and supraspinal control of the tail. Propriospinal neurons were identified throughout laminae V-VIII and X at all levels of the spinal cord. The greatest density of labeling was in the lumbar enlargement, followed by the cervical enlargement, with least in the thoracic spinal cord. Within a given cord level, labeling was greatest within the intermediate zone. In addition, other prominent spinal cord collections included neurons in 1) lamina V of the lumbar enlargement, 2) dorsal lamina X of the cervical enlargement, and 3) the lateral spinal nucleus within the cervical enlargement. Supraspinal cells were identified within raphe nuclei, reticular formation nuclei, dorsal column nuclei, vestibular nuclei, noradrenergic groups, the red nucleus, the periaqueductal gray, the hypothalamus, and the motor cortex. These data indicate that there are significant descending projections to the sacrocaudal spinal cord, with distributions similar to those of other cord levels. Functionally, important supraspinal and propriospinal influences on tail, pelvic viscera and limbs, such as with locomotion, balance, defense, micturition, defecation, and sexual functions, may be mediated by these connections.

Crossed and uncrossed projections to cat sacrocaudal spinal cord: II. Axons from muscle spindle primary endings.

The terminal fields of primary afferent fibers from tail muscle spindle primary endings were mapped within cat sacrocaudal spinal cord (S3-Ca7), using intra-axonal recording and horseradish peroxidase staining techniques. We sought to determine the ipsilateral and contralateral projection patterns and to relate these to the fibers' muscles of origin. Fifty-three group Ia fibers were successfully stained. Segmental collaterals originated from either the ascending or descending branch within the dorsal columns. Collaterals coursed rostromedially within the dorsal columns and traversed the medial aspect of the dorsal horn. Ipsilateral terminations were similar for all fibers. Within the ventral horn, boutons were consistently observed in the medial or central portions of lamina VII. In lamina VIII, a variable number of boutons was seen on fine branches emerging from larger fibers coursing ventrally. Clusters of terminals were plentiful in the regions of motoneurons, i.e., lamina IX and the nucleus commissuralis. Terminals were found in the adjacent white matter. In addition to ipsilateral terminations, some group Ia fibers (20 of 53) had collateral branches that crossed ventrally to the central canal, terminating within the midline ventral gray commissure and/or the contralateral ventral horn. Crossed projections always originated in medial (dorsal or ventral), but not lateral, muscles of the tail. These data suggest that ipsilateral projections of group Ia fibers make connections on sacrocaudal motoneurons, on neurons mediating segmental reflex functions and on neurons conveying ascending information. It is speculated that crossed and uncrossed connections between group Ia fibers from medial muscles and bilateral dendritic trees of motoneurons subserve synchronized co-contraction of synergistic muscles located on the two sides of the body, such as with dorsal or ventral flexion of the tail. Group Ia projections from lateral muscles, that are entirely ipsilateral, would be involved with lateral movements of the tail.

Pulmonary microvascular cytology. A new diagnostic application of the pulmonary artery catheter.

When pulmonary disorders involve primarily the microvasculature, definitive diagnosis is difficult and, in some cases, is not possible until autopsy. In patients with amniotic fluid embolism, fat embolism, and lymphangitic carcinomatosis, terminal pulmonary arterioles and capillaries contain abundant diagnostic material. We hypothesized that withdrawal of blood from a pulmonary artery catheter, particularly in the wedge position, should recover diagnostic cells and debris in patients with these disorders. We describe the technique of pulmonary microvascular cytology and show examples of the recovery of fetal squames in amniotic fluid embolism, fat globules in fat embolism, and malignant cells in lymphangitic carcinomatosis. Megakaryocytes, normal inhabitants of the pulmonary capillary bed, are readily seen in wedged blood and confirm the microvascular origin of a blood sample.

Amniotic fluid embolism.

Amniotic fluid embolism is the most unpredictable and catastrophic complication of pregnancy, accounting for 10% to 20% of maternal deaths. The pulmonary edema commonly seen in this syndrome is probably due primarily to alveolar capillary leakage and may be potentiated by high maternal extracellular volume, low colloid osmotic pressure, and, in some patients, by depressed myocardial function. In patients in whom resuscitation is successful, diuresis leads to rapid resolution of pulmonary edema. Amniotic fluid does not ordinarily enter the maternal circulation, and the identification of large numbers of fetal squames in the postpartum pulmonary microvasculature is probably of clinical significance.

Embolization of a dural arteriovenous fistula of the ventral cervical spinal canal in a nine-year-old boy.

A 9-year-old patient presented with an acute left hemiparesis secondary to an intradural hemorrhage of the cervical spinal cord. Angiography revealed a dural arteriovenous (AV) fistula with multiple venous aneurysms fed by a radicular branch of the right vertebral artery. This AV fistula did not contribute blood flow to the cervical segment of the spinal cord, which was tested by an intra-arterial injection of methohexital. Interruption of the fistula was possible by transluminal embolization with polyvinyl alcohol and silk. At a 6-month follow-up, the patient was neurologically intact, and angiography demonstrated no AV fistula. This case illustrates an unusual presentation of a dural AV fistula. Dural AV fistulas are rare in the cervical region and extremely unusual in patients less than 20 years of age. The lesion proved to be amenable to transluminal embolization alone, without the need for surgery, with a dramatic resolution of the neurological deficit.

Aneurysmal intracerebral hemorrhage.

Approximately 20% of all massive nontraumatic intracerebral hemorrhages are caused by ruptured intracranial aneurysms. The possibility for repeated and catastrophic rebleeds, potentially reversible increased intracranial pressure effects, and the need for cerebral vasospasm treatment make the early identification of this cause of hematoma mandatory.

[Study of neurological manifestations of chronic lymphatic leukemia (lymphosis). Role of associated globulin anomalies (apropos of 8 cases)]. / Contribution à l'étude des manifestations neurologiques des leucémies lymphoïdes chroniques (lymphoses). Role des anomalies globuliniques associées (a propos de huit observations)

The authors emphasize the relative frequency of neurological symptoms in lymphatic leukaemia. Clinically, these cause more or less diffuse encephalitic or multineuritic syndromes, generally a combination of the two. Their pathogenesis is usually connected with lymphoid tissue infiltration into either the meninges or the vascular sheaths of the central nervous system or the sheaths of the roots or of the peripheral nerves. The authors stress the possible function of immunoglobulin abnormalities of the C.S.F. indicative of the presence of the leukaemic process within the nervous system. This pathogenesis prompts the use of therapeutic methods directly attacking leukaemic infiltration of the nervous system (focal cobalt therapy, intrathecal chemotherapy) and the authors have found that these give favourable results.

[Use of local cobalt therapy in peripheral neuropathies associated with chronic lymphopathies (lymphoses). 2 cases with histo-immunologic and ultrastructural records]. / Intérêt de la cobaltothérapie locale dans les neuropathies périphériques des lymphopathies chroniques (lymphoses). Deux observations avec documents histo-immunologiques et ultrastructuraux.

In two cases of peripheral neuropathy, associated with a chronic lymphopathy, cobalt therapy to the lower limbs provided considerable relief of pain, with partial motor recovery. The disappearance after cobalt therapy of the lymphoid infiltrate of the peripheral nerve leads to discussion of the pathogeni role of this infiltrate. Immunofluorescent and electron microscopic studies form the basis of a discussion of the mechanism of involvement of the peripheral nerve non-secreting lymphopathies (chronic lymphoid leukaemia) and in secreting lymphopathies (Waldenström's disease).