Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP MIM 615704) is a very recently described entity of syndromic inherited poikiloderma. ...Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.
Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.
Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes.
HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.
Ketamine and midazolam can produce analgesia following intrathecal administration in rabbits. However, neurotoxicity studies are required before these agents can be considered safe for clinical use. ...The aim of this study was to evaluate by histologic and blood-brain barrier (BBB) studies whether ketamine or midazolam could be used as an alternative to local anesthetics or opioids to produce spinal analgesia. Forty white New Zealand rabbits were randomly assigned to four groups of 10. In the conscious animal, 0.3 ml 0.9% saline solution, 1% lidocaine, 1% ketamine, or 0.1% midazolam was intrathecally injected intracisternally using a modification of the technique of Yaksh et al. Light and fluorescence microscopy were performed on transverse spinal cord sections by a neuropathologist unaware of the administered agents. All spinal cord section slides were scored within four zones: upper cervical, lower cervical, median thoracic, and lumbar segments. Spinal cord homogeneous lesions with higher scores than those of lidocaine-treated animals were considered abnormal. The BBB study showed evidence of neurotoxicity for ketamine, whereas light microscopy indicated no significant differences in comparison with saline and lidocaine. Midazolam-treated rabbits showed significant changes in both BBB and light microscopy studies. In view of these results, the intrathecal use of midazolam should be avoided in humans. Lesions observed following ketamine suggest the need for further experimental studies of the solvent and different ketamine enantiomers to establish definitively the safety of intrathecal free ketamine in humans.
Monoclonal gammopathy-associated demyelinating neuropathy is a common and probably under-recognized peripheral neuropathy in elderly patients. The presence of serum anti-myelin-associated ...glycoprotein antibodies, immunoglobulin M and complement deposits on the myelin sheaths, as well as animal models, favor an immune-mediated disease supporting the use of immune therapies.
Abstract only
Adherent‐invasive
Escherichia coli
(AIEC), associated with Crohn's disease, are likely candidate contributory factors in the disease. However, signaling pathways involved in human ...intestinal mucosa innate host response to AIEC remain unknown. Here we use a 3‐D model of human intestinal mucosa explant culture to explore the effects of the AIEC strain LF82, on two innate immunity platforms, i.e. the inflammasome through evaluation of caspase‐1 status, and NFkB signaling. We showed that LF82 bacteria enter and survive within a few intestinal epithelial cells and lamina propria macrophages, without altering the mucosa overall architecture. While 4h infection with a
Salmonella
strain caused crypt disorganization, caspase‐1 activation and mature IL‐18 production, LF82 bacteria were unable to activate caspase‐1 and induce IL‐18 production. In parallel, LF82 bacteria activated NFkB signaling in epithelial cells through IkBα phosphorylation, NFkBp65 nuclear translocation and TNFα secretion. In addition, pharmacological blockade of NFkB activation using the SN50 peptide showed that NFkB activation was crucial for the maintenance of epithelial homeostasis upon LF82 infection. In conclusion, here we decipher at the whole mucosa level the mechanisms of the LF82‐induced subversion of innate immunity that, by maintaining host cell integrity, ensure intracellular bacteria survival.
Head drop is an abnormal forward flexion of the cervical spine that increases while standing and typically disappears in the supine position. Patients are able to straighten their head with the aid ...of a support. We report a case of head drop suggesting inflammatory myopathy in an 80-year-old woman. Adapted from the source document.
Clinical Reminder Riaudel, Typhaine; Khatchatourian, Lydie; Chevalet, Pascal ...
Age and ageing,
01/2013, Volume:
42, Issue:
1
Journal Article
Peer reviewed
Riadel et al report a case of head drop suggesting inflammatory myopathy in an 80-year-old woman. An 80-year-old woman presented with a two-month history of mechanical back pain, weight loss and ...difficulty in standing up straight. Physical examination showed an involuntary neck flexion in orthostatism that resolved in supine position. They found elevated levels of creatine kinase, antinuclear antibodies and a pulmonary fibrosis. Deltoid muscle biopsy showed inflammatory myopathy. The patient presented autoimmune inflammatory myositis associated with positive auto-antibodies and pulmonary fibrosis, suggesting overlap myositis.
Experiments were performed on rabbits randomly assigned to intracisternally receive 0.3 mL of plain bupivacaine 5 mg/mL, liposomal bupivacaine 5 mg/mL, bupivacaine-free liposomes, or isotonic ...phosphate-buffered saline. Mechanical ventilation was initiated or intravenous dopamine was infused when respiratory depression or hypotension occurred. Seven days after the injection, the whole spinal cord was removed and histopathologic characteristics were studied on transverse sections. All preparations were devoid of phosphatidylcholine hydrolysis or oxidation compounds. Solutions without bupivacaine produced transient irritative signs that required sedation in most rabbits. Despite the similar duration of respiratory depression in groups receiving liposomal or plain bupivacaine, liposomes produced significantly prolonged motor blockade (126 vs 70 min). Correction of hypotension after plain bupivacaine required a longer dopamine infusion and larger doses than after liposomal bupivacaine (28 vs 18 min and 74 vs 47 mg). Necrosis was observed in the cervical area of two rabbits (one in the liposomal bupivacaine group and another in the phosphate buffer group). No demyelinated areas were noted in spinal cord examinations. We conclude that liposomal bupivacaine leads to a less severe sympathetic block and to a prolonged motor block, whereas histologic changes are not significantly different among groups.
Multilamellar liposomes containing bupivacaine administered intracisternally to rabbits produce spinal cord histopathologic changes not significantly different from those observed with plain bupivacaine. Sustained release of bupivacaine from liposomes is suggested by the prolonged motor blockade and the reduced severity of arterial hypotension. Use of these liposomes could prolong the local anesthetic effects of bupivacaine.
Chester-Erdheim disease is a rare non-langerhans cell histiocytosis characterized by a xanthomatous infiltration of foamy macrophages. The cause and pathogenesis remain unclear. The aim of the ...present study was to determine whether Chester-Erdheim disease is a polyclonal reactive disease or a clonal neoplastic disorder. The clonal status of samples obtained from five patients with Chester-Erdheim disease was studied. DNA was extracted from fixed and paraffin-embedded sections after microdissection and clonal status was studied using the X-chromosome inactivation pattern of the human androgen receptor gene (HUMARA assay). One patient was homozygous for the HUMARA gene and noninformative. Three other cases were monoclonal. One was polyclonal, and this case showed a dense reactive infiltrate in association with spumous macrophages. This study suggests strongly that Chester-Erdheim disease is a monoclonal lesion consistent with neoplastic disorder. Thus, Chester-Erdheim disease may be considered as the “macrophage” counterpart of Langerhan's cell histiocytosis in the histiocytosis spectrum. Further studies are needed to establish the origin of this clonal proliferation.
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