Subversion of human intestinal mucosa innate immunity by a Crohn's disease-associated E. coli.

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 3D 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 NFκB signaling. We showed that LF82 bacteria enter and survive within a few intestinal epithelial cells and macrophages, without altering the mucosa overall architecture. Although 4-h 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 NFκB signaling in epithelial cells through IκBα phosphorylation, NFκBp65 nuclear translocation, and TNFα secretion. In addition, NFκB 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.

Late-onset cervicoscapular muscle atrophy and weakness after radiotherapy for Hodgkin disease: a case series.

Patients with cervical or mediastinal Hodgkin disease (HD) classically underwent chemotherapy plus extended-field radiation therapy. We report six patients who gradually developed severe atrophy and weakness of cervical paraspinal and shoulder girdle muscles 5-30 years after mantle irradiation for HD. Although clinical presentation was uniform, including a dropped head syndrome, electrophysiological and pathological findings were rather heterogeneous. Either neurogenic or myogenic processes may be involved and sometimes combined. We discuss the pathophysiological mechanisms underlying these cervicoscapular motor complications of mantle irradiation in HD.

[Macrophagic myofasciitis. Study and Research Group on Acquired and Dysimmunity-related muscular diseases (GERMMAD)]. / La myofasciite à macrophages. Groupe d'Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD).

UNLABELLED: MACROPHAGIC MYOFASCIITIS: A most unusual inflammatory myopathy, first described by Germmad had been reported with increasing frequency since 1993 in the leading French myopathology centers. We present our experience with this new disease: macrophagic myofasciitis. CLINICAL FEATURES: By November 1999, 70 cases of macrophagic myofasciitis had been recorded since our first description. The first 22 patients (sex ratio M/F = 1:3) referred with the presumptive diagnosis of polymyositis (n = 11), polymyalgia rheumatica (n = 5), mitochondrial cytopathy (n = 4), and congenital myopathy or muscle dystrophy (n = 1 each). Symptoms included myalgia (91%), anthralgia (68%), marked asthenia (55%), muscle weakness (45%), and fever (32%). LABORATORY FINDINGS: Abnormal laboratory findings included elevated CK levels (50%), markedly increased erythrocyte sedimentation rate (37%), and myopathic EMG (35%). Muscle biopsy showed a unique myopathological pattern characterized by: i) centripetal infiltration of epimysium, perimysium and perifascicular endomysium by sheets of large cells of the monocyte/macrophage lineage (CD68+, CD1a-, S100-, with a PAS-positive content; ii) absence of necrosis, of both epithelioid and giant cells, and of mitotic figures; iii) presence of occasional CD8+ T-cells; iv) inconspicuous muscle fiber damage. The picture was easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. The infectious diseases know to be associated with reactive histiocytes, including Whippleís disease, Mycobacterium avium intracellulare infection and malakoplakia, could not be documented. Patients improved under corticosteroid therapy and/or immunomodulatory therapeutic CONCLUSION: A new inflammatory muscle disorder, characterized by a distinctive pathological pattern of macrophagic myofasciitis is emerging in France.

Chester-Erdheim disease: a neoplastic disorder.

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 Xchromosome 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.

[Macrophagic myofasciitis: description and etiopathogenic hypotheses. Study and Research Group on Acquired and Dysimmunity-related Muscular Diseases (GERMMAD) of the French Association against Myopathies (AFM)]. / La myofasciite à macrophages: description, hypothèses étiopathogéniques. Groupe d'Etudes et de Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l'Association Française contre les Myopathies (AFM).

PURPOSE: A new type of inflammatory myopathy of unknown etiology has recently been described in France. The myopathy, called macrophagic myofasciitis, had never been described in the literature. METHODS: In December 1998, 35 cases of macrophagic myofasciitis were reported, showing an increase in its incidence since the description of the first case in 1993. The first 22 cases are described. RESULTS: The 22 patients were each referred with a presumptive diagnosis of either polymyositis (11 patients), polymyalgia rheumatica (5 patients), mitochondrial cytopathy (4 patients), or congenital myopathy or muscle dystrophy (1 patient for each). Clinical symptoms included myalgias (91%), arthralgias (68%), marked asthenia (55%), muscle weakness (45%), and fever (32%). Laboratory findings included elevated CK levels (50%) and a marked increased in the erythrocyte sedimentation rate (37%). Electromyographic recordings showed the existence of myopathy (35%). Muscle biopsy showed a unique pattern characterized by: (i) centripetal infiltration of the epimysium, perimysium and perifascicular endomysium by non epitheloid, cells of the monocyte/macrophage lineage (CD68+, CD1a-, S100-) with both large cytoplasm and PAS-positive content; (ii) absence of necrosis, of both epithelioid and giant cells, and of mitotic figures; (iii) occasional CD8+ T-cells; and, (iiii) minimal myocyte suffering. The disease symptoms were easily distinguishable from those of sarcoid myopathy and fasciitis-panniculitis syndromes. Infectious diseases known to be associated with reactive histiocytosis, including Whipple's disease, Mycobacterium avium intracellulare infection and malakoplakia, could not be documented. Patients' condition improved under corticosteroid therapy, associated or not with non-specific antibiotic therapy. CONCLUSION: A new inflammatory muscle disorder of unknown etiology, characterized by a distinctive pathological pattern of macrophagic myofasciitis, is emerging in France. Diagnosis is based on muscular biopsy. Numerous clinical, epidemiological and etiopathologic studies initiated by the GERMMAD (Groupe d'études et de recherche sur les maladies musculaires acquises) are in progress.

Marked systemic amyloid angiopathy in patients with val 107 transthyretin mutation.

We report three non-inbred patients with Val 107 transthyretin (TTR) amyloidosis. Clinical features were remarkable by the combination of peripheral polyneuropathy, carpal tunnel syndrome, cardiomyopathy, and epilepsy. Pathologic examination disclosed unusual striking systemic amyloid angiopathy in all studied tissues including nerve, muscle, gut, lung, salivary glands, and synovial membrane. It appears that the rare TTR Val 107 variant causes a peculiar familial amyloid syndrome characterized by both widespread systemic TTR amyloidosis and central nervous system deposition sufficient to cause seizures, pointing out the extent of TTR amyloidosis phenotypic heterogeneity.

Macrophagic myofasciitis: an emerging entity. Groupe d'Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l'Association Française contre les Myopathies (AFM).

BACKGROUND: An unusual inflammatory myopathy characterised by an infiltration of non-epithelioid histiocytic cells has been recorded with increasing frequency in the past 5 years in France. We reassessed some of these cases. METHODS: We did a retrospective analysis of 18 such cases seen in five myopathology centres between May, 1993, and December, 1997. The myopathological changes were reassessed at a clinopathology seminar. FINDINGS: Detailed clinical information was available for 14 patients. The main presumptive diagnoses were polymyositis and polymyalgia rheumatica. Symptoms included myalgias in 12 patients, arthralgias in nine, muscle weakness in six, pronounced asthenia in five, and fever in four. Abnormal laboratory findings were occasionally observed, and included raised creatine kinase concentrations, increased erythrocyte sedimentation rate, and myopathic electromyography. Muscle biopsy showed infiltration of the subcutaneous tissue, epimysium, perimysium, and perifascicular endomysium by sheets of large macrophages, with a finely granular PAS-positive content. Also present were occasional CD8 T cells, and inconspicuous muscle-fibre damage. Epithelioid and giant cells, necrosis, and mitotic figures were not seen. The images were easily distinguishable from sarcoid myopathy and fasciitis-panniculitis syndromes. Whipple's disease, Mycobacterium avium intracellulare infection, and malakoplakia could not be confirmed. Ten patients were treated with various combinations of steroids and antibiotics; symptoms improved in eight patients, and stabilised in two. INTERPRETATION: A new inflammatory muscle disorder of unknown cause, characterised by a distinctive pathological pattern of macrophagic myofasciitis, is emerging in France.

Pathology of the central nervous system in Chester-Erdheim disease: report of three cases.

Chester-Erdheim disease is a rare form of non-Langerhans cell histiocytosis consisting of disseminated xanthogranulomatous infiltration and fibrosis that primarily involves the bones, visceral organs and systemic fatty spaces. Involvement of the central nervous system is variable, and neuropathological features have seldom been documented. We report the neuropathological findings in 3 autopsy cases. One patient had radiological and pathological bone changes characteristic of Chester-Erdheim disease. Neuropathology revealed multiple characteristic xanthogranulomas disseminated in the cerebral hemispheres, hypothalamus, cerebellum, and brainstem. The second patient presented first with cutaneous lesions characteristic of Langerhans cell histiocytosis. She subsequently developed bone abnormalities suggestive of Chester-Erdheim disease, which was confirmed by autopsy, raising the possibility of a common spectrum of histiocytosis including both diseases. Gross examination of the brain was normal, however, microscopy showed infiltration of the brain by characteristic non-Langerhans cell xanthogranulomas. The third patient presented with systemic features characteristic of Chester-Erdheim disease. Neurological signs included gait disturbance, seizures and confusion. Examination of the brain did not show any histiocytic infiltration, but did show changes suggestive of Hallervorden-Spatz syndrome. Association of Chester-Erdheim disease and Hallervorden-Spatz syndrome has not been previously reported. The relationship between both conditions is unclear.

Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study.

BACKGROUND: Graft-versus-host disease (GVHD) is a major complication after bone marrow transplantation, which may be refractory to immunosuppressive drugs. As preliminary case reports suggested that extracorporeal photochemotherapy (ECP) using a Therakos device might be beneficial, we conducted a pilot study to assess the efficacy and safety of a new ECP method that does not require administration of 8-methoxypsoralen (8-MOP) to the patient. METHODS: ECP was performed three times a week for 3 weeks and then tapered according to the patient's course. Soluble 8-MOP was added ex vivo to an enriched mononuclear cell suspension obtained by a cell separator. This cellular suspension was then ultraviolet A irradiated and reinfused into the patient. Evaluation was performed using specific objective tests depending on clinical conditions. RESULTS: The two patients in the study with acute GVHD and severe liver dysfunction resistant to steroid pulse showed no improvement with ECP treatment. The five patients with chronic GVHD (c-GVHD) had the following clinical features: three patients had myositis and two patients had severe cutaneous c-GVHD, including one patient with sclerodermoid lesions, one with bronchiolitis obliterans, one with bronchitis, and one with liver involvement. Immunosuppressive drugs were either prohibited or ineffective. The number of procedures for each patient ranged from 13 to 30. Cytapheresis required the use of a double-lumen catheter (4/5) or an arteriovenous fistula (1/5). No side effects were related to 8-MOP or ultraviolet A irradiation. Four of five patients improved after ECP; one patient with bronchiolitis obliterans, a fibrotic condition, remained stable. CONCLUSIONS: ECP treatment may be helpful for the treatment of severe c-GVHD and the avoidance of increased immunosuppression.

Long-term prognosis of 69 patients with dermatomyositis or polymyositis.

OBJECTIVES: To assess the long-term prognosis of dermatomyositis and pol myositis. METHODS: 69 patients with dermatomyositis or polymyositis were selected according to the diagnostic criteria of Bohan and Peter and were followed up for a minimum of 6.3 years (for surviving patients) (mean 11.6 years). Clinical and biological features, and pulmonary and muscle parameters were considered as prognostic factors for death. Functional disability was assessed using a 4-stage grading system. RESULTS: 30 deaths (43.5%) occurred mainly due to cardiovascular (8), pulmonary (8), carcinomatous (5) and iatrogenic complications (5). Survival rates were 82.6% at 1 year, 73.9% at 2.66, 7% at 5 and 55.4% at 9. Significant prognostic factors for death (Cox model with time-dependent covariates) were old age (p < 0.0001), dysphonia (p < 0.001), pulmonary interstitial fibrosis (p < 0.02), absence of dysphagia (p < 0.02) and asthenia-anorexia (p < 0.05). Dermatomyositis and polymyositis subgroups had slightly different significant prognostic factors for death: old age, cancer, pulmonary interstitial fibrosis and asthenia-anorexia for dermatomyositis; old age, failure to improve muscle strength in response to treatment after one month, and the absence of myalgia as presenting symptom for polymyositis. At the end of the follow-up, 33/39 surviving patients (84.6%) had no or insignificant muscular disability, whereas 3 children were bedridden due to generalized calcinosis. CONCLUSIONS: High mortality occurred in the first year, and the survival rate decreased continually up to 9 years. The main prognostic factor for death is old age, but dermatomyositis and polymyositis must be considered separately. General features (pulmonary fibrosis, cancer, asthenia-anorexia) are involved in dermatomyositis, whereas muscular symptoms are the most significant in polymyositis. The long-term functional prognosis was fairly good, except for generalized calcinosis, which tended to occur in childhood dermatomyositis.

[Cutaneous and neurologic vasculitis disclosing EBV-selective immunodeficiency]. / Vasculite cutanée et neurologique révélatrice d'un déficit immunitaire sélectif vis-à-vis du virus d'Epstein-Barr.

INTRODUCTION: Purtilo's syndrome or X-linked lymphoproliferative syndrome (XLP) is a rare genetic disorder affecting boys who have a selective immunodeficit towards Epstein Barr Virus (EBV) and who develop extremely severe forms of EBV infection, of which there are four major types: severe or fatal infectious mononucleosis (60 p. 100), lymphoma (23 p. 100), acquired hypo- or agamaglobulinemia (25 p. 100) and anemia or pancytopenia. We report a case of vasculitis (cutaneous and neurologic) which led to the discovery of a selective immunodeficit towards EBV, similar to Purtilo's syndrome. CASE REPORT: A 17 year-old male with no significant past medical history presented with an eruption initially felt to be consistent with pityriasis lichenoid. Treatment with erythromycin was initiated, this did not prevent the subsequent eruptions of cutaneous vasculitis lesions which were severe, prolonged, debilitating, and associated with fever and general deterioration of the patient condition. All etiologic studies were negative. A course of systemic corticosteroids was begun, but the cutaneous eruptions persisted; and in addition the patient developed signs of polyneuropathy in the lower extremities secondary to neurologic vasculitic lesions. New studies revealed an abnormal EBV serology (absence of anti-EBNA antibodies) as well as hypogammaglobulinemia, suggestive of a selective immunodeficit towards EBV resembling Purtilo's syndrome. DISCUSSION: In our patient, the development of an extensive vasculitis, characterized histologically by an intense lymphocytic infiltrate, positive for EBV, associated with hypogammaglobulinemia, and with abnormal serology suggests an anomaly in the immune response to EBV. Although the age of the patient and absence of family history make the Purtilo's syndrome uncertain, the nature of the immunodeficit is very similar and the patient could well develop a lymphoma. This case is significant in that the disease initially manifested itself as a cutaneous vasculitis, which was not been described previously.

[Cerebral atrophy of vascular origin in the course of neurofibromatosis]. / Atrophie cérébrale d'origine vasculaire au cours d'une neurofibromatose.

The authors report the case of a 39-year-old woman with type I neurofibromatosis who presented a right incomplete proportional hemiplegia which progressively worsened over a 6-month period. Left hemispheric atrophy with heterogeneous features, predominant in the temporoparietal region, was revealed by computerized tomography. Atrophy was associated with diffuse vascular lesions in the distal part of the left sylvian and anterior cerebral arteries, leading to major cortical hypoperfusion. Vascular examination showed no hypertension nor any sign of arterial involvement in another region. This case illustrates the nature of vasculopathy associated with neurofibromatosis. Its expression is polymorphous, with lesions inducing stenosis (the most common ones), aneurysmal lesions or veritable angiodysplasias (either hypo- or hyperplastic). The vascular expression of neurofibromatosis is often overlooked. However, in the presence of an inexplicable occlusive or aneurysmal vasculopathy, it is advisable to search for signs of neurofibromatosis since ill-defined forms exist.

[Paraneoplastic dermatopolymyositis]. / Dermatopolymyosites paranéoplasiques.

In a retrospective study covering 11 years, 59 adult cases of dermatomyositis or polymyositis were reviewed. The disease was of paraneoplastic origin in 9 cases (15,25 p. 100), the same proportion as that found in the literature (14,6 p.100). The striking female predominance (8/9 cases) and the patients' mean age (61.11 years) were higher than those noted in non-paraneoplastic dermato- and polymyositis in adults (female predominance 34/50, mean age 52.9 years). Clinically, out of 9 patients 7 had dermatomyositis and 2 had polymyositis. The disease was discovered at the same time as the neoplasia in 7 of the 9 cases. Muscle histology showed that in contrast with non-paraneoplastic cases of dermatomyositis-polymyositis those of paraneoplastic origin had moderate lesions without fibrosis.

[Neurotoxicity of mitotane therapy of adrenocortical carcinoma (5 cases) and Cushing's syndrome (7 cases)]. / Neurotoxicité du traitement par le mitotane des cortico-surrénalomes (5 cas) et des syndromes de Cushing (7 cas).

Twelve patients were treated with op'DDD over a 9-year period. All presented with mild neurological symptoms, and half of them had major complications. There was no relation between the occurrence of these symptoms and the dose or duration of op'DDD therapy. The mechanisms of this neurological toxicity, both central and peripheral, are not well known, but they appear to be similar to those of certain op'DDD-related chemicals used in industry.

[Primary Gougerot-Sjögren syndrome with necrotizing polymyositis: favorable effect of hydroxychloroquine]. / Syndrome de Gougerot-Sjögren primitif avec polymyosite necrosante: effet favorable de l'hydroxychloroquine.

A 61-year-old woman was admitted for acute arthralgias and proximal weakness in all four limbs. Clinical examination found xerostomia, xerophthalmia, enlarged parotid glands. The Schirmer test was positive and the salivary gland biopsy showed a mononuclear, lymphoid, sometimes nodular infiltrate. A muscle biopsy showed necrotizing myopathy with perifascicular atrophy. The patient refused steroids and was given hydroxychloroquine (600 mg daily). She improved gradually, and one year later there were no further complications. The favorable course both of Sjögren's syndrome and polymyositis with hydroxychloroquine treatment is unexpected. This led us to suppose that both could have had a common cause.