Caspase-independent apoptosis in infected macrophages triggered by sulforaphane via Nrf2/p38 signaling pathways.

Mycobacterium abscessus (Mabs), a non-tuberculous mycobacterium, is an emerging and rapidly growing opportunistic pathogen that is frequently found in patients with cystic fibrosis and in immunosuppressed patients. Its high tolerance to antibiotics is of great concern for public health. In this study, our results showed that human THP-1-derived macrophages infected with M. abscessus presented an increase in ROS production and cell necrosis. In addition, M. abscessus infection triggered activation of the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway, and the induction of HO-1 and NQO1 expression levels. Interestingly, pretreatment of macrophages with sulforaphane (SFN), an activator of the antioxidant key regulator Nrf2, followed by M. abscessus infection significantly decreased mycobacterial burden. We demonstrated that this reduction in mycobacterial growth was due to an activation in cell apoptosis in SFN-pretreated and M. abscessus-infected macrophages. Pretreatment with specific MAPK inhibitors, PD98059, SP600125, and SB203580 to ERK, JNK, and p38 respectively, failed to inhibit induction of Nrf2 expression, suggesting that Nrf2 signaling pathway was upstream of MAPK signaling. Activation of cell apoptosis was caspase 3/7 independent but p38 MAPK dependent. Moreover, p38 MAPK induction was abolished in macrophages transfected with Nrf2 siRNA. In addition, p38 inhibitor abolished Nrf2-dependent apoptosis in infected macrophages. Taken together, our results indicate that modulation of the Nrf2 signaling using Nrf2 activators may help potentiate the actual drug therapies used to treat mycobacterial infection.

Assessment of articular cartilage and subchondral bone: subtle and progressive changes in experimental osteoarthritis using 50 MHz echography in vitro.

The main objectives of this work were to demonstrate the potential of 50 MHz echography for assessing initial and progressive morphological and structural changes of articular cartilage and bone developed in an experimental model of osteoarthritis (OA). Degenerative lesions were induced in rat knees by the unilateral intra-articular injection of a 3 mg dose of mono-iodo-acetic acid. To assess the lesion progression, the animals (n = 30) were sacrificed at different time intervals up to 8 weeks after the injection. Three-dimensional echographic data were acquired in vitro on patellar cartilage and bone at various stages of the remodeling process using a scanning ultrasound microscope. Changes involving the OA cartilage characteristics are discussed relative to those of the contralateral control joint which received a placebo. Images of control cartilage showed a smooth hyperechoic articular surface and an echoic matrix. The cartilage thickness was 266 +/- 44 microns (mean +/- SD) in the central region of the tissue. The precision of ultrasonic thickness measurements was better than 1.3%. First changes in cartilage internal structure and subchondral bone appeared on ultrasound images 3 days after the injection and were even more evident by day 7. They resulted in a slight thinning of the cartilage, a 30% increase of its internal structure echogenicity, and the appearance of echoic zones in subchondral bone. Histologic findings confirmed chondrocyte depletion and degeneration, decrease of matrix proteoglycans, and fibrovascular connective tissue proliferation at the subchondral plate. Progressive and severe lesions at both bone and cartilage surface and internal structure were assessed and correlated to histologic features. These results show that high resolution echography is sensitive to subtle and progressive osteochondral remodeling. This technique has the potential to be used for intra-articular quantitative imaging and assessment of early changes in bone and cartilage structure associated with natural human disease.

Subcellular localization of cytochrome P450, and activities of several enzymes responsible for drug metabolism in the human brain.

We studied the subcellular distribution of cytochrome P450 and related monooxygenase activities in six regions of human brains removed at autopsy. The content of total cytochrome P450 was found to be at least nine times higher in the mitochondrial fraction than in the microsomes in all the regions studied. However, cytochrome P450-dependent enzymatic activities which are representative of different isoforms metabolizing exogenous molecules exhibited a microsomal prevalence, a situation previously observed in rat brain. The other drug-metabolizing enzymes catalysing functionalization and conjugation reactions, presented the following characteristics in human brain: (i) a low activity of NADPH-cytochrome P450 reductase, which also catalyses the reduction of some xenobiotics; (ii) a high specific activity of the membrane-bound epoxide hydrolase; (iii) among the enzymes catalysing conjugation reactions, 1-naphthol-UDP-glucuronosyltransferase activity was barely or not detectable, whereas the mean glutathione-S-transferase activity was 15 times higher than the activity measured in rat brain. The presence of several drug-metabolizing enzyme activities in human brain microvessels, and particularly the high activity of epoxide hydrolase, suggests a participation of these enzymes in the metabolic blood-brain barrier.

Medullary thyroid carcinoma: search for histological predictors of survival (109 proband cases analysis).

A group of 13 pathologists belonging to the French Calcitonin Tumor Study Group (GETC: Groupe d'Etude des Tumeurs à Calcitonine) examined the histological slides and medical records of 109 proband cases of medullary thyroid carcinoma (MTC) diagnosed on clinical features. The cases belonged to the various forms of the disease (80 sporadic and 29 familial MTC). The aim of the study was to detect histological predictors for survival by comparing morphological data from patients killed by the disease versus the others. Twenty-seven histological parameters were considered, including cellular heterogeneity, shape of the cells, and cytoplasmic characteristics. Other parameters such as sex, age, and phenotype of the disease were also studied. First, predictive parameters of interest on survival function were selected by univariate analysis (Mantel-Cox test). Then, the extracted parameters were tested in a multifactorial analysis using the Cox's forward stepping proportional hazard model. Five parameters were significantly associated with a lower survival function: presence of necrosis in the tumor (P = .001), squamous pattern (P = .002), age over 45 years (P = .004), presence of oxyphil cells in the tumor and absence of cells with intermediate cytoplasm (P = .025), less than 50% of calcitonin immunoreactive cells in the tumor (P = .04).

Phytosterols have an unfavourable effect on bacterial activity and no evident protective effect on colon carcinogenesis.

The effects of physiological dietary phytosterol supplements on intestinal microflora activity and faecal sterols and their capacity to protect rats fed a normal or high saturated fatty-acid diet against tumour development were studied. A group of 80 female Wistar rats were fed an 8% lipid diet for 4 weeks (adaptation period) and then randomly assigned in a factorial experimental design study to diets containing 8% or 24% hydrogenated coconut oil, with or without a 24-mg/day/rat phytosterol supplement. They were instilled intrarectally with saline or methyl-nitroso-urea (MNU). Faecal sterol output was analysed for one week each month. Pathological analysis was done at the end of the 30-week experiment. Animals treated with MNU and given phytosterol supplements had tumour frequencies (8/20) similar to those not fed phytosterols (11/20). The fat-supplemented diet had no significant influence. Colonic glands were found in area of lymphoid follicles in all the groups, but were more frequent in rats on high-fat diets (P < 0.01). The coprostanol and the cholesterol excretion of the phytosterol-supplemented rats was significantly enhanced. Therefore phytosterols have an unfavourable effect on bacterial activity. These data confirm the capacity of phytosterols to decrease cholesterol absorption, but indicate that a large excess of phytosterol must be avoided until further research on its effects on carcinogenesis has been done.

[Multiple systemic atrophies, mental retardation, neurogenic amyotrophy and congenital bone fragility. A new neuro-generative disorder]. / Atrophies systématisées multiples, arriération mentale, amyotrophie neurogéne et fragilité osseuse congénitale. Une nouvell affection neuro-dégénérative

Five cases of a congenital neurological disorder are reported. Four patients, born after a breech delivery, belong to one sibship while the fifth patient is the only child in another family. The clinical features include quadriplegia, amyotrophy, a peripheral neuropathy, severe mental retardation and a subluxation of the hips. X-rays reveal diffuse osteoporosis and multiple spontaneous fractures. Autopsies in 3 patients showed multiple system atrophies involving the spinal cord and the cerebellum, coarse cerebral gyri and a marked reduction in volume of the white matter. These various pathological features are compared with the lesions found in a few other cases reported in the literature, none of which can be considered to be identical to the ones described. It is therefore felt that the condition under discussion represents a new syndrome to be classified, at least temporarily, within the group of multiple system atrophies.

Osteogenic anaplastic carcinoma of the thyroid.

An unusual osteogenic anaplastic carcinoma of the thyroid developed in a 68-year-old man and showed follicular and osteosarcomatous components. Seven months after surgery and 70 mCi 131I treatment, a local tumor recurrence was found and showed an intense uptake of 99mTc-MDP on the bone scan. After a second operation, pathologic and immunostaining analysis revealed no more thyroid carcinoma but only osteosarcomatous cells. Chemotherapy was ineffective and the patient died with diffuse pulmonary metastases 26 months after the diagnosis. The importance of osteogenic sarcomatous differentiation is proven by the bone scan. Osteosarcoma of the thyroid is a rare but well known tumor. Usually these tumors do not contain any cells originating from the thyroid epithelium and only comprise sarcomatous components. Ten cases of undifferentiated carcinoma of thyroid origin with osteogenic component have been reported. These tumors have been recently included in undifferentiated carcinomas in the second edition of the WHO classification. The evolution and pathologic findings favor the hypothesis of a transdifferentiation of the thyroid cell into osteogenic cells.

[Histological and immunohistochemical diagnosis of bone marrow metastases of neuroblastomas]. / Diagnostic histologique et immunohistochimique des métastases ostéomédullaires des neuroblastomes.

A retrospective, morphological and immunochemical study was performed on 60 bone marrow biopsies (BOM) and 12 tumor specimens surgically excised, from 9 patients with neuroblastoma (NB). Immunochemistry concerned "neuron-specific enolase" (NSE), chromogranin A (CGA) and synaptophysin (SP). The results of immunochemical stains and the study of reticulin network on the argentic stain were compared to the results of morphological evaluation on the routine stain. NSE, CGA and SP staining of tumor cells (part or all of them) was obtained from all surgical specimens. 17/75 BOM (20%) were discarded because of poor material. NB cells were observed in 24 BOM from 3 patients. Tumor cells formed large strands (1 patient) or nests (2 patients) associated with segregated cells. Diagnosis of metastatic BM involvement was negative or doubtful for 6 BOM (3 obtained at the same time, 2 patients), in which NB cells were clearly demonstrated by immunochemical staining of NSE and/or CGA. Reticulin and/or collagen myelofibrosis was present in 32/35 BOM from the 3 patients metastatic in bone marrow (BM+) even if NB cells could not be demonstrated in these samples.

[Right ventricular dysplasia; a study in 7 cases]. / Les dysplasies ventriculaires droites: a propos de 7 observations.

Seven new cases of right ventricular dysplasia are described, five of which were complicated by ventricular tachycardia. The frontiers of this syndrome are unclear and it is uncertain whether it should be considered as a separate disease entity, or as a minor form of "paper thin" right ventricle or Uhl's disease.

[Malignant quadrivalvular dysplasia of Marfan syndrome in a neonate]. / Dysplasie quadrivavulaire maligne de la maladie de Marfan à révélation néonatale.

The authors report the case of a neonate who died early of refractory heart failure and presented with all the characteristics of Marfan's syndrome in its early form with articular retractions. There was clinical evidence of mitral, tricuspid and major aortic regurgitation. Two-dimensional and doppler echocardiography confirmed the prolapse of highly dystrophic valves and the quadrivalvar regurgitation. Typical lesions of the connective-elastic tissue were found at autopsy. The occurrence of malignant Marfan's syndrome in neonates seems to be exceptional; the syndrome may take the rare "en contractures" form. Death is not always ascribable to the cardiac pathology, this pathology being often less generalized than in our case which seems to be the first one where such diffuse and massive valval lesions have been observed. This particular form was comparable to the "congenital polyvalvular disease" described by Bahrati and Lev, except that the skeletal and visceral abnormalities of Marfan's syndrome are absent in that disease.

[Intraneural cyst: a rare cause of peroneal nerve palsy]. / Kyste intraneural: une cause rare de paralysie du nerf sciatique poplité externe.

A 30 year-old man presented with progressive left peroneal nerve palsy. At surgery, an intraneural cystic tumour was found in the common peroneal nerve. Pathological examination showed that the tumour was of synovial origin.

[Hansen's neuritis in the form of pseudysyringomyelia. Clinical, diagnostic and therapeutic consideration a propos of 3 cases]. / Névrite hansénienne à forme pseudosyringomyélique. Considérations cliniques, diagnostiques et thérapeutiques à propos de trois cas

Three cases of neuropathic leprosy (one Moroccan, two non-colonial immigrants) enable attention to be drawn to two aspects of theproblem of Hansen's neuritis: 1) such cases should no longer be considered exceptional, infection occuring in countries where leprosy is endemic but the disease developing years later in any country; 2) among the various neurological aspects of neuritis due to Hansen's bacillus, great stress is laid on sensory disorders of the syringomyelic type, with thermalgesic dissociation; although these symptoms have been considered typical (our three cases are an illustration of this), they seem to occur fairly rarely and are the cause of difficulties in diagnosis as it is the last thing one would think of. Treatment of these neural forms is not encouraging, in spite of a therapeutic arsenal which in theory is considered effective.

[Chemodectomas of the vagus nerve. Pathogenic hypothesis based on a review of 100 cases]. / Les chémodectomes du vague. Hypothèses pathogéniques à partir d'une revue de cent cas

In connection with a personal case, 100 chemodectomas of the vagus described in the literature have been collected: revealing themselves in 75p. 100 of the cases in the form of cervical and pharyngeal tumours, 50p. 100 of the tumours of the vagal glomus involve some neurological manifestations mainly in the form of lesion of the lower cranial nerves. These appear to be either affected in isolation (41 p. 100) or in a dissociated manner (59 p. 100). Intra-cranial extension is rare (7 p. 100 of the cases) and delayed. Carotid angiography is characteristic. 76 p 100 are intra-vagal, 24 p. 100 are para-vagal and 60 p. 100 are located in the plexiform ganglion. Multifocal forms which account for 17 p. 100 of the cases are more usually, but not exclusively, familial. Surgical treatment is followed by sequelae or complications in more than half the cases. Close attention has been paid to pathogenetic theories: chemodectomas of the vagus may develop from type I chemoreceptor cells of the carotid glomera or from distinct cells with different properties (S.I.F. cells). They may equally well develop from nonchromaffin paraganglionic cells which have not migrated in the normal manner. The finding of such cells in the nerves of new-born babies and adults supports this theory, at least for some chemodectomas of the vagus.

[Neurological manifestations of alveolar echinococcosis]. / Manifestations neurologiques de l'échinococcose alvéolaire.

Among 78 cases of alveolar echinococcosis reported in Lorraine, France, 5 had neurologic complications which in 3 cases revealed the disease. Results of parasitic tests are discussed and emphasis is placed on differences between this disease and hydatidosis. Encephalic localizations (3 cases) were multiple making neurosurgery impossible. The outcome was fatal in 2 cases: 1 month after the initial neurologic signs in the absence of treatment (case 1) and 4 months after treatment with flubendazole (case 2). This drug was however effective in the 3rd case (hepatic, pulmonary and cerebral form) with follow-up now at 4 years. Epidemiologic, histopathologic, clinical, diagnostic characteristics and course of these encephalic localizations are reviewed. Spinal localizations (2 cases) presented with a picture of spinal cord compression. After laminectomy and flubendazole, the course was marked by relapse with death in one case and a satisfactory neurologic course with a 4 year follow-up in the other one.

[Familial presenile dementia: Gerstmann-Sträussler-Scheinker's syndrome (author's transl)]. / Démence pré-sénile familiale: syndrome de Gerstmann-Sträussler-Scheinker.

A similar affection has developed in eight members from four generations of a family living in the Alsace. The disease is characterized by the onset of a pyramidal, pseudobulbar syndrome and dementia during the third or fourth decade of life. The outcome is fatal after a mean period of three years. Cerebral biopsies in three cases have demonstrated multicentric amyloid plaques differing from senile plaques. Clinical and pathological findings are similar to those currently reported in the literature as being typical of Gerstmann-Sträussler-Scheinker's syndrome. The affection appears as a separate entity: the multicentric plaques, clinical symptomatology, pyramidal or pseudobulbar, cerebellar syndromes, usually preceding dementia, age of onset, course, and familial character or the disorder distinguish it among presenile dementias. Its clinical profile and course are very similar to that of familial cases of Alzheimer's disease, some of which are probably cases of Gerstmann-Strässler-Scheinker's syndrome. Transmission to animals, though inconstant, places it within the group of transmissible dementias among kuru, Creutzfeldt-Jakob's, and familial forms of Alzheimer's disease. The familial nature of the affection and the variability of clinical and pathological features in the same family illustrate the complex relationships between hosts and pathogenic agents in the clinicopathological expression of a disease.

[Actinomycosis and non-Hodgkin's malignant lymphoma: fortuitous association?]. / Actinomycose et lymphome malin non hodgkinien: association fortuite?

Two cases of actinomycosis associated with non Hodgkin's lymphoma (NHL) are reported. In one case, low grade NHL was diagnosed many years after actinomycosis because of the persistence of abdominal lymphadenopathy in spite of antibiotic therapy. In the second case, hepatic metastasis were initially suspected until actinomycosis diagnosis was made by percutaneous liver biopsy under scanography. High grade NHL was diagnosed by laparotomy and liver biopsy performed 6 weeks after the onset of antibiotic therapy as no improvement in hepatic lesions was obtained. These two case reports outline the difficulties encountered in the diagnosis of actinomycosis and the indication of a repeat biopsy when actinomycosis does not respond to antimicrobial therapy because of the possibility of concomitant malignancy.

[Neuromuscular hamartoma]. / Hamartome neuromusculaire.

Neuromuscular hamartoma is a pseudotumour characterized by the presence of striated muscle fibers in a nerve trunk. The reported case was located in the left sciatic nerve in a 4-year-old girl with equinism and spasticity. A first surgical procedure, with muscle biopsy, did not permit diagnosis of hamartoma. It was followed by the occurrence of a firm mass at the same location. Partial excision was performed; the mass revealed to be fibrous. Further aggravation of functional symptoms lead to leg amputation and correct diagnosis. Discussion is focused on the unique features of this rare disorder, for which therapeutic attempts might be avoided, whereas diagnosis proved to be sometimes difficult.

[Bifocal lesion of striated muscle (hamartoma or focal myositis) in the course of Proteus syndrome]. / Lésion musculaire striée bifocale (hamartome ou myosite focale) au cours d'un syndrome de Protée.

We report a case of bifocal recurrent lesion developed in muscles of the left thigh in a 5 year-old-girl with Proteus syndrome (rare congenital hamartomatous disorder). We discuss the diagnosis of focal myositis versus hamartoma. The clinical and morphological features favour the second hypothesis.

[Olfactory esthesioneuroma (esthesioneuroblastoma). A pathologic study of 7 cases]. / Les esthésioneuromes (esthésioneuroblastomes) olfactifs. Etude anatomopathologique à propos de 7 observations.

With an histological, immunohistochemical study of 7 cases of olfactory esthesioneuromas (4 of them had an ultrastructural study), our purpose was to revise the problem of the too often ambiguous terminology and of the different histological lower classes classifications of these tumors. Our own results and the literature demonstrate that they are polymorphic. In standard histology, they are often right diagnosed but an immunohistochemical study can be useful and an ultrastructural study absolutely necessary for a reliable diagnosis. For an easier nomenclature, we advise to use only one terminology for these tumors = olfactory esthesioneuroma. But, because of their important polymorphism, we keep to an histological lower classes classification according to their degree of differentiation in light microscopy: well differentiated tumors (old esthesioneuroepitheliomas), moderately differentiated tumors (old esthesioneurocytomas), poorly differentiated tumors (old esthesioneuroblastomas and so on described as neuro-endocrine carcinomas by Silva and al).

[Intestinal ganglioneuromatosis: histochemical, histoenzymological and ultrastructural study of a case]. / La ganglioneuromatose intestinale: étude histochimique, histo-enzymologique et ultrastructurale d'une observation.

Report of a child with disseminated ganglioneuromatosis of the gut. The complexity of the intestinal nervous system malformation is proved by histochemical, histoenzymological and ultrastructural studies. The malformation is characterized by: hyperplasia and hypertrophy of enteric plexus and nerves bundles in the meso, high acetylcholinesterase activity, aplasia of the sympathetic innervation with the exception of perivascular plexus, qualitative and likely quantitative integrity of the endocrine digestive system. These data are compared with similar observations in the literature.