CNTN6 mutations are risk factors for abnormal auditory sensory perception in autism spectrum disorders.

Contactin genes CNTN5 and CNTN6 code for neuronal cell adhesion molecules that promote neurite outgrowth in sensory-motor neuronal pathways. Mutations of CNTN5 and CNTN6 have previously been reported in individuals with autism spectrum disorders (ASDs), but very little is known on their prevalence and clinical impact. In this study, we identified CNTN5 and CNTN6 deleterious variants in individuals with ASD. Among the carriers, a girl with ASD and attention-deficit/hyperactivity disorder was carrying five copies of CNTN5. For CNTN6, both deletions (6/1534 ASD vs 1/8936 controls; P=0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls; P=0.0005) were enriched in individuals with ASD. Among the rare CNTN6 variants, two deletions were transmitted by fathers diagnosed with ASD, one stop mutation CNTN6W923X was transmitted by a mother to her two sons with ASD and one variant CNTN6P770L was found de novo in a boy with ASD. Clinical investigations of the patients carrying CNTN5 or CNTN6 variants showed that they were hypersensitive to sounds (a condition called hyperacusis) and displayed changes in wave latency within the auditory pathway. These results reinforce the hypothesis of abnormal neuronal connectivity in the pathophysiology of ASD and shed new light on the genes that increase risk for abnormal sensory perception in ASD.

[Long-term results of exclusive radiotherapy and brachytherapy of breast cancer]. / Cancer du sein traité exclusivement par l'association d'une irradiation externe et d'une curiethérapie exclusive: résultats à long terme.

PURPOSE: To report retrospective long-term results of historical experience of breast radiotherapy (RT) including external beam radiotherapy (EBRT) followed by low dose rate (LDR) brachytherapy. PATIENTS AND METHODS: Between 1971 and 1983, at our service 474 breast cancer patients underwent exclusive conserving radiotherapy treatment. The RT included an initial external irradiation followed by interstitial LDR brachytherapy (37Gy) to the residual tumour. The local regional nodes received 47.5Gy followed by a 15Gy boost delivered to the mammary nodes internal (IMN) and 25Gy axilla. RESULTS: Median follow-up was 139months (8-342). There were 40 T1, 356 T2, and 78 T3. Local recurrences (LR) were observed in 20% of cases. The rate of recurrences free at 5, 10, 15 and 20years were 86%, 77%, 73% and 67% respectively. At 5, 10, 15 and 20-year, the disease-free survival rates were 63%, 42%, 32% and 24%. Overall survival rates at 5, 10, 15 and 20-years were 75%, 53%, 34% and 25% respectively. CONCLUSION: Although the historical retrospective character of these series, it is interesting to have this experience and to analyse it according to our new knowledge and advances. The described technique was a standard for many years and could be still used in some cases.

Evaluating the suitability of nicotinic acetylcholine receptor antibodies for standard immunodetection procedures.

Nicotinic acetylcholine receptors play important roles in numerous cognitive processes as well as in several debilitating central nervous system (CNS) disorders. In order to fully elucidate the diverse roles of nicotinic acetylcholine receptors in CNS function and dysfunction, a detailed knowledge of their cellular and subcellular localizations is essential. To date, methods to precisely localize nicotinic acetylcholine receptors in the CNS have predominantly relied on the use of anti-receptor subunit antibodies. Although data obtained by immunohistology and immunoblotting are generally in accordance with ligand binding studies, some discrepancies remain, in particular with electrophysiological findings. In this context, nicotinic acetylcholine receptor subunit-deficient mice should be ideal tools for testing the specificity of subunit-directed antibodies. Here, we used standard protocols for immunohistochemistry and western blotting to examine the antibodies raised against the alpha3-, alpha4-, alpha7-, beta2-, and beta4-nicotinic acetylcholine receptor subunits on brain tissues of the respective knock-out mice. Unexpectedly, for each of the antibodies tested, immunoreactivity was the same in wild-type and knock-out mice. These data imply that, under commonly used conditions, these antibodies are not suited for immunolocalization. Thus, particular caution should be exerted with regards to the experimental approach used to visualize nicotinic acetylcholine receptors in the brain.

Preliminary report on AED deployment on the entire Air France commercial fleet: a joint venture with Paris XII University Training Programme.

The positive effect of early defibrillation on survival from cardiac arrest has been demonstrated. We describe the use of AEDs over 1 year following the training of flight attendants. Air France and the University of Paris XII together designed a 1 year training programme for 14000 flight attendants. The university emergency departments (SAMU) provided 250 instructors. AEDs training and certification was conducted for crew members between November 2001 and November 2002. By January 2003, all aircraft were fully equipped with AEDs. All cases of cardiac arrest that occurred during the study were reviewed comprehensively. Comments from the crew were collected. Twelve cardiac arrests were reported between November 2002 and November 2003 out of 4194 cases of emergency care delivered to passengers. Shock treatment was advised initially in 5/12 cases. The survival rate after in-flight cardiac arrest was 3/12. The survival rate at discharge from hospital following in flight shock was 2/5. No complications arose from the use of AEDs. Training by professionals gave the flight attendants confidence and allowed for the survival of two young passengers. Our study highlights the ability of flight attendants to give better onboard care for the future. The next step is to consolidate the network between in-flight care and the medical dispatch centre in Paris.

Critical role of the C-terminal segment in the maturation and export to the cell surface of the homopentameric alpha 7-5HT3A receptor.

Many neurological pathologies are related to misfolded proteins. During folding and assembly in the endoplasmic reticulum, the nicotinic acetylcholine receptor (nAChR) subunits undergo several conformational changes to acquire the ability to bind ligands. After folding and maturation, by mechanisms largely unknown, receptors are exported to the cell surface. We investigated the maturational role of the extracellular C-terminal segment located at the boundary between the extracellular and the transmembrane domains. In the functional chimeric alpha7-5HT3A receptor used as a model system, amino acids from the C-terminal segment were successively deleted or mutated. Upon progressive shortening of the peptide we observed less and less alpha-bungarotoxin binding sites until no sites could be detected when the entire peptide had been deleted (chimera Del 5). Protein synthesis and pentameric assembly were not altered. In Del 5 transfected cells, pentameric receptors present in the endoplasmic reticulum were not detected on the cell surface where Del 5 proteins appeared as patches. With the Del 5 chimera, export of proteins to the cell surface diminished to about half that of wild-type. We propose that the C-terminal segment plays a double role: (i) through an interaction between the penultimate tyrosine residue of the C-terminal segment and the Cys loop of the N-terminal domain, it locks the receptor in a mature alpha-bungarotoxin binding conformation; (ii) this mature conformation, in turn, masks a retention signal present in the first transmembrane segment allowing properly assembled and matured receptors to escape to the cell surface.

An in vitro study of the sub-cellular distribution of nicotinic receptors.

Nicotinic and serotoninergic 5HT3 receptors share important sequence identities except for their cytoplasmic loop. Both ends of this loop display conserved 3D helical structures with distinct primary sequences. We decided to check whether these two helices named F and G play a role in the sub-cellular distribution of different nicotinic receptors. We systematically exchanged each helix with the equivalent sequence of neuronal nicotinic and alpha4, beta2 and alpha7 subunits in the functional chimeric alpha7-5HT3 receptor used as a model system. The new chimeras were expressed in vitro in polarized epithelial cells from pig kidney. We quantified synthesis and export of the receptors to the cell surface by measuring alpha-bungarotoxin binding sites. Immunogold labelling was used, at the electron microscope level, to determine the amount of each chimera present at either domain, apical and/or basolateral, of these cells. We noticed that in epithelial cells the majority of alpha-bungarotoxin binding sites remained sequestered in the cytoplasm as already observed in neurons in vivo. The majority of the pentamers present at the cell surface were located at the apical domain. Our results suggest that helix F and G differently regulate assembly and export to the cell surface of alpha-bungarotoxin binding receptors.

Combination of vinorelbine, epirubicin, and cyclophosphamide as neoadjuvant chemotherapy for locally advanced breast cancer: phase II study.

Achievement of a pathologic complete response after primary chemotherapy in breast cancer can predict long-term outcome. We have investigated a combination of epirubicin, cyclophosphamide, and vinorelbine as neoadjuvant chemotherapy in locally advanced breast cancer (LABC). From January 1997 to May 1999, 30 chemonaive patients were treated (T2 or T3 histologically proven invasive breast carcinoma). Treatment was vinorelbine 25 mg/m2 day 1 and day 3, epirubicin 30 mg/m2/d, days 1 to 3, cyclophosphamide 350 mg/m2/d, days 1 to 3, every 14 days for 4 courses. Twenty-nine patients were evaluable. Median age: 48 years (range: 28-66 years); 26 had ductal invasive carcinoma and 4 lobular invasive carcinoma; median tumor size: 7 cm; median number of induction cycles: four. Clinical objective response was seen in 24 patients (relative risk: 86%), 14 complete responses, 10 partial responses, four stable disease (no significant changes). Twenty-nine patients had surgical treatment. Pathologic response rate was complete response in 32% (no residual tumor), in situ carcinoma: 11%, invasive or unchanged tumor remaining: 57%. Ninety-eight cycles were administered; major toxicities were hematologic: grade IV Hb in 5% and grade IV neutropenia in 60% of cycles. Ten patients required hospitalization for febrile neutropenia. Other toxicities were mild to moderate. The vinorelbine/epirubicin/cyclophosphamide regimen resulted in a high pathologic complete response rate in LABC with a good tolerance profile, and warrants further evaluation.

[Hodgkin's disease: from gross tumor volume to clinical target volume, firm data and unresolved problems]. / Maladie de Hodgkin: du volume tumoral macroscopique au volume-cible anatomoclinique, données acquises et problèmes non résolus.

The purpose of this article is to specify the target volumes, using ICRU criteria in the treatment of Hodgkin's disease. Because of the complexity of irradiation fields, the literature was carefully reviewed. However, with the variations of the recommendations and in the absence of large-scale studies, usual criteria can still be used. A consensus about the precise specification of the target volumes on CAT scan is still urgently awaited.

Long-term results of neoadjuvant radiation therapy for breast cancer.

Our aim was to determine the long-term outcome and the possible role of neoadjuvant (preoperative) radiation therapy for breast cancers unsuitable for primary conservative surgery. From 1977 to 1992, 75 unifocal non-inflammatory and non-metastatic T2 and T3 breast cancers were treated in our department. All these patients underwent initial radiotherapy, followed by secondary limited surgery. A population of 74 patients, aged from 32 to 82 years (median 56 years), presenting 49 T2 and 26 T3 tumors, was studied. Seventy-two patients (96%) underwent secondary tumorectomy and three patients (4%) reduction mammaplasty. The secondary tumorectomy was followed by a postoperative boost. There were nine recurrences, treated by mastectomy in eight cases and by tumorectomy in one case. Twenty-five patients showed secondary dissemination. Forty-seven patients are still alive and free of disease. The cosmetic results were considered excellent or satisfactory in 71 cases. Under good conditions, preoperative radiotherapy (as well as preoperative chemotherapy) allows the possibility of conservative surgery for cancers of more than 3 cm. The choice between the two modalities depends on the patient's condition and on a precise analysis of all prognostic factors that would justify the need for systemic treatment.

Radiotherapy in the management of cutaneous B-cell lymphoma. Our experience in 25 cases.

PURPOSE: To report our results in the treatment with radiation therapy of 25 patients affected by B-cell lymphoma with initial cutaneous presentation. MATERIALS AND METHODS: From October 1978 to June 1997, we have treated 25 patients with cutaneous B-cell lymphoma (CBCL) by cutaneous irradiation. There were 17 males and eight females, aged from 23 to 89 years (median age 50 years). The mean follow-up time for the series was 3.9 years (range from 0.2 to 15 years) from the completion of radiation therapy. All patients were staged as follows: in group 1, single lesion; group 2, multiple lesions; group 3, disseminated lesions. There were six (24%) patients in group 1, 15 (60%) patients in group 2, and four (16%) in group 3. There were nine patients with head and neck lesions, 11 patients with trunk lesions, and five patients with leg lesions. Thirteen patients (52%) had previously received chemotherapy for CBCL. Extended field irradiation was used to treat six patients (24%). Localized field irradiation (LFI) was performed for the other 19 patients (76%). RESULTS: The overall survival rate at 5 years was 73%. The complete response (CR) to the treatment for our series was 92%. The length of complete remission ranged from 2 to 180 months. There were three patients (8%) who obtained partial response (PR). Disease-free survival (DFS) at 1 year was 91% and at 5 years was 75%. Radiotherapy was generally well tolerated. CONCLUSIONS: Localized field irradiation is an effective treatment for some localized forms of primary cutaneous B-cell lymphoma and can obtain prolonged remissions. The patients with wide-spread skin involvement are usually candidates for extended field irradiation and/or chemotherapy. For the advanced stages of cutaneous B-cell lymphoma, where the chemotherapy is the treatment of choice, some good palliation can be achieved using local field irradiation.

Radiotherapy in the management of mycosis fungoides: indications, results, prognosis. Twenty years experience.

PURPOSE: To determine the role of total skin electron beam therapy (TSEBT) and the prognosis of patients with mycosis fungoides. MATERIALS AND METHODS: From 1978 to 1996, 66 consecutive patients with mycosis fungoides received 30 Gy TSEBT delivered in 12 fractions over 40 days as treatment of their relapsed after topical or/and systemic therapy. All patients were staged as follows: stage A, superficial lesions covering less than 50% of the body surface; stage B, superficial lesions covering more than 50% of the body surface; Stage C. tumors involving the skin, lymph nodes and/or visceral organs. RESULTS: The median age was 50 years (ranging from 13-78 years). There were 39 males and 27 females. The minimum follow-up was 12 months (range 12-192 months). There were 24 (36%) stage A patients, 22 (33%) stage B patients, and 20 (30%) stage C patients. The overall survival at 5 years for our series was as follows: 93% for stage A; 79% for stage B, and 44% for stage C disease (P = 0.002). For the entire cohort, the complete remission rate was 65%, the progression-free survival (PFS) at 5 years and 10 years was 30 and 18% respectively. For the group A, PFS was 62% at 5 years and 46% at 10 years; for group B, PFS was 19% at 5 years. CONCLUSIONS: This study suggests that TSEBT gives good results for relapsed stage A disease. Total skin electron beam therapy combined with local fields irradiation or other local treatment (puvatherapy or topical nitrogen mustard) might further improve permanent complete response for stage B patients. The most advanced stages of mycosis fungoides are not controlled by TSEBT, but the radiation therapy offers good palliation results.

Ultrastructural localization of the alpha4-subunit of the neuronal acetylcholine nicotinic receptor in the rat substantia nigra.

The distribution of the alpha4-subunit of the neuronal nicotinic acetylcholine receptor (nAChR) in the rat brain was examined at light and electron microscopy levels using immunohistochemical staining. In the present study we demonstrate the specificity, in both tissue homogenates and brain sections, of a polyclonal antibody raised against the rat nAChR alpha4-subunit. The characterization of this antibody involved: (1) Western blot analysis of rat brain homogenates and membrane extracts from cells previously transfected with diverse combinations of neuronal nAChR subunits, and (2) immunohistochemistry using transfected cells and rat brain tissue. At the light microscope level, the alpha4-subunit-like-immunoreactivity (LI) was widely distributed in the rat brain and matched the distribution of the alpha4-subunit transcripts observed previously by in situ hybridization. Strong immunohistochemical labeling was detected in the mesencephalic dopaminergic nuclei. The nAChRs in this region are thought to be responsible for the modulation of dopaminergic transmission. The neurotransmitter identity of alpha4-immunolabeled neurons in the substantia nigra pars compacta (SNpc) and the ventral tegmental area was thus assessed by investigating the possible colocalization of the nAChR alpha4-subunit with tyrosine hydroxylase using confocal microscopy. The double labeling experiments unambiguously indicated that the alpha4-subunit-LI is present in dopaminergic neurons. At the electron microscope level, the neurons in the SNpc exhibited alpha4-subunit-LI in association with a minority of postsynaptic densities, suggesting that the alpha4-subunit may be a component of functional nAChRs mediating synaptic transmission between midbrain cholinergic neurons and mesencephalic dopaminergic neurons.

Metastasis of a breast carcinoma in a mature teratoma of the ovary.

Metastatic tumors in ovaries from breast carcinoma are well known. Breast carcinoma metastases in primary ovarian tumors are much more uncommon. The authors present a case of a primary breast carcinoma, with a lobular component (signet ring cells), which metastasized into a mature cystic teratoma of the ovary. The problem of differential diagnosis with other primary ovarian tumors or metastatic tumors and the problem of particular behavior of metastatic lobular components are discussed.

[Radiotherapy of cutaneous lymphomas]. / Radiothérapie des lymphomes cutanés.

Radiotherapy plays an important role in the treatment of cutaneous lymphomas. In the treatment of Mycosis fungoides, total skin electron beam radiation therapy is efficient for patients with limited and superficial forms of the disease. Radiotherapy is also efficient for the locally advanced forms of non-epidermotropic lymphomas. The palliative radiotherapy is indicated for advanced, nodular and treatment resistant forms of cutaneous lymphomas and for voluminous lymphadenopathies.

Radiotherapy as palliative treatment for metastatic melanoma.

This study aimed to assess the response rate and efficacy of palliative radiation therapy in patients with metastatic melanoma. From 1993 to 1999, 28 patients with 35 irradiated areas were treated with palliative radiotherapy for metastatic melanoma in the Radiotherapy Department of the Henri Mondor University Hospital, Créteil, France. Of these, 19 (68%) patients had bone and soft tissue metastases, seven (25%) patients had brain metastases and two (7%) patients had both types of metastases. Most of the patients were treated with 30 Gy of irradiation in 10 fractions over 2 weeks or 20 Gy in five fractions over 1.5 weeks. Of those with bone metastases, 67% responded to palliative bone treatment with good pain relief and/or decompression. Of the patients with brain metastases, 57% had amelioration of neurological function deficits, 29% did not respond, and one patient showed aggravation of his disease and did not finish the course of irradiation. Two patients with unresectable disease obtained partial remission and good palliation of symptoms. In conclusion, short-course radiotherapy has a role to play in the palliation of metastatic melanoma, with good relief of symptoms.

Stewart-Treves syndrome after treatment for breast cancer.

This study reviews 3 cases of angiosarcoma of the upper extremity after mastectomy and radiotherapy for breast cancer (Stewart-Treves syndrome). Angiosarcoma was diagnosed an average 14 years (from 6.5 to 26 years) after treatment for breast cancer. Presenting signs included a red raised lesion, a palpable mass, a blister appearance (in one case). Two of our three patients underwent surgical treatment: one patient underwent local excision followed by chemotherapy, and the other patient wide excision, followed by external beam radiotherapy. Local recurrence occurred in one of these two patients and was followed by the development of lung metastases. The second patient who had treatment is free of disease without problems. The third patient refused any treatment and died 5 months later. The purpose of this article is to add to the literature 3 new cases of Stewart-Treves syndrome and to discuss some specific problems of this rare tumour.

[Radiotherapy and skin tumors]. / Radiothérapie et tumeurs cutanées.

Radiotherapy plays an important role in the treatment of skin tumours. For skin carcinomas, external irradiation (kilovoltage X-rays or electrons according to clinical characteristics) is more valuable than interstitial brachytherapy, which is recommended for tumours of the lip and of the nasal vestibule. In mycosis fungoides, total cutaneous electron beam radiation therapy is efficient for patients with limited superficial plaques. In the classical form of Kaposi's sarcoma, radiotherapy can achieve local control whereas it obtains good palliative results in the epidemic form.

[Radiation-induced sarcoma after breast cancer. Apropos of 8 cases and review of the literature]. / Sarcomes radio-induits après cancer du sein. A propos de huit cas et revue de la littérature.

PURPOSE: Retrospective analysis of eight new cases of radiation-induced sarcomas following radiotherapy for breast carcinoma and literature review. PATIENTS AND METHODS: Eleven patients presenting with radiation-induced sarcoma after radiotherapy for breast cancer have been treated between 1983 and 1997 at Henri Mondor University Hospital (France). Eight of these patients respected the criteria established by Cahan et al. The others had Stewart-Treves Syndrome and were thus excluded from the analysis. Only one of the eight patients had received chemotherapy. All of the patients at the time of diagnosis of radiation-induced sarcoma were free of breast cancer recurrence. Radiation-induced sarcoma appeared with a latency period of 5 to 18 years (mean: 10.3 years). Patients' ages ranged from 39 to 88 years (mean: 57.6 years) at the time of diagnosis of sarcoma. Three sarcomas occurred in the treated breast, two in the chest wall, one in the preclavicular area and two in the axillary region. There were two angiosarcomas, three fibrosarcomas, one osteosarcoma, one malignant fibrous histiocytoma (MFH), and one undifferentiated sarcoma. All patients have received treatment for their sarcoma: all of them underwent surgery, one patient combined radiotherapy and chemotherapy, and three patients chemotherapy. RESULTS: Two patients were alive and free from disease. Six patients died (5-34 months); all six had local and/or metastatic recurrence. CONCLUSIONS: Radiotherapy can induce malignancies after a latent period of several years. Radiation-induced sarcomas are associated with poor overall prognosis. The treatment in most of the cases is late and ineffective, therefore careful follow-up is needed. There are still many uncertainties and questions about radiation-induced sarcomas.