Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Genome-wide re-sequencing of multidrug-resistant Mycobacterium leprae Airaku-3.

Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae.

Stochastic phase oscillators and circadian bioluminescence recordings.

Cultured circadian oscillators from peripheral tissues were recently shown to be both cell-autonomous and self-sustained. Therefore, the dominant cause for amplitude reduction observed in bioluminescence recordings of cultured fibroblasts is desynchronization, rather than the damping of individual oscillators. Here, we review a generic model for quantifying luminescence signals from biochemical oscillators, based on noisy-phase oscillators. Our model incorporates three essential features of circadian clocks: the stability of the limit cycle, fluctuations, and intercellular coupling. The model is then used to analyze bioluminescence recordings from immortalized and primary fibroblasts. Fits to population recordings allow simultaneous estimation of the stability of the limit cycle (or equivalently, the stiffness of individual frequencies), the period dispersion, and the interaction strength between cells. Consistent with other work, coupling is found to be weak and insufficient to synchronize cells. Interestingly, we find that frequency fluctuations remain correlated for longer periods than one clock cycle, which is confirmed from individual cell recordings. We discuss briefly how to link the generic model with more microscopic models, which suggests mechanisms by which circadian oscillators resist fluctuations and maintain accurate timing in the periphery.

Feature extraction and signal processing for nylon DNA microarrays.

BACKGROUND: High-density DNA microarrays require automatic feature extraction methodologies and softwares. These can be a potential source of non-reproducibility of gene expression measurements. Variation in feature location or in signal integration methodology may be a significant contribution to the observed variance in gene expression levels. RESULTS: We explore sources of variability in feature extraction from DNA microarrays on Nylon membrane with radioactive detection. We introduce a mathematical model of the signal emission and derive methods for correcting biases such as overshining, saturation or variation in probe amount. We also provide a quality metric which can be used qualitatively to flag weak or untrusted signals or quantitatively to modulate the weight of each experiment or gene in higher level analyses (clustering or discriminant analysis). CONCLUSIONS: Our novel feature extraction methodology, based on a mathematical model of the radioactive emission, reduces variability due to saturation, neighbourhood effects and variable probe amount. Furthermore, we provide a fully automatic feature extraction software, BZScan, which implements the algorithms described in this paper.

[Catheterization of the inferior petrosal sinus. Its role in the diagnosis of Cushing's syndrome. Experience with 23 explorations]. / Le cathétérisme des sinus pétreux inférieurs. Sa place dans le diagnostic du syndrome de Cushing. Expérience de 23 explorations.

Selective catheterization of the inferior petrosal sinus has been performed in 23 patients: 11 Cushing's disease, 5 lung carcinoid tumors whose diagnosis has been confirmed by surgery and 7 ACTH-dependent hypercortisolism whose final diagnosis has not yet been proved. The pituitary origin of hormone secretion is accepted if the central-to-peripheral ratio (C/PR) is equal or greater than 2 on basal values and/or during CRF test. On basal values, all subjects but one with confirmed pituitary lesions exhibited a C/PR > or = 2; the carcinoid tumors never exceeded the value of 1.3. After CRF injection, all the pituitary tumors showed an increase in C/PR; one patient with a lung carcinoid tumor (CRF-negative) showed a pituitary ACTH secretion (C/PR = 3.7). The localization of pituitary adenoma by the lateralization of hormone secretion is disappointing, except, perhaps, for very small extremely lateral adenomas. No accident occurred in our series, nor in the literature. This investigation seems the most reliable approach to prove the pituitary origin of hormonal hypersecretion. We recommend it to be performed in ACTH-dependent Cushing's syndrome when the secretory pattern is not typical and/or pituitary imaging is normal.

Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus.

The usefulness of high-frequency stimulation of the ventral intermediate nucleus (Vim) as the first neurosurgical procedure in disabling tremor was assessed in 26 patients with Parkinson's disease and 6 with essential tremor. 7 of these patients had already undergone thalamotomy contralateral to the stimulated side, and 11 others had bilateral Vim stimulation at the same time. Chronic stimulating electrodes connected to a pulse generator were implanted in the Vim. Tremor amplitude at rest, during posture holding, and during action and intention manoeuvres was assessed by means of accelerometry. Of the 43 thalami stimulated, 27 showed complete relief from tremor and 11 major improvement (88%). The improvement was maintained for up to 29 months (mean follow-up 13 [SD 9] months). Adverse effects were mild and could be eradicated by reduction or cessation of stimulation. This reversibility and adaptability, allowing control of side-effects, make thalamic stimulation preferable to thalamotomy, especially when treatment of both sides of the brain is needed.

[Memory disorders following rupture of anterior communicating artery aneurysm. 22 cases]. / Troubles mnésiques après rupture d'anévrysme de l'artère communicante antérieure. 22 cas.

Twenty-two patients who underwent surgery for ruptured aneurysm of the anterior communicating artery were investigated by a battery of neuropsychological tests, including memory evaluation tests. According to the results obtained at these tests the patients were divided into three groups: 1) 7 patients had no memory disorders; 2) 10 patients presented with memory disorders affecting memory; their complaints concerned behavior, and the memory deficit was discovered at neuropsychological examination; 3) 5 patients presented with an obvious amnesic syndrome, and the tests confirmed a severe learning deficit and a severe forgetting while recognition remained normal in 4 patients. Age, residual lesions at CT and electrophysiological signs of focalization correlated well with the residual neuropsychological disorders. Leaving aside quantitative aspects, the memory deficits observed in the second and third groups seemed to be qualitatively different and might correspond to different anatomical and functional sequelae.

[Association of 5-FU, CDDP and hypofractionated radiotherapy in recurrences of subtentorial astrocytomas and malignant gliomas in adults]. / L'association 5-FU/CDDP/radiothérapie hypofractionnée dans les récidives des astrocytomes et des gliomes malins sustentoriels de l'adulte.

Twenty-seven patients who had a relapse of astrocytomas or supra-tentorial malignant gliomas, previously treated by radio-surgical combination or exclusive irradiation, underwent a combination of 3 courses of 5-FU, cis-platyl and hypofractionated irradiation. No objective response was observed, but there was a progression of the tumor in 33% of the cases, and no change in 67%. Overall median survival was 7 +/- 1.5 months. The 20 patients with grade III or IV astrocytomas had a lower median rate than the 7 patients with grade II astrocytomas or oligodendrogliomas: 6 +/- 1.8 months versus 18 +/- 3.2 (P = 0.16). Median survival was 14 +/- 2.7 months for neurological responders and 6 +/- 2.1 months for non-responders (P = 0.017).

[Surgery of acoustic neurinoma. Apropos of a personal series. Development of techniques and results]. / La chirurgie du neurinome de l'acoustique. A propos d'une série personnelle. Evolution des techniques et résultats.

Between 1973 and 1987, 125 acoustic neurinomas were operated on in oto-neuro-surgery. The sub-occipital approach route was used for Stages III and IV up to 1982 (30 cases). Subsequently, surgery for all the neurinomas used the translabyrinthine approach route (82 cases), except for those cases where an attempt was made to preserve hearing by a supra-petrosal route (6 cases) or a retrosigmoid route (6 cases). The translabyrinthine approach route provided the simplest sequellae and the best preservation of the function of the facial nerve: grades I and II in 68% of cases (in 80% of cases by excluding Stage IV). Preservation of hearing was perfect in 2 cases, and partial in 2 cases, out of 12 attempts. The use of a facial nerve monitor proved highly satisfactory.

[Treatment of Parkinson tremor by chronic stimulation of the ventral intermediate nucleus of the thalamus]. / Traitement du tremblement parkinsonien par stimulation chronique du noyau ventral intermédaire du thalamus.

Stereotactic ventral intermediate nucleus (Vim) thalamotomy may improve drug resistant severe parkinsonian tremor. However, tremor may recur and bilateral thalamotomy is known to induce unacceptable side effects in a proportion of patients. A high frequency (130 Hz) chronic Vim stimulation was performed in 4 parkinsonian patients, 2 of them having previously undergone a thalamotomy on the other side. Tremor was suppressed in all patients at the price of slight paresthesias. This improvement has been lasting from 2 to 14 months. Beneficial and adverse effects were suppressed at once each time the stimulation was stopped. These preliminary results are encouraging but a longer delay and more patients are obviously needed.

[Multiple correlative studies of stereotaxic biopsies of brain tumors]. / Etudes correlatives multiples sur biopsies stéreótaxiques de tumeurs cérébrales.

The opportunity of having several samples at the same site which could be spatially localized allows an intensive exploitation of stereotactic biopsies of brain tumors: the pathological data may be correlated to other measures, performed at the same site (electrical impedance X ray absorption coefficient) or on other samples (NMR relaxation times, water content, nucleic acids). These samples are available for oncology experiments in cellular biology (cell cultures, grafts on nude mice) or in molecular biology (DNA and RNA hybridization with specific nucleic acid probes). We were therefore able: 1) to study the diagnostic homologies between pathology and histology examinations; 2) to show that T1 and T2 NMR relaxation times are 2 times longer in tumor tissues than in normal brain; 3) to show that the electrical impedance is decreased by a factor 2 in brain tumors; 4) to show the absence of integrated viral genomic sequences and the existence of oncogenes association patterns in brain tumors by hybridization of specific sequences; 5) to establish permanent cell lines, the tumorigenicity of which is assayed by grafting on nude mice. Therefore, stereotactic biopsies appear to be, provided they are intensively and rationally exploited, a major research tool in an area which remains unsensitive to the various therapeutic approaches.

Removable, adjustable and reusable implants for stereotactic interstitial radiosurgery of brain tumors.

Sixty primary brain tumors (gliomas) were treated by interstitial radiosurgery using 192Ir according to a protocol based on the size of the tumor. In all cases, the radioactive wires were left in place for periods ranging from 5 to 10 days, according to dosimetry calculations, and then removed, which was made possible by the use of removable implants. The stainless steel tubes are occluded on their inner side and adjustable in length depending on the depth of the tumor, and are introduced through screws inserted into the skull in an array depending on the preliminary dosimetry. The tubes were afterloaded with 192Ir and removed at the end of the calculated time. Forty-six patients (18 low-grade and 28 malignant gliomas) were treated using this method. One small hematoma was evacuated and no sepsis occurred.

Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease.

Stereotactic thalamotomy of the thalamic nucleus ventralis intermedius (VIM) is routinely used for movement disorders. During this procedure, it has been observed that high-frequency (100 Hz) stimulation of VIM was able to stop the extrapyramidal tremor. In patients with bilateral tremor of extrapyramidal origin, who were resistant to drug therapy, the therapeutic protocol associated (1) a radiofrequency VIM thalamotomy for the most disabled side, and (2) a continuous VIM stimulation for the other side using stereotactically implanted electrodes, connected to subcutaneous stimulators. VIM thalamotomy relieved the tremor in all operated cases. Side effects were mild and regressive. VIM stimulation strongly decreased the tremor but failed to suppress it as completely as thalamotomy did. This was due in part to the fact that programmable stimulator frequency rate is limited to 130 Hz, while it appeared that the optimal stimulation frequency was 200 Hz. This therapeutic protocol appears to be of interest for patients with bilateral extrapyramidal movement disorders.

[Technical considerations on lumbar disk surgery. Results of a survey of 49 centers]. / Considérations techniques sur la chirurgie discale lombaire. Résultats d'une enquête portant sur 49 centres.

The lumbar discectomy, how do you see it? That could be the title of this inquiry which 49 neurosurgeons answered. At first we discuss the timing of the operation (as a rule sooner than the conventional indication of the third month) the use of operative microscope which is still uncommon (11 surgeons out of 49) and the operative policy. The more specific technical features regarding the different stages of the operation are then analysed. Opinions of neurosurgeons differ on many points particularly on the ligament and bone removal which exposes the disco-radicular conflict: whereas one third of the neurosurgeons refuse to open the lumbar facet joint, one third always open it widely and the remaining third take a mid-way position. On the whole, this inquiry points cut both a great diversity in technical details, but also a stagnation because this operation hardy improved and only slightly benefited from the technical progress.

[Our experience with surgery of neuromas of the 8th nerve]. / Notre expérience de la chirurgie des neurinomes du VIII.

Before 1982 the suboccipital approach was reserved for neurinomas larger than 2 cm diameter, whereas since that date the translabyrinthine approach has been employed in all cases where no attempt was made to preserve hearing. Of the 85 patients operated upon between 1978 and 1985, 5 were through a supra-petrous approach, 35 a retro-sigmoid approach, 44 a translabyrinthine approach and one by a transotic approach. Translabyrinthine approaches allowed the best postoperative course and conservation of normal facial motility in 22 patients of 33 with stages II and III lesions. An attempt was made to preserve hearing in 9 patients, with one reasonable result by the supra-petrous approach and 2 satisfactory results including one perfect operated upon using a rectosigmoid approach.

[The metastatic meningoradiculitis. An exceptional detection of a gastric cancer. Review of the literature about one case (author's transl)]. / La méningoradiculite métastatique: un mode de révélation exceptionnel de cancer gastrique. Revue de la littérature à propos d'un cas.

The authors relate a case of gastric cancer on a 47 years woman, revealed by the presence of nerve roots metastasis whose evolution was fatal in 13 months. They are pointing out the singularity of this pathology as only 29 cases have been published to date. The clinical and radiological diagnosis must cancel the existence of paraneoplasic polyradiculoneuritis, only by histological examination of the roots. The primary cancer concerns often the breast, the lungs and the stomach. But 25% of cases remain unknown. Among the various terms proposed to define this neurological complication of visceral neoplasms, the authors are selecting the expression of "metastatic meningoradiculitis", as the best reflecting of the anatomical scheme.

[Semiologic aspects of traumatic coma (author's transl)]. / Aspects séméiologiques des comas traumatiques.

After studying 85 patients with severe traumatic coma and reviewing the published literature, the authors propose a simple clinical procedure for the diagnostic of such cases. This classification is based on signs without any ambiguity, easily recognized by different physicians, and of pathognomonic significance. These include reaction to pain, testing four reflexes integrated at different levels in the brain stem, pupil morphology, and spontaneous ocular movements. The clinical features corresponding to different levels of dysfunction in the brain are described and their characteristics outlined. The importance of motor reactivity to pain associated to the brain stem reflexes (fronto-orbicular, photomotor, horizontal and vertical oculo-encephalic) is stressed.