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The low-dose-rate response of five bipolar integrated circuits is evaluated on the basis of switching experiments. Such experiments consist of performing first a high-dose-rate irradiation followed by a low-dose-rate irradiation. Based on these experiments, a time-saving method to predict the low-dose-rate degradation of bipolar linear microcircuits is proposed. This approach provides a good estimate of the low-dose-rate degradation. Index Terms--Bipolar technology, dose rate, enhanced low-dose-rate sensitivity (ELDRS), integrated circuit, switching experiment, total dose.

The total-dose response of bipolar microcircuits is investigated. A recovery of the degradation is observed for high total dose in the saturation region. The circuit response in this region is studied based on room temperature annealing. The role of the electric feld is studied and the results are discussed in terms of hardness assurance. Index Terms--Bipolar transistor, device characterization, dose rate, hardness assurance, linear microcircuit, saturation region, total dose.

The influence of an electrostatic barrier in the oxide bulk on the radiation-induced degradation of bipolar technologies is investigated by performing a thermal annealing operation before switching the dose rate from high to low. It is shown that, in our test conditions, no significant electrostatic barrier effect is at play in the device degradation. Index Terms--Bipolar, dose, dose rate, enhanced low dose rate sensitivity (ELDRS), ICs, thermal annealing.

The loss of sensitivity induced by the displacement damage effect on the optically stimulated luminescent dosimeter is investigated. A new architecture is proposed and successfully tested to harden the sensor at system level. Index Terms--Dosimeter, dosimetry, hardening, OSL, sensor.

A large set of InGaAs photodiodes from different manufacturers has been irradiated with electrons of 0.5–20 MeV, with protons of 60, 100, and 170 MeV, and with atmospheric-like neutron spectrum. Depending on the type of incident particles and energy, the deposited damage dose has been evaluated in the ~ 5 × 106 to 5 × 109 MeV/g range. The dark current damage factor has been extracted from measurements at different fluence levels. The dark current data right after irradiation and 2 months later allow for evaluating any possible annealing processes. The damage factor measured after about 2 months has been scaled with nonionizing energy loss (NIEL). Finally, the validity of NIEL scaling is discussed for InGaAs materials. [ABSTRACT FROM AUTHOR]

This paper presents a compact model of latchup considering design and process dependence. The new approach is more realistic and inspirited from the classical model. This model was used to confirm the single-event latchup (SEL) robustness of D-flip-flops (DFFs) used in Readout Circuit of Infrared-sensors developed by Sofradir. SEL cross sections are presented by the mean of the Monte Carlo tool MUSCA SEP3 in order to validate the new latchup modeling approach. [ABSTRACT FROM AUTHOR]

This paper presents a modeling approach of single-event functional interrupt (SEFI) which takes into account all the physical and electrical processes from the radiation particle down to the event at the system level. This paper is focused on the evaluation of SEFI sensitivity by experimental and simulation analyses of a readout integrated circuit (ROIC) designed by Sofradir for their infrared image sensors. Relevant correlations between simulation and experimental results of SEFI cross sections for heavy ions are presented and discussed. The simulation results confirm the strong SEFI robustness of the ROIC at 57 K. [ABSTRACT FROM AUTHOR]

This paper highlights the impact of design on the single-event upset (SEU) sensitivity of D-flip-flops (DFFs) used in a readout circuit (ROIC) under heavy ions. New experimental data obtained at the University of Louvain for several designs are presented. The single-event effect (SEE) prediction tool multi-scale single event phenomena predictive platform is used to investigate the failure occurrences at the circuit level as a function of the design. In some cases, design specificities allow for increasing in the SEU robustness of the DFF. However, it appeared that cryogenic temperatures limit the impact of the design on the SEU sensitivity of DFFs. The results show a very limited impact of the temperature on the SEU occurrence, independent of the layout. These results are consistent with the experimental data presented in recent works regarding single-event transient and single-event functional interrupt. These results allow for performing irradiation tests of complementary metal–oxide–semiconductor IR detector (ROIC) at room temperature instead of cooling down the device during the SEE measurements. [ABSTRACT FROM AUTHOR]

This paper presents the impact of cryogenic temperatures, down to 50 K, on the single-event transient (SET) sensitivity of two readout circuits of infrared image sensor designed by Sofradir. Experimental SETs data obtained under heavy ions at the Université Catholique de Louvain la Neuve facility are described, and the temperature impact on the SET cross sections is presented. The analysis of experimental sensitivity trends is completed by means of MUSCA SEP3 tool. [ABSTRACT FROM PUBLISHER]

This paper presents a physical investigation of the mechanisms induced by the low temperature on single-event latchup in CMOS inverters for a range of technology nodes (250 nm from Sofradir and 180 nm from IBM). For the first time, the TCAD simulations show a good agreement of latchup characteristics with the experimental measurements at cryogenic temperatures. Additionally, a more robust technology provided by Sofradir was demonstrated. [ABSTRACT FROM PUBLISHER]

This paper presents for the first time the impact of cryogenic temperatures, down to 77 K, on the SEU sensitivity of D-Flip-Flop (DFF) of infrared image sensor. Estimations and a failure analysis at circuit level are presented and investigated considering the stored data configuration and the temperature. The comparisons with experimental data obtained under heavy ion at UCL are presented and consistent. A good correlation of SEU cross sections is revealed. A saturation effect is observed below 200 K. [ABSTRACT FROM PUBLISHER]

Silicon transistor test vehicles used in infrared detectors were exposed to total dose at cryogenic temperatures. We present the degradation of the leakage current and threshold voltage of different transistor topologies at different dose rates and temperatures. The results show that the degradation occurs in the lateral parts of the transistors. Moreover, a different degradation was observed at 83 and 108 K. The higher temperature corresponds to the higher degradation; this can be explained by a more efficient hole transport process at these temperature. Measurements during the warming process of the devices show that a competition exists between the hole transport and their annealing, suggesting that a worst case of degradation could be found between nitrogen and room temperature. [ABSTRACT FROM PUBLISHER]

Objective:Palliative sedation is a last resort medical act aimed at relieving intolerable suffering induced by intractable symptoms in patients at the end-of-life. This act is generally accepted as being medically indicated under certain circumstances. A controversy remains in the literature as to its ethical validity. There is a certain vagueness in the literature regarding the legitimacy of palliative sedation in cases of non-physical refractory symptoms, especially “existential suffering.” This pilot study aims to measure the influence of two independent variables (short/long prognosis and physical/existential suffering) on the physicians' attitudes toward palliative sedation (dependent variable).Methods:We used a 2 × 2 experimental design as described by Blondeau et al. Four clinical vignettes were developed (vignette 1: short prognosis/existential suffering; vignette 2: long prognosis/existential suffering; vignette 3: short prognosis/physical suffering; vignette 4: long prognosis/physical suffering). Each vignette presented a terminally ill patient with a summary description of his physical and psychological condition, medication, and family situation. The respondents' attitude towards sedation was assessed with a six-point Likert scale. A total of 240 vignettes were sent to selected Swiss physicians.Results:74 vignettes were completed (36%). The means scores for attitudes were 2.62 ± 2.06 (v1), 1.88 ± 1.54 (v2), 4.54 ± 1.67 (v3), and 4.75 ± 1.71 (v4). General linear model analyses indicated that only the type of suffering had a significant impact on the attitude towards sedation (F = 33.92, df = 1, p = 0.000).Significance of the results:The French Swiss physicians' attitude toward palliative sedation is more favorable in case of physical suffering than in existential suffering. These results are in line with those found in the study of Blondeau et al. with Canadian physicians and will be discussed in light of the arguments given by physicians to explain their decisions. [ABSTRACT FROM PUBLISHER]

The degradation of discrete and integrated-circuit bipolar technologies irradiated at High Dose Rate (HDR) and then switched to Low Dose Rates (LDR) is studied. It is shown that the degradation rate of switched devices is equal to that found at low dose rates for all the tested devices. [ABSTRACT FROM AUTHOR]

The neurodevelopmental outcome and school performance of 50 appropriate for gestational age (AGA) and 33 small for gestational age (SGA) very-low-birth-weight (VLBW) infants, compared to a control group (41 Term infants) were assessed at 8 years of age. The incidence of major handicaps among AGA and SGA/VLBW infants respectively, was 16% and 6%. No major handicap was found in the control group. The incidence of neurodevelopmental abnormalities (NDA) among AGA's (40%) and SGA's (57.6%) compared with the control group (31.7%) was found to be significantly higher. School failure occurred more frequently among VLBW infants (22.9%) and was related in children with NDA--and more particularly among AGA's--to the presence of language disorders or associated NDA. Evaluation of the consequences of NDA and school problems for later academic and professional achievement now requires further follow-up studies. [ABSTRACT FROM AUTHOR]

Predicting the low-dose-rate degradation of bipolar technologies is one of the main issues for circuits intended for use in the ionizing-radiation environment of space because of the enhanced low-dose-rate sensitivity (ELDRS). In this letter, ELDRS is shown to be related to competition between trapping and recombination of radiation-induced carriers in the oxide. The presented model is shown to be in good agreement with experimental data. It is also shown that this effect is strongly dependent on the oxide quality. [ABSTRACT FROM AUTHOR]

Abstract Background Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of Hoxa2, the only Hox gene expressed up to r2, and of Krox20, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of Hoxa2 by Krox20 in r3. Results We found that Hoxa2 mutants displayed an impaired oro-buccal reflex, similarly to Krox20 mutants. In contrast, while Krox20 is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency, Hoxa2 inactivation did not affect neonatal breathing frequency. Instead, we found that Hoxa2-/- but not Krox20-/- mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of Hoxa2 expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory. Conclusion Thus, inspiratory shaping and respiratory frequency are under the control of distinct Hox-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.

Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development., (© 2023. The Author(s).)

Providing appropriate positional identity and patterning information to distinct rostrocaudal subpopulations of cranial neural crest cells (CNCCs) is central to vertebrate craniofacial morphogenesis. Hox genes are not expressed in frontonasal and first pharyngeal arch (PA1) CNCCs, whereas a single Hox gene, Hoxa2 , is necessary to provide patterning information to second pharyngeal arch (PA2) CNCCs. In frog, chick and mouse embryos, ectopic expression of Hoxa2 in Hox -negative CNCCs induced hypoplastic phenotypes of CNCC derivatives of variable severity, associated or not with homeotic transformation of a subset of PA1 structures into a PA2-like identity. Whether these different morphological outcomes are directly related to distinct Hoxa2 overexpression levels is unknown. To address this issue, we selectively induced Hoxa2 overexpression in mouse CNCCs, using a panel of mouse lines expressing different Hoxa2 ectopic expression levels, including a newly generated Hoxa2 knocked-in mouse line. While ectopic Hoxa2 expression at only 60% of its physiological levels was sufficient for pinna duplication, ectopic Hoxa2 expression at 100% of its normal level was required for complete homeotic repatterning of a subset of PA1 skeletal elements into a duplicated set of PA2-like elements. On the other hand, ectopic Hoxa2 overexpression at non-physiological levels (200% of normal levels) led to an almost complete loss of craniofacial skeletal structures. Moreover, ectopic Hoxa5 overexpression in CNCCs, while also resulting in severe craniofacial defects, did not induce homeotic changes of PA1-derived CNCCs, indicating Hoxa2 specificity in repatterning a subset of Hox -negative CNCCs. These results reconcile some discrepancies in previously published experiments and indicate that distinct subpopulations of CNCCs are differentially sensitive to ectopic levels of Hox expression.

Rapid cellular responses to environmental stimuli are fundamental for development and maturation. Immediate early genes can be transcriptionally induced within minutes in response to a variety of signals. How their induction levels are regulated and their untimely activation by spurious signals prevented during development is poorly understood. We found that in developing sensory neurons, before perinatal sensory-activity-dependent induction, immediate early genes are embedded into a unique bipartite Polycomb chromatin signature, carrying active H3K27ac on promoters but repressive Ezh2-dependent H3K27me3 on gene bodies. This bipartite signature is widely present in developing cell types, including embryonic stem cells. Polycomb marking of gene bodies inhibits mRNA elongation, dampening productive transcription, while still allowing for fast stimulus-dependent mark removal and bipartite gene induction. We reveal a developmental epigenetic mechanism regulating the rapidity and amplitude of the transcriptional response to relevant stimuli, while preventing inappropriate activation of stimulus-response genes.

The mammalian precerebellar pontine nucleus (PN) has a main role in relaying cortical information to the cerebellum. The molecular determinants establishing ordered connectivity patterns between cortical afferents and precerebellar neurons are largely unknown. We show that expression of Hox5 transcription factors is induced in specific subsets of postmitotic PN neurons at migration onset. Hox5 induction is achieved by response to retinoic acid signaling, resulting in Jmjd3-dependent derepression of Polycomb chromatin and 3D conformational changes. Hoxa5 drives neurons to settle posteriorly in the PN, where they are monosynaptically targeted by cortical neuron subsets mainly carrying limb somatosensation. Furthermore, Hoxa5 postmigratory ectopic expression in PN neurons is sufficient to attract cortical somatosensory inputs regardless of position and avoid visual afferents. Transcriptome analysis further suggests that Hoxa5 is involved in circuit formation. Thus, Hoxa5 coordinates postmitotic specification, migration, settling position, and sub-circuit assembly of PN neuron subsets in the cortico-cerebellar pathway., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

This paper review presents Single Event Effects (SEE) irradiation tests under heavy ions of the test-chip of D-Flip-Flop (DFF) cells and complete readout integrated circuits (ROIC) as a function of temperature, down to 50 K. The analyses of the experimental data are completed using the SEE prediction tool MUSCA SEP3. The conclusions derived from the experimental measurements and related analyses allow to update the current SEE radiation hardness assurance (RHA) for readout integrated circuits of infrared image sensors used at cryogenic temperatures. The current RHA update is performed on SEE irradiation tests at room temperature, as opposed to the operational cryogenic temperature. These tests include SET (Single Event Transient), SEU (Single Event Upset) and SEFI (Single Event Functional Interrupt) irradiation tests. This update allows for reducing the cost of ROIC qualifications and the test setup complexity for each space mission., Competing Interests: The authors declare no conflicts of interest.

The cerebral cortex is organized into specialized sensory areas, whose initial territory is determined by intracortical molecular determinants. Yet, sensory cortical area size appears to be fine tuned during development to respond to functional adaptations. Here we demonstrate the existence of a prenatal sub-cortical mechanism that regulates the cortical areas size in mice. This mechanism is mediated by spontaneous thalamic calcium waves that propagate among sensory-modality thalamic nuclei up to the cortex and that provide a means of communication among sensory systems. Wave pattern alterations in one nucleus lead to changes in the pattern of the remaining ones, triggering changes in thalamic gene expression and cortical area size. Thus, silencing calcium waves in the auditory thalamus induces Rorβ upregulation in a neighbouring somatosensory nucleus preluding the enlargement of the barrel-field. These findings reveal that embryonic thalamic calcium waves coordinate cortical sensory area patterning and plasticity prior to sensory information processing., Competing Interests: The authors declare no competing financial interests.

Tonotopy is a hallmark of auditory pathways and provides the basis for sound discrimination. Little is known about the involvement of transcription factors in brainstem cochlear neurons orchestrating the tonotopic precision of pre-synaptic input. We found that in the absence of Hoxa2 and Hoxb2 function in Atoh1-derived glutamatergic bushy cells of the anterior ventral cochlear nucleus, broad input topography and sound transmission were largely preserved. However, fine-scale synaptic refinement and sharpening of isofrequency bands of cochlear neuron activation upon pure tone stimulation were impaired in Hox2 mutants, resulting in defective sound-frequency discrimination in behavioral tests. These results establish a role for Hox factors in tonotopic refinement of connectivity and in ensuring the precision of sound transmission in the mammalian auditory circuit., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mouse whiskers are somatotopically mapped in brainstem trigeminal nuclei as neuronal modules known as barrelettes. Whisker-related afferents form barrelettes in ventral principal sensory (vPrV) nucleus, whereas mandibular input targets dorsal PrV (dPrV). How barrelette neuron identity and circuitry is established is poorly understood. We found that ectopic Hoxa2 expression in dPrV neurons is sufficient to attract whisker-related afferents, induce asymmetrical dendrite arbors, and allow ectopic barrelette map formation. Moreover, the thalamic area forming whisker-related barreloids is prenatally targeted by both vPrV and dPrV axons followed by perinatal large-scale pruning of dPrV axons and refinement of vPrV barrelette input. Ectopic Hoxa2 expression allows topographically directed targeting and refinement of dPrV axons with vPrV axons into a single whisker-related barreloid map. Thus, a single HOX transcription factor is sufficient to switch dPrV into a vPrV barrelette neuron program and coordinate input-output topographic connectivity of a dermatome-specific circuit module., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

External ear abnormalities are frequent in newborns ranging from microtia to partial auricle duplication. Little is known about the molecular mechanisms orchestrating external ear morphogenesis. In humans, HOXA2 partial loss of function induces a bilateral microtia associated with an abnormal shape of the auricle. In mice, Hoxa2 inactivation at early gestational stages results in external auditory canal (EAC) duplication and absence of the auricle, whereas its late inactivation results in a hypomorphic auricle, mimicking the human HOXA2 mutant condition. By genetic fate mapping we found that the mouse auricle (or pinna) derives from the Hoxa2-expressing neural crest-derived mesenchyme of the second pharyngeal arch, and not from a composite of first and second arch mesenchyme as previously proposed based on morphological observation of human embryos. Moreover, the mouse EAC is entirely lined by Hoxa2-negative first arch mesenchyme and does not develop at the first pharyngeal cleft, as previously assumed. Conditional ectopic Hoxa2 expression in first arch neural crest is sufficient to induce a complete duplication of the pinna and a loss of the EAC, suggesting transformation of the first arch neural crest-derived mesenchyme lining the EAC into an ectopic pinna. Hoxa2 partly controls the morphogenesis of the pinna through the BMP signalling pathway and expression of Eya1, which in humans is involved in branchio-oto-renal syndrome. Thus, Hoxa2 loss- and gain-of-function approaches in mice provide a suitable model to investigate the molecular aetiology of microtia and auricle duplication.

We investigated the role of histone methyltransferase Ezh2 in tangential migration of mouse precerebellar pontine nuclei, the main relay between neocortex and cerebellum. By counteracting the sonic hedgehog pathway, Ezh2 represses Netrin1 in dorsal hindbrain, which allows normal pontine neuron migration. In Ezh2 mutants, ectopic Netrin1 derepression results in abnormal migration and supernumerary nuclei integrating in brain circuitry. Moreover, intrinsic topographic organization of pontine nuclei according to rostrocaudal progenitor origin is maintained throughout migration and correlates with patterned cortical input. Ezh2 maintains spatially restricted Hox expression, which, in turn, regulates differential expression of the repulsive receptor Unc5b in migrating neurons; together, they generate subsets with distinct responsiveness to environmental Netrin1. Thus, Ezh2-dependent epigenetic regulation of intrinsic and extrinsic transcriptional programs controls topographic neuronal guidance and connectivity in the cortico-ponto-cerebellar pathway.

Oligodendrocytes are the myelin-forming cells of the vertebrate CNS. Little is known about the molecular control of region-specific oligodendrocyte development. Here, we show that oligodendrogenesis in the mouse rostral hindbrain, which is organized in a metameric series of rhombomere-derived (rd) territories, follows a rhombomere-specific pattern, with extensive production of oligodendrocytes in the pontine territory (r4d) and delayed and reduced oligodendrocyte production in the prepontine region (r2d, r3d). We demonstrate that segmental organization of oligodendrocytes is controlled by Hox genes, namely Hoxa2 and Hoxb2. Specifically, Hoxa2 loss of function induced a dorsoventral enlargement of the Olig2/Nkx2.2-expressing oligodendrocyte progenitor domain, whereas conditional Hoxa2 overexpression in the Olig2(+) domain inhibited oligodendrogenesis throughout the brain. In contrast, Hoxb2 deletion resulted in a reduction of the pontine oligodendrogenic domain. Compound Hoxa2(-/-)/Hoxb2(-/-) mutant mice displayed the phenotype of Hoxb2(-/-) mutants in territories coexpressing Hoxa2 and Hoxb2 (rd3, rd4), indicating that Hoxb2 antagonizes Hoxa2 during rostral hindbrain oligodendrogenesis. This study provides the first in vivo evidence that Hox genes determine oligodendrocyte regional identity in the mammalian brain.

In vertebrate embryos, retinoic acid (RA) synthesized in the mesoderm by Raldh2 emanates to the hindbrain neuroepithelium, where it induces anteroposterior (AP)-restricted Hox expression patterns and rhombomere segmentation. However, how appropriate spatiotemporal RA activity is generated in the hindbrain is poorly understood. By analyzing Pbx1/Pbx2 and Hoxa1/Pbx1 null mice, we found that Raldh2 is itself under the transcriptional control of these factors and that the resulting RA-deficient phenotypes can be partially rescued by exogenous RA. Hoxa1-Pbx1/2-Meis2 directly binds a specific regulatory element that is required to maintain normal Raldh2 expression levels in vivo. Mesoderm-specific Xhoxa1 and Xpbx1b knockdowns in Xenopus embryos also result in Xraldh2 downregulation and hindbrain defects similar to mouse mutants, demonstrating conservation of this Hox-Pbx-dependent regulatory pathway. These findings reveal a feed-forward mechanism linking Hox-Pbx-dependent RA synthesis during early axial patterning with the establishment of spatially restricted Hox-Pbx activity in the developing hindbrain., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The pontine neurons (PN) represent a major source of mossy fiber projections to the cerebellum. During mouse hindbrain development, PN migrate tangentially and sequentially along both the anteroposterior (AP) and dorsoventral (DV) axes. Unlike DV migration, which is controlled by the Netrin-1/Dcc attractive pathway, little is known about the molecular mechanisms guiding PN migration along the AP axis. Here, we show that Hoxa2 and Hoxb2 are required both intrinsically and extrinsically to maintain normal AP migration of subsets of PN, by preventing their premature ventral attraction towards the midline. Moreover, the migration defects observed in Hoxa2 and Hoxb2 mutant mice were phenocopied in compound Robo1;Robo2, Slit1;Slit2, and Robo2;Slit2 knockout animals, indicating that these guidance molecules act downstream of Hox genes to control PN migration. Indeed, using chromatin immunoprecipitation assays, we further demonstrated that Robo2 is a direct target of Hoxa2 in vivo and that maintenance of high Robo and Slit expression levels was impaired in Hoxa2 mutant mice. Lastly, the analysis of Phox2b-deficient mice indicated that the facial motor nucleus is a major Slit signaling source required to prevent premature ventral migration of PN. These findings provide novel insights into the molecular control of neuronal migration from transcription factor to regulation of guidance receptor and ligand expression. Specifically, they address the question of how exposure to multiple guidance cues along the AP and DV axes is regulated at the transcriptional level and in turn translated into stereotyped migratory responses during tangential migration of neurons in the developing mammalian brain.

Background: Little is known about the involvement of molecular determinants of segmental patterning of rhombomeres (r) in the development of rhythmic neural networks in the mouse hindbrain. Here, we compare the phenotypes of mice carrying targeted inactivations of Hoxa2, the only Hox gene expressed up to r2, and of Krox20, expressed in r3 and r5. We investigated the impact of such mutations on the neural circuits controlling jaw opening and breathing in newborn mice, compatible with Hoxa2-dependent trigeminal defects and direct regulation of Hoxa2 by Krox20 in r3., Results: We found that Hoxa2 mutants displayed an impaired oro-buccal reflex, similarly to Krox20 mutants. In contrast, while Krox20 is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency, Hoxa2 inactivation did not affect neonatal breathing frequency. Instead, we found that Hoxa2-/- but not Krox20-/- mutation leads to the elimination of a transient control of the inspiratory amplitude normally occurring during the first hours following birth. Tracing of r2-specific progenies of Hoxa2 expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory., Conclusion: Thus, inspiratory shaping and respiratory frequency are under the control of distinct Hox-dependent segmental cues in the mammalian brain. Moreover, these data point to the importance of rhombomere-specific genetic control in the development of modular neural networks in the mammalian hindbrain.

Documentation in palliative care is often restricted to medical and sociodemographic information, and the assessment of physical and psychological symptoms or the quality of life. In order to overcome the lack of comprehensive information, we have evaluated the utility of the INTERMED-a biopsychosocial assessment method to document integrated information of patients' needs-in 82 consecutive patients for whom a palliative care consultation was requested. Results confirm the biopsychosocial heterogeneity of the sample, and the importance of integrated information to clinical, scientific, educational, and health care policy agendas. The INTERMED could become a useful method to tailor interdisciplinary interventions based on comprehensive patient needs assessment.

Outcome at five years of age of 110 high risk AGA, 71 high risk SGA preterm infants with similar birth weight and 102 term control infants was studied. Mean IQ in the 3 groups was not statistically different. Major handicaps were found in 16.3% of the AGA and in 8.5% of the SGA preterms. There was no major handicap among the controls. Minor neurodevelopmental abnormalities were present in 25.6% of AGA, 28.2% of SGA and 19.6% of controls. The types of neurodevelopmental handicaps were different in the 3 groups and generally more severe in the AGA group. All the major handicaps among AGA preterms were found in children with severe neonatal complications. In the SGA preterm group, only 1/3 of the major handicaps can be related to perinatal complications. Affective and behavior disorders were probably related in some way to neurodevelopmental achievement. This study showed that preterm infants with GA less than or equal to 32 weeks are more at risk than more mature SGA preterms with similar birth weight.

Two groups of 41 children with high perinatal risk were studied. All children of the study group (SG) had neurodevelopmental abnormalities (NDA) at the age of 5 years, without major handicap. The control group (CG) consisted of 41 children matched for sex, neonatal pathology, birthweight, gestational age and socioeconomic status, without NDA at 5 years. In the SG 85.4% of the children had persistent NDA at school age. In the CG 36.6% of the children presented NDA, but less severe than those of the SG. The SG children had more often associated NDA than those of the CG. The outcome of NDA diagnosed at preschool age and the results of psychometric tests are described. Associated NDA or a borderline IQ, with emotional and behavioral problems, have a gloomy school prognosis. 46.3% of the children in the SG had major schooling problems and 12.2% of children in the CG. These results show the possibility to detect children at risk of school achievement problems before school entrance; they might be useful in counselling and preventing behavioral and educational difficulties.