Distinct roles of Hoxa2 and Krox20 in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening

<p>Abstract</p> <p>Background</p> <p>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 <it>Hoxa2</it>, the only <it>Hox </it>gene expressed up to r2, and of <it>Krox20</it>, 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 <it>Hoxa2 </it>by Krox20 in r3.</p> <p>Results</p> <p>We found that <it>Hoxa2 </it>mutants displayed an impaired oro-buccal reflex, similarly to <it>Krox20 </it>mutants. In contrast, while <it>Krox20 </it>is required for the development of the rhythm-promoting parafacial respiratory group (pFRG) modulating respiratory frequency,<it> Hoxa2 </it>inactivation did not affect neonatal breathing frequency. Instead, we found that <it>Hoxa2</it>^-/-but not <it>Krox20</it>^-/-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 <it>Hoxa2 </it>expressing cells indicated that the control of inspiratory activity resides in rostral pontine areas and required an intact r2-derived territory.</p> <p>Conclusion</p> <p>Thus, inspiratory shaping and respiratory frequency are under the control of distinct <it>Hox</it>-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.</p

Phenotypic traits of mutants at birth: impaired oro-buccal behavior and increased tidal volume

<p><b>Copyright information:</b></p><p>Taken from "Distinct roles of and in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening"</p><p>http://www.neuraldevelopment.com/content/2/1/19</p><p>Neural Development 2007;2():19-19.</p><p>Published online 26 Sep 2007</p><p>PMCID:PMC2098766.</p><p></p> Plethsymographic recordings of wild-type (top), and heterozygous (middle) and homozygous (bottom) mutant mice at P0. Inspiration is upward. Note that in mice, there is a two-fold increase in tidal volume compared with and wild-type littermates, whereas the frequency is the same (about 110 breaths/minute). Individual data relating tidal volume (V, abscissa) and number (nb) of jaw openings (ordinates) at P0.1. Each symbol corresponds to one animal. Black triangles are for mutants (b, c), open circles represent mutants (c) and open squares correspond to wild-type animals (b). Note that mutants can be separated from other genotypes at P0.1, due to their two-fold increased tidal volume and their reduced number of jaw openings. Broken lines indicate the values used to calculate penetrance of the phenotype (V, all data inferior to mean – 1 standard deviation; jaw openings, all data superior to mean + 1 standard deviation)

Naloxone treatment was effective on ventilation in mice but did not increase survival

<p><b>Copyright information:</b></p><p>Taken from "Distinct roles of and in the development of rhythmic neural networks controlling inspiratory depth, respiratory frequency, and jaw opening"</p><p>http://www.neuraldevelopment.com/content/2/1/19</p><p>Neural Development 2007;2():19-19.</p><p>Published online 26 Sep 2007</p><p>PMCID:PMC2098766.</p><p></p> Plethysmographic recordings before (control) and after naloxone (NLX) treatment in animals. Note the frequency increase and the reduction of apneas. Effects of the subcutanueous injection of NLX (1 mg/kg) at P0.5 upon mean ± standard error of the mean respiratory frequency calculated without apneic episodes in wild-type, , and animals (b) or survival in the same genotypes (c). In (b, c) white bars indicate control values and black bars labeled NLX indicate values in the same animals one hour (b) (respiratory frequency) or 1.5 days (c) (survival) after NLX injection. Although NLX eliminates apneas (a) and increases respiratory frequency (by 31 + 11% in and 51 ± 37 % in ) (b), it does not allow survival of mutants (c)

Intensive chemotherapy followed by autologous stem cell transplantation in primary central nervous system lymphomas (PCNSLs). Therapeutic outcomes in real life-experience of the French network

International audienceWe analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n\,=\,147) or at relapse (n\,=\,119). The median age at IC-ASCT was 57 years (range: 22-74). IC consisted of thiotepa-BCNU (n\,=\,64), thiotepa-busulfan (n\,=\,24), BCNU-etoposide-cytarabine-melphalan (BEAM, n\,=\,36) and thiotepa-busulfan-cyclophosphamide (n\,=\,142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC