Cough determinants in patients with neuromuscular disease

Neuromuscular disease leads to cough impairment. Cough augmentation can be achieved by mechanical insufflation (MI) or manually assisted coughing (MAC). Many studies have compared these two methods, but few have evaluated them in combination. In 155 neuromuscular patients, we assessed determinants of peak cough flow (PCF) using stepwise correlation. Maximal inspiratory capacity contributed 44% of the variance (p<0.001), expiratory reserve volume 13%, and maximal expiratory pressure 2%. Thus, augmenting inspiration seems crucial. However, parameters dependent on expiratory muscles independently influence PCF. We measured vital capacity and PCF in 10 neuromuscular patients during cough augmentation by MI, MAC, or both. MI or MAC significantly improved VC and PCF (p<0.01) as compared to the basal condition and VC and PCF were higher during MI plus MAC than during MAC or MI alone (p<0.01). In conclusion, combining MAC and MI is useful for improving cough in neuromuscular patients.     

Expression of collapsin response mediator proteins 1, 2 and 5 is differentially regulated in newly generated and mature neurons of the adult olfactory system

Collapsin-response mediator proteins (CRMPs) are highly expressed in the developing brain where they take part in several aspects of neuronal differentiation. CRMPs are still present postnatally, but their function remains speculative in the adult brain. We studied the expression and localization of CRMP1, CRMP2 and CRMP5 in two areas of the nervous system with persistent neurogenesis in adult mice, the olfactory mucosa and the olfactory bulb. In the olfactory mucosa, we have established that CRMP expression is restricted to postmitotic cells of the olfactory neurons lineage. CRMP5 is coexpressed with growth associated protein of 43 kDa (GAP43) in immature olfactory neurons and is down-regulated in olfactory marker protein-positive mature neurons. In contrast, CRMP1 and CRMP2 persist at all stages of differentiation from immature GAP43-positive to fully mature olfactory neurons. In the olfactory bulb, CRMP1, CRMP2 and CRMP5 are abundant in neuronal progenitors of the subependymal layer and in differentiating interneurons. In both areas, the subcellular distribution of CRMP1 or CRMP2 is different in mature vs. immature neurons, suggesting that these proteins are sequentially involved in various cellular events during neuronal lifetime. The variations of CRMP expression following axotomy are consistent with their differential localization and functional involvement in immature vs. mature neurons of the olfactory system. Our data bring new insight to the putative functions of CRMPs within areas of the adult nervous system with permanent neurogenesis, some related to differentiation of newly generated neurons but others occurring in mature neurons with a limited lifespan.     

Rapid categorization of natural scenes in monkeys: target predictability and processing speed

Three monkeys performed a categorization task and a recognition task with briefly flashed natural images, using in alternation either a large variety of familiar target images (animal or food) or a single (totally predictable) target. The processing time was 20 ms shorter in the recognition task in which false alarms showed that monkeys relied on low-level cues (color, form, orientation, etc.). The 20-ms additional delay necessary in monkeys to perform the categorization task is compared with the 40-ms delay previously found for humans performing similar tasks. With such short additional processing time, it is argued that neither monkeys nor humans have time to develop a fully integrated object representation in the categorization task and must rely on coarse intermediate representations.     

L-arginine improves dystrophic phenotype in mdx mice

A possible treatment for Duchenne muscular dystrophies would be to compensate for dystrophin loss by increasing the expression of utrophin, another cytoskeletal protein of the muscle membrane. We previously found that L-arginine, the substrate for nitric oxide synthase, significantly increased utrophin level in muscle and targeted it to the sarcolemma. Here, we have addressed the expected benefit in the mdx mice. Magnetic resonance imaging of lower limbs revealed a 35% reduction of the necrotic zones, confirmed by histological staining of muscles. This regression of the necrosis was also supported by the drastic reduction of Evans blue incorporation, a cell impermeable dye. The creatine kinase level in the serum decreased by 57%. Utrophin level increased 2- to 3-fold in muscles. Beta-dystroglycan was relocalised with utrophin to the membrane. In the diaphragm, the most affected muscle in mdx mice, the isometric tension increased by 30%, with regression of collagen and of cytoplasmic lipid overloading. Finally, molsidomine, a therapeutic agent that is converted to a NO donor, also attenuated the dystrophic phenotype. Our results suggest that pharmacological activators of the NO pathway may constitute a realistic treatment for Duchenne and Becker muscular dystrophies.     

Rapid up-regulation of the neuronal serotoninergic phenotype by brain-derived neurotrophic factor and cyclic adenosine monophosphate: relations with raphe astrocytes

Up-regulation of the neuronal serotoninergic phenotype in relation to astrocytic population was studied in primary cultures of rat embryonic rostral raphe. Short treatments (18 hr at day in vitro 4) with brain-derived neurotrophic factor (BDNF) or dibutyryl-cAMP (dBcAMP) increased the number of serotoninergic neurons by approximately 80% and approximately 40%, respectively, and markedly enhanced the branching (by 11-fold and 5-fold, respectively) and total length (by 4-fold and 2.5-fold, respectively) of their neurites. Concomitantly, under BDNF treatment, the astrocyte population was decreased by half and became mostly protoplasmic-like. In contrast, dBcAMP treatment also reduced the astrocytic cell density (by one-third) but induced a stellate morphology. Similar short treatment with the astrocyte-derived S100beta factor induced no modification of the serotonin (5-HT) neuronal phenotype nor of astrocytes morphology. Both BDNF- and cAMP-induced effects were abolished by simultaneous treatment with the specific tyrosine kinase inhibitor genistein, suggesting a role for the high-affinity BDNF receptor tyrosine kinase (TrkB). These data suggest that BDNF and cAMP, but not S100beta, rapidly induce both an up-regulation of the 5-HT neuronal phenotype and modifications of the neighboring astrocytes in a TrkB-dependent manner.     

The risk of birth defects in children born after assisted reproductive technologies

PURPOSE OF REVIEW: This review addresses the question of whether there is evidence of an increased risk of birth defects in children born following assisted reproductive technologies compared with spontaneously conceived children. RECENT FINDINGS: Three recent studies added relatively little new information given their modest size (56-472 assisted reproductive technology children). We therefore considered all published papers that compared birth defects in children born following assisted reproductive technologies with those in children born following spontaneous conception. Overall, only six of the 26 relevant papers concluded there was an increased risk of birth defects following assisted reproductive technologies. The interpretation of many studies was based on statistical significance testing alone. When results showed a greater proportion of defects in the assisted reproductive technology group compared with the spontaneous group, but the results were not statistically significant, this was often interpreted as showing no increase in risk, rather than an increase in risk that may have been due to chance. The vast majority of individual studies were too small to have sufficient power to detect, as statistically significant, clinically relevant results. We found that although only eight (30%) of the studies had statistically significant results, 24 (89%) had an odds ratio estimate comparing assisted reproductive technology with spontaneously conceived children of over 1.0; 19 (70%) had an estimate of 1.20 or greater; and 14 (52%) had an estimate of 1.5 or greater. SUMMARY: Current evidence suggests there is an elevated risk of birth defects in children born following assisted reproductive technologies. Whilst others may disagree with our interpretation, one certainly cannot exclude this possibility on the basis of the current evidence.     

Heterotopic en bloc tracheobronchial transplantation with direct revascularization in pigs

OBJECTIVE: This article describes the application of a novel aortic tube technique for directly revascularized tracheobronchial transplantation with dual blood supply in pigs. METHODS: Eleven adult Large White pigs underwent heterotopic tracheal transplantation with a dual revascularization technique (inferior thyroid artery and bronchial artery). Seven tracheobronchial grafts were perfused ex vivo, and hemodynamic data were collected. RESULTS: At the last evaluation, 6 pigs had normally epithelialized mucus-producing allografts with correct morphologic conformation and cartilage viability. The histopathologic examination revealed homogeneous tissue regardless of biopsy site (trachea, carina, or bronchi), demonstrating the efficacy of the revascularization procedure. Four animals had early ischemic necrosis develop, 2 from acute rejection and 2 from technical mishap. One additional pig had acute rejection starting on the 14th postoperative day. The CD4(+)/CD8(+) ratio was maintained close to or above 0.8 in the subgroup with rejection and below 0.6 in the animals that were correctly immunosuppressed. Pressure-flow curves in 7 ex vivo tracheobronchial grafts showed a nonsignificant difference (P <.12) in vascular resistance between the bronchial artery territory (lower resistance) and the inferior thyroid artery territory. CONCLUSIONS: For the first time, a transplantation technique encompassing the entire trachea, carina, and stem bronchi has been made possible. By means of the dual inferior thyroid and bronchial artery axis, we were able to obtain a structurally healthy and functional graft to replace the main airway.     

The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.