Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to rescue developing motoneurons in vivo and in vitro from both naturally occurring and axotomy-induced cell death. To test whether GDNF has trophic effects on adult motoneurons, we used a mouse model of injury-induced adult motoneuron degeneration. Injuring adult motoneuron axons at the exit point of the nerve from the spinal cord (avulsion) resulted in a 70% loss of motoneurons by 3 weeks following surgery and a complete loss by 6 weeks. Half of the loss was prevented by GDNF treatment. GDNF also induced an increase (hypertrophy) in the size of surviving motoneurons. These data provide strong evidence that the survival of injured adult mammalian motoneurons can be promoted by a known neurotrophic factor, suggesting the potential use of GDNF in therapeutic approaches to adult-onset motoneuron diseases such as amyotrophic lateral sclerosis.

Mammalian masticatory apparatus / [by] William D. Turnbull --

v.18:no.2(1970)

Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo

The ciliary neurotrophic factor alpha-receptor(CNTFRalpha) is required for motoneuron survival during development, but the relevant ligand(s) has not been determined. One candidate is the heterodimer formed by cardiotrophin-like cytokine (CLC) and cytokine-like factor 1 (CLF). CLC/CLF binds to CNTFRalpha and enhances the survival of developing motoneurons in vitro; whether this novel trophic factor plays a role in neural development in vivo has not been tested. We examined motor and sensory neurons in embryonic chicks treated with CLC and in mice with a targeted deletion of the clf gene. Treatment with CLC increased the number of lumbar spinal cord motoneurons that survived the cell death period in chicks. However, this effect was regionally specific, because brachial and thoracic motoneurons were unaffected. Similarly, newborn clf -/- mice exhibited a significant reduction in lumbar motoneurons, with no change in the brachial or thoracic cord. Clf deletion also affected brainstem motor nuclei in a regionally specific manner; the number of motoneurons in the facial but not hypoglossal nucleus was significantly reduced. Sensory neurons of the dorsal root ganglia were not affected by either CLC treatment or clf gene deletion. Finally, mRNA for both clc and clf was found in skeletal muscle fibers of embryonic mice during the motoneuron cell death period. These findings support the view that CLC/CLF is a target-derived factor required for the survival of specific pools of motoneurons. The in vivo actions of CLC and CLF can account for many of the effects of CNTFRalpha on developing motoneurons.

Does a mandibular RDP and new maxillary CD improve masticatory efficiency and quality of life in patients with a mandibular Kennedy class I arch?

Objectives To evaluate the change in masticatory efficiency and quality of life of patients treated with mandibular Kennedy class I removable partial dentures (RPDs) and maxillary complete dentures at the Department of Dentistry of the Federal University of Rio Grande do Norte. Materials and methods A total of 33 Kennedy class I patients were rehabilitated with maxillary complete dentures, and mandibular RPDs were selected for this non-randomized prospective intervention study. The patients had a mean age of 59.1 years. Masticatory efficiency was evaluated by colorimetric assay using fuchsin capsules. The measurements were conducted at baseline and 2 and 6 months after prosthesis insertion. Quality of life was evaluated using the Oral Health Impact Profile (OHIP-14) at baseline and 6 months after denture insertion. The Kolmogorov-Smirnov normality test was applied. Masticatory efficiency was evaluated by repeated measures ANOVA. Oral health-related quality of life was compared using the paired t test. Results There was no statistically significant difference in masticatory efficiency after denture insertion (p = 0.101). Significant differences were found (p = 0.010) for oral health-related quality of life. A significant improvement in psychological discomfort (p < 0.01) and psychological disability (p < 0.01) was observed. Mean difference value (95 % confidence interval) was 6.8 (3.8 to 9.7) points, reflecting a low impact of oral health on quality of life, considering the 0–56 range of variation of the OHIP-14 and a Cohen’s d of 1.13. Conclusion According to the results of the present study, rehabilitation with Kennedy class I RPDs and complete dentures did not influence masticatory efficiency but improved oral health-related quality of life. Clinical relevance The association between the patient’s quality of life and the masticatory efficiency is important for treatment predictability.

Botulinum toxin in masticatory muscles of the adult rat induces bone loss at the condyle and alveolar regions of the mandible associated with a bone proliferation at a muscle enthesis

International audience

A novel ACVR1 mutation in the glycine/serine-rich domain found in the most benign case of a fibrodysplasia ossificans progressiva variant reported to date

Fibrodysplasia Ossificans Progressiva (FOP) is a rare, autosomal dominant condition, classically characterised by heterotopic ossification beginning in childhood and congenital great toe malformations; occurring in response to a c.617 G>A ACVR1 mutation in the functionally important glycine/serine-rich domain of exon 6. Here we describe a novel c.587 T>C mutation in the glycine/serine-rich domain of ACVR1, associated with delayed onset of heterotopic ossification and an exceptionally mild clinical course. Absence of great toe malformations, the presence of early ossification of the cervical spine facets joints, plus mild bilateral camptodactyly of the 5th fingers, together with a novel ACVR1 mutation, are consistent with the 'FOP-variant' syndrome. The c.587 T>C mutation replaces a conserved leucine with proline at residue 196. Modelling of the mutant protein reveals a steric clash with the kinase domain that will weaken interactions with FKBP12 and induce exposure of the glycine/serine-rich repeat. The mutant receptor is predicted to be hypersensitive to ligand stimulation rather than being constitutively active, consistent with the mild clinical phenotype. This case extends our understanding of the 'FOP-variant' syndrome.

GDNF Receptors: Veterans and Novices

Neurotrophic factors play essential role in the development and functioning of the nervous system and other organs. Glial cell line-Derived Neurotrophic Factor (GDNF) family ligands (GFLs) are of particular interest because they promote the survival of dopaminergic neurons in vitro, in Parkinson s disease animal models and in patients. GDNF is also a potent survival factor for the central motoneurons and thus is considered as a potential lead for the treatment of amyotrophic lateral sclerosis. The survival promoting receptor complex for GFLs consists of a ligand-specific co-receptor, GFRα and a signal transducing module, receptor tyrosine kinase RET. At least GDNF and persephin, a GFL, have established functions outside central nervous system. GDNF is crucial for enteric nervous system and kidney development as well as for spermatogenesis. Persephin controls calcitonin secretion. Communication between cells often occurs in the extracellular matrix (ECM), a meshwork, which is secreted and deposited by the cells and is mainly composed of fibrillar proteins and polymerized sugars. We evaluated the relationship between GFLs and extracellular matrix components and demonstrated that three GFLs - GDNF, neurturin and artemin bind heparan sulfates with nanomolar affinities. The fourth member of the family - persephin binds these polysaccharides thousand times less tightly. GDNF, neurturin and artemin also bind with high affinity to heparan sulfate proteoglycan (HSPG) isolated from the nervous system, syndecan-3. GDNF signals through HSPGs, evoking Src family kinase activation. This signaling induces cell spreading, hippocampal neurite outgrowth in vitro and cellular migration. Specifically, GDNF signaling through syndecan-3 is important for embryonic cortical neuron migration. Syndecan-3-deficient mice, similarly to mice lacking GDNF, have less GABAergic neurons in their cortex, as compared to the wild-type mice. This fact provides indirect evidence that GDNF interaction with syndecan-3 is important for cortical brain development. Noteworthy, in non-neuronal tissues GFLs may signal via other syndecans. We also present the structural model for a GDNF co-receptor, GFRα1. The X-ray structure of the GFRα1 domain 3 was solved with 1.8 Å resolution, revealing a new protein fold. Later we also solved the structure of the truncated GFRα1 in the complex with GDNF and this model was confirmed by site-directed mutagenesis. In summary, our work contributed to the structural characterization of GFRα-based receptor complex and revealed a new receptor for GDNF, neurturin and artemin the HSPG syndecan-3. This information is critically important for the development of GFRα/RET agonists for the treatment of neurodegenerative diseases.

Developmental-like responses in injured mature central neurons

Traumatic insults to the central nervous system are frequently followed by profound and irreversible neuronal loss as well as the inability of the damaged neurons to regenerate. One of the major therapeutic challenges is to increase the amount of surviving neurons after trauma. Thus it is crucial to understand how injury affects neuronal responses and which conditions are optimal for survival to prevent neuronal loss. During development neuronal survival is thought to be dependent on the competition for the availability of survival-promoting molecules called neurotrophic factors. Much less is known on the survival mechanisms of mature neurons under traumatic conditions. Increasing amount of evidence points towards the possibility that after injury neuronal responses might aquire some developmental characteristics. One of the important examples is the change in the responses to the neurotransmitter GABA: it is inhibitory in the intact mature neurons, but can induce excitation during development and after trauma. An important step in the maturation of GABAergic transmission in the CNS is the developmental shift in the action of GABAA receptor from depolarization in immature neurons to hyperpolarization in mature neurons. GABAA-mediated responses are tightly linked to the homeostasis of the chloride anion (Cl-), which in neurons is mainly regulated by Na+-K+-2Cl- cotransporter NKCC1 and K+-Cl- cotransporter KCC2. Trauma-induced functional downregulation of KCC2 promotes a shift from hyperpolarizing GABAA-mediated responses to depolarizing. Other important consequences of neuronal trauma are the emergence of dependency of central neurons on brain-derived neuro¬trophic factor (BDNF) for survival, as well as the upregulation of neurotrophin receptor p75NTR. Our aim was to answer the question whether these post-traumatic events are interrelated, and whether the regulation of BDNF and KCC2 expression is different under traumatic conditions and in intact neurons. To study responses of injured mature central neurons, we used an in vitro and in vivo axotomy models. For in vitro studies, we lesioned organotypic hippocampal slices between CA3 and CA1 regions, which resulted in selective axotomy of the CA3 neurons and denervation of the CA1 neurons. Some experiments were repeated in vivo by lesioning the neurons of the corticospinal tract at the internal capsule level, or by lesioning spinal motoneurons at the ventral root. We show that intact mature neurons do not require BDNF for survival, whereas in axotomized neurons apoptosis is induced upon BDNF deprivation. We further show that post-traumatic dependency on BDNF is mediated by injury-induced upregulation of p75NTR. Post-traumatic increase in p75NTR is induced by GABAA-mediated depolarization, consequent opening of voltage-gated Ca2+ channels, and the activation of Rho kinase ROCK. Thus, post-traumatic KCC2 downregulation leads to the dependency on BDNF through the induction of p75NTR upregulation. Neurons that survive after axotomy over longer period of time lose BDNF dependency and regain normal KCC2 levels. This phenomenon is promoted by BDNF itself, since after axotomy contrary to normal conditions KCC2 is upregulated by BDNF. The developmentally important thyroid hormone thyroxin regulates BDNF expression during development. We show that in mature intact neurons thyroxin downregulates BDNF, whereas after axotomy thyroxin upregulates BDNF. The elevation of BDNF expression by thyroxin promoted survival of injured neurons. In addition, thyroxin also enhanced axonal regeneration and promoted the regaining of normal levels of KCC2. Thus we show that this hormone acts at several levels on the axotomy-initiated chain of events described in the present work, and could be a potential therapeutic agent for the injured neurons. We have also characterized a previously unknown downregulatory interaction between thyroxin and KCC2 in intact neurons. In conclusion, we identified several important interactions at the neurotrophin-protein and hormone-neurotrophin level that acquire immature-like characteristics after axotomy and elucidated an important part of the mechanism by which axotomy leads to the requirement of BDNF trophic support. Based on these findings, we propose a new potential therapeutic strategy where developmentally crucial agents could be used to enhance survival and regeneration of axotomized mature central neurons.

Early Functional Deficit and Microglial Disturbances in a Mouse Model of Amyotrophic Lateral Sclerosis

11 p.

Unlike Physical Exercise, Modified Environment Increases the Lifespan of SOD1(G93A) Mice However Both Conditions Induce Cellular Changes

8 p.

Control mechanisms in the human binocular oculomotor system

A study of human eye movements was made in order to elucidate the nature of the control mechanism in the binocular oculomotor system.

We first examined spontaneous eye movements during monocular and binocular fixation in order to determine the corrective roles of flicks and drifts. It was found that both types of motion correct fixational errors, although flicks are somewhat more active in this respect. Vergence error is a stimulus for correction by drifts but not by flicks, while binocular vertical discrepancy of the visual axes does not trigger corrective movements.

Second, we investigated the non-linearities of the oculomotor system by examining the eye movement responses to point targets moving in two dimensions in a subjectively unpredictable manner. Such motions consisted of hand-limited Gaussian random motion and also of the sum of several non-integrally related sinusoids. We found that there is no direct relationship between the phase and the gain of the oculomotor system. Delay of eye movements relative to target motion is determined by the necessity of generating a minimum afferent (input) signal at the retina in order to trigger corrective eye movements. The amplitude of the response is a function of the biological constraints of the efferent (output) portion of the system: for target motions of narrow bandwidth, the system responds preferentially to the highest frequency; for large bandwidth motions, the system distributes the available energy equally over all frequencies. Third, the power spectra of spontaneous eye movements were compared with the spectra of tracking eye movements for Gaussian random target motions of varying bandwidths. It was found that there is essentially no difference among the various curves. The oculomotor system tracks a target, not by increasing the mean rate of impulses along the motoneurons of the extra-ocular muscles, but rather by coordinating those spontaneous impulses which propagate along the motoneurons during stationary fixation. Thus, the system operates at full output at all times.

Fourth, we examined the relative magnitude and phase of motions of the left and the right visual axes during monocular and binocular viewing. We found that the two visual axes move vertically in perfect synchronization at all frequencies for any viewing condition. This is not true for horizontal motions: the amount of vergence noise is highest for stationary fixation and diminishes for tracking tasks as the bandwidth of the target motion increases. Furthermore, movements of the occluded eye are larger than those of the seeing eye in monocular viewing. This effect is more pronounced for horizontal motions, for stationary fixation, and for lower frequencies.

Finally, we have related our findings to previously known facts about the pertinent nerve pathways in order to postulate a model for the neurological binocular control of the visual axes.

Avaliação da percepção da dor no tratamento ortodôntico: ensaio clínico randomizado

O objetivo deste trabalho foi avaliar através de questionários de escalas visuais analógicas a percepção da dor após a inserção do primeiro arco ortodôntico, comparando-se o efeito analgésico de ibuprofeno, acetaminofeno, placebo e goma de mascar. Este trabalho também partiu da hipótese de que ibuprofeno, acetaminofeno e gomas de mascar seriam mais eficazes que placebo no controle da dor de origem ortodôntica e que gomas de mascar poderiam ser uma alternativa ao uso de ibuprofeno e acetaminofeno no manejo da dor dentária de origem ortodôntica. Neste estudo, tomaram parte 41 pacientes da Clínica de Ortodontia da Faculdade de Odontologia da Universidade do Estado do Rio de Janeiro. Os pacientes foram aleatoriamente distribuídos em cinco diferentes grupos: placebo, acetaminofeno 500 miligramas, ibuprofeno 400 miligramas, goma de mascar e controle. Todos os indivíduos tiveram bráquetes com slots .022" colados em seus dentes e molares bandados em uma das arcadas. Os grupos placebo, ibuprofeno e acetaminofeno foram orientados a tomar 01 cápsula do respectivo composto logo após a inserção do arco inicial de liga de níquel-titânio de dimensão .014 e, se a dor persistisse, a cada 6 horas por uma semana.O grupo goma de mascar foi orientado a mascar um tablete de goma por 5 minutos imediatamente após a inserção do arco inicial de liga de níquel-titânio de dimensão .014 e a cada 6 horas por 5 minutos durante uma semana, caso a dor persistisse. O grupo controle recebeu nenhum método de controle da dor. Os indivíduos foram orientados a marcar nas escalas visuais analógicas nas primeiras 24 horas, às 09:00, 13:00, 17:00, 21:00 a percepção de dor espontânea e durante a mastigação. Do terceiro até o vigésimo primeiro dia as marcações foram feitas somente em dois tempos às 09:00 e 21:00. Através da análise estatística descritiva, concluiu-se que o placebo foi mais eficiente que ibuprofeno, acetaminofeno e goma de mascar no controle da dor ortodôntica, tanto em dor espontânea quanto em dor durante a mastigação. O grupo goma de mascar foi tão eficiente quanto o acetaminofeno no controle da dor espontânea 24 horas após a inserção do arco inicial. Para alívio da dor durante a mastigação, a goma de mascar pode ser uma alternativa à atuação medicamentosa no controle da dor ortodôntica.

Mandibular morphometric variation among Chinese cercopithecoids and the unique structure of the snub-nosed monkey (Rhinopithecus) mandible

In order to understand how mandibular structure differs among the Chinese cercopithecoids (Rhinopithecus, Trachypithecus and Macaca), particularly the uniqueness of the snub-nosed monkeys (Rhinopithecus), we analysed ten mandibular measurements by principal components analysis (PCA), and examined scaling patterns. The results provided by the PCA illustrated differences due to size among the cercopithecoids and the relationship between colobines (Trachypithecus and Rhinopithecus) and cercopithecines, in which macaques (Macaca) are included. Allometric analysis indicated that, biomechanically, there is not a marked difference between macaques and leaf-eating monkeys. This may be associated with the fact that both share some similar ecology and niches in south and southwest China. The snub-nosed monkeys exhibit a significantly more robust mandible, evident in the symphysis, corpus, condyle, and masticatory momentum arm. This supports the hypothesis, based on the study of dental structure, that Rhinopithecus is a unique group in Asian Old World monkeys (OWMs) and has developed some unique characteristics in order to adapt to the tough food available in the severe cold climate of the Plateaux of Qinghai-Tibet, Yun-Gui and Qingling in China.

MANDIBULAR MORPHOMETRICS AMONG MACAQUES - THE CASE OF MACACCA-THIBETANA

Recent field studies suggest that Macaca thibetana, a large endemic Chinese macaque, may be quite folivorous, distinguishing it from most other macaque species, which tend to be primarily frugivorous. To understand how this diet affects its masticatory system, we conducted a comparative morphometric study of mandibular dimensions. We took linear measurements from male and female mandibles of this species as well as four other macaques-M. fascicularis, M. nemestrina, M. arctoides, and M. assamensis-and four species of Presbytis-P. obscura, P. rubicunda, P. cristata, and P. phayrei-and subjected to them to a variety of analyses. Based on analyses of variances and discriminant analyses on each sex individually, the mandible of M. thibetana corresponds to expected patterns for folivorous primates with respect to its wide condyles and thick corpora: However, the height of the corpus and symphysis are lower, and the anteroposterior length of the condyle is longer than predicted for a folivore. In addition to interpretations specifically relating to M. thibetana, we also discuss the functional morphology of the other species in light of what is published about their diets.