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Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients. [ABSTRACT FROM AUTHOR]

The article discusses a research study on mucopolysaccharidosis (MPS) types I and VII and the hispathologic changes in the ears of canine models. Study subjects were 10 male dogs from 1.6 to 9.3 months old and the external ear canals, middle ear cavities and ear drums were examined while middle and inner ear structures including the tympanic membrane and malleus were thoroughly observed and compared with control animals. Results showed that middle and inner ear lesions of MPS I and VII dogs were different while control animals had no ear lesions.

Objectives: The study examines the impact of changes on dental education and practice in Europe, including the development of new practice models such as investor-owned dental centers and practice chains., Method and Materials: This study aimed to collect and critically examine data regarding the care environment, education, and organizational structures of the dental profession across European Regional Organization of the FDI World Dental Federation (ERO) member states and other countries in the World Health Organization European region. A questionnaire from the ERO was used., Results: National dental associations across 45 countries participated. An average of 1,459.79 (SD ± 800.80) inhabitants per dental practitioner was found, with independent practices being the most prevalent form of dental practice (48.65% ± 28.28%) followed by employment in private practice (24.32% ± 20.33%), and joint practices (15.27% ± 20.39%). There are statistically significantly more state universities than private universities (P .01); the percentage of females attending dental schools was statistically significantly higher than males (P .01). Two-thirds of the participating countries (n = 30, 66.67%) have legal frameworks allowing various stakeholders, including investors, and local communities, to establish dental health care centers., Conclusions: The findings highlight the evolving landscape of the dental profession in Europe and its regulatory context. There is a clear need for ongoing evaluations and adjustments in educational and practice frameworks to ensure and maintain high-quality oral health care. Future research should delve into the various professional dental practice forms and incorporate qualitative, care-related, and patient-centered considerations for a more thorough understanding of Europe's oral health care dynamics. (Quintessence Int 2024;55:744-755; doi: 10.3290/j.qi.b5714883).

The identification of the most efficient method for whole central nervous system targeting that is translatable to humans and the safest route of adeno-associated virus (AAV) administration is a major concern for future applications in clinics. Additionally, as many AAV serotypes were identified for gene introduction into the brain and the spinal cord, another key to human gene-therapy success is to determine the most efficient serotype. In this study, we compared lumbar intrathecal administration through catheter implantation and intracerebroventricular administration in the cynomolgus macaque. We also evaluated and compared two AAV serotypes that are currently used in clinical trials: AAV9 and AAVrh10. We demonstrated that AAV9 lumbar intrathecal delivery using a catheter achieved consistent transgene expression in the motor neurons of the spinal cord and in the neurons/glial cells of several brain regions, whereas AAV9 intracerebroventricular delivery led to a consistent transgene expression in the brain. In contrast, AAVrh10 lumbar intrathecal delivery led to rare motor neuron targeting. Finally, we found that AAV9 efficiently targets respiratory and skeletal muscles after injection into the cerebrospinal fluid (CSF), which represents an outstanding new property that can be useful for the treatment of diseases affecting both the central nervous system and muscle., (© 2020.)

Research in the field of Obstructive Sleep Apnea (OSA) has been organized, and has profoundly transformed the quality of life of apneic patients, while even inviting dentofacial orthopedists to contribute to their symptomatic treatment. However, among the points still to be elucidated, the initial cause of the snoring that destabilizes the pharynx occupies a place apart. The objective of this article was to develop the proposal by Jacques Talmant regarding a mechanism capable of explaining the onset of OSA and for a therapy to treat pharyngeal destabilization during sleep. Based on published data, the etiopathogenesis of snoring and its consequences are described. Structural changes secondary to the vibratory trauma caused by snoring can affect each component of the pharyngeal structures and contribute to the collapsibility of this airway segment. By directly optimizing the development of ventilatory capabilities in their patients, orthodontists contribute, indirectly, to optimizing their cardiovascular and neuropsychological functions.

Pompe disease, which is due to acid alpha-glucosidase deficiency, is characterized by skeletal muscle dysfunction attributed to the accumulation of glycogen-filled lysosomes and autophagic buildup. Despite the extensive tissue damages, a failure of satellite cell (SC) activation and lack of muscle regeneration have been reported in patients. However, the origin of this defective program is unknown. Additionally, whether these deficits occur gradually over the disease course is unclear. Using a longitudinal pathophysiological study of two muscles in a Pompe mouse model, here, we report that the enzymatic defect results in a premature saturating glycogen overload and a high number of enlarged lysosomes. The muscles gradually display profound remodeling as the number of autophagic vesicles, centronucleated fibers, and split fibers increases and larger fibers are lost. Only a few regenerated fibers were observed regardless of age, although the SC pool was preserved. Except for the early age, during which higher numbers of activated SCs and myoblasts were observed, no myogenic commitment was observed in response to the damage. Following in vivo injury, we established that muscle retains regenerative potential, demonstrating that the failure of SC participation in repair is related to an activation signal defect. Altogether, our findings provide new insight into the pathophysiology of Pompe disease and highlight that the activation signal defect of SCs compromises muscle repair, which could be related to the abnormal energetic supply following autophagic flux impairment.

No treatment is available for early-onset forms of metachromatic leukodystrophy (MLD), a lysosomal storage disease caused by autosomal recessive defect in arylsulfatase A (ARSA) gene causing severe demyelination in central and peripheral nervous systems. We have developed a gene therapy approach, based on intracerebral administration of AAVrh.10-hARSA vector, coding for human ARSA enzyme. We have previously demonstrated potency of this approach in MLD mice lacking ARSA expression. We describe herein the preclinical efficacy, safety, and biodistribution profile of intracerebral administration of AAVrh.10-hARSA to nonhuman primates (NHPs). NHPs received either the dose planned for patients adjusted to the brain volume ratio between child and NHP (1×dose, 1.1×10(11) vg/hemisphere, unilateral or bilateral injection) or 5-fold this dose (5×dose, 5.5×10(11) vg/hemisphere, bilateral injection). NHPs were subjected to clinical, biological, and brain imaging observations and were euthanized 7 or 90 days after injection. There was no toxicity based on clinical and biological parameters, nor treatment-related histological findings in peripheral organs. A neuroinflammatory process correlating with brain MRI T2 hypersignals was observed in the brain 90 days after administration of the 5×dose, but was absent or minimal after administration of the 1×dose. Antibody response to AAVrh.10 and hARSA was detected, without correlation with brain lesions. After injection of the 1×dose, AAVrh.10-hARSA vector was detected in a large part of the injected hemisphere, while ARSA activity exceeded the normal endogenous activity level by 14-31%. Consistently with other reports, vector genome was detected in off-target organs such as liver, spleen, lymph nodes, or blood, but not in gonads. Importantly, AAVrh.10-hARSA vector was no longer detectable in urine at day 7. Our data demonstrate requisite safe and effective profile for intracerebral AAVrh.10-hARSA delivery in NHPs, supporting its clinical use in children affected with MLD.

Iatrogenic effects of orthodontic forces, in particular root resorption, are described in the literature. However, our knowledge on the risk of osseous defects induced by orthodontic treatment is still scarce. After an overview of histological and biological principles of orthodontically-induced tooth movement, this study focuses on the recent data concerning the occurrence and the treatment of bone resorption associated with orthodontic treatment.

The neonatal respiratory distress observed in the event of a solitary median maxillary central incisor compels us to reconsider some of the traditional concepts relative to the transverse growth of the nasal level of the face. The "container-contents" connections associating maxillary incisor odontogenesis with the development of the premaxillary and facial envelopes draw the attention to the significant geometrical and mechanical expression of this morphogenesis. They require attributing to the maxillary incisors an important motor role in this development. They lead to granting the ontogenetic bonds, between malocclusions and disturbed nasal breathing, the place they deserve, taking into account the morphological integration combining them. They eventually open a new therapeutic prospect: the optimization of the development of the growing face, with regard to the various tissue mechanics and physiologies, becoming the best guarantor for the prevention of relapse after dentofacial orthopedics.

Data acquired by means of color Doppler ultrasound very explicitly suggest what the role of the fetal ventilation and nasal capsules in the morphogenesis of the maxillary prognathism, turbinates, nasal valves and nasopharynx could be. Furthermore, the dysmorphologies observed in Apert or Crouzon craniosynostosis, achondroplasia or unilateral cleft lip would also testify that the influence of the fetal ventilatory dynamics goes beyond the limits of the face and extends to the cranial base and the cranium. The wealth of raised hypothesis thanks to the contribution of this imaging system could question the validity of some conceptions of the fetal craniomaxillary morphogenesis.

Cause and effect relationships existing between "nasal breathing impairment" and "relapse" have inherited from controversies which have animated the debate between the different schools of orthodontics for more than a century. Those differences of opinion seem to have their origin in the lack of accuracy inherent with the general acceptance of the two concepts of "normal nasal ventilation" and "relapse". Rather than retracing their history, we would like to put forward a few proposals aimed at getting rid of the doubtful trouble the present difficulty confronts us with. We have therefore endeavored: 1. to define most exactly our concepts of "optimal nasal ventilation" and "relapse"; 2. to determine, afterwards, the mechanics responsible for facial shape alterations due to nasal obstruction; 3. hence, to deduce the therapeutic behavior enabling us to master those alterations more extensively. Bearing in mind that, in order to legitimate the risk of a treatment, acknowledge its benefit and justify its cost (which may become prohibitive because of relapse), the clinician has to base his options on a body of consistent arguments.