4-aminopyridine improves evoked potentials and ambulation in the taiep rat: A model of hypomyelination with atrophy of basal ganglia and cerebellum.

The taiep rat is a tubulin mutant with an early hypomyelination followed by progressive demyelination of the central nervous system due to a point mutation in the Tubb4a gene. It shows clinical, radiological, and pathological signs like those of the human leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Taiep rats had tremor, ataxia, immobility episodes, epilepsy, and paralysis; the acronym of these signs given the name to this autosomal recessive trait. The aim of this study was to analyze the characteristics of somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) in adult taiep rats and in a patient suffering from H-ABC. Additionally, we evaluated the effects of 4-aminopyridine (4-AP) on sensory responses and locomotion and finally, we compared myelin loss in the spinal cord of adult taiep and wild type (WT) rats using immunostaining. Our results showed delayed SSEPs in the upper and the absence of them in the lower extremities in a human patient. In taiep rats SSEPs had a delayed second negative evoked responses and were more susceptible to delayed responses with iterative stimulation with respect to WT. MEPs were produced by bipolar stimulation of the primary motor cortex generating a direct wave in WT rats followed by several indirect waves, but taiep rats had fused MEPs. Importantly, taiep SSEPs improved after systemic administration of 4-AP, a potassium channel blocker, and this drug induced an increase in the horizontal displacement measured in a novelty-induced locomotor test. In taiep subjects have a significant decrease in the immunostaining of myelin in the anterior and ventral funiculi of the lumbar spinal cord with respect to WT rats. In conclusion, evoked potentials are useful to evaluate myelin alterations in a leukodystrophy, which improved after systemic administration of 4-AP. Our results have a translational value because our findings have implications in future medical trials for H-ABC patients or with other leukodystrophies.

Impact of Antimicrobial Stewardship Program Intervention Acceptance on Hospital Length of Stay.

Background: Inappropriate antibiotic use is a major public health concern. Excessive exposure to antibiotics results in the proliferation of multidrug-resistant bacteria, increase in potentially avoidable adverse drug reactions, healthcare utilization, and cost. Currently, systematic reviews and controlled trials assessing the effects of antimicrobial stewardship programs (ASP) on hospital length of stay (LOS), mortality, and cost-savings are conflicting. Some studies reported a significant cost-savings driven by shorter hospital LOS while the others found no effect and, in some cases, prolonged LOS. Shortening the time to appropriate therapy and reducing unnecessary days of therapy have been shown to reduce hospital LOS. Objective: The purpose of this study was to evaluate the effects of prescriber acceptance to ASP interventions on hospital LOS. Methods: Between January 2018 and December 2019, 764 charts were retrospectively reviewed for patients who received antimicrobial treatment and in whom an ASP intervention was performed. Patients were allocated into 2 groups: those whose ASP interventions were accepted and those whose were rejected. Provider responses were then documented within 24 hours of being communicated. The primary outcome was hospital LOS. Secondary outcomes included 30-day readmission rates and inpatient antimicrobial duration of therapy (DOT). Results: There were 384 patients with an accepted ASP intervention and 380 with a denied intervention. Baseline characteristics were similar between both groups, except for a difference in the types of intervention performed (P < 0.001). The median hospital LOS for patients in the accepted intervention group was 6.5 days compared to 7 days in the rejected intervention group (P = 0.009). Antimicrobial DOT was also shorter in the accepted intervention group (5 vs 7 days; P < 0.001). There was no difference in 30-day readmission rates (P = 0.98). Conclusion: Prescriber acceptance to ASP interventions decreases hospital LOS and antimicrobial DOT without affecting 30-day readmission rates.

COVID-19: A Review of Potential Treatments (Corticosteroids, Remdesivir, Tocilizumab, Bamlanivimab/Etesevimab, and Casirivimab/Imdevimab) and Pharmacological Considerations.

Objectives: In light of the ongoing global pandemic, this paper reviews data on a number of potential and approved agents for COVID-19 disease management, including corticosteroids, remdesivir, tocilizumab, and monoclonal antibody combinations. Dose considerations, potential drug-drug interactions, and access issues are discussed. Key findings: Remdesivir is the first antiviral agent approved for the treatment of COVID-19, based on results from large clinical trials showing reduction in recovery time, faster clinical improvement, and decrease in time to discharge with remdesivir. Dexamethasone and tocilizumab have demonstrated mortality benefits in large, randomized controlled trials. Consequently, the use of corticosteroids has become the standard of care for hospitalized patients with severe or critical COVID-19, while tocilizumab is recommended for use in combination with a corticosteroid in certain hospitalized patients. Recently, monoclonal antibody combinations bamlanivimab/etesevimab and casirivimab/imdevimab received emergency use authorizations for use in non-hospitalized patients with mild-to-moderate COVID-19 at high risk of disease progression. Summary: As data from large clinical trials emerge, the paradigm of COVID-19 treatments has shifted significantly. The use of corticosteroids, remdesivir, and tocilizumab depend on disease severity. Emerging data on monoclonal antibody combinations are promising, but further data are required. Pharmacists can play a role in ensuring appropriate access, correct administration, and safe use of COVID-19 treatments and are encouraged to stay abreast of new developments.

Vestibular Nuclei: A New Neural Stem Cell Niche?

We previously reported adult reactive neurogliogenesis in the deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline and the rodent model. Recently, we demonstrated that UVN induced a significant increase in a population of cells colocalizing the transcription factor sex determining region Y-box 2 (SOX2) and the glial fibrillary acidic protein (GFAP) three days after the lesion in the deafferented medial vestibular nucleus. These two markers expressed on the same cell population could indicate the presence of lesion-reactive multipotent neural stem cells in the vestibular nuclei. The aim of our study was to provide insight into the potential neurogenic niche status of the vestibular nuclei in physiological conditions by using specific markers of stem cells (Nestin, SOX2, GFAP), cell proliferation (BrdU) and neuronal differentiation (NeuN). The present study confirmed the presence of quiescent and activated adult neural stem cells generating some new neurons in the vestibular nuclei of control rats. These unique features provide evidence that the vestibular nuclei represent a novel NSC site for the generation of neurons and/or glia in the adult rodent under physiological conditions.

L-Thyroxine Improves Vestibular Compensation in a Rat Model of Acute Peripheral Vestibulopathy: Cellular and Behavioral Aspects.

Unilateral vestibular lesions induce a vestibular syndrome, which recovers over time due to vestibular compensation. The therapeutic effect of L-Thyroxine (L-T4) on vestibular compensation was investigated by behavioral testing and immunohistochemical analysis in a rat model of unilateral vestibular neurectomy (UVN). We demonstrated that a short-term L-T4 treatment reduced the vestibular syndrome and significantly promoted vestibular compensation. Thyroid hormone receptors (TRα and TRß) and type II iodothyronine deiodinase (DIO2) were present in the vestibular nuclei (VN), supporting a local action of L-T4. We confirmed the T4-induced metabolic effects by demonstrating an increase in the number of cytochrome oxidase-labeled neurons in the VN three days after the lesion. L-T4 treatment modulated glial reaction by decreasing both microglia and oligodendrocytes in the deafferented VN three days after UVN and increased cell proliferation. Survival of newly generated cells in the deafferented vestibular nuclei was not affected, but microglial rather than neuronal differentiation was favored by L-T4 treatment.

Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

[Effectiveness and safety of the surgical closure of permeable arteriosus conduct by the general pediatric surgeon: clinical trial]. / Eficacia y seguridad del cierre quirúrgico del conducto arterioso permeable por el cirujano pediatra general: ensayo clínico.

Antecedentes: El conducto arterioso permeable (CAP) es un defecto cardiaco congénito y se considera un problema de salud pública. Se presenta en un alto porcentaje de recién nacidos y en algunos mayores de 1 mes. El cierre farmacológico es el tratamiento inicial preferido, ya que ha tenido excelentes resultados; sin embargo, en aquellos casos en los que no es posible, está indicado el cierre quirúrgico. Objetivo: Evaluar la eficacia y la seguridad del cierre quirúrgico del CAP por cirujanos pediatras sin especialidad en cirugía cardiovascular. Método: Ensayo clínico realizado en pacientes del Hospital General de Occidente, centro hospitalario público de segundo nivel, con diagnóstico de CAP, que requirieron corrección quirúrgica. Se revisaron en forma retrospectiva los expedientes de enero de 2001 a diciembre de 2018. Resultados: Se incluyeron 224 pacientes divididos en dos grupos: grupo I, con 184 (82%) recién nacidos, y grupo II, con 40 (18%) niños grandes de 2 meses a 8 años de edad. A todos se les realizó cierre quirúrgico: 3 por toracoscopía y 221 por toracotomía posterolateral izquierda. Presentaron complicaciones 36 pacientes, lo que representa el 16% del total; solo el 5.3% fueron complicaciones mayores. Fallecieron 24 pacientes en el posoperatorio, lo que representa una mortalidad del 10.7%; ninguno falleció por complicaciones transquirúrgicas. El CAP es un defecto cardíaco congénito que se presenta en alto porcentaje en pacientes prematuros. El cierre farmacológico es el principal tratamiento por tener excelentes resultados en recién nacidos; sin embargo, en aquellos casos en los que no sea posible está indicado el cierre quirúrgico. Todos los pacientes fueron operados por cirujanos pediatras generales, con una sobrevida global del 92%. Conclusiones: En los hospitales donde no hay cirujano cardiovascular pediátrico ni cardiólogo intervencionista, la corrección quirúrgica del CAP puede ser llevada a cabo por un cirujano pediatra. La técnica es reproducible, fácil de realizar y con mínimas complicaciones. Background: The Patent Ductus Arteriosus (PDA) is congenital heart defect and is considered a public health problem. It occurs in a high percentage of newborns and in some older than 1 month. Pharmacological closure is the preferred initial treatment, as it has had excellent results; however, in those cases where it is not possible, surgical closure is indicated. Objective: The objective is to evaluate the efficacy and safety of the surgical closure of the patent PDA when it is carried out by pediatric surgeons without specialization in cardiovascular surgery. Methods: This study was conducted at the West General Hospital, a 2nd level public hospital, with the diagnosis of patent ductus arteriosus that required surgical correction. For the collection of the information, the files from January 2001 to December 2018 were retrospectively reviewed. Results: 224 patients were included; divided into two groups: Group I: 184 (82%) "newborns" and Group II: 40 (18%) "big children" with ages from 2 months to 8 years. All had a surgical closure; 3 by thoracoscopy and 221 by left posterolateral thoracotomy. 36 patients presented complications representing 16% of the total of patients, only 5.3% were major complications. 24 patients died in the postoperative period, representing a mortality of 10.7%, none died due to trans-surgical complications. PDA is a congenital heart defect that occurs in a high percentage of premature patients. The pharmacological closure is the principal treatment because it has had excellent results in newborns; however, in those cases where it is not possible, surgical closure it´s indicated. All patients were operated by general pediatric surgeons, with a global survival of 92%. Conclusions: We conclude that in hospitals where there is no pediatric cardiovascular surgeon or interventional cardiologist, the surgical correction of the PDA can be carried out by a general pediatric surgeon. The technique is reproducible, easy to perform and with minimal complications.

Eficacia y seguridad del cierre quirúrgico del conducto arterioso permeable por el cirujano pediatra general: ensayo clínico / Effectiveness and safety of the surgical closure of permeable arteriosus conduct by the general pediatric surgeon: clinical trial

Resumen Antecedentes: El conducto arterioso permeable (CAP) es un defecto cardiaco congénito y se considera un problema de salud pública. Se presenta en un alto porcentaje de recién nacidos y en algunos mayores de 1 mes. El cierre farmacológico es el tratamiento inicial preferido, ya que ha tenido excelentes resultados; sin embargo, en aquellos casos en los que no es posible, está indicado el cierre quirúrgico. Objetivo: Evaluar la eficacia y la seguridad del cierre quirúrgico del CAP por cirujanos pediatras sin especialidad en cirugía cardiovascular. Método: Ensayo clínico realizado en pacientes del Hospital General de Occidente, centro hospitalario público de segundo nivel, con diagnóstico de CAP, que requirieron corrección quirúrgica. Se revisaron en forma retrospectiva los expedientes de enero de 2001 a diciembre de 2018. Resultados: Se incluyeron 224 pacientes divididos en dos grupos: grupo I, con 184 (82%) recién nacidos, y grupo II, con 40 (18%) niños grandes de 2 meses a 8 años de edad. A todos se les realizó cierre quirúrgico: 3 por toracoscopía y 221 por toracotomía posterolateral izquierda. Presentaron complicaciones 36 pacientes, lo que representa el 16% del total; solo el 5.3% fueron complicaciones mayores. Fallecieron 24 pacientes en el posoperatorio, lo que representa una mortalidad del 10.7%; ninguno falleció por complicaciones transquirúrgicas. El CAP es un defecto cardíaco congénito que se presenta en alto porcentaje en pacientes prematuros. El cierre farmacológico es el principal tratamiento por tener excelentes resultados en recién nacidos; sin embargo, en aquellos casos en los que no sea posible está indicado el cierre quirúrgico. Todos los pacientes fueron operados por cirujanos pediatras generales, con una sobrevida global del 92%. Conclusiones: En los hospitales donde no hay cirujano cardiovascular pediátrico ni cardiólogo intervencionista, la corrección quirúrgica del CAP puede ser llevada a cabo por un cirujano pediatra. La técnica es reproducible, fácil de realizar y con mínimas complicaciones.

Abstract Background: The Patent Ductus Arteriosus (PDA) is congenital heart defect and is considered a public health problem. It occurs in a high percentage of newborns and in some older than 1 month. Pharmacological closure is the preferred initial treatment, as it has had excellent results; however, in those cases where it is not possible, surgical closure is indicated. Objective: The objective is to evaluate the efficacy and safety of the surgical closure of the patent PDA when it is carried out by pediatric surgeons without specialization in cardiovascular surgery. Methods: This study was conducted at the West General Hospital, a 2nd level public hospital, with the diagnosis of patent ductus arteriosus that required surgical correction. For the collection of the information, the files from January 2001 to December 2018 were retrospectively reviewed. Results: 224 patients were included; divided into two groups: Group I: 184 (82%) "newborns" and Group II: 40 (18%) "big children" with ages from 2 months to 8 years. All had a surgical closure; 3 by thoracoscopy and 221 by left posterolateral thoracotomy. 36 patients presented complications representing 16% of the total of patients, only 5.3% were major complications. 24 patients died in the postoperative period, representing a mortality of 10.7%, none died due to trans-surgical complications. PDA is a congenital heart defect that occurs in a high percentage of premature patients. The pharmacological closure is the principal treatment because it has had excellent results in newborns; however, in those cases where it is not possible, surgical closure it´s indicated. All patients were operated by general pediatric surgeons, with a global survival of 92%. Conclusions: We conclude that in hospitals where there is no pediatric cardiovascular surgeon or interventional cardiologist, the surgical correction of the PDA can be carried out by a general pediatric surgeon. The technique is reproducible, easy to perform and with minimal complications.

Auditory impairment in H-ABC tubulinopathy.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H-ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H-ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II-IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H-ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

Adult and endemic neurogenesis in the vestibular nuclei after unilateral vestibular neurectomy.

We previously revealed adult reactive neurogenesis in deafferented vestibular nuclei following unilateral vestibular neurectomy (UVN) in the feline model. We recently replicated the same surgery in a rodent model and aimed to elucidate the origin and fate of newly generated cells following UVN. We used specific markers of cell proliferation, glial reaction, and cell differentiation in the medial vestibular nucleus (MVN) of adult rats. UVN induced an intense cell proliferation and glial reaction with an increase of GFAP-Immunoreactive (Ir), IBA1-Ir and Olig2-Ir cells 3 days after the lesion in the deafferented MVN. Most of the newly generated cells survived after UVN and differentiated into oligodendrocytes, astrocytes, microglial cells and GABAergic neurons. Interestingly, UVN induced a significant increase in a population of cells colocalizing SOX2 and GFAP 3 days after lesion in the deafferented MVN indicating the probable presence of multipotent cells in the vestibular nuclei. The concomitant increase in BrdU- and SOX2-Ir cells with the presence of SOX2 and GFAP colocalization 3 days after UVN in the deafferented MVN may support local mitotic activity of endemic quiescent neural stem cells in the parenchyma of vestibular nuclei.

Indicaciones de tratamiento en lesiones del manguito rotador: variación entre cirujanos ortopédicos / Variation among Argentinean orthopedic surgeons in the therapeutic indications for rotator cuff tears

Introducción: Aún se discuten ampliamente las indicaciones terapéuticas (tratamiento quirúrgico y no quirúrgico) para las lesiones del manguito rotador. El objetivo de este estudio fue evaluar la variabilidad entre cirujanos ortopédicos argentinos respecto de las indicaciones de tratamiento para diferentes lesiones del manguito rotador. Materiales y Métodos: Se diseñó un cuestionario basado en el estudio de Dunn y cols. para recopilar las opiniones de cirujanos ortopedistas sobre la decisión del tratamiento para lesiones del manguito rotador. El cuestionario se distribuyó a 2 grupos, cirujanos traumatólogos y especialistas en hombro, tomando las indicaciones dadas durante 2017, tanto de tratamiento quirúrgico como de no quirúrgico. El cuestionario constaba de 2 secciones: 4 casos clínicos hipotéticos y 11 preguntas sobre factores que pueden influir en la toma de decisiones por parte del cirujano. Resultados: Se enviaron 556 cuestionarios, 117 traumatólogos y 45 especialistas lo respondieron. Los especialistas comunicaron realizar, en su mayoría, reparaciones artroscópicas (60%) y los traumatólogos, reparaciones por técnica abierta con pequeños abordajes (49%) y método abierto convencional (22%). El porcentaje de fracaso estimado en pacientes sometidos a reparación del manguito rotador es del 20%, sin diferencias entre los profesionales (p = 0,42). Ambos grupos reportaron opiniones semejantes (p = 0,74) en relación con la contraindicación del uso de corticoides en posibles candidatos quirúrgicos. Conclusión: Se observó una variabilidad considerable en las indicaciones de tratamiento y manejo de estos pacientes en gran parte de los casos presentados de lesiones potencialmente controvertidas, esto dificulta establecer protocolos o consensuar guías que ayuden a estandarizar tratamientos de elección para estas lesiones. Nivel de Evidencia: IIb

Introduction: Indications in the operative and nonoperative treatment of rotator cuff tears are widely discussed and not standardized. The aim of this study is to evaluate the variability among Argentinean orthopedic surgeons regarding the indications of treatment for different rotator cuff injuries. Materials and Methods: A questionnaire was developed based on the study carried out by Dunn et al. Our aim was to gather the opinions of Argentinean orthopedic surgeons on decision-making concerning the treatment of different rotator cuff lesions. The questionnaire was sent to 2 groups: general orthopedic surgeons and shoulder specialist surgeons, included according to the number of shoulders treated surgically and non-surgically in 2017. The questionnaire has two sections: 4 hypothetical clinical cases and 11 questions on factors that could influence treatment selection. Results: Out of 556 questionnaires sent, 162 were completed, 117 by general orthopedic surgeons and 45 by shoulder specialists. The specialists reported mostly arthroscopic repairs (60%), general orthopedic surgeons reported repairing these injuries mainly by mini-open or by standard open technique (49% and 22% respectively). The failure rate was considered to be 20%, not evidencing differences between professionals (P=0.42). There was also agreement in the contraindication of the use of corticosteroids before surgery (P=0.74). Conclusion: This study evidences significant variability in the management of these patients (for which we selected potentially controversial injuries), making it difficult to establish protocols or consensus guidelines to help standardize treatments for these injuries. Level of Evidence: IIb

¿Tardan más en consolidar las fracturas asociadas a bifosfonatos? / Does bone healing take longer in fractures treated with bisphosphonates?

Introducción: Los bifosfonatos evolucionaron como el pilar para el tratamiento de la osteoporosis, reduciendo la incidencia de fracturas. Recientemente, varias publicaciones describieron la aparición de fracturas atípicas de fémur de baja energía asociadas con el uso de bifosfonatos. El objetivo de este estudio fue evaluar el tiempo promedio de consolidación de las fracturas atípicas de fémur asociadas al tratamiento con bifosfonatos comparado con el de un grupo de control. Materiales y Métodos: Se evaluó, en forma retrospectiva, a 34 mujeres (edad promedio 74 años) con fracturas atípicas; 16 de ellas habían recibido bifosfonatos, al menos, por cinco años. Fueron tratadas entre 2006 y 2017, y estabilizadas con un clavo cefalomedular. Este grupo fue comparado con un grupo de control de similares características. Resultados: Veintidós tenían fracturas subtrocantéricas y 12, diafisarias. El 14% de las que tomaron bifosfonatos y fueron operadas requirió una revisión frente al 5,5% del grupo de control. El tiempo promedio de consolidación fue mayor en las tratadas con bifosfonatos (8.5 vs. 6 meses), con una diferencia estadísticamente significativa (p <0,001). Conclusiones: El beneficio del tratamiento con bifosfonatos en la prevención de fracturas es superior al riesgo de fracturas atípicas; sin embargo, es importante evaluar la relación riesgo-beneficio en cada paciente al comienzo y durante el tratamiento, teniendo en cuenta que, pese a esto, el tiempo de curación es más largo. Nivel de Evidencia: IV

Objectives: Bisphosphonates have become the gold standard treatment for osteoporosis, since they reduce the incidence of fractures. Recently, several papers described the occurrence of low-energy atypical femoral fractures associated with the use of bisphosphonates. The objective of this study was to compare the average time to healing of atypical femoral fractures in patients who received bisphosphonates and in a control group. Materials and Methods: We retrospectively evaluated 34 patients with atypical femoral fractures, 16 of whom had received treatment with bisphosphonates for at least 5 years, between 2006 and 2017, and whose fractures were stabilized with a cephalomedullary nail. They were compared with a control group of similar characteristics. Results: All the patients were female, with an average age of 74 years. Twenty-two fractures were subtrochanteric, while 12 involved the femoral shaft. Fourteen percent (14%) of the patients who received bisphosphonates and surgical management required a revision surgery, while 5.5% of the control group did not. The average time to bone healing was longer in those treated with bisphosphonates (8.5 months vs. 6 months), which was statistically significant (p <0.001). Conclusions: The benefits of using bisphosphonates for fracture prevention outweigh the risk of atypical fractures. However, it is important to evaluate the risk-benefit ratio in each patient at the beginning of the treatment and during the course of it, since, despite the benefits, healing time is longer. Level of Evidence: IV

Engraftment of Human Stem Cell-Derived Otic Progenitors in the Damaged Cochlea.

Most cases of sensorineural deafness are caused by degeneration of hair cells. Although stem/progenitor cell therapy is becoming a promising treatment strategy in a variety of organ systems, cell engraftment in the adult mammalian cochlea has not yet been demonstrated. In this study, we generated human otic progenitor cells (hOPCs) from induced pluripotent stem cells (iPSCs) in vitro and identified these cells by the expression of known otic markers. We showed successful cell transplantation of iPSC-derived-hOPCs in an in vivo adult guinea pig model of ototoxicity. The delivered hOPCs migrated throughout the cochlea, engrafted in non-sensory regions, and survived up to 4 weeks post-transplantation. Some of the engrafted hOPCs responded to environmental cues within the cochlear sensory epithelium and displayed molecular features of early sensory differentiation. We confirmed these results with hair cell progenitors derived from Atoh1-GFP mice as donor cells. These mouse otic progenitors transplanted using the same in vivo delivery system migrated into damaged cochlear sensory epithelium and adopted a partial sensory cell fate. This is the first report of the survival and differentiation of hOPCs in ototoxic-injured mature cochlear epithelium, and it should stimulate further research into cell-based therapies for treatment of deafness.

Modeling human early otic sensory cell development with induced pluripotent stem cells.

The inner ear represents a promising system to develop cell-based therapies from human induced pluripotent stem cells (hiPSCs). In the developing ear, Notch signaling plays multiple roles in otic region specification and for cell fate determination. Optimizing hiPSC induction for the generation of appropriate numbers of otic progenitors and derivatives, such as hair cells, may provide an unlimited supply of cells for research and cell-based therapy. In this study, we used monolayer cultures, otic-inducing agents, Notch modulation, and marker expression to track early and otic sensory lineages during hiPSC differentiation. Otic/placodal progenitors were derived from hiPSC cultures in medium supplemented with FGF3/FGF10 for 13 days. These progenitor cells were then treated for 7 days with retinoic acid (RA) and epidermal growth factor (EGF) or a Notch inhibitor. The differentiated cultures were analyzed in parallel by qPCR and immunocytochemistry. After the 13 day induction, hiPSC-derived cells displayed an upregulated expression of a panel of otic/placodal markers. Strikingly, a subset of these induced progenitor cells displayed key-otic sensory markers, the percentage of which was increased in cultures under Notch inhibition as compared to RA/EGF-treated cultures. Our results show that modulating Notch pathway during in vitro differentiation of hiPSC-derived otic/placodal progenitors is a valuable strategy to promote the expression of human otic sensory lineage genes.

Enriched Differentiation of Human Otic Sensory Progenitor Cells Derived From Induced Pluripotent Stem Cells.

Age-related neurosensory deficit of the inner ear is mostly due to a loss of hair cells (HCs). Development of stem cell-based therapy requires a better understanding of factors and signals that drive stem cells into otic sensory progenitor cells (OSPCs) to replace lost HCs. Human induced pluripotent stem cells (hiPSCs) theoretically represent an unlimited supply for the generation of human OSPCs in vitro. In this study, we developed a monolayer-based differentiation system to generate an enriched population of OSPCs via a stepwise differentiation of hiPSCs. Gene and protein expression analyses revealed the efficient induction of a comprehensive panel of otic/placodal and late otic markers over the course of the differentiation. Furthermore, whole transcriptome analysis confirmed a developmental path of OSPC differentiation from hiPSCs. We found that modulation of WNT and transforming growth factor-ß (TGF-ß) signaling combined with fibroblast growth factor 3 (FGF3) and FGF10 treatment over a 6-day period drives the expression of early otic/placodal markers followed by late otic sensory markers within 13 days, indicative of a differentiation into embryonic-like HCs. In summary, we report a rapid and efficient strategy to generate an enriched population of OSPCs from hiPSCs, thereby establishing the value of this approach for disease modeling and cell-based therapies of the inner ear.

Nogo receptor inhibition enhances functional recovery following lysolecithin-induced demyelination in mouse optic chiasm.

BACKGROUND: Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm. METHODOLOGY/PRINCIPAL FINDINGS: A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time. CONCLUSIONS/SIGNIFICANCE: Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.

Educación diabetológica en la atención primaria / Diabetes education in primary care

Recientemente, en el Instituto Mexicano del Seguro Social se implementó el programa educativo DiabetIMSS, alcanzándose una mejora en los parámetros clínicos y bioquímicos; sin embargo, los resultados no han sido contrastados con los de la estrategia educativa habitual. Objetivos: Comparar la efectividad de DiabetIMSS y de la educación grupal tradicional sobre el conocimiento y la capacidad de autocuidado. Material y métodos: Estudio cuasi experimental que se realizó en dos unidades de medicina familiar con pacientes con diabetes tipo 2, mayores de 19 años de edad, que supieran leer y escribir. El muestreo fue por casos consecutivos y la asignación a los grupos fue no aleatorizada. El conocimiento se midió con el Cuestionario de Conocimientos en Diabetes-24 y la capacidad de autocuidado con el Cuestionario Resumido sobre Actividades de Autocuidado en Diabetes. Resultados: El grupo DiabetIMSS estuvo conformado por 53 sujetos, y el de educación tradicional, por 63. En el grupo DiabetIMSS el nivel de conocimiento inicial fue suficiente en el 17% (n = 9) y en el 60.4% (n = 32) al final del estudio(p < 0.05). En los pacientes asignados a educación grupal tradicional el nivel de conocimiento inicial fue suficiente en el 9.5% (n = 6) y en el 34.9% (n = 22) al término de la intervención (p < 0.05). En cuanto a las capacidades de autocuidado, sólo se observaron cambios significativos en la actividad física y en la revisión de los pies, en ambos grupos. Conclusiones: El programa DiabetIMSS es más efectivo para la adquisición de conocimiento, no así para mejorar la capacidad de autocuidado...

Thyroid hormone signaling acts as a neurogenic switch by repressing Sox2 in the adult neural stem cell niche.

The subventricular zone (SVZ) neural stem cell niche contains mixed populations of stem cells, transit-amplifying cells, and migrating neuroblasts. Deciphering how endogenous signals, such as hormones, affect the balance between these cell types is essential for understanding the physiology of niche plasticity and homeostasis. We show that Thyroid Hormone (T(3)) and its receptor, TRα1, are directly involved in maintaining this balance. TRα1 is expressed in amplifying and migrating cells. In vivo gain- and loss-of-function experiments demonstrate first, that T(3)/TRα1 directly repress Sox2 expression, and second, that TRα1 overexpression in the niche favors the appearance of DCX+ migrating neuroblasts. Lack of TRα increases numbers of SOX2+ cells in the SVZ. Hypothyroidism increases proportions of cells in interphase. Thus, in the adult SVZ, T(3)/TRα1 together favor neural stem cell commitment and progression toward a migrating neuroblast phenotype; this transition correlates with T(3)/TRα1-dependent transcriptional repression of Sox2.