Developmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders

Developmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders

Postoperative complications in patients treated in the course of Surgery A (FOUNLP) years 2018-2019

Las principales complicaciones registradas son: la Alveolitis (seca o húmeda) y la hemorragia. De dichas complicaciones se percibe que la alveolitis es la complicación más frecuente de la exodoncia dentaria. El dolor es probablemente el principal motivo de consulta en las urgencias estomatológicas. En las mismas, el estomatólogo se enfrenta a diario con dolores principalmente agudos, provenientes de estructuras dentarias o de los tejidos subyacentes. Los distintos estudios realizados por diversos autores revelan que la frecuencia varía entre el 1 y 4 % de todas las extracciones dentales y puede llegar del 20 al 30 % en terceros molares mandibulares. Es más frecuente en el sexo femenino y la mayoría de los casos se observan entre la tercera y cuarta décadas de la vida. Esta urgencia estomatológica tiene gran repercusión, ya que a pesar de que el dolor que sufre el paciente puede ser moderado, casi siempre es constante, perturbador, de carácter insoportable, irradiado, persiste por varios días e impide, en la mayoría de los casos, la actividad normal del paciente, por lo que limita su desenvolvimiento laboral y social, en algunos casos, hasta por 20 días. Los objetivos de este trabajo son: describir la frecuencia de alveolitis dentaria y específicamente relacionar la alveolitis dentaria con edad, relacionar la alveolitis dentaria con sexo, relacionar la alveolitis dentaria con grupo dentario, relacionar la alveolitis dentaria con localización (maxilar superior o inferior), relacionar la alveolitis dentaria con tabaquismo.The main complications are: alveolitis (dry or wet) and bleeding. From these complications it is perceived that alveolitis is the most frequent complication of dental extraction. Pain is probably the main reason for consultation in stomatologic emergencies. In these, the stomatologist confronts daily with mainly acute pains, coming from dental structures or underlying tissues. The different studies performed by different authors reveal that the frequency varies between 1 and 4% of all dental extractions and can reach 20 to 30% in third mandibular molars. It is more frequent in the female sex and most cases are seen between the third and fourth decades of life. This stomatological urgency has great repercussion, since although the pain that the patient suffers may be moderate, it is almost always constant, disturbing, unbearable, irradiated, persists for several days and prevents, in most cases, The normal activity of the patient, so limiting their work and social development, in some cases, up to 20 days. To describe the frequency of dental alveolitis and to relate dental alveolitis to age, to relate dental alveolitis to sex, to relate dental alveolitis to dental group, to relate dental alveolitis with location (upper or lower jaw), to relate alveolitis with smoking.Facultad de Odontologí

Postoperative complications in patients treated in the course of Surgery A (FOUNLP) years 2018-2019

Las principales complicaciones registradas son: la Alveolitis (seca o húmeda) y la hemorragia. De dichas complicaciones se percibe que la alveolitis es la complicación más frecuente de la exodoncia dentaria. El dolor es probablemente el principal motivo de consulta en las urgencias estomatológicas. En las mismas, el estomatólogo se enfrenta a diario con dolores principalmente agudos, provenientes de estructuras dentarias o de los tejidos subyacentes. Los distintos estudios realizados por diversos autores revelan que la frecuencia varía entre el 1 y 4 % de todas las extracciones dentales y puede llegar del 20 al 30 % en terceros molares mandibulares. Es más frecuente en el sexo femenino y la mayoría de los casos se observan entre la tercera y cuarta décadas de la vida. Esta urgencia estomatológica tiene gran repercusión, ya que a pesar de que el dolor que sufre el paciente puede ser moderado, casi siempre es constante, perturbador, de carácter insoportable, irradiado, persiste por varios días e impide, en la mayoría de los casos, la actividad normal del paciente, por lo que limita su desenvolvimiento laboral y social, en algunos casos, hasta por 20 días. Los objetivos de este trabajo son: describir la frecuencia de alveolitis dentaria y específicamente relacionar la alveolitis dentaria con edad, relacionar la alveolitis dentaria con sexo, relacionar la alveolitis dentaria con grupo dentario, relacionar la alveolitis dentaria con localización (maxilar superior o inferior), relacionar la alveolitis dentaria con tabaquismo.The main complications are: alveolitis (dry or wet) and bleeding. From these complications it is perceived that alveolitis is the most frequent complication of dental extraction. Pain is probably the main reason for consultation in stomatologic emergencies. In these, the stomatologist confronts daily with mainly acute pains, coming from dental structures or underlying tissues. The different studies performed by different authors reveal that the frequency varies between 1 and 4% of all dental extractions and can reach 20 to 30% in third mandibular molars. It is more frequent in the female sex and most cases are seen between the third and fourth decades of life. This stomatological urgency has great repercussion, since although the pain that the patient suffers may be moderate, it is almost always constant, disturbing, unbearable, irradiated, persists for several days and prevents, in most cases, The normal activity of the patient, so limiting their work and social development, in some cases, up to 20 days. To describe the frequency of dental alveolitis and to relate dental alveolitis to age, to relate dental alveolitis to sex, to relate dental alveolitis to dental group, to relate dental alveolitis with location (upper or lower jaw), to relate alveolitis with smoking.Facultad de Odontologí

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Pax6 Developmental Synaptome Atlas

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to repair themselves. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show synaptome remodelling confers resilience to neurodevelopmental disorders.Laura, Tomas-Roca; Qiu, Zhen; Fransén, Erik; Grant, Seth. (2021). Pax6 Developmental Synaptome Atlas, 2016-2021 [dataset]. University of Edinburgh. Centre for Clinical Brain Sciences. https://doi.org/10.7488/ds/3264

Pax6 Developmental Synaptome Atlas

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.Tomas-Roca, Laura; Qiu, Zhen; Fransén, Erik; Grant, Seth. (2022). Pax6 Developmental Synaptome Atlas, [dataset]. University of Edinburgh, Centre for Clinical Brain Sciences. https://doi.org/10.7488/ds/3770