Architecture and regulation of a GDNF-GFRα1 synaptic adhesion assembly.

Glial-cell line derived neurotrophic factor (GDNF) bound to its co-receptor GFRα1 stimulates the RET receptor tyrosine kinase, promoting neuronal survival and neuroprotection. The GDNF-GFRα1 complex also supports synaptic cell adhesion independently of RET. Here, we describe the structure of a decameric GDNF-GFRα1 assembly determined by crystallography and electron microscopy, revealing two GFRα1 pentamers bridged by five GDNF dimers. We reconsitituted the assembly between adhering liposomes and used cryo-electron tomography to visualize how the complex fulfils its membrane adhesion function. The GFRα1:GFRα1 pentameric interface was further validated both in vitro by native PAGE and in cellulo by cell-clustering and dendritic spine assays. Finally, we provide biochemical and cell-based evidence that RET and heparan sulfate cooperate to prevent assembly of the adhesion complex by competing for the adhesion interface. Our results provide a mechanistic framework to understand GDNF-driven cell adhesion, its relationship to trophic signalling, and the central role played by GFRα1.

Impacto de la diabetes, la desnutrición y la sarcopenia en el pronóstico de los pacientes hospitalizados en Medicina Interna / Impact of diabetes, malnutrition and sarcopenia on the prognosis of patients admitted to Internal Medicine

Objetivo Describir los pacientes hospitalizados en medicina interna en términos de desnutrición y sarcopenia, en función de la presencia o no de diabetes mellitus tipo 2 (DM2), así como evaluar la mortalidad a corto y largo plazo relacionada con ambas. Métodos Estudio de cohortes, unicéntrico, que recoge pacientes consecutivos ingresados en Medicina Interna en mayo y octubre del 2021. La desnutrición se determinó mediante el Mini Nutritional Assessment-Short Form (MNA-SF) y la sarcopenia mediante SARC-F y dinamometría. Se excluyó a los pacientes hospitalizados más de 48 h. Resultados Se analiza a 511 pacientes, 49,1% varones, edad media de 75,2±15 años, 210 (41,1%) DM2. Se generan 6 grupos (diseño 2 × 3) en función de la presencia de DM2 y del estado nutricional acorde con el resultado del MNA-SF: 12-14 puntos, sin riesgo; MNA-SF 8-12 puntos, alto riesgo; MNA-SF 0-7 puntos, desnutridos. Los pacientes con DM2 y desnutridos tenían significativamente mayor sarcopenia, comorbilidad, inflamación y úlceras por presión. Los principales determinantes de mortalidad intrahospitalaria fueron la sarcopenia (OR 1,27, IC del 95%, 1,06-1,54, p=0,01), la comorbilidad (OR 1,27, IC del 95%, 1,08-1,49, p=0,003) y la inflamación (OR 1,01, IC del 95%, 1,00-1,02, p=0,02). El pronóstico a 120 días fue peor entre los pacientes desnutridos (p=0,042). Conclusión Los pacientes ingresados con DM2 presentan similar grado de desnutrición que el resto, pero con mayor sarcopenia. Esta sarcopenia, junto a la inflamación y la comorbilidad determinan un peor pronóstico. La identificación activa y temprana de la desnutrición y la sarcopenia, y su abordaje posterior podrían mejorar el pronóstico de los pacientes (AU)

Objective To describe patients hospitalized in internal medicine in terms of malnutrition and sarcopenia, depending on the presence or absence of type 2 diabetes mellitus (DM2), as well as to evaluate short- and long-term mortality related to both. Methods Cross-sectional, single-center study, which included consecutive patients admitted to internal medicine in May and October 2021. Malnutrition was determined using the Mini Nutritional Assessment-Short Form (MNA-SF) and sarcopenia using SARC-F and handgrip strength. Patients hospitalized for more than 48h are excluded. Results Five hundred and 11patients were analyzed, 49.1% male, mean age 75.2±15 years, 210 (41.1%) DM2. Six groups (2×3 design) are generated based on the presence of DM2 and the nutritional status according to the result of the MNA-SF: 12–14 points, without risk; MNA-SF 8–12 points, high risk; MNA-SF 0–7 points, malnourished. Malnourished patients with DM2 had significantly higher sarcopenia, comorbidity, inflammation, and pressure ulcers. The main determinants of in-hospital mortality were sarcopenia (OR 1.27, 95% CI: 1.06–1.54, p=0.01), comorbidity (OR 1.27, 95% CI: 1.08–1.49, p=0.003) and inflammation (OR 1.01, 95% CI: 1.00–1.02, p=0.02). The 120-day prognosis was worse among malnourished patients (p=0.042). Conclusion Patients admitted with DM2 have a similar degree of malnutrition than the rest, but with greater sarcopenia. This sarcopenia, together with inflammation and comorbidity determine a worse prognosis. The active and early identification of malnutrition and sarcopenia and their subsequent approach could improve the prognosis of patients (AU)

Impact of diabetes, malnutrition and sarcopenia on the prognosis of patients admitted to internal medicine.

OBJECTIVE: To describe patients hospitalized in internal medicine in terms of malnutrition and sarcopenia, depending on the presence or absence of type 2 diabetes mellitus (DM2), as well as to evaluate short- and long-term mortality related to both. METHODS: Cross-sectional, single-center study, which included consecutive patients admitted to internal medicine in May and October 2021. Malnutrition was determined using the Mini Nutritional Assessment-Short Form (MNA-SF) and sarcopenia using SARC-F and handgrip strength. Patients hospitalized for more than 48 h are excluded. RESULTS: 511 patients were analyzed, 49.1% male, mean age 75.2 +/- 15 years, 210 (41.1%) DM2. 6 groups (2 × 3 design) are generated based on the presence of DM2 and the nutritional status according to the result of the MNA-SF: 12-14 points, without risk; MNA-SF 8-12 points, high risk; MNA-SF 0-7 points, malnourished. Malnourished patients with DM2 had significantly higher sarcopenia, comorbidity, inflammation, and pressure ulcers. The main determinants of in-hospital mortality were sarcopenia (OR 1.27, 95%CI 1.06-1.54, p = 0.01), comorbidity (OR 1.27, 95%CI 1,08-1,49, p = 0.003) and inflammation (OR 1.01, 95%CI 1.00-1.02, p = 0.02). The 120-day prognosis was worse among malnourished patients (p = 0.042). CONCLUSION: Patients admitted with DM2 have a similar degree of malnutrition than the rest, but with greater sarcopenia. This sarcopenia, together with inflammation and comorbidity determine a worse prognosis. The active and early identification of malnutrition and sarcopenia and their subsequent approach could improve the prognosis of patients.

Neonatal nicotine exposure alters leptin signaling in the hypothalamus-pituitary-thyroid axis in the late postnatal period and adulthood in rats.

AIMS: Postnatal nicotine exposure causes precocious primary hypothyroidism and programs for overweight, hyperleptinemia and secondary hypothyroidism in adulthood. As leptin and thyroid hormones share the ability to increase energy expenditure, we studied the effects of maternal nicotine exposure during lactation on the leptin signaling in the hypothalamus-pituitary-thyroid axis of suckling and adult offspring. MAIN METHODS: Two days after delivery, osmotic minipumps were implanted in lactating rats, and nicotine (NIC, 6 mg/kg/day s.c.) or saline (C) was administered for 14days. Offspring were killed at 15 and 180 days-old. Proteins belonging to leptin signaling were analyzed by Western blot. Significant differences had p<0.05. KEY FINDINGS: In the hypothalamus, NIC offspring showed higher OB-R and pSTAT-3 content (+58%,+1.34x) at 15 days, and lower OB-R, JAK-2 and pSTAT-3 (-61%, -42%, -56%) at 180 days. In the pituitary gland, NIC offspring showed lower JAK-2 content (-52%) at 15 days, but no differences in adulthood. In the thyroid gland, the NIC group presented lower OB-R, JAK-2 and STAT-3 (-44%, -50%, -47%) and higher pSTAT-3 expression (+80%) at 15 days. At 180 days-old, NIC offspring presented higher thyroid OB-R (+1.54x) and lower pSTAT-3 content (-34%). SIGNIFICANCE: Neonatal primary hypothyroidism induced by maternal nicotine exposure during lactation may be partially explained by decreased leptin signaling in the thyroid, though the early stimulation of the central leptin pathway did not prevent the thyroid dysfunction. Long-term effects of postnatal nicotine exposure on leptin signaling in the hypothalamus and thyroid appear to involve central and peripheral leptin resistance in adulthood.

Short- and long-term effects of maternal nicotine exposure during lactation on body adiposity, lipid profile, and thyroid function of rat offspring.

Epidemiological studies show a higher prevalence of obesity in children from smoking mothers and smoking may affect human thyroid function. To evaluate the mechanism of smoking as an imprinting factor for these dysfunctions, we evaluated the programming effects of maternal nicotine (NIC) exposure during lactation. Two days after birth, osmotic minipumps were implanted in lactating rats, divided into: NIC (6 mg/kg per day s.c.) for 14 days; Control - saline. All the significant data were P<0.05 or less. Body weight was increased from 165 days old onwards in NIC offspring. Both during exposure (at 15 days old) and in adulthood (180 days old), NIC group showed higher total fat (27 and 33%). In addition, NIC offspring presented increased visceral fat and total body protein. Lipid profile was not changed in adulthood. Leptinemia was higher at 15 and 180 days old (36 and 113%), with no changes in food intake. Concerning the thyroid status, the 15-days-old NIC offspring showed lower serum-free tri-iodothyronine (FT(3)) and thyroxine (FT(4)) with higher TSH. The 180-days-old NIC offspring exhibited lower TSH, FT(3), and FT(4)). In both periods, liver type 1 deiodinase was lower (26 and 55%). We evidenced that NIC imprints a neonatal thyroid dysfunction and programs for a higher adiposity, hyperleptinemia, and secondary hypothyroidism in adulthood. Our study identifies lactation as a critical period to NIC programming for obesity, with hypothyroidism being a possible contributing factor.

Effect of long-term beta-blockade on aortic root compliance in patients with Marfan syndrome.

BACKGROUND: This study was undertaken to assess the effect of long-term beta-blockade on the aortic root stiffness index and distensibility in patients with Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were calculated according to the formulas of Stefanadis and Hirai, respectively, with 2-dimensional guided M-mode echocardiogram before and after an average of 26 months of atenolol administration. RESULTS: Twenty-three asymptomatic patients were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4 +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d). Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21 +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68 +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were identified. Compared with baseline values 15 (65%) patients who responded to treatment had increased distensibility and decreased stiffness index of the aortic root (P =.05). Eight patients (35%) who did not respond to treatment had no significant change. Body weight >91 kg and baseline end-diastolic aortic root diameter >40 mm were significantly associated with no response (P =.05). Two patients in the nonresponding group had echocardiographic progression of aortic insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root elastic properties after long-term treatment with atenolol in asymptomatic patients with Marfan syndrome. Stiffness index and distensibility are more likely to respond when the baseline end-diastolic aortic root diameter is <40 mm.