Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy.

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice.

We previously reported that mice with low neuronal pH drink more alcohol, demonstrating the importance of pH for alcohol reward and motivation. In this study, we tested whether systemic pH affects alcohol consumption and if so, whether it occurs by changing the alcohol reward. C57BL/6J mice were given NaHCO3 to raise their blood pH, and the animals' alcohol consumption was measured in the drinking-in-the-dark and two-bottle free choice paradigms. Alcohol consumption was also assessed after suppressing the bitterness of NaHCO3 with sucrose. Alcohol reward was evaluated using a conditioned place preference. In addition, taste sensitivity was assessed by determining quinine and sucrose preference. The results revealed that a pH increase by NaHCO3 caused mice to decrease their alcohol consumption. The decrease in high alcohol contents (20%) was significant and observed at different ages, as well as in both males and females. Alcohol consumption was also decreased after suppressing NaHCO3 bitterness. Oral gavage of NaHCO3 did not alter quinine and sucrose preference. In the conditioned place preference, NaHCO3-treated mice spent less time in the alcohol-injected chamber. Conclusively, the results show that raising systemic pH with NaHCO3 decreases alcohol consumption, as it decreases the alcohol reward value.

Hypophysitis Secondary to Small Vessel ANCA Vasculitis Treated With Rituximab.

Background/Objective: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis is a rare small vessel vasculitis that can cause pituitary hypophysitis. Hypophysitis is difficult to treat, often requiring high doses of glucocorticoids with frequent flaring as glucocorticoids are tapered. We present a case of ANCA vasculitis involving the pituitary gland successfully treated with rituximab. Case Report: Fifty-one-year-old woman developed progressive frontal headaches, congestion, and epistaxis. Sinus computed tomography scan showed pituitary enlargement and chronic mucosal disease. Pituitary magnetic resonance imaging (MRI) confirmed a diffusely enlarged pituitary with a thickened pituitary stalk. Serologic evaluation revealed elevated inflammatory markers, positive perinuclear ANCA (p-ANCA), and an elevated serum anti-proteinase 3 (anti-PR3) antibody. The patient underwent pituitary biopsy, which showed adenohypophysitis with dense lymphoplasmacytic infiltration, some arranged perivascularly, compatible with involvement of the pituitary gland by ANCA vasculitis. The patient began rituximab and reported resolution of daily headaches, congestion, and epistaxis. Pituitary MRI scan 6 months after rituximab showed reduction in pituitary gland size and stalk thickening. Discussion: ANCA vasculitis is a rare etiology of pituitary hypophysitis, which can present a diagnostic and therapeutic challenge. Pituitary involvement of ANCA vasculitis can be identified through p-ANCA or cytoplasmic ANCA (c-ANCA) and biopsy of the involved tissue. Rituximab, a monoclonal antibody against CD20, has been successfully used to treat ANCA vasculitis and in this case, led to clinical improvements and reduction in the size of the pituitary gland. Conclusion: Pituitary biopsy enabled confirmation of ANCA hypophysitis and facilitated treatment with a steroid-sparing agent.

Pellagra in the USA: unusual manifestations of a rare entity.

The case involves a 62-year-old female native of the USA with a history of bipolar disorder and chronic obstructive pulmonary disease who presented with intractable diarrhoea. Prior to the index admission, she was admitted to the intensive care unit and required pericardiocentesis for an idiopathic pericardial effusion with tamponade physiology. Following discharge, she suffered intractable diarrhoea and represented for medical evaluation. She had a painful, swollen tongue as well as persistent hypoglycaemia and required glucose infusions. She had adrenal function testing which revealed adrenal insufficiency. Vitamin testing revealed normal B12 and folate levels but undetectable levels of thiamine, riboflavin and niacin. Her symptoms and signs resolved entirely with appropriate vitamin supplementation. Niacin (vitamin B3) is essential for multiple metabolic pathways, and severe deficiency may cause clinical syndrome of pellagra which is most commonly associated with diarrhoea, delirium and dermatitis. Additional physiological derangements may include adrenal insufficiency, insulin hypersensitivity and pericarditis.

Metabolic and inflammatory postprandial effect of a highly saturated fat meal and its relationship to abdominal obesity

Introduction: The postprandial stage is associated with the increase of markers related to cardiovascular risk, and its intensity depends on the metabolic state. Objective: To determine the impact of a high-fat meal intake on the metabolic and inflammatory profile, and its relationship to abdominal obesity. Materials and methods: This clinical trial included 42 individuals (21 with abdominal obesity). We measured glucose, insulin, lipid profile, reactive C protein, lipopolysaccharides, and interleukin 6 in fasting blood, and four hours after eating. Results: Besides obesity, we found insulin resistance and higher levels of fasting triacylglycerides and C-reactive protein. There were higher postprandial responses to glucose, insulin, and triacylglycerides. Interleukin 6 decreased in the non-obese group, and lipopolysaccharides increased in both groups. Conclusions: A saturated high-fat food intake produced a greater impact on the glycemic variables in the group with obesity, while it affected the lipids in both groups. However, the increase of triacylglycerides was higher in the presence of a high basal concentration, and it promoted the increase of lipopolysaccharides. The basal and postprandial inflammatory state affected the group with obesity more. The postprandial moment reflected the most frequent state of the individuals on a normal day and evidenced the capacity of the metabolic response to food intake, as well as early metabolic risk states.

Impacto metabólico e inflamatorio de una comida rica en grasas saturadas y su relación con la obesidad abdominal / Metabolic and inflammatory postprandial effect of a highly saturated fat meal and its relationship to abdominal obesity

Resumen Introducción. La etapa posprandial se asocia con el incremento de marcadores relacionados con el riesgo cardiovascular, cuya intensidad depende del estado metabólico. Objetivo. Determinar el impacto de la ingestión de una comida rica en grasas saturadas sobre el perfil metabólico e inflamatorio y su relación con la obesidad abdominal. Materiales y métodos. Se hizo un ensayo clínico en 42 individuos (21 con obesidad abdominal). Se midieron, en sangre, la glucosa, la insulina, el perfil lipídico, la proteína C reactiva, los lipopolisacáridos y la interleucina 6, en ayunas y después de la ingestión. Resultados. Además de la obesidad, se registró la presencia de resistencia a la insulina y de niveles elevados de triacilglicéridos y proteína C reactiva en ayunas. Asimismo, se detectaron niveles posprandiales más elevados de glucosa, insulina y triacilglicéridos. La interleucina 6 disminuyó en el grupo de personas sin obesidad y los lipopolisacáridos aumentaron en ambos grupos. Conclusión. La ingestión de una comida rica en grasas saturadas produjo un mayor impacto en las variables glucémicas en el grupo con obesidad y, aunque afectó de forma similar los lípidos en ambos grupos, el incremento de triacilglicéridos fue mayor en presencia de una concentración basal elevada y promovió el aumento de lipopolisacáridos. El estado inflamatorio basal y posprandial afectó en mayor medida al grupo con obesidad. El momento posprandial reflejó el estado más frecuente de los individuos en un día normal y permitió evidenciar la capacidad de respuesta metabólica frente a la ingestión de alimentos, así como los estados tempranos de riesgo metabólico.

Abstract Introduction: The postprandial stage is associated with the increase of markers related to cardiovascular risk, and its intensity depends on the metabolic state. Objective: To determine the impact of a high-fat meal intake on the metabolic and inflammatory profile, and its relationship to abdominal obesity. Materials and methods: This clinical trial included 42 individuals (21 with abdominal obesity). We measured glucose, insulin, lipid profile, reactive C protein, lipopolysaccharides, and interleukin 6 in fasting blood, and four hours after eating. Results: Besides obesity, we found insulin resistance and higher levels of fasting triacylglycerides and C-reactive protein. There were higher postprandial responses to glucose, insulin, and triacylglycerides. Interleukin 6 decreased in the non-obese group, and lipopolysaccharides increased in both groups. Conclusions: A saturated high-fat food intake produced a greater impact on the glycemic variables in the group with obesity, while it affected the lipids in both groups. However, the increase of triacylglycerides was higher in the presence of a high basal concentration, and it promoted the increase of lipopolysaccharides. The basal and postprandial inflammatory state affected the group with obesity more. The postprandial moment reflected the most frequent state of the individuals on a normal day and evidenced the capacity of the metabolic response to food intake, as well as early metabolic risk states.

Presión Arterial Media en trabajadores obreros y oficinistas

Introducción: Los cambios en el estilo de vida y en las demandas en los tipos de trabajo han llevado una mayor tasa de sedentarismo y de tiempo de estar sentado durante el día. Se ha observado que el tiempo que un individuo pasa sentado durante el día está asociado a un incremento en el riesgo de padecer una enfermedad cardiovascular independientemente de la actividad física realizada por el individuo. El objetivo del estudio fue determinar si existe evidencia estadísticamente significativa entre los valores de presión arterial media y de índice de masa corporal entre un grupo de trabajadores de oficina y uno de trabajadores de bodega. Métodos: Estudio prospectivo longitudinal de 200 personas, 100 trabajadores de bodega, 100 de oficina, de diferentes empresas de la Ciudad de Guatemala de 20 a 40 años de edad. Resultados: Se evidenció diferencia estadísticamente significativa entre los valores de presión arterial media (PAM) de los grupos de bodega y oficina (88.03mmHg vs. 89.63mmHg). Los individuos que trabajan en bodega presentaron un mayor índice de masa corporal, el 46% de estos presentaron sobrepeso y el 24% obesidad. Los trabajadores de oficina presentaron un 27% y 12% respectivamente Conclusiones: Existe diferencia entre los valores de IMC y de PAM entre ambos grupos. Respecto al peso, se encontraron mayores valores en el grupo de bodega, el cual pasa menos tiempo sentado, lo cual se considera puede ser resultado de menor nivel de educación y status socioeconómico, lo que lleva a una menor conciencia de la salud y peores elecciones alimentarias entre otros. Palabras Clave: Riesgo cardiovascular, sobrepeso, obesidad, presión arterial, Índice de masa corporal

Introduction: Daily life changes and work demands have lead to a major sedentary life being seating for long periods of time during the day. It has been observed that the time an individual spend seated during the day is associated to an increased risk in cardiovascular disease independent of physical activity. The purpose of this study was to determine if there is statistically significant evidence between mean arterial blood pressure (MABP) and BMI (body mass index) in a group of white and blue collar workers. Methods: This is a prospective longitudinal study with 200 subjects, 100 blue collar workers and 100 white collar workers 20-40 years of age from different businesses in Guatemala City. Results: There was significant difference between BP (88.03mmHg vs. 89.63mmHg) and BMI 46% vs. 27% were overweight and 24% vs.12% were obese between both groups, in which the blue collar workers showed higher values. Conclusion: There is a difference between BMI and mean BP between both groups. We found higher values in the blue collar group, which spend less time seated, and this could be attributed to a lower education level and social status which leads to a lower health awareness and poor food choices among other things. Keywords: cardiovascular risk, overweight, obesity, blood pressure, body mass index