Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010-2020: a cross-sectional study.

BACKGROUND AND AIM: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia. METHODS: A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis. RESULTS: In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected. CONCLUSION: This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.

Bacterial approaches to sensing and responding to respiration and respiration metabolites.

Bacterial respiration of diverse substrates is a primary contributor to the diversity of life. Respiration also drives alterations in the geosphere and tethers ecological nodes together. It provides organisms with a means to dissipate reductants and generate potential energy in the form of an electrochemical gradient. Mechanisms have evolved to sense flux through respiratory pathways and sense the altered concentrations of respiration substrates or byproducts. These genetic regulatory systems promote efficient utilization of respiration substrates, as well as fine-tune metabolism to promote cellular fitness and negate the accumulation of toxic byproducts. Many bacteria can respire one or more chemicals, and these regulatory systems promote the prioritization of high-energy metabolites. Herein, we focus on regulatory paradigms and discuss systems that sense the concentrations of respiration substrates and flux through respiratory pathways. This is a broad field of study, and therefore we focus on key fundamental and recent developments and highlight specific systems that capture the diversity of sensing mechanisms.

Sam68 contributes to intestinal inflammation in experimental and human colitis.

Sam68 is an RNA-binding protein with an adaptor role in signal transduction. Our previous work identified critical proinflammatory and apoptotic functions for Sam68, downstream of the TNF/TNFR1 and TLR2/3/4 pathways. Recent studies have shown elevated Sam68 in inflamed tissues from rheumatoid arthritis and ulcerative colitis (UC) patients, suggesting that Sam68 contributes to chronic inflammatory diseases. Here, we hypothesized that deletion of Sam68 is protective against experimental colitis in vivo, via reductions in TNF-associated inflammatory signaling. We used Sam68 knockout (KO) mice to study the role of Sam68 in experimental colitis, including its contributions to TNF-induced inflammatory gene expression in three-dimensional intestinal organoid cultures. We also studied the expression of Sam68 and inflammatory genes in colon tissues of UC patients. Sam68 KO mice treated with an acute course of DSS exhibited significantly less weight loss and histopathological inflammation compared to wild-type controls, suggesting that Sam68 contributes to experimental colitis. Bone marrow transplants showed no pathologic role for hematopoietic cell-specific Sam68, suggesting that non-hematopoietic Sam68 drives intestinal inflammation. Gene expression analyses showed that Sam68 deficiency reduced the expression of proinflammatory genes in colon tissues from DSS-treated mice, as well as TNF-treated three-dimensional colonic organoids. We also found that inflammatory genes, such as TNF, CCR2, CSF2, IL33 and CXCL10, as well as Sam68 protein, were upregulated in inflamed colon tissues of UC patients. This report identifies Sam68 as an important inflammatory driver in response to intestinal epithelial damage, suggesting that targeting Sam68 may hold promise to treat UC patients.

Negative regulation of FOXP3 expression by c-Rel O-GlcNAcylation.

O-GlcNAcylation is a reversible post-translational protein modification that regulates fundamental cellular processes including immune responses and autoimmunity. Previously, we showed that hyperglycemia increases O-GlcNAcylation of the transcription factor, nuclear factor kappaB c-Rel at serine residue 350 and enhances the transcription of the c-Rel-dependent proautoimmune cytokines interleukin-2, interferon gamma and granulocyte macrophage colony stimulating factor in T cells. c-Rel also plays a critical role in the transcriptional regulation of forkhead box P3 (FOXP3)-the master transcription factor that governs development and function of Treg cells. Here we show that the regulatory effect of c-Rel O-GlcNAcylation is gene-dependent, and in contrast to its role in enhancing the expression of proautoimmune cytokines, it suppresses the expression of FOXP3. Hyperglycemia-induced O-GlcNAcylation-dependent suppression of FOXP3 expression was found in vivo in two mouse models of autoimmune diabetes; streptozotocin-induced diabetes and spontaneous diabetes in nonobese diabetic mice. Mechanistically, we show that both hyperglycemia-induced and chemically enhanced cellular O-GlcNAcylation decreases c-Rel binding at the FOXP3 promoter and negatively regulates FOXP3 expression. Mutation of the O-GlcNAcylation site in c-Rel, (serine 350 to alanine), augments T cell receptor-induced FOXP3 expression and resists the O-GlcNAcylation-dependent repression of FOXP3 expression. This study reveals c-Rel S350 O-GlcNAcylation as a novel molecular mechanism inversely regulating immunosuppressive FOXP3 expression and proautoimmune gene expression in autoimmune diabetes with potential therapeutic implications.

Tools, Strains, and Strategies To Effectively Conduct Anaerobic and Aerobic Transcriptional Reporter Screens and Assays in Staphylococcus aureus.

Transcriptional reporters are reliable and time-tested tools to study gene regulation. In Staphylococcus aureus, ß-galactosidase (lacZ)-based genetic screens are not widely used because of the necessity of selectable markers for strain construction and the production of staphyloxanthin pigment, which obfuscates results. We describe a series of vectors that allow for markerless insertion of codon-optimized lacZ-based transcriptional reporters. The vectors code for different ribosomal binding sites, allowing for tailored lacZ expression. A ΔcrtM::kanR deletion insertion mutant was constructed that prevents the synthesis of staphyloxanthin, thereby permitting blue-white screening without the interference of carotenoid production. We demonstrate the utility of these vectors to monitor aerobic and anaerobic transcriptional activities. For the latter, we describe the use of a ferrocyanide-ferricyanide redox system [Fe(CN)63-/4-] permitting blue-white screening in the absence of oxygen. We also describe additional reporter systems and methods for monitoring transcriptional activity during anaerobic culture, including an FAD-binding fluorescent protein (EcFbFP), alpha-hemolysin (hla), or lipase (geh). The systems and methods described are compatible with vectors utilized to create and screen high-density transposon mutant libraries. IMPORTANCE Staphylococcus aureus is a human pathogen and a leading cause of infectious disease-related illness and death worldwide. For S. aureus to successfully colonize and invade host tissues, it must tightly control the expression of genes encoding virulence factors. Oxygen tension varies greatly at infection sites, and many abscesses are devoid of oxygen. In this study, we have developed novel tools and methods to study how and when S. aureus alters transcription of genes. A key advantage of these methods and tools is that they can be utilized in the presence and absence of oxygen. A better understanding of anaerobic gene expression in S. aureus will provide important insights into the regulation of genes in low-oxygen environments.

Development of a targeted naloxone coprescribing program in a primary care practice.

OBJECTIVES: To develop a targeted naloxone coprescribing program in a primary care practice. SETTING: Large academic family medicine practice in western North Carolina. PRACTICE DESCRIPTION: A robust pain management program was developed at this institution in 2012 which incorporated many of the recommendations later outlined in the 2016 Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain. The only guideline-recommended initiative that was not addressed involves providing naloxone to patients on chronic opioid therapy at high risk for opioid overdose. PRACTICE INNOVATION: Pharmacists embedded in this practice developed a targeted naloxone coprescribing program for patients who are on chronic opioid therapy and have doses of 50 mg or more morphine equivalents daily (MED), are taking benzodiazepines, have a history of substance use disorder, or have a history of overdose. EVALUATION: A retrospective chart review was conducted to determine the number of patients on chronic opioid therapy who meet the CDC guidelines for offering naloxone. RESULTS: A total of 1297 patients were identified, and 709 met the criteria for chronic opioid use. Nearly one-half (n = 350; 49.4%) of these patients met the criteria for naloxone, although only 3.4% had naloxone on their medication list. Doses of 50 mg or more MED was the primary reason for needing naloxone (n = 216; 61%) with concomitant benzodiazepine use as the second most likely reason (n = 130; 37.1%). For patients taking 50 mg or more MED, 37.5% were also on a benzodiazepine and 4.1% also had a history of substance use disorder. CONCLUSION: Pharmacists embedded in a primary care practice are well poised to develop a targeted naloxone coprescribing program to increase patients' access to naloxone.

Extra-plaque rotational atherectomy for treating a balloon uncrossable ostial right coronary artery chronic total occlusion.

Performing atherectomy in the subintimal space remains controversial. We describe a case of successful ostial right coronary artery CTO recanalization using rotational atherectomy in subintimal space.

Case Study: Personalized Oral Low-dose Naltrexone Titration for Pain Management.

Naltrexone is a competitive opioid receptor antagonist indicated to treat opioid and alcohol dependence. In the U.S., naltrexone is commercially available as 50-mg tablets, and the adult dosage strength typically ranges between 50 mg once daily and 100 mg once daily. However, there is evidence to suggest that naltrexone prescribed in low doses, about 1/10th of the daily standard dosage, may be effective in managing a myriad of chronic conditions, including pain refractory to conventional pharmacological treatments. The U.S. Food and Drug Administration recently granted an orphan drug designation for low-dose naltrexone for the treatment of complex regional pain syndrome. This article provides a case study of a patient who was treated with a low dose of naltrexone for pain associated with the diagnosis of idiopathic hypereosinophilic syndrome.

Emergent Endovascular Repair of a Ruptured Ascending Aorta Pseudoaneurysm With Thoracic Aortic Stent Graft.

Pseudoaneurysm of the ascending aorta is a rare complication of cardiac surgery due to tissue degeneration at the site of graft anastomosis, aortotomy, or extracorporeal circulation cannulation. We describe the case of a patient who developed an ascending aorta pseudoaneurysm after coronary artery bypass graft surgery, which initially required percutaneous closure with an atrial septal defect occlusion device. However, three years later the patient presented again with active external bleeding secondary to pseudoaneurysm enlargement and rupture, which was emergently repaired by percutaneous endovascular repair with a thoracic aortic stent graft. At one-year follow-up the patient is in good conditions and asymptomatic.

Diabetes mellitus en ancianos, caracterización epidemiológica y comportamiento clínico terapéutico en San Antonio de los Baños / Diabetes mellitus in old men, epidemiology characterization and clinic therapeutic behaviour in San Antonio de los Baños

El envejecimiento poblacional es un problema mundial, aparejado a elevada prevalencia de Diabetes Mellitus (DM) según avanzan los años. Se realizó un estudio transversal durante un año, para analizar variables epidemiológicas, clínicas y terapéuticas, asociadas a la morbilidad en diabéticos con 65 años y más, de San Antonio de los Baños, Habana. Quedó definido como objetivos: precisar frecuencia por edades y sexo, modalidad terapéutica empleada y control de la glicemia, complicaciones más frecuentes de órganos diana, según tiempo de evolución de la Diabetes Mellitus. Se obtuvo una media global de 86.3 años con una distribución Gaussiana a la derecha, aumentando la frecuencia de DM en mujeres según envejecían, aunque los hombres fueron discreta mayoría (razón 1.4/1). El 37.5 por ciento usaba hipoglicemiantes orales, aunque aquellos que solo cumplían la dieta presentaron mejor control glicémico. La cardiopatía isquémica predominó (33 por ciento) en 94 por ciento de los complicados, aumentando la frecuencia acorde evolucionó en años su enfermedad de base. Envejecidos, hiperglicémicos, con complicaciones de órganos diana y con años de evolución de su enfermedad son los ancianos diabéticos un problema de salud aún sin resolver en San Antonio de los Baños, Habana, Cuba.

Population aging is a world problem, harnessed with high prevalence of diabetes mellitus (DM) according to years advance. It carried out one transversals study during one year determining epidemiology; clinic and therapeutic problems associated a diabetic mobility people with 65 years and more in San Antonio de los Baños, Havana. It was defined as objectives: bigger frequency for ages and sexes, use therapeutics modality and glicemia controls, more frequently complications a reveille organs according the evolutions of diabetes mellitus time. It was obtained global mediates at 86.3 years with right Gaussians distributions, increasing the frequency of DM in women as they aged, although men was discreetly majority (reason1.4/1). 37.5 percent used diabetic's oral treatment, although those that only completed diet presented better blood sugar controls. Ischemic cardiopathy prevailed (33 percent) in a 94 percent of complicated, frequency increasing according Diabetes Mellitus evolved at years. Aged, not blood sugar controls, withy several complications a reveille organ and a long time of evolutions; diabetic's old people are health problem still will not solution at San Antonio de los Baños Town, Havana.

Hipotensión postratamiento en preeclámpticas graves, una forma sencilla y eficaz de prevenirlo / Post-treatment hypotension in severe pre-eclampsia, a simple and effective way to prevent it

La preeclampsia grave incluye para su manejo varios medicamentos, en gestantes muchas veces necesitadas de cesárea de urgencia, la hipotensión arterial es una complicación frecuente y potencialmente evitable con la administración de una hidratación previa. Se realizó un estudio de cohorte analizando la utilidad de la hidratación con electrolitos, antes de la intervención quirúrgica, como prevención de la hipotensión postratamiento en preeclámpticas graves cesareadas atendidas en Unidad de Cuidados Perinatales (UCP) del Hospital Iván Portuondo, San Antonio de los Baños durante dos años. Se seleccionaron aleatoriamente 2 grupos con 45 pacientes. El grupo A (empleó de 5-10 ml/Kg. de solución salina fisiológica) y B (sin hidratación). Se determinaron fallas orgánicas, complicaciones inmediatas según tiempo de recuperación posoperatorio, estadía en UCP para cada grupo, además de complicaciones perinatales más frecuentes. El riñón fue el órgano más afectado (64,4 % del total) sin diferencias significativas en los complementarios entre grupos. Las pacientes del grupo B tuvieron más complicaciones posoperatorias (55 % bajo gasto), necesitaron un tiempo más prolongado para recuperarse. Un 82 % del grupo A fue dado de alta en UCP antes de las 24 h, mientras que en las pacientes del grupo B la estadía fue más prolongada. Los recién nacidos con bajo peso en el grupo A fue del 35 %, predominó en B el Síndrome de dificultad respiratoria y no se reportaron muertes. Un manejo adecuado de los líquidos y electrolitos en la gestante con preeclampsia grave que necesita ser sometida a operación cesárea, mejora las condiciones para su recuperación posoperatoria, disminuye la estadía hospitalaria y contribuye a tener un recién nacido en mejores condiciones

The worse pre-eclampsia includes for its handling several medications, in pregnant women many needy times of Cesarean operation of urgency, being the arterial hypotension a frequent and potentially avoidable complication with the administration of a previous hydrate. It was carried out a cohort study analyzing the utility of the hydrate with electrolytes, before the surgical intervention, as prevention of the hypotension post-treatments in worse pre-eclampsia women's s Cesarean assisted in Unit of Perinatal Cares (UCP) of the Hospital Ivan Portuondo, San Antonio de los Ba±os City during two years. It selected aleatorally to 2 groups with 45 patients, Group A (it used of 5-10 ml/Kg of physiologic saline solution) and B (without hydrate). Determining: fail organic, immediate complications according to postoperative time of recovery, demurrage in UCP for each group, besides more frequent perinatal complications. Kidney was the affected organ (64.3 percent of the total) without significant differences of the complementary ones among groups. The patients of the group B had more postoperative complications (55 percent lowers expense) needing a more lingering time to recover. 82 percent of the group A it was given of high in UCP before the 24 hours, while in the patients of the group B the demurrage was more lingering. The newly born ones with under weight in the Group A it was of 35 percent, prevailed in B the Syndrome of Breathing Difficulty and deaths were not reported. Conclusions: In pregnancy women with serious preeclampsia and Caesareans operation indications, the use preservative of solutions electrolytic improvement the clinical evolution, the maternal-fetal presage and it reduces the hospital demurrage