Plasma insulin-like growth factor-II (IGF-II) and IGF-II/IGF-I ratio in a chilean case of Doege-Potter Syndrome / Factor de crecimiento similar a la insulina-II (IGF-II) y razón IGF-II/ IGF-I en un caso chileno de síndrome de Doege-Potter

INTRODUCTION: Doege-Potter syndrome is a rare clinical entity characterized by recurrent hypoglycemic events caused by non-pancreatic tumors secreting an incompletely processed high-molecular-weight form of Insulin-like Growth factor-II (IGF-II). AIM: To report IGF-II and IGF-I circulating levels in a Chilean case of Doege-Potter syndrome and control individuals, and to identify the high-molecular-weight form of IGF-II. METHODS: We measured IGF-II and IGF-I plasma levels using enzyme-linked immunoassays (ELISA) in the patient and ten controls. We identified the high-molecular-weight form of IGF-II performed by Western blot. RESULTS: The plasma concentration of IGF-II in the patient was 868.9 ng/mL, which is only slightly > 80th percentile of controls (681,4 ± 212,8 ng/mL; mean ± standard deviation). In contrast, IGF-I plasma concentration in the patient was 17.6 ng/mL, which is notoriously lower than the corresponding levels in controls (109.1 ± 19.1 ng/mL). The IGF-II/IGF-I ratio in the patient was 49.4 (normal value < 10), which is 7.8 times higher compared to the average ratio of controls (6.3 ± 1.5). The high-molecular form of IGF-II presence in samples was confirmed through Western blot. CONCLUSIONS: The plasma IGF-II/IGF-I ratio better indicates the Doege-Potter syndrome's metabolic impairment than isolated measurements of circulating IGF-II or IGF-I levels.

INTRODUCCIÓN: El síndrome de Doege-Potter es una rara entidad clínica caracterizada por eventos hipoglicémicos recurrentes causados por tumores no-pancreáticos que secretan una forma incompletamente procesada con alto peso molecular del factor de crecimiento similar a la insulina-II (IGF-II). OBJETIVO: Reportar los niveles circulantes de IGF-II e IGF-I en un caso chileno de síndrome de Doege-Potter y en controles, así como identificar la forma de alto peso molecular de IGF-II. MÉTODOS: Los niveles plasmáticos de IGF-II e IGF-I se determinaron mediante inmunoensayos de tipo ELISA en el caso índice y en 10 controles. La forma de alto peso molecular de IGF-II se identificó mediante western-blot. RESULTADOS: La concentración plasmática de IGF-II en el paciente fue de 868,9 ng/mL, que es sólo ligeramente superior al percentil 80 del grupo control (681,4 ± 212,8 ng/mL; media ± desviación estándar). Sin embargo, la concentración plasmática de IGF-I en el paciente fue de 17,6 ng/ mL, que es notoriamente inferior a la de los controles (109,1 ± 19,1 ng/mL). La razón IGF-II/IGF-I en el paciente fue de 49,4 (valor normal < 10), que es 7,8 veces superior a la media de los controles (6,3 ± 1,5). La presencia de la forma de alto peso molecular de IGF-II se confirmó mediante western-blot. CONCLUSIONES: La razón IGF-II/IGF-I en plasma es un mejor indicador de las alteraciones metabólicas del síndrome de Doege-Potter que las mediciones aisladas de IGF-II o IGF-I circulantes.

Plasma insulin-like growth factor-II (IGF-II) and IGF-II/IGF-I ratio in a chilean case of Doege-Potter Syndrome.

INTRODUCTION: Doege-Potter syndrome is a rare clinical entity characterized by recurrent hypoglycemic events caused by non-pancreatic tumors secreting an incompletely processed high-molecular-weight form of Insulin-like Growth factor-II (IGF-II). AIM: To report IGF-II and IGF-I circulating levels in a Chilean case of Doege-Potter syndrome and control individuals, and to identify the high-molecular-weight form of IGF-II. METHODS: We measured IGF-II and IGF-I plasma levels using enzyme-linked immunoassays (ELISA) in the patient and ten controls. We identified the high-molecular-weight form of IGF-II performed by Western blot. RESULTS: The plasma concentration of IGF-II in the patient was 868.9 ng/mL, which is only slightly > 80th percentile of controls (681,4 ± 212,8 ng/mL; mean ± standard deviation). In contrast, IGF-I plasma concentration in the patient was 17.6 ng/mL, which is notoriously lower than the corresponding levels in controls (109.1 ± 19.1 ng/mL). The IGF-II/IGF-I ratio in the patient was 49.4 (normal value < 10), which is 7.8 times higher compared to the average ratio of controls (6.3 ± 1.5). The high-molecular form of IGF-II presence in samples was confirmed through Western blot. CONCLUSIONS: The plasma IGF-II/IGF-I ratio better indicates the Doege-Potter syndrome's metabolic impairment than isolated measurements of circulating IGF-II or IGF-I levels.

Vólvulo gástrico en una paciente nonagenaria: intervención endoscópica y laparoscópica. Reporte de caso / Gastric volvulus in a nonagenarian patient: endoscopic and laparoscopic intervention. Case report

Resumen El vólvulo gástrico es una entidad rara que puede presentarse de manera aguda o crónica y se acompaña de síntomas inespecíficos. Es fundamental su rápida identificación, ya que tiene alta mortalidad y el tratamiento oportuno de esta patología determina el pronóstico del paciente. A continuación, presentamos el caso de una paciente femenina de 89 años, que consulta por cuadro clínico de dolor torácico atípico, con documentación en radiografía de tórax de vólvulo gástrico organoaxial, en quien se realiza inicialmente devolvulación endoscópica con éxito. Sin embargo, en las imágenes de control se evidencia recurrencia del vólvulo, por lo cual se realizó manejo quirúrgico con hiatoplastia y funduplicatura tipo Toupet, además de gastrostomía percutánea de fijación, procedimiento realizado sin complicaciones, con los que se logró la devolvulación completa sin recurrencia.

Abstract Gastric volvulus is a rare condition that can occur acutely or chronically and is accompanied by nonspecific symptoms. Its rapid identification is critical since it has high mortality rate and timely treatment determines the patient's prognosis. The following is the case of an 89-year-old female patient who presented with atypical chest pain, with organoaxial gastric volvulus on chest X-ray, in whom endoscopic devolvulation was initially performed successfully. However, control imaging scans revealed recurrence. Therefore, surgical management included hiatoplasty and Toupet fundoplication, as well as percutaneous fixation gastrostomy, a procedure that was completed without complications and resulted in complete devolvulation without recurrence.

Rumiación cognitiva y afecto negativo como predictores diferenciales de los síntomas psicopatológicos internalizantes / Cognitive rumination and negative affect as differential predictors of internalizing psychopathological symptoms

Resumen Los modelos transdiagnósticos para los problemas de ansiedad, depresión y somatización han tenido evidencia para variables como la rumiación cognitiva y el afecto negativo; sin embargo, las asociaciones diferenciales entre estas dos variables en la explicación psicopatológica requiere aún ser investigada. El objetivo fue analizar la relación entre la rumiación cognitiva según las dimensiones de la rumiación: reproche y reflexión, con el afecto negativo y los síntomas psicopatológicos internalizantes depresivos, ansiosos y psicosomáticos en adultos colombianos. Se llevó a cabo una investigación cuantitativa con un diseño transversal explicativo, en el que se definió una red estructural de relaciones entre constructos mediante un diagrama de senderos y ecuaciones estructurales. Se contó con una muestra final de 640 personas, con una edad media de 31.07 años (DE = 11.27). Los resultados indicaron correlaciones significativas parciales y de orden cero entre las variables transdiagnósticas y las sintomáticas internalizantes, mediante un modelo ajustado que permitió explicar en un 74 % estas problemáticas a partir de la rumiación cognitiva y la función mediadora parcial del afecto negativo. En los síntomas depresivos y ansiosos se obtuvo que están mediados parcialmente por el afecto negativo, mientras que la medida de somatización obtuvo un coeficiente de regresión significativo con el afecto negativo como predictor independiente. Estos resultados aportan a la comprensión de la interacción de la rumiación y el afecto en la aparición de los síntomas internalizantes de manera diferencial. Se recomendó contar con una muestra clínica que ayudaría a identificar con mayor precisión la varianza explicada del modelo obtenido, lo que favorecerá los actuales tratamientos transdiagnósticos disponibles.

Abstract The transdiagnostic models of anxiety, depression and somatization problems have had evidence for variables such as cognitive rumination and negative affect, however, the differential associations between these two variables in the psychopathological explanation, still need to be investigated. The aim was to analyze the relationship between cognitive rumination according to the two dimensions: brooding and reflection, with negative affect and depressive, anxious, and psychosomatic internalizing psychopathological symptoms. A quantitative research was carried out with an explanatory cross-sectional design in which a structural network of relationships between constructs was defined by a path diagram and structural equations. There was a final sample of 640 people with a mean age of 31.07 years (SD = 11.27). The results indicated significant partial and zero-order correlations between transdiagnostic and internalizing symptomatic variables, using an adjusted model that allowed explaining these problems in 74% from cognitive rumination, and the partial mediating function of negative affect. In depressive and anxious symptoms, they were partially mediated by the negative affect, while the somatization measure obtained a significant regression coefficient with the negative affect as an independent predictor. These results contribute to the understanding of the interaction of rumination and affect in the appearance of differential internalizing symptoms. It was recommended to have a clinical sample that would help to more accurately identify the explained variance of the obtained model, as well as favor the current and available transdiagnostic treatments.

Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia.

BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of LCAT mutations. METHODS: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239 T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In-silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. RESULTS: LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband's plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels. CONCLUSION: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT deficiency.

Experiencia con los stents metálicos autoexpandibles para el manejo de cáncer gástrico distal / Auto-expandable metal stent in the management of distal stomach cancer

Objetivos: Establecer la eficacia y seguridad de los stents metálicos antroduodenales para el tratamiento del síndrome pilórico en pacientes con cáncer gástrico distal. Materiales y métodos: Se obtuvo datos de 31 pacientes mayores de 18 años que tenían diagnóstico de cáncer gástrico distal entre el año 2009 y el año 2017, quienes presentaban síndrome pilórico asociado a estenosis antroduodenal documentada por endoscopia o radiografía de vías digestivas altas, siendo manejados con stent metálico autoexpandible antroduodenal en la unidad de gastroenterología del Hospital Universitario San Ignacio (HUSI) de Bogotá D.C, Colombia. Resultados: El principal síntoma documentado que motivó a consultar fue la presencia de vómito en el 45,1%, seguido por pérdida de peso 16,13% y hemorragia de vías digestivas altas 19,35%, realizándose el diagnóstico en el 74,19% de los casos con endoscopia de vías digestivas altas. El 96,7% de los pacientes presentaban metástasis al momento del diagnóstico de síndrome pilórico. El 100% de los pacientes tuvo éxito técnico en relación al implante del stent con posterior resolución de síntomas en el 96,77%, siendo la complicación más frecuente el desplazamiento en un 16,13%. Conclusiones: Los stents metálicos autoexpandibles para el manejo de la obstrucción al tracto de salida gástrico secundario a cáncer gástrico distal es un método seguro y eficaz como tratamiento paliativo, mejorando la morbilidad y mortalidad en comparación con el manejo quirúrgico.

Objectives: To establish the efficacy and safety of antroduodenal metal stents for the treatment of pyloric syndrome in patients with distal gastric cancer. Materials and methods: Data were obtained from 31 patients older than 18 years who had a diagnosis of distal gastric cancer between 2009 and 2017, who presented pyloric syndrome associated with antroduodenal stenosis documented by endoscopy or X-ray of upper digestive tract, being managed with an antroduodenal auto-expandable metal stent in the gastroenterology unit of the San Ignacio University Hospital (HUSI) in Bogotá DC, Colombia. Results: The main documented symptom that led to consultation was the presence of vomiting in 45.1%, followed by weight loss 16.13% and upper digestive tract bleeding 19.35%, the diagnosis being made in 74.19 % of cases with endoscopy of upper digestive tract. 96.7% of the patients presented metastases at the time of diagnosis of pyloric syndrome. 100% of patients had technical success in relation to stenting with subsequent resolution of symptoms in 96.77%, the most frequent complication being displacement in 16.13%. Conclusions: Auto-expandable metal stents for the management of gastric outlet tract obstruction secondary to distal gastric cancer is a safe and effective method as a palliative treatment, improving morbidity and mortality compared to surgical management.

[Auto-expandable metal stent in the management of distal stomach cancer]. / Experiencia con los stents metálicos autoexpandibles para el manejo de cáncer gástrico distal.

OBJECTIVES: To establish the efficacy and safety of antroduodenal metal stents for the treatment of pyloric syndrome in patients with distal gastric cancer. MATERIALS AND METHODS: Data were obtained from 31 patients older than 18 years who had a diagnosis of distal gastric cancer between 2009 and 2017, who presented pyloric syndrome associated with antroduodenal stenosis documented by endoscopy or X-ray of upper digestive tract, being managed with an antroduodenal auto-expandable metal stent in the gastroenterology unit of the San Ignacio University Hospital (HUSI) in Bogotá DC, Colombia. RESULTS: The main documented symptom that led to consultation was the presence of vomiting in 45.1%, followed by weight loss 16.13% and upper digestive tract bleeding 19.35%, the diagnosis being made in 74.19 % of cases with endoscopy of upper digestive tract. 96.7% of the patients presented metastases at the time of diagnosis of pyloric syndrome. 100% of patients had technical success in relation to stenting with subsequent resolution of symptoms in 96.77%, the most frequent complication being displacement in 16.13%. CONCLUSIONS: Auto-expandable metal stents for the management of gastric outlet tract obstruction secondary to distal gastric cancer is a safe and effective method as a palliative treatment, improving morbidity and mortality compared to surgical management.

[Shared decision making in patients with diabetes mellitus]. / Toma de decisiones compartidas en la atención de pacientes con diabetes mellitus: un desafío para Latinoamérica.

Patients with diabetes mellitus often have several medical problems and carry a burden imposed by their illness and treatment. Health care often ignores the values, preferences and context of patients, leading to treatments that do not fit into patients’ overwhelmed lives. Shared Decision Making (SDM) emerges as a way to answer the question: “What’s best for the patient?”. SDM promotes an empathic conversation between patients and clinicians that integrates the best evidence available with their values, preferences and context. We discuss three SDM approaches for patients with diabetes: one focused on sharing information, another on making choices, and a third one on helping patients and clinicians to talk about how to address the problems of living with diabetes and its comorbidities. Despite the benefits demonstrated in studies conducted in the U.S. and Europe, the implementation of SDM continues to be a challenge. In Latin America, healthcare and socio-economic conditions render the implementation of SDM more challenging. Research aimed to respond to this challenge is necessary. Meanwhile, clinicians can practice SDM by sharing evidence-based information, giving voice to patients’ values and preferences in making choices, and creating empathic conversations aimed at decisions aligned with patients’ context, dreams, goals, and life expectations.

Toma de decisiones compartidas en la atención de pacientes con diabetes mellitus: un desafío para Latinoamérica / Shared decision making in patients with diabetes mellitus

Patients with diabetes mellitus often have several medical problems and carry a burden imposed by their illness and treatment. Health care often ignores the values, preferences and context of patients, leading to treatments that do not fit into patients’ overwhelmed lives. Shared Decision Making (SDM) emerges as a way to answer the question: “What’s best for the patient?”. SDM promotes an empathic conversation between patients and clinicians that integrates the best evidence available with their values, preferences and context. We discuss three SDM approaches for patients with diabetes: one focused on sharing information, another on making choices, and a third one on helping patients and clinicians to talk about how to address the problems of living with diabetes and its comorbidities. Despite the benefits demonstrated in studies conducted in the U.S. and Europe, the implementation of SDM continues to be a challenge. In Latin America, healthcare and socio-economic conditions render the implementation of SDM more challenging. Research aimed to respond to this challenge is necessary. Meanwhile, clinicians can practice SDM by sharing evidence-based information, giving voice to patients’ values and preferences in making choices, and creating empathic conversations aimed at decisions aligned with patients’ context, dreams, goals, and life expectations.

Oxytocin for preventing postpartum haemorrhage (PPH) in non-facility birth settings.

BACKGROUND: Postpartum haemorrhage (PPH) is the single leading cause of maternal mortality worldwide. Most of the deaths associated with PPH occur in resource-poor settings where effective methods of prevention and treatment - such as oxytocin - are not accessible because many births still occur at home, or in community settings, far from a health facility. Likewise, most of the evidence supporting oxytocin effectiveness comes from hospital settings in high-income countries, mainly because of the need of well-organised care for its administration and monitoring. Easier methods for oxytocin administration have been developed for use in resource-poor settings, but as far as we know, its effectiveness has not been assessed in a systematic review. OBJECTIVES: To assess the effectiveness and safety of oxytocin provided in non-facility birth settings by any way in the third stage of labour to prevent PPH. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, the WHO International Clinical Trials Registry Platform (ICTRP), ClinicalTrials.gov (12 November 2015), and reference lists of retrieved reports. SELECTION CRITERIA: All published, unpublished or ongoing randomised or quasi-randomised controlled trials comparing the administration of oxytocin with no intervention, or usual/standard care for the management of the third stage of labour in non-facility birth settings were considered for inclusion.Quasi-randomised controlled trials and randomised controlled trials published in abstract form only were eligible for inclusion but none were identified. Cross-over trials were not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility, assessed risk of bias and extracted the data using an agreed data extraction form. Data were checked for accuracy. MAIN RESULTS: We included one cluster-randomised trial conducted in four rural districts in Ghana that randomised 28 community health officers (CHOs) (serving 2404 potentially eligible pregnant women) to the intervention group and 26 CHOs (serving 3515 potentially eligible pregnant women) to the control group. Overall, the trial had a high risk of bias. CHOs delivered the intervention in the experimental group (injection of 10 IU (international units) of oxytocin in the thigh one minute following birth using a prefilled, auto-disposable syringe). In the control group, CHOs did not provide this prophylactic injection to the women they observed. CHOs had no midwifery skills and did not in any way manage the birth. All other CHO activities (outcome measurement, data collection, and early treatment and referral when necessary) were identical across the control and oxytocin CHOs.Although only one of the nine cases of severe PPH (blood loss greater or equal to 1000 mL) occurred in the oxytocin group, the effect estimate for this outcome was very imprecise and it is uncertain whether the intervention prevents severe PPH (risk ratio (RR) 0.16, 95% confidence interval (CI) 0.02 to 1.30; 1570 women (very low-quality evidence)). Similarly, because of the lack of cases of severe maternal morbidity (e.g. uterine rupture) and maternal deaths, it was not possible to obtain effect estimates for those outcomes (both very low-quality evidence).Oxytocin compared with the control group decreased the incidence of PPH (> 500 mL) in both our unadjusted (RR 0.48, 95% CI 0.28 to 0.81; 1569 women) and adjusted (RR 0.49, 95% CI 0.27 to 0.90; 1174 women (both low-quality evidence)) analyses. There was little or no difference between the oxytocin and control groups on the rates of transfer or referral of the mother to a healthcare facility (RR 0.72, 95% CI 0.34 to 1.56; 1586 women (low-quality evidence)), stillbirths (RR 1.27, 95% CI 0.67 to 2.40; 2006 infants (low-quality evidence)); andearly infant deaths (0 to three days) (RR 1.03, 95% CI 0.35 to 3.07; 1969 infants (low-quality evidence)). There were no cases of needle-stick injury or any other maternal major or minor adverse event or unanticipated harmful event. There were no cases of oxytocin use during labour.There were no data reported for some of this review's secondary outcomes: manual removal of placenta, maternal anaemia, neonatal death within 28 days, neonatal transfer to health facility for advanced care, breastfeeding rates. Similarly, the women's or the provider's satisfaction with the intervention was not reported. AUTHORS' CONCLUSIONS: It is uncertain if oxytocin administered by CHO in non-facility settings compared with a control group reduces the incidence of severe PPH (>1000 mL), severe maternal morbidity or maternal deaths. However, the intervention probably decreases the incidence of PPH (> 500 mL).The quality of the one trial included in this review was limited because of the risk of attrition and recruitment biases related to limitations in the follow-up of pregnant women in both arms of the trials and some baseline imbalance on the size of babies at birth. Additionally, there was serious imprecision of the effect estimates for most of the primary outcomes mainly because of the size of the trial, very few or no events and CIs around both relative and absolute estimates of effect that include both appreciable benefit and appreciable harm.Although the trial presented data both for primary and secondary outcomes, it seemed to be underpowered to detect differences in the primary outcomes that are the ones more relevant for making judgments about the potential applicability of the intervention in other settings (especially severe PPH).Therefore, taking into account the extreme setting where the intervention was implemented, the limited role of the CHO in the trial and the lack of power for detecting effects on primary (relevant) outcomes, the applicability of the evidence found seems to be rather limited.Further well-executed and adequately-powered randomised controlled trials assessing the effects of using oxytocin in pre-filled injection devices or other new delivery systems (spray-dried ultrafine formulation of oxytocin) on severe PPH are urgently needed. Likewise, other important outcomes like possible adverse events and acceptability of the intervention by mothers and other community stakeholders should also be assessed.

[Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia]. / El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia.

BACKGROUND: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. AIM: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. MATERIAL AND METHODS: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. RESULTS: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. CONCLUSIONS: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

El ácido nicotínico aumenta el transporte celular de colesterol de las lipoproteínas de alta densidad en pacientes con hipoalfalipoproteinemia / Nicotinic acid increases cellular transport of high density lipoprotein cholesterol in patients with hypoalphalipoproteinemia

Background: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. Aim: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. Material and Methods: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. Results: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. Conclusions: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

Cetoacidosis diabética: Casuística 2008-2012, epidemiología y fisiopatología / Treatment of diabetic ketoacidosis using 2009 American Diabetes Association guidelines

Background: During 2009, new guidelines for the treatment of diabetic ketoacidosis were published by the American Diabetes Association. Aim: To assess the impact of new treatment guidelines on the evolution of patients treated for diabetic ketoacidosis (KAD). Patients and Methods: Anonymous data was obtained from computational medical records of patients treated for KAD at our institution two years before (“Traditional Protocol”) and TWO years after (“ADA-2009 Protocol”) the publication of the 2009 American Diabetes Association (ADA) KAD guidelines. Results: Twenty three patients aged 36.5 ± 15.1 years were treated with the traditional method and 23 patients aged 44.4 ± 21.1 years were treated following 2009 ADA guidelines. Among patients treated with the traditional protocol and treated following ADA 2009 guidelines, the diabetes type 1/type 2 ratio was18/5 and 19/16 respectively (p = NS), the glycosylated hemoglobin on admission was 12.6 ± 2.5 and 14.3 ± 2.7% respectively (p = 0.03), minimal blood pH was 7.15 ± 0.14 and 7.19 ± 0.09 respectively (p = NS), bicarbonate was required in seven and no patient respectively (p = 0.01), hypokalemia < 3.5 mEq/L occurred in 78.2 and 48.5% of patients (p = 0.03), the lapse until resolution was 28.7 ± 28.0 and 28.8 ± 20.6 hours (p = NS). Only one patient, treated following ADA 2009 guidelines, died. Conclusions: Introduction of the ADA-2009 protocol for the treatment of KAD resulted in decrease in the use of intravenous bicarbonate and a reduction in the incidence of hypokalemia. There was no impact neither in the lapse until resolution or lethality.

[Treatment of diabetic ketoacidosis using 2009 American Diabetes Association guidelines]. / Cetoacidosis diabética: Casuística 2008-2012, epidemiología y fisiopatología.

BACKGROUND: During 2009, new guidelines for the treatment of diabetic ketoacidosis were published by the American Diabetes Association. AIM: To assess the impact of new treatment guidelines on the evolution of patients treated for diabetic ketoacidosis (KAD). PATIENTS AND METHODS: Anonymous data was obtained from computational medical records of patients treated for KAD at our institution two years before ("Traditional Protocol") and TWO years after ("ADA-2009 Protocol") the publication of the 2009 American Diabetes Association (ADA) KAD guidelines. RESULTS: Twenty three patients aged 36.5 ± 15.1 years were treated with the traditional method and 23 patients aged 44.4 ± 21.1 years were treated following 2009 ADA guidelines. Among patients treated with the traditional protocol and treated following ADA 2009 guidelines, the diabetes type 1/type 2 ratio was 18/5 and 19/16 respectively (p = NS), the glycosylated hemoglobin on admission was 12.6 ± 2.5 and 14.3 ± 2.7% respectively (p = 0.03), minimal blood pH was 7.15 ± 0.14 and 7.19 ± 0.09 respectively (p = NS), bicarbonate was required in seven and no patient respectively (p = 0.01), hypokalemia < 3.5 mEq/L occurred in 78.2 and 48.5% of patients (p = 0.03), the lapse until resolution was 28.7 ± 28.0 and 28.8 ± 20.6 hours (p = NS). Only one patient, treated following ADA 2009 guidelines, died. CONCLUSIONS: Introduction of the ADA-2009 protocol for the treatment of KAD resulted in decrease in the use of intravenous bicarbonate and a reduction in the incidence of hypokalemia. There was no impact neither in the lapse until resolution or lethality.

APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

BACKGROUND: Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. METHODS: We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. RESULTS: A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. CONCLUSION: The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

Mitochondrial diabetes and deafness: possible dysfunction of strial marginal cells of the inner ear.

OBJECTIVE: Some patients with the syndrome of mitochondrial diabetes and deafness (MIDD) have a m.3243A>G mutation of the MTTL1 gene encoding transfer ribonucleic acid for the amino acid leucine (tRNALeu(UUR)). One of our MIDD patients inspired us to propose an integrated view on how a single mutation of the mitochondrial deoxyribonucleic acid (DNA) affects both the glucose metabolism and the inner ear physiology. DESIGN: (a) Study of mitochondrial DNA in a patient with MIDD. (b) REVIEW OF THE LITERATURE on the impact of the m.3243A>G mutation on glucose metabolism and on the physiology of the hearing process. SETTINGS: Outpatient diabetes and nutrition department and molecular nutrition laboratory. METHODS: (a) Polymerase chain reaction followed by restriction fragment analysis identified the m.3243A>G mutation. (b) REVIEW OF THE LITERATURE from 1994 to 2009. RESULTS: (a) Molecular study: the m.3243A>G mutation was detected with an appreciable level of heteroplasmy. (b) REVIEW OF THE LITERATURE: the strial marginal cells located near the organ of Corti fulfill two characteristics: they are rich in mitochondria, and their dysfunction may produce neurosensorial deafness by means of a reduction in the potassium ion concentration of the endolymph. CONCLUSIONS: The m.3243A>G mutation not only underlies a dysfunction of the insulin-producing beta cell of the pancreas but also results in a reduction in adenosine triphosphate production of the strial marginal cells of the inner ear, thus diminishing the energy (in the form of potassium ion gradient) needed for the outer hair cells of the organ of Corti to amplify the soundwaves, particularly at high frequencies.