David Callacondo

Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders.

The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.

Giant insulinoma: a report of 3 cases and review of the literature.

Abstract Insulinoma is a rare pancreatic neuroendocrine tumor that is usually described as benign, sporadic, and very small (<2 cm). However, there have been rare case reports of insulinoma presenting as a giant tumor. We describe 3 cases of giant insulinomas, all of which developed liver metastases. The patients were aged 38, 63, and 67 years. Clinically, all patients presented with Whipple’s triad associated with a large mass located in the pancreatic tail. The tumors ranged in size from 10 to 15 cm. On microscopic examination, the tumors were well differentiated with amyloid deposition ranging between 20% and 30%. Immunohistochemically, all 3 tumors showed strong diffuse expression of chromogranin and synaptophysin, whereas they were only focally positive for insulin. One patient developed liver recurrence 3 years after resection of the primary tumor yet remained asymptomatic without treatment. Another patient with liver recurrence underwent right hepatectomy and has been free of disease for 2 years. The third patient died of metastatic disease 13 years after initial surgery. Giant insulinomas are characterized by focal expression of insulin and high rates of liver metastases. Long-term follow-up is mandatory in these patients, as recurrence is expected after primary surgery.

Medication Possession Ratio Predicts Antiretroviral Regimens Persistence in Peru

Objectives In developing nations, the use of operational parameters (OPs) in the prediction of clinical care represents a missed opportunity to enhance the care process. We modeled the impact of multiple measurements of antiretroviral treatment (ART) adherence on antiretroviral treatment outcomes in Peru. Design And Methods Retrospective cohort study including ART naïve, non-pregnant, adults initiating therapy at Hospital Nacional Cayetano Heredia, Lima-Peru (2006-2010). Three OPs were defined: 1) Medication possession ratio (MPR): days with antiretrovirals dispensed/days on first-line therapy; 2) Laboratory monitory constancy (LMC): proportion of 6 months intervals with ≥1 viral load or CD4 reported; 3) Clinic visit constancy (CVC): proportion of 6 months intervals with ≥1 clinic visit. Three multi-variable Cox proportional hazard (PH) models (one per OP) were fit for (1) time of first-line ART persistence and (2) time to second-line virologic failure. All models were adjusted for socio-demographic, clinical and laboratory variables. Results 856 patients were included in first-line persistence analyses, median age was 35.6 years [29.4-42.9] and most were male (624; 73%). In multivariable PH models, MPR (per 10% increase HR=0.66; 95%CI=0.61-0.71) and LMC (per 10% increase 0.83; 0.71-0.96) were associated with prolonged time on first-line therapies. Among 79 individuals included in time to second-line virologic failure analyses, MPR was the only OP independently associated with prolonged time to second-line virologic failure (per 10% increase 0.88; 0.77-0.99). Conclusions The capture and utilization of program level parameters such as MPR can provide valuable insight into patient-level treatment outcomes.

Reference values for oxygen saturation from sea level to the highest human habitation in the Andes in acclimatised persons

Oxygen saturation, measured by pulse oximetry (SpO2), is a vital clinical measure. Our descriptive, cross-sectional study describes SpO2 measurements from 6289 healthy subjects from age 1 to 80 years at 15 locations from sea level up to the highest permanent human habitation. Oxygen saturation measurements are illustrated as percentiles. As altitude increased, SpO2 decreased, especially at altitudes above 2500 m. The increase in altitude had a significant impact on SpO2 measurements for all age groups. Our data provide a reference range for expected SpO2 measurements in people from 1 to 80 years from sea level to the highest city in the world.

Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness

Patients with chronic mountain sickness (CMS) suffer from hypoxemia, erythrocytosis, and numerous neurologic deficits. Here we used induced pluripotent stem cell (iPSC)-derived neurons from both CMS and non-CMS subjects to study CMS neuropathology. Using transmission electron microscopy, we report that CMS neurons have a decreased mitochondrial volume density, length, and less cristae membrane surface area. Real-time PCR confirmed a decreased mitochondrial fusion gene optic atrophy 1 (OPA1) expression. Immunoblot analysis showed an accumulation of the short isoform of OPA1 (S-OPA1) in CMS neurons, which have reduced ATP levels under normoxia and increased lactate dehydrogenase (LDH) release and caspase 3 activation after hypoxia. Improving the balance between the long isoform of OPA1 and S-OPA1 in CMS neurons increased the ATP levels and attenuated LDH release under hypoxia. Our data provide initial evidence for altered mitochondrial morphology and function in CMS neurons, and reveal increased cell death under hypoxia due in part to altered mitochondrial dynamics. NEW & NOTEWORTHY Induced pluripotent stem cell-derived neurons from chronic mountain sickness (CMS) subjects have altered mitochondrial morphology and dynamics, and increased sensitivity to hypoxic stress. Modification of OPA1 can attenuate cell death after hypoxic treatment, providing evidence that altered mitochondrial dynamics play an important role in increased vulnerability under stress in CMS neurons.

Factores asociados a complicaciones de la colangiopancreatografía retrógrada endoscópica en un hospital de alta complejidad

Endoscopic treatment of the bile duct diseases is possible thanks to the ERCP (endoscopic retrograde cholangio pancreatography), nevertheless, it is not free of complications. Objectives. To describe the characteristics and indications of the ERCP and determine the factors associated to the development of complications after performing the procedure. Materials and methods. An observational retrospective study was done in the Gastroenterology Department of the Hospital Guillermo Almenara Irigoyen in Lima, Peru, from March 2002 to June 2005. Results. 294 registers on 280 patients were evaluated, the median age was 58 and 155 (52.7%) were women, five procedures we done in the intensive care unit (ICU). The most frequent indication was choledochus litiasis in 67.3% cases. 205 (69.7%) procedures were successful, only 33 presented complications. The most frequent complications were acute pancreatitis and hemorrhage, in 16 and 13 patients respectively. There were no cases of perforation or death. Pancreatic duct cannulation more than once was an associated factor (OR=2.01; 95%CI: 1.11-5.92; p=0.03). Conclusions. 11.2% of cases presented complications, being acute pancreatitis and mild hemorrhage the most frequent complications. Only pancreatic duct cannulation more than once is an associated factor for having complications.