Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Cognitive Impairment Related to Chronic Kidney Disease Is Associated with a Decreased Abundance of Membrane-Bound Klotho in the Cerebral Cortex.

Cognitive impairment (CI) is a complication of chronic kidney disease (CKD) that is frequently observed among patients. The aim of this study was to evaluate the potential crosstalk between changes in cognitive function and the levels of Klotho in the brain cortex in an experimental model of CKD. To induce renal damage, Wistar rats received a diet containing 0.25% adenine for six weeks, while the control group was fed a standard diet. The animals underwent different tests for the assessment of cognitive function. At sacrifice, changes in the parameters of mineral metabolism and the expression of Klotho in the kidney and frontal cortex were evaluated. The animals with CKD exhibited impaired behavior in the cognitive tests in comparison with the rats with normal renal function. At sacrifice, CKD-associated mineral disorder was confirmed by the presence of the expected disturbances in the plasma phosphorus, PTH, and both intact and c-terminal FGF23, along with a reduced abundance of renal Klotho. Interestingly, a marked and significant decrease in Klotho was observed in the cerebral cortex of the animals with renal dysfunction. In sum, the loss in cerebral Klotho observed in experimental CKD may contribute to the cognitive dysfunction frequently observed among patients. Although further studies are required, Klotho might have a relevant role in the development of CKD-associated CI and represent a potential target in the management of this complication.

Anxiety but not menopausal status influences the risk of long-COVID-19 syndrome in women living in Latin America.

OBJECTIVE: To study sociodemographic and clinical factors associated with the long-COVID-19 syndrome among women living in Latin American countries using undirected and directed methods. METHOD: We studied 347 patients with COVID-19 (confirmed by polymerase chain reaction) living in nine Latin American countries between May 2021 and July 2022, including 70 premenopausal, 48 perimenopausal, and 229 postmenopausal women. We compared the sociodemographic and general health information of women with (n = 164) and without (n = 183) the long-COVID-19 syndrome. They also completed the Connor-Davidson Resilience Scale, the Fear of COVID-19 Scale, the Jenkins Sleep Scale, and the Menopause Rating Scale to define the minimum set of variables for adjustment. We designed a directed acyclic graph (DAG) to identify factors related to the long-COVID-19 syndrome. Data were submitted to categorical logistic regression analyses. Results are reported as means and standard deviations or ß-coefficients and 95 % confidence intervals. RESULTS: Women with long-COVID-19 syndrome had a poor lifestyle, severe menopause symptoms, hypertension, insomnia, depression, anxiety, chronic diseases/conditions, risk of hospitalization, sleep disturbance, and low menopause-related quality of life compared to women without the syndrome. The DAG identified the following long-COVID-19 covariates: age, obesity, anxiety, depression, cancer, lifestyle, smoking, and menstrual status. A multivariable logistic model with these covariates indicated that anxiety is the only factor to be significantly associated with long-COVID-19 syndrome, whereas other covariates were confounding factors. There was no significant influence of menopausal status on the long-COVID-19 syndrome. CONCLUSION: Among factors selected by the DAG, only anxiety was significantly associated with the long-COVID-19. There was no significant influence of the menopause status on the long-COVID-19 syndrome in the studied population.

Post-COVID-19 syndrome in a sample of climacteric women living in Latin America.

OBJECTIVE: The aim of this study was to assess resilience, fear of COVID-19, sleep disorders, and menopause-related symptoms after the acute phase of COVID-19 in middle-aged women with positive reverse transcription-polymerase chain reaction and noninfected women. METHODS: This is a cross-sectional, analytical study of climacteric women from 9 Latin American countries, aged 40-64 years, attending a routine health checkup. We evaluated clinical characteristics and used the Connor-Davidson Resilience Scale, the Fear of COVID-19 Scale, the Jenkins Sleep Scale, and the Menopause Rating Scale to evaluate their health. RESULTS: A total of 1,238 women were studied, including 304 who were positive for COVID-19 reverse transcription-polymerase chain reaction. The median (interquartile range) age was 53 (12) years; years of studies, 16 (6); body mass index, 25.6 (5.1) kg/m 2 ; and time since first COVID-19 symptom, 8 (6) months. COVID-19 patients reported fatigability (18.8%), joint and muscular discomfort (14.1%), and anosmia (9.5%). They had a significantly lower resilience score (26.87 ± 8.94 vs 29.94 ± 6.65), higher Fear of COVID-19 score (17.55 ± 7.44 vs 15.61 ± 6.34), and a higher Jenkins Scale score (6.10 ± 5.70 vs 5.09 ± 5.32) compared with control women. A logistic regression model confirmed these results. There was not a significant difference in the total Menopause Rating Scale score, although the odds ratios for both severe menopausal symptoms (1.34; 95% confidence interval, 1.02-1.76) and the use of hypnotics were higher in women with COVID-19 (1.80; 95% confidence interval, 1.29-2.50) compared with those without infection. We found no decrease in studied outcomes between the initial 7 months versus those reported after 8 to 18 months since first COVID-19 symptoms. CONCLUSIONS: COVID-19 climacteric women have sleep disorders, lower resilience and higher fear of COVID-19.

Hypomagnesemia and 25-hydroxyvitamin D deficiency in patients with long COVID.

Clinical manifestations related to hypomagnesemia and/or deficiency of vitamin D are frequent in patients with an extended course of coronavirus disease-2019 (long COVID). To evaluate hypomagnesemia and hydroxyvitamin D deficiency in patients with long COVID. A total of 125 adults with a diagnosis of long COVID were enrolled in a cross-sectional study. Participants were allocated into a risk (hypomagnesemia and hydroxyvitamin D deficiency) or control (serum magnesium and hydroxyvitamin D within normal ranges) group. Hypomagnesemia and 25-hydroxyvitamin D deficiency were defined based on serum level ≤1.8 mg/dL and <30 ng/mL, respectively. The number of clinical manifestations of long COVID were significantly higher in the risk compared to the control group. Fatigue, memory loss, attention disorders, joint pain, anxiety, sleep disorders, myalgia, and depression, all of which are related to hypomagnesemia and/or 25-hydroxyvitamin D deficiency, were among the 10 most frequent manifestations in the risk group. The adjusted odds ratio for the association between hypomagnesemia and hydroxyvitamin D deficiency during long COVID was 3.1; 95% CI 2.3-12.4, p=0.005. Our results show that patients suffering with long COVID had a deficiency in magnesium and 25-hydroxyvitamin D which correlated with the number of associated clinical manifestations.

BehÒ«et's disease: A diagnostic challenge

BehÒ«et's disease is a low prevalence disorder that is difficult to diagnose. Its forms of presentation are often confused with infectious processes that involve multiple treatments and prolonged hospital stays. This article presents the case of a 30-year-old man who consulted with non-specific symptoms that represented a diagnostic challenge for the medical team.

La enfermedad de BehÒ«et es una patología de baja prevalencia y difícil diagnóstico; sus formas clínicas de presentación suelen confundirse con procesos infecciosos que implican múltiples tratamientos y estancias hospitalarias prolongadas. Este artículo presenta el caso de un hombre de 30 arios quien consulta de manera repetitiva con síntomas inespecíficos, lo que representa un reto diagnóstico para el equipo médico.

Frontal alpha asymmetry: A potential biomarker of approach-withdrawal motivation towards pain.

Pain-related catastrophising is a maladaptive coping strategy known to have a strong influence on clinical pain outcomes and treatment efficacy. Notwithstanding, little is known about its neurophysiological correlates. There is evidence to suggest catastrophising is associated with resting-state EEG frontal alpha asymmetry (FAA) patterns reflective of greater relative right frontal activity, which is known to be linked to withdrawal motivation and avoidance of aversive stimuli. The present study aims to investigate whether such a relationship occurs in the situational context of experimental pain. A placebo intervention was also included to evaluate effects of a potential pain-relieving intervention on FAA. 35 participants, including both chronic pain patients and healthy subjects, completed the Pain Catastrophising Scale (PCS) questionnaire followed by EEG recordings during cold pressor test (CPT)-induced tonic pain with or without prior application of placebo cream. There was a negative correlation between FAA and PCS-subscale helplessness scores, but not rumination or magnification, during the pre-placebo CPT condition. Moreover, FAA scores were shown to increase significantly in response to pain, indicative of greater relative left frontal activity that relates to approach-oriented behaviours. Placebo treatment elicited a decrease in FAA in low helplessness scorers, but no significant effects in individuals scoring above the mean on PCS-helplessness. These findings suggest that, during painful events, FAA may reflect the motivational drive to obtain reward of pain relief, which may be diminished in individuals who are prone to feel helpless about their pain. This study provides valuable insights into biomarkers of pain-related catastrophising and prospects of identifying promising targets of brain-based therapies for chronic pain management.

Factors affecting climacteric women with SARS-CoV-2 infection: A multinational Latin America study (REDLINC XI).

OBJECTIVE: To evaluate the association between factors, especially those linked to the climacteric, and a history of COVID-19 infection. METHODS: This was an observational, cross-sectional, and analytical study in which women from ten Latin American countries, aged 40-64, who attended a routine health check-up were invited to participate. A positive history for COVID-19 was based on reverse transcription-polymerase chain reaction reports. We evaluated sociodemographic, clinical, lifestyle, anthropometric variables, and menopausal symptoms using the Menopause Rating Scale (MRS). RESULTS: A total of 1238 women were included for analysis, of whom 304 (24.6 %) had a positive history for COVID-19. The median [interquartile range: IQR] age of participants was 53 [IQR 12] years, duration of formal education was 16 [6] years, body mass index 25.6 [5.1] kg/m2, and total MRS score 10 [13]. In a logistic regression model, factors positively associated with COVID-19 included postmenopausal status and having a family history of dementia (OR: 1.53; 95 % CI: 1.13-2.07, and 2.40; 1.65-3.48, respectively), whereas negatively associated were use of menopausal hormone therapy (current or past), being a housewife, and being nulliparous (OR: 0.47; 95 % CI: 0.30-0.73; 0.72; 0.53-0.97 and 0.56; 0.34-0.92, respectively). Smoking, being sexually active, and use of hypnotics were also factors positively associated with COVID-19. CONCLUSION: Postmenopausal status and a family history of dementia were more frequent among women who had had COVID-19, and the infection was less frequent among current or past menopause hormone therapy users and in those with less physical contact.

Utilización del catéter venoso central de inserción periférica en la Unidad de Cuidados Intensivos Neonatales del Instituto Nacional de Salud Del Niño Breña, 2017-2019 / Use of peripherally inserted central venous catheter in the Neonatal Intensive Care Unit of Instituto Nacional de Salud Del Niño Breña, 2017-2019

RESUMEN Introducción. Actualmente la tasa de nacimientos a nivel mundial es de 18,8% y en el Perú es de 10%. Las principales causas de mortalidad neonatal son los partos pre termino, infecciones y defectos congénitos. La unidad de cuidados intensivos neonatales es el área que se encarga de la atención de los recién nacidos en estado crítico, siendo indispensable la obtención de una vía de acceso venoso central adecuada para su tratamiento. Objetivo. Describir la utilización del catéter percutáneo de inserción periférica en la Unidad de Cuidados Intensivos Neonatales del Instituto Nacional de Salud del Niño Breña, periodo junio 2017 - junio 2019. Métodos. Estudio descriptivo, observacional, retrospectivo, transversal. La muestra fue intencional conformada aproximadamente por 110 historias clínicas de recién nacidos que estuvieron hospitalizados en la unidad de cuidados intensivos neonatales. La técnica la observación y el instrumento la lista de chequeo. Resultados. El 51,8% fueron neonatos con patología quirúrgica. Asimismo, el 36,4% tuvieron una edad gestacional menor o igual de 32 semanas, la vena más usada fue la basílica con un 27,3%, el 37,3% de los catéteres fueron retirados por sospecha de sepsis y las puntas enviadas a cultivo. Conclusiones. El cuidado en el procedimiento y mantenimiento del catéter percutáneo fue el adecuado, presentándose un bajo número de complicaciones.

ABSTRACT Introduction. Currently the birth rate worldwide is 18.8% and in Peru it is 10%. The main causes of neonatal mortality are preterm births, infections and congenital defects. The neonatal intensive care unit is the area that is responsible for the care of newborns in critical condition, obtaining an adequate central venous access route for their treatment is essential. Objective. To describe the use of the percutaneous peripheral insertion catheter in the Neonatal Intensive Care Unit of the Instituto Nacional de Salud del Niño Breña, period June 2017 - June 2019. Methods. The study was descriptive, observational, retrospective, cross-sectional. The intentional sample was made up of approximately 110 medical records of newborns who were hospitalized in the neonatal intensive care unit. The technique the observation and the instrument the checklist. Results. 51.8% were neonates with surgical pathology. Likewise, 36.4% had a gestational age less than or equal to 32 weeks, the most used vein was the basilica with 27.3%, 37.3% of the catheters were removed due to suspected Sepsis and the tips were sent for culture. Conclusions. The care in the procedure and maintenance of the percutaneous catheter was adequate, presenting a low number of complications.

An Upgrade on the Surveillance System of SARS-CoV-2: Deployment of New Methods for Genetic Inspection.

SARS-CoV-2 variants surveillance is a worldwide task that has been approached with techniques such as Next Generation Sequencing (NGS); however, this technology is not widely available in developing countries because of the lack of equipment and limited funding in science. An option is to deploy a RT-qPCR screening test which aids in the analysis of a higher number of samples, in a shorter time and at a lower cost. In this study, variants present in samples positive for SARS-CoV-2 were identified with a RT-qPCR mutation screening kit and were later confirmed by NGS. A sample with an abnormal result was found with the screening test, suggesting the simultaneous presence of two viral populations with different mutations. The DRAGEN Lineage analysis identified the Delta variant, but there was no information about the other three mutations previously detected. When the sequenced data was deeply analyzed, there were reads with differential mutation patterns, that could be identified and classified in terms of relative abundance, whereas only the dominant population was reported by DRAGEN software. Since most of the software developed to analyze SARS-CoV-2 sequences was aimed at obtaining the consensus sequence quickly, the information about viral populations within a sample is scarce. Here, we present a faster and deeper SARS-CoV-2 surveillance method, from RT-qPCR screening to NGS analysis.

Plasmodium vivax and Neisseria meningitidis co-infection in a newborn.

Invasive infections due to Neisseria meningitidis in Colombia are unusual in newborns, in contrast to infections due to Plasmodium vivax which is one of the main pathogens related to the presentation of fever in this age group, especially in the indigenous population. We report a case of co-infection of these two microorganisms in a child.

Histoplasmosis cerebral / Cerebral histoplasmosis

RESUMEN La histoplasmosis cerebral primaria es poco frecuente, en la mayoría de los casos se presenta en forma secundaria a la diseminación desde un foco primario pulmonar. El histoplasma es un hongo dimórfico y endémico que ha sido identificado en Estados Unidos, Canadá, México, Centro y Sudamérica, y es menos común en África, Asia y Europa. La infección se produce por la inhalación inadvertida de las conidias contenidas en los cuerpos fructíferos; el pulmón es el sitio de infección primaria. De las infecciones documentadas por histoplasma en individuos inmunocompetentes, entre el 50 % y el 90 % son asintomáticas, y de las infecciones sintomáticas, el 80 % no requiere terapia y resuelve en forma espontánea; sin embargo, el histoplasma puede diseminarse por toda la economía, incluyendo el sistema nervioso central (SNC). La presentación clínica de histoplasmosis con compromiso del SNC es inespecífica y puede simular otras patologías más comunes. El diagnóstico es particularmente difícil en casos en los que solamente se presenta compromiso aislado del SNC. La histoplasmosis diseminada conlleva un alto riesgo de mortalidad; el tratamiento consta de una fase de inducción seguida de una fase de mantenimiento.

SUMMARY Primary cerebral histoplasmosis is rare and in the majority of cases presents in secondary to dissemination from a primary pulmonary focus. Histoplasma is a dimorphic and endemic fungus. It has been identified in the United States, Canada, central Mexico and South America and is less common in Africa, Asia, and Europe. The infection is caused by inadvertent inhalation of the conidia contained in the fruiting bodies, the lung is the site of primary infection. Of documented histoplasma infections in individuals immunocompetent, between 50 % and 90 % are asymptomatic, and of symptomatic infections, 80 % do not require therapy and resolve spontaneously, however, histoplasma can spread throughout the economy including the central nervous system (CNS). The presentation Histoplasmosis with CNS involvement is nonspecific and can mimic other most common pathologies. Diagnosis is particularly difficult in cases where it only presents isolated CNS involvement. Disseminated histoplasmosis carries a high risk of mortality; treatment consists of an induction phase followed by a maintenance.

Alpha entrainment drives pain relief using visual stimulation in a sample of chronic pain patients: a proof-of-concept controlled study.

One-third of the population in the UK and worldwide struggle with chronic pain. Entraining brain alpha activity through noninvasive visual stimulation has been shown to reduce experimental pain in healthy volunteers. Neural oscillations entrainment offers a potential noninvasive and nonpharmacological intervention for patients with chronic pain, which can be delivered in the home setting and has the potential to reduce use of medications. However, evidence supporting its use in patients with chronic pain is lacking. This study explores whether (a) alpha entrainment increase alpha power in patients and (b) whether this increase in alpha correlates with analgesia. In total, 28 patients with chronic pain sat in a comfortable position and underwent 4-min visual stimulation using customised goggles at 10 Hz (alpha) and 7 Hz (control) frequency blocks in a randomised cross-over design. 64-channel electroencephalography and 11-point numeric rating scale pain intensity and pain unpleasantness scores were recorded before and after stimulation. Electroencephalography analysis revealed frontal alpha power was significantly higher when stimulating at 10 Hz when compared to 7 Hz. There was a significant positive correlation between increased frontal alpha and reduction in pain intensity (r = 0.33; P < 0.05) and pain unpleasantness (r = 0.40; P < 0.05) in the 10 Hz block. This study provides the first proof of concept that changes in alpha power resulting from entrainment correlate with an analgesic response in patients with chronic pain. Further studies are warranted to investigate dose-response parameters and equivalence to analgesia provided by medications.

Doxycycline-induced idiopathic intracranial hypertension in a patient with Lyme disease.

ABSTRACT: Doxycycline is widely used to treat early and disseminated Lyme disease. Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a rare but serious adverse reaction to this medication. This article reviews the pathophysiology, presentation, diagnosis, and treatment of a patient with disseminated Lyme disease complicated by doxycycline-induced IIH.

Validity of the patient health questionnaire-2 (PHQ-2) for the detection of depression in primary care in Colombia.

BACKGROUND: The PHQ-2 is a screening test for major depressive disorder (MDD) derived from PHQ-9, which has shown to be useful in the detection of cases of clinical significance in previous studies. The psychometric properties of PHQ-2 in the Colombian population are unknown. METHODS: PHQ-2 were assessed in 243 patients in general medical consultations using the Mini-International Neuropsychiatric Interview (MINI) as the gold standard. Internal consistency, convergent validity and criterion validity were calculated by analyzing the Receptor Operating Characteristics (ROC) and the area under the curve (AUC). RESULTS: Cronbach's alpha and McDonald's omega coefficients were 0.71. Spearman's rho coefficients for correlations with PHQ-9 and HADS-D scores were 0.63 and 0.59 (p<0.01). AUC was 0.89. The optimal cut point was ≥2 with the following indicators: sensitivity 0.87 specificity 0.74; Youden index 0.60; PPV 0.47; NPV 0.95; (LR+) 3.24; (LR-) 0.18 (95% CI 0.09-0.37). Kappa coefficient between PHQ-2 and MINI for depression was .458 and 0.46 for HADS-D. LIMITATIONS: Since this study was done with people attending hospital, which could has implications for the prevalence of depression, affecting the validity indicators of the instrument. CONCLUSIONS: PHQ-2 show an acceptable test performance in the context of the study. However, the test could yield a considerable amount of false positives that would require specialized evaluation to establish a reliable diagnosis.

Linfoma de Burkitt en paciente adulto inmunocompetente que se presenta como rotura esplénica espontánea / Burkitt's lymphoma in an immunocompetent adult patient presenting as spontaneous splenic rupture

RESUMEN El linfoma de Burkitt es un linfoma no Hodgkin de células B que ha sido denominado por la mayoría de los investigadores como el tumor humano de crecimiento más rápido, pues es capaz de lograr una tasa de duplicación celular entre 24 y 26 horas. Se presentó un paciente masculino de 48 años de edad, con diagnóstico de linfoma de Burkitt, inmunocompetente, con esplenomegalia gigante y rotura esplénica espontánea como complicación. El paciente tuvo una evolución desfavorable en un breve período de tiempo. El linfoma de Burkitt es una enfermedad altamente agresiva, donde la falta de sospecha clínica y diagnóstico no oportuno ensombrecen el pronóstico.

ABSTRACT Burkitt's lymphoma is a B-cell non-Hodgkin lymphoma that has been called by most researchers the fastest growing human tumor, as it is capable of achieving a cell doubling rate between 24 and 26 hours. We present a 48-year-old male patient with a diagnosis of Burkitt's lymphoma, immunocompetent, with giant splenomegaly and spontaneous splenic rupture as a complication. The patient had an unfavorable evolution in a short period of time. Burkitt's lymphoma is a highly aggressive disease, where lack of clinical suspicion and untimely diagnosis overshadow the prognosis.

Impact of the Film Array Meningitis/Encephalitis panel in adults with meningitis and encephalitis in Colombia.

The Biofire® Film Array Meningitis Encephalitis (FAME) panel can rapidly diagnose common aetiologies but its impact in Colombia is unknown. A retrospective study of adults with CNS infections in one tertiary hospital in Colombia. The cohort was divided into two time periods: before and after the implementation of the Biofire® FAME panel in May 2016. A total of 98 patients were enrolled, 52 and 46 were enrolled in the Standard of Care (SOC) group and in the FAME group, respectively. The most common comorbidity was human immunodeficiency virus infection (47.4%). The median time to a change in therapy was significantly shorter in the FAME group than in the SOC group (3 vs. 137.3 h, P < 0.001). This difference was driven by the timing to appropriate therapy (2.1 vs. 195 h, P < 0.001) by identifying viral aetiologies. Overall outcomes and length of stay were no different between both groups (P > 0.2). The FAME panel detected six aetiologies that had negative cultures but missed identifying one patient with Cryptococcus neoformans. The introduction of the Biofire FAME panel in Colombia has facilitated the identification of viral pathogens and has significantly reduced the time to the adjustment of empirical antimicrobial therapy.

In vitro inhibition of brain phosphate-activated glutaminase by ammonia and manganese.

INTRODUCTION: As a consequence of the loss of liver function in chronic liver disease, increased levels of ammonia, manganese, and glutamine have been observed in the brain of hepatic encephalopathy patients. OBJECTIVE: In the present study, we explored phosphate activated glutaminase (PAG) activity in mitochondrial enriched fractions under treatment with ammonia and manganese. METHODS: We dissected out the brain cortex, striatum, and cerebellum of male Wistar rats 250-280 g weight; brain sections were pooled to obtain enriched mitochondrial fractions by differential centrifugation. Aliquots equivalent to 200 µg of protein were incubated with semi-log increasing concentrations of ammonia and/or manganese both as chloride salts (from 0 to 10 000 µM) and glutamine (4 mM) for 30 min. Then, the glutamate produced by the reaction was determined by HPLC coupled with fluorescence detection. RESULTS AND DISCUSSION: Both manganese and ammonia inhibited PAG in a concentration-dependent manner. Non-linear modeling was used to determine IC50 and IC20 for ammonia (120 µM) and manganese (2 mM). We found that PAG activity under the combination of IC20 of ammonia and manganese was equivalent to the sum of the effects of both substances, being PAG inhibition more pronounced in mitochondrial fractions from cerebellum. The PAG inhibition observed here could potentially explain a pathway for glutamine accumulation, by means of the inhibition of PAG activity as a consequence of increased concentrations of manganese and ammonia in the brain under liver damage conditions.