An Unusual Case of Paroxysmal Third-Degree Atrioventricular Block: Thinking Outside the Box.

During the assessment of a third-degree atrioventricular (AV) block in a patient with syncope, different etiologies should be considered and evaluated. Extrinsic vagal paroxysmal AV block, extrinsic idiopathic AV block and intrinsic paroxysmal AV block are among the types of third-degree AV block in the differential diagnoses. Extrinsic vagal paroxysmal third-degree atrioventricular block (EV-AVB) is linked to parasympathetic influence on cardiac conduction and can be observed in bladder distention and urinary retention. Topical and ophthalmic beta-blockers have shown systemic effects such as bradycardia with and without syncope. We present the case of an 80-year-old male with symptomatic EV-AVB likely precipitated by bladder outlet obstruction and chronic use of an ophthalmic beta-blocker, often overlooked causes of third-degree AV block.

Design and Implementation of a Prototype Seismogeodetic System for Tectonic Monitoring.

This manuscript describes the design, development, and implementation of a prototype system based on seismogeodetic techniques, consisting of a low-cost MEMS seismometer/accelerometer, a biaxial inclinometer, a multi-frequency GNSS receiver, and a meteorological sensor, installed at the Doñana Biological Station (Huelva, Spain) that transmits multiparameter data in real and/or deferred time to the control center at the University of Cadiz. The main objective of this system is to know, detect, and monitor the tectonic activity in the Gulf of Cadiz region and adjacent areas in which important seismic events occur produced by the interaction of the Eurasian and African plates, in addition to the ability to integrate into a regional early warning system (EWS) to minimize the consequences of dangerous geological phenomena.

ST-Segment Elevation Myocardial Infarction and Bleeding Complications in JAK2-Negative Polycythemia.

Thrombotic and bleeding complications are major causes of morbidity and mortality in patients with polycythemia vera, who predominantly present with an alteration in the JAK2 gene. Because of their hypercoagulable state and risk of hemorrhage, patients with polycythemia vera who present with an acute myocardial infarction pose a challenge to physicians. This case report describes the presentation and treatment of a Hispanic patient with JAK2 V617F-negative primary polycythemia who developed cardiac arrest and ST-segment elevation myocardial infarction owing to complete occlusion of the left anterior descending artery as well as bleeding complications and postmyocardial pericarditis.

Schimke immuno-osseous dysplasia. A case report in Colombia.

Background: Schimke immune-osseous dysplasia (SIOD) is an ultra-rare multisystemic, monogenic, and autosomal recessive inherited disease caused by biallelic mutations in the SMARCAL1 gene. Approximately 100 cases have been reported worldwide. The disease is characterized by skeletal, renal, and immunological abnormalities. Case description: This is a 6-year-old female patient who debuted with nephrotic syndrome at five years of age, with a switch to corticosteroid resistance and poor response to immunosuppressive treatment received. The patient was admitted and referred to our institution due to convulsive status. During her hospitalization, thrombosis was found in the left renal vein, and a renal biopsy report of Collapsing Focal and Segmental Glomerulosclerosis (FSGS) was obtained. The patient had multiple infections during hospitalization, with T lymphocyte lymphopenia and severe IgG hypogammaglobulinemia. Additionally, given dysmorphic facies, delayed weight-height development, and spondyloepiphyseal dysplasia, exome sequencing was performed, finding an homozygous pathogenic variant c.1933C > T p.Arg645Cys in SMARCAL1, compatible with the diagnosis of SIOD. Discussion: We present the case of a patient that exhibited a severe phenotype of the disease, with skeletal, renal, severe combined immunological compromise and cerebrovascular involvement during follow-up, and the available proposed mechanisms of the disease focused on the clinical manifestations of this patient. It is the first case of SIOD reported in Colombia and the first comprehensive characterization reported in the literature of a patient with homozygosity of the known variant c.1933C > T p.Arg645Cys. Conclusion: A severe phenotype of the disease with cerebrovascular involvement by homozygosity of the known variant c.1933C > T p.Arg645Cys in the SMARCAL1 gene can be expected.

Comparison of the anesthetic effect of alkalized lidocaine versus non-alkalized lidocaine administered at a slow rate in mandibular primary molars.

Background: There are several invasive dental procedures that require local anesthetics. However, its infiltration is usually associated with anxiety and fear, increasing the perception of pain in pediatric patients. For this reason, it is important to evaluate different strategies for its application. We compared the anesthetic effect of the administration of 2% lidocaine with epinephrine 1:80000 non-alkalized at slow speed and alkalized at fast speed to block the inferior alveolar nerve in deciduous molars. Methods: A crossover clinical trial was carried out whose sample consisted of 38 patients between 6-10 years who required bilateral pulp treatment in their first mandibular primary molars. At the first appointment, they received 2% lidocaine with 1:80000 alkalinized epinephrine administered at a fast rate, and at the second appointment, 2% lidocaine with 1:80000 non-alkalized epinephrine administered at a low speed. We evaluated the onset of action, duration of the anesthetic effect, and intensity of pain during its infiltration. Results: We found that non-alkalized lidocaine at slow speed had a shorter onset time of action (57.21±22.21 seconds) and longer duration of effect (170.82±43.75 minutes) compared to administration of alkalinized lidocaine at fast speed (74.03±22.09 seconds, 148.24±36.24 minutes, respectively). There was no difference in the level of pain intensity. Conclusion: In this study, the slow administration of the non-alkalized local anesthetic showed a shorter onset time of action and a longer duration of the anesthetic effect in comparison with the alkalized local anesthetic administered at a rapid rate in the blockade of the inferior alveolar nerve in deciduous molars.

Proteinuria en la infancia: a propósito de un caso de enfermedad de Dent

Introducción: la proteinuria en la edad pediátrica es una entidad relativamente frecuente, la cual puede ser fisiológica o patológica. La segunda, por una alteración a nivel glomerular con pérdida de proteínas de gran tamaño o a nivel tubular, caracterizada por pérdida de proteínas de bajo peso molecular y alteraciones en la excreción de iones. Entre las enfermedades hereditarias que cursan con proteinuria tubular, se ha descrito la enfermedad de Dent, una patología ligada al cromosoma X. Esta enfermedad se manifiesta principalmente en varones, pero las mujeres pueden ser portadoras y tener manifestaciones clínicas leves de la enfermedad. La primera descripción de esta enfermedad fue hecha por Dent y Friedman en 1964. La mayoría de los casos recientemente reportados han sido en China y Alemania. Objetivo: realizar una revisión general de la enfermedad de Dent y del enfoque diagnóstico de la proteinuria en la infancia con base en nuestro caso, para así, sospechar de esta enfermedad. Descripción del caso: se presenta el caso de un paciente masculino sin antecedentes prenatales ni personales de importancia, quien presenta proteinuria persistente desde los primeros meses de vida y a quien, a los 7 años de edad, se le documenta la presencia de una variante ya conocida en el gen CLCN5, causante de la enfermedad de Dent tipo 1. Discusión: la proteinuria persistente patológica en la infancia debe ser estudiada debido a su posible relación con patologías que pueden afectar la función renal. Además de la diferenciación de la proteinuria persistente, de origen glomerular y tubular, la evaluación de alteraciones en la excreción de electrolitos, puede guiarnos hacia la realización de estudios genéticos y, por ende, al diagnóstico de patologías infrecuentes como la enfermedad de Dent. Conclusión: el enfoque diagnóstico de causas poco frecuentes de proteinuria tubular en la infancia, como la enfermedad de Dent, requiere de la valoración conjunta entre nefrología pediátrica y genética clínica.

Background: In pediatric patients, proteinuria is a relatively frequent entity that can be physiological or pathological. The second one, due to an alteration at the glomerular level with the loss of large proteins or at the tubular level, characterized mainly by the loss of low molecular weight proteins and changes in the excretion of ions. Among the hereditary diseases that present with tubular proteinuria, Dent disease is a disease linked to the X chromosome. Therefore, it manifests essentially in males, but women can be carriers and have minor clinical manifestations of the disease. Dent and Friedman made the first description of this disease in 1964. Recently, most of the cases have been reported in China and Germany. Objective: To perform a revision of Dent disease, as well as the diagnostic approach of childhood proteinuria based in our case in order to suspect this disease. Case description: This is the case of a masculine patient, without relevant prenatal and personal antecedents, the son of a father with polycystic renal disease, who presents persistent proteinuria from the first months of life, and who, at seven years old, the presence of a variant in the CLCN5 gene -causing of type 1 Dent disease- was documented. Discussion: The persistent pathological proteinuria in childhood must be studied due to its possible relation with pathologies that could affect renal function. Moreover, the differentiation among glomerular and tubular proteinuria can guide us to perform additional studies, including genetic tests to diagnose infrequent pathologies like Dent disease. Conclusion: The diagnostic approach to rare causes of tubular proteinuria in childhood, such as Dent's disease, requires joint assessment between pediatric nephrology and clinical genetics.

Sleep is required to consolidate odor memory and remodel olfactory synapses.

Animals with complex nervous systems demand sleep for memory consolidation and synaptic remodeling. Here, we show that, although the Caenorhabditis elegans nervous system has a limited number of neurons, sleep is necessary for both processes. In addition, it is unclear if, in any system, sleep collaborates with experience to alter synapses between specific neurons and whether this ultimately affects behavior. C. elegans neurons have defined connections and well-described contributions to behavior. We show that spaced odor-training and post-training sleep induce long-term memory. Memory consolidation, but not acquisition, requires a pair of interneurons, the AIYs, which play a role in odor-seeking behavior. In worms that consolidate memory, both sleep and odor conditioning are required to diminish inhibitory synaptic connections between the AWC chemosensory neurons and the AIYs. Thus, we demonstrate in a living organism that sleep is required for events immediately after training that drive memory consolidation and alter synaptic structures.

Fluorosis dental en adolescentes de instituciones educativas de Lima, Perú / Dental fluorosis in adolescents from Educational Institutions in Lima, Peru

Introducción: La fluorosis dental es una patología endémica causada por la ingestión excesiva de fluoruros que pueden producir una alteración durante el desarrollo del esmalte, y es considerado un importante problema de salud pública porque afecta la salud bucal y sistémica de la población. Objetivo: Este estudio tuvo como idea principal determinar la frecuencia y los niveles de fluorosis dental en escolares de 12 a 15 años pertenecientes a dos instituciones educativas de Lima - Perú. Método: Se realizó un estudio descriptivo de tipo transversal, la muestra estuvo conformada por 252 estudiantes, entre 12 y 15 años de dos centros educativos de Lima. El muestreo fue por selección sistemática de elementos muestrales. La fluorosis dental se evalúo mediante el Índice de Dean. Para determinar la frecuencia y los niveles de fluorosis dental, se realizó un examen clínico bucal y se desarrolló un cuestionario validado previamente. Resultados: La frecuencia de fluorosis dental fue de 44,8% (n=113) afectando más a los varones en un 27,39% (n=69) y a los adolescentes de 13 años (15,1%). En relación con los niveles de fluorosis, predominó el tipo "muy leve" (34,9%). También se encontró una asociación entre la presencia y el nivel de fluorosis con el número de aplicaciones de flúor (p<0,05). Además, se dijo que el índice comunitario de fluorosis de Dean fue de 0,43. Conclusiones: En la población escolar evaluada, la frecuencia de fluorosis fue de 44,8% y el nivel predominante de fluorosis fue muy leve. Además, el índice comunitario fue de 0,43, el cual mostró un nivel límite de importancia para la salud pública. Por lo que se puede considerar que el número de aplicaciones tópicas de flúor recibido por la población sin una planificación adecuada se podría convertir en un factor de riesgo para causar fluorosis dental.

Introduction: Dental fluorosis is an endemic pathology caused by the excessive ingestion of fluorides that can produce an alteration during the development of the enamel and is considered an important public health problema because it affects the oral and systemic health of the population. Objective: The objective of this study was to determine the frequency and levels of dental fluorosis in school children between 12 and 15 years of age belonging to two educational institutions in Lima, Peru. Method: A descriptive cross-sectional study was carried out, the sample consisted of 252 students between 12 and 15 years of age from two educational centers in Lima. Sampling was by systematic selection of sample elements. Dental fluorosis was evaluated using the Dean Index. To determine the frequency and levels of dental fluorosis a clinical oral examination was carried out and a previously validated questionnaire was developed. Results: The frequency of dental fluorosis was 44.8% (n=113) affecting more males by 27.39% (n=69) and adolescents aged 13 years (15.1%). In relation to the levels of fluorosis, the "very mild" type predominated (34.9%). An association was also found between the presence and level of fluorosis with the number of fluoride applications (p<0.05). In addition, Dean's community fluorosis index was reported to be 0.43. Conclusions: In the school population evaluated, the frequency of fluorosis was 44.8% and the predominant level of fluorosis was very mild. In addition, the community index was 0.43, which indicated a borderline level of public health importance. Therefore, it can be considered that the number of topical fluoride applications received by the population without adequate planning could become a risk factor for causing dental fluorosis.

Effectiveness and safety of available preventive tuberculosis treatment regimens for children and adolescents: protocol for a systematic review and network meta-analysis.

INTRODUCTION: Approximately 5%-10% of individuals with untreated latent tuberculosis infection (LTBI) will progress to active tuberculosis (TB). Children are at a higher risk for progression to TB disease than adults. Isoniazid prophylaxis treatment period is long and can cause liver damage. Alternatives to isoniazid, such as rifamycin containing regimens, should be considered for prophylaxis. Previous systematic reviews, with different study designs and data combining results on children and adults, have evaluated the comparative efficacy and harms of LTBI treatment regimens. We aim to determine the effectiveness and safety of all the different regimens available for the treatment of LTBI for children and adolescents less than 18 years of age, contacts of drug-susceptible TB, without HIV infection. METHODS AND ANALYSIS: MEDLINE, Embase and Cochrane Central Register of Controlled Trials will be systematically searched for randomised controlled trials without any language or publication date restriction. Screening and extraction will be performed in duplicate. Risk of bias will be performed in duplicate with Cochrane Risk of Bias tool V.2. Pairwise meta-analysis of direct comparisons and network meta-analyses (NMAs) will be performed. Heterogeneity will be assessed using I2 and Cochrane thresholds. Direct and indirect estimates in an NMA will be combined if justifiable. Subgroups analyses will be performed in different mean age and study year groups. Sensitivity analysis based on the risk of bias will be conducted. Publication bias will be investigated using funnel plots and Egger's regression test. Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria will assess certainty of the evidence for the direct comparisons. GRADE approach for NMA will assess the quality of the evidence from the indirect and NMA. ETHICS AND DISSEMINATION: Ethical approval is not required as no primary data are collected. This systematic review will be disseminated in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021271512.

Dose-response effects of alcohol on biochemical markers of bone turnover in non-human primates: Effects of species, sex and age of onset of drinking.

PURPOSE: Alcohol consumption suppressed bone turnover in male non-human primates; however, it is unclear the extent to which this effect depends upon biological variables. Using archived plasma samples, we investigated whether sex, age of onset of alcohol intake, and species influence the effects of graded increases in alcohol consumption on bone turnover markers. METHODS: 91 male and female macaques (rhesus and cynomolgus), ranging in age from 4 years (adolescent) to 10 years (adult) were required to increase their consumption of ethanol in 30-day increments: 0 g/kg/day, followed by 0.5 g/kg/day, 1.0 g/kg/day, and, finally, 1.5 g/kg/day. Plasma osteocalcin (formation), plasma CTX (resorption) and osteocalcin to CTX ratio (turnover balance) were measured during these intervals to assess the dose-response effects of alcohol. RESULTS: We detected no relationship between dose and osteocalcin when all monkeys were combined, but there was a significant effect of sex (lower levels in females) and interactions between alcohol dose and sex (osteocalcin levels increased with dose in rhesus females). In contrast, we detected a negative linear dose-response relationship for ethanol and CTX. We did not detect a relationship between dose and osteocalcin to CTX ratio overall, but there was a significant positive relationship detected in females (no change in males). Increased age predicted lower biomarker levels for both osteocalcin and CTX. Species was a significant predictor for osteocalcin and the osteocalcin to CTX ratio in these models. CONCLUSION: These findings indicate that age, sex, and species influence bone turnover and support the concept that factors beyond quantity of alcohol affect skeletal response to alcohol consumption.

Characterization of DREADD receptor expression and function in rhesus macaques trained to discriminate ethanol.

Circuit manipulation has been a staple technique in neuroscience to identify how the brain functions to control complex behaviors. Chemogenetics, including designer receptors exclusively activated by designer drugs (DREADDs), have proven to be a powerful tool for the reversible modulation of discrete brain circuitry without the need for implantable devices, thereby making them especially useful in awake and unrestrained animals. This study used a DREADD approach to query the role of the nucleus accumbens (NAc) in mediating the interoceptive effects of 1.0 g/kg ethanol (i.g.) in rhesus monkeys (n = 7) using a drug discrimination procedure. After training, stereotaxic surgery was performed to introduce an AAV carrying the human muscarinic 4 receptor DREADD (hM4Di) bilaterally into the NAc. The hypothesis was that decreasing the output of the NAc by activation of hM4Di with the DREADD actuator, clozapine-n-oxide (CNO), would potentiate the discriminative stimulus effect of ethanol (i.e., a leftward shift the ethanol dose discrimination curve). The results showed individual variability shifts of the ethanol dose-response determination under DREADD activation. Characterization of the expression and function of hM4Di with MRI, immunohistochemical, and electrophysiological techniques found the selectivity of NAc transduction was proportional to behavioral effect. Specifically, the proportion of hM4Di expression restricted to the NAc was associated with the potency of the discriminative stimulus effects of ethanol. Together, these experiments highlight the NAc in mediating the interoceptive effects of ethanol, provide a framework for validation of chemogenetic tools in primates, and underscore the importance of robust within-subjects examination of DREADD expression for interpretation of behavioral findings.

Synaptic effects of IL-1ß and CRF in the central amygdala after protracted alcohol abstinence in male rhesus macaques.

A major barrier to remission from an alcohol use disorder (AUD) is the continued risk of relapse during abstinence. Assessing the neuroadaptations after chronic alcohol and repeated abstinence is important to identify mechanisms that may contribute to relapse. In this study, we used a rhesus macaque model of long-term alcohol use and repeated abstinence, providing a platform to extend mechanistic findings from rodents to primates. The central amygdala (CeA) displays elevated GABA release following chronic alcohol in rodents and in abstinent male macaques, highlighting this neuroadaptation as a conserved mechanism that may underlie excessive alcohol consumption. Here, we determined circulating interleukin-1ß (IL-1ß) levels, CeA transcriptomic changes, and the effects of IL-1ß and corticotropin releasing factor (CRF) signaling on CeA GABA transmission in male controls and abstinent drinkers. While no significant differences in peripheral IL-1ß or the CeA transcriptome were observed, pathway analysis identified several canonical immune-related pathways. We addressed this potential dysregulation of CeA immune signaling in abstient drinkers with an electrophysiological approach. We found that IL-1ß decreased CeA GABA release in controls while abstinent drinkers were less sensitive to IL-1ß's effects, suggesting adaptations in the neuromodulatory role of IL-1ß. In contrast, CRF enhanced CeA GABA release similarly in controls and abstinent drinkers, consistent with rodent studies. Notably, CeA CRF expression was inversely correlated with intoxication, suggesting that CRF levels during abstinence may predict future intoxication. Together, our findings highlight conserved and divergent actions of chronic alcohol on neuroimmune and stress signaling on CeA GABA transmission across rodents and macaques.

Synergistic anti-inflammatory effect of NSAIDs plus B vitamins administered pre and postoperatively in third molar surgery: randomized clinical trial / Efeito anti-inflamatório sinérgico da associação de AINEs e vitaminas do complexo B administrada no pré e pós-operatório de cirurgia de terceiros molares: ensaio clínico randomizado

Objective : The aim of the present study was to evaluate the synergistic anti-inflammatory effect of Non-steroidal anti-inflammatory drugs (NSAIDs) plus B vitamins administered pre and postoperatively in surgeries of impacted mandibular third molars. Material and Methods : Double-blind randomized clinical trial, sixty-six patients participated and were randomized into 2 groups. The control group was administered meloxicam 15 mg intramuscularly plus placebo orally and to the experimental group, meloxicam 15 mg intramuscularly plus vitamins B [B1, B6, and B12] orally; both treatments were administered preoperatively. The anti-inflammatory effect was evaluated by pain intensity, facial swelling (facial contour measurements), and mouth opening (distance between the upper and lower incisors) during the post-surgical phase. Student's t-test was performed for independent samples. Results : In all the evaluated times (1 hour, 6 hours, 12 hours, 24 hours, 2 days, and 3 days after the end of the surgery) the experimental group presented a significantly lower intensity of pain compared to the control group (p<0.05). The highest pain intensity was recorded at 6 hours (17.7 ± 9.1 mm in the experimental group and 34.5 ± 21.3 mm in the control group). Swelling and mouth opening were similar in both groups, at all times evaluated (p>0.05). Conclusion : In the present study, the administration of NSAIDs plus B vitamins (B1, B6, B12) produced lower intensity of pain compared to the administration of only NSAIDs. Nevertheless, swelling and mouth opening were similar in all evaluations for both study groups (AU)

Objetivo : O objetivo do presente estudo foi avaliar o efeito anti-inflamatório sinérgico de anti-inflamatórios não esteroidais (AINEs) com vitaminas do complexo B administrados no pré e pós-operatório de cirurgias de terceiros molares inferiores impactados. Material e Métodos: Ensaio clínico randomizado duplo-cego, 66 participantesque foram randomizados em 2 grupos. O grupo controle recebeu Meloxicam 15 mg por via intramuscular + placebo por via oral e o grupo experimental, Meloxicam 15 mg por via intramuscular + vitaminas B [B1, B6 e B12] por via oral; ambos os tratamentos foram administrados no pré-operatório. O efeito anti-inflamatório foi avaliado pela intensidade da dor, edema facial (medidas do contorno facial) e abertura da boca (distância entre os incisivos superiores e inferiores) durante a fase pós-cirúrgica. Foi aplicado o teste t de Student para amostras independentes. Resultados: Em todos os tempos avaliados (1 hora, 6 horas, 12 horas, 24 horas, 2 dias e 3 dias após o término da cirurgia) o grupo experimental apresentou uma intensidade de dor significativamente menor em relação ao grupo controle (p <0,05). A maior intensidade de dor foi registrada em 6 horas (17,7 ± 9,1 mm no grupo experimental e 34,5 ± 21,3 mm no grupo controle). Edema e abertura bucal foram semelhantes nos dois grupos, em todos os momentos avaliados (p>0,05). Conclusão: No presente estudo, a administração de AINEs com vitaminas do complexo B (B1, B6, B12) resultou em menor intensidade de dor em comparação com a administração apenas de AINEs. No entanto, o edema e a abertura da boca foram semelhantes em todas as avaliações para ambos os grupos de estudo (AU).

Between-subject and within-subject variability in measures of biochemical markers of bone turnover in cynomolgus and rhesus macaques.

Development of optimal bone mass during early adulthood is determined by the balance between bone formation and resorption. The utility of minimally invasive biomarkers for monitoring bone turnover balance in maturing non-human primates has received limited attention. This study evaluated the biological variation of osteocalcin (a marker of bone formation), carboxyterminal cross-linking telopeptide of type 1 collagen (CTX, a marker of bone resorption), and the ratio of osteocalcin to CTX (reflecting bone turnover balance), in 136 rhesus and cynomolgus macaques aged 3.8-11.6 years. In a subsample of the animals (n = 28), blood samples were collected at monthly intervals over 4 months. Between-subject analysis revealed that there were no sex or species differences for CTX. Osteocalcin and the ratio of osteocalcin to CTX were higher in males than in females, and in rhesus macaques than in cynomolgus macaques. There were no changes in osteocalcin, CTX, or the ratio of osteocalcin to CTX across 4 months for any of the groups. In contrast, there was considerable within-subject variation in osteocalcin and CTX concentrations. However, differences in values exhibited no discernible pattern, suggesting that within-subject variation can be reduced by averaging repeat measurements. In summary, the data provide reference values for male and female rhesus and cynomolgus macaques and support the utility of osteocalcin and CTX as biomarkers to monitor bone turnover at the population level.

Transcriptional, Epigenetic, and Functional Reprogramming of Monocytes From Non-Human Primates Following Chronic Alcohol Drinking.

Chronic heavy drinking (CHD) of alcohol is a known risk factor for increased susceptibility to bacterial and viral infection as well as impaired wound healing. Evidence suggests that these defects are mediated by a dysregulated inflammatory response originating from myeloid cells, notably monocytes and macrophages, but the mechanisms remain poorly understood. Our ability to study CHD is impacted by the complexities of human drinking patterns and behavior as well as comorbidities and confounding risk factors for patients with alcohol use disorders. To overcome these challenges, we utilized a translational rhesus macaque model of voluntary ethanol self-administration that closely recapitulates human drinking patterns and chronicity. In this study, we examined the effects of CHD on blood monocytes in control and CHD female macaques after 12 months of daily ethanol consumption. While monocytes from CHD female macaques generated a hyper-inflammatory response to ex vivo LPS stimulation, their response to E. coli was dampened. In depth scRNA-Seq analysis of purified monocytes revealed significant shifts in classical monocyte subsets with accumulation of cells expressing markers of hypoxia (HIF1A) and inflammation (NFkB signaling pathway) in CHD macaques. The increased presence of monocyte subsets skewed towards inflammatory phenotypes was complemented by epigenetic analysis, which revealed higher accessibility of promoter regions that regulate genes involved in cytokine signaling pathways. Collectively, data presented in this manuscript demonstrate that CHD shifts classical monocyte subset composition and primes the monocytes towards a more hyper-inflammatory response to LPS, but compromised pathogen response.

Phosphatidylethanol in whole blood of rhesus monkeys correlates with ethanol consumption.

BACKGROUND: Phosphatidylethanol (PEth) homologs are ethanol metabolites used to identify and monitor alcohol drinking in humans. In this study, we measured levels of the 2 most abundant homologs, PEth 16:0/18:1 and PEth 16:0/18:2, in whole blood samples from rhesus macaque monkeys that drank ethanol daily ad libitum to assess the relationship between PEth levels and recent ethanol exposure in this animal model. METHODS: Blood samples were obtained from The Monkey Alcohol Tissue Research Resource. The monkeys were first induced to consume 4% (w/v) ethanol in water from a panel attached to their home cage. Then, monkeys were allowed to drink ethanol and water ad libitum 22 h daily for 12 months and the daily amount of ethanol each monkey consumed was measured. Whole, uncoagulated blood was collected from each animal at the end of the entire experimental procedure. PEth 16:0/18:1 and PEth 16:0/18:2 levels were analyzed by HPLC with tandem mass spectrometry, and the ethanol consumed during the preceding 14 days was measured. Combined PEth was the sum of the concentrations of both homologs. RESULTS: Our results show that (1) PEth accumulates in the blood of rhesus monkeys after ethanol consumption; (2) PEth homolog levels were correlated with the daily average ethanol intake during the 14-day period immediately preceding blood collection; (3) the application of established human PEth 16:0/18:1 cutoff concentrations indicative of light social or no ethanol consumption (<20 ng/ml), moderate ethanol consumption (≥ 20 and < 200 ng/ml) and heavy ethanol consumption (≥ 200 ng/ml) predicted significantly different ethanol intake in these animals. PEth homologs were not detected in ethanol-naïve controls. CONCLUSIONS: This study confirms that PEth is a sensitive biomarker for ethanol consumption in rhesus macaque monkeys. This nonhuman primate model may prove useful in evaluating sources of variability previously shown to exist between ethanol consumption and PEth homolog levels among humans.

Mitochondrial DNA deletion and duplication in Kearns-Sayre Syndrome (KSS) with initial presentation as Pearson Marrow-Pancreas Syndrome (PMPS): Two case reports in Barranquilla, Colombia.

BACKGROUND: Kearns-Sayre Syndrome (KSS) and Pearson Marrow-Pancreas Syndrome (PMPS) are among the classic phenotypes caused by mitochondrial DNA (mtDNA) deletions. KSS is a rare mitochondrial disease defined by a classic triad of progressive external ophthalmoplegia, atypical pigmentary retinopathy, and onset before 20 years. PMPS presents in the first year of life with bone marrow failure and exocrine pancreatic dysfunction, and can evolve into KSS later in life. Even though an mtDNA deletion is the most frequent mutation in KSS and PMPS, cases of duplications and molecular rearrangements have also been described. In Colombia, few case reports of KSS and PMPS have been published in indexed journals or have been registered in scientific events. METHODS: We discuss clinical and genetic aspects of two case reports of pediatric female patients, with initial clinical diagnosis of PMPS who later evolved into KSS, with confirmatory molecular studies of an mtDNA deletion and an mtDNA duplication. RESULTS: A large-scale mtDNA deletion, NC_012920.1:m.8286_14416del, was confirmed by Southern Blot in patient 1. An mtDNA duplication of 7.9 kb was confirmed by MLPA in patient 2. CONCLUSIONS: Our findings are compatible with the phenotypic and genetic presentation of PMPS and KSS. We present the first molecularly confirmed case reports of Colombian patients, diagnosed initially with PMPS, who later evolved to KSS.

Mifepristone Decreases Chronic Voluntary Ethanol Consumption in Rhesus Macaques.

The efficacy of short-term treatment with mifepristone (MIFE), a high-affinity, nonselective glucocorticoid receptor antagonist, to reduce ethanol drinking was tested in a rhesus macaque model. Stable individual daily ethanol intakes were established, ranging from 1.6 to 4.0 g/kg per day (n = 9 monkeys). After establishment of chronic ethanol intake, a MIFE dosing regimen that modeled a study of rodent drinking and human alcohol craving was evaluated. Three doses of MIFE (17, 30, and 56 mg/kg per day) were each administered for four consecutive days. Both 30 and 56 mg/kg decreased ethanol intake compared with baseline drinking levels without a change in water intake. The dose of 56 mg/kg per day of MIFE produced the largest reduction in ethanol self-administration, with the average intake at 57% of baseline intakes. Cortisol was elevated during MIFE dosing, and a mediation analysis revealed that the effect on ethanol drinking was fully mediated through cortisol. During a forced abstinence phase, access to 1.5 g/kg ethanol resulted in relapse in all drinkers and was not altered by treatment with 56 mg/kg MIFE. Overall, these results show that during active drinking MIFE is efficacious in reducing heavy alcohol intake in a monkey model, an effect that was related to MIFE-induced increase in cortisol. However, MIFE treatment did not eliminate ethanol drinking. Further, cessation of MIFE treatment resulted in a rapid return to baseline intakes, and MIFE was not effective in preventing a relapse during early abstinence. SIGNIFICANCE STATEMENT: Mifepristone reliably decreases average daily ethanol self-administration in a nonhuman primate model. This effect was mediated by cortisol, was most effective during open-access conditions, and did not prevent or reduce relapse drinking.

Characterization of patients with early vs. late-onset Alzheimers dementia / Caracterización de pacientes con demencia de tipo Alzheimer precoz vs tardío

Introduction: Alzheimer's dementia (AD) has an early and a late onset. More information is needed regarding risk factors according to the age of onset of AD. The objective is to characterize the sociodemographic, anthropometric, laboratory and genetic variables as well as the history of patients with ade novodiagnosis of AD, by age of onset, at the Hospital Universitario C.A.R.I.'s mental health site over a period of two years. Methods: a cross-sectional descriptive study of 39 patients with ade novodiagnosis of AD. A questionnaire was completed, paraclinical studies were ordered and a blood sample was obtained for APOE genotyping. The IBM SPSS 21 software was used for analysis. Results: 82.05% had late-onset and 17.95% had early-onset AD. Of those with early-onset AD, 57.14% were females, as were 71.90% of those with late-onset AD. 71.44% of those with early-onset AD were married and 53.12% with late-onset AD were widowed. Only 14.29% with early-onset and 18.75% with late-onset AD had optimal LDL levels. Altogether, 79.49% of the population was heterozygous for the ε4 allele. 71.43% of those with early-onset AD had a family history of dementia. Discussion: age is the main factor associated with AD and females were more frequent in both groups. Social relationships play a role in early detection of symptoms. Lipid profile abnormalities were seen in both groups. Having at least one ε4 allele is a frequent finding in AD. Having a first-degree relative with dementia and/or Alzheimer's was more frequent in early-onset AD.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1316).

Introducción: la demencia de tipo Alzheimer (DTA) tiene presentación precoz o tardía. Es necesaria mayor información sobre factores de riesgo según edad de aparición de DTA. El objetivo es caracterizar variables sociodemográficas, antropométricas, de laboratorio, genéticas y antecedentes en pacientes con diagnósticode novode DTA según edad de aparición en el Hospital Universitario C.A.R.I. sede salud mental en un periodo de dos años. Metodología: estudio descriptivo transversal con 39 pacientes con diagnósticode novode DTA. Se realizó un cuestionario, solicitaron paraclínicos y se obtuvo una muestra sanguínea para genotipificación deAPOE.Se utilizó el software IBM SPSS 21 para análisis. Resultados: el 82.05% tenían DTA tardío y 17.95% DTA precoz. El 57.14% con DTA precoz y 71.90% con DTA tardía eran de sexo femenino. El 71.44% con DTA precoz eran casados y 53.12% con DTA tardío eran viudos. Solo 14.29% con DTA precoz y 18.75% con DTA tardío tenían niveles óptimos de LDL. El 79.49% de la población era heterocigoto para el alelo ε4. El 71.43% con DTA precoz tenía antecedente familiar de demencia. Discusión: la edad es el principal factor asociado a DTA y el sexo femenino fue más frecuente en ambos grupos. Las relaciones sociales juegan un rol en la identificación temprana de la sintomatología. Las alteraciones del perfil lipídico se evidenciaron en ambos grupos. Tener al menos un alelo ε4 es un hallazgo frecuente de DTA. Tener un familiar con demencia y/o Alzheimer de primer grado de consanguinidad fue más frecuente en DTA precoz.(Acta Med Colomb 2020; 45. DOI:https://doi.org/10.36104/amc.2020.1316).