The impact of implementing a non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) embryo culture protocol on embryo viability and clinical outcomes.

STUDY QUESTION: Are modifications in the embryo culture protocol needed to perform non-invasive preimplantation genetic testing for aneuploidies (niPGT-A) affecting clinical reproductive outcomes, including blastocyst development and pregnancy outcomes? SUMMARY ANSWER: The implementation of an embryo culture protocol to accommodate niPGT-A has no impact on blastocyst viability or pregnancy outcomes. WHAT IS KNOWN ALREADY: The recent identification of embryo cell-free (cf) DNA in spent blastocyst media has created the possibility of simplifying PGT-A. Concerns, however, have arisen at two levels. First, the representativeness of that cfDNA to the real ploidy status of the embryo. Second, the logistical changes that need to be implemented by the IVF laboratory when performing niPGT-A and their effect on reproductive outcomes. Concordance rates of niPGT-A to invasive PGT-A have gradually improved; however, the impact of culture protocol changes is not as well understood. STUDY DESIGN, SIZE, DURATION: As part of a trial examining concordance rates of niPGT-A versus invasive PGT-A, the IVF clinics implemented a specific niPGT-A embryo culture protocol. Briefly, this involved initial culture of fertilized oocytes following each laboratory standard routine up to Day 4. On Day 4, embryos were washed and cultured individually in 10 µl of fresh media. On Day 6 or 7, blastocysts were then biopsied, vitrified, and media collected for the niPGT-A analysis. Six IVF clinics from the previously mentioned trial were enrolled in this analysis. In the concordance trial, Clinic A cultured all embryos (97 cycles and 355 embryos) up to Day 6 or 7, whereas in the remaining clinics (B-F) (379 cycles), nearly a quarter of all the blastocysts (231/985: 23.5%) were biopsied on Day 5, with the remaining blastocysts following the niPGT-A protocol (754/985: 76.5%). During the same period (April 2018-December 2020), the IVF clinics also performed standard invasive PGT-A, which involved culture of embryos up to Days 5, 6, or 7 when blastocysts were biopsied and vitrified. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 428 (476 cycles) patients were in the niPGT-A study group. Embryos from 1392 patients underwent the standard PGT-A culture protocol and formed the control group. Clinical information was obtained and analyzed from all the patients. Statistical comparisons were performed between the study and the control groups according to the day of biopsy. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age, number of oocytes, fertilization rates, and number of blastocysts biopsied were not significantly different for the study and the control group. Regarding the overall pregnancy outcomes, no significant effect was observed on clinical pregnancy rate, miscarriage rate, or ongoing pregnancy rate (≥12 weeks) in the study group compared to the control group when stratified by day of biopsy. LIMITATIONS, REASONS FOR CAUTION: The limitations are intrinsic to the retrospective nature of the study, and to the fact that the study was conducted in invasive PGT-A patients and not specifically using niPGT-A cases. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that modifying current IVF laboratory protocols to adopt niPGT-A has no impact on the number of blastocysts available for transfer and overall clinical outcomes of transferred embryos. Whether removal of the invasive biopsy step leads to further improvements in pregnancy rates awaits further studies. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Igenomix. C.R., L.N.-S., and D.V. are employees of Igenomix. D.S. was on the Scientific Advisory Board of Igenomix during the study. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03520933).

Culture time to optimize embryo cell-free DNA analysis for frozen-thawed blastocysts undergoing noninvasive preimplantation genetic testing for aneuploidy.

OBJECTIVE: To investigate the ideal time in culture to optimize embryo cell-free deoxyribonucleic acid (cfDNA) analysis in frozen-thawed blastocysts undergoing noninvasive preimplantation genetic testing for aneuploidy (PGT-A). Cell-free DNA is released into the spent blastocyst media (spent media) by the embryo. However, the optimal timing to determine maximal cfDNA in the case of frozen-thawed blastocysts undergoing noninvasive PGT-A remains to be elucidated. DESIGN: In this prospective observational study, 135 spent media and corresponding whole blastocysts were collected from January 2021 through March 2022. SETTING: Private fertility clinics. PATIENTS: Day-5 frozen-thawed blastocysts were cultured for 8 hours (Day-5 Short) or 24 hours (Day-5 Long), whereas day-6 frozen-thawed blastocysts were cultured for 8 hours (Day-6 Short). The spent media and whole blastocysts were then collected for further analysis. Spent media and whole blastocysts were amplified using whole genome amplification and sequenced using next-generation sequencing. MAIN OUTCOME MEASURES: Informativity and concordance rates between cfDNA in spent media and whole blastocyst DNA were compared according to the different times in culture. RESULTS: When comparing time in culture, informativity rates for spent media were significantly higher for Day-5 Long and Day-6 Short (>91%) compared with the Day-5 Short group (<60%). A similar trend was observed for cases with and without a previous PGT-A. Regarding blastocyst expansion grade, informativity rates were lower on Day-5 Short compared with Day-5 Long and Day-6 Short, regardless of expansion degree. This decrease was significant for Gardner-grade expansion grades 3, 4, and 5-6. In addition, for a similar time in culture, the grade of expansion did not have an impact on the informativity rates. For concordance rates, no significant differences were observed among the 3 groups. In all cases, concordance rates were 90.5% for Day-5 Short, 93.6% for Day-5 Long, and 92.3% for Day-6 Short. No impact of the expansion grade was observed on concordance rates. CONCLUSION: Noninvasive PGT-A in frozen-thawed blastocysts yields very high concordance rates with whole blastocysts, possibly limiting the need for invasive PGT-A and making it available for a wider range of patients.

Effect of aging on the human myometrium at single-cell resolution.

Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.

Lung and blood perioperative metalloproteinases in patients undergoing oncologic lung surgery: Prognostic implications.

BACKGROUND: Metalloproteinases (MMPs) have been reported to be related to oncologic outcomes. The main goal of the study was to study the relationship between these proteins and the long-term prognosis of patients undergoing oncologic lung resection surgery. METHODS: This was a substudy of the phase IV randomized control trial (NCT02168751). We analyzed MMP-2, -3, -7, and -9 in blood samples and bronchoalveolar lavage (LBA) and the relationship between MMPs and long postoperative outcomes (survival and disease-free time of oncologic recurrence). RESULTS: Survival was longer in patients who had lower MMP-2 levels than those with higher MMP-2 in blood samples taken 6 h after surgery (6.8 vs. 5.22 years; p = 0.012) and MMP-3 (6.82 vs. 5.35 years; p = 0.03). In contrast, survival was longer when MMP-3 levels were higher in LBA from oncologic lung patients than those with lower MMP-3 (7.96 vs. 6.02 years; p = 0.005). Recurrence-free time was longer in patients who had lower MMP-3 levels in blood samples versus higher (5.97 vs. 4.23 years; p = 0.034) as well as lower MMP-7 (5.96 vs. 4.5 years; p = 0.041) or lower MMP-9 in LBA samples (6.21 vs. 4.18 years; p = 0.012). CONCLUSION: MMPs were monitored during the perioperative period of oncologic lung resection surgery. These biomarkers were associated with mortality and recurrence-free time. The role of the different MMPs analyzed during the study do not have the same prognostic implications after this kind of surgery.

Vertical transmission of maternal DNA through extracellular vesicles associates with altered embryo bioenergetics during the periconception period.

The transmission of DNA through extracellular vesicles (EVs) represents a novel genetic material transfer mechanism that may impact genome evolution and tumorigenesis. We aimed to investigate the potential for vertical DNA transmission within maternal endometrial EVs to the pre-implantation embryo and describe any effect on embryo bioenergetics. We discovered that the human endometrium secretes all three general subtypes of EV - apoptotic bodies (ABs), microvesicles (MVs), and exosomes (EXOs) - into the human endometrial fluid (EF) within the uterine cavity. EVs become uniformly secreted into the EF during the menstrual cycle, with the proportion of different EV populations remaining constant; however, MVs contain significantly higher levels of mitochondrial (mt)DNA than ABs or EXOs. During the window of implantation, MVs contain an eleven-fold higher level of mtDNA when compared to cells-of-origin within the receptive endometrium, which possesses a lower mtDNA content and displays the upregulated expression of mitophagy-related genes. Furthermore, we demonstrate the internalization of EV-derived nuclear-encoded (n)DNA/mtDNA by trophoblast cells of murine embryos, which associates with a reduction in mitochondrial respiration and ATP production. These findings suggest that the maternal endometrium suffers a reduction in mtDNA content during the preconceptional period, that nDNA/mtDNA become packaged into secreted EVs that the embryo uptakes, and that the transfer of DNA to the embryo within EVs occurs alongside the modulation of bioenergetics during implantation.

Predictive value of plasma cytokines for acute kidney injury following lung resection surgery: prospective observational study / Valor preditivo das citocinas plasmáticas para lesão renal aguda após cirurgia de ressecção pulmonar: estudo observacional prospectivo

Abstract Background and objectives: Patients undergoing lung resection surgery are at risk of developing postoperative acute kidney injury. Determination of cytokine levels allows the detection of an early inflammatory response. We investigated any temporal relationship among perioperative inflammatory status and development of acute kidney injury after lung resection surgery. Furthermore, we evaluated the impact of acute kidney injury on outcome and analyzed the feasibility of cytokines to predict acute kidney injury. Methods: We prospectively analyzed 174 patients scheduled for elective lung resection surgery with intra-operative periods of one-lung ventilation periods. Fiberoptic broncho-alveolar lavage was performed in each lung before and after one-lung ventilation periods for cytokine analysis. As well, cytokine levels were measured from arterial blood samples at five time points. acute kidney injury was diagnosed within 48 h of surgery based on acute kidney injury criteria. We analyzed the association between acute kidney injury and cardiopulmonary complications, length of intensive care unit and hospital stays, intensive care unit re-admission, and short-term and long-term mortality. Results: The incidence of acute kidney injury in our study was 6.9% (12/174). Acute kidney injury patients showed higher plasma cytokine levels after surgery but differences in alveolar cytokines were not detected. Although no patient required renal replacement therapy, acute kidney injury patients had higher incidence of cardiopulmonary complications and increased overall mortality. Plasma interleukin-6 at 6 h was the most predictive cytokine of acute kidney injury (cut-off point at 4.89 pg.mL-1). Conclusions: Increased postoperative plasma cytokine levels are associated with acute kidney injury after lung resection surgery in our study, which worsens the prognosis. Plasma interleukin-6 may be used as an early indicator for patients at risk of developing acute kidney injury after lung resection surgery.

Resumo Justificativa e objetivos: Os pacientes submetidos à cirurgia de ressecção pulmonar apresentam risco de desenvolver lesão renal aguda pós-operatória. A determinação dos níveis de citocinas permite detectar uma resposta inflamatória precoce. Investigamos a relação temporal entre o estado inflamatório perioperatório e o desenvolvimento de lesão renal aguda após cirurgia de ressecção pulmonar. Além disso, avaliamos o impacto da lesão renal aguda no desfecho e analisamos a viabilidade das citocinas para prever este tipo de lesão. Métodos: No total, foram analisados prospectivamente 174 pacientes agendados para cirurgia eletiva de ressecção pulmonar com períodos intraoperatórios de ventilação monopulmonar. Lavado bronco-alveolar com fibra óptica foi realizado em cada pulmão antes e após os períodos de ventilação monopulmonar para análise das citocinas. Os níveis de citocina foram medidos a partir de amostras de sangue arterial em cinco momentos. A lesão renal aguda foi diagnosticada dentro de 48 horas após a cirurgia, com base nos critérios para sua verificação. Analisamos a associação entre lesão renal aguda e complicações cardiopulmonares, tempo de internação em unidade de terapia intensiva e de internação hospitalar, reinternação em unidade de terapia intensiva e mortalidade a curto e longo prazos. Resultados: A incidência de lesão renal aguda no estudo foi de 6,9% (12/174). Os pacientes com lesão renal aguda apresentaram níveis mais altos de citocinas plasmáticas após a cirurgia, mas não foram detectadas diferenças nas citocinas alveolares. Embora nenhum paciente tenha precisado de terapia renal substitutiva, os com lesão renal aguda apresentaram maior incidência de complicações cardiopulmonares e aumento da mortalidade geral. A interleucina-6 plasmática em seis horas foi a citocina mais preditiva de lesão renal aguda (ponto de corte em 4,89 pg.mL-1). Conclusões: O aumento dos níveis plasmáticos de citocinas no pós-operatório está associado à lesão renal aguda após cirurgia de ressecção pulmonar no estudo, o que piora o prognóstico. A interleucina-6 plasmática pode ser usada como um indicador precoce para pacientes com risco de desenvolver lesão renal aguda após cirurgia de ressecção pulmonar.

The effect of anesthetic preconditioning with sevoflurane on intracellular signal-transduction pathways and apoptosis, in a lung autotransplant experimental model / O efeito do pré-condicionamento anestésico com sevoflurano sobre as vias de transdução de sinal intracelular e a apoptose, em modelo experimental de autotransplante pulmonar

Abstract Background: Anesthetic pre-conditioning attenuates inflammatory response during ischemia-reperfusion lung injury. The molecular mechanisms to explain it are not fully understood. The aim of our investigation was to analyze the molecular mechanism that explain the anti-inflammatory effects of anesthetic pre-conditioning with sevoflurane focusing on its effects on MAPKs (mitogen-activated protein kinases), NF-κB (nuclear factor kappa beta) pathways, and apoptosis in an experimental lung autotransplant model. Methods: Twenty large white pigs undergoing pneumonectomy plus lung autotransplant were divided into two 10-member groups on the basis of the anesthetic received (propofol or sevoflurane). Anesthetic pre-conditioning group received sevoflurane 3% after anesthesia induction and it stopped when one-lung ventilation get started. Control group did not receive sevoflurane in any moment during the whole study period. Intracellular signal-transduction pathways (MAPK family), transcription factor (NF-κB), and apoptosis (caspases 3 and 9) were analyzed during experiment. Results: Pigs that received anesthetic pre-conditioning with sevoflurane have shown significant lower values of MAPK-p38, MAPK-P-p38, JNK (c-Jun N-terminal kinases), NF-κB p50 intranuclear, and caspases (p < 0.05) than pigs anesthetized with intravenous propofol. Conclusions: Lung protection of anesthetic pre-conditioning with sevoflurane during experimental lung autotransplant is, at least, partially associated with MAPKs and NF κB pathways attenuation, and antiapoptotic effects.

Resumo Justificativa: O pré-condicionamento anestésico atenua a resposta inflamatória durante a lesão de isquemia-reperfusão do pulmão. Os mecanismos moleculares para explicá-lo não são totalmente compreendidos. O objetivo de nossa investigação foi analisar o mecanismo molecular que explica os efeitos anti-inflamatórios do pré-condicionamento anestésico com sevoflurano, enfocar seus efeitos sobre as proteínas quinases ativadas por mitógenos (MAPKs), o fator nuclear kappa beta (NF-κB) e a apoptose em modelo experimental de autotransplante pulmonar. Métodos: Vinte porcos Large White submetidos à pneumonectomia e autoimplante de pulmão foram divididos em dois grupos de 10 membros com base no anestésico recebido (propofol ou sevoflurano). O grupo de pré-condicionamento anestésico recebeu sevoflurano a 3% após a indução da anestesia, que foi descontinuado quando a ventilação monopulmonar foi iniciada. O grupo controle não recebeu sevoflurano em qualquer momento durante todo o período do estudo. As vias de transdução de sinal intracelular (família MAPK), o fator de transcrição (NF-κB) e a apoptose (caspases 3 e 9) foram analisados durante o experimento. Resultados: Os suínos que receberam pré-condicionamento anestésico com sevoflurano apresentaram valores mais baixos de MAPK-p38, MAPK-P-p38, c-Jun N-terminal quinases (JNK), NF-κB p50 intranuclear e caspases (p < 0,05) do que os suínos anestesiados com propofol intravenoso. Conclusões: A proteção pulmonar do pré-condicionamento anestésico com sevoflurano durante o autotransplante pulmonar experimental está, pelo menos, parcialmente associada à atenuação das vias de MAPKs e NF κB e aos efeitos antiapoptóticos.

Calidad de la atención de los síndromes coronarios agudos: implementación de una ruta crítica / Quality of care in acute coronary syndromes: a critical path implementation

Antecedentes: En los últimos años se han realizado avances importantes en el manejo del síndrome coronario agudo, lo cual se ha traducido en una disminución de la mortalidad en este grupo de pacientes. Objetivo: Describir los resultados de la implementación de una ruta crítica para el manejo de los síndromes coronarios agudos en el Servicio de Urgencias del Hospital San José de Bogotá, entre el 1 de marzo de 2012 y el 28 de febrero de 2013. Métodos: Se realizó un estudio observacional descriptivo prospectivo. La ruta crítica fue estructurada mediante el consenso de los servicios de Medicina Interna, Urgencias y Cardiología, para ser aplicada en las primeras 24 horas del tratamiento del paciente con síndrome coronario agudo definitivo. Resultados Se reclutaron 156 pacientes, de los cuales 25 correspondieron a síndrome coronario agudo con elevación del ST y 131 a síndrome sin elevación del ST. De los síndromes coronarios agudos con elevación del ST el 96% fue sometido a alguna estrategia de reperfusión; 2 (9,5%) pacientes fallecieron. En cuanto al síndrome coronario agudo sin elevación del ST, 33 (25,1%) pacientes presentaron infarto, 98 (74,9%) angina inestable, y 4 (3,2%) fallecieron. El uso de aspirina, betabloqueador, estatina e inhibidor de la enzima convertidora de angiotensina o antagonistas de los receptores de angiotensina II durante las primeras 24 horas fue superior al 90% en toda la muestra. Conclusiones: Se alcanzó un nivel superior de cumplimiento de las medidas de desempeño de la atención de los síndromes coronarios agudos después de la implementación de una ruta crítica.

Background: In recent years there have been important advances in acute coronary syndrome (ACS) management, which translates into a drop in mortality in this group of patients. Objective: To describe the results of the implementation of a critical path for the management of ACS, at the emergency service of the Hospital San José in Bogotá, between March 1st, 2012 and February 28th, 2013. Methods: A prospective descriptive observational study was carried out. The critical pathway was structured upon consensus among the services of internal medicine, emergency, and cardiology. This pathway was structured to be applied within the first 24 hours of the patient's treatment with the final ACS. Results: 156 patients were selected, 25 had ST segment elevation ACS and 131 had ACS non-ST segment elevation. 96% of ST segment elevation ACS underwent some reperfusion strategy, 2 (9.5%) patients died. As far as non-ST segment elevation ACS patients are concerned, 33 (25.1%) patients exhibited infarction and 98 (74.9%) unstable angina, with a mortality of 4 (3.2%) patients. The use of aspirin, betablockers, statin, and ACEI or ARA II during the first 24 hours was above 90% in the totality of the sample. Conclusions: It is demonstrated that a higher level of fulfillment is achieved for the performance measures for ACS care upon a critical pathway implementation.

Estructuración e implementación de una ruta crítica para el manejo de pacientes con síndrome coronario agudo en el Servicio de Urgencias del Hospital San José de Bogotá / Structuring and implementation of a critical pathway for the management of patients with acute coronary syndrome in the Emergency Department of San José Hospital in Bogotá

Introducción: el síndrome coronario agudo es una patología de alto impacto clínico en nuestro medio y en el mundo. A pesar de la evidencia de un número de medidas que benefician el resultado de estos pacientes, se ha demostrado que su utilización no es la mejor. Una de las estrategias diseñadas para mejorar esta situación, es la utilización de las rutas críticas (critical pathways), que consisten en una secuencia óptima y guiada por tiempo de intervenciones realizadas por los miembros del equipo de salud, para un diagnóstico o procedimiento particular, con el objetivo de minimizar retrasos, mejorar la utilización de recursos y maximizar la calidad del cuidado de la salud. Métodos: como parte de un proceso de mejoramiento de la calidad de la atención, se decidió realizar la estructuración e implementación de una ruta crítica en el manejo del síndrome coronario agudo durante las primeras 24 horas de atención. Para su realización se tuvo en cuenta la información observada en la literatura luego de una revisión amplia del tema. Resultados: posterior al proceso de diseño, divulgación y concertación con los servicios implicados en el manejo de los eventos coronarios, y con base en las guías institucionales, se estructuró una ruta crítica que consta de tres documentos: el primero para la evaluación inicial del dolor torácico, el segundo para el manejo de los eventos coronarios con elevación del segmento ST y el tercero para eventos coronarios sin elevación del segmento ST. Conclusiones: las rutas críticas se han posicionado en el mundo como herramientas que impactan en un alto grado la calidad de la atención de los pacientes con síndrome coronario agudo, ya que minimizan los retrasos, optimizan la utilización de los recursos y controlan las variaciones de dicha atención. Se describe la estructuración e implementación de una ruta crítica para el manejo de estos pacientes en un hospital de cuarto nivel en Colombia.

Introduction: acute coronary syndrome is a disease with high clinical impact on our environment and the world. Despite the evidence of a number of measures that benefit the outcome of these patients, it has been shown that its use is not the best. One of the strategies designed to improve this situation is the use of critical pathways, which consist of an optimal sequence guided by time of interventions performed by members of the health team for a particular procedure or diagnosis, in order to minimize delays, improve the utilization of resources and maximize the quality of health care. Methods: as part of a process of improvement of the quality of care, we decided to perform the structuring and implementation of a critical pathway in the management of acute coronary syndrome during the first 24 hours of care. To achieve this, we took into account the data observed in the literature after an extensive revision of the topic. Results: posterior to the design process, disclosure and agreement with the departments involved in the management of coronary events, and based on institutional guidelines, we structured a critical pathway consisting of three documents: the first for the initial chest pain assessment, the second for the management of coronary events with ST segment elevation and the third for coronary events without ST segment elevation. Conclusions: critical pathways have been positioned in the world as tools that highly impact the quality of care of patients with acute coronary syndrome, as they minimize delays, optimize the use of resources and control variations of such attention. We describe the structuring and implementation of a critical pathway for the management of these patients in a fourth-level hospital in Colombia.

Azoospermias secretoras: posibilidades terapèuticas actuales / Secretory azoospermias: current therapeutic possibilities

En este trabajo pretendemos presentar los resultados del Instituto Valenciano de Infertilidd obtenidos tras la ICSI con espermatozoides procedentes de testículo en pacientes con azoospermias no obstructivas

Escleroterapia de varices esofágicas / Sclerotherapy of esophageal varices

La primera publicación sobre esclerosis de varices esofágicas se realizó hace 50 años, pero es sólo en la última década en que se ha generalizado su uso. Los criterios en relación a las indicaciones, la técnica, el sitio de la inyección y el tipo de sustancias esclerosante a utilizar han evolucionado en los últimos años. Actualmente se acepta que es efectiva para el control del episodio agudo de hemorragia por ruptura de las várices y que probablemente constituye el procedimiento inicial de elección en estos casos. La tendencia actual es de continuar esclerosando los cordones venosos dilatados luego de superado el episodio de sangramiento agudo. La esclerosis de pacientes con várices que nunca han sangrado sigue siendo muy controversial, al respecto se intenta establecer los parámetros que identifiquen al grupo de enfermos con mayor riesgo de sangramiento y en quienes por tanto estaría justificado la esclerosis profiláctica

Bursitis perianal / Perianal bursitis

En el presente trabajo se pone a consideración un caso de bursitis perianal, interpretado equivocadamente como absceso perianal; se evalúan los diagnóstico diferenciales con: a) Esteatopigia; b) Quiste sinovial; c) Hernia ciática; d) Bursitis isquioglútea. Se describe la técnica quirúrgica efectuada en el caso en cuestión, pero queda abierto el interrogante con respecto a la exacta etiología del mismo