Morbimortality assessment in abdominal surgery: are we predicting or overreacting?

BACKGROUND: High-risk surgical procedures represent a fundamental part of general surgery practice due to its significant rates of morbidity and mortality. Different predictive tools have been created in order to quantify perioperative morbidity and mortality risk. POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and morbidity) is one of the most widely validated predictive scores considering physiological and operative variables to precisely define morbimortality risk. Nevertheless, seeking greater accuracy in predictions P-POSSUM was proposed. We aimed to compare POSSUM and P-POSSUM for patients undergoing abdominal surgery. METHODS: A retrospective observational study with a prospective database was conducted. Patients over 18 years old who complied with inclusion criteria between 2015 and 2016 were included. Variables included in the POSSUM and P-POSSUM Scores were analyzed. Descriptive statistics of all study parameters were provided. The analysis included socio-demographic data, laboratory values ​​, and imaging. Bivariate analysis was performed. RESULTS: 350 Patients were included in the analysis, 55.1% were female. The mean age was 55.9 ± 20.4 years old. POSSUM revealed a moderated index score in 61.7% of the patients, mean score of 12.85 points ± 5.61. 89.1% of patients had no neoplastic diagnosis associated. Overall morbidity and mortality rate was 14.2% and 7.1%. P-POSSUM could predict more precisely mortality (p < 0.00). CONCLUSIONS: The POSSUM score is likely to overestimate the risk of morbidity and mortality in patients with high/moderate risk, while the P-POSSUM score seems to be a more accurate predictor of mortality risk. Further studies are needed to confirm our results.

The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation.

Normal physiology relies on the precise coordination of intracellular signaling pathways that respond to nutrient availability to balance cell growth and cell death. The canonical mitogen-activated protein kinase pathway consists of the RAF-MEK-ERK signaling cascade and represents one of the most well-defined axes within eukaryotic cells to promote cell proliferation, which underscores its frequent mutational activation in human cancers. Our recent studies illuminated a function for the redox-active micronutrient copper (Cu) as an intracellular mediator of signaling by connecting Cu to the amplitude of mitogen-activated protein kinase signaling via a direct interaction between Cu and the kinases MEK1 and MEK2. Given the large quantities of molecules such as glutathione and metallothionein that limit cellular toxicity from free Cu ions, evolutionarily conserved Cu chaperones facilitate efficient delivery of Cu to cuproenzymes. Thus, a dedicated cellular delivery mechanism of Cu to MEK1/2 likely exists. Using surface plasmon resonance and proximity-dependent biotin ligase studies, we report here that the Cu chaperone for superoxide dismutase (CCS) selectively bound to and facilitated Cu transfer to MEK1. Mutants of CCS that disrupt Cu(I) acquisition and exchange or a CCS small-molecule inhibitor were used and resulted in reduced Cu-stimulated MEK1 kinase activity. Our findings indicate that the Cu chaperone CCS provides fidelity within a complex biological system to achieve appropriate installation of Cu within the MEK1 kinase active site that in turn modulates kinase activity and supports the development of novel MEK1/2 inhibitors that target the Cu structural interface or blunt dedicated Cu delivery mechanisms via CCS.

DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion.

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mechanism for other disease-associated mutations affecting the interaction between the two POLγ subunits. We suggest that targeting POLγA turnover can be exploited as a target for the development of future therapies.

Copper Chaperone Atox1 Interacts with Cell Cycle Proteins.

The anaphase-promoting complex (APC) is involved in several processes in the cell cycle, most prominently it facilitates the separation of the sister chromatids during mitosis, before cell division. Because of the key role in the cell cycle, APC is suggested as a putative target for anticancer agents. We here show that the copper chaperone Atox1, known for shuttling copper in the cytoplasm from Ctr1 to ATP7A/B in the secretory pathway, interacts with several APC subunits. Atox1 interactions with APC subunits were discovered by mass spectrometry of co-immunoprecipitated samples and further confirmed using proximity ligation assays in HEK293T cells. Upon comparing wild-type cells with those in which the Atox1 gene had been knocked out, we found that in the absence of Atox1 protein, cells have prolonged G2/M phases and a slower proliferation rate. Thus, in addition to copper transport for loading of copper-dependent enzymes, Atox1 may modulate the cell cycle by interacting with APC subunits.

Targeting antisense mitochondrial ncRNAs inhibits murine melanoma tumor growth and metastasis through reduction in survival and invasion factors.

We reported that knockdown of the antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptotic death of several human tumor cell lines, but not normal cells, suggesting this approach for selective therapy against different types of cancer. In order to translate these results to a preclinical scenario, we characterized the murine noncoding mitochondrial RNAs (ncmtRNAs) and performed in vivo knockdown in syngeneic murine melanoma models. Mouse ncmtRNAs display structures similar to the human counterparts, including long double-stranded regions arising from the presence of inverted repeats. Knockdown of ASncmtRNAs with specific antisense oligonucleotides (ASO) reduces murine melanoma B16F10 cell proliferation and induces apoptosis in vitro through downregulation of pro-survival and metastasis markers, particularly survivin. For in vivo studies, subcutaneous B16F10 melanoma tumors in C57BL/6 mice were treated systemically with specific and control antisense oligonucleotides (ASO). For metastasis studies, tumors were resected, followed by systemic administration of ASOs and the presence of metastatic nodules in lungs and liver was assessed. Treatment with specific ASO inhibited tumor growth and metastasis after primary tumor resection. In a metastasis-only assay, mice inoculated intravenously with cells and treated with the same ASO displayed reduced number and size of melanoma nodules in the lungs, compared to controls. Our results suggest that ASncmtRNAs could be potent targets for melanoma therapy. To our knowledge, the ASncmtRNAs are the first potential non-nuclear targets for melanoma therapy.

[Giant Meckel's diverticulum in an adult]. / Divertículo de Meckel gigante en un adulto.

Meckel's diverticulum results from a partial persistence of the omphalomesenteric duct and is the most common congenital anomaly of the gastrointestinal tract, affecting about 2% of the general population. Its presentation as a giant Meckel's diverticulum (>5 cm) is rare and is associated with major complications. We report a case of a 53 year-old woman with constipation for at least ten years. A colonoscopy from eight years ago suggested megacolon. The patient consults in the last month for abdominal pain associated with anorexia. The computed tomography scan image suggested an ileal megadiverticulum. An exploratory laparotomy revealed a saccular dilatation of the distal ileum of 6 x 15.5 cm, located 20 cm away from the ileocecal valve. We resected the involved segment of distal ileum and performed a manual ileo-ascendo anastomosis. The biopsy showed a saccular dilatation of the wall, lined by small intestinal mucosa with areas of gastric metaplasia, supporting the diagnosis of giant Meckel's diverticulum.

El divertículo de Meckel corresponde a la persistencia parcial del conducto onfalomesentérico, representa la anomalía congénita más frecuente del tracto gastrointestinal y afecta alrededor del 2% de la población general. La presentación como divertículo de Meckel gigante (>5 cm) es infrecuente y está asociada a una mayor tasa de complicaciones. Se presenta el caso de una mujer de 53 años que refiere constipación de al menos diez años; una colonoscopía de hace ocho años sugiere un megacolon y en el último mes la paciente ha presentado dolor abdominal asociado a anorexia. Se realiza una tomografía computarizada con imagen que sugiere la presencia de megadivertículo ileal, por lo que se decide realizar una laparotomía exploradora que evidencia una dilatación sacular del íleon distal a 20 cm de la válvula ileocecal de 15,5 x 6 cm aproximadamente. Se reseca el segmento comprometido del íleon distal, que queda cerrado a nivel de la válvula ileocecal, y se realiza una íleo-ascendo anastomosis manual. La biopsia informa dilatación sacular de la pared, revestida por mucosa de intestino delgado con áreas de metaplasia gástrica, hallazgos compatibles con un divertículo de Meckel gigante.

Experiencia de prevención en salud mental pediátrica: psicoprofilaxis quirúrgica en pacientes sometidos a cirugía de escoliosis / Prevention experience in pediatric mental health: surgical pychoprophylaxis in patients undergoing scoliosis surgery

El presente artículo presenta un proyecto piloto de Psicoprofilaxis Quirúrgica en el Departamento de Traumatología, Unidad de Escoliosis, Hospital de niños Dr. Luis Calvo Mackenna. La Psicoprofilaxis Quirúrgica, enmarcada dentro de la psicología de la salud, tiene por objetivo apoyar al paciente que será sometido a cirugía, en el manejo de emociones, actitudes y comportamientos que se derivan de la situación quirúrgica, a través de una intervención psicoterapéutica preventiva, breve y focalizada. Se planteó una intervención psicológica para pacientes que debían ser sometidos a cirugía correctiva de escoliosis. Esta constó de 3 instancias: (a) entrevista inicial y evaluación de ansiedad, (b) intervención intrahospitalaria y (c) control postquirúrgico. En todas ellas se midió Nivel Anímico, Nivel de Actividad, Calidad del Sueño y Calidad de la Alimentación. Los resultados sugieren que si los pacientes tienen un adecuado conocimiento del proceso al cual se enfrentarán, aumentaría su sensación de control de la situación y por ende, disminuiría su ansiedad pre-quirúrgica. No obstante, no basta informar, sino que además es necesario adecuarse a las características de cada paciente al hacer entrega de la información, siendo este factor el que permitiría el cambio en los niveles de ansiedad pre-quirúrgica.

This article presents a trial scheme of surgical psychoprophylaxis in the Scoliosis Unit of the Traumatology department at “Doctor Luis Calvo Mackenna childrens” Hospital. This project arises from The surgical psychoprophylaxis is to an area within Health Psychology that aims to support the patient that will undergo surgery, by performing a brief preventive psychotherapeutic intervention that helps him/her to handle possible emotions, attitudes and behaviors that may appear as a result of the surgical experience. The intervention had three stages: (a) Initial interview and anxiety assessment (b) intra- hospital intervention (c) post surgical control. In each stage mood level was measured as well as activity level, sleep quality and feeding behavior quality. The results suggest that, if patients have adequate knowledge of the process they are going to face their feeling of control over the situation would increase and thus reduce preoperative anxiety. Nevertheless, informing is not enough but it is also necessary to adapt the delivery of information to each patient’s characteristics, for this would be the main factor that would allow changes in preoperative anxiety levels.