Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells.

BACKGROUND: The advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved. METHODS: Human colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed. RESULTS: Our results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities. CONCLUSION: Our results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

The role of double-strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression-clinicopathological data and survival.

BACKGROUND AND OBJECTIVES: DNA repair is a new and important pathway that explains colorectal carcinogenesis. This study will evaluate the prognostic value of molecular modulation of double-strand break repair (XRCC2 and XRCC5); DNA damage tolerance/translesion synthesis (POLH, POLK, and POLQ), and interstrand crosslink repair (DCLRE1A) in sporadic colorectal cancer (CRC). METHODS: Tumor specimens and matched healthy mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ, and DCLRE1A; protein expression of Polk, Ku80, p53, Ki67, and mismatch repair MLH1 and MSH2 components; CpG island promoter methylation of XRCC5, POLH, POLK, POLQ, and DCLRE1A was performed. RESULTS: Neoplastic tissues exhibited induction of POLK (P < .001) and DCLRE1A (P < .001) expression and low expression of POLH (P < .001) and POLQ (P < .001) in comparison to healthy paired mucosa. Low expression of POLH was associated with mucinous histology and T1-T2 tumors (P = .038); low tumor expression of POLK was associated with distant metastases (P = .042). CRC harboring POLK promoter methylation exhibited better disease-free survival (DFS) (P = .005). CONCLUSIONS: This study demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylation was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.

Exploring the basis of heterogeneity of cancer aggressiveness among the mutated POLE variants.

Germline pathogenic variants in the exonuclease domain of the replicative DNA polymerase Pol ε encoded by the POLE gene, predispose essentially to colorectal and endometrial tumors by inducing an ultramutator phenotype. It is still unclear whether all the POLE alterations influence similar strength tumorigenesis, immune microenvironment, and treatment response. In this review, we summarize the current understanding of the mechanisms and consequences of POLE mutations in human malignancies; we highlight the heterogeneity of mutation rate and cancer aggressiveness among POLE variants, propose some mechanistic basis underlining such heterogeneity, and discuss novel considerations for the choice and efficacy of therapies of POLE tumors.

High Expression of MRE11A Is Associated with Shorter Survival and a Higher Risk of Death in CRC Patients.

BACKGROUND: Homologous recombination repair (HR) is the most accurate repair pathway for double-strand breaks and replication fork disruption that is capable of faithfully restoring the original nucleotide sequence of the broken DNA. The deficiency of this mechanism is a frequent event in tumorigenesis. Therapies that exploit defects in HR have been explored essentially in breast, ovarian, pancreatic, and prostate cancers, but poorly in colorectal cancers (CRC), although CRC ranks second in mortality worldwide. METHODS: Tumor specimens and matched healthy tissues from 63 patients with CRC were assessed for gene expression of key HR components and mismatch repair (MMR) status, which correlated with clinicopathological features, progression-free survival, and overall survival (OS). RESULTS: Enhanced expression of MRE11 homolog (MRE11A), the gene encoding a key molecular actor for resection, is significantly overexpressed in CRC, is associated with the occurrence of primary tumors, particularly T3-T4, and is found in more than 90% of the right-side of CRC, the location with the worst prognosis. Importantly, we also found that high MRE11A transcript abundance is associated with 16.7 months shorter OS and a 3.5 higher risk of death. CONCLUSION: Monitoring of MRE11 expression could be used both as a predictor of outcome and as a marker to select CRC patients for treatments thus far adapted for HR-deficient cancers.

The Impact of Donor Risk Index, Recipients' and Operative Characteristics on Post Liver Transplant One-Year Graft Failure: A Cohort Analysis.

Background and Aims: The donor risk index (DRI) quantifies donor-related characteristics potentially associated with increased risk of early graft failure. We aimed to assess the impact of the DRI, recipient and perioperative factors on post liver transplant (LT) outcomes. Methods: This was a single-center retrospective cohort study including all adult (≥18 years) patients who underwent LT from 01/2019 to 12/2019 at Curry Cabral Hospital, Lisbon, Portugal. Primary endpoint was 1-year graft failure post LT. Associations were studied with logistic regression. Results: A total of 131 cadaveric donor LT procedures were performed in 116 recipients. Recipients' median (IQR) age was 57 (47-64) years and 101/131 (77.1%) were males. Cirrhosis was the underlying etiology in 95/131 (81.2%) transplants. Based on 8 predefined donors' characteristics, median (IQR) DRI was 1.96 (1.67-2.16). Following adjustment for MELDNa score pre LT and SOFA score (adjusted odds ratio [aOR], 95% confidence interval [CI] = 0.91 [0.56-1.47]) or lactate (aOR [95% CI] = 2.76 [0.71-10.7]) upon intensive care unit (ICU) admission post LT, DRI was not associated with 1-year graft failure. However, higher SOFA score (aOR [95% CI] = 1.20 [1.05-1.37]) or lactate (aOR [95% CI] = 1.27 [1.10-1.46]) upon ICU admission post LT were independently associated with higher odds of 1-year graft failure. Conclusions: In a recent cohort of patients who underwent LT, DRI, despite being high, was not associated with 1-year graft failure, but SOFA score or lactate upon ICU admission post LT were.

Introdução: O índice de risco do dador (DRI) quantifica as características relacionadas com o dador potencialmente associadas com risco acrescido de falência precoce do enxerto. Procurou-se avaliar o impacto do DRI e factores relacionados com os receptores e cirurgia nos resultados clínicos após transplante hepático (LT). Materiais e Métodos: Estudo coorte retrospectivo de centro único incluindo todos os doentes adultos (≥18 anos) que receberam LT entre 01/2019 e 12/2019 no Hospital Curry Cabral, Lisboa, Portugal. O endpoint primário foi a falência do enxerto após um ano do LT. As associações foram estudadas com regressão logística. Resultados: Um total de 131 transplantes de dadores cadavéricos foram realizados em 116 receptores. A idade mediana (IQR) destes foi 57 (47­64) anos e 101/131 (77.1%) eram homens. A cirrose foi a etiologia subjacente em 95/131 (81.2%) transplantes. Com base nas 8 características dos dadores predefinidas, o DRI mediano (IQR) foi 1.96 (1.67­2.16). Após ajuste para o score MELDNa pre LT e o score SOFA (odds ratio ajustado [aOR], intervalo de confiança 95% [CI] = 0.91 [0.56­1.47]) ou o lactato (aOR [95% CI] = 2.76 [0.71­10.7]) após admissão na unidade de cuidados intensivos (ICU) pós LT, o DRI não se associou com a falência do enxerto um ano depois do LT. Contudo, um maior score SOFA (aOR [95% CI] = 1.20 [1.05­1.37]) ou lactato (aOR [95% CI] = 1.27 [1.10­1.46]) após admissão na ICU depois do LT associaram-se independentemente com a falência do enxerto um ano depois do LT. Conclusões: Num coorte recente de doentes submetidos a LT, o DRI, apesar de alto, não se associou com a falência precoce do enxerto precoce. Contudo, o score SOFA ou lactato após admissão na ICU depois do LT associaram-se com a falência precoce do enxerto.

Alcohol Consumption Post-Liver Transplantation: A Cross-Sectional Study.

Background: Listing patients with alcohol-associated liver disease (ALD) for liver transplant (LT) remains challenging especially due to the risk of alcohol resumption post-LT. We aimed to evaluate post-LT alcohol consumption at a Portuguese transplant center. Methods: We conducted a cross-sectional study including LT recipients from 2019 at Curry Cabral Hospital, Lisbon, Portugal. A pretested survey and a validated Portuguese translation of the Alcohol Use Disorder Identification Test (AUDIT) were applied via a telephone call. Alcohol consumption was defined by patients' self-reports or a positive AUDIT. Results: In 2019, 122 patients underwent LT, and 99 patients answered the survey (June 2021). The mean (SD) age was 57 (10) years, 70 patients (70.7%) were males, and 49 (49.5%) underwent ALD-related LT. During a median (IQR) follow-up of 24 (20-26) months post-index LT, 22 (22.2%) recipients consumed any amount of alcohol: 14 had a drink monthly or less and 8 drank 2-4 times/month. On drinking days, 18 patients usually consumed 1-2 drinks and the remainder no more than 3-4 drinks. One patient reported having drunk ≥6 drinks on one occasion. All post-LT drinking recipients were considered low risk (score <8) as per the AUDIT score (median [IQR] of 1 [1-2]). No patient reported alcohol-related problems, whether self-inflicted or toward others. Drinking recipients were younger (53 vs. 59 years, p = 0.020), had more non-ALD-related LT (72.7 vs. 44.2%, p = 0.018) and active smoking (31.8 vs. 10.4%, p = 0.037) than abstinent ones. Conclusion: In our cohort, about a quarter of LT recipients consumed alcohol early posttransplant, all with a low-risk pattern according to the AUDIT score.

Introdução: Incluir doentes com doença hepática associada ao álcool (DHA) em lista ativa de transplante hepático (TH) é desafiante, especialmente pelo risco de recidiva de consumo de álcool pós-TH. O objetivo foi avaliar o consumo de álcool pós-TH num centro de transplantação português. Métodos: Realizamos um estudo transversal incluindo doentes submetidos a TH em 2019 no Hospital Curry Cabral, Lisboa, Portugal. Foi realizado um questionário previamente testado e uma tradução validada para o português do Alcohol Use Disorder Identification Test (AUDIT), através de uma chamada telefónica. O consumo de álcool foi definido pelo autorrelato do doente ou por um AUDIT positivo. Resultados: Durante 2019, 122 doentes foram submetidos a TH e 99 responderam ao questionário (junho de 2021). A idade média (SD) foi de 57 (10) anos, 70 doentes (70,7%) eram do sexo masculino e 49 (49,5%) foram submetidos a TH relacionado com DHA. Com uma mediana (IQR) de follow-up de 24 (20­26) meses após o TH-índex, 22 (22,2%) doentes admitiram algum consumo de álcool: 14 beberam mensalmente ou menos e oito beberam 2­4 vezes/mês. Nos dias em que bebiam, 18 consumiam normalmente 1­2 bebidas e os restantes não mais do que 3­4 bebidas. Um doente reportou o consumo de ≥6 bebidas em uma ocasião. Todos os doentes transplantados com consumo alcoólico pós-TH foram considerados de baixo risco (pontuação >8) de acordo com o AUDIT (mediana [IQR] de 1 [1­2]). Nenhum doente reportou problemas relacionados com o álcool, tanto autoinfligido como a terceiros. Os indivíduos transplantados com consumo alcoólico eram mais jovens (53 vs. 59 anos, p = 0,020), o motivo de TH era mais frequentemente não relacionado com DHA (72,7 vs. 44,2%, p = 0,018) e apresentavam mais tabagismo ativo (31,8 vs. 10,4%, p = 0,037) quando comparado com os abstinentes. Conclusão: Na nossa coorte, cerca de um quarto dos doentes transplantados hepáticos consumiram álcool no período pós-transplante precoce, todos com um padrão de baixo risco, de acordo com o AUDIT.

Eradication of hepatitis C virus reduces the risk of hepatocellular carcinoma in patients with compensated cirrhosis.

BACKGROUND: The effect of a sustained virological response (SVR) to interferon (IFN) on clinical outcomes of hepatitis C virus (HCV)-related cirrhosis is controversial. AIMS: Evaluate the effect of SVR to IFN on the incidence of hepatocellular carcinoma (HCC) and mortality in patients with compensated HCV-induced cirrhosis. METHODS: A cohort of 130 consecutive patients (92 men, mean age 51.7 years) with histologically proven cirrhosis who received one or more courses of IFN monotherapy or combination therapy with ribavirin were analyzed. SVR was defined as undetectable serum HCV RNA by real-time polymerase chain reaction (PCR) 24 weeks after IFN discontinuation. HCC was assessed by alfa-fetoprotein and ultrasound every 6 months. Predictors of clinical outcomes, defined as HCC, orthotopic liver transplantation (OLT) and mortality, were assessed by Cox regression analysis. RESULTS: The mean follow-up was 6.4 ± 4.0 years (range 1-18). HCC developed in 21 patients: one with SVR versus 20 with non-SVR (P = 0.017). Logistic regression analysis showed that non-SVR (odds ratio [OR] = 27.0; confidence interval [CI], 1.6-452.1), male (OR = 11.6; CI, 1.8-75.4), and greater number of treatments (OR = 4.7; CI, 1.4-16.0) increased the probability of HCC development. Multivariate analysis found that SVR was associated with lower risk of HCC (HR 0.09; CI, 0.01-0.77), OLT (HR 0.04; CI, 0.003-0.63) and any event (HR 0.11; CI, 0.02-0.46) as compared to non-SVR. CONCLUSIONS: In compensated HCV-related cirrhosis, SVR markedly reduces the risk of HCC and improves survival. Clearance of the virus should be intensively attempted in these patients.

Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer.

OBJECTIVE: to evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. METHODS: Pre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polß, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. RESULTS: Higher levels of MPG, Polß and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polß overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. CONCLUSIONS: Our results suggest that increased expression of MPG, Polß and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer.

Imbalance in DNA repair machinery is associated with BRAFV600E mutation and tumor aggressiveness in papillary thyroid carcinoma.

The involvement of alterations in MLH1, an essential mismatch repair component, in BRAFV600E mutated papillary thyroid carcinoma (PTC) has been suggested to be associated with features of tumor aggressiveness. Thirty-two PTC and surrounding normal thyroid tissues were evaluated for 11 representative DNA repair genes expression. BRAFV600E mutational status assessment and clinicopathological correlations were evaluated for their gene and protein expression. BRAFV600E PTC is associated with lower levels of XPD and MLH1 gene expression. Decrease in MLH1 and XPD mRNA levels in BRAFV600E PTC (but not their protein products) are associated with predictors of poor patient outcomes. Considering the complete subset of patients, MGMT and XRCC2 genes were shown down and upregulated, respectively, in PTC tissues. Low expression of MGMT gene and weak XRCC2 protein expression were correlated with characteristics of tumor aggressiveness. These results suggest that an imbalance in DNA repair gene expression in PTC is associated with aggressive clinicopathological features and BRAFV600E mutation.

Base excision repair imbalance in colorectal cancer has prognostic value and modulates response to chemotherapy.

Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients' clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG, OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG, but not XRCC1, sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

Tuberculosis in Liver Transplant Recipients: A Report of Eight Cases During a Five Year Period.

INTRODUCTION: Tuberculosis incidence in Portugal ranged from 20 to 22 cases per 100 000 inhabitants between 2010 and 2014. Tuberculosis incidence in liver transplant recipients is not precisely known, but it is estimated to be higher than among the general population. Tuberculosis in liver transplant recipients is particularly challenging because of the atypical clinical presentation and side effects of the antibacillary drugs and their potential interactions with immunosuppressive therapies. MATERIAL AND METHODS: We retrospectively reviewed the clinical records of liver transplant recipients with post-transplant tuberculosis occurring from January 2010 to December 2014 at a liver transplantation unit in Lisbon, Portugal. Demographic data, baseline and clinical features, as well as treatment regimen, toxicities and outcomes, were analyzed. RESULTS: Among 1005 recipients, active tuberculosis was diagnosed in eight patients between January 2010 and December 2014 (frequency = 0.8%). Late onset tuberculosis was more frequent than early tuberculosis. Mycobacterium tuberculosis complex was isolated from cultures in almost every case (7; 87.5%). Extra-pulmonary involvement and disseminated tuberculosis were frequent. Two patients developed rejection without allograft loss. Crude mortality was 37.5%, with 2 deaths being related to tuberculosis. DISCUSSION: Despite the uncertainty regarding treatment duration in liver transplant recipients, disease severity, as well as number of active drugs against TB infection, should be taken into account. There was a need for a rifampin-free regimen and immunosuppression adjustment in patients who experienced acute graf rejection. CONCLUSION: Although the number of cases of tuberculosis is low, its post-transplant frequency is significant and the observed mortality rate is not to be neglected. The cases of hepatotoxicity and graft rejection seen in this case series demonstrate the challenges associated with tuberculosis diagnosis in liver transplant recipients and management of the interactions between immunosuppressors and rifampin. This study strengthens the recommendation of latent tuberculosis infection screening and treatment in liver transplant candidates or recipients.

Introdução: A incidência de tuberculose em Portugal entre 2010 - 2014 foi de 20 a 22 casos por 100 000 habitantes. A incidência de tuberculose em transplantados hepáticos não é conhecida, estimando-se que seja mais elevada do que a da população em geral. O manejo da tuberculose em transplantados hepáticos constitui um desafio, não só pela apresentação clínica frequentemente atípica, mas também pelos efeitos secundários da terapêutica antibacilar e suas interações farmacológicas com a medicação imunossupressora, necessária no período pós-transplante. Material e Métodos: Os autores fizeram uma revisão retrospetiva dos casos de doentes transplantados hepáticos com tuberculose pós- transplante diagnosticada durante o período entre janeiro 2010 e dezembro 2014 num centro de transplantação hepática em Lisboa, Portugal. Foram analisados os dados demográficos, características clínicas, a par do regime antibacilar, toxicidade e evolução. Resultados: Num total de 1005 transplantados foi diagnosticada tuberculose ativa em oito doentes entre janeiro de 2010 e dezembro de 2014 (frequência de 0,8%). O desenvolvimento de tuberculose tardia foi mais frequente do que a doença precoce. Foi isolado Mycobacterium tuberculosis complex no exame cultural de sete doentes (87,5%). Foram frequentes a presença de envolvimento extrapulmonar, assim como doença tuberculosa disseminada. Dois doentes desenvolveram rejeição aguda, sem perda de enxerto. A taxa de mortalidade global foi de 37,5%, com duas mortes directamente atribuíveis à tuberculose. Discussão: Apesar da incerteza quanto à duração do tratamento da tuberculose em transplantados hepáticos, deverão ser tidos em conta a gravidade da doença, assim como o número de fármacos com actividade antibacilar. Nesta série, os doentes que desenvolveram rejeição aguda necessitaram da utilização de um regime sem rifampicina, e ajuste da terapêutica imunossupressora. Conclusão: Apesar do baixo número de casos de tuberculose, a sua frequência pós-transplante é significativa e a mortalidade associada não é negligenciável. Os casos de hepatotoxicidade e rejeição de enxerto demonstram os desafios no diagnóstico da tuberculose em transplantados hepáticos e a dificuldade do manejo das interações entre imunossupressores e a rifampicina. Este estudo reforça a recomendação de rastreio e tratamento de tuberculose latente em transplantados ou candidatos a transplante hepático.

Factors associated with the development of cirrhosis in patients with HCV chronic infection.

BACKGROUND/AIMS: The natural history of chronic hepatitis C virus (HCV) infection still has some details to be established, namely in what concerns progression to hepatic cirrhosis (HC). The study aims to define predictive factors for progression to HC in patients with HCV chronic infection. METHODOLOGY: A cross-sectional study was performed on 129 patients consecutively submitted to liver biopsy. Thirty-six percent (n=46) had HC at histological evaluation. RESULTS: Patients with HC did not show statistically significant differences on gender, viruses genotypes, alcohol consumption or proportion of positivity to markers of previous hepatitis B virus (HBV) infection - anti-HBc/anti-HBs+. Patients with HC seem to have had their infection sporadically (50%) or post-transfusion (35%) -p=0.052, and iv drugs addiction was related to non-HC patients (39%) -p=0.006. Age at infection, time of infection and positivity for anti-HBc/anti-HBs were factors independently related to HC (multivariate analysis). Patients older than 40 years by the time of infection [OR=4.5 (95% CI=1.9-10.8], those with less than 5 years of time of infection [OR=4.2 (95% CI=1.6-10.8)], and patients with previous HBV infection [OR=2.51 (1.00-6.69)] are at higher risk for HC. CONCLUSIONS: We argue that older patients, with a shorter time interval between HCV infection and diagnosis, and namely those with markers for previous HBV infection represent patients with higher risk for progression to hepatic cirrhosis.

La dificultad analítica del rezago temporal en la denuncia y su relevancia en el análisis de los índices de criminalidad en Colombia (2005-2018) / The analytical difficulty of the time lag in reporting and its relevance for the analysis of crime indicators in Colombia (2005-2018) / A dificuldade analítica do lapso de tempo na denúncia e sua na análise dos índices de criminalidade na Colômbia (2005-2018)

Resumen El objetivo De este artículo es visibilizar y cuantificar la dificultad analítica que se presenta al momento de interpretar los índices de criminalidad, debido al rezago temporal del registro en el instante en que se comete el delito y la fecha de ingreso de la denuncia. Ese rezago temporal genera un sesgo benévolo en la medición del crimen y la interpretación criminal para la toma de decisiones, cuando se comparan periodos parciales (años anteriores y vigencia actual). La metodología Utilizada es exploratoria con un enfoque cuantitativo en el tratamiento de los datos registrados desde el año 2005 hasta el 2018, y consolidados en los sistemas Penal Oral Acusatorio (SPOA) de la Fiscalía General de la Nación y de Información Estadístico Delincuencial, Contravencional y Operativo (SIEDCO) de la Policía Nacional de Colombia. Para el análisis se compararon los datos de los delitos de homicidio, hurto, lesiones personales, violencia intrafamiliar y delitos sexuales durante los primeros cuatro y cinco meses de cada periodo anual con los siguientes meses del año. Como Resultado Se evidenció que el rezago temporal promedio en los homicidios fue del 2,85%; en el hurto del 11,8%; en las lesiones personales del 12,7%; en la violencia intrafamiliar del 18,9% y en los delitos sexuales del 30,5%.

Abstract The purpose Of this article is to visualize and quantify the analytic difficulty that arises in interpreting crime indicators due to the time lag between the time when the crime took place and the date on which the crime report was filed2. This time lag creates a lenient bias in crime measurement and interpretation for decision-making effects when time periods are compared (previous periods against the current period). The methodology Used is exploratory with a quantitative approach in the treatment of data recorded from 2005 to 2018, and consolidated in the Oral Criminal Prosecution System (SPOA, for the Spanish original) of the National Prosecutor's Office (Fiscalía) and in the Crime, Infraction and Operations Statistical System (SIEDCO, for the Spanish original) of the National Police of Colombia. Data on the crimes of homicide, theft, personal injuries, intra-family violence and sexual crimes during the first four and five months of each annual period were compared to the data from the subsequent months of the year. As a result It was found that the average time lag was 2.85% for homicides; 11.8% for theft; 12.7% for personal injuries; 18.9% for intra-family violence and 30.5% for sexual crimes.

Resumo O objetivo Deste artigo é tornar visível e quantificar a dificuldade analítica que surge na interpretação dos índices de criminalidade, devido à defasagem temporal do registro no momento em que o crime é cometido e na data de apresentação da denúncia3. Esse lapso temporal gera um viés benevolente na medição e interpretação do crime para a tomada de decisões, quando são comparados períodos parciais (anos anteriores e validade atual). A metodologia Utilizada é exploratória com abordagem quantitativa no tratamento dos dados registados de 2005 a 2018, e consolidados no sistema Penal Oral Acusatório (SPOA) da Procuradoria Geral da Nação e no sistema de Informação Estatístico Delinquencial, Contravencional e Operativo (SIEDCO) da Polícia Nacional da Colômbia. Para a análise foram comparados os dados dos crimes de homicídio, furto, lesões pessoais, violência doméstica e crimes sexuais durante os primeiros quatro e cinco meses de cada período anual com os meses seguintes do ano. Como resultado Constatou-se que a média do lapso temporal nos homicídios foi de 2,85%; no furto de 11,8%; nas lesões pessoais de 12,7%; na violência doméstica de 18,9% e nos crimes sexuais foi de 30,5%.

Avances metodológicos para la determinación del origen de enfermedades laborales relacionadas con el estrés: la experiencia colombiana / Methodological advances in the determination of the origin of stress-related occupational diseases: the Colombian experience

Contexto: La inclusión de las enfermedades generadas por el estrés en el trabajo en la legislación colombiana planteó la necesidad de disponer de herramientas que faciliten la valoración de los casos de forma estandarizada. Objetivo: Diseñar un método homogéneo y válido para el análisis, evaluación y establecimiento de relaciones causales entre exposiciones psicosociales en el trabajo y la presentación de enfermedades en la población trabajadora. Método: La metodología bajo la cual opera el protocolo está compuesta por siete etapas consecutivas que se extienden de la verificación del diagnóstico a la valoración de factores de riesgo tanto psicosociales como no psicosociales, los cuales se califican en una matriz de valoración que permite estimar el peso relativo de cada uno de ellos. Resultados: El protocolo se validó con un conjunto de casos de enfermedades presuntamente relacionadas con estrés en el trabajo. Se calcularon los indicadores de sensibilidad y especificidad generales, así como particulares para cada una de las enfermedades incluidas en el protocolo. Conclusiones: Esta herramienta fue asumida por el Ministerio de Trabajo de Colombia como de uso obligatorio por los equipos de calificadores de las diferentes instancias de la seguridad social. Luego de diez años de utilización, se analizó su pertinencia y funcionalidad, y se inició el proceso de actualización de la evidencia científica que la respalda.

Background: The inclusion of stress-related diseases in the Colombian legislation raised the need for tools that facilitate the assessment of cases in a standardized manner. Objective: To design a homogeneous and valid method for analysis, evaluation and establishment of causal relationships between psychosocial exposures at work and occurrence of diseases among the working population. Method: The protocol comprises seven consecutive steps from the verification of the diagnosis to assessment of psychosocial and non-psychosocial risk factors, which are scored on a valuation matrix that allows estimating the relative weight of each of them. Results: The protocol was validated with a set of cases of diseases possibly related with stress at work. General sensitivity and specificity indicators were calculated, as well as the ones particular for each disease included in the protocol. Conclusions: The Labor Ministry of Colombia established the protocol described here as mandatory reference for assessment teams at the various social security levels. Its relevance and applicability were assessed after ten years of use, and the process to update its supporting evidence was started.

Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder.

Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

Hipotiroidismo neonatal / Neonatal hypothyroidism

El presente trabajo descriptivo pretende demostrar la importancia del reconocimiento precóz de ésta patología, mediante test sceening como la valoración por radioinmunoanálisis de TSH neonatal, una prueba de fácil realización que consiste en la aplicación de tres gotas de sangre de talón o cordón umbilical en papel filtro que pueda consevarse por varios meses hasta completar el número de set reactivo, logrando así disminuir los costos. Además por tener alta sensibilidad permite detectar todos los casos para el inicio temprano de la terapia especifica evitando las secuelas especialmente de tipo neurológico por ser la endocrinopatía mas frecuente en la infancia y causa mas directa y usual de retardo mental prevenible. Con tal motivo se tomó una muestra de cuarenta (4) pacientes en forma aleatoria en el Hospital Lorencita Villegas de Santos; simultáneamente se aplicó a las madres un cuestionario que incluye los factores asociados conocidos como complemento de la investigación. Con dichos procedimientos detectamos la normalidad de la función tiroidea en la toralidad de la muestra, lo cual excluye la necesidad de realizarles otros estudios y encontramos que este es un valioso test de screening, con notorias ventajas en relación a otras pruebas, con accesibilidad económica, orientación terapéutica temparana que permiten plantear la necesidad de incluirla en políticas de salud vigentes en la atención primaria

Situacion de la vejez en Colombia / Situation of the aged in Colombia

A partir de los anos 60 se ha incrementado la poblacion entre los 60 ylos 69 anos, principalmente femenina, concentrada en el sector urbano y en los departamentos de Antioquia, Valle y en la ciudad de Bogota, esto sumado a los cambios en la conformacion, tamano y funciones de la familia y en el comportamiento de sus miembros han sido factores importantes en el aislamiento social, el deterioro fisico y mental y la problematica economica del anciano en Colombia. Desde 1827, cuando surgen las primeras disposiciones legales para la proteccion de la vejez e invalidez hasta la ley 91 de 1988 se han hecho importantes progresos en las politicas y las normas para proteger al anciano a la vez que se han creado organismos tales como el Instituo Colombiano de Bienestar Familiar, el Instituto de Seguros Sociales y la Caja Nacional de Prevision que asumen las pensiones y el cuidado de los pensionados, sino que al mismo tiempo se han creado y desarrollado programas para la vejez. Se presenta un analisis de la legislacion Colombianaal respecto; se describen los factores socioeconomicos de la poblacion y se proponen orientaciones para la organizacion institucional y se sintetizan las tendencias de los programas actuales.

Efectos socio-economicos del envejecimiento en el desarrollo del pais / Socio-economic effects of aging in the country development

La inversion progresiva de la estructura demografica colombiana a partir de los anos 60, muestra incremento de la poblacion entre 60 y 69 anos principalmente femenina, concentrada en el sector urbano y en los departamentos de Antioquia, Valle y en la ciudad de Bogota. La situacion economica de los ancianos esta determinada por la estructura laboral tradicional. En la zona urbana, las personas que estan llegando a los 60 anos se clasifican en 3 grupos economicos: pensionados, rentistas y carentes de medios para su propia subsistencia, mientras que en el medio rural, vivien con su familia o conservan sus viviendas aun cuando esten solos; alli, los niveles de escolaridad son bajos especialmente en las mujeres. Los cambios en la conformacion, tamano y funciones de la familia y los del comportamiento de sus miembros ha incidido en forma importante en el modo de vida y en el cuidado del anciano que se ha convertido en una carga costosa e inutil para la familia, la viudez, la separacion y la solteria han sido tambien factores de aislamiento social y deterioro fisico y mental. Las caracteristias de la familia colombiana influenciadas por las subculturas y por los estratos socioeconomicos origen de las diferencias con que envejecen las personas generan 4 subgrupos de riesgo, que requieren atencion y acciones especificas; indigentes, abandonados, dependientes o invalidos y ancianos con restricciones familiares de convivencia.

Analisis de la legislacion colombiana sobre la tercera edad / Analysis of colombian legislation on third age

Presenta el marco legal y juridico de la proteccion al anciano desde 1827 hasta hoy, dentro del cual se concibe como un " exedente " social por cuyo bienestar debe velar el estado a traves de los organismos fundamentales de la sociedad, como son la familia las relaciones de parentesco y de pareja, y de los organismos estatales tales como las cajas de prevision social, el seguro social, bienestar familiar, las cajas de compensacion, los empleadores, las fuerzas militares y la. La legislacion colombiana relacionada con el anciano define las funciones y responsabilidades sociales de estos organismos y establece mecanismos para garantizar su soporte economico en el Fondo Nacional para la Ancianidad, la obligacion alimentaria entre parientes, conyuges y concubinas, el regimen de pensiones y de jubilacion, la prestacion de servicios de salud y los hogares para ancianos. Asi mismo determina sanciones civiles y penales para quienes incumplan con lo establecido por la ley.