Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice.

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2-9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3',4'-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Mechanistic interrogation of mutation-independent disease modulators of RDEB identifies the small leucine-rich proteoglycan PRELP as a TGF-ß antagonist and inhibitor of fibrosis.

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic extracellular matrix disease caused by deficiency in type VII collagen (Col VII). The disease manifests with devastating mucocutaneous fragility leading to progressive fibrosis and metastatic squamous cell carcinomas. Although Col VII abundance is considered the main predictor of symptom course, previous studies have revealed the existence of mutation-independent mechanisms that control disease progression. Here, to investigate and validate new molecular modifiers of wound healing and fibrosis in a natural human setting, and toward development of disease-modulating treatment of RDEB, we performed gene expression profiling of primary fibroblast from RDEB siblings with marked phenotypic variations, despite having equal COL7A1 genotype. Gene enrichment analysis suggested that severe RDEB was associated with enhanced response to TGF-ß stimulus, oxidoreductase activity, and cell contraction. Consistently, we found an increased response to TGF-ß, higher levels of basal and induced reactive oxygen species (ROS), and greater contractile ability in collagen lattices in RDEB fibroblasts (RDEBFs) from donors with severe RDEB vs mild RDEB. Treatment with antioxidants allowed a reduction of the pro-fibrotic and contractile phenotype. Importantly, our analyses revealed higher expression and deposition in skin of the relatively uncharacterized small leucine-rich extracellular proteoglycan PRELP/prolargin associated with milder RDEB manifestations. Mechanistic investigations showed that PRELP effectively attenuated fibroblasts' response to TGF-ß1 stimulus and cell contractile capacity. Moreover, PRELP overexpression in RDEBFs enhanced RDEB keratinocyte attachment to fibroblast-derived extracellular matrix in the absence of Col VII. Our results highlight the clinical relevance of pro-oxidant status and hyper-responsiveness to TGF-ß in RDEB severity and progression. Of note, our study also reveals PRELP as a novel and natural TGF-ß antagonist with a likely dermo-epidermal pro-adhesive capacity.

Analysis of mortality after surgical treatment of periprosthetic distal femur fractures. / Análisis de la mortalidad tras el tratamiento quirúrgico de las fracturas periprotésicas de fémur distal.

INTRODUCTION: The incidence of periprosthetic fractures of the knee is increasing due to the increase in the number of total knee arthroplasties performed, together with population aging. We found few studies that analyze mortality in our setting after surgery. Our objective was to evaluate mortality and survival after surgical treatment of periprosthetic fractures of the distal femur in our environment. MATERIAL AND METHOD: We conducted a retrospective observational study of a consecutive series of 97 patients surgically treated in our centre for periprosthetic knee fracture between 2007-2015, with a minimum follow-up of 12months. Diverse sociodemographic, clinical and surgical variables were analyzed. A consultation was made to the National Death Index of the Ministry of Health for the analysis of mortality and survival was analyzed using the Kaplan-Meier method. RESULTS: We reviewed a total of 97 patients with an average age of 75years, of which 86 were women and 11 were men. Of the patients, 50.5% of patients had some comorbidity. The average delay until the intervention was 3.1days. With respect to the treatment, 45 patients were operated by osteosynthesis with plate (49.5%), 40 with intramedullary nail (41.2%) and 9 with revision of the arthroplasty (9.3%). A total of 30 deaths were recorded during the follow-up, with cumulative mortality in the first year, at 3 and at 10 years of 7.2%, 17.5% and 30.9%, respectively, progressively increasing in people over 75years. There was no significant difference in mortality rates with the osteosynthesis method. The main complication was pseudoarthrosis (6.2%). CONCLUSIONS: Periprosthetic knee fractures are associated with high rates of complications and mortality. The patient's age and the lesion itself are non-modifiable factors that can influence mortality after surgery, while other variables such as the type of intervention or surgical delay did not show differences in mortality rates in our study.

Surgical treatment of periprosthetic humerus fractures and algorithm. / Tratamiento quirúrgico de las fracturas periprotésicas de húmero y algoritmo de actuación.

INTRODUCTION: Periprosthetic humerus fractures are infrequent and sometimes difficult to treat. There is limited literature and no consensus on the handling of these fractures. The objective of this study was to compare our results with those published in the literature, in order to improve our care and propose a management algorithm. MATERIAL AND METHOD: Observational study of 10cases of periprosthetic humerus fractures with a mean follow-up of the patients of 23months. An analysis of sociodemographic, radiological and surgical variables was performed. They were reviewed clinically and by telephone using the UCLA Shoulder Score and Quick-DASH scales. A systematic search was made in Pubmed for periprosthetic humerus fractures, for a literature review with which to compare our series. RESULTS: We analysed 10patients with an average age of 69.4years (37-91). Of the patients, 90% underwent surgery through open reduction and internal fixation. Nine of the ten patients consolidated in a mean time of 6.2months (range 5-12), the remaining suffered a new fracture 5months after the intervention, who were reoperated and a new osteosynthesis performed with bone allograft. In the UCLA scale there was a decrease of 10.66points, and an increase of 27.3points in the Quick-DASH, at the end of the follow-up. CONCLUSIONS: In our series of cases we found similarities in the literature, in relation to demographic aspects and obtaining good radiographic results, which do not correspond to the functional outcome of patients.

Estudio de frecuencia y asociación de los polimorfismos RS965513 y RS1867277 del gen FOXE1 con el carcinoma papilar de tiroides y su riesgo de recurrencia en población chilena / Frequency and association of the polymorphisms RS965513 and RS1867277 of the FOXE1 gene with papillary thyroid carcinoma and its risk of recurrence in Chilean population

Introducción: El gen FOXE1 (Forkhead box E1) codifica para un factor de transcripción involucrado en la morfogénesis tiroidea. El cáncer papilar de tiroides (CPT) se ha asociado con polimorfismos (SNP) de FOXE1 rs1867277 y rs965513 en población asiática y europea. Nuestro objetivo fue investigar la frecuencia y asociación de SNP rs1867277 y rs965513 con CPT y el riesgo de recurrencia de CPT en sujetos chilenos. Métodos: Se reclutaron sujetos con y sin CPT, se describieron sus características epidemiológicas y la forma de presentación clínica (AJCC VIII y MINSAL 2013). Se aisló ADN de leucocitos periféricos y evaluó ambos SNP mediante PCR-HRM y secuencia. Se compararon las frecuencias alélicas y genotípicas entre casos CPT y controles, y entre pacientes CPT de distintos riesgos de recurrencia. Se compararon frecuencia y se estimó el riesgo con test de Fisher y cálculo de odds-ratio (OR). Resultados: De los 184 sujetos, 156 (85%) eran mujeres, edad 39,3±12,3 años; 90 con CPT y 94 sin CPT 26 (28,9%) pacientes eran de riesgo muy bajo, 45 (50%) bajo, 16 (17,8%) intermedio y 3 (3,3%) alto según MINSAL 2013. En relación a la frecuencia de alelo menor (MAF) calculada en sujetos control y CPT, fue 31,7% y 24,5% (SNP rs965513), y 36,7% y 30,1% 8 (rs1867277), respectivamente (p NS). Tampoco fueron diferentes las MAF calculados y comparados entre pacientes con CPT de riesgo bajo e intermedio/alto. Sin embargo, la combinación de los genotipos rs1867277GG y rs965513AA se asoció a mayor riesgo de CPT. Conclusiones: En pacientes chilenos, se describe una frecuencia MAF de los SNP rs1867277 y rs965513 cercana a un 30%, las cuales no se asocian a CPT ni riesgo de recurrencia, sin embargo, sujetos con una combinación genotípica particular podrían tener mayor riesgo de CPT.

FOXE1 gene (Forkhead E1 box) codes for a transcription factor involved in thyroid morphogenesis. Papillary thyroid cancer (PTC) has been associated with FOXE1 polymorphisms (SNPs) rs1867277 and rs965513 in Asian and European population. Our aim was to investigate the frequency and the association of SNPs rs1867277 and rs965513 with PTC and the risk of recurrence of PTC in Chilean subjects. Methods: We recruited subjects with and without PTC. In those with PTC, their epidemiological characteristics and clinical features presentation are described according to AJCC VIII and MINSAL 2013 scales. Peripheral leukocyte DNA was isolated and both SNPs were evaluated using PCR-HRM and sequencing. Allelic and genotypic frequencies were compared between PTC cases and controls, and between PTC patients with different recurrence risks. Results: Of the 184 subjects, 156 (85%) were women, age 39.3 ± 12.3 years; 94 (51%) without PTC and 90 with PTC (49%): 26 (28.9%) patients had very low, 45 (50%) low, 16 (17.8%) intermediate and 3 (3.3%) high risk of recurence according to MINSAL 2013. Regarding the minor allele frequency (MAF) calculated on control and PTC subjects, was 31.7% and 24.5% (SNP rs965513), and 36.7% and 30.1% (rs1867277), respectively (p NS). In patients with PTC, MAFs were not different between patients with low and intermediate/high risk PTC. However, the combination of rs1867277GG and rs965513AA genotypes were associated with an increased risk of PTC. Conclusions: In Chilean patients, the MAF frequency of SNPs rs1867277 and rs965513 is near 30%, and they are are not associated with PTC or its risk of recurrence. However, subjects with a particular genotypic combination may have an increased risk of PTC.

What have we learned from reporting safety incidents in the Surgical Block?: Cross-sectional descriptive study of two-years of activity of a multidisciplinary analytical group. / ¿Qué hemos aprendido de la notificación de incidentes de seguridad en el Bloque Quirúrgico?: estudio descriptivo transversal de 2 años de actividad de un grupo analizador multidisciplinar.

BACKGROUND AND OBJECTIVES: Incident Reporting Systems (IRS) are considered a tool that facilitates learning and safety culture. Using the experience gained with SENSAR, we evaluated the feasibility and the activity of a multidisciplinary group analyzing incidents in the surgical patient notified to a general community system, that of the Observatory for Patient Safety (OPS). MATERIAL AND METHOD: Cross-sectional observational study planned for two years. After training in the analysis, a multidisciplinary group was created in terms of specialties and professional categories, which would analyze the incidents in the surgical patient notified to the OPS. Incidents are classified and their circumstances analyzed. RESULTS: Between March 2015 and 2017, 95 incidents were reported (4 by non-professionals). Doctors reported more than nurses, at 54 (56.84%) vs. 37 (38.94%). The anaesthesia unit reported most at 46 (48.42%) (P=.025). The types of incidents mainly related to the care procedure (30.52%); to the preoperative period (42.10%); and to the place, the surgical area (48.42%). Significant differences were detected according to the origin of the notifier (P=.03). No harm, or minor morbidity, constituted 88% of the incidents. Errors were identified in 79%. The analysis of the incidents directed the measures to be taken. CONCLUSIONS: The activity undertaken by the multidisciplinary analytical group during the period of study facilitated knowledge of the system among the professionals and enabled the identification of areas for improvement in the Surgical Block at different levels.

Incidental Leydig Cell Tumor in Patient with Hormone Resistant Prostate Cancer.

We hereby present the case of a 55 years old patient with clinical diagnosis of high-risk prostate cancer T2bN1Mo Gleason 9 (4 + 5) treated with androgen deprivation therapy and external beam radiotherapy. Despite treatment, castration levels were not achieved and clinical progression was evidenced by the appearance of bone metastases and progression of PSA. After several hormonal treatments without any PSA or testosterone response, surgical castration was performed by bilateral orchiectomy. The pathology results showed an incidental Leydig cell tumor in the right testicle.

Effect of natural antioxidants in Spanish salchichón elaborated with encapsulated n-3 long chain fatty acids in konjac glucomannan matrix.

The effect of natural antioxidants on physicochemical properties, lipid and protein oxidation, volatile compounds and free fatty acids (FFA) were determined in Spanish salchichón enriched with n-3 fatty acids encapsulated and stabilized in konjac matrix. Phenolic compounds of beer residue extract (BRE), chestnut leaves extract (CLE) and peanut skin extract (PSE) were also identified and quantified. Five batches of salchichón were prepared: control (CON, without antioxidants), butylated hydroxytoluene (BHT), BRE, CLE and PSE. The main phenolic compounds were catechin and benzoic acid for BRE, gallic acid and catechin for CLE and catechin and protocatechuic acid for PSE. Statistical analysis did not show significant differences on chemical composition among treatments. Reductions in luminosity (P<0.05) and pH (P<0.001) were observed with the CLE batch, whereas the other colour parameters were not affected by the addition of natural antioxidants. Finally, the inclusion of antioxidants (P<0.001) decreased the hexanal content, whereas the FFA content increased by the addition of natural extracts.

[Anaesthetic management of excision of a cervical intraspinal tumor with intraoperative neurophysiologic monitoring in a pregnant woman at 29 weeks]. / Manejo anestésico en la extirpación de una tumoración intrarraquídea cervical con monitorización neurofisiológica intraoperatoria en una paciente gestante de 29 semanas.

The intraoperative neurophysiological monitoring is a technique used to test and monitor nervous function. This technique has become essential in some neurosurgery interventions, since it avoids neurological injuries during surgery and reduces morbidity. The experience of intraoperative neurophysiological monitoring is limited in some clinical cases due to the low incidence of pregnant women undergoing a surgical procedure. A case is presented of a 29-weeks pregnant woman suffering from a cervical intraspinal tumour with intense pain, which required surgery. The collaboration of a multidisciplinary team composed of anaesthesiologists, neurosurgeons, neurophysiologists and obstetricians, the continuous monitoring of the foetus, the intraoperative neurophysiological monitoring, and maintaining the neurophysiological and utero-placental variables were crucial for the proper development of the surgery. According to our experience and the limited publications in the literature, no damaging effects of this technique were detected at maternal-foetal level. On the contrary, it brings important benefits during the surgery and for the final result.

Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model for first-line pazopanib in metastatic renal carcinoma: the Spanish Oncologic Genitourinary Group (SOGUG) SPAZO study.

BACKGROUND: Patients with metastatic renal carcinoma (mRCC) treated with first-line pazopanib were not included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. SPAZO (NCT02282579) was a nation-wide retrospective observational study designed to assess the effectiveness and validate the IMDC prognostic model in patients treated with first-line pazopanib in clinical practice. PATIENTS AND METHODS: Data of 278 patients, treated with first-line pazopanib for mRCC in 34 centres in Spain, were locally recorded and externally validated. Mean age was 66 years, there were 68.3% male, 93.5% clear-cell type, 74.8% nephrectomized, and 81.3% had ECOG 0-1. Metastatic sites were: lung 70.9%, lymph node 43.9%, bone 26.3%, soft tissue/skin 20.1%, liver 15.1%, CNS 7.2%, adrenal gland 6.5%, pleura/peritoneum 5.8%, pancreas 5%, and kidney 2.2%. After median follow-up of 23 months, 76.4% had discontinued pazopanib (57.2% due to progression), 47.9% had received second-line targeted therapy, and 48.9% had died. RESULTS: According to IMDC prognostic model, 19.4% had favourable risk (FR), 57.2% intermediate risk (IR), and 23.4% poor risk (PR). No unexpected toxicities were recorded. Response rate was 30.3% (FR: 44%, IR: 30% PR: 17.3%). Median progression-free survival (whole population) was 11 months (32 in FR, 11 in IR, 4 in PR). Median and 2-year overall survival (whole population) were 22 months and 48.1%, respectively (FR: not reached and 81.6%, IR: 22 and 48.7%, PR: 7 and 18.8%). These estimations and their 95% confidence intervals are fully consistent with the outcomes predicted by the IMDC prognostic model. CONCLUSION: Our results validate the IMDC model for first-line pazopanib in mRCC and confirm the effectiveness and safety of this treatment.

[Perioperative considerations for performing a brain biopsy on a patient with subtype VV2 sporadic Creutzfeldt-Jakob disease]. / Consideraciones perioperatorias para la realización de una biopsia cerebral en un paciente con enfermedad de Creutzfeldt-Jakob esporádica subtipo VV2.

Creutzfeldt-Jakob disease (CJD) is the most common transmissible spongiform encephalopathy. It is an infectious, progressive, degenerative neurological disorder, with a presumably long incubation period, but a rapid fatal course. CJD is transmitted by a proteinaceous infectious agent, or «prion¼. Because the prions are difficult to eradicate and are resistant to the currently used sterilization methods, special precautions must be taken with all surgical instruments. It is recommended the single-use equipment, destruction of contaminated equipment, decontamination of reusable instruments, use of protective clothing, and storing and quarantining surgical instruments. The single-use equipment and some tissues and body fluids from the patient with CJD are highly infectious and must be incinerated. We report a case of a patient who had undergone brain biopsy for suspected of CJD, being confirmed to have sporadic CJD. Specific preventive measures were taken to reduce the risk of transmission to healthcare workers.

[Perioperative management for liver transplant in a patient with familial amyloid polyneuropathy with heart involvement]. / Manejo perioperatorio del trasplante hepático en la polineuropatía amiloidótica familiar con afectación cardíaca.

Familial amyloid polyneuropathy (FAP) is a systemic amyloidosis caused by mutated transthyretin. Cardiac amyloidosis, the major prognostic determinant in systemic amyloidosis, is characterized by infiltration of the myocardium, leading to cardiomyopathy and conduction disturbances. Liver transplantation is the only curative option for patients with FAP. The case is presented of a 36-year-old patient with type i FAP with cardiac involvement, proposed for liver transplant surgery, which was successfully performed without any preoperative event of interest.