Is immediate weight bearing safe for subtrochanteric femur fractures in elderly patients treated by cephalomedullary nailing? A multicentric study in one hundred eighty-two patients.

PURPOSE: Biomechanical superiority of intramedullary nails over extramedullary implants has been proved for subtrochanteric fractures. Nevertheless, postoperative management of these patients has not changed, with high rates of protected weight-bearing after intramedullary nailing. The purpose of this study is to determine the mechanical complications of immediate postoperative full weigh-bearing for subtrochanteric femur fractures in elderly patients treated with a cephalomedullary nail. METHODS: We performed a retrospective case series study from patients treated with a cephalomedullary nail for subtrochanteric fractures (AO/OTA 31A.3 and 32A-32C) over a nine-year period. Patients in the immediate full weight-bearing (IFWB) group received orders for immediate full weight bear as tolerated on postoperative 48 h. Patients in the non- or limited- weight-bearing (NLWB) group received orders not to full weight bear in the immediate postoperative. RESULTS: There were five (2.7%) cases of implant failure including four cutouts and one nail breakage that needed a reoperation. Of them, one (2.2%) followed the NLWB protocol and four (2.9%) followed the IFWB protocol. Mean length of stay was 7.9 days (median 8, range 3-21) in the NLWB group and 10.7 days (median 8, range 2-60) in the IWBAT group. The NLWB group observed a 2.8-day shorter postoperative length of stay when compared to the IFWB, but the median remained equal. CONCLUSION: This study suggests that geriatric patients with subtrochanteric fractures treated by intramedullary nailing and in which a good fracture reduction was achieved, may be able to tolerate immediate postoperative full weight-bearing, not increasing reoperation rates due to implant failure.

Clinical prediction rules in acute appendicitis: which combination of variables is more effective at predicting?

BACKGROUND: Clinical prediction rules have been designed to reduce variability and improve the diagnostic process. However, there are no unanimous criteria regarding which of them is the most efficient for the diagnosis of acute appendicitis. AIM: The primary aim of this study was to assess the diagnostic efficacy of the most commonly used clinical prediction rules. The second aim was to identify the combination of the smallest number of clinical and analytical variables that would allow a cost-effective diagnostic approach. METHODS: A retrospective observational study was conducted of 458 patients who were evaluated for right iliac fossa pain between January 2010 and December 2016. The scores tested were Alvarado, AIR, RIPASA, and AAS. Univariate and multiple regressions were used for validation. RESULTS: Alvarado one was the most efficient to establish a positive diagnosis of acute appendicitis. However, the most simplified and predictive combination variables included anorexia, white blood cell count > 8275 leukocytes/mL, neutrophilia (> 75%), abdominal pain < 48 h, migrating pain, and temperature out the range of 37-39ºC. CONCLUSIONS: A new and effective CPR (HMC score) for predicting appendicitis in patients presenting with the right iliac fossa pain has been established.

INTRODUCCIÓN: Las escalas de predicción diagnóstica (EPD) se han diseñado con el objetivo de reducir la variabilidad y mejorar el proceso de diagnóstico. Sin embargo, no existen criterios unánimes sobre cuál de ellas es la más el más eficiente para el diagnóstico de apendicitis aguda. OBJETIVO: El objetivo principal de este estudio fue evaluar la eficacia diagnóstica de las escalas de predicción diagnóstica más utilizadas. El segundo objetivo fue identificar la combinación del menor número de variables clínicas y analíticas que permitieran un enfoque diagnóstico más eficiente. MÉTODOS: Se realizó un estudio observacional retrospectivo de 458 pacientes que fueron evaluados por dolor en la fosa ilíaca derecha entre enero de 2010 y diciembre de 2016. Las escalas evaluadas fueron las de Alvarado, AIR, RIPASA y AAS. Se utilizaron la regresion univariada y la múltiple para la validación de los resultados. RESULTADOS: la escala de Alvarado fue la más eficiente para establecer un diagnóstico de apendicitis aguda. No obstante, la combinación de las siguientes variables: anorexia, recuento de leucocitos > 8275 leucocitos/mL, neutrofilia (> 75%), dolor abdominal < 48 horas, dolor migratorio y temperatura fuera del rango de 37-39ºC, demostró ser la más eficiente para establecer un diagnóstico positivo de apendicitis aguda. CONCLUSIONES: Se ha desarrollada una nueva EPD (escala HMDC) para determinar la presencia de apendicitis en pacientes evaluados por dolor en la fosa ilíaca derecha.

Manejo laparoscópico de las hernias ventrales mediante abordaje totalmente extraperitoneal (eTEP): experiencia inicial y resultados a corto plazo / Laparoscopic Management of Ventral Hernias by Totally Extraperitoneal (eTEP) Approach: Initial Experience and Short-Term Results / Manejo laparoscópico de hérnias ventrais usando uma abordagem totalmente extraperitoneal (eTEP): experiência inicial e resultados em curto prazo

Introducción. El manejo de la hernia ventral sigue siendo un desafío para los cirujanos. Su reparación mediante técnicas mínimamente invasivas, como la totalmente extraperitoneal (eTEP) laparoscópica, permite una amplia disección del espacio a reparar, una recuperación postoperatoria más rápida, menor dolor postoperatorio y estancia hospitalaria. El abordaje eTEP es un enfoque novedoso que utiliza el espacio retromuscular para colocar material protésico y fortalecer la pared abdominal. El objetivo es describir los resultados a corto plazo de nuestra experiencia inicial con la técnica eTEP en el manejo de las hernias ventrales. Metodología. Estudio observacional, descriptivo, retrospectivo, donde se incluyen pacientes con el diagnóstico de hernia ventral, sometidos a cirugía laparoscópicaeTEP, entre julio-2021 y junio-2022. Resultados. De un total de 21 pacientes, el 61.9% fueron hombres. El 47.6% tenían sobrepeso y el 52.4% obesidad. Estancia hospitalaria media: 1.6 días. El 66.7% fueron hernias incisionales. Las técnicas quirúrgicas realizadas fueron: Rives-Stoppa (71.4%) asociándose liberación del músculo transverso en el 28.6%. El 19% de los pacientes presentaron complicaciones globales y solo uno fue grave, requiriendo reintervención quirúrgica. Se observó la presencia de seroma clínico en el 9.5% y ecográfico en 57.1%. No se evidenciaron hematomas, infección de herida quirúrgica ni casos de recidiva herniaria. Discusión y conclusiones. El abordaje laparoscópico eTEP Rives-Stoppa, asociado o no a separación posterior de componentes, en el manejo de las hernias ventrales ofrece buenos resultados asociando una baja incidencia de complicaciones postoperatorias, corta estancia hospitalaria, baja incidencia de recidivas herniarias, por lo que podría considerarse una técnica segura y efectiva en el tratamiento de las hernias ventrales.

Introduction. Managing ventral hernia remains a challenge for surgeons. Repairing it using minimally invasive techniques, such as laparoscopic totally extraperitoneal (eTEP), which allows for a wide dissection of the space to be repaired, faster postoperative recovery, less postoperative pain and shorter hospital stay. The eTEP approach is a novel technique that focus on the uses of the retromuscular space to place prosthetic material and strengthen the abdominal wall. The objective is to describe the short-term results of our initial experience with the eTEP technique in the management of ventral hernias. Methodology. Observational, descriptive, retrospective, study, which included patients with a diagnosis of ventral hernia, undergoing laparoscopic eTEP surgery, between July-2021 and June-2022. Results. Of a total of 21 patients, 61.9% were men. 47.6% were overweight and 52.4% were obese. Average hospital stay: 1.6 days. 66.7% were incisional hernias. The surgical techniques performed were: Rives-Stoppa (71.4%) with associated transversus abdominis muscle release in 28.6%. 19% of the patients presented global complications and only one was severe, requiring surgical reintervention. The presence of clinical seroma was observed in 9.5% and ultrasound in 57.1%. There was no evidence of hematomas, surgical wound infection or cases of hernia recurrence. Discussion and conclusions. The laparoscopic-eTEP Rives-Stoppa approach, associated or not with posterior separation of components, in the management of ventral hernias offers good results with a low incidence of postoperative complications, short hospital stay, low incidence of hernia recurrences, so it could be considered a safe and effective technique in the treatment of ventral hernias.

Introdução. O manejo da hérnia ventral continua sendo um desafio para os cirurgiões. Seu reparo por meio de técnicas minimamente invasivas, como a totalmente extraperitoneal (eTEP) laparoscópica, permite ampla dissecção do espaço a ser reparado, recuperação pós-operatória mais rápida, menor dor pós-operatória e menor tempo de internação. A abordagem eTEP é uma nova abordagem que usa o espaço retromuscular para colocar material protético e fortalecer a parede abdominal. O objetivo é descrever os resultados de curto prazo de nossa experiência inicial com a técnica eTEP no manejo de hérnias ventrais. Metodologia. Estudo observacional, descritivo, retrospectivo, longitudinal, que inclui pacientes com diagnóstico de hérnia ventral, submetidos a cirurgia laparoscópica-eTEP, entre julho-2021 e junho-2022. Resultados. De um total de 21 pacientes, 61.9% eram homens; 47.6% estavam com sobrepeso e 52.4% obesos. Tempo médio de internação: 1.6 dias; 66.7% eran hérnias incisionais. As técnicas cirúrgicas realizadas foram: Rives-Stoppa (71.4%) associada à liberação do músculo transverso em 28.6%. 19% dos pacientes apresentaram complicações globais e apenas um foi grave, necesitando de reintervenção cirúrgica. A presença de seroma clínico foi observada em 9.5% e ultrassonográfica em 57.1%. Não houve evidência de hematoma, infecção de ferida cirúrgica ou casos de recidiva de hérnia. Discussão e conclusões. A abordagem laparoscópica eTEP Rives-Stoppa, associada ou não à separação posterior dos componentes, no manejo das hérnias ventrais oferece bons resultados associando baixa incidência de complicações pós-operatórias, curto tempo de internação, baixa incidência de recidivas de hérnias, pelo que pode ser considerada uma técnica segura e eficaz no tratamento das hérnias ventrais.

Fluoroscopic landmarks to recognize iatrogenic varus displacement (wedge effect) during cephalomedullary nailing of intertrochanteric fractures.

AIMS: Iatrogenic varus malreduction after intramedullary nailing of intertrochanteric fractures (wedge effect) may be more common than previously reported. The aim of study is to determine its incidence and to define easy fluoroscopic landmarks to recognize it intraoperatively. PATIENTS AND METHODS: We included surgical procedures with residual varus malreduction and sufficient intraoperative fluoroscopy images to assess an intraoperative anatomical reduction at the beginning of the procedure. Two intraoperative fluoroscopic landmarks were defined to assess varus in the anteroposterior view: the position of the greater trochanter (GT) related to the femoral shaft (medialized GT sign), and the position (superior, centre or inferior) of the guide wire in both the neck and the head of the femur (cross wire sign). We describe our current method of treatment to avoid this complication. RESULTS: A total of 369 extracapsular hip fractures were treated using PFNA and Gamma 3 systems. We found 55 (14.9%) fractures with a varus malreduction. Six were underreduced and fixed in varus. Thirty-five (9.48%) were well reduced by closed reduction but suffered a iatrogenic varus displacement when introducing the nail. 31 were female; mean age was 86.6 (range 70-97). Mean postoperative head-shaft angle was 119,2° range (113°-123°). Mean TAD was 24,37 range (14-36 mm). CONCLUSION: Wedge effect (iatrogenic varus displacement of a well reduced intertrochanteric fracture when introducing the nail) could occur in at least 10% of intertrochanteric fractures. The medialized GT and the "crossing wire sign" seem to be good predictors of iatrogenic varus malalignement.

Incidence of diabetes mellitus and associated risk factors in the adult population of the Basque country, Spain.

The aim of this study was to estimate the incidence of diabetes mellitus in the Basque Country and the risk factors involved in the disease by reassessing an adult population after 7 years of follow-up. In the previous prevalence study, 847 people older than 18 years were randomly selected from all over the Basque Country and were invited to answer a medical questionnaire, followed by a physical examination and an oral glucose tolerance test. In the reassessment, the same variables were collected and the resulting cohort comprised 517 individuals of whom 43 had diabetes at baseline. The cumulative incidence of diabetes was 4.64% in 7 years and the raw incidence rate was 6.56 cases/1000 person-years (95%CI: 4.11-9.93). Among the incident cases, 59% were undiagnosed. The most strongly associated markers by univariate analyses were age > 60 years, dyslipidaemia, prediabetes and insulin resistance. We also found association with hypertension, obesity, family history of diabetes and low education level. Multivariate analysis adjusted for age and sex showed that a set of risk factors assessed together (dyslipidaemia, waist-to-hip-ratio and family history of diabetes) had great predictive value (AUC-ROC = 0.899, 95%CI: 0.846-0.953, p = 0.942), which suggests the need for early intervention before the onset of prediabetes.

Laparoscopic Appendectomy in the Setting of Clinical Prediction Rules.

PURPOSE: Acute appendicitis (AA) is the most frequent surgical entity in the emergency department, but its correct diagnosis remains challenging. To improve diagnosis, clinical prediction rules (CPRs) have been created to establish objective scores for the probability of suffering AA. In this study, we establish scores indicating whether laparoscopy would be superior to clinical observation or repeat diagnostic test. METHODS: A retrospective observational study was conducted with 433 patients submitted to surgery for suspected AA using a laparoscopic approach. The Alvarado, Raja Isteri Pengiran Anak Saleha Appendicitis, appendicitis inflammatory response, and adult appendicitis score scales were applied in each case to establish a high, medium, or low probability of suffering AA. RESULTS: Of the 433 patients analyzed, 381 (88.0%) had AA. Twelve (2.8%) were converted to open surgery, and complications were observed in 54 (12.5%) cases. The CPRs studied showed statistically significant differences between AA and negative appendectomies. However, in patients with intermediate probability scores, the diagnostic accuracy of the CPRs evaluated was not adequate. CONCLUSIONS: Laparoscopic surgery can serve as a diagnostic tool for patients with intermediate AA probability scores because of its low associated morbidity and mortality and because it affords a direct diagnosis of the problem, allowing determination of the appropriate treatment.

miR-28 regulates the germinal center reaction and blocks tumor growth in preclinical models of non-Hodgkin lymphoma.

Non-Hodgkin lymphoma comprises a variety of neoplasms, many of which arise from germinal center (GC)-experienced B cells. microRNA-28 (miR-28) is a GC-specific miRNA whose expression is lost in numerous mature B-cell neoplasms. Here we show that miR-28 regulates the GC reaction in primary B cells by impairing class switch recombination and memory B and plasma cell differentiation. Deep quantitative proteomics combined with transcriptome analysis identified miR-28 targets involved in cell-cycle and B-cell receptor signaling. Accordingly, we found that miR-28 expression diminished proliferation in primary and lymphoma cells in vitro. Importantly, miR-28 reexpression in human Burkitt (BL) and diffuse large B-cell lymphoma (DLBCL) xenografts blocked tumor growth, both when delivered in viral vectors or as synthetic, clinically amenable, molecules. Further, the antitumoral effect of miR-28 is conserved in a primary murine in vivo model of BL. Thus, miR-28 replacement is uncovered as a novel therapeutic strategy for DLBCL and BL treatment.

[THE ROLE OF MATERNAL DIET IN METABOLIC AND BEHAVIOURAL PROGRAMMING: REVIEW OF BIOLOGIC MECHANISMS INVOLVED]. / EL PAPEL DE LA DIETA MATERNA EN LA PROGRAMACIÓN METABÓLICA Y CONDUCTUAL: REVISIÓN DE LOS MECANISMOS BIOLÓGICOS IMPLICADOS.

Over the last few years, a considerable amount of studies have focused on the effect of undernutrition and overnutrition during critical periods of offspring development and their risk of developing metabolic diseases later in life. Additionally, inadequate maternal diets have been involved in the malprogramming of brain functions and some behaviours. Several mechanisms have been associated with the process of malprogramming such as epigenetics modifications, excessive oxidative stress or hypothalamic alterations. This evidence supports the idea that nutritional prevention strategies must be considered for offspring during early development stages that include the preconceptional period. Additionally, studying involved mechanisms could be particularly useful in the search of efficient therapies against malprogramming.

En los últimos años, un importante número de investigaciones se han centrado en el estudio de los efectos de la subnutrición y sobrenutrición durante periodos críticos del desarrollo así como en el riesgo de desarrollar enfermedades metabólicas en etapas posteriores. Adicionalmente, las dietas maternas inadecuadas han sido implicadas en la programación errónea de las funciones cerebrales y ciertos comportamientos. Se han asociado con el proceso de una mala programación diferentes mecanismos tales como modificaciones epigenéticas, excesivo estrés oxidativo o alteraciones hipotalámicas. Estas evidencias apoyan la idea de que la prevención nutricional debe ser considerada desde estadios tempranos del desarrollo que incluyan el periodo preconcepcional. Además, la investigación sobre los mecanismos implicados puede resultar particularmente útil en la búsqueda de terapias eficientes para hacer frente a una mala programación.

El papel de la dieta materna en la programación metabólica y conductual: revisión de los mecanismos biológicos implicados / The role of maternal diet in metabolic and behavioural programming: review of biologic mechanisms involved

En los últimos años, un importante número de investigaciones se han centrado en el estudio de los efectos de la subnutrición y sobrenutrición durante periodos críticos del desarrollo así como en el riesgo de desarrollar enfermedades metabólicas en etapas posteriores. Adicionalmente, las dietas maternas inadecuadas han sido implicadas en la programación errónea de las funciones cerebrales y ciertos comportamientos. Se han asociado con el proceso de una mala programación diferentes mecanismos tales como modificaciones epigenéticas, excesivo estrés oxidativo o alteraciones hipotalámicas. Estas evidencias apoyan la idea de que la prevención nutricional debe ser considerada desde estadios tempranos del desarrollo que incluyan el periodo preconcepcional. Además, la investigación sobre los mecanismos implicados puede resultar particularmente útil en la búsqueda de terapias eficientes para hacer frente a una mala programación (AU)

Over the last few years, a considerable amount of studies have focused on the effect of undernutrition and overnutrition during critical periods of offspring development and their risk of developing metabolic diseases later in life. Additionally, inadequate maternal diets have been involved in the malprogramming of brain functions and some behaviours. Several mechanisms have been associated with the process of malprogramming such as epigenetics modifications, excessive oxidative stress or hypothalamic alterations. This evidence supports the idea that nutritional prevention strategies must be considered for offspring during early development stages that include the preconceptional period. Additionally, studying involved mechanisms could be particularly useful in the search of efficient therapies against malprogramming (AU)

Comparative study of the second and third generation of gamma nail for trochanteric fractures: review of 218 cases.

OBJECTIVES: The aim of this study was to compare the complications of the trochanteric gamma nail (TGN) and the Gamma3 Nail (G3), focusing on cutout failure. DESIGN: Retrospective comparative cohort analysis. SETTING: Level II Teaching Trauma Center academic trauma center. PATIENTS/METHODS: Two hundred eighteen trochanteric fractures with a mean follow-up of 15 months were included in the study. They were treated either with the TGN or the G3 between January 2005 and December 2010. Bivariate, stratified, and logistic regression analysis was conducted to determine the association between cutout and the independent variables. INTERVENTION: Proximal anterograde nailing with either the TGN or the G3. MAIN OUTCOME MEASUREMENTS: Patient age, sex, type of intramedullary device, stability fracture pattern, tip-apex distance (TAD), distraction at the fracture site, cervical angle, and cutout. RESULTS: The relative risk (RR) of cutout was 4.71 times higher in the group treated with G3 (P < 0.01). RR of cutout for unstable fractures compared with stable fractures was 3.07 (1.01-9.35). In unstable fractures, the RR of cutout was 8.78 times higher in patients with G3 (P < 0.01). RR of cutout was 1.54 times higher with TAD >25 mm (P = 0.4). DISCUSSION: We have not found any relationship between cutout rate and TAD. Only the fracture pattern and the type of implant have shown to be associated with cutout risk. In our study, Gamma3 Nail has higher cutout rates than TGN in unstable fractures. LEVEL OF EVIDENCE: Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence.

How to reduce the laparoscopic colorectal learning curve.

BACKGROUND: The laparoscopic approach for colorectal pathologies is becoming more widely used, and surgeons have had to learn how to perform this new technique. The purpose of this work is to study the indicators of the learning curve for laparoscopic colectomy in a community hospital and to find when the group begins to improve. METHODOLOGY: From January 1 2005 to December 31 2012, 313 consecutive laparoscopic colorectal surgeries were performed (105 rectal and 208 colonic) by at least 60% of the same surgical team (6 members) in each operation. We evaluate the learning curve by moving averages and cumulative sums (CUSUM) for different variables related to the surgery outcomes. RESULTS: Moving average curves for postoperative stay, fasting, and second step analgesia show a stabilizing trend toward improvement as we get more experience. However, intensive care unit stay, number of lymph nodes achieved, and operating time did not show a clear decreasing tendency. CUSUM curves of conversion, specimens<12 lymph nodes, and complications all show a clear turning point marked on all the charts around the procedure 60, accumulating a positive trend toward improvement. The CUSUM curve of the "learning variable" shows this improvement point at procedure 70. CONCLUSIONS: The laparoscopic colectomy learning curve accelerates with a collective team involvement in each procedure. The CUSUM and moving average curves are useful for initial and ongoing monitoring of new surgical procedures. The markers of the learning curve evidenced in our study are the conversion rate, postoperative surgical morbidity, and the number of patients with a lymph node count<12. WHAT IS NEW IN THIS PAPER?: The significance of this study is the evaluation of the learning curve, in laparoscopic colorectal surgery, of a surgical team in a community hospital, using moving average and CUSUM curves. This study demonstrated that the number of patients needed to achieve skilful practice decreased when there is collective team involvement in each procedure.

Alterations in adipocytokines and cGMP homeostasis in morbid obesity patients reverse after bariatric surgery.

OBJECTIVE: Obesity-associated nonalcoholic fatty liver disease (NAFLD), covering from simple steatosis to nonalcoholic steatohepatitis (NASH), is a common cause of chronic liver disease. Aberrant production of adipocytokines seems to play a main role in most obesity-associated disorders. Changes in adipocytokines in obesity could be mediated by alterations in cyclic GMP (cGMP) homeostasis. The aims of this work were: (1) to study the role of altered cGMP homeostasis in altered adipocytokines in morbid obesity, (2) to assess whether these alterations are different in simple steatosis or NASH, and (3) to assess whether these changes reverse in obese patients after bariatric surgery. DESIGN AND METHODS: In 47 patients with morbid obesity and 45 control subjects, the levels in blood of adipocytokines, cGMP, nitric oxide (NO) metabolites, and atrial natriuretic peptide (ANP) were studied. Whether weight loss after a bariatric surgery reverses the changes in these parameters was evaluated. RESULTS: NO metabolites and leptin increase (and adiponectin decreases) similarly in patients with steatosis or NASH, suggesting that these changes are due to morbid obesity and not to liver disease. Inflammation and cGMP homeostasis are affected both by morbid obesity and by liver disease. The increases in interleukin 6 (IL-6), interleukin 18 (IL-18), plasma cGMP, ANP, and the decrease in cGMP in lymphocytes are stronger in patients with NASH than with steatosis. All these changes reverse completely after bariatric surgery and weight loss, except IL-18. CONCLUSION: Altered cGMP homeostasis seems to contribute more than inflammation to changes in leptin and adiponectin in morbid obesity.

Safety and efficacy of treatment with pegylated interferon alpha-2a with ribavirin in chronic hepatitis C genotype 4.

The hepatitis C virus (HCV) genotype is an important predictive outcome parameter for pegylated interferon plus ribavirin therapy. Most published therapeutic trials to date have enrolled mainly patients with HCV genotypes 1, 2 and 3. Limited studies have focused on genotype 4 patients, who have had a poor representation in pivotal trials. Our aim was to evaluate the efficacy and safety of treatment with standard dose pegylated interferon alfa-2a in combination with weight-based ribavirin in patients with chronic hepatitis C genotype 4. In this prospective observational study, 198 patients with HCV-4 were included in this study from February 2004 to August 2005,188 patients who received at least 1 dose of drugs were included in the ITT analysis and they were treated with pegylated interferon alfa-2a and ribavirin for 48 weeks. Baseline and demographic characteristics, response to treatment at weeks 12, 48 and 72, and the nature and frequency of adverse effects were analyzed. Virological response at week 12 was achieved in 144 patients (76.6%). Virological response at the end of treatment was present in 110 patients (58.5%). At week 72, 99 patients presented SVR (52.7%). The reported adverse events were similar to those found in the literature for treatments of similar dose and duration. In conclusion, combined treatment with pegylated interferon alfa-2a and ribavirin was well tolerated and effective in chronic hepatitis C genotype 4, yielding response rates between those reported for genotype 1 and those of genotypes 2-3.

Unsaturated fatty alcohol derivatives of olive oil phenolic compounds with potential low-density lipoprotein (LDL) antioxidant and antiobesity properties.

A new route for the synthesis of fatty alcohol derivatives of hydroxytyrosol and other olive oil phenolic compounds was developed to allow the preparation of unsaturated derivatives. The biological activity of synthesized compounds was evaluated. Most of the compounds presented a significant antioxidant activity on low-density lipoprotein (LDL) particles. The activity of the tested products was significantly influenced by the number and position of unsaturations as well as modifications on the polar head of the synthesized compounds. Some of them presented modulation of food intake in rats and, due to their molecular similarity with CB(1) endogenous ligands, the endocannabinoid system and PPAR-α were also evaluated as potential targets. The pharmacodynamics could not be totally explained by CB(1) and PPAR-α receptor interactions because only two of the four compounds with biological activity showed a CB(1) activity and all of them presented low PPAR-α affinity, not justifying its whole in vivo activity. The hydroxytyrosol linoleylether (7) increased LDL resistance to oxidation with a capacity similar to that of hydroxytyrosol and was the most active in vivo compound with a hypophagic effect comparable to that of oleoylethanolamine. We consider that this compound could be a good lead compound for future drug development in obesity treatments.

3-nitro-tyrosine as a peripheral biomarker of minimal hepatic encephalopathy in patients with liver cirrhosis.

OBJECTIVES: Between 30 and 50% of the cirrhotic patients who do not show symptoms of clinical hepatic encephalopathy (HE) present minimal hepatic encephalopathy (MHE), with mild cognitive impairment. MHE impairs the quality of life, increases the risk of suffering accidents, predicts the appearance of clinical HE, and is associated with shortened lifespan. Early detection of MHE would be very useful. The "gold standard" for MHE diagnosis is the psychometric hepatic encephalopathy score (PHES). However, it is time consuming and needs adjusting for age and educational level. It would be very useful to have some blood biomarker reflecting the presence of MHE in cirrhotic patients. The aim of this work was to identify serum molecules useful as biomarkers for MHE. METHODS: We measured in 63 controls, 43 cirrhotic patients without MHE, and 44 patients with MHE, from Hospital Clinico de Valencia, serum levels of different amino acids, cyclic guanosine monophosphate (cGMP), nitrites+nitrates, and 3-nitrotyrosine. We analyzed for each parameter its diagnostic accuracy as an indicator of MHE, as assessed using the PHES. RESULTS: These studies supported that 3-nitro-tyrosine is a good marker for MHE. To validate its utility as a biomarker for MHE, we analyzed in a second cohort of 44 cirrhotic patients without MHE and 18 patients with MHE, from Hospital Arnau de Vilanova, serum levels of 3-nitro-tyrosine, methionine, and citrulline. Citrulline (173±17%), methionine (173±16%), and 3-nitro-tyrosine (857±92%) were increased in sera from patients with MHE when compared with those without MHE. The receiver operating characteristic (ROC) curve analysis of 3-nitro-tyrosine for the diagnosis of MHE in the first cohort showed an area under the curve (AUC) value of 0.96 (95% confidence interval 0.93-0.99). At the cutoff of 14 nM, the specificity was 93%, sensitivity 89%, and positive and negative predictive values were both 91%. When the same cutoff was applied to the second cohort, the specificity was 83% and sensitivity was 94%. The positive and negative predictive values were 70 and 97%, respectively. CONCLUSIONS: This pilot study, to be validated in a larger cohort, shows that determination of 3-nitro-tyrosine in serum, which is easy and not time consuming, is useful to identify patients with MHE, with good sensitivity, specificity, and positive and negative predictive values.

Metabolic profile of chronic liver disease by NMR spectroscopy of human biopsies.

Among the different processes occurring during the evolution of liver disease, fibrosis has a predominant role. Liver fibrosis mechanisms are fairly constant irrespective of the underlying etiology. Cirrhosis is the end-stage of this reaction. Metabolic profiles, which are affected by many physiological and pathological processes, may provide further insight into the metabolic consequences of this severe liver disease. The aim of this study was to demonstrate the applicability of 1H high resolution magic angle spinning (HR-MAS) NMR spectroscopy in the biochemical profile determination of human liver needle biopsy samples for the characterization of metabolic alterations related to the severity of liver disease. We recorded and analyzed HR-MAS spectra of 68 liver tissue samples obtained by needle biopsy from patients with chronic liver disease. Multivariate analysis was applied to these data to obtain discrimination patterns and to reveal relevant metabolites. The metabolic characterization of liver tissue from needle biopsies by HR-MAS NMR spectroscopy provided differential patterns for cirrhotic and non-cirrhotic chronic liver disease tissue. Metabolites closely related to the liver metabolism such as some fatty acids, glucose and amino acids show differences between the two groups. Phospholipid precursors, which have been previously correlated with hepatic lesions also show differences. Furthermore, the correlation between histologically assessed liver disease stages and the levels of the most discriminative metabolites show that liver dysfunction is present at the initial stages of chronic hepatic lesions. Overall, this work suggests that the additional information obtained by NMR metabolomics applied to needle biopsies of human liver may be useful for assessing metabolic alterations and liver dysfunction in chronic liver disease.

Unchanged plasma levels of dimethylarginines and nitric oxide in chronic hepatitis C.

OBJECTIVE: Previous studies have shown that asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and nitric oxide (NO) play a prominent role in liver dysfunction. The objective of this study was to determine whether plasma levels of ADMA, SDMA and NO are altered in patients with chronic hepatitis C. MATERIAL AND METHODS: Plasma levels of ADMA, SDMA and NO (nitrite plus nitrate) were measured in 22 patients with chronic hepatitis C and 24 patients with sustained virologic response after treatment with peginterferon plus ribavirin. Seven healthy volunteers served as controls. RESULTS: Plasma levels of ADMA, SDMA and NO were not significantly different between groups: chronic hepatitis C, ADMA 0.55+/-0.06, SDMA 0.22+/-0.03, NO 36.3+/-5.9 micromol/l; treated patients, ADMA 0.60+/-0.15, SDMA 0.31+/-0.05, NO 36.1+/-5.5 micromol/l; controls, ADMA 0.65+/-0.08, SDMA 0.28+/-0.05, NO 40.7+/-8.9 micromol/l). CONCLUSIONS: Our results show that plasma NO, ADMA and SDMA concentrations are not changed in patients with chronic hepatitis C without superimposed signs of acute inflammatory activity. Furthermore, no significant differences in plasma values of NO and dimethylarginines were observed between the group of untreated patients and the group of patients treated with interferon plus ribavirin.

IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy.

BACKGROUND AND AIMS: Patients with liver cirrhosis may present minimal hepatic encephalopathy (MHE) that can be unveiled using specific neuropsychologic examination. Evaluation of MHE in cirrhotic patients might have prognostic value. The psychometric HE score (PHES) has been recommended as the "gold standard" in the diagnosis of MHE. It has been proposed that critical flicker frequency (CFF) analysis would be useful for easier detection of MHE. It would also be useful to have some peripheral parameter that could reflect the presence of MHE. It has been recently proposed that inflammation-associated alterations and hyperammonemia may cooperate in the induction of hepatic encephalopathy. The aim of the present work was to assess whether there is a correlation between the alterations in parameters reflecting inflammation, hyperammonemia, and the presence of MHE. METHODS: We have studied in 55 patients with liver cirrhosis and 26 controls the performance in the PHES battery and the CFF, ammonia, and some interleukins (ILs) as inflammatory markers. RESULTS: IL-6 and IL-18 were significantly higher (2.5-fold and 2.2-fold, respectively) in patients with MHE than in those without MHE. There were significant correlations between IL-6 or IL-18 levels and PHES score and CFF. Moreover, all patients with MHE had IL-6 levels higher than 11 ng/mL, whereas all patients without MHE had IL-6 levels lower than 11 ng/mL. CONCLUSIONS: Inflammatory alterations related with IL-6 and IL-18 may contribute to MHE. Serum concentration of IL-6 and IL-18 may be useful to discriminate cirrhotic patients with and without MHE.