Interferon-free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review.

Treatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct-acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3-infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon-free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV-HCV-coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult-to-treat subgroup in the near future.

[Cortical spreading depolarization phenomena in patients with traumatic and ischemic brain injuries. Results of a pilot study]. / Fenómenos de despolarización cortical propagada en los pacientes con lesiones cerebrales traumáticas e isquémicas. Resultados de un estudio piloto.

OBJECTIVES: To determine the frequency and duration of cortical spreading depolarization (CSD) and CSD-like episodes in patients with traumatic brain injury (TBI) and malignant middle cerebral artery infarction (MMCAI) requiring craniotomy. DESIGN: A descriptive observational study was carried out during 19 months. SETTING: Neurocritical patients. PATIENTS: Sixteen patients were included: 9 with MMCAI and 7 with moderate or severe TBI, requiring surgical treatment. INTERVENTIONS: A 6-electrode subdural electrocorticographic (ECoG) strip was placed onto the perilesional cortex. MAIN VARIABLES OF INTEREST: An analysis was made of the time profile and the number and duration of CSD and CSD-like episodes recorded from the ECoGs. RESULTS: Of the 16 patients enrolled, 9 presented episodes of CSD or CSD-like phenomena, of highly variable frequency and duration. CONCLUSIONS: Episodes of CSD and CSD-like phenomena are frequently detected in the ischemic penumbra and/or traumatic cortical regions of patients with MMCAI who require decompressive craniectomy or of patients with contusional TBI.

[Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients]. / ¿Es el lactato un buen indicador de hipoxia tisular? Resultados de un estudio piloto en 21 pacientes con un traumatismo craneoencefálico.

UNLABELLED: Lactate and the lactate-pyruvate index (LPI) are two hypoxia markers widely used to detect brain tissue hypoxia in patients with acute traumatic brain injury. These two markers have a more complex behavior than expected as they can be abnormally high in circumstances with no detectable brain hypoxia. This condition must be considered in the differential diagnosis because it also reflects an alteration of brain energy metabolism. OBJECTIVES: 1. To describe cerebral energy metabolism characteristics observed in the acute phase of traumatic brain injury (TBI) based on two traditional indicators of anaerobic metabolism: lactate and LPI, 2. To determine the concordance between these two biomarkers in order to classify the incidence of anaerobic metabolism and 3. To classify the different types of metabolic abnormalities found in patients with moderate and severe TBI using both lactate and LPI. MATERIALS AND METHODS: Twenty-one patients were randomly selected from a cohort of moderate or severe TBI patients admitted to the neurotraumatology intensive care unit. All of them who underwent both cerebral microdialysis and brain tissue oxygen monitoring (PtiO(2)). We analyzed the levels of lactate and the LPI for every microvial within the first 96 hours after head trauma. These data were correlated with PtiO(2) values. RESULTS: Lactate levels and the LPI were respectively increased during 49.5% and 38.4% of the monitoring time. The incidence and behavior of high levels of both markers were extremely heterogeneous. The concordance between these two biomarkers to determine episodes of dysfunctional metabolism was very weak (Kappa Index=0.29; IC 95%: 0.24-0.34). Based on the levels of lactate and the LPI, we defined four metabolic patterns: I: L>2.5 mmol/L and LPR>25; II: L>2.5 mmol/L and LPR< or = 25; III: L< or = 2.5 mmol/L and LPR< or = 25; IV: L< or = 2.5 mmol/L and LPR>25). In more than 80% of cases in which lactate or LPI were increased, PtiO(2) values were within the normal range (PtiO(2)> 15 mmHg). CONCLUSIONS: Increased lactate and LPI were frequent findings after acute TBI and in most cases they were not related to episodes of brain tissue hypoxia. Furthermore, the concordance between both biomarkers to classify metabolic dysfunction was weak. LPI and lactate should not be used indistinctly in everyday clinical practice because of the weak correlation between these two markers, the difficulty in their interpretation and the heterogeneous and complex nature of the pathophysiology. Other differential diagnoses apart from tissue hypoxia should always be considered when high lactate and/or LPI are detected in the acute injured brain.

Influence of KRAS mutations on clinical outcome in patients with curatively resected stage III colon cancer treated with adjuvant chemotherapy.

OBJECTIVE: To profile and correlate KRAS mutations with outcome in stage III colon cancer (CC) patients who underwent adjuvant chemotherapy following curative resection surgery. PATIENTS AND METHODS: In this retrospective study, eligible patients were those with resected stage III CC who underwent 6-months adjuvant chemotherapy, either with fluoropyrimidine monotherapy (FP) or with oxaliplatin-based regimens (O-FP). Disease-free survival (DFS) and overall survival (OS) were analyzed and computed using the Kaplan-Meier method and the log-rank test. RESULTS: The study population included 148 patients (n=65 FP and n=83 O-FP). We identified KRAS mutations in 41/148 (27%) patients, of which 18 (44%) received FP and 23 (56%) O-FP. Five-year DFS and OS were significantly higher in patients with KRAS wild-type vs. mutant [DFS: 78 vs. 56%, HR: 0.47 (95% CI: 0.25; 0.87), p=0.01; OS: 73 vs. 68%, HR: 0.44 (95% CI: 0.21; 0.88), p=0.01]. In patients treated with FP, the 5-year DFS and OS was significantly improved in the KRAS wild-type vs. mutant group, respectively [DFS: 80 vs. 43%, HR: 2.88 (95% CI: 0.67; 3.76), p=0.014; OS: 85 vs. 68%, HR: 0.27 (95% CI: 0.10; 0.73), p=0.005]. Conversely, 5-year DFS and OS were not statistically different for patients with KRAS wild-type vs. mutations treated with O-FP, respectively [DFS: 78 vs. 65%, HR: 1.59 (95% CI: 0.67; 3.76), p=0.281; OS: 80 vs. 75%, HR: 0.73 (95% CI: 0.55; 2.12), p=0.57)]. CONCLUSIONS: Our results suggest that curatively resected stage III CC patients exhibiting wild-type KRAS status might benefit from FP alone. Conversely, an oxaliplatin-containing regimen should be recommended in KRAS mutated patients.

Brain contusions induce a strong local overexpression of MMP-9. Results of a pilot study.

BACKGROUND: Brain contusions are inflammatory evolutive lesions that induce intracranial pressure increase and edema, contributing to neurological outcome. Matrix metalloproteinases (MMPs) 2 and 9 can degrade the majority of the extracellular matrix components, and are implicated in blood-brain barrier disruption and edema formation. The aim of this study was to investigate MMP-2 and MMP-9 profiles in human brain contusions using zymography. METHODS: A prospective study was conducted in 20 traumatic brain injury patients where contusion brain tissue was resected. Brain tissues from lobectomies were used as controls. Brain homogenates were analysed by gelatin zymography and in situ zimography was performed to confirm results, on one control and one brain contusion tissue sample. FINDINGS: MMP-2 and MMP-9 levels were higher in brain contusions when compared to controls. MMP-9 was high during the first 24 hours and at 48 to 96 hours, whereas MMP-2 was slightly high at 24 to 96 hours. In situ zymography confirmed gelatin zymography results. A relation between outcome and MMP-9 levels was found; MMP-9 levels were higher in patients with worst outcome. CONCLUSIONS: Our results indicate strong time-dependent gelatinase expression primarily from MMP-9, suggesting that the inflammatory response induced by focal lesions should be considered as a new therapeutic target.

[Recent advances in regional cerebral monitoring in the neurocritical patient: brain tissue oxygen pressure monitoring, cerebral microdialysis and near-infrared spectroscopy]. / Actualizaciones en los métados de monitorización cerebral regional en los pacientes neurocríticos: presión tisular de oxígeno, microdiálisis cerebral y técnicas de espectroscopía por infrarrojos.

The long term outcome of head-injured patients depends not only on the primary brain lesions but also to a large extent on the secondary lesions. The diagnosis of many secondary lesions, and specially that of brain ischemia, is based on simultaneous monitoring of several intracranial and systemic variables. Continuous intracranial pressure (ICP) monitoring is currently considered indispensable in the management of all patients with a severe head injury and intracranial lesions. However, the information provided by this technique is insufficient to diagnose some of the complex physiopathological processes that characterize traumatic brain lesions. Consequently, the use of methods to estimate cerebral blood flow such as transcranial Doppler and jugular oximetry to complement ICP monitoring is becoming increasingly widespread. Nevertheless, determining the effect of tissue lesions and therapeutic measures on cerebral metabolism currently requires direct access to the brain parenchyma at the bedside. In this review we focus on three methods of regional cerebral monitoring: oxygen tissue pressure (PtiO(2)) monitoring, microdialysis and near-infrared spectroscopy. The bases of each method and reference values for the variables analyzed will be discussed. We also make a series of recommendations on how results should be interpreted in light of current knowledge.

[Variability in the surgical indications for posttraumatic intradural lesions]. / Variabilidad en las indicaciones quirúrgicas de las lesiones intradurales postraumáticas.

INTRODUCTION: The surgical treatment of focal intradural lesions is still a matter of considerable debate. This is especially important in the decision to evacuate brain contusions. We present the results of a prospective observational study in which the main goal was to analyze intracenter variability in the indication for surgery in focal posttraumatic intradural lesions in a department of Neurosurgery of a University Hospital with a specialized neurotrauma unit. CLINICAL MATERIAL AND METHODS: Between May 1 and December 31, 2001, 32 patients with a closed traumatic brain injury and an intradural posttraumatic focal lesion were included. The patients studied were a subgroup included in the European multicenter observational study of the management of intradural lesions conducted under the aegis of the European Brain Injury Consortium (EBIC). RESULTS: Intradural lesions > 25 cc were immediately evacuated. Nine out of thirteen patients with lesions < 25 cc also underwent surgery due to intracranial hypertension or neuroworsening. In all patients in whom lesions were surgically evacuated, the postoperative CT-scan showed neuroradiological improvement of the signs of mass effect or midline shift. CONCLUSIONS: In our center, we found no evidence of significant variability in the indications for surgery in intradural lesions of more than 25 cc. However, significant differences were detected among neurosurgeons in the surgical indications for lesions below 25 cc. The small sample analyzed precludes generalization of these conclusions. The definitive results of the EBIC study will provide the neurosurgical community with a better understanding of variability in the management of these lesions.

Epilepsy in patients with malignant middle cerebral artery infarcts and decompressive craniectomies.

UNLABELLED: Patients with malignant middle cerebral artery (MCA) infarctions who have undergone craniectomy are susceptible to the development of vascular epilepsy. Our objective was to study the factors that might influence the occurrence of seizures in this group of patients. MATERIALS AND METHODS: All patients who developed malignant MCA infarction and had undergone decompressive craniectomy in our center between November 2002 and January 2014 were evaluated. In the subsequent follow-up, we evaluated the clinical outcomes and attempted to identify the factors that were related to the occurrence of seizures. RESULTS: We evaluated a total of 80 patients. The median time at which the craniectomy was performed was 40.5h after the stroke. Seizures occurred in 47.5% of all patients. The mortality rate within the first week was 16%, and of those who survived 53.7% developed seizures; 9% of these seizures were acute symptomatic, and 44.8% were remote. The median onset of remote seizures was seven months, and the majority of these were motor seizures with generalization. Notably, the patients with seizures exhibited longer delays from stroke to craniectomy, greater involvements of the temporal lobe and a higher rate of post-craniectomy recanalization of the occluded artery. Regarding the timing of the surgeries, a significantly greater proportion of those who underwent surgery more than 42h after the stroke developed epilepsy (p=0.004). Logistic regression revealed that only prolonged delay (>42h) independently predicted the development of epilepsy (OR 5.166; IC 95% 1.451-18.389; p=0.011). CONCLUSIONS: More than half of patients with malignant MCA infarcts who underwent decompressive craniectomy developed epilepsy. The occurrence of seizures in these patients was related to the delay to the performance of the craniectomy.

Effects of fluoxetine on the immunosuppressive response to stress in mice.

Mice exposed to a chronic auditory stressor and treated with fluoxetine (5 mg/kg) showed a reduction in stress-induced suppression of thymus and spleen cellularity, and in peripheral T lymphocyte population. The blastogenic response of spleen lymphoid cells and the delayed type hypersensitivity response (DTH) to sheep red blood cells (SRBC) were also assessed and fluoxetine was found to partially reverse the inhibitory effect of stress on both parameters.

Coumarins: old compounds with novel promising therapeutic perspectives.

Natural as well as synthetic coumarins have recently drawn much attention due to its broad pharmacological activities. Many coumarins and their derivatives exert anti-coagulant, anti-tumor, anti-viral, anti-inflammatory and anti-oxidant effects, as well as anti-microbial and enzyme inhibition properties. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. The different substituents in the coumarin nucleus strongly influence the biological activity of the resulting derivatives. Although some coumarins have been already characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity for other pharmacological targets and define their mechanism of action to achieve new therapeutic drugs. The present review highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anti-cancer agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the treatment of cancer.

Successful treatment with liposomal amphotericin B of an intraabdomianl abscess due to Candida norvegensis associated with a Gore-Tex mesh infection.

There are few reports of severe infections caused by Candida norvegensis. We here describe a case of C. norvegensis-associated intraabdominal abscess and Gore-Tex mesh-associated infection, successfully treated with liposomal amphotericin B and removal of the mesh. This is, to our knowledge, the first report of C. norvegensis causing this type of infection.

Mallas intraperitoneales y adherencias: estudio comparativo: polipropileno vs. poliglactina 910 / Intraperitoneal meshes and adherences: comparative study: polypropylene vs. polyglactin 910

Los autores realizaron un estudio prospectivo y pareado de la reacción plástico adherencial frente a dos mallas protésicas intraperitoneales. Se utilizó como animal de experimentación, 20 perros mestizos que se abordaron por laparotomía mediana y se colocó una malla de polipropileno a la derecha y una de poliglactina 910 a la izquierda, en la cara profunda del peritoneo parietal anterior. Se analizó la presencia y firmeza de adherencias viscerales frente a ambas mallas. Los resultados, analizados mediante el test de x2 mostraron diferencias significativas en cuanto a la formación y firmeza de las adherencias frente a cada una de las mallas, siendo éstas más frecuentes y firmes frente a la de polipropileno