Inhibition of mitochondrial fission by Drp-1 blockade by short-term leptin and Mdivi-1 treatment improves white adipose tissue abnormalities in obesity and diabetes.

BACKGROUND: Obesity and type 2 diabetes are chronic diseases characterized by insulin resistance, mitochondrial dysfunction and morphological abnormalities. OBJECTIVE: We have investigated if dysregulation of mitochondrial dynamics and biogenesis is involved in an animal model of obesity and diabetes. METHODS: The effect of short-term leptin and mdivi-1 - a selective inhibitor of Drp-1 fission-protein - treatment on mitochondrial dynamics and biogenesis was evaluated in epididymal white adipose tissue (WAT) from male ob/ob mice. RESULTS: An increase in Drp-1 protein levels and a decrease in Mfn2 and OPA-1 protein expression were observed with enhanced and sustained mitochondrial fragmentation in ob/ob mice compared to wt C57BL/6 animals (p < 0.05). The content of mitochondrial DNA and PGC-1α mRNA expression -both parameters of mitochondrial biogenesis- were reduced in ob/ob mice (p < 0.05). Treatment with leptin and mdivi-1 significantly increased mitochondrial biogenesis, improved fusion-to-fission balance and attenuated mitochondrial dysfunction, thus inducing white-to-beige adipocyte transdifferentiation. Measurements of glucose and lipid oxidation in adipocytes revealed that both leptin and mdivi-1 increase substrates oxidation while in vivo determination of blood glucose concentration showed decreased levels by 50% in ob/ob mice, almost to the wt level. CONCLUSIONS: Pharmacological targeting of Drp-1 fission protein may be a potential novel therapeutic tool for obesity and type 2 diabetes.

Altered nitrogen metabolism in biocontrol strains of Penicillium rubens.

The importance of the metabolic route of nitrogen in the fungus Penicillium rubens (strain PO212) is studied in relation to its biocontrol activity (BA). PO212 can resist a high concentration of chlorate anion and displays a classical nitrate-deficiency (nit-) phenotype resulting in poor colonial growth when nitrate is used as the main source of nitrogen. Analyses of genes implicated in nitrate assimilation evidenced the strong sequence conservation of PO212 and CH8 genome with penicillin producers such as reference strain P. rubens Wisconsin 54-1255, P2niaD18 and Pc3, however also revealed the presence of mutations. PO212 carries a mutation in the gene coding for zinc-binuclear cluster transcription factor NirA that specifically mediates the regulation of genes involved in nitrate assimilation. The nirA1 mutation causes an early stop of NirA factor, losing 66% of its sequence. The NirA1 mutant form is unable to mediate a nitrate-dependent regulation of nitrate and nitrite reductase coding genes. In this study, we study another isolate, CH8, with potential BA and nit- phenotype. A mutation in the nitrate permease coding gene crnA was found in CH8. An insertion of a guanine in the coding sequence cause a frameshift in CrnA with the loss of the last two transmembrane domains. Analysis of PO212 and CH8 isolates and complementation strains show the importance of NirA regulator in maintaining correct transcriptional levels of nitrate and nitrite reductases and suggest CrnA as the main nitrate transporter. the presence of alternative transporter for chlorate and the existence of a mechanism for preventing nitrite derived toxicity in Penicillum. BA of PO212 is partially altered when nirA1 mutation was complemented. This result and the finding of CH8, a novel biocontrol P. rubens strain with a nit- phenotype, suggest that nitrogen metabolism is a component of biocontrol capacity.

Sub-acute herpes simplex virus myelitis in a patient with esophageal cancer on chemo-radiation with 5-fluorouracil: a case report.

No reported cases to date describe herpes simplex virus (HSV) myelitis in association with cancer and chemo-radiation. We report a case of sub-acute HSV myelitis in a 54-year-old man receiving chemo-radiation with 5-flourouracil for esophageal cancer who presented to the emergency department with increasing numbness in both lower limbs that gradually spread to waist level. Magnetic resonance imaging with gadobutrol contrast 1 week later showed transverse myelitis involving the dorsal columns. Radiation-induced myelitis was suspected, and the patient was initially treated with dexamethasone; however, CSF analysis revealed HSV myelitis. Treatment with antivirals resolved much of the numbness. HSV myelitis can be confused with complications of radiation or malignancy in patients presenting with focal neurological deficits.

Aggression and prosocial behaviors in social conflicts mediating the influence of cold social intelligence and affective empathy on children's social preference.

This study proposes a model in which aggressive and prosocial behaviors exhibited in social conflicts mediate the influence of empathy and social intelligence to children's social preference by same-sex peers. Data were obtained from kindergarten to the end of the first grade. The sample yielded 117 Spanish children (64 girls and 53 boys) with a mean age of 62.8 months (SD = 3.3) at the beginning of the study. For boys, affective empathy contributed to boys' social preference through a decrease in physical aggression as responses to social conflict. For girls, affective empathy had an indirect effect on girls' preference by increasing assistance to others in their conflicts. No mediating effect in the contribution of social intelligence on girls' social preference was detected. Our results suggest that, only for girls, cold social intelligence can promote both indirect aggression (coercive strategic that do not leave social preference, at least at these ages) and behaviors that lead social preference (such as prosocial behaviors).

Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.

Our understanding of the mechanisms by which nonalcoholic fatty liver disease (NAFLD) progresses from simple steatosis to steatohepatitis (NASH) is still very limited. Despite the growing number of studies linking the disease with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. We studied 467 biopsied individuals with normal liver histology (n=90) or diagnosed with NAFLD (steatosis, n=246; NASH, n=131), randomly divided into estimation (80% of all patients) and validation (20% of all patients) groups. Qualitative determinations of 540 serum metabolite variables were performed using ultraperformance liquid chromatography coupled to mass spectrometry (UPLC-MS). The metabolic profile was dependent on patient body-mass index (BMI), suggesting that the NAFLD pathogenesis mechanism may be quite different depending on an individual's level of obesity. A BMI-stratified multivariate model based on the NAFLD serum metabolic profile was used to separate patients with and without NASH. The area under the receiver operating characteristic curve was 0.87 in the estimation and 0.85 in the validation group. The cutoff (0.54) corresponding to maximum average diagnostic accuracy (0.82) predicted NASH with a sensitivity of 0.71 and a specificity of 0.92 (negative/positive predictive values=0.82/0.84). The present data, indicating that a BMI-dependent serum metabolic profile may be able to reliably distinguish NASH from steatosis patients, have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention.

Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors.

BACKGROUND: Elderly breast cancer patients are usually excluded from clinical trials. Nevertheless, with the increasing use of trastuzumab, there is a need to address trastuzumab-related cardiotoxicity in this population. PATIENTS AND METHODS: Records for patients ≥ 70 years treated with trastuzumab since 2005 were reviewed. New York Heart Association classification was used to document symptomatic cardiotoxicity. Asymptomatic cardiotoxicity was defined as an absolute drop ≥ 10% with a final left ventricular ejection fraction < 50% or an absolute drop > 20%. RESULTS: Forty-five patients, median age 75.9 years (range 70-92), were identified. Three of 24 (12.5%) early breast cancer patients and 5 of 21 (23.8%) with advanced disease experienced asymptomatic cardiotoxicity. Four of 45 patients (8.9%), all with advanced breast cancer, developed symptomatic congestive heart failure. All but one of them recovered in a median time of 5 weeks (range 3-21). Patients with trastuzumab-related cardiotoxicity presented more often with cardiovascular risk factors, such as history of cardiac disease (33% versus 9.1%, P = 0.017) and diabetes (33.3% versus 6.1%, P = 0.010), compared with those without. CONCLUSIONS: Elderly breast cancer patients with a history of cardiac disease and/or diabetes treated with trastuzumab have an increased incidence of cardiotoxicity. Continuous cardiac monitoring is especially advised in this population.

Mobile robotic platforms for the acoustic tracking of deep-sea demersal fishery resources.

Knowing the displacement capacity and mobility patterns of industrially exploited (i.e., fished) marine resources is key to establishing effective conservation management strategies in human-impacted marine ecosystems. Acquiring accurate behavioral information of deep-sea fished ecosystems is necessary to establish the sizes of marine protected areas within the framework of large international societal programs (e.g., European Community H2020, as part of the Blue Growth economic strategy). However, such information is currently scarce, and high-frequency and prolonged data collection is rarely available. Here, we report the implementation of autonomous underwater vehicles and remotely operated vehicles as an aid for acoustic long-baseline localization systems for autonomous tracking of Norway lobster (Nephrops norvegicus), one of the key living resources exploited in European waters. In combination with seafloor moored acoustic receivers, we detected and tracked the movements of 33 tagged lobsters at 400-m depth for more than 3 months. We also identified the best procedures to localize both the acoustic receivers and the tagged lobsters, based on algorithms designed for off-the-shelf acoustic tags identification. Autonomous mobile platforms that deliver data on animal behavior beyond traditional fixed platform capabilities represent an advance for prolonged, in situ monitoring of deep-sea benthic animal behavior at meter spatial scales.

Intracellular antimicrobial activity appearing as a relevant factor in antibiotic efficacy against an experimental foreign-body infection caused by Staphylococcus aureus.

OBJECTIVES: The presence of bacterial biofilm, tolerance to antibiotics and dysfunctional activity of phagocytic cells are all related to difficulties in eradicating foreign-body infections. We aimed to quantify the presence of intracellular Staphylococcus aureus and to study the extent to which the intracellular activity of antibiotics might determine their efficacy against an experimental rat tissue-cage model of foreign-body infection. METHODS: Using this model, animals were treated for 7 days with 100 mg/kg/day levofloxacin or 200 mg/kg/12 h cloxacillin, or were left untreated. Antibiotic efficacy was evaluated by means of bacterial counts from tissue-cage fluid (TCF); these counts were derived separately in total, intracellular and extracellular bacteria. The presence of intracellular bacteria was checked by electron microscopy. Population analysis was performed with surviving bacteria recovered at the end of levofloxacin therapy. RESULTS: Among a total number of bacteria (mean log cfu/mL +/- SD) from TCF of 6.86 +/- 0.6, we identified 6.38 +/- 0.8 intracellular bacteria and 5.57 +/- 0.5 extracellular bacteria. Levofloxacin was more efficient than cloxacillin (P < 0.05) against both intracellular and extracellular bacteria. The killing activity of levofloxacin against the intracellular population was higher than against the extracellular bacteria (P = 0.1). The frequency of levofloxacin-resistant mutants among surviving bacteria at the end of levofloxacin therapy was similar to that for the wild-type strain. CONCLUSIONS: Intracellular bacteria accounted for the largest proportion of the total inoculum in this model of foreign-body infection. The intracellular activity of an antibiotic seems to be an additional relevant factor in the antibiotic response to these infections.

Usefulness of multiparametric computerized tomography findings in the differential diagnosis of stroke mimics of epileptic origin: A preliminary study. / Utilidad de la tomografía computarizada cerebral multiparamétrica en el diagnóstico diferencial de patología comicial en el código ictus. Estudio preliminar.

OBJECTIVE: Thirty percent of the patients for whom code stroke is activated have stroke mimics, the most common being epilepsy. Our purpose was to evaluate the usefulness of multiparametric CT for differentiating between seizure-related symptoms and vascular events. MATERIAL AND METHODS: We conducted a retrospective observational study; data were gathered prospectively during one year. We studied multiparametric CT images of patients admitted following code stroke activation and finally diagnosed with epilepsy. RESULTS: The study included a total of 11 patients; 36% were men and mean age was 74.5 years. Three patients had right hemisphere syndrome, 4 displayed left hemisphere syndrome, and the remaining 4 had isolated aphasia. Maximum time from symptom onset to multiparametric CT study was 8.16hours. Perfusion CT results were normal in 2 patients. Nine patients showed longer or shorter times to peak (Tmax); cerebral blood volume (CBV) and cerebral blood flow (CBF) maps varied. EEG was performed a maximum of 47.6hours after symptom onset. Four patients showed findings compatible with status epilepticus, 2 displayed focal epileptiform activity, and 5 showed post-ictal slowing ipsilateral to perfusion CT abnormalities. CONCLUSION: The most sensitive parameter for differentiating between stroke and epilepsy in our series was increased time to peak in multilobar cortical locations in the absence of large-vessel occlusion and basal ganglia involvement. Multiparametric CT is a fast, readily available, and useful tool for the differential diagnosis of acute-onset neurological signs of epileptic origin in patients initially attended after code stroke activation.

A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease.

BACKGROUND: Dyslipidaemia and insulin resistance are two important risk factors for non-alcoholic fatty liver disease. Both factors can improve with fenofibrate. AIMS: To evaluate the effect of fenofibrate on the clinical, analytical and histological evolution of patients with non-alcoholic fatty liver disease. SUBJECTS AND METHODS: Sixteen consecutive patients with biopsy-confirmed non-alcoholic fatty liver disease were treated with 200mg/day of fenofibrate for 48 weeks. A clinical and biochemical follow-up was done every 3 months. A new liver biopsy was performed in all patients at the end of therapy. RESULTS: All patients completed 48 weeks of therapy with fenofibrate, without adverse events. At the end of the study, a significant decrease in triglyceride, glucose, alkaline phosphatase and gamma-glutamyl transpeptidase and an increase of apolipoprotein A1 levels were found. Insulin levels and insulin resistance showed a trend to decrease. Moreover, a reduction in the proportion of patients with abnormal aminotransferase levels (>45IU/L) was observed (alanine aminotransferase: 93.7% vs. 62.5%, p=0.02; aspartate aminotransferase: 50% vs. 18.7%, p=0.02). The body mass index did not show any significant change, but the proportion of patients with metabolic syndrome decreased significantly (43.7% vs. 18.7%, p=0.04). A control biopsy after treatment revealed a decrease in the grade of hepatocellular ballooning degeneration (p=0.03), but the grade of steatosis, lobular inflammation, fibrosis or non-alcoholic fatty liver disease activity score did not change significantly. CONCLUSIONS: In patients with non-alcoholic fatty liver disease, treatment with fenofibrate is safe and improves metabolic syndrome, glucose and liver tests. However, its effects on liver histology are minimal.

Arthroplasty knee registry of Catalonia: What scientific evidence supports the implantation of our prosthesis? / Registro de artroplastias de rodilla de Cataluña: ¿qué evidencia científica respalda la implantación de nuestras prótesis?

INTRODUCTION: In our environment, it is increasingly necessary to perform an activity based on scientific evidence and the field of prosthetic surgery should be governed by the same principles. The national arthroplasty registries allow us to obtain a large amount of data in order to evaluate this technique. The aim of our study is to analyse the scientific evidence that supports the primary total knee arthroplasties implanted in Catalonian public hospitals, based on the Arthoplasty Registry of Catalonia (RACat) MATERIAL AND METHODS: A review of the literature was carried out on knee prostheses (cruciate retaining, posterior stabilized, constricted and rotational) recorded in RACat between the period 2005-2013 in the following databases: Orthopedic Data Evaluation Panel, PubMed, TripDatabase and Google Scholar. The prostheses implanted in fewer than 10 units (1,358 prostheses corresponding to 62 models) were excluded. RESULTS: 41,947 prostheses (96.86%) were analysed out of 43,305 implanted, corresponding to 74 different models. In 13 models (n = 4,715) (11.24%) no clinical evidence to support their use was found. In the remaining 36 models (n = 13,609) (32.45%), level iv studies were the most predominant evidence. CONCLUSIONS: There was a significant number of implanted prostheses (11.24%) for which no clinical evidence was found. The number of models should be noted, 36 out of 110, with fewer than 10 units implanted. The use of arthroplasty registries has proved an extremely useful tool that allows us to analyse and draw conclusions in order to improve the efficiency of this surgical technique.

Pancreatic cancer heterogeneity and response to Mek inhibition.

Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.

Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction.

Non-alcoholic fatty liver disease represents a set of liver lesions similar to those induced by alcohol that develop in individuals with no alcohol abuse. When lesions consist of fatty and hydropic degeneration, inflammation, and eventually fibrosis, the condition is designated non-alcoholic steatohepatitis (NASH). The pathogenesis of these lesions is not clearly understood, but they are associated with insulin resistance in most cases. As a result, abdominal fat tissue lipolysis and excessive fatty acid uptake by the liver occur. This, together with a disturbance of triglyceride export as VLDL, results in fatty liver development. Both the inflammatory and hepatocellular degenerative components of NASH are attributed to oxidative stress. Mitochondrial respiratory chain loss of activity plays a critical role in the genesis of latter stress. This may be initiated by an increase in the hepatic TNFalpha, iNOS induction, peroxynitrite formation, tyrosine nitration and inactivation of enzymes making up this chain. Consequences of oxidative stress include: lipid peroxidation in cell membranes, stellate cell activation in the liver, liver fibrosis, chronic inflammation, and apoptosis.

[Epidemic outbreak of tuberculosis in a daycare centre in Zaragoza (Spain)]. / Brote epidémico de tuberculosis en una guardería de Zaragoza.

OBJECTIVE: To describe the clinical and radiological features, diagnosis, and treatment of an epidemic outbreak of tuberculosis in a daycare centre in Zaragoza. MATERIAL AND METHODS: The index case was a teaching assistant with a late diagnosis of bacilliferous tuberculosis. Mantoux testing was carried out in all children. In those with a positive Mantoux test, a chest X-ray was performed. Children with an abnormal chest X-ray underwent microbiological investigations. RESULTS: Among all the children in the daycare center, the Mantoux test was positive in 11 children. Chest X-ray was abnormal in 10 children. Of these, seven (70 %) were symptomatic. Chest X-ray showed dense opacification in nine children (90 %) and mediastinal lymph adenopathy in five (50 %). Three children (30 %) had lobar atelectasis requiring bronchoscopy and subsequent steroid therapy. Bacilloscopy was positive in only one child. Gastric juice culture was positive in seven children and the amplified Mycobacterium tuberculosis direct test was positive in a further seven. All microbiological investigations were negative in only one child. CONCLUSIONS: Establishing a definitive diagnosis of tuberculosis in children remains difficult and frequently relies on a constellation of clinical findings, radiology and epidemiology in children with a positive Mantoux test. The amplified Mycobacterium tuberculosis direct test has high sensitivity and provides fast results. Epidemic outbreaks continue to be frequent in Spain. Study of contacts shows high efficiency in controlling outbreaks.

[Epstein-Barr virus infection and acute cholestatic hepatitis]. / Infección por el virus de Epstein-Barr y hepatitis aguda colestásica.

Epstein-Barr virus (EBV) is a herpesvirus whose only reservoir host is the human. It is transmitted by oropharyngeal secretions. Primary EBV infection is usually asymptomatic, but sometimes it causes infectious mononucleosis with fever, lymphadenopathies, splenomegaly and pharyngitis. Acute infection is diagnosed by serology (heterophile or specific antibodies). Immunofluorescence and molecular biologic techniques may be used to demonstrate the presence of EBV in biopsy specimens. Mild and transient elevations of serum aminotransferases are common, thus liver biopsy is usually not necessary to confirm the diagnosis. Severe cholestasis is rare (5%). We describe a patient with cholestatic hepatitis and acute EBV infection with atypical lymphocytes and positive anti-VCA IgM. The patient had taken drugs (ibuprofen, paracetamol and valerian). The bad evolution of the patient, the history of exposure to drugs, and the few cases of cholestatic hepatitis due to EBV infection reported, led us to consider liver biopsy. Molecular biologic techniques confirmed the presence of EBV in liver tissue however histologic features did not exclude the toxic aetiology or the concomitant effect of drugs and EBV infection.

[Multiple cerebral haemorrhages secondary to disseminated intravascular coagulation in a patient with COVID-19]. / Hemorragias cerebrales múltiples secundarias a coagulación intravascular diseminada en un paciente con COVID-19.

TITLE: Hemorragias cerebrales múltiples secundarias a coagulación intravascular diseminada en un paciente con COVID-19.

Anandamide excites central terminals of dorsal root ganglion neurons via vanilloid receptor-1 activation.

Recently, the cannabinoid (CB) receptor agonist anandamide (AEA) has been shown to excite perivascular terminals of primary sensory neurons via activation of the vanilloid receptor-1 (VR-1). To determine whether AEA stimulates central terminals of these neurons, via VR-1 activation, we studied the release of calcitonin gene-related peptide (CGRP)- and substance P (SP)-like immunoreactivities (LI) from slices of rat dorsal spinal cord. Mobilization of Ca(2+) in rat dorsal root ganglion (DRG) neurons in culture was also studied. AEA (0.1-10 micrometer) increased the outflow of CGRP-LI and SP-LI from slices of the rat dorsal spinal cord in a Ca(2+)-dependent manner and increased [Ca(2+)](i) in capsaicin-sensitive cultured DRG neurons. Both effects of AEA were abolished by capsaicin pretreatment and by the VR-1 antagonist capsazepine but not affected by the CB receptor antagonists AM281 or AM630. Both neuropeptide release and Ca(2+) mobilization induced by electrical field stimulation (EFS) were inhibited by a low concentration of AEA (10 nm). Inhibition by AEA of EFS-induced responses was reversed by AM281 and AM630, but was not affected by capsazepine. Results indicate that stimulation of VR-1 with high concentrations of AEA excites central terminals of capsaicin-sensitive DRG neurons, thus causing neuropeptide release in the dorsal spinal cord. This novel activity opposes the CB receptor-mediated inhibitory action of low concentrations AEA. However, only if large amounts of endogenous AEA could be produced at the level of the dorsal spinal cord, they may not inhibit, but rather activate, nociceptive sensory neurons.