[Evolutionism. Where does Homo sapiens come from?] / El evolucionismo. ¿De dónde viene el Homo sapiens?

TITLE: El evolucionismo. ¿De dónde viene el Homo sapiens?

Serotonin disruption at gestation alters expression of genes associated with serotonin synthesis and reuptake at weaning.

RATIONALE: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. OBJECTIVE: We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. METHODS: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. RESULTS: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. CONCLUSION: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.

Glyceraldehyde-3-phosphate Dehydrogenase Common Peptides of Listeria monocytogenes, Mycobacterium marinum and Streptococcus pneumoniae as Universal Vaccines.

Universal vaccines can be prepared with antigens common to different pathogens. In this regard, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a common virulence factor among pathogenic bacteria of the genera Listeria, Mycobacterium and Streptococcus. Their N-terminal 22 amino acid peptides, GAPDH-L1 (Listeria), GAPDH-M1 (Mycobacterium) and GAPDH-S1 (Streptococcus), share 95-98.55% sequence homology, biochemical and MHC binding abilities and, therefore, are good candidates for universal vaccine designs. Here, we used dendritic cells (DC) as vaccine platforms to test GAPDH epitopes that conferred protection against Listeria monocytogenes, Mycobacterium marinum or Streptococcus pneumoniae in our search of epitopes for universal vaccines. DC loaded with GAPDH-L1, GAPDH-M1 or GAPDH-S1 peptides show high immunogenicity measured by the cellular DTH responses in mice, lacked toxicity and were capable of cross-protection immunity against mice infections with each one of the pathogens. Vaccine efficiency correlated with high titers of anti-GAPDH-L1 antibodies in sera of vaccinated mice, a Th1 cytokine pattern and high frequencies of GAPDH-L1-specific CD4+ and CD8+ T cells and IFN-γ producers in the spleens. We concluded that GAPDH-L1 peptide was the best epitope for universal vaccines in the Listeria, Mycobacterium or Streptococcus taxonomic groups, whose pathogenic strains caused relevant morbidities in adults and especially in the elderly.

Epitopes for Multivalent Vaccines Against Listeria, Mycobacterium and Streptococcus spp: A Novel Role for Glyceraldehyde-3-Phosphate Dehydrogenase.

The glycolytic enzyme and bacterial virulence factor of Listeria monocytogenes, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Lmo2459), ADP-ribosylated the small GTPase, Rab5a, and blocked phagosome maturation. This inhibitory activity localized within the NAD binding domain of GAPDH at the N-terminal 1-22 peptides, also conferred listeriosis protection when used in dendritic cell-based vaccines. In this study, we explore GAPDH of Listeria, Mycobacterium, and Streptococcus spp. taxonomic groups to search for epitopes that confer broad protection against pathogenic strains of these bacteria. GAPDH multivalent epitopes are selected if they induce inhibitory actions and wide-ranging immune responses. Proteomic isolation of GAPDH from dendritic cells infected with Listeria, Mycobacterium, or Streptococcus confirmed similar enzymatic, Rab5a inhibitory and immune stimulation abilities. We identified by bioinformatics and functional analyses GAPDH N-terminal 1-22 peptides from Listeria, Mycobacterium, and Streptococcus that shared 95% sequence homology, enzymatic activity, and B and T cell immune domains. Sera obtained from patients or mice infected with hypervirulent pathogenic Listeria, Mycobacterium, or Streptococcus presented high levels of anti-GAPDH 1-22 antibodies and Th2 cytokines. Monocyte derived dendritic cells from healthy donors loaded with GAPDH 1-22 peptides from Listeria, Mycobacterium, or Streptococcus showed activation patterns that correspond to cross-immunity abilities. In summary, GAPDH 1-22 peptides appeared as putative candidates to include in multivalent dendritic based vaccine platforms for Listeria, Mycobacterium, or Streptococcus.

Splenic volume as a biomarker of hepatic damage after chemotherapy in patients with resected colorectal liver metastases (CRLM).

BACKGROUND: Chemotherapy-associated liver injury (CALI) is a matter of concern for hepatobiliary surgeons as it can entail postoperative liver failure after an extensive hepatectomy. Recent studies have taken special interest in liver function parameters which can correlate with CALI to decrease this adverse event. Therefore, the current study investigates the usefulness of splenic volume as a biomarker of CALI through a portal hypertension mechanism, in patients with colorectal liver metastases (CRLM). STUDY DESIGN: We carried out a study in patients with CRLM operated on between 2009 and 2014 in our center. All samples of healthy liver were graded for non-alcoholic fatty liver disease (NAFLD) and sinusoidal obstructive syndrome. Computarized tomography scans for spleen volumetry were analyzed for each patient at CRLM diagnosis, after neoadjuvant chemotherapy, 1 and 6 months after resection. RESULTS: A group of 65 consecutive patients with CRLM of large bowel adenocarcinoma submitted to liver resection were included. Patients receiving neoadjuvant chemotherapy had a greater spleen volume increase than those who did not receive treatment (p = 0.053), finding a statistically significant spleen growth in patients with NAFLD (p = 0.036). There was no correlation between spleen enlargement and postoperative complications or average stay. However, survival was decreased in patients with spleen growth and CALI. CONCLUSIONS: Patients who receive neoadjuvant chemotherapy for liver metastasis surgery have a greater splenic volume increase, which correlates with NAFLD and a lower survival.

Réplica de los autores: Aclaraciones sobre el artículo "Recomendaciones basadas en la evidencia para el manejo del dolor neuropático (revisión de la literatura)" / Author's reply: Explanations on the article "Recommendations based on evidence for the management of neuropathic pain (review of the literature)"

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Intracranial self stimulation upregulates the expression of synaptic plasticity related genes and Arc protein expression in rat hippocampus.

Post-training lateral hypothalamus (LH) intracranial self stimulation (ICSS) has a reliable enhancing effect on explicit memory formation evaluated in hippocampus-dependent tasks such as the Morris water maze. In this study, the effects of ICSS on gene expression in the hippocampus are examined 4.5 h post treatment by using oligonucleotide microarray and real-time PCR, and by measuring Arc protein levels in the different layers of hippocampal subfields through immunofluorescence. The microarray data analysis resulted in 65 significantly regulated genes in rat ICSS hippocampi compared to sham, including cAMP-mediated signaling as one of the most significantly enriched Database for Annotation, Visualization and Integrated Discovery (DAVID) functional categories. In particular, expression of CREB-dependent synaptic plasticity related genes (c-Fos, Arc, Bdnf, Ptgs-2 and Crem and Icer) was regulated in a time-dependent manner following treatment administration. Immunofluorescence results showed that ICSS treatment induced a significant increase in Arc protein expression in CA1 and DG hippocampal subfields. This empirical evidence supports our hypothesis that the effect of ICSS on improved or restored memory functions might be mediated by increased hippocampal expression of activity-dependent synaptic plasticity related genes, including Arc protein expression, as neural mechanisms related to memory consolidation.

Learning and memory consolidation: linking molecular and behavioral data.

This paper puts together and links some classic and recent molecular data and hypothesis from different authors and laboratories related to learning and memory consolidation. Mainly addressed to non-specialists, it describes how the glutamatergic activation of plastic synapses in the hippocampus can give rise to new or enlarged dendritic spines which may constitute the main structural basis of some kind of memories. To establish learning and memory, the nervous system can use part of the same mechanisms which make the basic structure of neurons during the ontogenetic development of the brain. Through different families of kinases, phosphatases and other proteins, the activated N-methyl-d-aspartate (NMDA) receptors and different intracellular signals originated in the post-synaptic membranes can promote the synthesis of new proteins and the dynamic of actin. The consecutive morphological changes in the cytoskeleton of the neuron, later stabilized by new receptors inserted in the post-synaptic membranes, make possible memory consolidation. Short and long-term, as well as persistence, of memory mechanisms are related to these molecular processes. Recent research on system consolidation and memory allocation in neural circuits is also explained.

Intracranial self-stimulation induces expression of learning and memory-related genes in rat amygdala.

Intracranial self-stimulation (ICSS) in the lateral hypothalamus improves memory when administered immediately after a training session. In our laboratory, ICSS has been shown as a very reliable way to increase two-way active avoidance (TWAA) conditioning, an amygdala-dependent task. The aim of this work was to study, in the rat amygdala, anatomical and molecular aspects of ICSS, using the same parameters facilitating TWAA. First, we examined the activation of ipsilateral and contralateral lateral (LA) and basolateral (BLA) amygdala, the main amygdalar regions involved in the TWAA, by the immunohistochemical determination of c-Fos protein expression. Second, we tested the effects of the ICSS treatment on the expression of 14 genes related to learning and memory processes using real-time polymerase chain reaction. Results showed a bilateral increase in c-Fos protein expression in LA and BLA nuclei after ICSS treatment. We also found that Fos, brain-derived nerve growth factor (BDNF), Arc, inducible cAMP early repressor (ICER), COX-2, Dnajb1, FKpb5 and Ret genes were upregulated in the amygdala 90 min and 4.5 h post ICSS. From this set of genes, BDNF, Arc and ICER are functionally associated with the cAMP-responsive element-mediated gene transcription molecular pathway that plays a pivotal role in memory, whereas Dnajb1 and Ret are associated with protein folding required for plasticity or neuroprotection. Our results suggest that ICSS induces expression of genes related with synaptic plasticity and protein folding functions in the rat amygdaloid area, which may be involved in the molecular mechanisms by which ICSS may improve or restore memory functions related to this brain structure.

Infliximab safety profile and long-term applicability in inflammatory bowel disease: 9-year experience in clinical practice.

BACKGROUND: Most available data on infliximab therapy come from large, short-term, pivotal RCTs and concerns about long-term safety profile still remain. AIM: To evaluate the long-term safety profile of infliximab in inflammatory bowel disease (IBD) in a clinical practice setting. METHODS: Since 1999, all IBD patients treated with infliximab were registered and clinical outcomes prospectively recorded up to March 2008, loss of follow-up or patient's death. Infliximab regimens and preventive measures were in accordance with the prevalent guidelines or with the manufacturer's recommendations. RESULTS: One hundred fifty-two patients were included (121 Crohn's disease, 24 ulcerative colitis, 7 indeterminate colitis), with a median of 5 infliximab infusions (IQR 3-8) and 87% of patients received at least three infusions. Seventy-nine per cent of them received concomitant immunomodulators and 70% were pre-medicated with hydrocortisone from the first infusion. After a median follow-up of 142 weeks, 13% presented infusion reactions, 13% viral or bacterial infections and two patients developed neoplasia. The mortality rate was 2.6% (four patients). CONCLUSIONS: Infliximab therapy is safe when the recommended preventive measures are implemented, with a rate of serious adverse events less than 10%. No new safety signals were found.

Intracranial self-stimulation to the lateral hypothalamus, a memory improving treatment, results in hippocampal changes in gene expression.

Intracranial self-stimulation (ICSS) within the medial forebrain bundle of the lateral hypothalamus (LH) facilitates consolidation of implicit and explicit memories for a variety of learning paradigms in rats. However, the neural and molecular mechanisms involved in memory facilitation by ICSS are not known. Here, we investigated the influence of ICSS treatment on hippocampal gene expression in order to identify potential signaling pathways and cellular processes involved in ICSS-mediated cognitive improvements. Immunohistochemistry studies demonstrated that ICSS caused a rapid induction of c-Fos expression in hippocampal cornu ammonis (CA) 3 and dentatus gyrus areas. Moreover, using microarray or quantitative real-time polymerase chain reaction (PCR) analysis, we showed that ICSS modulates the expression of 62 hippocampal genes shortly after training. Most of the proteins encoded by these genes, such as calmodulin-dependent-phosphodiesterase 1 A (Pde1a), are part of signal transduction machineries or are related to anti-apoptosis, as heat shock 70 kDa protein 1A (Hspa1a). Importantly, 10 of the regulated genes have been previously related with learning and memory or neural plasticity, including the cocaine and amphetamine-regulated transcript (Cart), adenylate cyclase activating polypeptide 1 (Adcyap1), serum/glucocorticoid regulated kinase (Sgk), Ret proto-oncogene (Ret), and Fos. The fact that the Fos gene was differentially expressed in our microarray experiments validated our findings from our immunohistochemical studies mentioned above. In addition, using quantitative real-time PCR, we confirmed the observed expression changes for several of the genes identified by our microarray analyses. Our results suggest that ICSS may facilitate learning and memory by regulation of multiple signaling pathways in the hippocampus that may promote neuroplasticity.

Intracranial self-stimulation facilitates a spatial learning and memory task in the Morris water maze.

Learning and memory improvement by post-training intracranial self-stimulation has been observed mostly in implicit tasks, such as active avoidance, which are acquired with multiple trials and originate rigid behavioral responses, in rats. Here we wanted to know whether post-training self-stimulation is also able to facilitate a spatial task which requires a flexible behavioral response in the Morris water maze. Three experiments were run with Wistar rats. In each of them subjects were given at least five acquisition sessions, one daily, consisting of 2-min trials. Starting from a random variable position, rats had to swim in a pool until they located a hidden platform with a cue located on its opposite site. Each daily session was followed by an immediate treatment of intracranial self-stimulation. Control subjects did not receive the self-stimulation treatment but were instead placed in the self-stimulation box for 45 min after each training session. In the three successive experiments, independent groups of rats were given five, three and one trial per session, respectively. Temporal latencies and trajectories to locate the platform were measured for each subject. Three days after the last acquisition session, the animals were placed again in the pool for 60 s but without the platform and the time spent in each quadrant and the swim trajectories were registered for each subject. A strong and consistent improvement of performance was observed in the self-stimulated rats when they were given only one trial per session, i.e. when learning was more difficult. These findings agree with our previous data showing the capacity of post-training self-stimulation to improve memory especially in rats with little training or low conditioning levels, and clearly prove that post-training self-stimulation can also improve spatial learning and memory.

Tumores broncopulmonares primarios / Primary lung tumors

: La mayoría de las neoplasias pulmonares de los niños son metástasis. Aunque los tumores broncopulmonares primarios son raros en los niños, la mayoría son malignos. Debido a la rareza de estos tumores no se suelen incluir en el diagnóstico diferencial, por lo que se retrasa el tratamiento y esto repercute directamente en el pronóstico de la enfermedad. Exponemos cinco tumores primarios de la vía aérea: uno en la tráquea, tres en bronquios y uno en parénquima pulmonar. Estudiamos la clí- nica, las pruebas diagnósticas, el tratamiento y la anatomía patológica de cada uno. Dada su rareza es difícil pensar en ellos en el diagnóstico diferencial de las masas pulmonares, pero debemos tenerlos en cuenta ante niños con síntomas respiratorios que no mejoran con tratamiento médico convencional. Un diagnóstico precoz de este tipo de tumores permite un tratamiento adecuado y ofrece un mejor pronóstico a largo plazo (AU)

Pulmonary neoplasia in children is usually due to methastatic disease because primary lung tumors are very unfrequent. Due to its´rarity they are usually not included in the differential diagnosis of lung masses, so treatment is delayed and prognosis is worsened. Herein, we show our experience in the management of five primary tumors of the lung or the airway: one tracheal, three bronchial, and another intraparenchymatous. We study the clinical behaviour, diagnostic work-up, treatment, histology, and follow-up. Despite its rarity, a diagnosis of pulmonary tumor should be considered in any child with respiratory symptoms that does not improve with standard therapy. An early and accurate diagnosis and an adequate treatment are crutial in the prognosis of these patients (AU)

[Primary lung tumors]. / Tumores broncopulmonares primarios.

Pulmonary neoplasia in children is usually due to methastatic disease because primary lung tumors are very unfrequent. Due to its' rarity they are usually not included in the differential diagnosis of lung masses, so treatment is delayed and prognosis is worsened. Herein, we show our experience in the management of five primary tumors of the lung or the airway: one tracheal, three bronchial, and another intraparenchymatous. We study the clinical behaviour, diagnostic work-up, treatment, histology, and follow-up. Despite its rarity, a diagnosis of pulmonary tumor should be considered in any child with respiratory symptoms that does not improve with standard therapy. An early and accurate diagnosis and an adequate treatment are crutial in the prognosis of these patients.

Clinical evolution of luminal and perianal Crohn's disease after inducing remission with infliximab: how long should patients be treated?

BACKGROUND: Few data are available regarding the evolution of Crohn's disease after discontinuing a successful course of infliximab. AIM: To evaluate clinical outcome of Crohn's disease after induction of remission with three infliximab infusions (luminal disease) and after maintenance of remission with 1-year course of infliximab every 8 weeks (luminal and perianal). METHODS: Twenty-three patients with active luminal Crohn's disease who responded to three infusions of infliximab (0, 2, and 6 weeks), and 23 patients with sustained response to infliximab every 8 weeks during 1 year, were included. Patients were followed-up until relapse or for at least 6 months after infliximab discontinuation. Clinical outcomes and factors associated to relapse were evaluated. RESULTS: In luminal Crohn's disease, a three-infusion infliximab regimen achieved a sustained response in most patients, especially if a complete response occurred at the time of the third infusion. In patients treated for 1-year, infliximab discontinuation was also successful, with a cumulative probability of being free of relapse of 69% at 12 months. In perianal disease, early relapse was the rule after stopping infliximab treatment, with only 34% of patient maintaining remission at 1 year. CONCLUSIONS: Short regimens of infliximab might be evaluated in patients with luminal Crohn's disease. However, infliximab discontinuation is not recommended in perianal Crohn's disease, because of a high rate of early relapse.

[Autoimmune hemolytic anemia associated with ulcerative colitis]. / Anemia hemolítica autoinmunie asociada a colitis ulcerosa.

The incidence of immunological disorders has been reported to be greater in patients with inflammatory bowel disease than among the general population. The association of ulcerative colitis (UC) and autoimmune hemolytic anemia (AIHA) was first described in the early 1950s but no more than 50 cases have been described in the international literature. Detailed description of the pathogenic mechanisms involved in this association is lacking. The clinical course of AIHA and treatment response in these patients seems to be independent of UC, sometimes requiring immunosuppressive treatment and even surgery. We present 2 cases of AIHA associated with UC with distinct response to conventional treatment. We also review the literature on the subject.

Anemia hemolítica autoinmunie asociada a colitis ulcerosa / Autoimmune hemolytic anemia associated with ulcerative colitis

En pacientes con enfermedad inflamatoria intestinal se ha descrito una incidencia de enfermedades de base inmunológica mayor que la de la población general. La asociación de colitis ulcerosa (CU) y anemia hemolítica autoinmune (AHAI) se describió por primera vez a principios de la década de los cincuenta; sin embargo, no se han publicado más de 50 casos en la bibliografía mundial. Se desconoce cuáles son los mecanismos patogénicos detallados que se hallan implicados en esta asociación. La evolución clínica de la AHAI y la respuesta al tratamiento en estos pacientes parece cursar de forma independiente a la propia CU, requiriendo en ocasiones tratamiento inmunomodulador e incluso tratamiento quirúrgico. Se presentan 2 casos de AHAI asociada a CU, con distinta respuesta al tratamiento convencional, y se revisa la bibliografía al respecto

The incidence of immunological disorders has been reported to be greater in patients with inflammatory bowel disease than among the general population. The association of ulcerative colitis (UC) and autoimmune hemolytic anemia (AIHA) was first described in the early 1950s but no more than 50 cases have been described in the international literature. Detailed description of the pathogenic mechanisms involved in this association is lacking. The clinical course of AIHA and treatment response in these patients seems to be independent of UC, sometimes requiring immunosuppressive treatment and even surgery. We present 2 cases of AIHA associated with UC with distinct response to conventional treatment. We also review the literature on the subject

[Azathioprine and mesalazine in the prevention of postsurgical recurrence of Crohn's disease: a retrospective study]. / Azatioprina y mesalazina en la prevención de la recurrencia posquirúrgica en la enfermedad de Crohn: estudio retrospectivo.

OBJECTIVES: Surgical resection is still a mainstay of the treatment of Crohn's disease (CD). However, recurrence is the rule. The aim of the present study was to evaluate CD recurrence in a series of patients who underwent surgical resection with subsequent treatment with azathioprine (AZA) or mesalazine (5-ASA) and to identify the factors associated with recurrence. METHODS: The medical records of patients with CD who underwent bowel resection during a 4-year period were reviewed. Only patients who received AZA or 5-ASA as prophylaxis for recurrence were included. RESULTS: Thirty-three patients treated with AZA and 16 treated with 5-ASA were included. Endoscopic recurrence was found in 8.6% of the AZA group and in 87.5% of the 5-ASA group (p <0.001). Clinical recurrence occurred in 31.2% of patients in the 5-ASA group and in none in the AZA group (p=0.004). The accumulated probability of both clinical and endoscopic recurrence was significantly lower in the AZA group (p=0.0025 and p=0.005, respectively). Factors associated with a greater risk of endoscopic recurrence were termino-terminal anastomosis and 5-ASA treatment. The only factor associated with clinical recurrence was 5-ASA treatment. CONCLUSION: AZA seems to be more effective than 5-ASA in the prevention of postsurgical endoscopic recurrence of CD. Prospective studies with long-term follow-up are required to establish the true utility of AZA in the prophylaxis of CD recurrence.

[Opportunistic infections in patients with inflammatory bowel disease undergoing immunosuppressive therapy]. / Infecciones oportunistas en pacientes con enfermedad inflamatoria intestinal bajo tratamiento inmunosupresor.

Immunosuppressive agents (azathioprine, methotrexate) are increasingly being used in the treatment of inflammatory bowel disease. The use of immunosuppressive agents is associated with a greater risk of opportunistic infections, the most frequent of which are those caused by cytomegalovirus and varicella zoster virus. We present four cases of opportunistic infections due to Herpesviruses in patients undergoing immunosuppressive treatment with azathioprine for Crohn's disease. We also review the literature published on this topic. Two patients presented cutaneous varicella complicated by pneumonia and esophagitis respectively, one patient had cutaneous herpes zoster and the other had fatal pneumonia possibly caused by the Herpesvirus. In the first three the clinical course of the infection was favorable after withdrawing immunosuppressant treatment and initiating treatment with aziclovir. In patients Crohn's disease azathioprine treatment increases the risk of opportunistic infection by Herpesvirus. However, in the absence of other factors that increase immunosuppression, these infections usually have a benign course with specific antiviral therapy.