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Objective: To understand for what care of the patient at the end of life and their relatives means to ICU health professionals., Methods: Qualitative study with a Research-Action (AI) design, in two intensive care units of the city of Bogotá. Groups were formed in each unit and each group included at least six health professionals, the data collection techniques were: 4 participative assemblies and 6 clinical narratives, the data analysis was done through the preparation of the data, discovery of topics, coding and interpretation of data, relativisation and rigour of the data., Results: 20 ICU workers participated, the analysis of the data revealed four thematic categories: Multidisciplinary team of the ICU facing the end-of-life process, Management of critical patients and their families at the end of life in the ICU, Communication process between the patient, family and multidisciplinary team at the end of life, Ethical aspects at the end of life in the ICU CONCLUSIONS: The professionals consider preserving quality of life during the patient's stay in the ICU a therapeutic objective. The development of evidence-based guidelines that facilitate multidisciplinary management at the end of life, customisation of care, effective communication, fulfilling the physical, emotional and spiritual needs of the person and their family and favouring the patient's right of autonomy in decision making., (Copyright © 2020 Sociedad Española de Enfermería Intensiva y Unidades Coronarias (SEEIUC). Publicado por Elsevier España, S.L.U. All rights reserved.)

We sought to review literature on the prevalence of symptoms of depression in women with a diagnosis of breast cancer (BC) and in the Peruvian population determine the prevalence of symptoms of depression and to describe the association with sociodemographic characteristics. Descriptive cross-sectional analytical study of 254 patients from the National Cancer Institute of Peru (Instituto Nacional de Enfermedades Neoplásicas) with a diagnosis of clinical stage I or II BC. The patients included women aged between 26 and 67 years old. Symptoms of depression were monitored by the Beck Depression Inventory-II. Moreover, clinical features and patient sociodemographic characteristics were analyzed and their association with depression was assessed by logistic regression. The average age of the patients was 47.8 ± 9.2 years; 5.4% of the patients were postmenopausal at the time of the questionnaire. About 55% of women were from Lima, 58.3% had completed secondary education (11 ± 3.2 years), 45.7% were not working, and 46.5% were single. The prevalence of depression was 25.6% at the time of BC diagnosis. Of those patients with symptoms of depression, 16.9% showed symptoms of mild depression, 6.3% moderate, and 2.4% severe. A multivariable logistic regression model showed that in Peruvian women with a diagnosis of BC being married or employed significantly decreased the odds of presenting depressive symptoms (P = 0.029 and 0.017, respectively). Our main limitation was the lack of evaluation of depressive symptoms before the diagnosis, during or at the end of treatment. Another limitation was that the Beck Depression Inventory-II test could only identify depressive symptoms, but not depression as a disease. We have reviewed relevant literature on depression in women with a diagnosis of BC. The data presented suggests an association between both employment and marital status with depressive symptoms among Peruvian women with a diagnosis of BC. Pre-emptive support for women at risk could influence resilience and/or motivation for compliance with antineoplastic treatments., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Nuclear factor (NF)-κB controls the transcriptional response to inflammatory signals by translocating into the nucleus, but we lack a single-cell characterization of the resulting transcription dynamics. Here we show that upon tumor necrosis factor (TNF)-α transcription of NF-κB target genes is heterogeneous in individual cells but results in an average nascent transcription profile that is prompt (i.e., occurs almost immediately) and sharp (i.e., increases and decreases rapidly) compared with NF-κB nuclear localization. Using an NF-κB-controlled MS2 reporter we show that the single-cell nascent transcription is more heterogeneous than NF-κB translocation dynamics, with a fraction of synchronized "first responders" that shape the average transcriptional profile and are more prone to respond to multiple TNF-α stimulations. A mathematical model combining NF-κB-mediated gene activation and a gene refractory state is able to reproduce these features. Our work shows how the expression of target genes induced by transcriptional activators can be heterogeneous across single cells and yet time resolved on average., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Sunitinib (Su) is a tyrosine kinase inhibitor with antiangiogenic and antineoplastic effects that is recommended therapy for renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Arterial hypertension is one of the adverse effects observed in the treatment with Su. The aim of this work was to deepen our understanding of the underlying mechanisms involved in the development of this side effect. Studies on endothelial function, vascular remodeling and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) system were carried out in thoracic aortas from rats treated with Su for three weeks. Animals subjected to Su treatment presented with increased blood pressure and reduced endothelium-dependent vasodilation, the latter being reverted by NADPH oxidase blockade. Furthermore, vascular remodeling and stronger Masson trichrome staining, together with enhanced immunofluorescence signal for collagen 1 alpha 1 (Col1α1), were observed in aortas from treated animals. These results were accompanied by a significant elevation in superoxide anion production and the activity/protein/gene expression of NADPH oxidase isoforms (NOX1, NOX2, and NOX4), which was also prevented by NOX inhibition. Furthermore, a decrease in nitric oxide (NO) levels and endothelial nitric oxide synthase (eNOS) activation was observed in aortas from Su-treated animals. All these results indicate that endothelial dysfunction secondary to changes in vascular remodeling and oxidative stress might be responsible for the typical arterial hypertension that develops following treatment with Su.

Background: Recent studies showed a relevant role of hematogenous spread in ovarian cancer and the interest of circulating tumor cells (CTCs) monitoring as a prognosis marker. The aim of the present study was the characterization of CTCs from ovarian cancer patients, paying special attention to cell plasticity characteristics to better understand the biology of these cells., Methods: CTCs isolation was carried out in 38 patients with advanced high-grade serous ovarian cancer using in parallel CellSearch and an alternative EpCAM-based immunoisolation followed by RT-qPCR analysis to characterize these cells., Results: Epithelial CTCs were found in 21% of patients, being their presence higher in patients with extraperitoneal metastasis. Importantly, this population was characterized by the expression of epithelial markers as MUC1 and CK19 , but also by genes associated with mesenchymal and more malignant features as TIMP1, CXCR4 and the stem markers CD24 and CD44 . In addition, we evidenced the relevance of TIMP1 expression to promote tumor proliferation, suggesting its interest as a therapeutic target., Conclusions: Overall, we evidenced the utility of the molecular characterization of EpCAM + CTCs from advanced ovarian cancer patients to identify biomarkers with potential applicability for disseminated disease detection and as therapeutic targets such as TIMP1.

Extranodal NK/T-cell lymphoma (ENKTL) is an Epstein-Barr virus (EBV) associated lymphoma, prevalent in Asia and Latin America. Studies in Asian cohorts have identified some recurrent gene mutations in ENKTL; however, the mutational landscape of ENKTL in Latin America is unknown. In this study, we investigated the mutational profile and EBV strains of 71 ENKTL cases from Latin America (42 from Mexico, 17 from Peru, and 12 from Argentina) and compared it with Asian cohorts. The mutational analysis was performed by next generation sequencing (NGS) using an Ion AmpliSeq™ custom panel covering for the most frequently mutated genes identified in ENKTL. STAT3 was the most frequent mutated gene (16 cases: 23%), followed by MSN (10 cases; 14%), BCOR (9 cases; 13%), DDX3X (6 cases; 8%), TP53 (6 cases; 8%), MGA (3 cases; 4%), JAK3 (2 cases; 3%), and STAT5B (1 case; 1%). Mutations in STAT3, BCOR, and DDX3X were nearly mutually exclusive, suggesting different molecular pathways involved in the pathogenesis of ENKTL; whereas mutations in MGA, MSN, and TP53 were concomitant with other mutations. Most cases (75%) carried Type A EBV without the 30-bp LMP1 gene deletion. The overall survival was significantly associated with serum LDH level, Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) score, and therapy (p < 0.05), but not associated with any mutation, EBV strain or deletion in EBV LMP1 gene. In conclusion, mutational analysis of ENKTL from Latin America reveals frequent gene mutations leading to activation of the JAK-STAT pathway (25%), mostly STAT3. Compared to Asian cohorts, BCOR, DDX3X  and TP53 mutations were also identified but with different frequencies. None of these mutations were associated with prognosis.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2 + tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2 + tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2 + breast cancer suggests that the high incidence of HER2 + subtypes in Latinas might be due to population and subtype-specific genetic risk variants., (©2020 American Association for Cancer Research.)

Crime victimization is one of the most pressing public health concerns in Latin America. Young people in the region are at particularly high risk of victimization. The present study examined exposure to crime victimization as a risk factor for depressive symptoms and suicidal ideation, and the protective effects of familism and social support in a community sample of Colombian college students. Data ( N = 424) came from the Juventud Project (The Emergent Adults Project), a cross-sectional study of college students, 18 to 29 years old ( M = 20.8, SD = 2.5; 63% female; 75.5% lived with their families), attending an urban public university in Southern Colombia. Data were collected between March and June of 2014 through anonymous, self-administered surveys. Conditional process analysis was used to test a model in which crime victimization was directly and indirectly associated with suicidal ideation via depressive symptoms, with familism and social support as moderators of this association while controlling for gender, age, and socioeconomic status. Overall, 58.9% of participants reported at least one crime victimization event in the past year. The most common types of victimization were being robbed without the threat of harm (29.8%) and being robbed with a weapon (24.8%). Male participants reported more instances of crime victimization than female participants. Levels of depressive symptoms that could be clinically significant were reported by 30.2% of participants, and suicidal ideation was reported by 31% of participants. The association between crime victimization and suicidal ideation was fully mediated by depressive symptoms. Social support, but not familism, moderated this association; social support weakened the link between depressive symptoms and suicidal ideation. Findings suggest that crime victimization may be a significant risk for depressive symptoms and suicidal ideation among college students in Colombia, and that social support may protect from the harmful mental health effects of crime victimization.

Following publication of the original article [1], an error in reference 18 was reported.

Introduction: New Mexico is currently ranked 17th in the United States for drug overdose death rates. Our project seeks to decrease opioid overdose deaths in a community by increasing the number of patients with naloxone in a local family medicine residency clinic., Methods: We developed a protocol wherein providers asked patients at risk of opioid overdose about naloxone access. Free naloxone was distributed in partner with the county health department, accompanied by teaching of use. We reviewed patient encounters during a 45-day control and study period to measure naloxone possession among patients at risk., Results: Nearly two-thirds of patients at risk of opioid overdose had no naloxone. A standardized protocol implemented to distribute an opioid reversal agent doubled naloxone prescribed by providers at visits (10.3%) compared to a control period (4.3%), but lacked statistical significance., Conclusion: Patients in a family medicine residency clinic who were at risk of opioid overdose overwhelmingly did not have naloxone, and a standardized protocol with a community-based partnership increased access to naloxone. Further project data will have implications for ongoing naloxone distribution programs in primary care., (© 2019 by the Society of Teachers of Family Medicine.)

Background: Inflammatory processes play an important role in the pathogenesis of glomerulopathies. Finding novel ways to suppress glomerular inflammation may offer a new way to stop disease progression. However, the molecular mechanisms that initiate and drive inflammation in the glomerulus are still poorly understood., Methods: We performed large-scale gene expression profiling of glomerulus-associated G protein-coupled receptors (GPCRs) to identify new potential therapeutic targets for glomerulopathies. The expression of Gprc5b in disease was analyzed using quantitative PCR and immunofluorescence, and by analyzing published microarray data sets. In vivo studies were carried out in a podocyte-specific Gprc5b knockout mouse line. Mechanistic studies were performed in cultured human podocytes., Results: We identified an orphan GPCR, Gprc5b, as a novel gene highly enriched in podocytes that was significantly upregulated in common human glomerulopathies, including diabetic nephropathy, IgA nephropathy, and lupus nephritis. Similar upregulation of Gprc5b was detected in LPS-induced nephropathy in mice. Studies in podocyte-specific Gprc5b knockout mice showed that Gprc5b was not essential for normal development of the glomerular filtration barrier. However, knockout mice were partially protected from LPS-induced proteinuria and recruitment of inflammatory cells. Mechanistically, RNA sequencing in Gprc5b knockouts mice and experiments in cultured human podocytes showed that Gpr5cb regulated inflammatory response in podocytes via NF- κ B signaling., Conclusions: GPRC5b is a novel podocyte-specific receptor that regulates inflammatory response in the glomerulus by modulating the NF- κ B signaling pathway. Upregulation of Gprc5b in human glomerulopathies suggests that it may play a role in their pathogenesis., (Copyright © 2019 by the American Society of Nephrology.)

Background: Intervention trials confirm that patients with advanced cancer receiving early palliative care experience a better quality of life and show improved knowledge about and use of palliative care services. To involve patients in future health-care decisions, health professionals should understand patients' perspectives. However, little is known about how patients' experience such interventions., Aim: To explore advanced cancer patients' experiences with a structured early palliative care intervention, its acceptability and impact on the patients' life including influencing factors., Design: Qualitative content analysis of in-depth, semi-structured interviews., Setting/participants: Patients with various advanced cancer diagnoses were enrolled in a multicenter randomized controlled trial (NCT01983956), which investigated the impact of "Symptoms, End-of-life decisions, Network, Support," a structured early palliative care intervention, on distress. Of these, 20 patients who underwent the intervention participated in this study., Results: Participants received the intervention well and gained a better understanding of their personal situation. Patients reported that the intervention can feel "confronting" but with the right timing it can be confirming and facilitate family conversations. Patients' personal background and the intervention timing within their personal disease trajectory influenced their emotional and cognitive experiences; it also impacted their understanding of palliative care and triggered actions toward future care planning., Conclusion: Early palliative care interventions like "Symptoms, End-of-life decisions, Network, Support" may provoke emotions and feel "confrontational" often because this is the first time when issues about one's end of life are openly discussed; yet, advanced cancer patients found it beneficial and felt it should be incorporated into routine care.

Podocytes have an important role in the pathogenesis of diabetic nephropathy (DN). Podocyte foot process effacement, mediated largely by the actin-based cytoskeleton of foot processes, is commonly detected in DN and is believed to be a key pathogenic event in the development of proteinuria. In this study, we identified coronin 2b (Coro2b), a member of known actin-regulating proteins, the coronins, as a highly podocyte-enriched molecule located at the cytoplasmic side of the apical plasma membrane. Studies in human renal biopsies show that glomerular Coro2b expression is significantly down-regulated in patients with DN. Studies in knockout mice indicate that Coro2b is not required for the development or maintenance of the glomerular filtration barrier. Moreover, inactivation of Coro2b specifically in podocytes does not affect the outcome of nephropathy in a streptozotocin-induced diabetes model. However, Coro2b seems to modulate the reorganization of foot processes under pathological conditions as Coro2b knockout podocytes are partially protected from protamine sulfate perfusion-induced foot process effacement. Taken together, our study suggests a role for Coro2b in the pathogenesis of glomerulopathies. Further studies regarding the involvement of Coro2b in podocyte health and diseases are warranted.

Background: Platinum-based chemotherapy remains the standard of care for most lung cancer cases. However chemoresistance is often developed during the treatment, limiting clinical utility of this drug. Recently, the ability of tumor cells to adapt their metabolism has been associated to resistance to therapies. In this study, we first described the metabolic reprogramming of Non-Small Cell Lung Cancer (NSCLC) in response to cisplatin treatment., Methods: Cisplatin-resistant versions of the A549, H1299, and H460 cell lines were generated by continuous drug exposure. The long-term metabolic changes, as well as, the early response to cisplatin treatment were analyzed in both, parental and cisplatin-resistant cell lines. In addition, four Patient-derived xenograft models treated with cisplatin along with paired pre- and post-treatment biopsies from patients were studied. Furthermore, metabolic targeting of these changes in cell lines was performed downregulating PGC-1α expression through siRNA or using OXPHOS inhibitors (metformin and rotenone)., Results: Two out of three cisplatin-resistant cell lines showed a stable increase in mitochondrial function, PGC1-α and mitochondrial mass with reduced glycolisis, that did not affect the cell cycle. This phenomenon was confirmed in vivo. Post-treatment NSCLC tumors showed an increase in mitochondrial mass, PGC-1α, and a decrease in the GAPDH/MT-CO1 ratio. In addition, we demonstrated how a ROS-mediated metabolism reprogramming, involving PGC-1α and increased mitochondrial mass, is induced during short-time cisplatin exposure. Moreover, we tested how cells with increased PGC-1a induced by ZLN005 treatment, showed reduced cisplatin-driven apoptosis. Remarkably, the long-term metabolic changes, as well as the metabolic reprogramming during short-time cisplatin exposure can be exploited as an Achilles' heel of NSCLC cells, as demonstrated by the increased sensitivity to PGC-1α interference or OXPHOS inhibition using metformin or rotenone., Conclusion: These results describe a new cisplatin resistance mechanism in NSCLC based on a metabolic reprogramming that is therapeutically exploitable through PGC-1α downregulation or OXPHOS inhibitors., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Nuclear positioning within cells is important for multiple cellular processes in development and regeneration. The most intriguing example of nuclear positioning occurs during skeletal muscle differentiation. Muscle fibers (myofibers) are multinucleated cells formed by the fusion of muscle precursor cells (myoblasts) derived from muscle stem cells (satellite cells) that undergo proliferation and differentiation. Correct nuclear positioning within myofibers is required for the proper muscle regeneration and function. The common procedure to assess myoblast differentiation and myofiber formation relies on fixed cells analyzed by immunofluorescence, which impedes the study of nuclear movement and cell behavior over time. Here, we describe a method for the analysis of myoblast differentiation and myofiber formation by live cell imaging. We provide a software for automated nuclear tracking to obtain a high-throughput quantitative characterization of nuclear dynamics and myoblast behavior (i.e., the trajectory) during differentiation and fusion.

Background: The Surprise Question (SQ) "would I be surprised if this patient were to die in the next 12 months?" has been suggested to help clinicians, and especially General Practitioners (GPs), identify people who might benefit from palliative care. The prognostic accuracy of this approach is unclear and little is known about how GPs use this tool in practice. Are GPs consistent, individually and as a group? Are there international differences in the use of the tool? Does including the alternative Surprise Question ("Would I be surprised if the patient were still alive after 12 months?") alter the response? What is the impact on the treatment plan in response to the SQ? This study aims to address these questions., Methods: An online study will be completed by 600 (100 per country) registered GPs. They will be asked to review 20 hypothetical patient vignettes. For each vignette they will be asked to provide a response to the following four questions: (1) the SQ [Yes/No]; (2) the alternative SQ [Yes/No]; (3) the percentage probability of dying [0% no chance - 100% certain death]; and (4) the proposed treatment plan [multiple choice]. A "surprise threshold" for each participant will be calculated by comparing the responses to the SQ with the probability estimates of death. We will use linear regression to explore any differences in thresholds between countries and other clinician-related factors, such as years of experience. We will describe the actions taken by the clinicians and explore the differences between groups. We will also investigate the relationship between the alternative SQ and the other responses. Participants will receive a certificate of completion and the option to receive feedback on their performance., Discussion: This study explores the extent to which the SQ is consistently used at an individual, group, and national level. The findings of this study will help to understand the clinical value of using the SQ in routine practice., Trial Registration: Clinicaltrials.gov NCT03697213 (05/10/2018). Prospectively registered.

Medullary thyroid carcinoma (MTC) is a malignant tumour of the calcitonin-secreting parafollicular C cells of the thyroid gland. Up to 25% of MTC are associated to pathogenic germinal variants on the proto-oncogene RET (locus 10q11.2), which cause Familial Medullary Thyroid Carcinoma (FMTC) or Multiple Endocrine Neoplasia type 2 (MEN2); genetic conditions inherited with autosomal dominant pattern. We present the first report of a Peruvian family with FMTC and a germinal pathogenic variant on RET proto-oncogene, identified with Sanger sequencing. This manuscript also shows a literature review of this hereditary cancer syndrome, where we highlight the relevance of primary prevention and the potential effect on public health in healthy carriers of germinal pathogenic variants., (Revista de la Facultad de Ciencias Médicas de Córdoba)

Peruvians currently preserve in their DNA the history of 2.5 million years of human evolution and 150,000 years of migration from Africa to Peru or the Americas. The development of Genetics and Genomics in the clinical and academic field is shown in this review., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Mitochondrial protein synthesis requires charging mt-tRNAs with their cognate amino acids by mitochondrial aminoacyl-tRNA synthetases, with the exception of glutaminyl mt-tRNA (mt-tRNA Gln ). mt-tRNA Gln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex. Defects involving the mitochondrial protein synthesis machinery cause a broad spectrum of disorders, with often fatal outcome. Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome. Functional studies reveal combined respiratory chain enzyme deficiencies and mitochondrial dysfunction. Aminoacylation of mt-tRNA Gln and mitochondrial protein translation are deficient in patients' fibroblasts cultured in the absence of glutamine but restore in high glutamine. Lentiviral rescue experiments and modeling in S. cerevisiae homologs confirm pathogenicity. Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex.

Criollo Limonero is a tropical Bos taurus breed for sustainable dual purpose (milk and beef) production in the South-American tropics, which is currently threatened with extinction. The objective was to perform a clinical evaluation and histopathological assessment of uterine biopsy samples of repeat breeder (RB) Criollo Limonero cattle to determine the occurrence of pathological conditions as potential causes of subfertility. Twenty-four Criollo Limonero cattle [18 cows (5-13 years old) and 6 heifers (6-7.5 years old)] that had failed to conceive after four or more services were considered for this study. Additionally, five cows with history of adequate reproductive performance were used as a control group. Animals were submitted to physical exam, vaginoscopy, and ultrasonographical evaluation of the reproductive tract. Uterine biopsy samples were collected for histopathological evaluation. Vaginoscopy revealed that 41.7% of the RB cattle had abnormal vaginal secretions, while abnormal secretions were not observed in any control cow. Ultrasonographical examination of the uterus revealed the presence of free uterine fluid in 20.8% of the RB animals, while none of the control cows had fluid in the uterine lumen. In addition, ovarian cysts were observed in 25.0% of the RB animals. Histopathological evaluation of the endometrial biopsies revealed that mononuclear leukocyte infiltration, dilated uterine glands, and periglandular fibrosis were the most prevalent lesions in the sub-fertile animals. Chronic endometritis characterized by inflammatory (mononuclear leukocyte infiltration) and degenerative (dilated glands and periglandular fibrosis) endometrial lesions, and ovarian cysts were the most frequent reproductive pathologies observed in the studied subfertile Criollo Limonero cattle, suggesting a strong association with their reduced fertility., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-&kappa;B regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-&kappa;B involvement in cancer is studied. We will also describe technical aspects of the studies performed in this context, including the use of different cellular models, culture conditions, microscopy approaches and quantification of the imaging data, balancing their strengths and limitations and pointing out to common features and to some open questions. Our emphasis in the methodology will allow a critical overview of literature and will show how these cutting-edge approaches can contribute to shed light on the involvement of NF-&kappa;B deregulation in tumour onset and progression. We hypothesize that this &ldquo;dynamic point of view&rdquo; can be fruitfully applied to untangle the complex relationship between NF-&kappa;B and cancer and to find new targets to restrain cancer growth.

Background: Fifth metatarsal base fractures of the metaphyseal-diaphyseal watershed junction (Jones fracture) are commonly treated with surgical fixation in athletes. Intramedullary screw fixation remains the most utilized construct, although plantar-lateral plating is an alternative. Purpose/Hypothesis: The purpose was to compare the mechanical strength of fracture fixation between an intramedullary screw and plantar-lateral plating. The hypothesis was that plantar-lateral plate fixation would allow for more cycles and higher peak loads before failure, as well as less fracture gapping, than would an intramedullary screw in cadaveric foot specimens with simulated Jones fractures exposed to cantilever bending., Study Design: Controlled laboratory study., Methods: Twelve pairs of male cadaver feet were separated into 2 groups (plate or screw) to conduct contralateral comparative testing of 2 devices with equally numbered right and left feet. For each fifth metatarsal, an osteotomy with a microsagittal saw was created to simulate a Jones fracture. The plate group underwent fixation with a 3.0-mm 4-hole low-profile titanium plate placed plantar-laterally with 3 locking screws and 1 nonlocking screw. The screw group underwent fixation with a 40- or 45-mm × 5.5-mm partially threaded solid titanium intramedullary screw. After fixation, the metatarsals were excised for biomechanical testing. Cyclic cantilever failure testing was conducted with a gradient-cycle method. Sinusoidal loading forces were applied, increasing by 5.0-pound-force increments per 10 cycles, until each specimen experienced mechanical failure of implant or bone. Failure mode, number of cycles to failure, peak failure load, gap width at the last mutual prefailure loading, and video data were recorded. Paired 2-tailed t test (α = 0.05) was used to compare groups ( P < .05 set for significance)., Results: Failure mode in both groups occurred predominantly at the bone-implant interface. Plate fixation resulted in significantly higher mean ± SD values for cycles to failure (63.9 ± 27.0 vs 37.3 ± 36.9, P = .01) and peak failure load (159.2 ± 60.5 N vs 96.5 ± 45.8 N, P = .01), with a significantly lower mean gap width (0.0 ± 0.0 mm vs 3.2 ± 2.4 mm, P < .01)., Conclusion: As compared with intramedullary screw fixation, plantar-lateral plating allowed for greater cycles to failure and peak load before failure, as well as less gap width, when applied to cadaver foot specimens with simulated Jones fractures exposed to cantilever bending in a load frame., Clinical Relevance: Early return to play among athletes before Jones fracture union is associated with increased risk of failure. This study introduces a plantar-lateral plating construct that performed more favorably than intramedullary screw fixation when applied to simulated Jones fractures in cadaveric foot specimens. Further clinical comparative studies are needed to assess the clinical use of this construct.

The kidney ultrafiltration barrier is formed of endothelial cells, the glomerular basement membrane and podocytes. Podocytes have a central role in normal physiology and disease pathogenesis of the glomerulus. Signaling through epidermal growth factor receptor (EGFR) in podocytes mediates development of many glomerular disease processes. In this work, we have identified zinc finger FYVE-type containing 28 (ZFYVE28) as a novel highly podocyte-enriched gene. We localize ZFYVE28 in podocyte foot processes in adult kidney. During glomerulogenesis, Zfyve28 is first expressed at the early capillary loop glomerulus. In cultured podocytes, we show that overexpression of ZFYVE28 promotes EGF-signaling, possibly by up-regulating EGFR expression and by modulating its localization. To study the role of ZFYVE28 in vivo, we generated both conventional and podocyte-specific knockout mouse lines. Kidneys developed normally in ZFYVE28-deficient mice. In adult mice, the absence of ZFYVE28 did not affect the maintenance of the filtration barrier. Moreover, ZFYVE28-deficiency did not affect the outcome of glomerular damage induced by injection of nephrotoxic serum. Taken together, we have identified Zfyve28 as a new molecular component of podocyte foot processes and show that it mediates EGF-signaling in podocytes. However, ZFYVE28 is not essential for the development or maintenance of the glomerulus filtration barrier.

The eukaryotic transcriptional regulator Nuclear Factor kappa B (NF-κB) plays a central role in the defense to pathogens. Despite this, few studies have analyzed NF-κB activity in single cells during infection. Here, we investigated at the single cell level how NF-κB nuclear localization - a proxy for NF-κB activity - oscillates in infected and uninfected fibroblasts co-existing in cultures exposed to Salmonella enterica serovar Typhimurium. Fibroblasts were used due to the capacity of S. Typhimurium to persist in this cell type. Real-time dynamics of NF-κB was examined in microfluidics, which prevents cytokine accumulation. In this condition, infected (ST+) cells translocate NF-κB to the nucleus at higher rate than the uninfected (ST-) cells. Surprisingly, in non-flow (static) culture conditions, ST- fibroblasts exhibited higher NF-κB nuclear translocation than the ST+ population, with these latter cells turning refractory to external stimuli such as TNF-α or a second infection. Sorting of ST+ and ST- cell populations confirmed enhanced expression of NF-κB target genes such as IL1B, NFKBIA, TNFAIP3, and TRAF1 in uninfected (ST-) fibroblasts. These observations proved that S. Typhimurium dampens the NF-κB response in the infected fibroblast. Higher expression of SOCS3, encoding a "suppressor of cytokine signaling," was also observed in the ST+ population. Intracellular S. Typhimurium subverts NF-κB activity using protein effectors translocated by the secretion systems encoded by pathogenicity islands 1 (T1) and 2 (T2). T1 is required for regulating expression of SOCS3 and all NF-κB target genes analyzed whereas T2 displayed no role in the control of SOCS3 and IL1B expression. Collectively, these data demonstrate that S. Typhimurium attenuates NF-κB signaling in fibroblasts, an effect only perceptible when ST+ and ST- populations are analyzed separately. This tune-down in a central host defense might be instrumental for S. Typhimurium to establish intracellular persistent infections.

l-Carnitine (LC) exerts beneficial effects in arterial hypertension due, in part, to its antioxidant capacity. We investigated the signalling pathways involved in the effect of LC on angiotensin II (Ang II)-induced NADPH oxidase activation in NRK-52E cells. Ang II increased the generation of superoxide anion from NADPH oxidase, as well as the amount of hydrogen peroxide and nitrotyrosine. Co-incubation with LC managed to prevent these alterations and also reverted the changes in NADPH oxidase expression triggered by Ang II. Cell signalling studies evidenced that LC did not modify Ang II-induced phosphorylation of Akt, p38 MAPK or ERK 1/2 . On the other hand, a significant decrease in PKC activity, and inhibition of nuclear factor kappa B (NF-kB) translocation, were attributable to LC incubation. In conclusion, LC counteracts the pro-oxidative response to Ang II by modulating NADPH oxidase enzyme via reducing the activity of PKC and the translocation of NF-kB to the nucleus., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Leptin is a protein involved in the regulation of food intake and in the immune and inflammatory responses, among other functions. Evidences demonstrate that obesity is directly associated with high levels of leptin, suggesting that leptin may directly link obesity with the elevated cardiovascular and renal risk associated with increased body weight. Adverse effects of leptin include oxidative stress mediated by activation of NADPH oxidase. The aim of this study was to evaluate the effect of L-carnitine (LC) in rat renal epithelial cells (NRK-52E) exposed to leptin in order to generate a state of oxidative stress characteristic of obesity. Leptin increased superoxide anion (O2 (•) -) generation from NADPH oxidase (via PI3 K/Akt pathway), NOX2 expression and nitrotyrosine levels. On the other hand, NOX4 expression and hydrogen peroxide (H2 O2 ) levels diminished after leptin treatment. Furthermore, the expression of antioxidant enzymes, catalase, and superoxide dismutase, was altered by leptin, and an increase in the mRNA expression of pro-inflammatory factors was also found in leptin-treated cells. LC restored all changes induced by leptin to those levels found in untreated cells. In conclusion, stimulation of NRK-52E cells with leptin induced a state of oxidative stress and inflammation that could be reversed by preincubation with LC. Interestingly, LC induced an upregulation of NOX4 and restored the release of its product, hydrogen peroxide, which suggests a protective role of NOX4 against leptin-induced renal damage. J. Cell. Biochem. 117: 2281-2288, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Sunitinib (Su) is currently approved for treatment of several malignances. However, along with the benefits of disease stabilization, cardiovascular toxicities have also been increasingly recognized. The aim of this study was to analyze which mechanisms are involved in the cardiotoxicity caused by Su, as well as to explore the potential cardioprotective effects of l-carnitine (LC). To this end, four groups of Wistar rats were used: (1) control; (2) rats treated with 400mg LC/kg/day; (3) rats treated with 25mg Su/kg/day; and (4) rats treated with LC+Su simultaneously. In addition, cultured rat cardiomyocytes were treated with an inhibitor of nuclear factor kappa B (NF-κB), in order to examine the role of this transcription factor in this process. An elevation in the myocardial expression of pro-inflammatory cytokines, together with an increase in the mRNA expression of NF-κB, was observed in Su-treated rats. These results were accompanied by an increase in the expression of pro-fibrotic factors, nitrotyrosine and NOX 2 subunit of NADPH oxidase; and by a decrease in that of collagen degradation factor. Higher blood pressure and heart rate levels were also found in Su-treated rats. All these alterations were inhibited by co-administration of LC. Furthermore, cardiotoxic effects of Su were blocked by NF-κB inhibition. Our results suggest that: (i) inflammatory and fibrotic processes are involved in the cardiac toxicity observed following treatment with Su; (ii) these processes might be mediated by the transcription factor NF-κB; (iii) LC exerts a protective effect against arterial hypertension, cardiac inflammation and fibrosis, which are all observed after Su treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Several transcription factors (TFs) oscillate, periodically relocating between the cytoplasm and the nucleus. NF-κB, which plays key roles in inflammation and cancer, displays oscillations whose biological advantage remains unclear. Recent work indicated that NF-κB displays sustained oscillations that can be entrained, that is, reach a persistent synchronized state through small periodic perturbations. We show here that for our GFP-p65 knock-in cells NF-κB behaves as a damped oscillator able to synchronize to a variety of periodic external perturbations with no memory. We imposed synchronous dynamics to prove that transcription of NF-κB-controlled genes also oscillates, but mature transcript levels follow three distinct patterns. Two sets of transcripts accumulate fast or slowly, respectively. Another set, comprising chemokine and chemokine receptor mRNAs, oscillates and resets at each new stimulus, with no memory of the past. We propose that TF oscillatory dynamics is a means of segmenting time to provide renewing opportunity windows for decision.

Gene expression is an inherently stochastic process that depends on the structure of the biochemical regulatory network in which the gene is embedded. Here we study the dynamical consequences of the interplay between stochastic gene switching and the widespread negative feedback regulatory loop in a simple model of a biochemical regulatory network. Using a simplified hybrid simulation approach, in which only the gene activation is modeled stochastically, we find that stochasticity in gene switching by itself can induce pulses in the system, providing also analytical insights into their origin. Furthermore, we find that this simple network is able to reproduce both exponential and peaked distributions of gene active and inactive times similar to those that have been observed experimentally. This simplified hybrid simulation approach also allows us to link these patterns to the dynamics of the system for each gene state.

The most common cause of death in the developed world is cardiovascular disease. For decades, this has provided a powerful motivation to study the effects of mechanical forces on vascular cells in a controlled setting, since these cells have been implicated in the development of disease. Early efforts in the 1970 s included the first use of a parallel-plate flow system to apply shear stress to endothelial cells (ECs) and the development of uniaxial substrate stretching techniques (Krueger et al., 1971, "An in Vitro Study of Flow Response by Cells," J. Biomech., 4(1), pp. 31-36 and Meikle et al., 1979, "Rabbit Cranial Sutures in Vitro: A New Experimental Model for Studying the Response of Fibrous Joints to Mechanical Stress," Calcif. Tissue Int., 28(2), pp. 13-144). Since then, a multitude of in vitro devices have been designed and developed for mechanical stimulation of vascular cells and tissues in an effort to better understand their response to in vivo physiologic mechanical conditions. This article reviews the functional attributes of mechanical bioreactors developed in the 21st century, including their major advantages and disadvantages. Each of these systems has been categorized in terms of their primary loading modality: fluid shear stress (FSS), substrate distention, combined distention and fluid shear, or other applied forces. The goal of this article is to provide researchers with a survey of useful methodologies that can be adapted to studies in this area, and to clarify future possibilities for improved research methods.

The mathematical modeling of the NF-κB oscillations has attracted considerable attention in recent times, but there is a lack of simple models in the literature that can capture the main features of the dynamics of this important transcription factor. For this reason we propose a simple model that summarizes the key steps of the NF-κB pathway. We show that the resulting 5-dimensional dynamical system can reproduce different phenomena observed in experiments. Our model can display smooth and spiky oscillations in the amount of nuclear NF-κB and can reproduce the variety of dynamics observed when different stimulations such as TNF-α and LPS are used. Furthermore we show that the model can be easily extended to reproduce the expression of early, intermediate and late genes upon stimulation. As a final example we show that our simple model can mimic the different transcriptional outputs observed when cells are treated with two different drugs leading to nuclear localization of NF-κB: Leptomycin B and Cycloheximide., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The hereditary sensory and autonomic neuropathies are genetic disorders characterized by the loss of sensation including pain, tactile and temperature. Its clinical and molecular features vary widely; the symptoms may begin from birth or be noticed in the first or second decade, with different types of complications of trauma to the extremities such as ulcers, mutilations and acral amputations. They are classified into six groups from I to VI, determined by the abnormality in eleven genes leading to phenotypic variations in the age of onset and the presence or absence of dysautonomia signs. With the exception of type I, all are autosomal recessive. The type II of these neuropathies is characterized by insensitivity to pain, heat and proprioception. We describe three members of a Mexican family with WNK1 gene mutation that caused hereditary neuropathy IIA., (Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.)

Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endothelial dysfunction in hypertension could result from lower L-carnitine transport in this cell type. L-Carnitine transport is mainly mediated by novel organic cation transporters 1 (Octn1, Na(+)-independent) and 2 (Octn2, Na(+)-dependent); however, their kinetic properties and potential consequences in hypertension are unknown. We hypothesize that L-carnitine transport kinetic properties will be altered in aortic endothelium from spontaneously hypertensive rats (SHR). L-Carnitine transport was measured at different extracellular pH (pHo 5.5-8.5) in the absence or presence of sodium in rat aortic endothelial cells (RAECs) from non-hypertensive Wistar-Kyoto (WKY) rats and SHR. Octn1 and Octn2 mRNA relative expression was also determined. Dilation of endothelium-intact or denuded aortic rings in response to calcitonine gene related peptide (CGRP, 0.1-100 nmol/L) was measured (myography) in the absence or presence of L-carnitine. Total L-carnitine transport was lower in cells from SHR compared with WKY rats, an effect due to reduced Na(+)-dependent (Na(+) dep ) compared with Na(+)-independent (Na(+) indep ) transport components. Saturable L-carnitine transport kinetics show maximal velocity (V max), without changes in apparent K m for Na(+) indep transport in SHR compared with WKY rats. Total and Na(+) dep component of transport were increased, but Na(+) indep transport was reduced by extracellular alkalization in WKY rats. However, alkalization reduced total and Na(+) indep transport in cells from SHR. Octn2 mRNA was higher than Octn-1 mRNA expression in cells from both conditions. Dilation of artery rings in response to CGRP was reduced in vessels from SHR compared with WKY rats. CGRP effect was endothelium-dependent and restored by L-carnitine. All together these results suggest that reduced L-carnitine transport (likely via Na(+)-dependent Octn2) could limit this compound's potential beneficial effects in RAECs from SHR.

Purpose: Arterial hypertension is associated with a high production of reactive oxygen species and a decrease in the antioxidant defense systems. Based on the lack of toxicity of L-carnitine (LC) and previous studies reporting beneficial effects of this compound in experimental models of hypertension, the aim of this work was to test the hypothesis that LC might protect the kidney against hypertension-induced oxidative damage, as well as to investigate the mechanisms involved in this effect. To this end, specific activities and protein/mRNA expression of the antioxidant enzymes (glutathione peroxidase, glutathione reductase, and superoxide dismutase), and those of NADPH oxidase (the main responsible for superoxide anion production in renal tissue) have been measured in renal cortex homogenates from NG-nitro-L-arginine methyl ester (L-NAME)-treated rats and control normotensive rats. In addition, components of the renin-angiotensin system (RAS) and redox-sensitive transcription factors (NF-κB, Nrf2, and PPARα) have also been evaluated., Methods: Male Wistar rats aged 6-8 weeks were divided into four groups of six animals each: (1) control, normotensive Wistar rats (with free access to tap water); (2) Wistar rats subjected to treatment with 25 mg of L-NAME/kg body weight/day dissolved in the drinking water, in order to develop L-NAME-induced hypertension; (3) Wistar rats subjected to treatment with 400 mg of LC/kg body weight/day (also dissolved in the drinking water); and (4) L-NAME-treated rats subjected to simultaneous treatment with LC at the indicated doses., Results: The beneficial effect of LC supplementation on oxidative damage in the renal cortex of hypertensive rats reversed hypertension-associated renal function damage and produced an upregulation of both antioxidant enzymes and eNOS, and with a downregulation of both NADPH oxidase and RAS components. LC improves the oxidative stress response through a specific modulation of NF-κB, Nrf2, and PPARα transcription factors. Thus, the low production of superoxide anions, subsequent to NADPH oxidase inhibition, might act by increasing the expression of Nrf2 and PPARα and by decreasing that of NF-κB, which, in turn, would enhance the antioxidant defense systems., Conclusions: Our results might support the use of LC to prevent hypertension-induced renal damage.

Cardiac fibrosis is a pathogenic factor in a variety of cardiovascular diseases and is characterized by an abnormal accumulation of extracellular matrix protein that leads to cardiac dysfunction. l-Carnitine (LC) plays an essential role in the β-oxidation of long-chain fatty acids in lipid metabolism. We have previously demonstrated the beneficial effects of LC in hypertensive rats. The aim of this study was to analyze the effect of LC on arterial hypertension-associated cardiac fibrosis and to explore the mechanisms of LC action. To this end, four groups of rats were used: Wistar (control), rats treated with 400mg/kg/day of LC, rats treated with 25mg/kg/day of l-NAME (to induce hypertension), and rats treated with LC+l-NAME simultaneously. We found an elevation in the myocardial expression of profibrotic factors (TGF-β1 and CTGF), types I and III of collagen, and NADPH oxidase subunits (NOX2 and NOX4), in hypertensive rats when compared with normotensive ones. In addition, an increase in myocardial fibrosis was also found in the l-NAME group. These results were accompanied by a down-regulation of PPAR-γ in the heart of hypertensive animals. When hypertensive rats were treated with LC, all these alterations were reversed. Moreover, a significant negative correlation was observed between myocardial interstitial fibrosis and mRNA expression of PPAR-γ. In conclusion, the reduction of cardiac fibrosis and the down-regulation of NOX2, NOX4, TGF-β1 and CTGF induced by LC might be, at least in part, mediated by an upregulation of PPAR-γ, which leads to a reduction on hypertension-related cardiac fibrosis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Captopril is an angiotensin-converting enzyme (ACE) inhibitor widely used in the treatment of arterial hypertension and cardiovascular diseases. Our objective was to study whether captopril is able to attenuate the cardiac inflammatory process associated with arterial hypertension., Methods: Left ventricle mRNA expression and plasma levels of pro-inflammatory (interleukin-1beta (IL-1beta) and IL-6) and anti-inflammatory (IL-10) cytokines, were measured in spontaneously hypertensive rats (SHR) and their control normotensive, Wistar-Kyoto (WKY) rats, with or without a 12-week treatment with captopril (80 mg/Kg/day; n = six animals per group). To understand the mechanisms involved in the effect of captopril, mRNA expression of ACE, angiotensin II type I receptor (AT1R) and p22phox (a subunit of NADPH oxidase), as well as NF-kappaB activation and expression, were measured in the left ventricle of these animals., Results: In SHR, the observed increases in blood pressures, heart rate, left ventricle relative weight, plasma levels and cardiac mRNA expression of IL-1beta and IL-6, as well as the reductions in the plasma levels and in the cardiac mRNA expression of IL-10, were reversed after the treatment with captopril. Moreover, the mRNA expressions of ACE, AT1R and p22phox, which were enhanced in the left ventricle of SHR, were reduced to normal values after captopril treatment. Finally, SHR presented an elevated cardiac mRNA expression and activation of the transcription nuclear factor, NF-kappaB, accompanied by a reduced expression of its inhibitor, IkappaB; captopril administration corrected the observed changes in all these parameters., Conclusion: These findings show that captopril decreases the inflammation process in the left ventricle of hypertensive rats and suggest that NF-kappaB-driven inflammatory reactivity might be responsible for this effect through an inactivation of NF-kappaB-dependent pro-inflammatory factors.

Dysembryoplastic neuroepithelial tumors (DNETs) have traditionally been viewed as benign "quasihamartomatous" tumors widely considered curable with surgery alone. More recently, case reports have described malignant gliomas arising after irradiation and recurrences following subtotal or even gross total resection. Herein, we describe five cases of DNET with recurrences 2-7 years after resection. Although the radiology was often alarming (e.g., new ring enhancing mass), the pathology remained benign in most cases. Nonetheless, a probably radiation induced anaplastic astrocytoma was encountered in one case 7 years after therapy. These findings suggest that these patients may need closer follow-up than initially suggested, lending further support to the notion that this tumor behaves more like a benign neoplasm, rather than a dysplastic or hamartomatous lesion.

In this paper we make a thorough exploration of the technique of partial control of chaotic systems. This control technique allows one to keep the trajectories of a dynamical system close to a chaotic saddle even if the control applied is smaller than the effects of environmental noise in the system, provided that the chaotic saddle is due to the existence of a horseshoelike mapping in phase space. We state this here in a mathematically precise way using the Conley-Moser conditions, and we prove that they imply that our partial control strategy can be applied. We also give an upper bound of the control-noise ratio needed to achieve this goal, and we describe how this technique can be applied for large noise values. Finally, we study in detail the effect of imperfect targeting in our control technique. All these results are illustrated numerically with the paradigmatic Hénon map.

In this paper we study how to avoid escapes in open dynamical systems in the presence of dissipation and forcing, as it occurs in realistic physical situations. We use as a prototype model the Helmholtz oscillator, which is the simplest nonlinear oscillator with escapes. For some parameter values, this oscillator presents a critical value of the forcing for which all particles escape from its single well. By using the phase control technique, weakly changing the shape of the potential via a periodic perturbation of suitable phase varphi , we avoid the escapes in different regions of the phase space. We provide numerical evidence, heuristic arguments, and an experimental implementation in an electronic circuit of this phenomenon. Finally, we expect that this method might be useful for avoiding escapes in more complicated physical situations.

In a region in phase space where there is a chaotic saddle, all initial conditions will escape from it after a transient with the exception of a set of points of zero Lebesgue measure. The action of an external noise makes all trajectories escape faster. Attempting to avoid those escapes by applying a control smaller than noise seems to be an impossible task. Here we show, however, that this goal is indeed possible, based on a geometrical property found typically in this situation: the existence of a horseshoe. The horseshoe implies that there exist what we call safe sets, which assures that there is a general strategy that allows one to keep trajectories inside that region with control smaller than noise. We call this type of control partial control of chaos.

We present a nonfeedback method to tame or enhance crisis-induced intermittency in dynamical systems. By adding a small harmonic perturbation to a parameter of the system, the intermittent behavior can be suppressed or enhanced depending on the value of the phase difference between the main driving and the perturbation. The validity of the method is shown both in the model and in an experiment with a CO2 laser. An analysis of this scheme applied to the quadratic map near crisis illustrates the role of phase control in nonlinear dynamical systems.

Objectives: This pilot study has been designed to collect preliminary data on the use of a new antiepileptic drug in the management of alcoholic patients. Oxcarbazepine (OXC) blocks voltage-sensitive sodium channels. Its metabolite reduces high-voltage-activated calcium currents in striatal and cortical neurons, thus reducing glutamatergic transmission at corticostriatal synapses. This reduction is of interest in the treatment of alcohol dependence, as acamprosate (ACP) modulates NMDA receptors, resulting in an inhibition of glutamatergic transmission. Furthermore, OXC has revealed a mood-stabilizing effect in bipolar affective disorders. We have compared OXC with ACP in relapse prevention in recently withdrawn alcohol-dependent patients., Methods: We investigated the efficacy and safety of OXC (vs ACP) by conducting a 24-week randomized, parallel-group, open-label, clinical trial on 30 acutely detoxified alcoholic patients. Survival analyses (Kaplan-Meier) were performed to look for evidence of a longer "survival" of patients receiving OXC. We assessed time to first severe relapse and additional secondary endpoints., Results: After withdrawal, time to severe relapse and time to first consumption of any ethanol by OXC patients were not longer than for ACP patients. Abstinent patients in both study groups showed a significantly lower obsessive compulsive drinking scale-German version (OCDS-G) than relapsed patients. No undesired effects occurred when OXC patients consumed alcohol., Conclusion: Our findings indicate that it could be worthwhile to test relapse prevention using OXC in an adequate sample. While the current sample size clearly limits further conclusions from this pilot study, it is noteworthy that OXC is well tolerated, even when alcohol is on board. Thus, in medication-based relapse prevention, OXC could be a promising alternative for alcoholic patients unable to benefit from ACP or naltrexone or those who have affective liability. OXC certainly merits a larger placebo-controlled trial.

A well-known method to suppress chaos in a periodically forced chaotic system is to add a harmonic perturbation. The phase control of chaos scheme uses the phase difference between a small added harmonic perturbation and the main driving to suppress chaos, leading the system to different periodic orbits. Using the Duffing oscillator as a paradigm, we present here an in-depth study of this technique. A thorough numerical exploration has been made focused in the important role played by the phase, from which new interesting patterns in parameter space have appeared. On the other hand, our novel experimental implementation of phase control in an electronic circuit confirms both the well-known features of this method and the new ones detected numerically. All this may help in future implementations of phase control of chaos, which is globally confirmed here to be robust and easy to implement experimentally.

Objective: Primary signet ring cell carcinoma of the colon and rectum is a rare form of adenocarcinoma of the large intestine. The purpose of this study was define the incidence, natural history and relation with hereditary nonpolyposis colorectal cancer (HNPCC)., Methods: We reviewed the medical records and pathology of 28 patients with primary signet ring cell carcinoma of the colon and rectum seen at the Instituto de Enfermedades Neoplasicas (INEN), between 1991 and 2002., Results: In the present study the incidence was 5.09% of large bowel adenocarcinoma. Most patients present with late stage disease (Dukes stage C and D). In most cases the signet ring cells diffusely infiltrated through all layers of the intestinal wall (Borrmann IV). Male to female ratio was of 1 : 1.5, mean age was 55.5 and median age was 57 years (range 11 - 83 years)., Conclusions: Comparison of our data with the literature showed some differences that could be related with biological characteristics of our people and different applied inclusion criteria. We couldn't define the relation between HNPCC and primary signet ring cell carcinoma of the colon and rectum.

We report the case of a female patient, sixteen years old who was diagnosed of signet ring cell carcinoma of sigmoid colon. We discuss the clinical presentation outstanding the early presentation of this unusual cancer.

We report a case of acute abdomen that is operated with the presumptive diagnosis of complicated acute appendicitis. In the histologic examination we make the diagnosis of complicated amoebic appendicitis. We discuss clinical manifestations and histopathologic findings of this unusual presentation of amoebic infection.

During the acute stage of a Wallenberg's syndrome ipsilateral appendicular dysmetria is frequently seen. The dysmetria is more apparent in the ipsilateral upper extremity. These patients also have a peculiar type of dysmetric eye movements that are characterized by hypermetric saccades toward the side of the lesion and hypometric saccades to the opposite side. We examined four patients with acute Wallenberg's syndrome and found horizontal dysmetria of the affected extremity. Hypermetric arm and hand movements were present to the side of the lesion and hypometric movements toward the opposite side. This type of dysmetria is probably related to the same patophysiological mechanism that underlies dysmetric eye movements in the Wallenberg's syndrome. The dysmetria tends to disappear with time although it continues to be present in some patients six months after the ischemic damage.