Impact of 5 fluorouracil chemotherapy on gut inflammation, functional parameters, and gut microbiota.

Emerging evidence suggests that gut microbiota may influence the response to chemotherapy. We sought to characterize the effects of 5 fluorouracil (5FU) chemotherapy on colon inflammation and functional measures in colorectal cancer (CRC) and to further determine whether gut microbiota can influence this response. 50 C57BL/6 were randomized into four groups; Control + Vehicle (n = 10), Control + 5FU (n = 10), AOM/DSS + Vehicle (n = 15), and AOM/DSS + 5FU (n = 15). CRC was induced chemically by a single 10 mg/kg injection of azoxymethane (AOM) followed by two cycles (2% and 1%) of dextran sodium sulfate (DSS). Mice were then treated with 3 cycles of vehicle or 5FU (cycle 1: 40 mg/kg, cycle 2 + 3: 20 mg/kg). Functional tests (grip strength and run-to-fatigue) were performed prior to 5FU treatment (baseline) and at the completion of the second cycle of 5FU. Following the third 5FU cycle, mice were euthanized and the colon was evaluated for expression of inflammatory genes using RT-qPCR and stool samples were profiled using 16S rRNA sequencing. A second experiment used fecal microbiota transplantation from 5FU treated mice to control mice (n = 10-15/group) to determine whether 5FU associated changes in the microbiota could influence functional measures and colon inflammation. 5FU reduced grip strength (p < 0.05) and caused a trending decrease in run-to-fatigue performance in cancer mice (p = 0.06). Select intestinal inflammatory genes were significantly elevated with 5FU treatment and this was further exacerbated with cancer (p < 0.05). Microbiota analysis revealed increased dissimilarity and alterations in bacterial taxonomy in 5FU and AOM/DSS-treated mice (p < 0.05). Fecal transplant from 5FU treated mice reduced functional performance (p < 0.05) and altered select colon inflammatory markers (p < 0.05). This study provides evidence of an effect of 5FU on inflammatory responses and functional measures in a mouse model of CRC and suggests that gut microbes may play a role in some, but not all, 5FU related perturbations.

Neuroradiologic correlation with aphasias. Cortico-subcortical map of language. / Correlación neurorradiológica de las afasias. Mapa cortico-subcortical del lenguaje.

Aphasia is an acquired language disorder due to a cerebral lesion; it is characterized by errors in production, denomination, or comprehension of language. Although most aphasias are mixed, from a practical point of view they are classified into different types according to their main clinical features: Broca's aphasia, Wernicke's aphasia, conduction aphasia, transcortical aphasia, and alexia with or without agraphia. We present the clinical findings for the main subtypes of aphasia, illustrating them with imaging cases, and we provide an up-to-date review of the language network with images from functional magnetic resonance imaging and tractography.

Essential Subcortical Tracts in Language and Reading. 3D-Tractography for Clinical Practice and Anatomic Correlation with Intraoperative Subcortical Electrostimulation.

Diffusion tensor imaging (DTI) and tractography provide the neurosurgeon with a valid 3D view of the white matter tracts of the brain for the presurgical planning of the treatment of lesions close to eloquent areas, this being one of the principal clinical applications of this technique. In this article, we describe through practical cases the anatomic relationships of white matter tracts that are essential for language and reading, based on DTI studies and the excellent anatomic correlation with the intraoperative subcortical map.

Deficiency of Kruppel-like factor KLF4 in myeloid-derived suppressor cells inhibits tumor pulmonary metastasis in mice accompanied by decreased fibrocytes.

The importance of immunosuppressive myeloid-derived suppressor cells (MDSCs) bearing monocyte markers in tumor metastasis has been well established. Recently, it was reported that these cells possess phenotypic plasticity and differentiate into fibrocytes, very distinct cells that are precursors of tumorigenic myofibroblasts. However, the importance of this transdifferentiation in tumor metastasis has not been explored. Here, we describe the role of MDSC-derived fibrocytes in tumor metastasis that is regulated by Kruppel-like factor 4 (KLF4), a transcription factor that is critical to monocyte differentiation and to promotion of cancer development. Using mouse metastasis models of melanoma and breast cancer, we found that KLF4 knockout was associated with significantly reduced pulmonary metastasis, which was accompanied by decreased populations of MDSCs, fibrocytes and myofibroblasts in the lung. Cause-effect studies by adoptive transfer revealed that KLF4 deficiency in MDSCs led to significantly reduced lung metastasis that was associated with fewer MDSC-derived fibrocytes and myofibroblasts. Mechanistically, KLF4 deficiency significantly compromised the generation of fibrocytes from MDSCs in vitro. During this process, KLF4 expression levels were tightly linked with those of fibroblast-specific protein-1 (FSP-1), deficiency of which resulted in no metastasis in mice as has been previously reported. In addition, KLF4 bound directly to the FSP-1 promoter as determined by chromatin immunoprecipitation and overexpression of KLF4 increased the FSP-1 promoter activities. Taken together, our results suggest that MDSCs not only execute their immunosuppressive function to promote metastatic seeding as reported before, but also boost metastatic tumor growth after they adopt a fibrocyte fate. Therefore, KLF4-mediated fibrocyte generation from MDSCs may represent a novel mechanism of MDSCs contributing to tumor metastasis and supports the feasibility of inhibiting KLF4 or FSP-1 to prevent tumor metastasis.

Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1.

Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5-fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1(-/-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia.

Benefits of exercise training on breast cancer progression and inflammation in C3(1)SV40Tag mice.

Many observational epidemiologic studies suggest an association between exercise and breast cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in breast cancer progression and exercise has been reported to reduce inflammation; however, the anti-inflammatory effects of exercise in breast cancer have yet to be established. We examined the relationship between exercise training and systemic inflammation in relation to breast cancer progression in C3(1)SV40Tag mice. Female C3(1)SV40Tag mice were assigned to either exercise (Ex) or sedentary (Sed) treatment (n=12-14/group). Beginning at 4 wks of age mice (Ex) were run on a treadmill for 60 min/d (20 m/min and 5% grade), 6 d/wk for a period of 20 wks. Mice were examined weekly for palpable tumors, and tumor number and volume were recorded. At 24 wks of age mice were sacrificed and a more direct measure of tumor number and volume, and spleen weight was recorded. Plasma was analyzed for MCP-1 and IL-6 concentration using ELISA. Ex reduced palpable tumor number at sacrifice (24 wks) by approximately 70% (P<0.05). Tumor volume was also reduced in Ex at 21-23 wks (P<0.05). This reduction in tumor progression by Ex was associated with a reduction in plasma concentration of MCP-1 and IL-6, and spleen weight (P<0.05). These data provide strong support for a beneficial effect of exercise training on tumor progression in the C3(1)SV40Tag mouse model of breast cancer that may be partly mediated by its anti-inflammatory potential.

Self-perception of health status, mental health and quality of life among adults with diabetes residing in a metropolitan area.

AIM: The study aimed to compare the self-perception of health, physiological distress and health-related quality of life (HRQL) in subjects with and without diabetes residing in a large metropolitan area (the city of Madrid), and to identify the variables associated with the poorest HRQL among diabetes patients. METHODS: In this case-control epidemiological study, we selected 358 patients with diabetes from the Madrid City Health Survey. For every patient, two controls without diabetes were randomly selected from the same database and matched for age, gender and health district. The resultant study population comprised 1074 subjects, who were analyzed according to their self-rated health status, with mental health assessed by the 12-item General Health Questionnaire (GHQ-12) and HRQL by the COOP/WONCA questionnaire. Independent variables included sociodemographic characteristics, lifestyle variables, associated chronic diseases and consumption of medications. Multivariate analyses were conducted using ANCOVA tests. RESULTS: The prevalence of health perceived as fair or poor was 64.12% in those with diabetes vs 38.57% in those without diabetes (P<0.05). The GHQ-12 results showed that mental health was also significantly worse among diabetes sufferers, and the COOP/WONCA questionnaire results indicated significantly poorer HRQL in those with diabetes. The variables that determined a poorer perception of HRQL among diabetes sufferers were female gender, older age, obesity, lack of physical exercise, coexistence of depression, use of sleeping pills, and Alzheimer's and cerebrovascular diseases. CONCLUSION: Self-rated health and psychological well-being, and HRQL, are all considerably poorer among patients with diabetes vs those without diabetes. The poorest quality of life among those with diabetes associated with female gender, depression, lack of exercise and obesity.

Biodegradation of phenol in a continuous process: comparative study of stirred tank and fluidized-bed bioreactors.

The paper presents the main results obtained from the study of the biodegradation process of phenol by a pure culture of Pseudomonas putida ATCC 17484. The experimental work was carried out in two different systems: a stirred tank where cells grew as a suspended culture and a fluidized bed where cells were immobilized within calcium alginate gel beads. The influence of the hydraulic residence time (HRT) and organic loading rate on the removal efficiency of phenol was determined for both bioreactors. Also, the stability of the fluidized-bed bioreactor (FBB) in terms of its ability to withstand sudden phenol overdoses is also reported. Experimental values indicated that both bioreactors showed high phenol degradation efficiencies, higher than 90%, even for a phenol loading rate in the influent as high as 4 g phenol/l day. The FBB showed better performance than the suspended-culture bioreactor due to its better control and because it could operate with lower HRT.

[Motives for consultation and demographic characteristics of a community of "undocumented" immigrants in the district of Usera-Villaverde (Madrid)]. / Motivos de consulta y características demográficas de una comunidad de inmigrantes "sin papeles" en el distrito de Usera-Villaverde (Madrid).

OBJECTIVE: The objectives of the present study are to describe to the social particularizations, reasons for consultation and diagnoses conducted in the adult immigrants without regularizing that they went to this doctor's office in the district of Villaverde-Usera (Madrid), excluding the data from obstetrics-gynecology and pediatric. DESIGN: One is a descriptive observational study, based on the registry of the daily activity of the consultation from 1996 to 1999. SETTING: Primary level of attention in the area of influence of the municipal districts of Villaverde-Usera. PARTICIPANTS: 1496 consultations to immigrants without regularizing adults, taken care of in our consultation are described in the mentioned period. MEASUREMENTS AND RESULTS: By means of the registry of daily activity social and demographic variables took shelter, of reason and type of consultation, as well as of the main diagnosis that brought to them to the consultation, en 1496 consultations of illegal immigrants (533 people). 31% of the consultations were new and a 14% of absences to the citation were registered. 67% of the consultations made women, the average age was of 34.9 years and in a 76% it referred like South America origin. The diseases that more consultations generated were acute respiratory infection 18%, depressives disorders 11% and the backache with also a 11%. The 48% the reasons for the consultation were acute and 60% took place to free demand. CONCLUSIONS: The group of consultations taken care of responds to the profile of a young South American woman, that fundamentally consults by acute respiratory infections, and very in proximity by depressive-anxious upheavals and lumbar affections, problems very in relation to his situation of immigrant. The irregularity adds to a risk when making difficult the access, most of the consultations are precise, failing in elevated occasions to the programmed consultation.

Motivos de consulta y características demográficas de una comunidad de inmigrantes 'sin papeles' en el distrito de Usera-Villaverde (madrid) / Reasons for medical consultation and demographic characteristics in the ilegal situation inmigrants comunity of usera-villaverde (madrid), spain

Objetivo. Los objetivos del presente estudio son describir las particularidades sociales, motivos de consulta y diagnósticos efectuados en los inmigrantes adultos sin regularizar que acudieron a este consultorio en el distrito de Villaverde-Usera (Madrid), excluyéndose los datos de obstetricia-ginecología y pediatría. Diseño. Se trata de un estudio observacional descriptivo, basado en el registro de la actividad diaria de la consulta desde 1996 a 1999. Emplazamiento. Nivel primario de atención en el área de influencia de los distritos municipales de Villaverde-Usera. Pacientes u otros participantes. Se describen 1.496 consultas a inmigrantes sin regularizar, adultos, atendidos en nuestra consulta, en el citado período. Medición y resultados. Mediante el registro de actividad diaria se recogieron variables sociodemográficas, de motivo y tipo de consulta, así como del principal diagnóstico que les trajo a la consulta, en 1.496 consultas de inmigrantes sin regularizar (533 personas). Un 31 por ciento de las consultas fueron nuevas y se registró un 14 por ciento de ausencias a la citación. El 67 por ciento de las consultas las realizaron mujeres, la edad media fue de 34,9 años y en un 76 por ciento refirió como procedencia Sudamérica. Las enfermedades que más consultas generaron fueron infección respiratoria aguda (18 por ciento), trastornos depresivos (11 por ciento) y dolor de espalda (11 por ciento). En un 48 por ciento los motivos de la consulta fueron agudos y el 60 por ciento se produjo a libre demanda. Conclusiones. El grupo de consultas atendido responde al perfil de una mujer joven, sudamericana, que consulta fundamentalmente por infecciones respiratorias agudas y casi en el mismo grado a causa de trastornos depresivo-ansiosos y lumbalgias, problemas muy en relación con su situación de inmigrante. La irregularidad añade un riesgo al dificultar el acceso; la mayor parte de las consultas son puntuales, pero en muchas ocasiones no se presentan a la consulta programada (AU)

Characterization of the Saccharomyces cerevisiae high affinity copper transporter Ctr3.

Copper is an essential nutrient required for the activity of a number of enzymes with diverse biological roles. In the bakers' yeast Saccharomyces cerevisiae, copper is transported into cells by two high affinity copper transport proteins, Ctr1 and Ctr3. Although Ctr1 and Ctr3 are functionally redundant, they bear little homology at the amino acid sequence level. In this report, we characterize Ctr3 with respect to its localization, assembly, and post-transcriptional regulation. Ctr3 is an integral membrane protein that assembles as a trimer to form a competent copper uptake permease at the plasma membrane. Whereas the CTR1 and CTR3 genes are similarly regulated at the transcriptional level in response to copper, post-transcriptional regulation of these proteins is distinct. Unlike Ctr1, the Ctr3 transporter is neither regulated at the level of protein degradation nor endocytosis as a function of elevated copper levels. Our studies suggest that Ctr3 constitutes a fundamental module found in all eukaryotic high affinity copper transporters to date, which is sufficient for copper uptake but lacks elements for post-transcriptional regulation by copper.

[Percutaneous treatment of retroperitoneal abscesses]. / Tratamiento percutáneo de los abscesos retroperitoneales.

UNLABELLED: The retroperitoneal abscess is an uncommon disease, that must be treated by drainage. The progressive use of the percutaneous drainage, under ultrasound or computed tomography guidance (CT), has changed the therapeutical management and has demonstrated to be a valid alternative to surgical drainage. From 1986 to 1998, 16 patients with retroperitoneal abscesses were treated by percutaneous drainage (14 with CT and 2 with ultrasound guidance). This method eradicated the abscess in 13 cases, in 2 was necessary a new function to cure the abscess, and 1 patient, with a severe sepsis, died. Percutaneous drainage was the unique treatment used in 12 patients. In the remaining four, the patients' clinical status improved after percutaneous drainage, and they were able to undergo subsequent elective nephrectomy. CONCLUSIONS: Percutaneous drainage of retroperitoneal abscesses has been established as a viable alternative to surgical intervention. This method can resolve the abscess or improve the patient' clinical status to undergo elective surgery.

Beneficial effects of increasing monounsaturated fat intake in adolescents with type 1 diabetes.

This study aimed to increase the monounsaturated fat content in the diet of outpatient adolescents with type 1 diabetes and to examine the metabolic effects after 12 weeks. Twenty-three adolescents were randomly allocated to either a high monounsaturated fat diet or a control diet. Their mean age was 16.9 (S.D. 2.1) years and median HbA(1c) was 9.1% [IQR 7.9-10.4%]. Dietary targets were not reached judged by their 4-day food diaries. However, the whole study group had a significant increase in monounsaturated fat as indexed by red cell phospholipid fatty acids (RCFAs), with an increase of n-9 RCFAs from 14.9% [IQR: 14.5-21.7%] to 21.7% [IQR: 18.8-25.6%] (P=0.002). Changes in n-9 RCFAs were inversely related to changes in HbA(1c) (R(2)=0.26, P=0.02), such that a 10% increase in n-9 RCFAs corresponded to a 0.64% improvement (decrease) in HbA(1c). Changes in n-9 RCFAs were also inversely related to changes in plasma total cholesterol (R(2)=0.38, P=0.002) and plasma LDL cholesterol (R(2)=0. 21, P=0.03). These changes were not associated with changes in insulin dose, body weight or physical activity. Overall, the results demonstrate that a modest increase in the monounsaturated fat content of an adolescent diet has the potential to improve glycaemic control and lipid profile.

Tratamiento percutáneo de los abscesos retroperitoneales / Percutaneous drainage of retroperitoneal abscesses

El absceso retroperitoneal es una entidad clínica poco frecuente, cuyo tratamiento se basa en el drenaje. La introducción progresiva de las técnicas percutáneas de drenaje, bien mediante control ecográfico o bien utilizando la tomografía axial computerizada (TAC), ha modificado su abordaje terapéutico, siendo alternativas válidas al tratamiento quirúrgico tradicional. Presentamos una serie de 16 pacientes diagnosticados de absceso retroperitoneal entre 1986 y 1998, que fueron tratados mediante punción percutánea (en 14 casos dirigida por TAC y en 2 median-te control ecográfico). Se consiguió la resolución del absceso en 13 casos, recurriendo en 2 (ambos fueron tratados mediante nueva punción) y falleciendo 1 paciente que presentaba una sepsis grave. En 12 de los pacientes fue el único tratamiento aplicado, practicándose en los 4 restantes nefrectomía tras la mejoría del estado de los pacientes. CONCLUSIONES: El tratamiento percutáneo de los abscesos retroperitoneales supone una alter-nativa válida al tratamiento quirúrgico tradicional, bien como tratamiento definitivo, bien como tratamiento paliativo que nos permite mejorar el estado clínico del paciente de forma previa a la cirugía (AU)

A copper-sensing transcription factor regulates iron uptake genes in Schizosaccharomyces pombe.

Copper and iron serve essential functions as catalytic co-factors in a wide variety of critical cellular enzymes. Studies in yeast have demonstrated an absolute dependence upon copper acquisition for proper assembly and function of the iron transport machinery. We have cloned genes for a high affinity copper transporter (Ctr4) and copper-sensing transcription factor (Cuf1) from Schizosaccharomyces pombe. Interestingly, the primary structure of Ctr4 and a putative human high affinity copper transport protein, hCtr1, suggests that they are derived from a fusion of the functionally redundant but structurally distinct Ctr1 and Ctr3 copper transporters from Saccharomyces cerevisiae. Furthermore, although Cuf1 activates ctr4(+) gene expression under copper starvation conditions, under these same conditions Cuf1 directly represses expression of genes encoding components of the iron transport machinery. These studies have identified an evolutionary step in which copper transport modules have been fused, and describe a mechanism by which a copper-sensing factor directly represses expression of the iron uptake genes under conditions in which the essential copper co-factor is scarce.

A delicate balance: homeostatic control of copper uptake and distribution.

The cellular uptake and intracellular distribution of the essential but highly toxic nutrient, copper, is a precisely orchestrated process. Copper homeostasis is coordinated by several proteins to ensure that it is delivered to specific subcellular compartments and copper-requiring proteins without releasing free copper ions that will cause damage to cellular components. Genetic studies in prokaryotic organisms and yeast have identified membrane-associated proteins that mediate the uptake or export of copper from cells. Within cells, small cytosolic proteins, called copper chaperones, have been identified that bind copper ions and deliver them to specific compartments and copper-requiring proteins. The identification of mammalian homologues of these proteins reveal a remarkable structural and functional conservation of copper metabolism between bacteria, yeast and humans. Furthermore, studies on the function and localization of the products of the Menkes and Wilson's disease genes, which are defective in patients afflicted with these diseases, have provided valuable insight into the mechanisms of copper balance and their role in maintaining appropriate copper distribution in mammals.

Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae.

The essential yet toxic nature of copper demands tight regulation of the copper homeostatic machinery to ensure that sufficient copper is present in the cell to drive essential biochemical processes yet prevent the accumulation to toxic levels. In Saccharomyces cerevisiae, the nutritional copper sensor Mac1p regulates the copper-dependent expression of the high affinity Cu(I) uptake genes CTR1, CTR3, and FRE1, while the toxic copper sensor Ace1p regulates the transcriptional activation of the detoxification genes CUP1, CRS5, and SOD1 in response to copper. In this study, we characterized the tandem regulation of the copper uptake and detoxification pathways in response to the chronic presence of elevated concentrations of copper ions in the growth medium. Upon addition of CuSO4, mRNA levels of CTR3 were rapidly reduced to eightfold the original basal level whereas the Ace1p-mediated transcriptional activation of CUP1 was rapid and potent but transient. CUP1 expression driven by an Ace1p DNA binding domain-herpes simplex virus VP16 transactivation domain fusion was also transient, demonstrating that this mode of regulation occurs via modulation of the Ace1p copper-activated DNA binding domain. In vivo dimethyl sulfate footprinting analysis of the CUP1 promoter demonstrated transient occupation of the metal response elements by Ace1p which paralleled CUP1 mRNA expression. Analysis of a Mac1p mutant, refractile for copper-dependent repression of the Cu(I) transport genes, showed an aberrant pattern of CUP1 expression and copper sensitivity. These studies (i) demonstrate that the nutritional and toxic copper metalloregulatory transcription factors Mac1p and Ace1p must sense and respond to copper ions in a dynamic fashion to appropriately regulate copper ion homeostasis and (ii) establish the requirement for a wild-type Mac1p for survival in the presence of toxic copper levels.

Copper differentially regulates the activity and degradation of yeast Mac1 transcription factor.

Copper is an essential metal ion that is toxic when accumulated to high intracellular concentrations. The yeast Mac1 protein is a copper-sensing transcription factor that is essential for both the activation and inactivation of genes required for high affinity copper ion transport. Here we demonstrate that in response to low copper ion concentrations Mac1 protein is rendered inactive for copper transporter gene transcription. Under high copper ion concentrations Mac1 is degraded in a rapid, copper-specific manner. This degradation is critical to prevent copper toxicity that would otherwise result from sustained expression of the copper transport genes. These results demonstrate that nutritional and toxic copper concentrations elicit distinct fates for the Mac1 copper-sensing transcription factor and establish a new mechanism by which trace metals regulate gene expression.

Copper-binding motifs in catalysis, transport, detoxification and signaling.

Copper is required for many biological processes but is toxic at high cellular concentrations, so levels in the cell must be strictly controlled. Copper-binding motifs have been identified and characterized in many proteins. The way in which copper is coordinated by these motifs is important for the transport and distribution of intracellular copper and for the effective functioning of copper-dependent enzymes.