Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs.

Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.

Nutrient attenuation dynamics in effluent dominated watercourses.

In-stream attenuation of dissolved and particulate forms of carbon, nitrogen and phosphorus are a crucial ecosystem service, especially in watercourses downstream of chemical pollution point-sources (i.e. wastewater treatment plants). Most chemical-fate models assume that attenuation is directly proportional to the concentration of available dissolved organic carbon, and inorganic nitrogen and phosphorus compounds in watercourses, but there are multiple evidences of saturation and even inhibition of attenuation at higher concentrations. Our current comprehension of nutrient attenuation kinetics in streams remains a limiting factor for the development and calibration of predictive models of the chemical fate of these compounds in rivers, thus hindering the development and implementation of more effective regulatory strategies. Here, we assessed the in-stream attenuation of dissolved organic carbon, inorganic nitrogen (NH4+, NO2-, NO3-) and phosphorus (PO43-) compounds at increasing concentrations of these compounds, and analyzed the interaction between attenuation kinetics and biofilm structure and function. Specifically, the net balances of these compounds were assessed in artificial streams exposed to eight treatments following the gradient of WWTP contribution to the river flow (0, 14, 29, 43, 58, 72, 86, and 100% of WWTP effluent water). Results indicate that biological in-stream attenuation by a given biofilm of an effluent dominated watercourse might be saturated if exposed for short periods to high nutrient concentrations such as during combined sewer overflow events, but that communities can adapt if exposed long enough to high concentrations, therefore avoiding or at least minimizing saturation. More attention should be therefore given to the management of effluent-dominated watercourses, as reductions in the temporal variability of the discharged wastewater by WWTP might enhance attenuation and thus reduce water quality issues downstream.

Mycobacterium marinum: reporte de un caso / Mycobacterium marinum: a case report

El Mycobacterium marinum es un tipo de micobacteria no tuberculosa (NTM). La infección por esta bacteria es frecuente en peces de agua dulce o salada y muy raramente, suele causar infecciones en la población humana. Presentamos el caso de un paciente varón de 60 años, que consulta por placa ulcerosa en dorso de mano izquierda. El estudio histopatológico de biopsia informa: hiperplasia epitelial con un denso infiltrado en dermis y escasos granulomas con células gigantes. Se solicitan distintas pruebas, siendo únicamente positiva el PCR para Mycobacterium marinum, por lo que se procede a instaurar regimen antimicrobiano con evolución favorable. El contagio por esta bacteria, se produce por inoculación directa del microorganismo, a través de heridas o erosiones cutáneas o por mordeduras de peces contaminados. Las formas de presentación clínica varían, siendo la más común la presencia de pápulas o nódulos solitarios en dedos o manos. También se puede manifestar en forma de linfangitis proximal o esporotricoide, extensión a órganos profundos y patrón esporotricoide facial. El diagnóstico requiere un alto índice de sospecha, debido a que la frecuencia de esta afección es muy baja, siendo de 0.04 a 0.27 por cada 100.000 habitantes. La biopsia de tejido proporciona el diagnóstico en solo la mitad de los casos. El cultivo confirma el diagnóstico, pero se reportan como positivos en 70 a 80% de los casos. Técnicas de amplificación de ácidos nucleicos, como la reacción en cadena polimerasa (PCR) son otros métodos para el diagnóstico, su mayor ventaja es la rapidez de sus resultados en comparación con el cultivo. Existen muchas modalidades terapéuticas: el tratamiento tópico, la administración sistémica de antimicrobianos, la cirugía, la termoterapia local y la terapia combinada. Sin embargo, los pacientes infectados con M. marinum por lo común, son tratados con antimicrobianos en monoterapia o combinados.

Introduction: Mycobacterium marinum is a type of non-tuberculous mycobacterium (NTM). Infection by this bacterium is frequent in freshwater or saltwater fish and very rarely causes infection in human population. Case report: we present the case of a 60-year-old male patient, who consulted for an ulcerative plaque on the back of his left hand. The histopathological study of biopsy reports: epithelial hyperplasia with a dense infiltrate in dermis and few granulomas with giant cells. Different tests were requested, PCR the only one positive for Mycobacterium marinum, which is why we proceeded to establish an antimicrobial regimen with favorable evolution. Discussion: infection by this bacterium is produced by direct inoculation of the microorganism through wounds or skin erosions or by contaminated fish bites. The forms of clinical presentation vary, being the most common the presence of solitary papules or nodules on fingers or hands. It can also manifest in the form of proximal or sporotrichoid lymphangitis, extension to deep organs, and facial sporotrichoid pattern. Diagnosis requires high index of suspicion, since the frequency of this condition is very low, from 0.04 to 0.27 per 100.000 habitants. Tissue biopsy provides the diagnosis in only half of the cases. Culture confirms the diagnosis, but they are reported as positive in 70 to 80% of cases. Nucleic acid amplification techniques, such as polymerase chain reaction (PCR) are other methods for diagnosis; its greatest advantage is the speed of its results compared to culture. There are many therapeutic modalities: topical treatment, systemic administration of antimicrobials, surgery, local thermotherapy and combination therapy. However, patients infected with M. marinum are usually treated with antimicrobials alone or in combination.

Oral magnesium supplementation improves glycaemic status in subjects with prediabetes and hypomagnesaemia: A double-blind placebo-controlled randomized trial.

AIM: This study evaluated the efficacy of oral magnesium supplementation in the reduction of plasma glucose levels in adults with prediabetes and hypomagnesaemia. METHODS: A total of 116 men and non-pregnant women, aged 30 to 65 years with hypomagnesaemia and newly diagnosed with prediabetes, were enrolled into a randomized double-blind placebo-controlled trial to receive either 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) or an inert placebo solution once daily for four months. The primary trial endpoint was the efficacy of magnesium supplementation in reducing plasma glucose levels. RESULTS: At baseline, there were no significant statistical differences in terms of anthropometric and biochemical variables between individuals in the supplement and placebo groups. At the end of follow-up, fasting (86.9 ± 7.9 and 98.3 ± 4.6 mg/dL, respectively; P = 0.004) and post-load glucose (124.7 ± 33.4 and 136.7 ± 23.9 mg/dL, respectively; P = 0.03) levels, HOMA-IR indices (2.85 ± 1.0 and 4.1 ± 2.7, respectively; P = 0.04) and triglycerides (166.4 ± 90.6 and 227.0 ± 89.7, respectively; P = 0.009) were significantly decreased, whereas HDL cholesterol (45.6 ± 10.9 and 46.8 ± 9.2 mg/dL, respectively; P = 0.04) and serum magnesium (1.96 ± 0.27 and 1.60 ± 0.26 mg/dL, respectively; P = 0.005) levels were significantly increased in those taking MgCl2 compared with the controls. A total of 34 (29.4%) people improved their glucose status (50.8% and 7.0% in the magnesium and placebo groups, respectively; P < 0.0005). CONCLUSION: Our results show that magnesium supplementation reduces plasma glucose levels, and improves the glycaemic status of adults with prediabetes and hypomagnesaemia.

Augmentation with amisulpride for schizophrenic patients non-responsive to risperidone monotherapy.

INTRODUCTION: The combination of antipsychotic drugs is a therapeutic resource in clinical practice. This study aimed to evaluate the efficacy and security of adding amisulpride in patients who at least partially responded to risperidone. METHODS: A 3-month, open, observational study was undertaken to evaluate the effectiveness of adding amisulpride in subjects who scored at least 25 on the brief psychiatric rating scale (BPRS) after risperidone monotherapy. Patients were evaluated with BPRS, the Clinical Global Impressions Severity of Illness scale (CGI-S) and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU) at baseline, 1 and 3 months. RESULTS: Coadjuvant treatment with amisulpride achieves a statistically significant improvement in mental status over a period of 3 months when measured with BPRS, CGI and UKU scales. The response rate was 70 (45%) in the oral risperidone and 74 (28%) in the parenteral risperidone groups. DISCUSSION: The addition of amisulpride could lead to an improvement in schizophrenia symptoms in patients that do not, or only partially, respond to risperidone. Further research is required into alternative therapies for poor responders.

Beta hydroxy beta methylbutyrate supplementation impairs peripheral insulin sensitivity in healthy sedentary Wistar rats.

AIM: Investigate, in healthy sedentary rats, the potential mechanisms involved on the effects of beta hydroxy beta methylbutyrate (HMB) supplementation upon the glycaemic homeostasis, by evaluating the insulin sensitivity in liver, skeletal muscle, and white adipose tissue. METHODS: Rats were supplemented with either beta hydroxy beta methylbutyrate (320 mg kg(-1)  BW) or saline by gavage for 4 weeks. After the experimental period, the animals were subjected to the glucose tolerance test (GTT) and plasma non-esterified fatty acids (NEFA) concentration measurements. The soleus skeletal muscle, liver and white adipose tissue were removed for molecular (western blotting and RT-PCR) and histological analysis. RESULTS: The beta hydroxy beta methylbutyrate supplemented rats presented: (i) higher ratio between the area under the curve (AUC) of insulinaemia and glycaemia during glucose tolerance test; (ii) impairment of insulin sensitivity on liver and soleus skeletal muscle after insulin overload; (iii) reduction of glucose transporter 4 (GLUT 4) total and plasma membrane content on soleus; (iv) increased hormone-sensitive lipase (HSL) mRNA and protein expression on white adipose tissue and plasma NEFA levels and (v) reduction of fibre cross-sectional area of soleus muscle. CONCLUSION: The data altogether indicate that beta hydroxy beta methylbutyrate supplementation impairs insulin sensitivity in healthy sedentary rats, which, in the long-term, could lead to an increased risk of developing type 2 diabetes.

Long-term evaluation of phrenic nerve pacing for respiratory failure due to high cervical spinal cord injury.

OBJECTIVES: Phrenic nerve pacing is a method of respiratory support that can replace mechanical ventilation in high-level cervical spinal cord injury patients with diaphragmatic paralysis. Our objective was to evaluate survival and long-term quality of life in patients with external respiratory support by PNP vs volumetric respirator in patients with severe respiratory insufficiency due to a high-level spinal cord injury. DESIGN: This is a retrospective review study of a prospectively collected database for evaluate the survival and a questionnaire for quality of life has been collected face-to-face or by telephone at present. PATIENTS: Cervical SCI patients with permanent respiratory support (PNP or MV). METHODS: Long-term evaluation of a cohort of PNP-supported patients. We performed a comparison between these patients and volumetric respirator-supported patients. For survival analysis, we used the Kaplan-Meier method and Cox proportional hazards model. The health-related quality of life was assessed with SF-36 questionnaire, a general HRQL evaluation. RESULTS: One hundred twenty six patients on permanent respiratory support were evaluated during the study period. Of these, 38 were on PNP and 88 were mechanically ventilated. Paced patients were younger and had a longer survival, but in a multivariate analysis adjusted for age using a multiple logistic correlation we found that length of survival was greater for PNP patients. In terms of HRQL, the PNP-supported patients showed better results in terms of social functioning. CONCLUSIONS: PNP is a stable and effective method of long-term respiratory support in this type of patients (SCI patients dependent on external respiratory support). In these patients it improves the length of survival and some social issues by quality of life when compared with patients under MV.

[Enteral nutrition in neurological patients: is there enough vitamin D content in commonly used formulas?]. / Nutrición enteral en el paciente neurológico: ¿es suficiente el contenido en vitamina D en las fórmulas de uso habitual?

INTRODUCTION: Vitamin D deficiency produces inadequate bone mineralization, proximal muscle weakness, abnormal gait and increased risk of falls and fractures. Moreover, in epidemiological studies, has been associated with increased risk of cancer, autoimmune diseases, type 1 and 2 diabetes, rheumatoid arthritis, multiple sclerosis, infectious diseases, cardiovascular diseases and depression. When synthesis through the skin by sun exposure is not possible and the patient can not eat by mouth, as in the advanced stages of various neurological diseases, the supply of vitamin D has to be done by enteral nutrition. OBJECTIVES: The aim of this study is to review the role of vitamin D in a common group of neurological conditions that often require artificial nutrition and analyze whether the vitamin D of different enteral nutrition formulas is adequate to meet the needs of this group of patients. RESULTS: Numerous studies have shown the association between vitamin D deficiency and increased incidence of dementia, stroke and other neurodegenerative diseases. Interventions aimed to increase levels of vit. D and its effects on functional (falls, pain, quality of life) and cardiovascular goals (cardiovascular death, stroke, myocardial infarction, cardiovascular risk factors) have obtained as highlight data a clear reduction of falls and fractures, while the evidence for the other parameters studied is still limited and inconsistent. The content of calcium and vitamin D of enteral formulas is legislated in our country. The total amount of vitamin D for a daily intake of 1,500-2,000 kcal ranges between 300 and 1,600 IU/d (mean ± SD: 32.9 ± 8.5 mg/100 kcal) in the complete formulas for enteral nutrition most commonly used. 50% of the diets studied, for an intake of 2,000 kcal/d, and 90% for an intake of 1,500 kcal/d, provide less than 600 IU/d of vitamin D. DISCUSSION: Some revised recently guidelines published recommendations of daily intake of vitamin D. The document published by the U.S. Institute of Medicine recommended for adults between 19 and 70 years, 600 IU/d and up from 70, proposes 800 IU/d of vitamin D. These amounts are deemed insufficient by other scientific societies to state that to achieve blood levels of 25 (OH) D equal or greater than 30 ng/ml may be required a daily intake of 1,500-2,000 IU and a number two or three times higher if previous deficiency exists. CONCLUSIONS: Further controlled studies are needed to ascertain which is the appropriate dose of vitamin D in advanced stages of neurological disease, where sun exposure is difficult and unlikely. We suggest that the vitamin D content should probably be reconsidered in enteral nutrition formulas, which, in light of recent publications appear as clearly insufficient for standard energy intakes (1,500-2,000 kcal).

Effect of aracnotoxin from Latrodectus mactans on bovine sperm function: modulatory action of bovine oviduct cells and their secretions.

Latrodectus mactans' aracnotoxin (Atx) induces changes in sperm function that could be used as a co-adjuvant in male contraceptive barrier methods. This effect includes the suppression of intracellular reactive oxygen species (ROS), an event necessary for capacitation, chemotaxis and acrosome reaction (AR). The sperm that are not trapped by the barrier method can reach the oviduct before fertilisation and be exposed to the secretions of the oviducts. This study evaluated the effect of bovine tubal explants (TU) and conditioned media (CM) from the ampullar and isthmal regions on spermatozoa exposed to Atx. Thawed bovine sperm were incubated with Atx, TU and CM from the ampullar and isthmal regions for 4 h and then DNA integrity, intracellular ROS and lysophosphatidylcholine-induced AR were determined. Spermatozoa exposed to Atx and co-incubated with TU and CM for 4 h produced an increase in sperm DNA damage, a decrease in ROS production and a decrease in %AR, compared with the control. A similar result was obtained from the co-incubation of spermatozoa with Atx. In conclusion, the effect of Atx is not modified by tubal cells or their secretions and this opens the door to future studies to evaluate the application of synthetic peptides obtained from Atx as a co-adjuvant of contraceptive barrier methods.

Estrategias nutricionales ante el estreñimiento y la deshidratación en las personas mayores / Nutritional strategies towards constipation and dehydration in older people

El estreñimiento puede ser definido por defecación infrecuente y esfuerzo defecatorio excesivo. Las causas más habituales son la deshidratación, la dieta pobre en fibra, el consumo de determinados fármacos y las enfermedades debilitantes, circunstancias especialmente frecuentes en la edad geriátrica. El estreñimiento en anciano puede asociarse a complicaciones derivadas de la impactación fecal y otras derivadas del excesivo esfuerzo para conseguir la defecación. Para que se produzca deshidratación, virtualmente en todos los casos, debe existir una alteración en la percepción de la sed o en la capacidad de ingerir agua. Cuando el déficit de agua supera al de sodio el paciente desarrolla un síndrome clínico de hipernatremia/hiperosmolaridad que siempre está asociada a un aumento de la osmolaridad plasmática efectiva y, por tanto, con una disminución del volumen intracelular. Las causas desencadenantes en el anciano son la infección, el uso excesivo de diuréticos, el ictus, tratamiento con corticoides, situación de postoperatorio, la suspensión de un tratamiento antidiabético o la diabetes insípida. El tratamiento de rehidratación debe realizarse preferiblemente por vía oral y de forma lenta para evitar el daño neurológico. La corrección debe incluir agua y electrolitos (sales de sodio y potasio) y obliga a un cálculo preciso del aporte, sobre todo cuando está alterado el estado de conciencia y precisamos de tratamiento intravenoso, para evitar la sobrehidratación y las alteraciones electrolíticas. El tratamiento del estreñimiento incluye, además de la rehidratación, la educación del paciente en un patrón horario, postural y de ejercicio físico para reforzar la prensa abdominal. Un cambio en los hábitos alimentarios para aumentar el contenido en fibra alimentaria en la dieta aumenta el tamaño del bolo fecal, mejora la consistencia de las heces y disminuye las molestias abdominales. Así mismo, el uso de prebióticos, complementado con fibra fermentable, logra aumentar la masa fecal. Los alimentos de uso común ricos en fibra son el salvado de trigo, legumbres, harinas integrales, frutas y verduras. Las recomendaciones sobre el consumo de fibra son de 10 a 13 g/1.000 kcal siendo el 70-75% de fibra insoluble y un 25-30% de fibra soluble. El uso juicioso de fármacos con efecto laxante tiene un papel en el tratamiento del estreñimiento cuando éste no responde a las medidas higiénico-dietéticas. Existen cuatro grupos farmacológicos de uso habitual: laxantes con efecto osmótico, estimulantes del peristaltismo, emolientes y aumentadores del bolo fecal con distintas indicaciones. En el paciente de edad avanzada, podemos iniciar el tratamiento con lactulosa o lactitiol o recurrir directamente a fármacos estimulantes como bisacodilo, picosulfato sódico o senósidos. Los azúcares osmóticos serán los laxantes recomendados para el uso crónico. Debemos usar con precaución los laxantes estimuladores del peristaltismo, ya que la secreción de agua y electrolitos a la luz intestinal es responsable de episodios de hipotensión ortostática que pueden ocasionar caídas en el paciente anciano (AU)

Constipation can be defined as infrequent defecation and straining at stool. The most common causes are dehydration, low-fiber diet, use of certain drugs and debilitating disease, particularly common conditions in geriatric patients. Constipation in the elderly may be associated with fecal impaction and other complications deriving from excessive straining to pass stools. Dehydration occurs, in virtually all cases, with an alteration in the perception of thirst or water intake capacity. When the water deficit exceeds that of sodium, the patient develops clinical signs and symptoms of hypernatremia/hyperosmolality, always associated with an increase in effective plasma osmolality and consequent decrease in intracellular volume. Precipitating causes in the elderly are infection, excessive use of diuretics, stroke, treatment with corticosteroids, postoperative status, suspension of antidiabetic drugs or diabetes insipidus. Rehydration should preferably be oral and done slowly to prevent neurological damage. Treatment should include water and electrolytes (sodium and potassium salts) and requires accurate calculation of input to prevent overload and electrolyte imbalance, especially in the case of altered consciousness with the patient needing intravenous therapy. In addition to rehydration, the treatment of constipation includes educating the patient about bowel training to establish a regular pattern, posture and physical exercise to strengthen the muscles in the abdominal wall. A change in eating habits to increase dietary fiber content increases the size of the feces, improves stool consistency and reduces abdominal discomfort. Likewise, the use of prebiotics, supplemented with fermentable fiber, helps increase fecal mass. Commonly-used foods rich in fiber are wheat bran, beans, whole flour, fruit and vegetables. Recommended fiber intake is 10 to 13 g/1,000 kcal with 70-75% insoluble fiber and 25-30% soluble fiber. Judicious use of laxative drugs does have a role in the treatment of constipation if patients do not respond to the toileting / dietary measures. There are four commonly used drug classes: osmotic laxatives, peristalsis stimulants, emollients and fecal enhancers, with different indications. In the older patient, we can begin treatment with lactulose or lactitiol or go directly to stimulant drugs such as bisacodyl, cassia extracts or sodium picosulfate. Sugar osmotic laxatives are recommended for long-term use. Stimulating peristalsis laxatives have to be used with caution since secretion of water and electrolytes into the intestinal lumen can be responsible for orthostatic hypotension, causing falls in the elderly (AU)

Polyphenolic profile and antiproliferative activity of bioaccessible fractions of zinc-fortified fruit beverages in human colon cancer cell lines / Perfil polifenólico y actividad antiproliferativa de las fracciones bioaccesibles de bebidas a base de zumo de frutas suplementadas con cinc en líneas celulares humanas de cáncer de colon

Introduction: Colorectal cancer risks could be reduced by polyphenol-rich diets that inhibit tumour cell growth. Aims: To determine the polyphenolic profile of four fruit beverages (FbZn, FbZnFe, FbZnM and FbZnFeM) as affected by the presence of Zn with/without Fe and with/without skimmed milk, and the digestion conditions. To evaluate the antiproliferative activity of bioaccessible fractions against Caco-2 and HT-29 cells. To clarify whether cell cycle arrest and/or apoptosis is involved in their possible antiproliferative activity. Methods: The polyphenolic profiles were analyzed by RP-HPLC-DAD before and after in vitro gastrointestinal digestion. Cell proliferation and viability were measured using Trypan blue test, mitochondrial enzyme activity by means MTT test, cell cycle distribution using flow cytometry and apoptosis by means Hoechst dye. Results and discussion: The presence of zinc, iron and/or milk decreased the soluble extractable phenolic content before digestion probably by chelate formation, FbZn and FbZnFe being the samples with the highest soluble extractable phenolics. After digestion, a decrease in phenolics was observed in all zinc-fortified samples (up to 32% with respect to the original fruit beverages) - the FbZnFeM sample showing the lowest soluble extractable phenolic content, though with the lowest percentage decrease in phenolics (14%). FbZnM digest (~50 μM total soluble extractable phenolics) was the sample that most inhibited Caco-2 and HT-29 cell proliferation after 24 h of incubation, without cytotoxicity. The specific combination of phytochemicals in FbZnM digest proved cytostatic and significantly suppressed proliferation through cell cycle arrest in the S-phase in both cell lines, without apoptosis (AU)

Introducción: Los riesgos de cáncer colorrectal podrían reducirse mediante dietas ricas en polifenoles, los cuales pueden inhibir el crecimiento de células tumorales. Objetivos: Determinar cómo el perfil polifenólico de cuatro bebidas a base de zumo de frutas (FbZn, FbZnFe, FbZnM and FbZnFeM) puede verse afectado por la presencia de Zn con/sin Fe y con/sin leche desnatada, así como por las condiciones de digestión gastrointestinal. Evaluar la actividad antiproliferativa de las fracciones bioaccesibles en células Caco-2 y HT-29. Averiguar si un arresto en el ciclo celular y/o apoptosis están implicados en su posible actividad antiproliferativa. Métodos: Los perfiles polifenólicos se analizaron mediante RP-HPLC-DAD antes y después de la digestión gastrointestinal in vitro. La proliferación y viabilidad celular se determinaron con el azul tripán, la actividad enzimática mitocondrial por medio del test MTT, la distribución del ciclo celular por citometría de flujo y la apoptosis mediante la sonda fluorescente Hoechst. Resultados y discusión: La presencia de cinc, hierro y/o leche disminuyó el contenido de polifenoles solubles extraíbles antes de la digestión, probablemente por formación de quelatos. Tras la digestión, se observa un descenso en los polifenoles en todas las muestras suplementadas con cinc (hasta un 32% con respecto a las bebidas de frutas originales), siendo la muestra FbZnFeM aquella con menor contenido de polifenoles solubles extraíbles, aunque con el menor porcentaje de descenso de polifenoles (14%). La muestra digerida de FbZnM (~50 μM polifenoles totales solubles extraíbles) fue la que más inhibió la proliferación de las células Caco-2 y HT-29 tras 24 h de incubación, sin citotoxicidad. La combinación específica de compuestos fitoquímicos en la fracción bioaccesible de FbZnM actuó de forma citostática, disminuyendo la proliferación celular de forma significativa mediante arresto del ciclo celular en la fase S en ambas líneas celulares, no acompañado de apoptosis (AU)

Polyphenolic profile and antiproliferative activity of bioaccessible fractions of zinc-fortified fruit beverages in human colon cancer cell lines.

INTRODUCTION: Colorectal cancer risks could be reduced by polyphenol-rich diets that inhibit tumour cell growth. AIMS: To determine the polyphenolic profile of four fruit beverages (FbZn, FbZnFe, FbZnM and FbZnFeM) as affected by the presence of Zn with/without Fe and with/without skimmed milk, and the digestion conditions. To evaluate the antiproliferative activity of bioaccessible fractions against Caco-2 and HT-29 cells. To clarify whether cell cycle arrest and/or apoptosis is involved in their possible antiproliferative activity. METHODS: The polyphenolic profiles were analyzed by RP-HPLC-DAD before and after in vitro gastrointestinal digestion. Cell proliferation and viability were measured using Trypan blue test, mitochondrial enzyme activity by means MTT test, cell cycle distribution using flow cytometry and apoptosis by means Hoechst dye. RESULTS AND DISCUSSION: The presence of zinc, iron and/or milk decreased the soluble extractable phenolic content before digestion probably by chelate formation, FbZn and FbZnFe being the samples with the highest soluble extractable phenolics. After digestion, a decrease in phenolics was observed in all zinc-fortified samples (up to 32% with respect to the original fruit beverages) - the FbZnFeM sample showing the lowest soluble extractable phenolic content, though with the lowest percentage decrease in phenolics (14%). FbZnM digest (approximately 50 microM total soluble extractable phenolics) was the sample that most inhibited Caco-2 and HT-29 cell proliferation after 24 h of incubation, without cytotoxicity. The specific combination of phytochemicals in FbZnM digest proved cytostatic and significantly suppressed proliferation through cell cycle arrest in the S-phase in both cell lines, without apoptosis.

The effect of lowering blood pressure by magnesium supplementation in diabetic hypertensive adults with low serum magnesium levels: a randomized, double-blind, placebo-controlled clinical trial.

To test the blood pressure (BP)-lowering effect of oral magnesium supplementation (that is, magnesium chloride (MgCl(2)) solution) in diabetic hypertensive adults with hypomagnesaemia not on diuretic treatment but receiving concurrent captopril, we conducted a double-blind, placebo-controlled trial. Eighty-two subjects between 40 and 75 years of age were randomly enrolled. Over 4 months, subjects in the intervention group received 2.5 g of MgCl(2) (50 ml of a solution containing 50 g of MgCl(2) per 1000 ml of solution) equivalent to 450 mg of elemental magnesium, and control subjects inert placebo. The primary trial end point was a reduction in systolic (SBP) and diastolic (DBP) blood pressure. Complete follow-up was achieved for 79 of the 82 randomized subjects. SBP (-20.4+/-15.9 versus -4.7 +/- 12.7 mm Hg, P=0.03) and DBP (-8.7+/-16.3 versus -1.2+/-12.6 mm Hg, P=0.02) showed significant decreases, and high-density lipoprotein-cholesterol (0.1+/-0.6 versus -0.1+/-0.7 mmol l(-1), P=0.04) a significant increase in the magnesium group compared to the placebo group. The adjusted odds ratio between serum magnesium and BP was 2.8 (95%CI: 1.4-6.9). Oral magnesium supplementation with MgCl(2) significantly reduces SBP and DBP in diabetic hypertensive adults with hypomagnesaemia.

Iron deficiency and anaemia in bariatric surgical patients: causes, diagnosis and proper management.

Obesity-induced chronic inflammation leads to activation of the immune system that causes alterations of iron homeostasis including hypoferraemia, iron-restricted erythropoiesis, and finally mild-to-moderate anaemia. Thus, preoperative anaemia and iron deficiency are common among obese patients scheduled for bariatric surgery (BS). Assessment of patients should include a complete haematological and biochemical laboratory work-up, including measurement of iron stores, vitamin B12 and folate. In addition, gastrointestinal evaluation is recommended for most patients with iron-deficiency anaemia. On the other hand, BS is a long-lasting inflammatory stimulus in itself and entails a reduction of the gastric capacity and/or exclusion from the gastrointestinal tract which impair nutrients absorption, including dietary iron. Chronic gastrointestinal blood loss and iron-losingenteropathy may also contribute to iron deficiency after BS. Perioperative anaemia has been linked to increased postoperative morbidity and mortality and decreased quality of life after major surgery, whereas treatment of perioperative anaemia, and even haematinic deficiency without anaemia, has been shown to improve patient outcomes and quality of life. However, long-term follow-up data in regard to prevalence, severity, and causes of anaemia after BS are mostly absent. Iron supplements should be administered to patients after BS, but compliance with oral iron is no good. In addition, once iron deficiency has developed, it may prove refractory to oral treatment. In these situations, IV iron (which can circumvent the iron blockade at enterocytes and macrophages) has emerged as a safe and effective alternative for perioperative anaemia management. Monitoring should continue indefinitely even after the initial iron repletion and anaemia resolution, and maintenance IV iron treatment should be provided as required. New IV preparations, such ferric carboxymaltose, are safe, easy to use and up to 1000 mg can be given in a single session, thus providing an excellent tool to avoid or treat iron deficiency in this patient population.

[Nutritional repercussions and management of chronic pancreatitis]. / Repercusiones nutricionales y manejo de la pancreatitis crónica.

The pancreas is a retroperitoneal organ that releases water, bicarbonate and digestive enzymes by the main pancreatic duct (MPD) into the duodenum. Chronic pancreatitis (CP) is typically caused, in adults, by chronic alcohol abuse and, less frequently hypertriglyceridemia, primary hyperparathyroidism or cystic fibrosis. Exocrine dysfunction results in malabsorption of fat and subsequent steatorrhea. Damage to pancreatic endocrine function is a late finding in CP and results in hyperglycaemia or overt diabetes mellitus. Care of patients with CP principally involves management of pain. A significant change in the pain pattern or the sudden onset of persistent symptoms suggests the need to rule out other potential etiologies, including peptic ulcer disease, biliary obstruction, pseudocysts, pancreatic carcinoma, and pancreatic duct stricture or stones, then is important to establish a secure diagnosis. Management of pain should then proceed in a judicious stepwise approach avoiding opioids dependence. Patients should be advised to stop alcohol intake. Fat malabsorption and other complications may also arise. Management of steatorrhea should begin with small meals and restriction in fat intake. Pancreatic enzyme supplements can relieve symptoms and reduce malabsorption in patients who do not respond to dietary restriction. Enzymes at high doses should be used with meals. Treatment with acid suppression to reduce inactivation of the enzymes from gastric acid are recommended. Supplementation with medium chain triglycerides and fat soluble vitamin replacement may be required. Management of other complications (such as pseudocysts, bile duct or duodenal obstruction, pancreatic ascites, splenic vein thrombosis and pseudoaneurysms) often requires aggressive approach with the patient kept on total parenteral nutrition to minimize pancreatic stimulation.

Repercusiones nutricionales y manejo de la pancreatitis crónica / Nutritional repercussions and management of chronic pancreatitis

El páncreas es un órgano retroperitoneal que segrega agua, bicarbonato y enzimas digestivos a través del conducto pancreático principal (CPP) al duodeno. La pancreatitis crónica (PC) está causada típicamente en el adulto por abuso crónico de alcohol, y, con menor frecuencia, hipertrigliceridemia, hiperparatiroidismo primario o fibrosis quística. La disfunción exocrina ocasiona malabsorción grasa y la consiguiente esteatorrea. El daño en la función endocrina es un hallazgo tardío que se presenta como hiperglucemia o diabetes mellitus franca. El cuidado de pacientes con PC conlleva, de forma primordial, el tratamiento del dolor. Un cambio significativo en su patrón o la aparición súbita y persistente de otros síntomas obligan a descartar otras entidades, incluyendo úlcera péptica, obstrucción biliar, pseudoquistes, cáncer de páncreas, estenosis de conductos pancreáticos o litiasis. Por tanto es importante asegurar el diagnóstico. El manejo del dolor debe realizarse de forma escalonada y prudente tratando de evitar la dependencia de opiáceos. Debe advertirse a los pacientes que interrumpan la ingesta de alcohol. El tratamiento de la mal absorcióngrasa comienza con pequeñas tomas de alimento y restricción grasa. El uso de suplementos de enzimas pancreáticos puede mejorar los síntomas y reducir la mala absorción en pacientes que no respondan al tratamiento dietético. Deben usarse dosis elevadas de enzimas con cada comida. Se recomienda tratamiento supresor dela acidez gástrica para evitar la inactivación de los enzimas. Puede ser necesaria la suplementación con triglicéridos de cadena media (MCT) y vitaminas liposolubles. El manejo de otras complicaciones (como pseudoquistes, obstrucción biliar o duodenal, ascitis pancreática, trombosis de la vena esplénica y pseusoaneurismas) con frecuencia requiere maniobras agresivas manteniendo al paciente bajo nutrición parenteral para minimizar la estimulación pancreática

The pancreas is a retroperitoneal organ that releaseswater, bicarbonate and digestive enzymes by the mainpancreatic duct (MPD) into the duodenum. Chronic pancreatitis (CP) is typically caused, in adults, by chronic alcohol abuse and, less frequently hypertriglyceridemia, primary hyperparathyroidism or chystic fibrosis. Exocrine dysfunction results in malabsorption of fat and subsequent steatorrhea. Damage to pancreatic endocrine function is a late finding in CP and results in hyperglycaemia or overt diabetes mellitus. Care of patients with CP principally involves management of pain. A significant change in the pain pattern or the sudden onset of persistent symptoms suggests the need to rule out other potentialetiologies, including peptic ulcer disease, biliaryobstruction, pseudocysts, pancreatic carcinoma, andpancreatic duct stricture or stones, then is important toestablish a secure diagnosis. Management of pain shouldthen proceed in a judicious stepwise approach avoidingopioids dependence. Patients should be advised to stopalcohol intake. Fat malabsorption and other complicationsmay also arise. Management of steatorrhea shouldbegin with small meals and restriction in fat intake. Pancreatic enzyme supplements can relieve symptoms andreduce malabsorption in patients who do not respond todietary restriction. Enzymes at high doses should be usedwith meals. Treatment with acid suppression to reduceinactivation of the enzymes from gastric acid are recommended. Supplementation with medium chain triglycerides and fat soluble vitamin replacement may be required. Management of other complications (such as pseudocysts, bile duct or duodenal obstruction, pancreatic ascites, splenic vein thrombosis and pseudoaneurysms)often requires aggressive approach with the patient kept on total parenteral nutrition to minimize pancreatic stimulation (AU)

3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline inhibitors of phenylethanolamine N-methyltransferase that display remarkable potency and selectivity.

Six 3-hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines (16-21) were synthesized and evaluated for their phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the alpha(2)-adrenoceptor. The addition of nonpolar substituents to the sulfonamide nitrogen of 9 (3-CH(2)OH-7-SO(2)NH(2)-THIQ) led to inhibitors (16-21) that have high PNMT inhibitory potency and high selectivity, and most of these (16-21) are predicted, on the basis of their calculated log P values, to be able to penetrate the blood-brain barrier. Compounds N-trifluoroethyl sulfonamide 20 (PNMT K(i) = 23 nM) and N-trifluoropropyl sulfonamide 21 (PNMT K(i) = 28 nM) are twice as potent at inhibiting PNMT compared to 9 and display excellent selectivity (alpha(2) K(i)/PNMT K(i) > or = 15,000).

Oral magnesium supplementation improves insulin sensitivity in non-diabetic subjects with insulin resistance. A double-blind placebo-controlled randomized trial.

OBJECTIVE: Although hypomagnesemia reduces insulin sensitivity, benefits of magnesium supplementation to non-diabetic insulin resistant subjects has not been established. Our purpose was to determine whether oral magnesium supplementation with magnesium chloride (MgCl2) 2.5 g daily modify insulin sensitivity in non-diabetic subjects. MATERIAL AND METHODS: This study was a 3 months randomized double-blind placebo-controlled trial. Apparently healthy subjects were eligible to participate if they had insulin resistance (HOMA-IR index equal or greater than 3.0) and hypomagnesemia (Serum magnesium levels equal or lower than 0.74 mmol/l). Subjects were randomized to receive either, MgCl2 2.5 g daily or placebo by 3-months. RESULTS: At baseline there were not significant anthropometric or laboratory differences between both groups. At ending of the study, magnesium-supplemented subjects significantly increased their serum magnesium levels (0.61 +/- 0.08 to 0.81 +/- 0.08 mmol/l, p<0.0001) and reduced HOMA-IR index (4.6 +/- 2.8 to 2.6 +/- 1.1, p<0.0001), whereas control subjects did not (0.62 +/- 0.08 to 0.61 +/- 0.08 mmol/l, p=0.063 and 5.2 +/- 1.9 to 5.3 +/- 2.9, p=0.087). CONCLUSIONS: Oral magnesium supplementation improves insulin sensitivity in hypomagnesemic non-diabetic subjects. Clinical implications of this finding have to be established.

The Effect of Natural Mulches on Crop Performance, Weed Suppression and Biochemical Constituents of Catnip and St. John's Wort.

Because of expanding markets for high-value niche crops, opportunities have increased for the production of medicinal herbs in the USA. An experiment was conducted in 2001 and 2002 near Gilbert, IA, to study crop performance, weed suppression, and environmental conditions associated with the use of several organic mulches in the production of two herbs, catnip (Nepeta cataria L.) and St. John's wort (Hypericum perforatum L. 'Helos'). Treatments were arranged in a completely randomized design and included a positive (hand-weeded) control, a negative (nonweeded) control, oat straw, a flax straw mat, and a nonwoven wool mat. Catnip plant height was significantly greater in the oat straw than the other treatments at 4 wk through 6 wk in 2001; at 4 to 8 wk in 2002, catnip plant height and width was significantly lower in the negative control compared with the other treatments. Catnip yield was significantly higher in the flax straw mat than all other treatments in 2001. In 2002, St. John's wort yields were not statistically different in any treatments. All weed management treatments had significantly fewer weeds than the non-weeded rows in 2002. Total weed density comparisons in each crop from 2 yr showed fewer weeds present in the flax straw and wool mat treatments compared with positive control plots. There was no significant weed management treatment effect on the concentration of the target compounds, nepetalactone in catnip and pseudohypericin-hypericin in St. John's wort, although there was a trend toward higher concentrations in the flax straw treatment.