Organic loading rate effect on the acidogenesis of cheese whey: a comparison between UASB and SBR reactors.

Volatile fatty acids (VFA) production and degree of acidification (DA) were investigated in the anaerobic treatment of cheese whey by comparison of two processes: a continuous process using a laboratory upflow anaerobic sludge blanket (UASB) reactor and a discontinuous process using a sequencing batch reactor (SBR). The main purpose of this work was to study the organic loading rate (OLR) effect on the yield of VFA in two kinds of reactors. The predominant products in the acidogenic process in both reactors were: acetate, propionate, butyrate and valerate. The maximum DA obtained was 98% in an SBR at OLR of 2.7 g COD L-1 d-1, and 97% in the UASB at OLR at 15.1 g COD L-1 d-1. The results revealed that the UASB reactor was more efficient at a medium OLR with a higher VFA yield, while with the SBR reactor, the maximum acidification was obtained at a lower OLR with changes in the VFA profile at different OLRs applied.

Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma.

Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors. We also found high expression of HSP90 and the PI3K/AKT/mTOR pathway proteins, 4EBP1 and AKT compared with healthy tissue and this correlated with poor overall survival of melanoma patients. The combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 showed a synergistic activity decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/AKT/mTOR pathways. These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients.

Active kinase profiling, genetic and pharmacological data define mTOR as an important common target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often seen in the metastatic setting. Therefore, identification of new therapeutic targets is required. With this aim, we have profiled the activation status of 44 receptor tyrosine kinases (RTKs) and their major signaling pathways in patient-derived TNBC tumors. Frequent co-activation of several RTKs as well as the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and mammalian target of rapamycin (mTOR) routes was found. Pharmacologic targeting of the activated kinases indicated that agents that attack the mTOR route are more potent and efficient antitumoral treatments than agents targeting RTKs. mTOR signals through two multiprotein complexes, mTORC1 and mTORC2. We used a genetic approach to explore the contribution of each of the two mTOR branches to the regulation of cell number of TNBC cells. RNA interference experiments indicated that mTORC1 predominated over mTORC2 in the control of TNBC cell proliferation. Moreover, RNA interference of mTOR had a superior antiproliferative action than separately acting on mTORC1 or mTORC2. To analyze the relevance of mTOR targeting in vivo, we used mice with TNBC. Treatment of these mice with BEZ235, a drug that targets mTOR, slowed tumor growth. Mechanistically, BEZ235 delayed cell cycle progression without affecting cell viability. Our results show that TNBCs are particularly sensitive to inhibition of the mTOR pathway, and indicate that mTOR targeting may be a more efficient anti-TNBC therapy than exclusively acting on the mTORC1 branch of the pathway. This is relevant as most mTOR inhibitors used in the clinic act on mTORC1. Collectively with the fact that BEZ235 synergized with drugs commonly used in the treatment of TNBC, our data support the clinical development of agents that act on mTOR as a therapy for this disease.

Identification of sperm subpopulations with defined motility characteristics in ejaculates from Ile de France rams.

The aims of this study were to identify different motile sperm subpopulations in fresh ejaculates from six Ile de France rams, by using a computer-assisted sperm motility analysis (CASA) system, and to evaluate the effects of individual ram and season on population distribution. Overall sperm motility and individual kinematic parameters of motile spermatozoa were evaluated for 125,312 spermatozoa, defined by curvilinear velocity (VCL), linear velocity (VSL), average path velocity (VAP), linearity coefficient (LIN), straightness coefficient (STR), wobble coefficient (WOB), mean amplitude of lateral head displacement (ALH) and frequency of head displacement (BCF). A multivariate cluster analysis was carried out to classify these spermatozoa into a reduced number of subpopulations according to their movement patterns. The statistical analysis clustered the whole motile sperm population into five separate groups: subpopulation 1, constituted by rapid, progressive and non sinuous spermatozoa (VCL=126.41 µm/s, STR=92.87% and LIN=86.47%); subpopulation 2, characterized by progressive spermatozoa with moderate velocity (VCL=74.74 µm/s and STR=84.03%); subpopulation 3, represented by rapid, progressive and sinuous spermatozoa (VCL=130.45 µm/s, STR=76.02% and LIN=47.68%); subpopulation 4 represents rapid nonprogressive spermatozoa (VCL=128.69 µm/s and STR=44.09%); subpopulation 5 includes poorly motile, nonprogressive spermatozoa with a very irregular trajectory (VCL=36.81 µm/s and STR=47.04%). Our results show the existence of five subpopulations of motile spermatozoa in ram ejaculates. The frequency distribution of spermatozoa within subpopulations was quite similar for the six rams, and the five subpopulations turned out to be very stable along seasons.

Dual renin-angiotensin system blockade: in patients with single functioning kidney and proteinuria.

AIM: Dual blockade of renin-angiotensin system (RAS) has increased antiproteinuric effects and it has been increasingly used on patients with proteinuria, but could have secondary effects when this kind of treatment is administered to patients with single functioning kidney. The aim of this study has been to assess the efficacy and safety of dual blockade of RAS in this group of patients. DESIGN AND METHODS: Sixteen patients with a single functioning kidney have been treated in our unit with dual RAS blockade due to proteinuria higher than 1 g/24 h. Mean age was 54.7+/-12.1 years, they were 12 males and 4 females. Analytical data of six months visit and last follow up visit have been retrospectively registered. Several different angiotensin conversor enzyme (ACE) inhibitors and angiotensin receptor blocking (ARB) drugs were used at the maximal dose tolerated by the patient. RESULTS: A small but not significant reduction of SBP and DBP were was observed throughout the study. Mean K+ increase in the second visit (from 4.65+/-0.67 to 5.01+/-1.02 mmol/l, not significant). There were no changes neither in plasmatic creatinine (baseline 1.86+/-0.67, 6 months 1.96+/-0.85) nor in creatinine clearance (baseline 65.2+/-26.9, 6 months 61.6+/-23.8 ml/min). Proteinuria was not reduced by dual RAS blockade (baseline 4.26+/-0.24, 6 months 4.25+/-0.39). CONCLUSIONS: Dual RAS blockade seems to be safe but unhelpful in renal patients with proteinuria associated to single functioning kidney.

An update on the biology of cancer stem cells in breast cancer

Breast cancer stem cells are defined as cancer cells with self-renewal capacity. These cells represent a small subpopulation endowed with the ability to form new tumours when injected in nude mice. Markers of differentiation have been used to identify these cancer cells. In the case of breast cancer, CD44+/CD24- select a population with stem cell properties. The fact that these cells have self-renewal ability has suggested that this population could be responsible for new tumour formation and cancer relapse. These cells have been shown to be more resistant to chemotherapy and radiotherapy than normal cancer cells. The identification of the molecular druggable alterations responsible for the initiation and maintenance of cancer stem cells is an important goal. In this article we will review all these points with special emphasis on the possible role of new drugs designed to interact with molecular pathways of cancer stem cells (AU)

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Papel de la cistatina C en la valoración de la función renal y su relación con el riesgo cardiovascular / Role of cystatin C in the assessment of renal function and its relationship with cardiovascular risk

Actualmente no hay consenso sobre la forma ideal de medir la función renal. Durante décadas se ha utilizado la creatinina plasmática como el principal método de medición de la función renal, pero es una medición grosera y con frecuentes resultados erróneos. Para salvar estos obstáculos se han introducido fórmulas para calcular el aclaramiento de creatinina (fórmula de Cockroft-Gault) o el filtrado glomerular (ecuación del estudio Modification of Diet in Renal Disease). Por otra parte, se ha propuesto la cistatina C como un buen marcador de la función renal. Desgraciadamente, y a pesar del entusiasmo despertado, la cistatina C sólo parece mejorar ligeramente el poder predictor de la creatinina. La necesidad de esta medición ha ganado en importancia tras comprobarse que incluso pacientes con leves reducciones de la función renal presentan una morbilidad y mortalidad cardiovasculares elevadas. En este sentido la cistatina C podría ser un marcador de importancia pronóstica de la aparición de acontecimientos cardiovasculares independientemente de la función renal

Currently there is no agreement on the ideal way to measure renal function. Plasma creatinine has been used for decades as the principal method of renal function measurement. However, it is a rude measurement with frequent erroneous results. To overcome these obstacles, formulas have been introduced to calculate creatinine clearance (Cockroft-Gault formula) or glomerular filtration rate (equation of the Modification of Diet in Renal Disease Study). On the other hand, cystatin C has been proposed as a good marker of renal function. Unfortunately, and in spite of the enthusiasm provoked, cystatin C only seems to slightly improve the predictive power of creatinine. The need for this measurement has gained importance after verifying that even patients with mild reductions in renal function have elevated cardiovascular morbidity and mortality. In this sense, cystatin C could be a marker of prognostic importance of the appearance of cardiovascular events independently of the renal function

Sobredosis de ciamida cálcica (carbimida): descripción de un caso y revisión bibliográfica / Carbimide overdosage: description of a case and review of the literature

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[Obesity and mortality in advanced chronic renal failure patients]. / Obesidad y mortalidad en pacientes con insuficiencia renal avanzada.

A protective effect of obesity on the mortality of end-stage renal failure patients has been observed in several studies. Most of these studies have been based on prevalent dialysis population. The aim of the present study was to evaluate if obesity has beneficial effects on the survival of advanced chronic renal failure patients. The study group consisted of 376 patients (mean age 63 +/- 15 years) with advanced chronic renal failure not yet on dialysis. Obesity was defined as a body mass index (BMI) > or = 30 kg/m2. Grade of comorbidity was quantified by the method devised by Davies. Survival was analyzed as time from the referral to the predialysis outpatient clinic to patient death, censoring from contributing additional survival data to the analysis following transplantation. Kaplan-Meier analysis was used to test survival differences according to quartiles of BMI, and between obese and nonobese patients. Further analysis were performed, stratifying survival curves by comorbid scores, lean body mass, age, and sex. Cox proportional hazard regression models were used to investigate the best determinants of mortality, and the role of obesity adjusted for other covariates. Median survival time was 1,453 days. During the follow-up time, 158 patients (42%) died. Survival differences among quartiles of BMI were statistically significant (Breslow = 10.7, p = 0.017). Patients within the lowest and the highest quartiles of BMI had higher mortality than the rest of patients. Survival curves between obese and non-obese patients did not differ significantly. However, when patients without comorbidity were studied apart, those with obesity showed worse survival than the rest of patients (log-rank = 7.42, p = 0.0064). Since the effect of obesity on mortality did not follow a proportional hazard pattern throughout the study period, multivariable analysis for mortality was stratified by 18 months intervals. The variables which fitted the best model were: age (Hazard Ratio: 1.04), comorbid score (HR: 2.17), serum albumin (HR: 0.62), GFR at the study entry (HR: 0.91), male gender (HR: 1.48), and obesity (HR: 1.51). In conclusion, obesity had no survival benefit in patients with advanced chronic renal failure. Obesity had a noteworthy impact on early mortality of advanced chronic kidney disease patients without comorbidities.

Intussusception in children: current concepts in diagnosis and enema reduction.

Intussusception cannot be reliably ruled out with clinical examination and plain radiography. However, a contrast material enema study and ultrasonography (US) allow definitive diagnosis of intussusception. The components of an intussusception produce characteristic appearances on US scans. These appearances include the multiple concentric ring sign and crescent-in-doughnut sign on axial scans and the sandwich sign and hayfork sign on longitudinal scans. Indicators of ischemia and irreducibility are trapped fluid at US and absence of blood flow at Doppler imaging. The aim of enema therapy is to reduce the greatest number of intussusceptions without producing perforation. Barium, water-soluble contrast media, water, electrolyte solutions, or air may be used with radiographic or US guidance. The differences in reduction and perforation rates between the various types of enemas are probably due more to perforations that occurred before enema therapy and the pressure exerted within the colon than to the contrast material used. The pressure within the colon is more constant with hydrostatic reduction than with air reduction; this fact may explain the lower risk of perforation with hydrostatic reduction. Radiation exposure is lower with air enema therapy than with barium enema therapy and is absent in US-guided enema therapy.

Effects of oral phosphorus supplementation on mineral metabolism of renal transplant recipients.

BACKGROUND: Persistent hyperparathyroidism (HPT) is frequently observed in kidney transplant recipients. Hypophosphataemia is a common biochemical consequence of HPT. Theoretically, oral phosphorus administration may induce negative effects on the control of HPT, though this point has never been demonstrated in kidney-transplant recipients. This study was designed to evaluate the effects of oral phosphorus supplementation on the mineral metabolism of successful kidney transplant recipients. METHODS: Thirty-two kidney transplant recipients with serum creatinine < 2 mg/dl and serum phosphate levels <3.5 mg/dl were included in the study. After a washout period in which oral phosphorus supplementation was discontinued, the following parameters were determined (F0 period): serum calcium, phosphate, alkaline phosphatase, uric acid, bicarbonate, PTH, 1,25-dihydroxyvitamin D3 (1,25 (OH)(2)D) and 25-hydroxyvitamin D3 (25OHD). Creatinine clearance, calcium, and phosphate excretion were determined from a 24-h urine sample. The same determinations were repeated (F1 period) after all patients received 1.5 g of oral phosphorus for 15 days. For data analysis, patients were divided into two subgroups (optimal and suboptimal) according to allograft function (Ccr>or < 70 ml/min/1.73 m2). RESULTS: In the F0 period, only nine of 32 patients had PTH levels within the normal range (<65 pg/ml). The mean concentrations of PTH, 1,25(OH)(2)D and 25OHD were 132+/-97pg/ml, 40.5+16pg/ml and 12.5+/-8.2 ng/ml respectively. Phosphorus supplementation led to significant reductions in serum calcium and 1,25(OH)(2)D concentrations, as well as in urinary calcium excretion in the whole group. On the contrary, serum phosphate, PTH, and urinary phosphate excretion increased significantly. The percentage increase in PTH concentrations after phosphorus supplementation were similar in patients with optimal and suboptimal allograft function (33 vs 36%). The reduction of 1,25 (OH)(2)D concentrations after phosphorus supplementation was observed mainly in the subgroup with optimal allograft function (21% reduction with respect to baseline values), while the mean 1,25(OH)(2)D concentrations in patients with suboptimal allograft function scarcely changed (1.4% increase). Changes in 1,25(OH)(2)D concentrations after phosphorus supplementation, expressed as a percentage of the initial concentrations, correlated positively with the percentage changes in PTH concentrations for the whole group, as well as for each subgroup. The best determinants for the percentage and the absolute increase in PTH concentration after phosphorus supplementation was the final serum phosphate concentration (F=4.84, r=0.37, P=0.035) and the increase in serum phosphate (F=7.69, r=0.45, P= 0.009) respectively. CONCLUSIONS: Oral phosphorus supplementation led to a significant increase in the PTH concentration of kidney transplant recipients. The mean 1,25(OH)(2)D concentration decreased mainly in recipients with optimal allograft function. The counterbalance effect of PTH on 1,25(OH)(2)D production may account for the relative preservation of 1,25(OH)2D levels in recipients with suboptimal allograft function.

Risk factors for developing peritonitis caused by micro-organisms of enteral origin in peritoneal dialysis patients.

OBJECTIVE: To investigate the risk factors associated with the development of peritonitis caused by enteral bacteria in peritoneal dialysis patients, including the prescription of gastric acid inhibitors as a potential risk factor. DESIGN: Retrospective single-center study. SETTING: Tertiary university hospital. PATIENTS AND MAIN OUTCOME MEASURES: Fifty-five patients who entered into our continuous ambulatory peritoneal dialysis (CAPD) program during the last 6 years were included. Multiple logistic regression analysis was used to establish the best determinants over the development of at least one episode of enteric peritonitis. The predictive variables included in the model were: age, gender, diabetic versus nondiabetic, polycystic versus nonpolycystic kidney diseases, history of constipation, presence or absence of moderate/severe malnutrition, peritoneal transport characteristics, peritoneal protein losses, rate of exit-site infections, rate of total peritonitis, intestinal abnormalities, and treatment with inhibitors of gastric acid secretion. RESULTS: The total number of peritonitis episodes during the studied period was 88, which clustered in 34 of 55 patients. Fourteen (16%) were caused by enteric micro-organisms in 10 patients: Escherichia coli (6), Klebsiella sp (2), Enterobacter sp (1), and Enterococcus sp (5). Nine of 10 patients who developed enteric peritonitis were on gastric acid inhibitors (3 patients on omeprazole and 6 patients on H2-antagonists), while 15 of 45 patients who did not develop enteric peritonitis were on gastric acid inhibitors (all of them on H2-blockers). There were temporal relationships between the start of gastric acid inhibitors and the development of enteric peritonitis in 6 of 9 patients who were on this medication. Four of 10 patients who developed enteric peritonitis had diverticulosis. Ten of 45 patients who did not develop enteric peritonitis had been diagnosed with diverticulosis of the colon or sigmoid prior to entry to CAPD. The unique patient who was not on gastric acid inhibitors and developed enteric peritonitis, had been diagnosed with chronic atrophic gastritis with achlorhydria. By multiple logistic regression analysis, the treatment with gastric acid inhibitors was the only independent variable that entered into the best predictive equation over the development of enteric peritonitis (log likelihood ratio = -26.077, odds ratio = 18; 95% CI odds ratio: 2 - 155). CONCLUSION: Gastric acid inhibitors may increase the risk for developing enteric peritonitis in peritoneal dialysis patients.

[Treatment with pravastatin of dyslipidemia associated with diabetic nephropathy]. / Tratamiento con pravastatina de la dislipemia asociada a nefropatía diabética.

OBJECTIVE: Patients with type II diabetes mellitus have an increased risk of coronary he disease. We investigated the efficacy and safety of pravastatin in the treatment of patients with diabetic nephropathy and hypercholesterolemia. METHOD: In this 6-months study, 12 patients (4 men, 8 women, mean age 60.5 +/- 10.8 years), with diabetic nephropathy and hypercholesterolemia (fasting plasma low-density lipoprotein cholesterol levels -LDL-C- > 130 mg/dl) received pravastatin 10 mg/day. The dose could be doubled after 4 weeks. Seven patients have chronic renal failure. RESULTS: Significant reductions in LDL-C (-19.1%, p < 0.05), total cholesterol (-16%, p < 0.01), very-low-density lipoprotein cholesterol (-29.2%, p < 0.05), apolipoprotein B (-21.5%, p < 0.05), and triglycerides (-26.0%, p < 0.01) were noted. No changes were found either in high-density-cholesterol or its fractions (HDL2 and HDL3) or in apolipoprotein A plasmatic levels. Pravastatin was well tolerated and no one side effect was detected. No clinically significant changes on the control of diabetes, renal function, as assessed by plasmatic creatinin and creatinin clearance, and proteinuria were seen during the follow-up time. CONCLUSIONS: The results of the study demonstrate that pravastatin is well tolerated and effective in lowering total cholesterol and LDL-C in patients with diabetic nephropathy and hypercholesterolemia.