COVID-19: clinical course and outcomes of 36 hemodialysis patients in Spain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia emerged in Wuhan, China in December 2019. Unfortunately, there is a lack of evidence about the optimal management of novel coronavirus disease 2019 (COVID-19), and even less is available in patients on maintenance hemodialysis therapy than in the general population. In this retrospective, observational, single-center study, we analyzed the clinical course and outcomes of all maintenance hemodialysis patients hospitalized with COVID-19 from March 12th to April 10th, 2020 as confirmed by real-time polymerase chain reaction. Baseline features, clinical course, laboratory data, and different therapies were compared between survivors and nonsurvivors to identify risk factors associated with mortality. Among the 36 patients, 11 (30.5%) died, and 7 were able to be discharged within the observation period. Clinical and radiological evolution during the first week of admission were predictive of mortality. Among the 36 patients, 18 had worsening of their clinical status, as defined by severe hypoxia with oxygen therapy requirements greater than 4 L/min and radiological worsening. Significantly, 11 of those 18 patients (61.1%) died. None of the classical cardiovascular risk factors in the general population were associated with higher mortality. Compared to survivors, nonsurvivors had significantly longer dialysis vintage, increased lactate dehydrogenase (490 U/l ± 120 U/l vs. 281 U/l ± 151 U/l, P = 0.008) and C-reactive protein levels (18.3 mg/dl ± 13.7 mg/dl vs. 8.1 mg/dl ± 8.1 mg/dl, P = 0.021), and a lower lymphocyte count (0.38 ×103/µl ± 0.14 ×103/µl vs. 0.76 ×103/µl ± 0.48 ×103/µl, P = 0.04) 1 week after clinical onset. Thus, the mortality among hospitalized hemodialysis patients diagnosed with COVID-19 is high. Certain laboratory tests can be used to predict a worsening clinical course.

Prognostic value of venous blood analysis at the start of CPR in non-traumatic out-of-hospital cardiac arrest: association with ROSC and the neurological outcome.

BACKGROUND: The knowledge of new prognostic factors in out-of-hospital cardiac arrest (OHCA) that can be evaluated since the beginning of cardiopulmonary resuscitation (CPR) manoeuvres could be helpful in the decision-making process of prehospital care. We aim to identify metabolic variables at the start of advanced CPR at the scene that may be associated with two main outcomes of CPR (recovery of spontaneous circulation (ROSC) and neurological outcome). METHODS: Prospective observational study of all non-traumatic OHCA in patients older than 17 years assisted by emergency medical services (EMS), with doctor and nurse on board, between January 2012 and December 2017. Venous blood gases were sampled upon initially obtaining venous access to determine the initial values of pH, pCO2, HCO3-, base excess (BE), Na+, K+, Ca2+ and lactate. ROSC upon arrival at the hospital and neurological status 30 days later (Cerebral Performance Categories (CPC) scale) were recorded. RESULTS: We included 1552 patients with OHCA with blood test data in a 6-year period. ROSC was achieved in 906 cases (58.4%), and good neurological recovery at 30 days (CPC I-II) occurred in 383 cases (24.68%). In multivariate analysis, we found a significant relationship between non-recovery of spontaneous circulation (no-ROSC) and low pH levels (adjusted odds ratio (OR) 0.03 (0.002-0.59), p = 0.020), high pCO2 levels (adjusted OR 1.03 [1.01-1.05], p = 0.008) and high potassium levels (adjusted OR 2.28 [1.43-3.61], p = 0.008). Poor neurological outcomes were associated with low pH levels (adjusted OR 0.06 [0.02-0.18], p < 0.001), high pCO2 (adjusted OR 1.05 [1.03-1.08], p < 0.001), low HCO3- (adjusted OR 0.97 [0.94-0.999], p = 0.044), low BE (adjusted OR 0.96 [0.93-0.98], p < 0.001) and high potassium levels (adjusted OR 1.37 [1.16-1.60], p < 0.001). CONCLUSION: There is a significant relationship between severe alterations of venous blood-gas variables and potassium at the start of CPR of non-traumatic OHCA and low-ROSC rate and neurological prognosis.

Urinary excretion of parathyroid hormone-related protein correlates with renal function in control rats and rats with cisplatin nephrotoxicity.

Parathyroid hormone-related protein (PTHrP) and its receptor are abundantly expressed throughout the renal parenchyma, where PTHrP exerts a modulatory action on renal function. PTHrP upregulation is a common event associated with the mechanism of renal injury and repair. However, no study has yet explored the putative excretion of PTHrP in urine, including its potential relationship with renal function. In the present study, we tested this hypothesis by studying the well-known rat model of acute renal injury induced by the chemotherapeutic agent cisplatin. Using Western blot analysis, we could detect a single protein band, corresponding to intact PTHrP, in the urine of both control and cisplatin-injected rats, whose levels were significantly higher in the latter group. PTHrP was detected in rat urine by dot blot, and its quantification with two specific ELISA kits showed that, compared with control rats, those treated with cisplatin displayed a significant increase in urinary PTHrP (expressed as the PTHrP-to-creatinine ratio or 24-h excretion). In addition, a positive correlation between urinary PTHrP excretion and serum creatinine was found in these animals. In conclusion, our data demonstrate that PTHrP is excreted in rat urine and that this excretion is higher with the decrease of renal function. This suggests that urinary PTHrP levels might be a renal function marker.

Lipid imaging for visualizing cilastatin amelioration of cisplatin-induced nephrotoxicity.

Nephrotoxicity is a major limitation to cisplatin antitumor therapies. Cilastatin, an inhibitor of renal dehydropeptidase-I, was recently proposed as a promising nephroprotector against cisplatin toxicity, preventing apoptotic cell death. In this work, cilastatin nephroprotection was further investigated in a rat model, with a focus on its effect on 76 renal lipids altered by cisplatin, including 13 new cisplatin-altered mitochondrial cardiolipin species. Lipid imaging was performed with MALDI mass spectrometry imaging (MALDI-MSI) in kidney sections from treated rats. Cilastatin was proved to significantly diminish the lipid distribution alterations caused by cisplatin, lipid levels being almost completely recovered to those of control samples. The extent of recovery of cisplatin-altered lipids by cilastatin turned out to be relevant for discriminating direct or secondary lipid alterations driven by cisplatin. Lipid peroxidation induced by cisplatin was also shown to be reduced when cilastatin was administered. Importantly, significant groups separation was achieved during multivariate analysis of cortex and outer-medullary lipids, indicating that damaged kidney can be discerned from the nephroprotected and healthy groups and classified according to lipid distribution. Therefore, we propose MALDI-MSI as a powerful potential tool offering multimolecule detection possibilities to visualize and evaluate nephrotoxicity and nephroprotection based on lipid analysis.

Efficacy, Biodistribution, and Nephrotoxicity of Experimental Amphotericin B-Deoxycholate Formulations for Pulmonary Aspergillosis.

An experimental micellar formulation of 1:1.5 amphotericin B-sodium deoxycholate (AMB:DCH 1:1.5) was obtained and characterized to determine its aggregation state and particle size. The biodistribution, nephrotoxicity, and efficacy against pulmonary aspergillosis in a murine model were studied and compared to the liposomal commercial formulation of amphotericin B after intravenous administration. The administration of 5 mg/kg AMB:DCH 1:1.5 presented 2.8-fold-higher lung concentrations (18.125 ± 3.985 µg/g after 6 daily doses) and lower kidney exposure (0.391 ± 0.167 µg/g) than liposomal commercial amphotericin B (6.567 ± 1.536 and 5.374 ± 1.157 µg/g in lungs and kidneys, respectively). The different biodistribution of AMB:DCH micelle systems compared to liposomal commercial amphotericin B was attributed to their different morphologies and particle sizes. The efficacy study has shown that both drugs administered at 5 mg/kg produced similar survival percentages and reductions of fungal burden. A slightly lower nephrotoxicity, associated with amphotericin B, was observed with AMB:DCH 1:1.5 than the one induced by the liposomal commercial formulation. However, AMB:DCH 1:1.5 reached higher AMB concentrations in lungs, which could represent a therapeutic advantage over liposomal commercial amphotericin B-based treatment of pulmonary aspergillosis. These results are encouraging to explore the usefulness of AMB:DCH 1:1.5 against this disease.

Dual Internal Standards with Metals and Molecules for MALDI Imaging of Kidney Lipids.

The quest for internal standards useful in MALDI imaging studies goes on to get not only lateral distribution but also reliable relative quantitative information. We developed a method based on application of matrix and dual internal standards to allow intra- and intersample normalization of lipids intensities in kidney sections of control and cisplatin-treated Wistar rats. An inkjet printer was used to deposit a custom-prepared ink with DHB as MALDI matrix, a primary lipids-based internal standard, and a spiked lanthanide as a secondary internal standard. We applied different laser energy and varied the amounts of matrix-internal standards mixture to evaluate the normalization potential of the internal standards. Successful correction of intensity artifacts caused by instrumental drifts was possible, but not those resulting from uneven matrix application. ICP-MS absolute quantification of the lanthanide in the printed layer ensured the reproducibility of the matrix and internal standards application with RSD of 10-15%. Internal standard-normalized data allowed intrasample modification of the MALDI image to make it compatible with the optical image. Normalization to internal standards corrected a 2-fold difference in lipids intensity, which allowed a meaningful comparison of tissue lipids in control and cisplatin-treated kidneys. More importantly, normalization of lipid relative abundances based on the same adduct type (H+, Na+, and K+) for analyte and internal standard corrected for different ionization efficiencies showing a realistic signal level and enabling reliable comparison of different samples on relative quantitative basis.

Cisplatin-induced renal inflammation is ameliorated by cilastatin nephroprotection.

BACKGROUND: Cisplatin is a potent chemotherapeutic drug whose nephrotoxic effect is a major complication and a dose-limiting factor for antitumoral therapy. There is much evidence that inflammation contributes to the pathogenesis of cisplatin-induced nephrotoxicity. We found that cilastatin, a renal dehydropeptidase-I inhibitor, has protective effects in vitro and in vivo against cisplatin-induced renal damage by inhibiting apoptosis and oxidation. Here, we investigated the potential use of cilastatin to protect against cisplatin-induced kidney injury and inflammation in rats. METHODS: Male Wistar rats were divided into four groups: control, cilastatin-control, cisplatin and cilastatin-cisplatin. Nephrotoxicity was assessed 5 days after administration of cisplatin based on blood urea nitrogen, creatinine, glomerular filtration rate (GFR), kidney injury molecule (KIM)-1 and renal morphology. Inflammation was measured using the electrophoretic mobility shift assay, immunohistochemical studies and evaluation of inflammatory mediators. RESULTS: Compared with the control rats, cisplatin-administered rats were affected by significant proximal tubule damage, decreased GFR, increased production of inflammatory mediators and elevations in urea, creatinine and tissue KIM-1 levels. Cilastatin prevented these changes in renal function and ameliorated histological damage in cisplatin-administered animals. Cilastatin also reduced pro-inflammatory cytokine levels, activation of nuclear factor-κB and CD68-positive cell concentrations. CONCLUSIONS: Cilastatin reduces cisplatin-induced nephrotoxicity, which is associated with decreased inflammation in vivo. Although the exact role of decreased inflammation in nephroprotection has not been fully elucidated, treatment with cilastatin could be a novel strategy for the prevention of cisplatin-induced acute kidney injury.

Successful treatment of multidrug-resistant Pseudomonas aeruginosa breakthrough bacteremia with ceftolozane/tazobactam.

INTRODUCTION: Ceftolozane/tazobactam is a novel antibiotic approved for the treatment of complicated intra-abdominal and complicated urinary tract infections. CASE DESCRIPTION: We describe the use of off-label ceftolozane/tazobactam in the management of a multidrug-resistant Pseudomonas aeruginosa bacteremia that was already being treated with colistin and amikacin, the only active antibiotics according to the antibiogram.

HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages.

OBJECTIVE: Although it is accepted that macrophage glycolysis is upregulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage proinflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque. APPROACH AND RESULTS: We studied the interplay between macrophage energy metabolism, polarization, and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed. We observed that macrophage energetics and inflammatory activation are closely and linearly related, resulting in dynamic calibration of glycolysis to keep pace with inflammatory activity. In addition, we show that macrophage glycolysis and proinflammatory activation mainly depend on hypoxia-inducible factor and on its impact on glucose uptake, and on the expression of hexokinase II and ubiquitous 6-phosphofructo-2-kinase. As a consequence, hypoxia potentiates inflammation and glycolysis mainly via these pathways. Moreover, when macrophages' ability to increase glycolysis through 6-phosphofructo-2-kinase is experimentally attenuated, cell viability is reduced if subjected to proinflammatory or hypoxic conditions, but unaffected under control conditions. In addition to this, granulocyte-macrophage colony-stimulating factor enhances anerobic glycolysis while exerting a mild proinflammatory activation. CONCLUSIONS: These findings, in human and murine cells and in an animal model, show that hypoxia potentiates macrophage glycolytic flux in concert with a proportional upregulation of proinflammatory activity, in a manner that is dependent on both hypoxia-inducible factor -1α and 6-phosphofructo-2-kinase.

Printing metal-spiked inks for LA-ICP-MS bioimaging internal standardization: comparison of the different nephrotoxic behavior of cisplatin, carboplatin, and oxaliplatin.

The study of the distribution of the cytostatic drugs cisplatin, carboplatin, and oxaliplatin along the kidney may help to understand their different nephrotoxic behavior. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) allows the acquisition of trace element images in biological tissues. However, results obtained are affected by several variations concerning the sample matrix and instrumental drifts. In this work, an internal standardization method based on printing an Ir-spiked ink onto the surface of the sample has been developed to evaluate the different distributions and accumulation levels of the aforementioned drugs along the kidney of a rat model. A conventional ink-jet printer was used to print fresh sagittal kidney tissue slices of 4 µm. A reproducible and homogenous deposition of the ink along the tissue was observed. The ink was partially absorbed on top of the tissue. Thus, this approach provides a pseudo-internal standardization, due to the fact that the ablation sample and internal standard take place subsequently and not simultaneously. A satisfactory normalization of LA-ICP-MS bioimages and therefore a reliable comparison of the kidney treated with different Pt-based drugs were achieved even for tissues analyzed on different days. Due to the complete ablation of the sample, the transport of the ablated internal standard and tissue to the inductively coupled plasma-mass spectrometry (ICP-MS) is practically taking place at the same time. Pt accumulation in the kidney was observed in accordance to the dosages administered for each drug. Although the accumulation rate of cisplatin and oxaliplatin is high in both cases, their Pt distributions differ. The strong nephrotoxicity observed for cisplatin and the absence of such side effect in the case of oxaliplatin could explain these distribution differences. The homogeneous distribution of oxaliplatin in the cortical and medullar areas could be related with its higher affinity for cellular transporters such as MATE2-k.

Do men perform better than women in trauma?

In recent decades, numerous studies have compared survival according to gender of patients admitted to general hospitals and particularly to intensive care units. In a previous issue of Critical Care, Schoeneberg and colleagues presented the results of a German observational study on a sample from a 10 year registry in a Level 1 trauma center. The conclusion is that there is a trend towards a higher mortality in women than in men.

Mitochondrial dysfunction and therapeutic approaches in respiratory and limb muscles of cancer cachectic mice.

NEW FINDINGS: What is the central question of this study? We explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles,and whether signalling pathways, proteasome and oxidative stress influence that process. What is the main finding and what is its importance? In cancer cachectic mice, MRC complexes and oxygen consumption were decreased in the diaphragm and gastrocnemius. Blockade of nuclear factor-κB and mitogen-activated protein kinase actions partly restored the muscle mass and force and corrected the MRC dysfunction,while concomitantly reducing tumour burden. Antioxidants improved mitochondrial oxygen consumption without eliciting effects on the loss of muscle mass and force or the tumour size,whereas bortezomib reduced tumour burden without influencing muscle mass and strength or MRC function. Abnormalities in mitochondrial content, morphology and function have been reported in several muscle-wasting conditions. We specifically explored whether experimental cancer-induced cachexia may alter mitochondrial respiratory chain (MRC) complexes and oxygen uptake in respiratory and peripheral muscles, and whether signalling pathways, proteasomes and oxidative stress may influence that process. We evaluated complex I, II and IV enzyme activities (specific activity assays) and MRC oxygen consumption (polarographic measurements) in diaphragm and gastrocnemius of cachectic mice bearing the LP07 lung tumour, with and without treatment with N-acetylcysteine, bortezomib and nuclear factor-κB (sulfasalazine) and mitogen-activated protein kinases (MAPK, U0126) inhibitors (n = 10 per group for all groups). Whole-body and muscle weights and limb muscle force were also assessed in all rodents at baseline and after 1 month. Compared with control animals, cancer cachectic mice showed a significant reduction in body weight gain, smaller sizes of the diaphragm and gastrocnemius, lower muscle strength, decreased activity of complexes I, II and IV and decreased oxygen consumption in both muscles. Blockade of nuclear factor-κB and MAPK actions restored muscle mass and force and corrected the MRC dysfunction in both muscles, while partly reducing tumour burden. Antioxidants improved mitochondrial oxygen uptake without eliciting significant effects on the loss of muscle mass and force or tumour size, whereas the proteasome inhibitor reduced tumour burden without significantly influencing muscle mass and strength or mitochondrial function. In conclusion, nuclear factor-κB and MAPK signalling pathways modulate muscle mass and performance and MRC function of respiratory and limb muscles in this model of experimental cancer cachexia, thus offering targets for therapeutic intervention.

Ventilatory improvement with mechanical ventilator versus bag in non-traumatic out-of-hospital cardiac arrest: SYMEVECA study, phase 1.

AIM: To analyze differences in ventilatory parameters and outcome with different ventilatory methods during CPR. METHODS: Pragmatic prospective quasi-experimental study in out-of-hospital urban environment. Patients over 18 years of age in non-traumatic cardiac arrest, attended by an emergency medical service between April 2021 and September 2022, were included. Two groups were compared according to the ventilatory method: mechanical ventilator (IPPV, tidal volume 7 ml/kg, frequency 10-12 bpm) or manual resuscitator bag. The main variables of interest are those of gasometry performed 15 minutes after intubation or when spontaneous circulation is recovered and final outcome. Patients were followed up to hospital discharge. RESULTS: Of the 359 patients attended, 150 were included (71 in IPPV and 79 with a bag). In patients with arterial blood gases, pCO2 was 67.8 ± 21.1 in the IPPV group vs 95.9 ± 39.0 mmHg in the bag group (p = 0.006) and pH was 7.00 ± 0.18 vs 6.92 ± 0.18 (p = 0.18). With a venous sample, the pCO2 was 68.1 ± 18.9 vs 89.5 ± 26.5 mmHg (p < 0.001) and the pH was 7.03 ± 0.15 vs 6.94 ± 0.17 (p = 0.005), respectively. Survival with CPC 1-2 to hospital discharge was 15.6% with IPPV and 11.3% with bag (p = 0.44). CONCLUSION: The use of a mechanical ventilator in IPPV was associated with a better ventilatory status during CPR compared to the use of the bag, without conclusive data regarding its clinical repercussion with the sample collected.

Prognostic value of metabolic parameters measured by first responders attending patients with severe trauma: associations with the New Injury Severity Score and mortality. / Valor pronóstico de los parámetros metabólicos medidos en la asistencia inicial a pacientes con trauma grave: asociación con la puntuación de la escala NISS y la mortalidad.

OBJECTIVES: Patients with severe or potentially severe trauma must be identified early, a challenge in prehospital settings. This study aimed to analyze the possible diagnostic and prognostic usefulness of analytical markers recorded in the early moments of care. MATERIAL AND METHODS: Observational study of information extracted from the prospective multicenter Code Trauma database for 2016-2019, excluding data for isolated head injuries. Using the New Injury Severity Score (NISS), we classified cases into 4 levels of severity. NISS and mortality were considered the dependent variables in inferential analyses. We calculated the areas under receiver operating characteristic curves, identified optimal cutoff points (Youden index), and calculated positive (PPV) and negative predictive values.. RESULTS: Of the 1039 trauma patients in the registry, 709 were included in the study. Their mean (SD) age was 40.4 (17.3) years, and 77.3% were men. Motorcycle accidents were the most common causes of trauma (in 21%), and mortality was 12.1%. Lactate concentration, pH, PCO2, hemoglobin concentration, hematocrit, and blood sugar were significantly associated with severity and mortality. The PPVs corresponding to pH for the 4 NISS score groups (34-41, 42-49, 50-59, and $ 60) and mortality, respectively, were 61.2, 64.1, 70.7, 62.2, and 66.6. The PPVs of traditionally used clinical variables were lower. CONCLUSION: Patients with more severe trauma had lower pH values and higher PCO2, lactate, and base excess values. PCO2, pH, and blood sugar findings were the best predictors of severity. Metabolic variables are better predictors than traditionally recorded hemodynamic variables.

OBJETIVO: En entornos de emergencia prehospitalarios, la detección temprana de un paciente con trauma grave o potencialmente crítico es un desafío. El objetivo es analizar las posibilidades diagnósticas y pronóstico de los parámetros analíticos obtenidos en los primeros momentos de la asistencia inicial. METODO: Estudio observacional multicéntrico de la base de datos prospectiva "Código Trauma" de 2016-2019 excluyendo el trauma craneoencefálico aislado. La evaluación de las lesiones se realizó utilizando el New Injury Severity Score (NISS). Los pacientes fueron clasificados en 4 grupos según nivel de gravedad. Para el análisis inferencial, las puntuaciones NISS y el resultado de mortalidad se consideraron variables dependientes. Se realizó el análisis de la curva ROC, puntos de corte óptimos mediante el índice de Youden y se calcularon los valores predictivos positivo (VPP) y negativo. RESULTADOS: De los 1.039 pacientes traumatizados del registro, 709 fueron incluidos en el estudio, con una edad media de 40,4 años (DE 17,3), 77,3% eran varones, el mecanismo lesional principal accidentes de moto (21%) y la mortalidad del 12,1%. El pH, lactato, pCO2, hemoglobina, hematocrito y glucemia influyeron significativamente en gravedad y mortalidad. El VPP de mortalidad para pH fue 61,2, 64,1, 70,7, 62,2 y 66,6 para los grupos de NISS 34- 41, 42-49, 50-59 y $ 60 puntos la mortalidad, respectivamente. Las variables clínicas clásicas obtuvieron valores más bajos. CONCLUSIONES: Los pacientes con mayor gravedad presentaron menor pH y concentraciones más altas de pCO2, lactato y exceso de bases. El pH, la pCO2 y la glucemia tuvieron la mayor capacidad predictiva de gravedad. La capacidad predictiva de los valores metabólicos es superior a la de los valores hemodinámicos clásicos.

Site of mitochondrial reactive oxygen species production in skeletal muscle of chronic obstructive pulmonary disease and its relationship with exercise oxidative stress.

Exercise triggers skeletal muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD). The objective of this research was to study the specific sites of reactive oxygen species (ROS) production in mitochondria isolated from skeletal muscle of patients with COPD and its relationship with local oxidative stress induced by exercise. Vastus lateralis biopsies were obtained in 16 patients with COPD (66 ± 10 yr; FEV(1), 54 ± 12% ref) and in 14 control subjects with normal lung function who required surgery because of lung cancer (65 ± 7 yr; FEV(1), 91 ± 14% ref) at rest and after exercise. In these biopsies we isolated mitochondria and mitochondrial membrane fragments and determined in vitro mitochondrial oxygen consumption (Mit$$\stackrel{.}{\hbox{ V }}$$o(2)) and ROS production before and after inhibition of complex I (rotenone), complex II (stigmatellin), and complex III (antimycin-A). We related the in vitro ROS production during state 3 respiration), which mostly corresponds to the mitochondria respiratory state during exercise, with skeletal muscle oxidative stress after exercise, as measured by thiobarbituric acid reactive substances.State 3 Mit$$\stackrel{.}{\hbox{ V }}$$o(2) was similar in patients with COPD and control subjects (191 ± 27 versus 229 ± 46 nmol/min/mg; P = 0.058), whereas H(2)O(2) production was higher in the former (147 ± 39 versus 51 ± 8 pmol/mg/h; P < 0.001). The addition of complexI, II, and III inhibitors identify complex III as the main site of H(2)O(2) release by mitochondria in patients with COPD and in control subjects. The mitochondrial production of H(2)O(2) in state 3 respiration was related (r = 0.69; P < 0.001) to postexercise muscle thiobarbituric acid reactive substance levels. Our results show that complex III is the main site of the enhanced mitochondrial H(2)O(2) production that occurs in skeletal muscle of patients with COPD, and the latter appears to contribute to muscle oxidative damage.

Cilastatin protects against cisplatin-induced nephrotoxicity without compromising its anticancer efficiency in rats.

Cisplatin is an anticancer agent marred by nephrotoxicity; however, limiting this adverse effect may allow the use of higher doses to improve its efficacy. Cilastatin, a small molecule inhibitor of renal dehydropeptidase I, prevents proximal tubular cells from undergoing cisplatin-induced apoptosis in vitro. Here, we explored the in vivo relevance of these findings and the specificity of protection for kidney cells in cisplatin-treated rats. Cisplatin increased serum blood urea nitrogen and creatinine levels, and the fractional excretion of sodium. Cisplatin decreased the glomerular filtration rate, promoted histological renal injury and the expression of many pro-apoptotic proteins in the renal cortex, increased the Bax/Bcl2 ratio, and oxidative stress in kidney tissue and urine. All these features were decreased by cilastatin, which preserved renal function but did not modify the pharmacokinetics of cisplatin area under the curve. The cisplatin-induced death of cervical, colon, breast, and bladder-derived cancer cell lines was not prevented by cilastatin. Thus, cilastatin has the potential to prevent cisplatin nephrotoxicity without compromising its anticancer efficacy.

Schwarzschild black holes can wear scalar wigs.

We study the evolution of a massive scalar field surrounding a Schwarzschild black hole and find configurations that can survive for arbitrarily long times, provided the black hole or the scalar field mass is small enough. In particular, both ultralight scalar field dark matter around supermassive black holes and axionlike scalar fields around primordial black holes can survive for cosmological times. Moreover, these results are quite generic in the sense that fairly arbitrary initial data evolve, at late times, as a combination of those long-lived configurations.

The mysterious death of the beer drinking champ: potential role for hyperacute water loading and acute hyponatremia.

Hyponatremia is acute when present for <48 h. Most cases of acute hyponatremia involve both excess free water intake and an at least partial urinary free water excretion defect. By contrast, hyperacute water intoxication may result from a large excess electrolyte-free water intake in such a short time that properly working urinary free water excretion mechanisms cannot cope. A hyperacute decrease in serum sodium may lead to death before medical intervention takes place. Well-documented cases have been published in the military medicine literature. In addition, news reports suggest the existence of cases of voluntary ingestion of excess free water by non-psychiatric individuals usually during 'dare' activities. Education of the public is required to prevent harm from these high-risk activities. Adequate training of emergency medical units may prevent lethal outcomes. Spanish media reported the case of a male who died following his triumph in a 20-min beer drinking contest. 'From a heart attack. Man dies after drinking six litres of beer in a contest' ran the news. We now review the physiology underlying hyperacute water intoxication and discuss the potential contribution of hyperacute water loading and acute hyponatremia to the demise of this patient.

Effects of exercise on mitochondrial DNA content in skeletal muscle of patients with COPD.

BACKGROUND: Exhausting exercise reduces the mitochondrial DNA (mtDNA) content in the skeletal muscle of healthy subjects due to oxidative damage. Since patients with chronic obstructive pulmonary disease (COPD) suffer enhanced oxidative stress during exercise, it was hypothesised that the mtDNA content will be further reduced. OBJECTIVE: To investigate the effects of exercise above and below the lactate threshold (LT) on the mtDNA content of skeletal muscle of patients with COPD. METHODS: Eleven patients with COPD (67 ± 8 years; forced expiratory volume in 1 s (FEV1) 45 ± 8%ref) and 10 healthy controls (66 ± 4 years; FEV1 90 ± 7% ref) cycled 45 min above LT (65% peak oxygen uptake (V'o2peak) and another 7 patients (65 ± 6 years; FEV1 50 ± 4%ref) and 7 controls (56 ± 9 years; FEV1 92 ± 6% ref) cycled 45 min below their LT (50% V'o2peak). Biopsies from the vastus lateralis muscle were obtained before exercise, immediately after and 1 h, 1 day and 1 week later to determine by PCR the mtDNA/nuclear DNA (nDNA) ratio (a marker of mtDNA content) and the expression of the peroxisome proliferator-activated receptor-γcoactivator-1α (PGC-1α) mRNA and the amount of reactive oxygen species produced during exercise was estimated from total V'o2. RESULTS: Skeletal muscle mtDNA/nDNA fell significantly after exercise above the LT both in controls and in patients with COPD, but the changes were greater in those with COPD. These changes correlated with production of reactive oxygen species, increases in manganese superoxide dismutase and PGC-1α mRNA and returned to baseline values 1 week later. This pattern of response was also observed, albeit minimised, in patients exercising below the LT. CONCLUSIONS: In patients with COPD, exercise enhances the decrease in mtDNA content of skeletal muscle and the expression of PGC-1α mRNA seen in healthy subjects, probably due to oxidative stress.

Elemental bioimaging in kidney by LA-ICP-MS as a tool to study nephrotoxicity and renal protective strategies in cisplatin therapies.

A laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS)-based methodology is presented for Pt, Cu, and Zn bioimaging on whole kidney 3 µm sagittal sections from rats treated with pharmacological doses of cisplatin, which were sacrificed once renal damage had taken place. Pt turned out to accumulate in the kidney cortex and corticomedullary junction, corresponding to areas where the proximal tubule S3 segments (the most sensitive cells to cisplatin nephrotoxicity) are located. This demonstrates the connection between platinum accumulation and renal damage proved by histological examination of HE-stained sections and evaluation of serum and urine biochemical parameters. Cu and Zn distribution maps revealed a significant displacement in cells by Pt, as compared to control tissues. A dramatic decrease in the Pt accumulation in the cortex was observed when cilastatin was coadministered with cisplatin, which can be related to its nephroprotective effect. Excellent imaging reproducibility, sensitivity (LOD 50 fg), and resolution (down to 8 µm) were achieved, demonstrating that LA-ICP-MS can be applied as a microscopic metal detector at cellular level in certain tissues. A simple and quick approach for the estimation of Pt tissue levels was proposed, based on tissue spiking.