Use of noninvasive measurement of the indocyanine green plasma disappearance rate in patients with septic shock.

OBJECTIVE: Our aim was to analyse the relation between serial values of the indocyanine green plasma disappearance rate (ICG-PDR) with hospital mortality in the first 48 hours of ICU admission in patients with septic shock. METHODS: A prospective observational study was carried out over 12 months of patients admitted to the ICU with septic shock. Each patient underwent noninvasive determination of ICG-PDR at 24 and 48 hours with the LiMON® module. Follow-up was performed until hospital discharge or exitus. RESULTS: 63 patients. Age 61.1±12.3 years. 60.3% men. SOFA score on admission 8.7±3.3, APACHE II score was 27.9±10.7 points. A total of 44.4% of patients died. The ICG-PDR values in the first 24 hours of ICU admission were lower in nonsurvivors: 10.5 (5.7-13.0)%/min vs. 15.9 (11.4-28.0)%/min, p <0.001. Furthermore, in nonsurvivors, there was no improvement in ICG-PDR between 24 h and 48 h, while in survivors, there was an increase of 25%: 15.9 (11.4-28.0)%/min and 20.9 (18.0-27.0)%/min, p=0.020. The silhouette measure of ICG-PDR cohesion and separation for the clusters analysed (nonsurvivors and survivors) was satisfactory (0.6). ICG-PDR<11.7%/min was related to in-hospital mortality, ICG-PDR> 18%/min to survival, and the interval between 11.7% and 18%/min covered a range of uncertainty. In the two-stage cluster, ICG-PDR, SOFA and APACHE II present satisfactory predictive scores 24 hours after patient admission. CONCLUSIONS: ICG-PDR in our setting is a useful clinical prognostic tool and could optimise the decision tree in patients with septic shock.

Perspectives of people with HIV and HIV clinicians on characteristics of antiretroviral treatment and HIV-related symptoms.

OBJECTIVES: We aimed to assess HIV symptoms from the perspective of both patients and HIV specialists and the impact of discontinuing antiretroviral treatment (ART) on symptomology. We gathered opinions from HIV specialists and people living with HIV about ideal ART parameters and treatment satisfaction. METHODS: Ex post-facto cross-sectional surveys were administered to 502 people living with HIV and 101 HIV clinicians in Spain (18 sites). RESULTS: The median age of participants with HIV was 43.2 years, 74.5% were male, and 91.6% had an undetectable viral load. The mean time since initiation of ART was 10.2 years. Between 54% and 67% of people living with HIV reported experiencing nervousness or anxiety, sadness, fatigue, sleep problems, or muscle/joint pain during the preceding 4 weeks. However, only 22%-27% of specialists acknowledged the presence of these symptoms. The most bothersome symptoms were related to mental health or the central nervous system. There were significant differences between the burden of symptoms reported by people living with HIV and those acknowledged by specialists. The symptoms that more frequently caused ART discontinuation were depression, dizziness, and sleep problems. Both people living with HIV and specialists prioritized ART efficacy and low toxicity, but their importance ratings differed for 5 of the 11 ART characteristics assessed. People living with HIV rated their satisfaction with ART at a mean (± standard deviation) of 8.9 ± 1.5 out of 10, whereas HIV specialists rated it lower, at 8.3 ± 0.7 (p < 0.001). CONCLUSIONS: Despite advances in HIV care and treatment, a large proportion of patients still experience symptoms. HIV specialists may not be fully aware of these. People living with HIV and HIV specialists are, overall, satisfied with ART. However, the importance they place on different ART characteristics may vary.

The hidden cost of disease: II. Impact of the first incidence of lameness on production and economic indicators of primiparous dairy cows.

Lameness is a persistent and underreported health and welfare problem in the dairy industry, resulting in reduced cow performance and profitability as well as early culling. The study objectives were (1) to quantify the impact of the first instance of lameness, at different stages of lactation, on production and economic performance, and (2) to further quantify the impacts of the first instance of lameness when only cows that remain in the herd for at least 100 d in milk (DIM) and those that remain for 305 DIM are included in the analysis. A retrospective longitudinal study was conducted using pre-existing data from animal health records and Dairy Herd Improvement Association records. Data were edited based on selected inclusion criteria, yielding a data set containing records from 15,159 first-lactation Holstein cows from 120 herds with year of first calving between 2003 and 2014. Lame cows were assigned to 1 of 4 groups based on when in the lactation the first event of lameness occurred: transition (1-21 DIM), early lactation (22-100 DIM), mid-lactation (101-200 DIM), or late lactation (201+ DIM). Mid- and late-lactation lame cows were also stratified by cumulative milk yield before the lameness event. Healthy cows (i.e., no recorded lameness event) were randomly assigned for each lactation stage, with mid-lactation healthy and late-lactation healthy cows similarly stratified. Production performance (cumulative milk, fat, and protein yield) and economic performance [milk value, margin over feed cost (MOFC), and gross profit] were analyzed using a mixed model with herd as a random effect. Cumulative milk yields were 811 to 1,290 kg lower for lame cows than for healthy cows, with milk component yields undergoing similar reductions. Reductions in milk yield contributed to losses in milk value (-Can$527 to -Can$1,083; -US$419 to -US$862) and MOFC (-Can$510 to -Can$774; -US$406 to -US$616). Higher losses were reported using gross profit (-Can$753 to -Can$1,052; -US$599 to -US$837), which includes all lameness-related costs. Production and performance losses were smaller when 100 DIM and 305 DIM thresholds were applied (i.e., exclusion of cows culled before 100 and 305 DIM, respectively), however, mid- and late-lactation lame cows maintained high levels of significant losses for all 6 variables analyzed. Lameness also led to higher levels of culling, masking losses for transition and early-lactation lame cows in the 305-DIM analysis. Increasing producer understanding of the costs associated with lameness not only serves to provide insight to producers for more informed culling decisions, but may also help producers weigh the costs of adopting new methods and technologies targeted at reducing on-farm lameness.

The hidden cost of disease: I. Impact of the first incidence of mastitis on production and economic indicators of primiparous dairy cows.

Mastitis is a highly prevalent disease, which negatively affects cow performance, profitability, welfare, and longevity. The objectives of this study were (1) to quantify the impact of the first instance of mastitis, at different stages of lactation, on production and economic performance, and (2) to further quantify the impact of the first instance of mastitis when only cows that remain in the herd for at least 100 d in milk (DIM) and those that remain for 305 DIM are included in the analysis. A retrospective longitudinal study was conducted using data from existing animal health record files and Dairy Herd Improvement records. After editing based on selected inclusion criteria and completeness of health records, data consisted of records from first-lactation Holstein cows, from 120 herds, that calved for the first time between 2003 and 2014, inclusive. Mastitic cows were assigned to 1 of 4 groups based on when in the lactation the first event of mastitis occurred: transition (1-21 DIM), early lactation (22-100 DIM), mid lactation (101-200 DIM), or late lactation (201+ DIM). Mid-lactation and late-lactation mastitic cows were also stratified by cumulative milk yield before the mastitis event. Healthy cows (i.e., no recorded mastitis event) were randomly assigned for each lactation stage, with mid-lactation healthy and late-lactation healthy cows similarly stratified. Production performance (cumulative milk, fat, and protein yield) and economic performance [milk value, margin over feed cost (MOFC), and gross profit] were analyzed using a mixed model with herd as a random effect. Significant losses in cumulative milk yield (-382 to -989 kg) and correspondingly lower fat and protein yields were found in mastitic cows, with transition and late-lactation mastitic cows having the highest losses. Drops in production translated to significant reductions in cumulative milk value (-Can$287 to -Can$591; -US$228 to -US$470), MOFC (-Can$243 to -Can$540; -US$193 to -US$429), and gross profit (-Can$649 to -Can$908; -US$516 to -US$722) for mastitic cows at all stages. Differences between mastitic and healthy cows in the early lactation and transition stages remained for all variables in the 100-DIM analysis, but, aside from gross profit, were nonsignificant in the 305-DIM analysis. Gross profit accounted for all costs associated with mastitis and thus continued to be lower for mastitic cows at all stages, even in the 305-DIM analysis in which culled cows were omitted (-Can$485 to -Can$979; -US$386 to -US$779). The research reflects the performance implications of mastitis, providing more information upon which the producer can make informed culling decisions and maximize both herd profitability and cow longevity.

In vitro assessment of the mutagenic and genotoxic potential of a pure stilbene extract.

Stilbenes are secondary metabolites of great interest produced by many plant species due to their important bioactive properties. These phytochemicals have become of increasing interest in the wine industry as a natural alternative to sulphur dioxide, which has been associated with human health risks. However, there is still little toxicological information on stilbenes and the results thus far have been contradictory. Considering the key role of genotoxicity in risk assessment and the need to offer safe products in the market, the aim of this study was to assess the mutagenic and genotoxic potential of a stilbene extract with 99% purity (ST-99 extract). A complete series of different in vitro tests (Ames test, micronucleus (MN) test, and standard and enzyme-modified comet assays) was performed before its use as a preservative in wines. The ST-99 extract induces a significant increase of binucleated cells with micronuclei only in presence of the metabolic fraction S9 at the highest concentration assayed. Neither the Ames test nor the comet assay revealed the extract's genotoxic potential. Further studies are necessary, including in vivo assays, to ensure consumer safety before it can be used.

Renal function at admission as a prognostic marker for patients hospitalised for a first episode of heart failure. Results of the PREDICE study. / Función renal al ingreso como marcador pronóstico en pacientes hospitalizados por un primer episodio de insuficiencia cardíaca. Resultados del estudio PREDICE.

BACKGROUND AND OBJECTIVE: Heart failure (HF) is a frequent condition that deteriorates quality of life and results in high morbidity and mortality. A considerable number of studies have been implemented in recent years to determine the factors that affect the prognosis of HF; however, few studies have assessed the prognosis of patients hospitalised for their first episode of HF. The aim of our study was to analyse the prognostic impact of renal function on patients hospitalised for a first episode of HF. MATERIAL AND METHODS: We recruited 600 patients hospitalised for a first episode of HF in 3 tertiary Spanish hospitals. We analysed the mortality risk during the first year of follow-up according to renal function at the time of admission. RESULTS: The patients with the highest degree of kidney failure at admission were older (P<.001), were more often women (p=.01) and presented a higher degree of dependence (P<.05), as well as a higher prevalence of arterial hypertension (P<.001), chronic renal failure (P<.001) and anaemia (P<.001). In the multivariate analysis, the degree of kidney failure at admission remained an independent predictor of increased mortality risk during the first year of follow-up. CONCLUSIONS: The presence of kidney failure at admission was a marker of poor prognosis in our cohort of patients hospitalised for a first episode of HF.

Delphi-RAND consensus of the Spanish Society of Internal Medicine on the controversies in anticoagulant therapy and prophylaxis in medical diseases. INTROMBIN Project (Uncertainty in thromboprophylaxis in internal medicine). / Consenso Delphi-RAND de la Sociedad Española de Medicina Interna sobre controversias en terapia y profilaxis anticoagulante en enfermedades médicas. Proyecto INTROMBIN (INcertidumbre en TROMBoprofilaxis en Medicina INterna).

The aim of this study was to determine the opinion of internists on the management of anticoagulation and thromboembolism prophylaxis in complex clinical scenarios in which the risk-benefit ratio of surgery is narrow and to develop a consensus document on the use of drugs anticoagulant therapy in this patient group. To this end, we identified by consensus the clinical areas of greatest uncertainty, a survey was created with 20 scenarios laid out in 40 clinical questions, and we reviewed the specific literature. The survey was distributed among the internists of the Spanish Society of Internal Medicine (SEMI) and was completed by 290 of its members. The consensus process was implemented by changing the Delphi-RAND appropriateness method in an anonymous, double-round process that enabled an expert panel to identify the areas of agreement and uncertainty. In our case, we also added the survey results to the panel, a methodological innovation that helps provide additional information on the standard clinical practice. The result of the process is a set of 19 recommendations formulated by SEMI experts, which helps establish guidelines for action on anticoagulant therapy in complex scenarios (high risk or active haemorrhage, short life expectancy, coexistence of antiplatelet therapy or comorbidities such as kidney disease and liver disease), which are not uncommon in standard clinical practice.

Xantogranuloma necrobiótico asociado a gammapatía monoclonal IgG kappa de significado incierto / Necrobiotic xanthogranuloma associated with monoclonal gammopathy of unknown significance

No disponible

Acetato de megestrol. ¿Es su uso tan inofensivo como parece? / Megestrol acetate. Is its use so harmless as it might seem?

No disponible

A subchronic 90-day oral toxicity study of Origanum vulgare essential oil in rats.

Oregano essential oil (Origanum vulgare L. virens) (OEO) is being used in the food industry due to its useful properties to develop new active packaging systems. In this concern, the safety assessment of this natural extract is of great interest before being commercialized. The European Food Safety Authority requests different in vivo assays to ensure the safety of food contact materials. One of these studies is a 90 days repeated-dose oral assay in rodents. In the present work, 40 male and 40 female Wistar rats were orally exposed to 50, 100 and 200 mg/kg body weight (b.w.) OEO during 90 days following the OECD guideline 408. Data revealed no mortality and no treatment-related adverse effects of the OEO in food/water consumption, body weight, haematology, biochemistry, necropsy, organ weight and histopathology. These findings suggest that the oral no-observed-adverse-effect level (NOAEL) of this OEO is 200 mg/kg b.w. in Wistar rats, the highest dose tested. In conclusion, the use of this OEO in food packaging appears to be safe based on the lack of toxicity during the subchronic study at doses 330-fold higher than those expected to be in contact consumers in the worst scenario of exposure.

Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation.

Bone remodeling is a continuous physiological process that requires constant generation of new osteoblasts from mesenchymal stem cells (MSCs). Differentiation of MSCs to osteoblast requires a metabolic switch from glycolysis to increased mitochondrial respiration to ensure the sufficient energy supply to complete this process. As a consequence of this increased mitochondrial metabolism, the levels of endogenous reactive oxygen species (ROS) rise. In the current study we analyzed the role of forkhead box O3 (FOXO3) in the control of ROS levels in human MSCs (hMSCs) during osteogenic differentiation. Treatment of hMSCs with H2O2 induced FOXO3 phosphorylation at Ser294 and nuclear translocation. This ROS-mediated activation of FOXO3 was dependent on mitogen-activated protein kinase 8 (MAPK8/JNK) activity. Upon FOXO3 downregulation, osteoblastic differentiation was impaired and hMSCs lost their ability to control elevated ROS levels. Our results also demonstrate that in response to elevated ROS levels, FOXO3 induces autophagy in hMSCs. In line with this, impairment of autophagy by autophagy-related 7 (ATG7) knockdown resulted in a reduced capacity of hMSCs to regulate elevated ROS levels, together with a reduced osteoblast differentiation. Taken together our findings are consistent with a model where in hMSCs, FOXO3 is required to induce autophagy and thereby reduce elevated ROS levels resulting from the increased mitochondrial respiration during osteoblast differentiation. These new molecular insights provide an important contribution to our better understanding of bone physiology.

Darunavir en situaciones especiales / Darunavir in special situations

La infección por VIH se ha convertido en una infección crónica gracias al tratamiento antirretroviral. Darunavir/ritonavir constituye uno de los inhibidores de la proteasa más utilizados, está incluido en la mayoría de guías de tratamiento dentro de las pautas de inicio de elección y, además, es el eje de los tratamientos de rescate. Con la indicación reciente de administrar tratamiento antirretroviral a todos los pacientes con VIH, es fundamental conocer el comportamiento de los antirretrovirales en distintos escenarios, teniendo en cuenta las comorbilidades y las características de los pacientes. Darunavir/ritonavir se metaboliza a nivel hepático y se excreta sobre todo a través de las heces. Pese a que se han comunicado casos de toxicidad hepática grave, en general es seguro. Se observa mayor elevación de transaminasas en pacientes coinfectados, por lo que se recomienda una mayor monitorización. Solo está contraindicado en situaciones de insuficiencia hepática grave. No precisa ajuste de dosis en pacientes con insuficiencia renal, incluso en diálisis. En mujeres se dispone de los datos de subestudios de los ensayos clínicos POWER y ARTEMIS y el estudio GRACE, el primero diseñado para detectar diferencias de eficacia y seguridad entre sexos. Además se han generado múltiples datos de farmacocinética en embarazadas que han permitido que sea el inhibidor de la proteasa de elección en las guías de transmisión perinatal DHHS. También se utiliza ampliamente en pediatría, donde es el fármaco de elección a partir de los 12 años. Solo faltarían datos en población de edad avanzada, que se están generando en estos momentos

HIV infection has become a chronic infection due to antiretroviral therapy. Darunavir/ritonavir is one of the most widely used protease inhibitors, is included in most treatment guidelines within the preferred initiation regimens and, moreover, is the cornerstone of rescue therapy. With the recent indication of antiretroviral therapy administration in all HIV-positive patients, it is essential to determine the behaviour of antiretroviral agents in distinct scenarios, bearing in mind comorbidities and patient characteristics. Darunavir/ritonavir is metabolized in the liver and is excreted mainly in faeces. Although there have been reports of severe liver toxicity, the combination is generally safe. There is higher transaminase elevation in coinfected patients, who should consequently be monitored more closely. Darunavir/ritonavir is only contraindicated in severe liver failure. Dosage adjustment is not required in patients with renal insufficiency, even in those under dialysis. In women, data are available from the substudies of the POWER and ARTEMIS clinical trials and the GRACE study, the first study designed to detect differences in efficacy and safety between men and women. In addition, multiple data on pharmacokinetics have been obtained in pregnant women, which have allowed darunavir to become the protease inhibitor of choice recommended in Department of Health and Human Services guidelines on perinatal transmission. Darunavir is widely used in paediatrics, where it is the preferred drug in patients aged 12 years and older. Data are still required in the population of advanced age, which are currently being generated

Toxic effects of prenatal exposure to alcohol, tobacco and other drugs.

Tobacco, alcohol, cannabis and cocaine are the most consumed psychoactive drugs throughout the population. Prenatal exposure to these drugs could alter normal foetal development and could threaten future welfare. The main changes observed in prenatal exposure to tobacco are caused by nicotine and carbon monoxide, which can impede nutrient and oxygen exchange between mother and foetus, restricting foetal growth. Memory, learning processes, hearing and behaviour can also be affected. Alcohol may cause physical and cognitive alterations in prenatally exposed infants, fundamentally caused by altered NMDAR and GABAR activity. Tetrahydrocannabinol, the psychoactive compound of cannabis, is capable of activating CB1R, inducing connectivity deficits during the foetal brain development. This fact could be linked to behavioural and cognitive deficits. Many of the effects from prenatal cocaine exposure are caused by altered cell proliferation, migration, differentiation and dendritic growth processes. Cocaine causes long term behavioural and cognitive alterations and also affects the uteroplacental unit.

Toxicological evaluation of an Allium-based commercial product in a 90-day feeding study in Sprague-Dawley rats.

Proallium AP(®) is a commercial Allium extract intended to be used in active food packaging as the antibacterial and antioxidant effects of some organosulfur compounds are well known. However, there is little information on its toxicity and the Scientific Committee on Food (UE) requires the safety assessment of substances used in food contact materials. Thus, the aim of this study was to conduct for the first time a subchronic oral toxicity study of Proallium AP(®) with groups of 10 males and 10 females Sprague-Dawley rats fed a diet containing 0, 25, 100, 400 mg/kg/d for 90 days. No treatment-related clinical signs or mortality were noted. Besides, no treatment-related effects with regard to any of the toxicological biomarkers considered were observed, including biochemical, haematological and histopathology parameters. In conclusion, the non-observed-adverse-effect-level (NOAEL) for Proallium AP(®) in rats was determined to be a dietary dose of 400 mg/kg/d under the present experimental conditions, a value 500-fold higher than the exposure derived from its potential use in active packaging.

Genotoxicity assessment of propyl thiosulfinate oxide, an organosulfur compound from Allium extract, intended to food active packaging.

Essential oils from onion (Allium cepa L.), garlic (Allium sativum L.), and their main components, such as propyl thiosulfinate oxide (PTSO) are being intended for active packaging with the purpose of maintaining and extending food product quality and shelf life. The present work aims to assess for the first time the potential mutagenicity/genotoxicity of PTSO (0-50 µM) using the following battery of genotoxicity tests: (1) the bacterial reverse-mutation assay in Salmonella typhimurium (Ames test, OECD 471); (2) the micronucleus test (OECD 487) (MN) and (3) the mouse lymphoma thymidine-kinase assay (OECD 476) (MLA) on L5178YTk(+/-), cells; and (4) the comet assay (with and without Endo III and FPG enzymes) on Caco-2 cells. The results revealed that PTSO was not mutagenic in the Ames test, however it was mutagenic in the MLA assay after 24 h of treatment (2.5-20 µM). The parent compound did not induce MN on mammalian cells; however, its metabolites (in the presence S9) produced positive results (from 15 µM). Data from the comet assay indicated that PTSO did not induce DNA breaks or oxidative DNA damage. Further in vivo genotoxicity tests are needed to confirm its safety before it is used as active additive in food packaging.

Contrasting energy allocation strategies of two sympatric Merluccius species in an upwelling system.

This study investigated the somatic growth and energy allocation strategy of two sympatric hake species (Merluccius polli and Merluccius senegalensis), coexisting under the strong influence of the Mauritanian upwelling. The results revealed that ontogeny, bathymetry, geography and reproduction shaped the differences found between the condition dynamics of the two species. Aside from species-specific differences, individuals were observed in better condition in the northernmost area (more influenced by the permanent upwelling) and in the deepest waters, probably the most favourable habitat for Merluccius spp. Both species also displayed contrasting trade-offs in energy allocation probably due to the dissimilarity of their habitats, which favours the existence of divergent adaptive strategies in response to different ontogenic requirements. It was hypothesized that M. polli invests in mass and energy reserves while sacrificing growth, as larger sizes may not provide an ecological advantage in a deeper and more stable environment. Moreover, M. senegalensis capitalizes on a steady growth without major disruptions, enabling earlier spawning at the expense of a lower somatic mass, which is fitting to a less stable shallower environment. This study sheds new light on differences in the biological traits and life strategies of Merluccius spp., which permit their overlap in a complex upwelling system and may contribute to the long-lasting scientific-based management of these species.