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The suitability of defatted soybean meal as a substitute for fishmeal was assessed in juvenile (25 g, average) tench, Tinca tinca, by feeding them diets containing 25 (S25), 37.5 (S37.5) and 50% (S50) soybean meal for 150 days. Soybean meal inclusion increased the relationship between essential and non-essential amino acids. Fish were hand-fed to apparent satiation; the feed intake ratio was not dependent upon the dietary soybean level. Survival was over 95% and unaffected by treatment. Growth was reduced at higher soybean meal levels. After 150 days, average weight for the fish fed soybean diets S25, S37.5 and S50 was 65.6, 59.2 and 51 g, respectively. Growth performance was evaluated on the basis of specific growth rate (SGR), final biomass, feed conversion ratio (FCR), and feed intake (FI). Maximum SGR (0.61-0.64) and final biomass (3022-3156 g) were recorded in tench fed diets containing 25 and 37.5% soybean meal. Nutritional parameters such as feed intake and feed conversion ratio were not affected by the soybean meal. Body composition was similar for tench fed the three different diets. [ABSTRACT FROM AUTHOR]

The highly prevalent metabolic dysfunction-associated steatohepatitis (MASH) is associated with liver steatosis, inflammation and hepatocyte injury that can lead to fibrosis and may progress to hepatocellular carcinoma and death. New treatment modalities such as gene therapy may be transformative for MASH patients. Here, we describe that one-time intramuscular administration of adeno-associated viral vectors of serotype 1 (AAV1) encoding native fibroblast growth factor 21 (FGF21), a key metabolic regulator, resulted in sustained increased circulating levels of the factor, which mediated long-term (>1 year) MASH and hepatic fibrosis reversion and halted development of liver tumors in obese male and female mouse models. AAV1-FGF21 treatment also counteracted obesity, adiposity, and insulin resistance, which are significant drivers of MASH. Scale-up to large animals successfully resulted in safe skeletal muscle biodistribution and biological activity in key metabolic tissues. Moreover, as a step towards the clinic, circulating FGF21 levels were characterized in obese, insulin resistant and MASH patients. Overall, these results underscore the potential of the muscle-directed AAV1-FGF21 gene therapy to treat MASH and support its clinical translation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Obesity and type 2 diabetes are two closely related diseases representing a serious threat worldwide. An increase in metabolic rate through enhancement of non-shivering thermogenesis in adipose tissue may represent a potential therapeutic strategy. Nevertheless, a better understanding of thermogenesis transcriptional regulation is needed to allow the development of new effective treatments. Here, we aimed to characterize the specific transcriptomic response of white and brown adipose tissues after thermogenic induction. Using cold exposure to induce thermogenesis in mice, we identified mRNAs and miRNAs that were differentially expressed in several adipose depots. In addition, integration of transcriptomic data in regulatory networks of miRNAs and transcription factors allowed the identification of key nodes likely controlling metabolism and immune response. Moreover, we identified the putative role of the transcription factor PU.1 in the regulation of PPARγ-mediated thermogenic response of subcutaneous white adipose tissue. Therefore, the present study provides new insights into the molecular mechanisms that regulate non-shivering thermogenesis., (© 2023. The Author(s).)

Objectives: To establish the epidemiological characteristics, ventilator management, and outcomes in patients with acute hypoxemic respiratory failure (AHRF), with or without acute respiratory distress syndrome (ARDS), in the era of lung-protective mechanical ventilation (MV)., Design: A 6-month prospective, epidemiological, observational study., Setting: A network of 22 multidisciplinary ICUs in Spain., Patients: Consecutive mechanically ventilated patients with AHRF (defined as Pao 2 /Fio 2 ≤ 300 mm Hg on positive end-expiratory pressure [PEEP] ≥ 5 cm H 2 O and Fio 2 ≥ 0.3) and followed-up until hospital discharge., Interventions: None., Measurements and Main Results: Primary outcomes were prevalence of AHRF and ICU mortality. Secondary outcomes included prevalence of ARDS, ventilatory management, and use of adjunctive therapies. During the study period, 9,803 patients were admitted: 4,456 (45.5%) received MV, 1,271 (13%) met AHRF criteria (1,241 were included into the study: 333 [26.8%] met Berlin ARDS criteria and 908 [73.2%] did not). At baseline, tidal volume was 6.9 ± 1.1 mL/kg predicted body weight, PEEP 8.4 ± 3.1 cm H 2 O, Fio 2 0.63 ± 0.22, and plateau pressure 21.5 ± 5.4 cm H 2 O. ARDS patients received higher Fio 2 and PEEP than non-ARDS (0.75 ± 0.22 vs 0.59 ± 0.20 cm H 2 O and 10.3 ± 3.4 vs 7.7 ± 2.6 cm H 2 O, respectively [ p < 0.0001]). Adjunctive therapies were rarely used in non-ARDS patients. Patients without ARDS had higher ventilator-free days than ARDS (12.2 ± 11.6 vs 9.3 ± 9.7 d; p < 0.001). All-cause ICU mortality was similar in AHRF with or without ARDS (34.8% [95% CI, 29.7-40.2] vs 35.5% [95% CI, 32.3-38.7]; p = 0.837)., Conclusions: AHRF without ARDS is a very common syndrome in the ICU with a high mortality that requires specific studies into its epidemiology and ventilatory management. We found that the prevalence of ARDS was much lower than reported in recent observational studies., Competing Interests: Dr. Villar received grants from Instituto de Salud Carlos III, Madrid, Spain (PI16/00049, PI19/00141), The European Regional Development’s Funds, and Asociación Científica Pulmón y Ventilación Mecánica, Las Palmas de Gran Canaria, Spain; he received grant support from Maquet-Getinge for conducting a clinical trial on mechanical ventilation. Drs. Villar, Añón, and C. Fernández received grant support from the Instituto de Salud Carlos III, Madrid, Spain (CB06/06/1088). Dr. Slutsky is funded by the Canadian Institutes of Health Research (grant number 137772 and FDN143285). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Type 2 diabetes, insulin resistance, and obesity are strongly associated and are a major health problem worldwide. Obesity largely results from a sustained imbalance between energy intake and expenditure. Therapeutic approaches targeting metabolic rate may counteract body weight gain and insulin resistance. Bone morphogenic protein 7 (BMP7) has proven to enhance energy expenditure by inducing non-shivering thermogenesis in short-term studies in mice treated with the recombinant protein or adenoviral vectors encoding BMP7 . To achieve long-term BMP7 effects, the use of adeno-associated viral (AAV) vectors would provide sustained production of the protein after a single administration. Here, we demonstrated that treatment of high-fat-diet-fed mice and ob/ob mice with liver-directed AAV-BMP7 vectors enabled a long-lasting increase in circulating levels of this factor. This rise in BMP7 concentration induced browning of white adipose tissue (WAT) and activation of brown adipose tissue, which enhanced energy expenditure, and reversed WAT hypertrophy, hepatic steatosis, and WAT and liver inflammation, ultimately resulting in normalization of body weight and insulin resistance. This study highlights the potential of AAV-BMP7-mediated gene therapy for the treatment of insulin resistance, type 2 diabetes, and obesity., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background/objectives: During obesity, hypertrophic enlargement of white adipose tissue (WAT) promotes ectopic lipid deposition and development of insulin resistance. In contrast, WAT hyperplasia is associated with preservation of insulin sensitivity. The complex network of factors that regulates white adipogenesis is not fully understood. Bone morphogenic protein 7 (BMP7) can induce brown adipogenesis, but its role on white adipogenesis remains to be elucidated. Here, we assessed BMP7-mediated effects on white adipogenesis in ob/ob mice., Methods: BMP7 was overexpressed in either WAT or liver of ob/ob mice using adeno-associated viral (AAV) vectors. Analysis of gene expression, histological and morphometric alterations, and metabolites and hormones concentrations were carried out., Results: Overexpression of BMP7 in adipocytes of subcutaneous and visceral WAT increased fat mass, the proportion of small-size adipocytes and the expression of adipogenic and mature adipocyte genes, suggesting induction of adipogenesis irrespective of fat depot. These changes were associated with reduced hepatic steatosis and improved insulin sensitivity. In contrast, liver-specific overproduction of BMP7 did not promote WAT hyperplasia despite BMP7 circulating levels were similar to those achieved after genetic engineering of WAT., Conclusions: This study unravels a new autocrine/paracrine role of BMP7 on white adipogenesis and highlights that BMP7 may modulate WAT plasticity and increase insulin sensitivity.

Purpose: Frailty is a common condition among critically ill patients. Usually evaluated in a mixed population of medical, cardiac and surgical patients, we aimed to assess the impact of frailty on short- and long-term mortality exclusively in critically ill older medical patients., Materials and Methods: We included 285 patients aged≥70 years admitted to ICU (2009-2017). Comorbidities, severity scores, treatment intensity and complications were recorded. Pre-hospital frailty, measured by Clinical Frailty Scale (CFS), was defined as a score ≥ 5 according to this scale., Results: Prevalence of frailty (CFS ≥ 5) of 18.6%. Frail patients were more likely to be female (64.2% vs. 35.6%, p < .001) or suffer from heart failure (17% vs. 6%,p = .021). Apache II score was higher in frail than in non-frail patients (27.4 ± 7.1 vs. 24.8 ± 8.6,p = .041). Age, comorbidities, treatment intensity, complications, and ICU and hospital length of stay were similar between frail and non-frail patients. Life-sustaining treatment limitation was more frequent in frail patients (47.2% vs. 20.7%,p < .001). Except for ICU mortality, frailty was an independent predictor of short- and long-term mortality after adjustment for sociodemographic, comorbidities, severity scores, treatment intensity and complications., Conclusions: Frailty (CFS ≥ 5) was independently associated with short- and long-term mortality in older patients admitted to ICU exclusively due to a medical reason., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Objective: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties., Methods: Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks., Results: In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice., Conclusions: Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a therapeutic strategy for autoimmune diabetes in humans.

Patients on renal replacement therapy (RRT) infected with the human immunodeficiency virus (HIV) are a special group with growing interest. In order to study the epidemiological data of HIV+ patients on RRT in Spain, we collected individual information from 2004-2011 (period of use of highly active antiretroviral therapy [HAART] in the Autonomous Communities of Andalusia, Aragon, Asturias, Catalonia, Valencia, Castilla la Mancha, Castilla León, Galicia, Madrid, La Rioja and the Basque Country, comprising 85% of the Spanish population. A total of 271 incident and 209 prevalent patients were analysed. They were compared with the remaining patients on RRT during the same period. The annual incidence was 0.8 patients per one million inhabitants, with a significant increase during the follow-up period. The proportion of prevalent HIV+ patients was 5.1 per 1,000 patients on RRT (95% confidence interval [CI] 4.4-5.8. Although glomerular diseases constituted the majority of cases (42%), diabetic nephropathy was the cause in 14% of patients. The nation-wide totals for these percentages were 13 and 25%, respectively. Compared to the total of patients in treatment, the risk of death was significantly higher in the HIV+ group: hazard ratio (HR) adjusted for age, sex and diabetes was 2.26 (95% CI 1.74 - 2.91). Hepatitis C coinfection increased the risk of death in the HIV+ group (HR 1.77; 95% CI 1.10 - 2.85). The probability of kidney transplantation in HIV+ was only 17% after 7 years, comparing with total RTT patients (HR 0.15; 95% CI: 0.10-0.24). Despite the use of HAART, the incidence of HIV+ patients on dialysis has increased; their mortality still exceeds non-HIV patients, and they have a very low rate of transplantation. It is necessary to further our knowledge of this disease in order to improve results., (Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Recently, dexmedetomidine has been marketed in Spain and other European countries. The published experience regarding its use has placed dexmedetomidine on current trends in sedo-analgesic strategies in the adult critically ill patient. Dexmedetomidine has sedative and analgesic properties, without respiratory depressant effects, inducing a degree of depth of sedation in which the patient can open its eyes to verbal stimulation, obey simple commands and cooperate in nursing care. It is therefore a very useful drug in patients who can be maintained on mechanical ventilation with these levels of sedation avoiding the deleterious effects of over or infrasedation. Because of its effects on α2-receptors, it's very useful for the control and prevention of tolerance and withdrawal to other sedatives and psychotropic drugs. The use of dexmedetomidine has been associated with lower incidence of delirium when compared with other sedatives. Moreover, it's a potentially useful drug for sedation of patients in non-invasive ventilation., (Copyright © 2013 Elsevier España, S.L. y SEMICYUC. All rights reserved.)

Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential. Here, we demonstrate that adeno-associated viral (AAV) vectors, especially serotypes 8 and 9, mediated efficient transduction of white (WAT) and brown adipose tissue (BAT) in adult lean and obese diabetic mice. The use of short versions of the adipocyte protein 2 or uncoupling protein-1 promoters or micro-RNA target sequences enabled highly specific, long-term AAV-mediated transgene expression in white or brown adipocytes. As proof of concept, delivery of AAV vectors encoding for hexokinase or vascular endothelial growth factor to WAT or BAT resulted in increased glucose uptake or increased vessel density in targeted depots. This method of gene transfer also enabled the secretion of stable high levels of the alkaline phosphatase marker protein into the bloodstream by transduced WAT. Therefore, AAV-mediated genetic engineering of adipose tissue represents a useful tool for the study of adipose pathophysiology and, likely, for the future development of new therapeutic strategies for obesity and diabetes.

Laryngeal leiomyosarcoma is a highly infrequent malignancy, with less than fifty reports in the scientific literature world-wide. Diagnosis is based on immunohistochemistry and, occasionally, on electron microscopy techniques, making it difficult to be done preoperatively. We report a new case of laryngeal leiomyosarcoma, with an up-to-date review of the differential diagnosis and the treatment strategy.

Epidermal cysts of parapharyngeal location are very unusual tumors, with a benign character, though when they reach a great size, adjacent zones and vascular and nervous structures of great importance can be affected. We are going to describe the clinical aspects of this case, the instructions and the surgical approach used: the Fabre inferior and internal jaw approach of the lateropharingeal space and infrasphenotemporal fossa, which avoids the aesthetics and functional aftereffects of other more common approaches.