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L’acustica è alla base delle più importanti tecnologie nelle telecomunicazioni subacquee, nonché nel rilevamento e nella determinazione dei target acustici nei mezzi acquatici. Le misure a multi-frequenza sono lo strumento principale per l’identificazione selettiva delle specie marine e per la pesca sostenibile. Lo sviluppo di sistemi a larga banda larga e le tecniche basate su sonar multi-beam costituiscono l'attuale sfida per gli scienziati e gli sviluppatori. Al contempo, sistemi più semplici ed economicamente efficienti, come boe satellitari, sono in grado di offrire informazioni per il monitoraggio degli ecosistemi o l’individuazione di specie bersaglio nella pesca marittima. ------ Acoustics is the basics of the most important technologies for underwater telecommunication, as well as for target detection and identification in the aquatic media. Multiple frequency measurements are the key for species discrimination and open the door for sustainable fisheries. The development of wider broadband systems and quantitative multi-beam sonars and processing techniques constitute the present challenge for scientists and developers. In parallel, simpler and cost-efficient systems like satellite buoys can offer clue information for marine ecosystem monitoring or target species fisheries.

SARS-CoV-2 infection in already-vaccinated individuals is still possible and may require hospitalization. The aim of the present study was to evaluate the clinical evolution of patients with COVID-19 admitted to a public hospital. The outcomes were assessed in relation to the predominant viral variant and the vaccination status. This retrospective study was performed on 1295 COVID-19-positive patients who attended a 352-bed university hospital between 2021 and 2022. Clinical variables and vaccination status were recorded. Of the patients, 799 had not been vaccinated (NV, 61.7%), 449 were partially vaccinated (PV, 34.7%), and 47 were completely vaccinated (CV, 3.6%). The mean age of the CV patients was significantly higher than that of PV and NV. Additionally, they had higher percentages of chronic diseases. The outcomes depended on age but not on vaccination status. There were 209 patients admitted during the Omicron-infection period, of whom 70 (33.5%) were NV, 135 (64.6%) were PV, and 4 (1.9%) were CV. In conclusion, correct vaccination greatly reduces the risk of acquiring severe COVID-19. Partial vaccination does not guarantee protection of the population. This highlights the need for continuous vaccination promotion with all recommended doses, while also investigating alternative treatments for those patients who do not respond to the vaccines.

Aim: To describe the prevalence of Peripheral Artery Disease (PAD) in a random population sample and to evaluate its relationship with Mediterranean diet and with other potential cardiovascular risk factors such as serum uric acid and pulse pressure in individuals ranged 45 to 74 years. Methods: Cross-sectional analysis of 1568 subjects (mean age 6.5 years, 43% males), randomly selected from the population. A fasting blood sample was obtained to determine glucose, lipids, and HbA1C levels. An oral glucose tolerance test was performed in non-diabetic subjects. PAD was evaluated by ankle–brachial index and/or having a prior diagnosis. Results: PAD prevalence was 3.81% (95% CI, 2.97–4.87) for all participants. In men, PAD prevalence was significantly higher than in women [5.17% (95% CI, 3.74–7.11) vs. 2.78% (95% CI, 1.89–4.07); p = 0.014]. Serum uric acid in the upper quartile was associated with the highest odds ratio (OR) of PAD (for uric acid > 6.1 mg/dl, OR = 4.31; 95% CI, 1.49–12.44). The remaining variables more strongly associated with PAD were: Heart rate >90 bpm (OR = 4.16; 95%CI, 1.62–10.65), pulse pressure in the upper quartile (≥ 54 mmHg) (OR = 3.82; 95%CI, 1.50–9.71), adherence to Mediterranean diet (OR = 2.73; 95% CI, 1.48–5.04), and former smoker status (OR = 2.04; 95%CI, 1.00–4.16). Conclusions: Our results show the existence of a low prevalence of peripheral artery disease in a population aged 45–74 years. Serum uric acid, pulse pressure and heart rate >90 bpm were strongly associated with peripheral artery disease. The direct association between Mediterranean diet and peripheral artery disease that we have found should be evaluated through a follow-up study under clinical practice conditions. [ABSTRACT FROM AUTHOR]

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Since the end of the 1990’s, the reinforcement of control over unemployed people in Western European countries raises two questions. From an old and traditionally marginal property of unemployment policies, how was control promoted to a major goal? Why do different national policies of unemployment support converge on this regard, even when the European Union does not have direct competence on this matter? To answer these questions, three levels of analyses are sketched. At first, the description of the historic evolutions that affected unemployment and its public treatment, specifically through the process of desobjectivation of unemployment and the instauration of socio-political power relations unfavourable to unemployed, that we widely find on an European scale. Then the establishment of elective affinities, in the sense of Max Weber, between the pattern of active social State promoted at the supranational plan, and the rigorist orientations of the treatment of the unemployed that we find at the national plan. In short, the analysis, starting from the French case, of the uses of international comparison shows how policies obeying to national logics can give them selves European tendencies that they, on their turn, contribute to achieve

Este artículo aborda el tema del proyecto urbano en OMA. Para ello aborda la propuesta presentada por el grupo de arquitectos holandeses para el concurso del Parque de la Villete en Paris, y lo compara con el del Bernard Tschumi, arquitecto ganador. El autor explora los conceptos que OMA maneja en su diseño, los compara con los de Tschumi y, nos introduce en el proyecto urbano de OMA, esquematizando los elementos que el grupo de arquitectos, dirigido por Rem Koolhaas, maneja.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients., (© 2024 The Authors. BioFactors published by Wiley Periodicals LLC on behalf of International Union of Biochemistry and Molecular Biology.)

Background . New applications of 3D printing have recently appeared in the fields of radiotherapy and radiology, but the knowledge of many radiological characteristics of the compounds involved is still limited. Therefore, studies are needed to improve our understanding about the transport and interaction of ionizing radiation in these materials. Purpose . The purpose of this study is to perform an analysis of the most important radiation interaction parameters in thermoplastic materials used in Fused Deposition Modeling 3D printing. Additionally, we propose improvements to bring their characteristics closer to those of water and use them as water substitutes in applications such as radiodiagnosis, external radiotherapy, and brachytherapy. Methods . We have calculated different magnitudes as mass linear attenuation, mass energy absorption coefficients, as well as stopping power and electronic density of several thermoplastic materials along with various compounds that have been used as water substitutes and in a new proposed blend. To perform these computations, we have used the XCOM and ESTAR databases from NIST and the EGSnrc code for Montecarlo simulations. Results . From the representation of the calculated interaction parameters, we have been able to establish relationships between their properties and the proportion of certain chemical elements. In addition, studying these same characteristics in different commercial solutions used as substitutes for water phantoms allows us to extrapolate improvements for these polymers. Conclusion . The radiological characteristics of the analyzed thermoplastic materials can be improved by adding some chemical elements with atomic numbers higher than oxygen and by using polyethylene in new blends., (© 2024 IOP Publishing Ltd.)

Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis displays similar symptoms, diverse factors can contribute to the progression of the disease and determine the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. In total, 7161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful in developing precision medicine approaches for patient care.

Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies., Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and simvastatin in a double-blind crossover study., Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin and required for the production of 12α-hydroxylated bile acids, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12α-hydroxylated bile acid levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30), as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and low-density lipoprotein cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20)., Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12α-hydroxylated bile acids, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in morbid obesity (MO). A considerable proportion of patients with MO have non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is the only procedure that reliably differentiates NASH from other stages of NAFLD, but its invasive nature prevents it from being generalisable. Hence, non-invasive assessment is critical in this group of patients., Objectives: To report NAFLD/NASH prevalence in a cohort of patients with MO and to identify predictors of NASH., Methods: Fifty-two consecutive patients subjected to bariatric surgery in a University hospital in Spain underwent LB. Anthropometric, clinical and biochemical variables were registered. According of the results of the LB, individuals were classified by whether they had NASH or not. Multiple logistic regression analysis was performed to identify independent factors associated with NASH., Results: NAFLD was reported in 94.2% of the patients, simple steatosis was present in 51.92% and NASH in 42.31%. Meanwhile, 17.3% of patients exhibited significant fibrosis (≥F2). HIGHT score for NASH risk was established using five independent predictors: systemic Hypertension, Insulin resistance, Gamma-glutamyl transferase, High density lipoprotein cholesterol and alanine Transaminase. This score ranges from 0 to 7 and was used to predict NASH in our cohort (area under the receiver operator characteristic curve 0.846). A score of 4 or greater implied high risk (sensitivity 77.3%, specificity 73.3%, positive predictive value 68%, negative predictive value 81.5%, accuracy 75%)., Conclusions: NAFLD is practically a constant in MO with a considerable proportion of patients presenting NASH. The combination of five independent predictors in a scoring system may help the clinician optimise the selection of patients with MO for LB., (Copyright © 2021 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

Purpose: The use of a tourniquet in total knee replacement has advantages and drawbacks. Some studies suggest that using ischaemia at low pressures could reduce its negative effects. Our objective is to verify whether the use of ischaemia at low pressures (100 mmHg above the systolic blood pressure) produces greater pain and loss of strength than surgery without a tourniquet., Methods: By the means of a prospective randomized clinical trial, patients were assigned to the control group (no tourniquet, NT) or the experimental group (tourniquet, T). The main variables measured were pain (VAS) and isometric muscle strength (preoperatively, 10 days and 3 months after surgery). Secondary variables were haemoglobin at 24 h, transfusion index, need for rescue drugs and days of admission., Results: A total of 71 patients (73 prosthesis) were studied. Both groups were homogeneous in terms of age, body mass index, sex ratio, preoperative strength and level of anesthetic risk. We did not find significative differences in any of the main variables (pain and strength) nor in the secondary ones. We could only find differences in the days of admission (2.77 vs. 3.05; p = 0.031)., Conclusions: Use of a tourniquet at low pressures (100 mmHg above systolic blood pressure) did not result in an increase in postoperative pain or a decrease in quadriceps extension force within the first 3 months after surgery., Level of Evidence: Level 1-Randomized controlled trial., (© 2021. European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in morbid obesity (MO). A considerable proportion of patients with MO have non-alcoholic steatohepatitis (NASH). Liver biopsy (LB) is the only procedure that reliably differentiates NASH from other stages of NAFLD, but its invasive nature prevents it from being generalisable. Hence, non-invasive assessment is critical in this group of patients., Objectives: To report NAFLD/NASH prevalence in a cohort of patients with MO and to identify predictors of NASH., Methods: Fifty-two consecutive patients subjected to bariatric surgery in a University hospital in Spain underwent LB. Anthropometric, clinical and biochemical variables were registered. According of the results of the LB, individuals were classified by whether they had NASH or not. Multiple logistic regression analysis was performed to identify independent factors associated with NASH., Results: NAFLD was reported in 94.2% of the patients, simple steatosis was present in 51.92% and NASH in 42.31%. Meanwhile, 17.3% of patients exhibited significant fibrosis (≥F2). HIGHT score for NASH risk was established using five independent predictors: systemic Hypertension, Insulin resistance, Gamma-glutamyl transferase, High density lipoprotein cholesterol and alanine Transaminase. This score ranges from 0 to 7 and was used to predict NASH in our cohort (area under the receiver operator characteristic curve 0.846). A score of 4 or greater implied high risk (sensitivity 77.3%, specificity 73.3%, positive predictive value 68%, negative predictive value 81.5%, accuracy 75%)., Conclusions: NAFLD is practically a constant in MO with a considerable proportion of patients presenting NASH. The combination of five independent predictors in a scoring system may help the clinician optimise the selection of patients with MO for LB., (Copyright © 2021 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. It is a spectrum of progressive alterations, with the final step in liver fibrosis which carries a high burden of long-term mortality. The scores used to predict liver fibrosis are not properly validated in morbid obesity (MO). Our aim was to evaluate the performance of seven risk scores in bariatric surgery (BS) patients., Methods: Cross-sectional analysis in a cohort of 60 patients with MO undergoing BS. Liver biopsy (LB) was taken and compared with fibrosis risk assessed by noninvasive scores: APRI, FIB-4, Forns, NFS (NAFLD fibrosis score), BARD, BAAT, and Hepamet. The area under the receiver operator characteristic curve (AUROC) and measures of diagnostic accuracy were calculated; performance of fibrosis scores was evaluated at standard threshold vs those suggested by ROC analysis., Results: LB was available in 50 patients; 9 (18%) had significant fibrosis (F2-F4). The BARD and Forns scores best predicted the absence of fibrosis, both with negative predictive value (NPV) of 95.5%, with AUROC of 0.761 and 0.667, respectively. Modification of standard thresholds (2 for BARD and 6.9 for Forns) to those suggested by ROC analysis (3 and 3.6, respectively) improved performance of scores. Basal glucose, glycated hemoglobin (HbA1c), aspartate transaminase (AST), and gamma glutamyl transferase (GGT) were identified by logistic regression analysis as independent predictor of fibrosis., Conclusions: Existing scoring systems are unable to stratify fibrosis risk in MO using established thresholds; its performance is improved if these cutoffs are modified.

Introduction: The presence of erectile dysfunction (ED) could be a warning of vascular disease in different arterial territories., Aim: The aim of this study was to investigate the association between ED and the presence of atherosclerosis in 2 different vascular beds: carotid and lower limbs., Methods: A total of 614 volunteers between 45 and 74 years of age (mean age 61.0 years) were randomly selected from the general population. ED was assessed using the International Index of Erectile Function (IIEF-5). Ankle-brachial index (ABI) measurement and carotid atherosclerosis were evaluated by echo-Doppler., Main Outcome Measures: Mean carotid intima-media thickness (IMT), prevalence of carotid plaques, mean ABI, and prevalence of ABI < 0.9 were the main outcome measures., Results: ED was present in 373 subjects (59.7%). Mean carotid IMT was significantly higher in men with ED (0.762 ± 0.151 mm vs 0.718 ± 0.114 mm, P < .001). Also the global prevalence of carotid plaques was more frequent in men with ED (63.8% vs 44.8%, P < .001), even after adjusting by age, cardiovascular risk factors, and ongoing treatment (P = .039). Both the IMT and the prevalence of carotid plaques increased significantly with ED severity (P trend .004 and <.001, respectively). There were no significant differences between groups neither in mean ABI nor in the prevalence of subjects with ABI < 0.9. However, there was a trend to a lower ABI and a higher prevalence of ABI < 0.9 with increasing ED severity., Conclusion: In the general population, the presence of ED identifies subjects with higher atherosclerosis burden in carotid arteries but not in the lower extremities., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

Background: Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS)., Methods: Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5 years; BMI, 48.0 ± 3.6 kg/m(2)) and 36 women (mean age, 44.6 ± 1.9 years; BMI, 44.9 ± 1.2 kg/m(2)), were classified as having MS (MS+, n = 20) or not (MS-, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction., Results: Hepatic mRNA levels of these genes were higher in obese patients with MS (11β-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS- obese patients were compared., Conclusions: Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.

Growth hormone (GH) secretion and serum insulin-like growth factor-I (IGF-I) decline with aging. This study addresses the role played by the hypothalamic regulators in the aging GH decline and investigates the mechanisms through which growth hormone secretagogues (GHS) activate GH secretion in the aging rats. Two groups of male Wistar rats were studied: young-adult (3 mo) and old (24 mo). Hypothalamic growth hormone-releasing hormone (GHRH) mRNA and immunoreactive (IR) GHRH dramatically decreased (P < 0.01 and P < 0.001) in the old rats, as did median eminence IR-GHRH. Decreases of hypothalamic IR-somatostatin (SS; P < 0.001) and SS mRNA (P < 0.01), and median eminence IR-SS were found in old rats as were GHS receptor and IGF-I mRNA (P < 0.01 and P < 0.05). Hypothalamic IGF-I receptor mRNA and protein were unmodified. Both young and old pituitary cells, cultured alone or cocultured with fetal hypothalamic cells, responded to ghrelin. Only in the presence of fetal hypothalamic cells did ghrelin elevate the age-related decrease of GH secretion to within normal adult range. In old rats, growth hormone-releasing peptide-6 returned the levels of GH and IGF-I secretion and liver IGF-I mRNA, and partially restored the lower pituitary IR-GH and GH mRNA levels to those of young untreated rats. These results suggest that the aging GH decline may result from decreased GHRH function rather than from increased SS action. The reduction of hypothalamic GHS-R gene expression might impair the action of ghrelin on GH release. The role of IGF-I is not altered. The aging GH/IGF-I axis decline could be rejuvenated by GHS treatment.

Both insulin and IGF-1 have been implicated in control of retinal endothelial cell growth, neovascularization, and diabetic retinopathy. To precisely define the role of insulin and IGF-1 signaling in endothelium in these processes, we have used the oxygen-induced retinopathy model to study mice with a vascular endothelial cell-specific knockout of the insulin receptor (VENIRKO) or IGF-1 receptor (VENIFARKO). Following relative hypoxia, VENIRKO mice show a 57% decrease in retinal neovascularization as compared with controls. This is associated with a blunted rise in VEGF, eNOS, and endothelin-1. By contrast, VENIFARKO mice show only a 34% reduction in neovascularization and a very modest reduction in mediator generation. These data indicate that both insulin and IGF-1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with the effect of insulin being most important in this process.

Insulin receptors (IRs) on vascular endothelial cells have been suggested to participate in insulin-regulated glucose homeostasis. To directly address the role of insulin action in endothelial function, we have generated a vascular endothelial cell IR knockout (VENIRKO) mouse using the Cre-loxP system. Cultured endothelium of VENIRKO mice exhibited complete rearrangement of the IR gene and a more than 95% decrease in IR mRNA. VENIRKO mice were born at the expected Mendelian ratio, grew normally, were fertile, and exhibited normal patterns of vasculature in the retina and other tissues. Glucose homeostasis under basal condition was comparable in VENIRKO mice. Both eNOS and endothelin-1 mRNA levels, however, were reduced by approximately 30-60% in endothelial cells, aorta, and heart, while vascular EGF expression was maintained at normal levels. Arterial pressure tended to be lower in VENIRKO mice on both low- and high-salt diets, and on a low-salt diet VENIRKO mice showed insulin resistance. Thus, inactivation of the IR on endothelial cell has no major consequences on vascular development or glucose homeostasis under basal conditions, but alters expression of vasoactive mediators and may play a role in maintaining vascular tone and regulation of insulin sensitivity to dietary salt intake.

On the basis of ex vivo studies using insulin-responsive cells, activation of a Class IA phosphoinositide 3-kinase (PI3K) seems to be required for a wide variety of cellular responses downstream of insulin. The Class IA PI3K enzymes are heterodimers of catalytic and regulatory subunits. In mammals, insulin-responsive tissues express both the p85alpha and p85beta isoforms of the regulatory subunit. Surprisingly, recent studies have revealed that disruption of the p85alpha gene in the mouse (p85alpha(-/-) mice) results in hypoglycemia with decreased plasma insulin, and the p85alpha(+/-) mice exhibit significantly increased insulin sensitivity. These results suggest either that p85alpha negatively regulates insulin signaling, or that p85beta, which mediates the major fraction of Class IA PI3K signaling in the absence of p85alpha, is more efficient than p85alpha in mediating insulin responses. To address this question, we have generated mice in which the p85beta gene is deleted (p85beta(-/-) mice). As with the p85alpha(-/-) mice, the p85beta(-/-) mice showed hypoinsulinemia, hypoglycemia, and improved insulin sensitivity. At the molecular level, PI3K activity associated with phosphotyrosine complexes was preserved despite a 20-30% reduction in the total protein level of the regulatory subunits. Moreover, insulin-induced activation of AKT was significantly up-regulated in muscle from the p85beta(-/-) mice. In addition, insulin-dependent tyrosine phosphorylation of insulin receptor substrate-2 was enhanced in the p85beta(-/-) mice, a phenotype not observed in the p85alpha(-/-) mice. These results indicate that in addition to their roles in recruiting the catalytic subunit of PI3K to the insulin receptor substrate proteins, both p85alpha and p85beta play negative roles in insulin signaling.

Rad is the prototypic member of a family of novel Ras-related GTPases that is normally expressed in heart, skeletal muscle, and lung and that has been shown to exhibit a novel form of bi-directional interaction with the nm23 metastasis suppressor. In the present study, we have investigated the expression of Rad in normal and neoplastic breast tissues by Western blot and immunohistochemistry and the functional effect of altered Rad expression in breast cancer cell lines. We found that, although Rad is frequently expressed in normal breast tissue (23/30 Rad+ve), expression is usually lost in adjacent invasive carcinoma (8/30 Rad+ve; P < 0.0001). However, where Rad expression persists in a small proportion of tumors, it is associated with higher grade, larger size, and extensive axillary nodal involvement (n = 48; P = 0.035, P = 0.016, P = 0.022, respectively). Furthermore, Rad is also highly expressed in a breast cancer cell line with high tumorigenic and metastatic potential (MDA-MB231). To further examine the role of Rad in breast cancer, we stably transfected a Rad-ve breast cancer cell line (MDA-MB435). We observed an increase in growth and marked increased colony formation in soft agar in vitro (P < 0.05) and an increase in tumor growth rate in nude mice (P < 0.05). Moreover, coexpression of nm23 with wild-type Rad inhibited the effect of Rad on growth of these cells in culture and markedly inhibited tumor growth in vivo. Additional transfection studies with mutated Rad cDNAs revealed that the growth-promoting effects of Rad appeared to be mediated through its NH2- and COOH-terminal regions, rather than its GTPase domain, and might involve acceleration of cell cycle transition. These findings suggest that Rad may act as an oncogenic protein in breast tissues and demonstrate a potential mechanism by which interaction between Rad and nm23 may regulate growth and tumorigenicity of breast cancer.

We have recently reported that skeletal muscle of the ob/ob mouse, an animal model of genetic obesity with extreme insulin resistance, exhibits alterations in the expression of multiple genes. Analysis and cloning of a full-length cDNA of one of the overexpressed mRNAs revealed a 300-amino-acid protein that could be identified as the mouse geranylgeranyl diphosphate synthase (GGPP synthase) based on its homology to proteins cloned from yeast and fungus. GGPP synthase catalyzes the synthesis of all-trans-geranylgeranyl diphosphate (GGPP), an isoprenoid used for protein isoprenylation in animal cells, and is a branch point enzyme in the mevalonic acid pathway. Three mRNAs for GGPP synthase of 4.3, 3.2, and 1.7 kb were detected in Northern blot analysis. Western blot analysis of tissue homogenates using specific antipeptide antibodies revealed a single band of 34.8 kDa. Expression level of this protein in different tissues correlated with expression of the 4.3- and 3.2-kb mRNAs. GGPP synthase mRNA expression was increased 5- to 20-fold in skeletal muscle, liver, and fat of ob/ob mice by Northern blot analysis. Western blot analysis also showed a twofold overexpression of the protein in muscle and fat but not in liver, where the dominant isoform is encoded by the 1.7-kb mRNA. Differentiation of 3T3-L1 fibroblasts into adipocytes induced GGPP synthase expression more than 20-fold. Using the immunoprecipitated protein, we found that mammalian GGPP synthase synthesizes not only GGPP but also its metabolic precursor farnesyl diphosphate. Thus, the expression of GGPP synthase is regulated in multiple tissues in obesity and is induced during adipocyte differentiation. Altered regulation in the synthesis of isoprenoids for protein prenylation in obesity might be a factor determining the ability of the cells to respond to hormonal stimulation requiring both Ras-related small GTPases and trimeric G protein-coupled receptors.

Both genetic and environmental factors contribute to the etiology of non-insulin-dependent diabetes. The genetic component is heterogeneous and in some patients is probably complex, involving multiple genes. Specific genetic defects have been identified for rate monogenic forms of NIDDM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40% of families), syndromes of extreme insulin resistance (which often involve the insulin receptor), and diabetes-deafness syndromes (with defects in mitochondrial genes). In contrast, the genes involved in common forms of NIDDM are still uncertain. Mutations have been extensively searched in genes regulating insulin signaling and secretion. Some evidence of involvement has been produced for insulin-receptor substrate-1, glycogen synthase, the glucagon receptor, a ras-related protein (Rad), histocompatibility antigens, PC-1, and fatty acid binding protein, but the contributions of these genes to NIDDM is probably small. Other candidate genes (e.g. insulin, insulin receptor, glucose transporters) have been excluded as major diabetogenes. New insights are expected in the near future from the systematic scanning of the genome for linkage with NIDDM.

A higher specific binding of GLP-1(7-36)amide is found in skeletal muscle plasma membranes from adult streptozotocin (STZ)-treated rats (insulin-dependent diabetes mellitus model) and from neonatal STZ-treated rats (non insulin-dependent diabetes mellitus model), as compared to that in normal controls; no apparent change in the affinity was observed, that indicating the presence in both diabetic models of an increased number of high affinity binding sites for the peptide. The maximal specific GLP-1(7-16)amide binding in the non insulin-dependent diabetes mellitus model was found to be significantly higher than that in the insulin-dependent diabetes mellitus model. As GLP-1(7-36)amide exerts a glycogenic effect in the rat skeletal muscle, the present data suggest that the action of the peptide in the muscle glucose metabolism may be increased in states of insulin deficiency accompanied or not by insulin resistance.

Both the monomethyl and dimethyl esters of succinic acid, administered intravenously to fasted and anesthetized rats, caused a rapid increase in plasma insulin. A positive insulin secretory response to succinic acid monomethyl ester was also observed after intraperitoneal injection to fed and conscious rats. On a molar basis, stimulation of the insulin release, evoked by succinic acid esters, represented about twice that caused by D-glucose. It is speculated that succinic acid esters may be efficient insulin secretagogues even in those models of noninsulin-dependent diabetes characterized by a site-specific defect in the transport of D-glucose or in the early steps of its catabolism in the pancreatic B-cell.

Severe dietary restriction delays the physical development of rodents and leads to adult animals of reduced body size but significantly increased life expectancy. We tried to find a similar relationship in human populations using demographical and statistical methods. We show for the total Spanish male population that the mean adult body height reliably reflects the regional living and nutritional conditions. This relation does not only hold for todays socioeconomic data but can also be reproduced using data on family income in the mid 19th century. We calculated the mean height of young men liable to the military service around 1860 and determined their longevity retrospectively using posterior census data. This was done separately for all the Spanish provinces. The linear regression between both parameters manifests a statistically highly significant relationship: the smaller the mean height at age 18 in a province, the higher the chance for people living there to reach high chronological ages. Migrational movements, selection, mortality due to epidemics or unreliability of the population censuses can be largely ruled out as explications for the described correlation. Furthermore, we determined the secular growth trend in Spain for the last 130 years. From 1860 to 1920 the mean height increased by 2.7 cm, from 1920 to 1987 by another 9.8 cm. Since 1950 the trend is above 2 cm per decade country-wide. From 1974 onwards it amounts to 2.89 +/- 0.17. Such high values were worldwide looked upon as isolated cases found only in geographically and socially isolated population subgroups during very limited periods.

The risk of atherosclerosis was assessed using a mathematical model of competition between LDL and HDL on 365 randomly selected persons. The results speak for the fact that the risk falls between the ages of 30 and 40 years for males, and 40 and 50 years for females. We are of the opinion that our procedure may be valid for sex comparison studies attempting to objectify the prevalence of atherosclerosis in population studies.

We calculated a theoretical vitality function as a reference curve, based on experimental results from 226 healthy individuals. This can be used to assess biological aging rates of geographically separate human populations. Only six parameters were used to assess vitality. Each parameter is associated with one of the two physiological compartments. We assume that one compartment keeps the system stable and the other maintains system fidelity. The results permit us to compare vitality curves within populations as well as to determine the age at which maximum vitality appears in each population. The differences between biological and chronological ages in each population and possible etiological interpretations are discussed. This mathematical model can be useful as a method to measure differences in aging rates and effects of aging in several human populations.

The reduction in muscular mass with age is well-known, and thus in order to obtain reference values, the behaviour of the LBM and corporal adiposity (FM) in a standard population was studied. Of a total of 217 patients considered a priori as healthy, 172 were selected following a strict application of criteria based on clinical examination, haematological analysis and biochemical parameters, as well as hormone concentrations, aimed showed urinary elimination of creatinine (Cro) of between (+ - DE) within the theoretical level for their weight and age. In this standard population, the behaviour of the LBM and FM was studied depending on age, using for this purpose creatinine at 24 hours, weight and size, and different calculation procedures. The reduction in LBM showed a better correlation with age when calculated based on Cro (r = 0.47; p < 0.01) than on height (r = -0.27; p < 0.01). The age correlation was similar for both sexes (women: r = -0.60; men: r = -0.65) and reduction in LBM started to be considerable from the fifth decade and could be calculated from the regression equation LBM = 64.6 - 0.00069. age (days). At the same time as this reduction in LBM, there was an increase in FM (p < 0.0001). Our results show that the reduction of LBM and increase in FM with age in a healthy Spanish population is similar to other foreign studies published. It is preferable to correct the LBM with age using Cro, which can be calculated using the above-mentioned linear regression equation, regardless of sex.