Diagnosis of heart failure with preserved ejection fraction: a systematic narrative review of the evidence.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a common condition in clinical practice, affecting more than half of patients with HF. HFpEF is associated with morbidity and mortality and with considerable healthcare resource utilization and costs. Therefore, early diagnosis is crucial to facilitate prompt management, particularly initiation of sodium-glucose co-transporter 2 inhibitors. Although European guidelines define HFpEF as the presence of symptoms with or without signs of HF, left ventricular EF ≥ 50%, and objective evidence of cardiac structural and/or functional abnormalities, together with elevated natriuretic peptide levels, the diagnosis of HFpEF remains challenging. First, there is no clear consensus on how HFpEF should be defined. Furthermore, diagnostic tools, such as natriuretic peptide levels and resting echocardiogram findings, are significantly limited in the diagnosis of HFpEF. As a result, some patients are overdiagnosed (i.e., elderly people with comorbidities that mimic HF), although in other cases, HFpEF is overlooked. In this manuscript, we perform a systematic narrative review of the diagnostic approach to patients with HFpEF. We also propose a comprehensible algorithm that can be easily applied in daily clinical practice and could prove useful for confirming or ruling out a diagnosis of HFpEF.

Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice.

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.

Circulating Insulin-Like Growth Factor I is Involved in the Effect of High Fat Diet on Peripheral Amyloid ß Clearance.

Obesity is a risk factor for Alzheimer's disease (AD), but underlying mechanisms are not clear. We analyzed peripheral clearance of amyloid ß (Aß) in overweight mice because its systemic elimination may impact brain Aß load, a major landmark of AD pathology. We also analyzed whether circulating insulin-like growth factor I (IGF-I) intervenes in the effects of overweight as this growth factor modulates brain Aß clearance and is increased in the serum of overweight mice. Overweight mice showed increased Aß accumulation by the liver, the major site of elimination of systemic Aß, but unaltered brain Aß levels. We also found that Aß accumulation by hepatocytes is stimulated by IGF-I, and that mice with low serum IGF-I levels show reduced liver Aß accumulation-ameliorated by IGF-I administration, and unchanged brain Aß levels. In the brain, IGF-I favored the association of its receptor (IGF-IR) with the Aß precursor protein (APP), and at the same time, stimulated non-amyloidogenic processing of APP in astrocytes, as indicated by an increased sAPPα/sAPPß ratio after IGF-I treatment. Since serum IGF-I enters into the brain in an activity-dependent manner, we analyzed in overweight mice the effect of brain activation by environmental enrichment (EE) on brain IGF-IR phosphorylation and its association to APP, as a readout of IGF-I activity. After EE, significantly reduced brain IGF-IR phosphorylation and APP/IGF-IR association were found in overweight mice as compared to lean controls. Collectively, these results indicate that a high-fat diet influences peripheral clearance of Aß without affecting brain Aß load. Increased serum IGF-I likely contributes to enhanced peripheral Aß clearance in overweight mice, without affecting brain Aß load probably because its brain entrance is reduced.

Mechanical Behavior of a Composite Lightweight Slab, Consisting of a Laminated Wooden Joist and Ecological Mortar.

The investigation reported in this paper is an evaluation of the mechanical behavior of full-scale ecological mortar slabs manufactured with a mixture of expanded clay and recycled concrete aggregates. The composite mortars form a compressive layer over laminated wooden joists to form a single construction unit. To do so, full-scale flexural tests are conducted of the composite laminated wood-ecological mortar slabs with different types of mortar designs: reference mortar (MR), lightweight mortar dosed with recycled concrete aggregates (MLC), and lightweight mortar dosed with recycled mixed aggregates (MLM). The test results showed that the mortar forming the compression layer and the laminated wooden joists worked in unison and withstood a higher maximum failure load under flexion than the failure load of the wooden joists in isolation. Moreover, the laboratory test results were compared with the simulated values of the theoretical model, generated in accordance with the technical specifications for structural calculations contained in the Spanish building code, and with the results calculated by a computer software package. From the analysis of the results of the calculation methods and the full-scale laboratory test results, it was concluded that the safety margin yielded by the calculations validated the use of those methods on this type of composite slab. In this way, a strong mixed wood-mortar slab was designed, contributing little dead-load to the building structure and its manufacture with recycled aggregate, also contributes to the circular economy of construction materials.

Ecological Design of New Efficient Energy-Performance Construction Materials with Rigid Polyurethane Foam Waste.

An ecological mortar is designed from industrial sub-products, with the objective of utilizing both the slag residues, generated during steel manufacturing processes, and the waste from Polyurethane Foam (PF) panels, generated during refrigerator chamber manufacturing processes. The ecological mortar design involves the dosing of Electric Arc Furnace (EAF) slag, together with finely ground Polyurethane Foam, cement, and additives. An energy efficient prefabricated block is designed with the mortar, for use in construction, and its energy performance is assessed as a material inserted within the envelope of a service sector (hospital) building, either as an exterior skin, or as an enclosing component within the façade interior. The main contribution of this research is the characterization of the thermo-physical and mechanical properties of a new prefabricated panel made with recycled materials. The full characterization of the properties of these new materials is presented and discussed. The new prefabricated panel demonstrates adequate thermo-mechanical characteristics as a substitute for traditional materials, while improving the sustainability of the building. As a secondary objective, the energy behaviour of the new panels when integrated in a real building is presented by means of a case study simulation. The use of computational thermal simulation confirmed that the properties of the prefabricated block influenced the annual thermal demand of the building for heating and cooling. Improvements to the thermal inertia of the building envelope were also confirmed with the inclusion of PF waste, giving the mortar an energy performance that was similar to conventional materials, in such a way that its use in façade construction may be validated, in addition to its environmental benefits, due to it having been manufactured with critical recycled industrial waste such as EAF slag and PF, thereby contributing to both the circular economy and sustainable development.

Design and Characterization of Gypsum Mortars Dosed with Polyurethane Foam Waste PFW.

The properties and the behaviour of plaster mortars designed with Polyurethane Foam Waste (PFW) are studied in this investigation. A characterization of the mixtures is completed, in accordance with the technical specifications of European Norms. The incorporation of polyurethane waste foam can yield porous and lighter mortars, with better resistance to water-vapour permeability, although with weaker mechanical strength and higher levels of absorbency. Nevertheless, suitable mechanical strengths were achieved, resulting in a new material that is compliant with the requirements of the construction industry. The use of PFW in the the manufacture of gypsum mortars for construction reduces the consumption of natural resources and, at the same time, recovers an industrial waste that is otherwise difficult to recycle.

The Registry of Accredited Companies in the Construction Sector in Spain: An Administrative Instrument for Risk-Prevention Control.

The degree of compliance with the RegistrodeEmpresasAcreditadas (REA) (Registry of Accredited Companies) and its implementation by the Public Administrations in Spain is compared with its implementation among private construction sector firms. The Registry of Accredited Companies is a tool for risk-prevention control that is defined by Law 32/2006 in Regulation of Subcontracting in the Construction Sector in Spain. On the basis of a quantitative analysis of the data obtained from public bodies registered with the REA, the study is limited to AyuntamientosyDiputacionesProvinciales (Municipal Town and City Councils and Provincial Councils of the Provincial Government). To do so, the registration records with the REA of both public administrations are analyzed within the 50 Provinces and the two Autonomous Cities that together constitute the 17 Autonomous Communities of the national territory of Spain. In parallel, a comparative study is performed of the registration records of private construction sector firms registered with the REA. Public digital data-management tools are used for the investigation, together with publicly available information known as the RelacióndePuestosdeTrabajo (RPT) (List of Employment Positions) of the corresponding public entities under analysis, with the objective of testing the information and validating its degree of reliability. Likewise, a survey is administered to gather data on the registration of private construction center firms, in addition to the use of the qualitative Focus Groups technique, so as to assure the reliability the survey data. The results revealed unequal treatment by the Labor Authority with regard to the imposition of similar administrative obligations. A clearly negative discrimination was noted with regard to private construction sector firms, in comparison with the permissive attitude and light administrative burden of the Public Administrations.

Dabrafenib for cutaneous melanoma infiltrating the vitreous: regression of metastasis and occurrence of uveitis as a secondary effect.

Intraocular metastasis of cutaneous melanoma is extremely infrequent. This typically occurs in advanced metastatic disease and has a poor survival prognosis. The most frequent reported treatment is radiotherapy. BRAF inhibitors are new, orally administered and very effective drugs used for metastatic cutaneous melanoma. Herein, we report a case of a 58-year-old patient with a recent diagnosis of cutaneous melanoma who consulted for floaters and presented vitreous opacities in both eyes. A diagnostic vitrectomy of his left eye was performed and pathologic analysis disclosed infiltrating melanoma cells in the vitreous. Treatment with dabrafenib (a type of BRAF inhibitor) achieved the regression of the intraocular metastasis in the right eye. Moreover, the patient presented a severe anterior uveitis due to dabrafenib, a well-known secondary effect of this drug.

Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I.

Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes.

The insulin-like growth factor I receptor regulates glucose transport by astrocytes.

Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016;64:1962-1971.

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aß peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aß clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.