Less favourable food consumption ratings in the Five-Color Nutri-Score are associated with incident frailty in older adults.

BACKGROUND: The Nutri-Score front-of-package labelling classifies food products according to their nutritional quality, so healthier food choices are easier when shopping. This study prospectively assesses the association of a diet rated according to the Nutri-Score system and incident frailty in community-dwelling older adults. METHODS: Cohort study with 1,875 individuals aged ≥60 recruited during 2008-2010 in Spain. At baseline, food consumption was assessed using a validated dietary history. Food was categorised into five Nutri-Score labels (A/green-best quality; B, C, D, E/red-worst quality) utilising an algorithm established in 2017 and currently in use. For each participant, a Five-Color Nutri-Score Dietary Index (5-CNS DI) in grams per day per kilogram was calculated. The 5-CNS DI sums up the grams per day of food consumed times their corresponding nutritional quality value (from A rated as 1 to E rated as 5) and divided by weight in kilograms. From baseline to December 2012, incident frailty was ascertained based on Fried's criteria. Statistical analyses were performed with logistic regression adjusted for main confounders. RESULTS: After a mean follow-up of 3.5 years, 136 cases of frailty were identified. The multivariable-adjusted odds ratios (95% confidence interval) of incident frailty across increasing quartiles of the 5-CNS DI were 1, 1.51 (0.86-2.68), 1.56 (0.82-2.98) and 2.32 (1.12-4.79); P-trend = 0.033. The risk of frailty increased by 28% (3-58%) with a 10-unit increment in this dietary index. Similar results were found with the Nutri-Score algorithm modified in 2022. CONCLUSIONS: consumption of a diet with less favourable Nutri-Score ratings doubles the risk of frailty among community-dwelling older adults.

Renal Denervation: A Review.

Uncontrolled hypertension persists as an important health issue despite the availability of many medications and nondrug therapies that lower blood pressure. Increasingly, nonadherence to medication is found in approximately 2 of every 5 patients with uncontrolled hypertension. In the search for interventions that lower blood pressure that do not rely on adherence to a regimen requiring daily ingestion of medication or repeated physical activity, device-based methods that denervate the renal arteries have emerged as a potential complement to standard antihypertensive treatments. At least 3 different approaches to renal artery denervation are under active investigation, including the use of radiofrequency energy, ultrasound, or the injection of neurolytic agents into the renal perivascular tissue. In this review, we cover what is currently known about the mechanisms of antihypertensive effects of renal denervation, summarize the efficacy and safety of renal denervation using recent controlled trial publications in a number of hypertensive populations, and conclude with some thoughts about challenges in the field, including the optimization of patient selection for the procedure and what the reader can expect in the near future in this rapidly developing field.

Insulin Signaling Disruption and INF-γ Upregulation Induce Aß1-42 and Hyperphosphorylated-Tau Proteins Synthesis and Cell Death after Paraquat Treatment of Primary Hippocampal Cells.

Acute and long-term paraquat (PQ) exposure produces hippocampal neurodegeneration and cognition decline. Although some mechanisms involved in these effects were found, the rest are unknown. PQ treatment, for 1 and 14 days, upregulated interferon-gamma signaling, which reduced insulin levels and downregulated the insulin pathway through phosphorylated-c-Jun N-terminal-kinase upregulation, increasing glucose levels and the production of Aß1-42 and phosphorylated-tau, by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) overexpression and phosphorylated-GSK3ß (p-GSK3ß; ser9) level reduction, respectively, which induced primary hippocampal neuronal loss. This novel information on the PQ mechanisms leading to hippocampal neurodegeneration could help reveal the PQ actions that lead to cognition dysfunction.

Olive oil consumption is associated with lower frailty risk: a prospective cohort study of community-dwelling older adults.

BACKGROUND: There is no evidence on the specific beneficial association of the main types of olive oil consumption with frailty. OBJECTIVE: The aim was to assess the relationship between olive oil consumption and incident frailty in community-dwelling older adults. DESIGN: Prospective cohort. SETTING: Participants were recruited in 2008-10 and follow-up through 2013. SUBJECTS: In total, 1,896 older adults aged 60+. METHODS: At baseline, olive oil and other food consumption was collected using a validated dietary history. Incident frailty was defined as having at least three of the following five Fried-based criteria: low physical activity, fatigue, slow walking, muscle weakness and unintentional weight loss. Analyses were performed with logistic regression and adjusted for the major confounders. RESULTS: Over a mean follow-up of 3.5 years, 135 incident frailty cases were identified. The odds ratio (95% confidence interval) of frailty across sex-specific tertiles of total olive oil consumption (12.7, 20 and 30.8 g/day, respectively) were: 1 (ref.), 0.52 (0.32, 0.83) and 0.47 (0.29, 0.78), P trend 0.003. When differentiating by olive oil types, the results held for virgin but did not for common (refined) olive oil. CONCLUSION: The highest total olive oil consumption (~3 tablespoons), especially if virgin, was associated with half the risk of frailty as the lowest consumption (~1 tablespoon) among older adults. This study suggests that virgin olive oil should be the preferent culinary olive oil type for frailty prevention. If confirmed in other settings, small doses of virgin olive oil could be added as a simple geriatric nutritional advice on the prevention of frailty.

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.

High Consumption of Ultra-Processed Food is Associated with Incident Dyslipidemia: A Prospective Study of Older Adults.

BACKGROUND: Ultra-processed food (UPF) consumption has been associated with higher cardiovascular disease (CVD) and mortality risks. OBJECTIVES: The aim of this study was to assess the relationship between UPF consumption and incident dyslipidemia in older adults, where evidence is limited. METHODS: We studied a prospective cohort of 1082 community-dwelling adults in Spain, older than 60 (mean age, 68 ± 6 years old). Participants (52% were women) were recruited between 2008-10 and followed up to 2015. At baseline, food intake data were collected using a validated computerized face-to-face dietary history. UPFs were identified according to the nature and extent of their industrial processing (NOVA classification). Triglycerides, HDL cholesterol, and LDL cholesterol were measured in fasting plasma samples collected at baseline and at follow-up. Statistical analyses were performed with logistic regression adjusted for the main potential confounders. RESULTS: Among those free of corresponding dyslipidemia at baseline, and after a follow-up of between 5 to 7 years, 60 (out of 895) developed incident hypertriglyceridemia (≥150 mg/dL), 112 (out of 878) had low HDL cholesterol (<40 in men/<50 mg/dL in women), and 54 (out of 472) had high LDL cholesterol (>129 mg/dL). The mean percentage of UPF consumption was 19% ± 11% of total energy intake. Those in the highest versus the lowest tertile of energy intake from UPFs had more than twice the odds of incident hypertriglyceridemia (OR, 2.66; 95% CI: 1.20-5.90; P-trend, 0.011) or low HDL cholesterol (OR, 2.23; 95% CI: 1.22-4.05; P-trend, 0.012). UPF consumption was not associated with high LDL cholesterol plasma concentrations. CONCLUSIONS: Although UPF consumption in Spain was low among older adults, high consumption of UPFs was clearly associated with incident dyslipidemia. The increase in CVD risk recently found to be associated with UPF consumption might be mediated by these atherogenic lipid abnormalities.

Aryl Hydrocarbon Receptor Activation Produces Heat Shock Protein 90 and 70 Overexpression, Prostaglandin E2/Wnt/ß-Catenin Signaling Disruption, and Cell Proliferation in MCF-7 and MDA-MB-231 Cells after 24 h and 14 Days of Chlorpyrifos Treatment.

The biocide chlorpyrifos (CPF) was described to increase breast cancer risk in humans, to produce breast cancer in animals, and to induce cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment. The entire mechanisms related to these CPF actions remain unknown. CPF induced cell proliferation in MCF-7 and MDA-MB-231 cells after 1 and 14 days of treatment by AhR activation through the PGE2/Wnt/ß-catenin pathway and HSP90 and HSP70 overexpression. Our results reveal new information on CPF toxic mechanisms induced in human breast cancer cell lines, which could assist in elucidating its involvement in breast cancer.

Paraquat Treatment Compromises the Clearance of ß-Amyloid and Tau Proteins and Induces Primary Hippocampal Neuronal Cell Death through HSP70, P20S, and TFEB Disruption.

The herbicide paraquat (PQ) induces hippocampal neuronal cell loss and cognitive dysfunction after one and repeated treatment. All the mechanisms involved in these effects are not well understood. Single and repeated PQ treatment increased Aß and tau protein levels, through HSP70 and TFEB downregulation and proteasome 20S inhibition, producing cell death in primary hippocampal neurons associated with cognitive decline. Our results reveal the mechanisms through which PQ could induce the accumulation of abnormal proteins and neurodegeneration that could originate the cognitive decline produced by it and could help managing its degenerative effects.

Fried-Food Consumption Does Not Increase the Risk of Stroke in the Spanish Cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

BACKGROUND: The nutritional determinants of stroke and, more specifically, the association of frying with the risk of incident stroke have rarely been studied. OBJECTIVES: Our aim was to evaluate prospectively the association between the consumption of fried food and the risk of incident stroke in the European Prospective Investigation into Cancer and Nutrition study using the Spanish cohort. METHODS: Participants included 40,328 healthy adults (62% women) aged 29-69 y at study entry who were enrolled between 1992 and 1996. Participants were followed up until 31 December, 2017, at which time incident stroke (the main outcome) was measured. The main exposure measure was the percentage of energy obtained from fried-food consumption. Sex-specific quintiles were calculated. RESULTS: During a follow-up period of 23.5 y, 975 cases of stroke occurred (750 ischemic, 185 hemorrhagic, and 40 undetermined). Compared with those in the first (lowest) quintile of fried-food consumption, the multivariate HRs (95% CIs) of incident stroke in the consecutive quintiles were 1.05 (0.86, 1.30), 1.11 (0.90, 1.36), 1.05 (0.84, 1.31), and 0.91 (0.72, 1.15; P-trend = 0.45). There were no differences identified when subtypes of stroke were considered. CONCLUSIONS: In this Spanish cohort, whose participants mainly used olive oil or sunflower oil when frying, the consumption of fried food was not associated with an increased risk of incident stroke.

Manganese increases Aß and Tau protein levels through proteasome 20S and heat shock proteins 90 and 70 alteration, leading to SN56 cholinergic cell death following single and repeated treatment.

Manganese (Mn) produces cholinergic neuronal loss in basal forebrain (BF) region that was related to cognitive dysfunction induced after single and repeated Mn treatment. All processes that generate cholinergic neuronal loss in BF remain to be understood. Mn exposure may produce the reduction of BF cholinergic neurons by increasing amyloid beta (Aß) and phosphorylated Tau (pTau) protein levels, altering heat shock proteins' (HSPs) expression, disrupting proteasome P20S activity and generating oxidative stress. These mechanisms, described to be altered by Mn in regions different than BF, could lead to the memory and learning process alteration produced after Mn exposure. The research performed shows that single and repeated Mn treatment of SN56 cholinergic neurons from BF induces P20S inhibition, increases Aß and pTau protein levels, produces HSP90 and HSP70 proteins expression alteration, and oxidative stress generation, being the last two effects mediated by NRF2 pathway alteration. The increment of Aß and pTau protein levels was mediated by HSPs and proteasome dysfunction. All these mechanisms mediated the cell decline observed after Mn treatment. Our results are relevant because they may assist to reveal the processes leading to the neurotoxicity and cognitive alterations observed after Mn exposure.

Proteasome 20S and Rab5 Alteration after 24 h and 14 Days Chlorpyrifos Exposure Lead to ß-Amyloid and Tau Protein Level Increases and SN56 Neuronal Cell Death.

The biocide chlorpyrifos (CPF) was shown to produce cognition impairment following single and long-term exposure. The complete mechanisms that lead to the CPF induced cognitive disorders remain to be discovered. Aß and tau proteins production was induced in basal forebrain SN56 cholinergic cells, by CPF, through proteasome 20S inhibition and Rab5 overexpression, leading to cell death both after acute and repeated administration, which was related with cognitive disorders induction. The results obtained in our study procure novel information related to the mechanisms involved in CPF neurodegeneration, which could be responsible for cognitive dysfunction and may lead to a promising alternative treatment of these effects.

Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature.

PurposeC-type natriuretic peptide (CNP) and its principal receptor, natriuretic peptide receptor B (NPR-B), have been shown to be important in skeletal development. CNP and NPR-B are encoded by natriuretic peptide precursor-C (NPPC) and natriuretic peptide receptor 2 (NPR2) genes, respectively. While NPR2 mutations have been described in patients with skeletal dysplasias and idiopathic short stature (ISS), and several Npr2 and Nppc skeletal dysplasia mouse models exist, no mutations in NPPC have been described in patients to date.MethodsNPPC was screened in 668 patients (357 with disproportionate short stature and 311 with autosomal dominant ISS) and 29 additional ISS families in an ongoing whole-exome sequencing study.ResultsTwo heterozygous NPPC mutations, located in the highly conserved CNP ring, were identified. Both showed significant reductions in cyclic guanosine monophosphate synthesis, confirming their pathogenicity. Interestingly, one has been previously linked to skeletal abnormalities in the spontaneous Nppc mouse long-bone abnormality (lbab) mutant.ConclusionsOur results demonstrate, for the first time, that NPPC mutations cause autosomal dominant short stature in humans. The NPPC mutations cosegregated with a short stature and small hands phenotype. A CNP analog, which is currently in clinical trials for the treatment of achondroplasia, seems a promising therapeutic approach, since it directly replaces the defective protein.

FGF9 mutation causes craniosynostosis along with multiple synostoses.

Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF-mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next-generation sequencing, we identified a novel missense mutation in FGF9. Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow-knee-synostosis, Eks, with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses.

Two novel POC1A mutations in the primordial dwarfism, SOFT syndrome: Clinical homogeneity but also unreported malformations.

Primordial dwarfism encompasses rare conditions characterized by severe intrauterine growth retardation and growth deficiency throughout life. Recently, three POC1A mutations have been reported in six families with the primordial dwarfism, SOFT syndrome (Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis). Using a custom-designed Next-generation sequencing skeletal dysplasia panel, we have identified two novel homozygous POC1A mutations in two individuals with primordial dwarfism. The severe growth retardation and the facial profiles are strikingly similar between our patients and those described previously. However, one of our patients was diagnosed with severe foramen magnum stenosis and subglottic tracheal stenosis, malformations not previously associated with this syndrome. Our findings confirm that POC1A mutations cause SOFT syndrome and that mutations in this gene should be considered in patients with severe pre- and postnatal short stature, symmetric shortening of long bones, triangular facies, sparse hair and short, thickened distal phalanges.

Increased Levels of Phosphorylated-P38α Induce WNT/ß-Catenin and NGF/P75NTR/TrkA Pathways Disruption and SN56 Cell Death following Single and Repeated Chlorpyrifos Treatment.

Chlorpyrifos (CPF) biocide, exposure to which is mainly produced in the human population through diet, induces several neurotoxic effects. CPF single and repeated exposure induces memory and learning disorders, although the mechanisms that produce these outcomes are complex and not well understood. CPF treatment (single and repeated) of cholinergic septal SN56 cells induced an increase in phosphorylated-P38α levels that led to WNT/ß-Catenin and NGF/P75NTR/TrkA pathways disruption and cell death. These results provide new knowledge on the mechanisms that mediate CPF basal forebrain cholinergic neuronal loss induced by CPF single and repeated exposure and can help unravel the way through which this compound produces cognitive decline and develop efficient treatments against these effects.

Less Favorable Nutri-Score Consumption Ratings Are Prospectively Associated with Abdominal Obesity in Older Adults.

Nutri-Score is a front-of-package (FOP) labeling designed to assist consumers in selecting healthier options at the point of purchase and ultimately enhance their health. This study aims to evaluate the association between the Nutri-Score system and incident abdominal obesity (AO) in community-dwelling older adults. A prospective cohort of 628 individuals aged ≥ 60 were recruited in Spain between 2008-2010 and were reexamined between 2015-2017. Dietary intake was evaluated utilizing a validated computerized dietary history. Food was categorized based on the Nutri-Score system into five levels from A (green, representing the best quality) to E (red, representing the poorest quality). A five-color Nutri-Score dietary index (5-CNS DI) in g/day/kg was calculated for each participant. AO was determined by a waist circumference (WC) of ≥102 cm for men and ≥88 cm for women. Logistic regression models were adjusted for the main potential confounders. During a mean six-year follow-up, 184 incident cases of AO occurred. The odds ratio (OR) and 95% confidence interval (CI) for AO, when comparing the highest and lowest quartiles of the 5-CNS DI, were 2.45 (1.17-5.14), with a p-value for trend of 0.035. In sensitivity analyses, the OR was 2.59 (1.22-5.52, p-trend: 0.032) after adjustment for WC at baseline, and 1.75 (0.74-4.18, p-trend: 0.316) after adjustment for ultra-processed food consumption. In conclusion, less favorable food-consumption ratings in the Nutri-Score are associated with incident AO in the elderly. These findings support the use of this FOP system to potentially improve metabolic health.

Off-label Use of Oral Immunotherapy for Rhinoconjunctivitis and Asthma due to Grass Pollen: A Safe and Effective Alternative in Patients over 65 Years Old: A Series of Case Reports.

INTRODUCTION: Allergic rhinoconjunctivitis and asthma are the most common IgE-mediated diseases worldwide. Allergen-specific immunotherapy (AIT) is currently the only modifying treatment for these IgE-mediated diseases in both children and adults. Subcutaneous immunotherapy is widely used, but in patients over 65 years old, there may be an increased risk of adverse reactions and a worse response to treatment. Oral immunotherapy (OIT) has been proven to be effective and safe, but currently, in most countries, it has been licensed only for patients up to 65 years old based on its technical datasheet. So far, no studies on the efficacy and safety of this type of immunotherapy in patients older than 65 years old have been published. CASE PRESENTATION: We present four patients older than 65 years old with a diagnosis of moderate seasonal rhinoconjunctivitis and moderate-persistent seasonal pollen-induced asthma. Off-label use of oral immunotherapy (OIT) for grass pollen was prescribed due to the severity of their rhinoconjunctivitis symptoms and the worsening of asthma symptoms during the spring. Improvement in the rhinoconjunctivitis and asthma symptoms was reported by all patients since the first spring season and was maintained during the following two years of follow-up. There were no systemic reactions, and only two patients initially had self-limiting oral pruritus. CONCLUSION: Oral immunotherapy for pollens appears to be a convenient, effective, and safe option in older patients (>65 years) with comorbidities after a three-year treatment. This is, to the best of our knowledge, the first report on the off-label use of OIT in patients over 65 years old with symptoms of allergic rhinoconjunctivitis and asthma.