A Multi-Gene Panel to Identify Lipedema-Predisposing Genetic Variants by a Next-Generation Sequencing Strategy.

Lipedema is a disabling disease characterized by symmetric enlargement of the lower and/or upper limbs due to deposits of subcutaneous fat, that is easily misdiagnosed. Lipedema can be primary or syndromic, and can be the main feature of phenotypically overlapping disorders. The aim of this study was to design a next-generation sequencing (NGS) panel to help in the diagnosis of lipedema by identifying genes specific for lipedema but also genes for overlapping diseases, and targets for tailored treatments. We developed an NGS gene panel consisting of 305 genes potentially associated with lipedema and putative overlapping diseases relevant to lipedema. The genomes of 162 Italian and American patients with lipedema were sequenced. Twenty-one deleterious variants, according to 3 out of 5 predictors, were detected in PLIN1, LIPE, ALDH18A1, PPARG, GHR, INSR, RYR1, NPC1, POMC, NR0B2, GCKR, PPARA in 17 patients. This extended NGS-based approach has identified a number of gene variants that may be important in the diagnosis of lipedema, that may affect the phenotypic presentation of lipedema or that may cause disorders that could be confused with lipedema. This tool may be important for the diagnosis and treatment of people with pathologic subcutaneous fat tissue accumulation.

Gut Microbiota and Cardiovascular Diseases: A Critical Review.

The human intestine contains the largest and most diverse ecosystem of microbes. The main function of the intestinal bacterial flora is to limit the growth of potentially pathogenic microorganisms. However, the intestinal microbiota is increasingly emerging as a risk factor for the development of cardiovascular disease (CVD). The gut microbiota-derived metabolites, such as short-chain fatty acids, trimethylamine-N-oxide, bile acids, and polyphenols play a pivotal role in maintaining healthy cardiovascular function, and when dysregulated, can potentially lead to CVD. In particular, changes in the composition and diversity of gut microbiota, known as dysbiosis, have been associated with atherosclerosis, hypertension, and heart failure. Nonetheless, the underlying mechanisms remain yet to be fully understood. Therefore, the microbiota and its metabolites have become a new therapeutic target for the prevention and treatment of CVD. In addition to a varied and balanced diet, the use of prebiotic and probiotic treatments or selective trimethylamine-N-oxide inhibitors could play a pivotal role in the prevention of CVD, especially in patients with a high metabolic risk.

Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases.

Neurological disorders like Parkinson disease and Alzheimer disease, spinal cord injury and stroke have some recurrent characteristics such as abnormal protein aggregation, oxidative stress induction, apoptosis, excitotoxicity, perturbation of intracellular Ca2+ homeostasis and inflammation. To date, there are few effective treatments available and the drugs currently used to manage the symptoms have important side effects. Therefore, research studies are focusing on natural phytochemicals present in diet as bioactive molecules potentially useful against neurodegenerative diseases. In this review, we will discuss the neuroprotective role of palmitoylethanolamide, hydroxytyrosol, and Bacopa monnieri extracts against neuroinflammation and neurodegeneration, thereby revealing their remarkable potential as novel therapeutic options for the treatment of neurodegenerative disorders.

Genetic test for the prescription of diets in support of physical activity.

Owing to the fields of nutrigenetics and nutrigenomics today we can think of devising approaches to optimize health, delay onset of diseases and reduce its severity according to our genetic blue print. However this requires a deep understanding of nutritional impact on expression of genes that may result in a specific phenotype. The extensive research and observational studies during last two decades reporting interactions between genes, diet and physical activity suggest a cross talk between various genetic and environmental factors and lifestyle interventions. Although considerable efforts have been made in unraveling the mechanisms of gene-diet interactions the scientific evidences behind developing commercial genetic tests for providing personalized nutrition recommendations are still scarce. In this scenario the current mini-review aims to provide useful insights into salient feature of nutrition based genetic research and its commercial application and the ethical issue and concerns related to its outcome.

Segregation Analysis of Rare NRP1 and NRP2 Variants in Families with Lymphedema.

Neuropilins are transmembrane coreceptors expressed by endothelial cells and neurons. NRP1 and NRP2 bind a variety of ligands, by which they trigger cell signaling, and are important in the development of lymphatic valves and lymphatic capillaries, respectively. This study focuses on identifying rare variants in the NRP1 and NRP2 genes that could be linked to the development of lymphatic malformations in patients diagnosed with lymphedema. Two hundred and thirty-five Italian lymphedema patients, who tested negative for variants in known lymphedema genes, were screened for variants in NRP1 and NRP2. Two probands carried variants in NRP1 and four in NRP2. The variants of both genes segregated with lymphedema in familial cases. Although further functional and biochemical studies are needed to clarify their involvement with lymphedema and to associate NRP1 and NRP2 with lymphedema, we suggest that it is worthwhile also screening lymphedema patients for these two new candidate genes.

Mutations in the ARAP3 Gene in Three Families with Primary Lymphedema Negative for Mutations in Known Lymphedema-Associated Genes.

BACKGROUND: ARAP3 is a small GTPase-activating protein regulator, which has important functions in lymphatic vessel organogenesis and modulation of cell adhesion and migration. Mutations in the ARAP3 gene are associated with impaired lymphatic vessel formation. OBJECTIVE: The aim of our study was to determine the genotypes of lymphedema patients in relation to variants in the ARAP3 gene in order to explore its role in the development of lymphedema. METHODS AND RESULTS: We applied next-generation sequencing to DNA samples of a cohort of 246 Italian patients with lymphatic malformations. When we tested probands for known lymphedema genes, 235 out of 246 were negative. Retrospectively, we tested the DNA of these 235 patients for new candidate lymphedema-associated genes, including ARAP3. Three out of 235 probands proved to carry rare missense heterozygous variants in ARAP3. In the case of two families, other family members were also tested and proved negative for the ARAP3 variant, besides being unaffected by lymphedema. According to in silico analysis, alterations due to these variants have a significant impact on the overall structure and stability of the resulting proteins. CONCLUSIONS: Based on our results, we propose that variants in ARAP3 could be included in genetic testing for lymphedema.

Monogenic hyperlipidemias.

Monogenic hyperlipidemias are a group of inherited disorders characterized by elevated plasma concentrations of lipids and lipoproteins. High plasma concentrations of lipids are the most frequent risk factor for cardiovascular disease. Monogenic hyperlipidemias are a minor cause with respect to multifactorial hyperlipidemias. Diagnosis is based on clinical findings and lipid panel measurements. Genetic testing is useful for confirming diagnosis and for differential diagnosis, recurrence risk calculation and prenatal diagnosis in families with a known mutation. Monogenic hyperlipidemias can have either autosomal dominant or recessive inheritance.

Mendelian non-syndromic obesity.

Obesity is highly heritable and arises from the interplay of many genes and environmental factors. It can be defined as the result of prolonged imbalance between calorie intake and energy utilization. About 5% of cases of non-syndromic obesity are monogenic (Mendelian obesity). The amount of adipose tissue in the body is mainly regulated by leptin, a hormone produced by adipocytes, and Mendelian obesity is mainly caused by mutations that disrupt the leptin/melanocortin pathway. In this article, we summarize the genes involved in genetic obesity and the test we use for genetic analysis.

Genetic syndromes with localized subcutaneous fat tissue accumulation.

Syndromes with localized accumulation of subcutaneous fatty tissue belong to a group of genetically and phenotypically heterogeneous disorders. These diseases may show some common signs, such as nodular fat, symmetrical fat masses, obesity, fatigue, lymphedema and symmetrical lipomas (painful or otherwise). Other symptoms may be specific for the different clinical entities, enabling correct differential diagnosis. Disorders belonging to this spectrum are lipedema, generalized diffuse or nodular forms of Dercum disease, localized nodular Dercum disease and multiple symmetric lipomatosis. Here we summarize the genes involved in syndromes with localized accumulation of subcutaneous fat and the test we use for genetic analysis.

May nutritional status worsen during hospital stay? A sub-group analysis from a cross-sectional study.

Hospital malnutrition is a detrimental prognostic factor regarding hospital mortality, complications, and length of stay. However, the role of hospitalization itself on nutritional status has not been fully elucidated. We report the results of a secondary analysis from the dataset of a recent cross-sectional study at Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Data from patients evaluated at admission and discharge were collected and compared. One hundred thirty-nine patients were evaluated. Mean length of stay was 13.6 (± 7.7) days. Patients at risk of malnutrition, according to NRS-2002, were 75 (53.9%), while 63 (45.3%) were malnourished according to ESPEN Criteria. Compared to admission, at discharge, patients reported a significant decrease in Mid-Upper Arm Circumference (MUAC)-from 26.5 cm (± 3.6) to 25.9 cm (± 3.7) (p = 0.016), a reduction in Phase angle (PhA)-from 4.25° (± 1.20) to 4.01° (± 1.15) (p = 0.005), fat-free mass (FFM)-from 47.5 kg (± 9.19) to 44.9 kg (± 9.4) (p = 0.03) and fat-free mass index (FFMI)-from 16.9 kg/m2 (± 2.3) to 15.8 kg/m2 (± 2.7) (p = 0.04). Laboratory data showed a reduction of albumin-from 29.2 (± 5.7) to 28.0 (± 5.9) (p = 0.01) and Onodera's PNI- from 29.1 (± 5.6) to 27.6 kg (± 5.6) (p = 0.039). At the multivariate linear regression analysis, the variables significantly associated with a worsening of PhA at discharge are the PhA value at admission and the diagnosis of malnutrition according to ESPEN Criteria. Hospitalization leads to significative changes in nutritional status. A clinical concern should be raised about the quality of hospital food and meal times and on the need for a clinical nutritionist on the ward.

Predictors of weight loss and reversal of comorbidities in malabsorptive bariatric surgery.

BACKGROUND: Cardiovascular and metabolic comorbidities are dramatically increased in severe obesity, a condition highly resistant to nonsurgical therapy. OBJECTIVE: The objective was to identify predictors of weight loss and reversal of comorbidity in obese patients undergoing malabsorptive bariatric surgery. DESIGN: Morbidly obese men and women (n = 107) were studied before and 2 y after biliopancreatic diversion (BPD). Body composition, serum lipid profile, oral glucose tolerance, and blood pressure were measured. Insulin sensitivity was determined by use of a euglycemic clamp. The length of the small intestine was measured during surgery. RESULTS: Intestinal length was 671 +/- 99 cm, and the residual absorbing intestine after BPD ranged from 54% to 24% of initial length. Patients lost an average of 36% of their initial weight, with approximately 50% of them reaching a body mass index (in kg/m(2)) < 30. Serum cholesterol decreased (from 4.58 +/- 1.11 to 3.34 +/- 0.73 mmol/L; P < 0.0001), as did serum triacylglycerols (from 1.52 +/- 0.59 to 0.88 +/- 0.35 mmol/L; P < 0.0001), whereas insulin sensitivity rose 150% (from 26 +/- 4 to 64 +/- 11 micromol . min(-1) . kg fat-free mass(-1); P < 0.0001). Diabetes (in 23% of patients before surgery) and hypertension (in 83%) were reduced (by 88% and 96%, respectively) after surgery. In a multivariate model (including sex, age, intestinal length, presence of diabetes, insulin sensitivity, and initial fat mass), age and diabetes were independent, negative predictors of weight loss, whereas initial fat mass was a strong positive predictor (r(2) = 0.51). CONCLUSIONS: Two years after BPD in morbidly obese patients, comorbidities are largely corrected and insulin resistance is fully reversed despite persistent obesity. Initial fat mass, but not residual intestinal length, is the strongest predictor of weight loss after BPD.