Nutrition and stem cell integrity in aging.

Adult stem cells (SCs) represent the regenerative capacity of organisms throughout their lifespan. The maintenance of robust SC populations capable of renewing organs and physiological systems is one hallmark of healthy aging. The local environment of SCs, referred to as the niche, includes the nutritional milieu, which is essential to maintain the quantity and quality of SCs available for renewal and regeneration. There is increased recognition that SCs have unique metabolism and conditional nutrient needs compared to fully differentiated cells. However, the contribution of SC nutrition to overall human nutritional requirements is an understudied and underappreciated area of investigation. Nutrient needs vary across the lifespan and are modified by many factors including individual health, disease, physiological states including pregnancy, age, sex, and during recovery from injury. Although current nutrition guidance is generally derived for apparently healthy populations and to prevent nutritional deficiency diseases, there are increased efforts to establish nutrient-based and food-based recommendations based on reducing chronic disease. Understanding the dynamics of SC nutritional needs throughout the life span, including the role of nutrition in extending biological age by blunting biological systems decay, is fundamental to establishing food and nutrient guidance for chronic disease reduction and health maintenance. This review summarizes a 3-day symposium of the Marabou Foundation (www.marabousymposium.org) held to examine the metabolic properties and unique nutritional needs of adult SCs and their role in healthy aging and age-related chronic disease.

Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia.

AIM: To investigate whether genotyping could be used as a cost-effective screening step, preceding next-generation sequencing (NGS), in molecular diagnosis of familial hypercholesterolaemia (FH) in Swedish patients. METHODS AND RESULTS: Three hundred patients of Swedish origin with clinical suspicion of heterozygous FH were analysed using a specific array genotyping panel embedding 112 FH-causing mutations in the LDLR, APOB and PCSK9 genes. The mutations had been selected from previous reports on FH patients in Scandinavia and Finland. Mutation-negative cases were further analysed by NGS. In 181 patients with probable or definite FH using the Dutch lipid clinics network (DLCN) criteria (score ≥ 6), a causative mutation was identified in 116 (64%). Of these, 94 (81%) were detected by genotyping. Ten mutations accounted for more than 50% of the positive cases, with APOB c.10580G>A being the most common. Mutations in LDLR predominated, with (c.2311+1_2312-1)(2514)del (FH Helsinki) and c.259T>G having the highest frequency. Two novel LDLR mutations were identified. In patients with DLCN score < 6, mutation detection rate was significantly higher at younger age. CONCLUSION: A limited number of mutations explain a major fraction of FH cases in Sweden. Combination of selective genotyping and NGS facilitates the clinical challenge of cost-effective genetic screening in suspected FH. The frequency of APOB c.10580G>A was higher than previously reported in Sweden. The lack of demonstrable mutations in the LDLR, APOB and PCSK9 genes in ~1/3 of patients with probable FH strongly suggests that additional genetic mechanisms are to be found in phenotypic FH.

Regulation of bile acid metabolism in biliary atresia: reduction of FGF19 by Kasai portoenterostomy and possible relation to early outcome.

BACKGROUND: Fibroblast growth factor 19 (FGF19) is produced in the small intestine and is involved in suppression of hepatic bile acid (BA) synthesis. FGF19 is also expressed in the liver and serum levels are elevated in adults with cholestatic liver disease. This may reflect a rescue mechanism to dampen liver injury caused by increased intrahepatic BAs. OBJECTIVES: To examine circulating FGF19 at early stages of biliary atresia and at short-term follow-up post-Kasai portoenterostomy (KPE) in relation to noncholestatic infants. The relationship between FGF19, BAs and markers for BA synthesis and hepatic gene expression of factors involved in BA metabolism were also evaluated. METHODS: Liver tissue, portal and peripheral blood samples were obtained from fifteen patients at KPE; additional blood was collected 4-6 months after surgery. Two control groups were included; to examine possible changes related to surgery and to compare FGF19 in biliary atresia to noncholestatic infants. RESULTS: Circulating FGF19 levels correlated to its hepatic gene expression at time of KPE in biliary atresia and levels were elevated compared to noncholestatic infants. At follow-up, FGF19 levels were markedly reduced, and the decline coincided with reductions in bilirubin and conjugated chenodeoxycholic acid and with increased levels of the BA synthesis marker C4. CONCLUSION: Elevated circulating FGF19 in biliary atresia is of hepatic origin and reduced following KPE. Changes in serum FGF19 may reflect the level of restoration of the enterohepatic circulation, and this warrants further long-term studies on the role of FGF19 in the cholestatic liver.

Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.

BACKGROUND AND OBJECTIVES: Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS: Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS: Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS: Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.

Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C-III.

BACKGROUND: The natural farnesoid X receptor (FXR) agonist chenodeoxycholic acid (CDCA) suppresses hepatic cholesterol and bile acid synthesis and reduces biliary cholesterol secretion and triglyceride production. Animal studies have shown that bile acids downregulate hepatic LDL receptors (LDLRs); however, information on LDL metabolism in humans is limited. METHODS: Kinetics of autologous 125 I-LDL were determined in 12 male subjects at baseline and during treatment with CDCA (15 mg kg-1 day-1 ). In seven patients with gallstones treated with CDCA for 3 weeks before cholecystectomy, liver biopsies were collected and analysed for enzyme activities and for specific LDLR binding. Serum samples obtained before treatment and at surgery were analysed for markers of lipid metabolism, lipoproteins and the LDLR modulator proprotein convertase subtilisin/kexin type 9 (PCSK9). RESULTS: Chenodeoxycholic acid treatment increased plasma LDL cholesterol by ~10% as a result of reduced clearance of plasma LDL-apolipoprotein (apo)B; LDL production was somewhat reduced. The reduction in LDL clearance occurred within 1 day after initiation of treatment. In CDCA-treated patients with gallstones, hepatic microsomal cholesterol 7α-hydroxylase and HMG-CoA reductase activities were reduced by 83% and 54%, respectively, and specific LDLR binding was reduced by 20%. During treatment, serum levels of fibroblast growth factor 19 and total and LDL cholesterol increased, whereas levels of 7α-hydroxy-4-cholesten-3-one, lathosterol, PCSK9, apoA-I, apoC-III, lipoprotein(a), triglycerides and insulin were reduced. CONCLUSIONS: Chenodeoxycholic acid has a broad influence on lipid metabolism, including reducing plasma clearance of LDL. The reduction in circulating PCSK9 may dampen its effect on hepatic LDLRs and plasma LDL cholesterol. Further studies of the effects of other FXR agonists on cholesterol metabolism in humans seem warranted, considering the renewed interest for such therapy in liver disease and diabetes.

Mental distress in treatment seeking young adults (18-25 years) with severe obesity compared with population controls of different body mass index levels: cohort study.

Young adults (18-25) with severe obesity constitute a challenging patient group, and there is limited evidence about their mental health status compared to population controls. Mental distress in treatment seeking young adults with severe obesity (n = 121, mean body mass index [BMI] = 39.8 kg m-2 ) was compared with matched (1:3 for age, gender and socioeconomic status) population controls of normal weight (n = 363, mean BMI = 22.4 kg m-2 ), as well as unmatched population controls with class I obesity (n = 105, mean BMI = 32.1 kg m-2 ) or severe obesity (n = 41, mean BMI = 39.7 kg m-2 ). Mental distress was measured by the General Health Questionnaire-12 (GHQ-12), and we quantified physician-diagnosed depression, present anxiety and suicide attempts. Poisson regression and linear regression analysis were used for analysing differences in mental distress between groups. Treatment seekers experienced more mental distress than normal weight controls as measured by continuous (adjusted mean: 3.9 vs. 2.2 points, P <0.001) and categorical (cut-off for mental distress ≥3 points, RR: 1.76, P <0.001) GHQ-12 scores, depression (RR: 2.18, P < 0.001), anxiety (RR: 1.97, P < 0.001) and suicide attempts (RR: 2.04; P = 0.034). Treatment seekers also experienced more mental distress as measured by continuous GHQ-12 than controls with class I obesity (adjusted mean: 2.3 points) or severe obesity (adjusted mean: 2.1; both, P < 0.001). Young adult treatment seekers with severe obesity constitute a risk group for mental distress compared to population controls of different BMI levels.

Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels.

BACKGROUND: Elevated LDL cholesterol is an important risk factor for atherosclerosis. Endothelial dysfunction, an early event in the development of atherosclerosis, is characterized by a reduction in nitric oxide (NO) bioavailability. Arginase has emerged as a key regulator of endothelial function through competition with NO synthase for the common substrate l-arginine. Arginase in endothelial cells is activated by oxidized LDL. The study aim was to investigate the importance of arginase for endothelial dysfunction in patients with familial hypercholesterolaemia (FH). METHODS AND RESULTS: Endothelial function was evaluated in 12 patients with heterozygous FH and 12 age-matched healthy normocholesterolaemic subjects using forearm venous occlusion plethysmography. The evaluations in FH patients occurred when they were on lipid-lowering therapy and 4 weeks after withdrawal of treatment. Endothelium-dependent vasodilatation (EDV) was assessed by intrabrachial artery infusion of serotonin, and endothelium-independent dilatation was assessed by infusion of nitroprusside before and after 120 min administration of the arginase inhibitor N (ω) -hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg min(-1)). In FH patients LDL cholesterol increased from 4.3 ± 0.9 mmol L(-1) at baseline to 7.6 ± 1.9 mmol L(-1) at follow-up (P < 0.001). Arginase inhibition enhanced EDV in FH patients by a similar degree independent of lipid-lowering therapy. The improvement in EDV by arginase inhibition was significantly greater in FH patients than in the control group. CONCLUSION: Arginase inhibition results in greater improvement in endothelial function in patients with FH compared to healthy controls irrespective of their cholesterol levels. Arginase may be a promising therapeutic target for improving endothelial function in patients with hypercholesterolaemia.

Diagnóstico prenatal de las cardiopatías congénitas / Prenatal diagnosis of congenital heart diseases

El desarrollo de la ecocardiografía fetal en los últimos años ha convertido a esta técnica en la principal modalidad para el diagnóstico y abordaje prenatal de la patología cardiaca fetal. El ecocardiograma nos permite diagnosticar la existencia de problemas estructurales, además de inferir e! mecanismo e!ectrofisiológico de las arritmia s fetales, así como la necesidad de iniciar el tratamiento médico en caso de ser este necesario. En esta monografía se presentan los resultados acaecidos en nuestro centro en los últimos 11 años. Se realizaron en la Sección de Cardiología Pediátrica de nuestro centro 6.246 ecocardiografías fetales. La edad materna fue 31 +/- 5 años y la edad gestacional en e! momento de la prueba de imagen de 24 +/- 5 semanas. Se detectaron un total 317 cardiopatías congénitas lo que representa un 5,07% de todas las exploraciones. Las cardiopatías congénitas diagnostícadas más frecuentementediagnosticadas fueron la comunicación interventricular ICIV) en un 31,5% de los casos, seguida de la tetralogía de Fallot en un 13,8% de los casos y de! síndrome de corazón izquierdo hipoplásico con un 13,5% de los casos. En conclusión la ecocardiografía fetal permite e! diagnóstico preciso de la mayor parte de las cardiopatías congénitas permitiendo realizar un diagnóstico preciso, establecer el pronóstico y preparar la estrategia adecuada (AU)

The development of the fetal echocardiography in recent years has con verted this technique in the main modality for prenatal diagnosis and approach of fetal heart disease. The echocardiogram allows us to diagnose the existence of structural problems and to deduce the e!ectrophysiological mechanism of fetal arrhythmias as well as the need to initiate medical treatment if necessary. The results occurring in our center in the last 11 years in are presented in this monograph. A total of 6246 fetal echocardiographies were performed in the pediatric cardiology section of our center. Maternal age was 31 +/- 5 years and gestational age at the time of the imaging test was 24 +/- 5 weeks. A total of 317 congenital heart diseases were detected, this representing 5.07% of all the studies. The congenital Heart diseases most frequently diagnosed were interventricular communication in 31.5% of the cases followed by Fallot's Tetralogy in 13.8% of the cases and hypoplastic left heart syndrome accounting for 13.5% of the cases. In conclusion, fetal echocardiography permits the precise diagnosis of most of the congenital heart diseases, making it possible to perform an exact diagnosis, establish the prognosis and prepare the adequate strategy (AU)

Taponamiento cardiaco atípico por reservorio venoso central. ¿Podemos prevenirlo? / Atypical cardiac tamponade due to central venous catheter. Can we prevent it?

No disponible

Influence of growth hormone on circulating fibroblast growth factor 21 levels in humans.

OBJECTIVE: Findings from animal studies indicate that growth hormone (GH) may stimulate the production of the putative metabolic regulator fibroblast growth factor 21 (FGF21). We investigated whether circulating FGF21 levels are altered in patients with GH deficiency and characterized how levels of this growth factor are influenced by acute and long-term administration of GH, and the potential relationship between FGF21 and nonesterified fatty acids (NEFAs). DESIGN AND SETTING: GH-deficient patients (n = 9) were studied prior to and during 1 year of replacement with GH. Healthy subjects (n = 8) received an intravenous bolus of GH with or without concomitant oral glucose. Healthy subjects and patients with heterozygous familial hypercholesterolaemia (n = 23) were monitored following increasing doses of GH for 3 weeks. The main outcome measures were serum FGF21 and NEFA levels. Studies were performed at two academic centres. RESULTS: GH-deficient patients had FGF21 levels within the normal range, and GH replacement did not influence circulating FGF21 or NEFA concentrations. Acute GH administration to healthy control subjects did not change FGF21 levels, whereas an oral glucose load increased serum FGF21 by 25% and reduced NEFA levels by 48%. Similar effects were seen on administration of glucose together with GH. However, FGF21 levels increased dose dependently up to 3.7-fold in control subjects treated with GH for 3 weeks; simultaneously NEFA levels were increased by 47%. CONCLUSIONS: GH is not critical for the maintenance of basal serum FGF21 levels in humans, but circulating FGF21 levels increase following administration of GH to healthy individuals. There is no correlation between plasma NEFA and circulating FGF21 levels.

Pronounced variation in bile acid synthesis in humans is related to gender, hypertriglyceridaemia and circulating levels of fibroblast growth factor 19.

BACKGROUND: Bile acid (BA) synthesis is essential in cholesterol and lipid homoeostasis. METHODS: Serum samples from 435 normal and 23 cholecystectomized subjects were obtained after overnight fasting and assayed for markers of BA and cholesterol synthesis, as well as cholesterol absorption. We determined whether BA synthesis was related to fibroblast growth factor 19 (FGF19; a circulating metabolic regulator that is thought to inhibit BA synthesis), gender, age and serum lipids. RESULTS: Bile acid synthesis varied more than 9-fold in normal individuals and was 29% higher in men than in women. Whilst low-density lipoprotein cholesterol increased with age, BA and cholesterol synthesis were stable. BA production was positively correlated with serum triglycerides (TGs), and 35% of individuals with a high level (>95th percentile) of BA synthesis had hypertriglyceridaemia (HTG) (>95th percentile). Serum FGF19 levels varied by 7-fold in normal individuals and were related inversely to BA synthesis but were not related to gender, plasma lipids or history of cholecystectomy. CONCLUSIONS: Bile acid synthesis has a wide inter-individual variation, is lower in women than in men and is correlated positively with serum TGs. High BA production is frequently linked to HTG. Age-related hypercholesterolaemia is not associated with changes in BA or cholesterol production, nor to an increase in cholesterol absorption. In humans, the circulating level of FGF19 may regulate hepatic BA production under fasting conditions.

Enfermedad de Chagas congénita. Tratamiento en el primer año de vida / Congenital Chagas. Treatment in the first year of life

Describimos el caso de una niña con enfermedad de Chagas congénita. Su diagnóstico se realizó a los 8 meses de edad por persistencia de la serología positiva, ya que no estaba disponible la reacción en cadena de la polimerasa (PCR) para esta enfermedad al nacimiento. Se trató a la paciente con benznidazol durante 60 días, sin que presentara reacciones adversas ni toxicidad. La serología disminuyó tras el tratamiento. Es importante detectar estos casos pediátricos lo antes posible. Para ello, debe realizarse un cribado de serología a Chagas en mujeres gestantes procedentes de áreas endémicas que emigran a Europa y, si es positiva, realizar una PCR y una serología en el niño (AU)

We present the case of a child affected by congenital Chagas disease. Her serology’s for the detection of Chagas persisted positive and she was diagnosed and treated at the age of 8 months. Chagas PCR was not available. She was treated with benznidazole for 60 days, without secondary effects or toxicity. After treatment her serologies decreased. It is important to detect these children as soon as possible. That is the reason why Chagas screening tests should be performed in pregnant women who come from endemic areas and emigrate to European countries and if it is positive, to do a PCR and serological tests to the child (AU)

Control of ACAT2 liver expression by HNF4{alpha}: lesson from MODY1 patients.

OBJECTIVE: ACAT2 is thought to be responsible for cholesteryl ester production in chylomicron and VLDL assembly. Recently, we identified HNF1alpha as an important regulator of the human ACAT2 promoter. Thus, we hypothesized that MODY3 (HNF1alpha gene mutations) and possibly MODY1 (HNF4alpha, upstream regulator of HNF1alpha, gene mutations) subjects may have lower VLDL esterified cholesterol. METHODS AND RESULTS: Serum analysis and lipoprotein separation using size-exclusion chromatography were performed in controls and MODY1 and MODY3 subjects. In vitro analyses included mutagenesis and cotransfections in HuH7 cells. Finally, the relevance in vivo of these findings was tested by ChIP assays in human liver. Whereas patients with MODY3 had normal lipoprotein composition, those with MODY1 had lower levels of VLDL and LDL esterified cholesterol, as well as of VLDL triglyceride. Mutagenesis revealed one important HNF4 binding site in the human ACAT2 promoter. ChIP assays and protein-to-protein interaction studies showed that HNF4alpha, directly or indirectly (via HNF1alpha), can bind to the ACAT2 promoter. CONCLUSIONS: We identified HNF4alpha as an important regulator of the hepatocyte-specific expression of the human ACAT2 promoter. Our results suggest that the lower levels of esterified cholesterol in VLDL- and LDL-particles in patients with MODY1 may-at least in part-be attributable to lower ACAT2 activity in these patients.

Dyslipidaemia and lipoprotein pattern in systemic lupus erythematosus (SLE) and SLE-related cardiovascular disease.

OBJECTIVE: This study focused on lipoprotein composition and properties in systemic lupus erythematosus (SLE). METHODS: The size distribution of plasma lipoproteins was studied by nuclear magnetic resonance (NMR). Cholesteryl ester transfer protein (CETP) activity was determined by enzyme-linked immunosorbent assay (ELISA). The affinity of low density lipoprotein (LDL) for proteoglycans was assayed. Twenty-six women (aged 52+/-8.2 years) with SLE and a history of cardiovascular disease (CVD) (SLE cases) were compared with 26 age-matched women with SLE and without CVD (SLE controls) and 26 age-matched population-based control women (controls). RESULTS: Very low density lipoprotein (VLDL) particles (nmol/L) were more prevalent among SLE cases than SLE controls (0.039) and tended to be more common in SLE cases than in controls (p = 0.073). By contrast, high density lipoprotein (HDL) particles (nmol/L) were more prevalent among controls than SLE cases (p = 0.024) whereas the number of LDL particles (nmol/L) did not differ significantly. Small dense (sd)LDL (nmol/L) were more common in controls and tended to be more common in SLE cases than in SLE controls (p = 0.036 and 0.086, respectively). Small high density lipoproteins (sHDL) (nmol/L) were more prevalent in controls than in SLE controls and SLE cases (p = 0.002 and p<0.001, respectively). VLDL or LDL size (nm) did not differ significantly between groups (data not shown) whereas HDL size (nm) was increased among SLE controls as compared to controls (p = 0.024) and tended to be increased among SLE cases as compared to controls (p = 0.070). The affinity of LDL for proteoglycans or CETP activity did not differ between groups (data not shown). CONCLUSIONS: sdLDL was not increased and SLE cases and SLE controls had decreased levels of sHDL. VLDL differentiates between SLE cases and SLE controls. The lipid pattern in SLE-related CVD was thus not similar to the pattern seen in diabetes or in CVD in general.

Diabetes MODY. Una causa frecuente de hiperglucemia / Maturity onset diabetes of the young (MODY)

La hiperglucemia es un motivo cada vez más frecuente de consulta en pediatría. Su enfoque diagnóstico depende del contexto en el que se encuentre. Bajo la denominación de diabetes se incluyen numerosas entidades clínicas distintas. La diabetes tipo MODY (maturity onset diabetes of the young) es, tras la diabetes tipo 1, el tipo de diabetes más frecuente en la infancia. Para su diagnóstico es necesario un alto índice de sospecha, y es fundamental tener en cuenta la historia familiar (AU)

Hyperglycemia is an increasing cause of consultation in Paediatrics. Diagnosis depends on the context. Under the name of diabetes numerous clinical entities are included. MODY (maturity onset diabetes of the young) is, after type 1 diabetes, the most frequent cause of diabetes in childhood. For its diagnosis, a high degree of suspicion is needed and we have to be aware of the family history (AU)