Gut microbiota markers in obese adolescent and adult patients: Age-dependent differential patterns

Obesity levels, especially in children, have dramatically increased over the last few decades. Recently, several studies highlighted the involvement of gut microbiota in the pathophysiology of obesity. We investigated the composition of gut microbiota in obese adolescents and adults compared to age-matched normal weight (NW) volunteers in order to assemble age- and obesity-related microbiota profiles. The composition of gut microbiota was analyzed by 16S rRNA-based metagenomics. Ecological representations of microbial communities were computed, and univariate, multivariate, and correlation analyses performed on bacterial profiles. The prediction of metagenome functional content from 16S rRNA gene surveys was carried out. Ecological analyses revealed a dissimilarity among the subgroups, and resultant microbiota profiles differed between obese adolescents and adults. Using statistical analyses, we assigned, as microbial markers, Faecalibacterium prausnitzii and Actinomyces to the microbiota of obese adolescents, and Parabacteroides, Rikenellaceae, Bacteroides caccae, Barnesiellaceae, and Oscillospira to the microbiota of NW adolescents. The predicted metabolic profiles resulted different in adolescent groups. Particularly, biosynthesis of primary bile acid and steroid acids, metabolism of fructose, mannose, galactose, butanoate, and pentose phosphate and glycolysis/gluconeogenesis were for the majority associated to obese, while biosynthesis and metabolism of glycan, biosynthesis of secondary bile acid, metabolism of steroid hormone and lipoic acid were associated to NW adolescents. Our study revealed unique features of gut microbiota in terms of ecological patterns, microbial composition and metabolism in obese patients. The assignment of novel obesity bacterial markers may open avenues for the development of patient-tailored treatments dependent on age-related microbiota profiles

Von Hippel-Lindau–dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster

AbstractChuvash polycythemia (MIM 263400) is an autosomal recessive disorder characterized by a high hemoglobin level, relatively high serum erythropoietin, and early death. It results from a Von Hippel-Lindau (VHL) gene mutation (C598T) that causes increased HIF-1α activity and erythrocyte production in the face of normoxia. This polycythemia is endemic in Chuvashia, whereas its worldwide frequency is very low. We investigated the incidence of the Chuvash-type VHL mutation in Campania (South Italy) and identified 14 affected subjects (5 families). Twelve live on the island of Ischia (Bay of Naples). From analysis of the mutated allele, we found that the disease was more frequent on Ischia (0.070) than in Chuvashia (0.057). The haplotype of all patients matched that identified in the Chuvash cluster, thereby supporting the single-founder hypothesis. We also found that nonaffected heterozygotes had increased HIF-1α activity, which might confer a biochemical advantage for mutation maintenance. In conclusion, we have identified the first large cluster of Chuvash erythrocytosis outside Chuvashia, which suggests that this familial polycythemia might be endemic in other regions of the world

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition

Abstract Vitamin A is a pivotal biochemical factor required for normal proliferation and differentiation as well as for specialized functions, such as vision. The dietary intake of 1500 IU/day is recommended in the first year of life. Here, we report the case of an infant who had been given 62 000 IU/day for 80 days. The infant showed several clinical signs of retinol intoxication, including severe anemia and thrombocytopenia. Bone marrow showed a remarkably reduced number of erythroid and megakaryocytic cells. The interruption of vitamin A treatment was immediately followed by clinical and biochemical recovery. To clarify whether the effects of retinol are due to a direct action on bone marrow cell proliferation, we investigated the activity of retinol (both the drug and the pure molecule) on the growth of K-562, a multipotent hematopoietic cell line, and on bone marrow mesenchymal stem cells. We observed that vitamin A strongly inhibited the proliferation of the cells at concentrations similar to those reached in vivo. Subsequent biochemical analyses of the cell cycle suggested that the effect was mediated by the up-regulation of cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1. These are the first findings to demonstrate that infant hypervitaminosis A causes a severe anemia and thrombocytopenia and that this is probably due to the direct effect of the molecule on the growth of all bone marrow cellular components. Our data also suggest potential bone marrow functional alterations after excessive vitamin A intake because of emerging social habits

Iron overload enhances human mesenchymal stromal cell growth and hampers matrix calcification

Background Iron overload syndromes include a wide range of diseases frequently associated with increased morbidity and mortality. Several organs are affected in patients with iron overload including liver, heart, joints, endocrine glands, and pancreas. Moreover, severe bone and hemopoietic tissue alterations are observed. Because of the role of bone marrow mesenchymal stromal cells (BM-MSCs) in bone turnover and hematopoiesis, iron effects on primary BM-MSCs cultures were evaluated. Methods Primary human BM-MSCs cultures were prepared and the effects of iron on their proliferation and differentiation were characterized by biochemical analyses and functional approaches. Results Addition of iron to the culture medium strongly increased BM-MSCs proliferation and induced their accelerated S phase entry. Iron enters BM-MSCs through both transferrin-dependent and transferrin-independent mechanisms, inducing the accumulation of cyclins E and A, the decrease of p27Kip1, and the activation of MAPK pathway. Conversely, neither apoptotic signs nor up-regulation of reactive oxygen species were observed. Iron inhibited both differentiation of BM-MSCs into osteoblasts and in vitro matrix calcification. These effects result from the merging of inhibitory activities on BM-MSCs osteoblastic commitment and on the ordered matrix calcification process. Conclusions We demonstrated that BM-MSCs are a target of iron overload. Iron accelerates BM-MSCs proliferation and affects BM-MSCs osteoblastic commitment, hampering matrix calcification. General Significance Our study reports, for the first time, that iron, at concentration found in overloaded patient sera, stimulates the growth of BM-MSCs, the BM multipotent stromal cell component. Moreover, iron modulates the physiological differentiation of these cells, affecting bone turnover and remodeling

Long-term outcomes of peritoneal dialysis started in infants below 6 months of age: An experience from two tertiary centres.

peer reviewedBACKGROUND: Little data are available for infants who started renal replacement therapy before 6 months of age. Because of extra-renal comorbidities and uncertain outcomes, whether renal replacement therapy in neonates is justified remains debatable. METHODS: We performed a retrospective analysis of all patients who began chronic peritoneal dialysis below 6 months between 2007 and 2017 in two tertiary centres. Results are presented as median (min;max). RESULTS: Seventeen patients (10 boys) were included (8 prenatal diagnoses, 6 premies), with the following diagnoses: congenital anomalies of kidney and urinary tract (n=9), oxalosis (n=5), congenital nephrotic syndrome (n=2) and renal vein thrombosis (n=1). Five patients had associated comorbidities. At peritoneal dialysis initiation, age was 2.6 (0.1;5.9) months, height-standard deviation score (SDS) -1.3 (-5.7;1.6) and weight-SDS -1.4 (-3.6;0.6). Peritoneal dialysis duration was 12 (2;32) months, and at peritoneal dialysis discontinuation height-SDS was -1.0 (-4.3;0.7) weight-SDS -0.7 (-3.2;0.2), parathyroid hormone 123 (44;1540) ng/L, and hemoglobin 110 (73;174) g/L. During the first 6 months of peritoneal dialysis, the median time of hospitalisation stay was 69 (15;182) days. Ten patients presented a total of 27 peritonitis episodes. Reasons for peritoneal dialysis discontinuation were switch to hemodialysis (n=6), transplantation (n=6), recovery of renal function (n=2) and death (n=1). After a follow-up of 4.3 (1.7;10.3) years, 12 patients were transplanted, 2 patients were still on peritoneal dialysis, 2 patients were dialysis free with severe chronic kidney disease and 1 patient had died. Seven patients displayed neurodevelopmental delay, of whom five needed special schooling. CONCLUSION: We confirm that most infants starting peritoneal dialysis before 6 months of age will be successfully transplanted and will have a favourable growth outcome. Their quality of life will be impacted by recurrent hospitalisations and neurodevelopmental delay is frequent

Effect of starvation on brain glucose metabolism and 18F-2-fluoro-2-deoxyglucose uptake: an experimental in-vivo and ex-vivo study

Background: The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. Methods: Thirty six-week-old BALB/c female mice were divided into two groups: \u201ccontrol\u201d group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining \u201cSTS\u201d mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose removal from the incubation medium (n = 3) or biochemical analyses (n = 3), respectively. Results: CMRGlu* was lower in starved than in control mice (46.1 \ub1 23.3 vs 119.5 \ub1 40.2 nmol 7 min 121 7 g 121 , respectively, p < 0.001). Ex vivo evaluation documented a remarkable stability of lumped constant as documented by the stability of GLUT expression, G6Pase activity, and kinetic features of hexokinase-catalyzed phosphorylation. However, brain SUV in STS mice was even (though not significantly) higher with respect to control mice. Conversely, a marked decrease in both SM-MRGlu* and SM-SUV was documented in STS mice with respect to controls. Conclusions: STS markedly decreases brain glucose consumption without altering measured FDG SUV in mouse experimental models. This apparent paradox does not reflect any change in lumped constant. Rather, it might be explained by the metabolic response of the whole body: the decrease in FDG sequestration by the skeletal muscle is as profound as to prolong tracer persistence in the bloodstream and thus its availability for brain uptak

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD

Prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage

Vos et al. compare the prevalence and prognosis of Alzheimer's disease at the mild cognitive impairment stage based on the IWG-1, IWG-2 and NIA-AA criteria. All three aid identification of early Alzheimer's disease, but combining amyloid and neuronal injury markers according to the NIA-AA criteria offers the most accurate prognosi

Biomarker counseling, disclosure of diagnosis and follow-up in patients with mild cognitive impairment:A European Alzheimer's Disease Consortium survey

Objectives: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. Methods: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. Results: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. Conclusions: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning