Resistin, visfatin, leptin and omentin are differently related to hormonal and metabolic parameters in growth hormone-deficient children

PURPOSE: The effect of growth hormone (GH) on adipose tissue and the role of adipokines in modulating metabolism are documented, but with discordant data. Our aim was to evaluate the impact of GH treatment on a series of selected adipokines known to have a metabolic role and poorly investigated in this setting. METHODS: This is a prospective study. Thirty-one prepubertal children (25 M, 6 F; aged 8.5 ± 1.6 years) with isolated GH deficiency treated with GH for at least 12 months and 30 matched controls were evaluated. Auxological and metabolic parameters, insulin sensitivity indexes, leptin, soluble leptin receptor, adiponectin, visfatin, resistin, omentin, adipocyte fatty acid-binding protein and retinol-binding protein-4 were evaluated before and after 12 months of treatment. RESULTS: At baseline, no significant difference in metabolic parameters was found between GHD children and controls, except for higher LDL cholesterol (p = 0.004) in the first group. At multivariate analysis, LDL cholesterol was independently associated with resistin (B 0.531; p = 0.002), while IGF-I was the only variable independently associated with visfatin (B 0.688; p < 0.001). After 12 months, a significant increase in fasting insulin (p = 0.008), Homa-IR (p = 0.007) and visfatin (p < 0.001) was found, with a concomitant decrease in LDL cholesterol (p = 0.015), QUICKI (p = 0.001), ISI Matsuda (p = 0.006), leptin (p = 0.015) and omentin (p = 0.003)]. At multivariate analysis, BMI was the only variable independently associated with leptin (B 0.485; p = 0.040). CONCLUSIONS: GH treatment modifies adipokine secretion and the perturbation of some adipokine levels could contribute to the clinical and metabolic changes observed during the follow-up

LONG-TERM METABOLIC EFFECTS OF GH THERAPY IN CHILDREN WITH IDIOPATHIC GH DEFICIENCY

Background Increased insulin levels during GH replacement therapy are often reported both in adults and in children with GH deficiency (GHD), although discordant data fully describe the behavior of metabolic parameters during GH therapy in children and overall the majority of published data are limited to the first 12 months of follow-up and in small populations. Aim To evaluate the long-term metabolic influences of GH replacement in a large selected cohort of prepubertal children with idiopathic GHD during GH therapy. Subjects and Methods Data of 194 prepubertal GHD children (150 M, 44 F; age 10.85 ± 2.77 yrs) were analyzed. Before GH therapy and yearly up to 36 months we measured body mass index (BMI), waist circumference (WC), IGF-1, total-, HDL- and LDL-cholesterol, triglycerides, glucose and insulin levels, Homa-IR and HbA1c. In a subgroup of 34 patients (28 M, 8 F) we performed yearly OGTT and calculated ISI-Matsuda (ISI), Insulinogenic Index (InsIn) and Oral Disposition Index (DIo). Results No subject showed overt dysglycemia or dyslipidemia at baseline and during GH therapy. Compared to baseline (17.62 ± 3.14 Kg/m2), BMI significantly increased after 12 (17.81 ± 3.36 Kg/m2; p<0.001), 24 (18.24 ± 3.22 Kg/m2; p<0.001) and 36 months (18.43 ± 3.58 Kg/m2; p=0.014), without significantly changes in WC. Glucose (88.24 ± 9.09 vs 82.52 ± 9.00 mg/dl; p<0.001), insulin (7.41 ± 4.40 vs 4.96 ± 4.20 mg/dl; p<0.047), Hba1c (5.07 ± 0.43 vs 4.78 ± 0.52 %; p<0.001) and triglycerides (73.62 ± 34.88 vs 66.59 ± 34.30 mg/dl; p=0.029) were significantly higher after 1 year of therapy when compared to baseline, although within the normal values, without additional increase at 24 and 36 months. Homa- IR significantly increased from baseline to 12 months (5.07 ± 0.43 vs 1.03 ± 1.01; p<0.001) with a subsequent significant reduction after 24 months (2.36 ± 1.64; p=0.020), without further modifications at 36 months (2.06 ± 1.45; p=0.242). In the subgroup of 34 children, ISI (7.22 ± 0.38), InsI (0.75 ± 0.04) and DIo (5.52 ± 1.34) did not significantly change during the entire follow-up. Conclusions A slight deterioration of glucose and lipid metabolism seems to occur during the first year of GH treatment, with a re-establishment in the subsequent years of follow-up, although no overt worsening in insulin sensitivity occurs. A longer follow-

Effect of a hay-based diet or different upland grazing systems on milk volatile compounds

International audience The effect of animal feeding on milk volatile organic compounds (VOCs) of metabolic origin was tested on a hay-based diet (H), a highly diversified pasture under continuous grazing (CG), or a less diversified pasture under rotational grazing (RG). Individual milk of 24 Montbeliarde cows (8 per treatment) were sampled after 2 weeks. Pasture-derived milk was richer (p < 0.05) in camphene, sabinene, beta-caryophyllene, and skatole than H milk. Neither milk yield nor fat content affected the majority of VOCs measured. Skatole increased slightly with milk yield, while indole and cineole decreased slightly with milk fat content but with poor regression (R(2) < 0.54). Multivariate analysis showed that, on the basis of those VOCs of metabolic origin whose concentration differed between treatment (dimethyl-sulfone, skatole, toluene, undecanoic acid, 1-octadecene, benzeneacetaldehyde, octanoic acid, and 2-pentanone-4-hydroxy-4-methyl), it was possible to obtain good discriminations among feeding systems. This study is promising for a future use of VOCs of metabolic origin to trace animal feeding systems

Expanding the clinical and molecular spectrum of psmd12-related neurodevelopmental syndrome: an additional patient and review

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process that eukaryotic cells use to regulate their functions and coordinate their signaling networks. In particular, it plays a crucial role in neuronal development regulating very important functional and morphological interplays of neurons, such as synaptic plasticity, neurotransmitter release and morphogenesis of axons. Pathogenic alterations of genes involved in the proteolysis by UPS have been associated with several neurodevelopmental disorders (NDDs) and human diseases, highlighting the importance of this regulatory mechanism to developmental processes and neurogenesis. Here, we describe a 19 years old male patient showing a syndromic form of NDD. The main clinical features are intellectual disability/speech delay, congenital anomalies and facial dysmorphisms. Through a targeted resequencing approach (TRS), we identified a missense variant in PSMD12, a gene recently associated to an emerging syndromic form of NDD, which encodes for the non-ATPase subunit of the 19S regulator of 26S proteasome complex. The variant described herein, inherited from the father with apparently borderline cognitive ability, is useful to expand the molecular spectrum of heterozygous PSMD12 mutations and to provide insight into the molecular pathogenesis of this new condition since it is, to the best of our knowledge, the first missense substitution to date reported in medical literature. More importantly, our study highlight once again the utility of next generation sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as NDDs, thus allowing a better diagnosis, counseling and management of affected patients and their families

What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo <i>KAT6A</i> Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition’s rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified

What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo KAT6A Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis

: Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C&gt;T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition's rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified

Cost-effectiveness of on-demand plerixafor added to chemotherapy and granulocyte-colony stimulating factor for peripheral blood stem cell mobilization in multiple myeloma

We here report final results of a phase II/III prospective study that evaluated in Multiple Myeloma the use of on-demand plerixafor (PLX) added to mobilizing chemotherapy for patients showing predictive signs of mobilization failure. A total of 111 patients with MM were registered, all received cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor (G-CSF). Overall, a successful CD34+ cell mobilization was achieved in 97.2% (108/111) of patients. Minimum harvest (≥2.0 × 106 CD34+ cells/kg) was achieved in 97.2% (108/111) and optimal harvest success (≥4.0 × 106 CD34+ cells/kg) was achieved in 84.6% (94/111). Multivariate analysis showed that patients who received on-demand PLX treatment had significantly higher likelihoods of successfully achieving both the minimal (p = .006) and optimal harvest (p = .05) in respect to a historical control group mobilized without any PLX. The incremental cost-effectiveness ratio, for each 1% increase in probability of achieving a successful minimal harvest, was €40.6 per patient

Deletions of Chromosome 7q Affect Nuclear Organization and HLXB9 Gene Expression in Hematological Disorders

© 2019 by the authors. The radial spatial positioning of individual gene loci within interphase nuclei has been associated with up- and downregulation of their expression. In cancer, the genome organization may become disturbed due to chromosomal abnormalities, such as translocations or deletions, resulting in the repositioning of genes and alteration of gene expression with oncogenic consequences. In this study, we analyzed the nuclear repositioning of HLXB9 (also called MNX1), mapping at 7q36.3, in patients with hematological disorders carrying interstitial deletions of 7q of various extents, with a distal breakpoint in 7q36. We observed that HLXB9 remains at the nuclear periphery, or is repositioned towards the nuclear interior, depending upon the compositional properties of the chromosomal regions involved in the rearrangement. For instance, a proximal breakpoint leading the guanine-cytosine (GC)-poor band 7q21 near 7q36 would bring HLXB9 to the nuclear periphery, whereas breakpoints that join the GC-rich band 7q22 to 7q36 would bring HLXB9 to the nuclear interior. This nuclear repositioning is associated with transcriptional changes, with HLXB9 in the nuclear interior becoming upregulated. Here we report an in cis rearrangement, involving one single chromosome altering gene behavior. Furthermore, we propose a mechanistic model for chromatin reorganization that affects gene expression via the influences of new chromatin neighborhoods.This research was funded by Research Plan 2016n2018 from Department of Biological, Geological and Environmental Sciences, University of Catania to C.F.” and “The APC was funded by Brunel University London; V.S., and F.B. are supported by a fellowship of the PhD program (University of Catania, Italy)