The macro- and microelement provision of preschool children with psychomotor developmental disorders. Literature review and authors’ research

Background. An integral part of a child’s physical and mental development is a balanced diet. Insufficient or inadequate for a child developing organism’s needs nutrition in preschool age leads to a delay in physical, cognitive, and mental development. The study was aimed to assess the macro-and micronutrient provision status of preschool children with psychomotor developmental delay, identify the presence of macro- and micronutrient deficiencies, define the connection between macro- and micronutrient levels in patient’s serum and psychomotor developmental disorders. Materials and methods. The study analyzed the results of biochemical blood tests of blood serum samples for total calcium, magnesium, and iron level in 30 preschool children with psychomotor developmental disorders. Results. Mental retardation was observed in 53.33 % of examined children, autism spectrum disorders — in 20 % of exami­ned children; minimal brain dysfunction — in 13.33 %, attention deficit hyperactivity disorder (ADHD) — in 13.33 %. 93.33 % of exami­ned children had a deficiency of total calcium, magnesium — in 63.33 %, iron — in 20 %. Ten percent of patients had a deficiency of both total calcium, magnesium, and iron; one child (3.33 %) had no deficits. The most common deficiency in almost all subgroups of examined children was a combined deficiency of total calcium and magnesium. Only in the minimal brain dysfunction subgroup, in 50 % of cases, there was a combined deficiency of total calcium and magnesium, and in other 50 % of cases — an isolated deficiency of total calcium. This study identified a reliable inverse correlation of moderate strength between the level of total calcium and psychomotor development disorders and between the level of magnesium and the hyperexcitability syndrome. This study detected a weak unreliable correlation between the levels of magnesium and neurological disorders; an inverse unreliable weak correlation was found between iron and psychomotor developmental disorders. Conclusions. The most common deficiency in almost all subgroups of examined children was a combined deficiency of total calcium and magnesium. This study identified a reliable inverse correlation of moderate strength between the level of total calcium and psychomotor developmental disorders and between the level of magnesium and the hyperexcitability syndrome. There is also a weak direct unreliable correlation between magnesium level and psychomotor disorders. An inverse unreliable weak correlation was detected between the concentration of iron and psychomotor disorders.

Idiopathic combined adrenocorticotropin and growth hormone deficiency mimicking chronic fatigue syndrome

A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics.

Clinical presentation and management of hypophysitis: An observational study of case series

Background: Hypophysitis is described as a rare chronic inflammatory affection of the pituitary gland. However, to date, its pathogenesis has not been completely cleared up. Clinical features are polymorphic, including symptoms related to inflammatory compression and/or hypopituitarism. Laboratory tests determine hormone deficiencies orientating replacement therapy’s protocol. MRI of the hypothalamic-pituitary region is crucial in exhibiting major radiological signs such as pituitary homogeneous enlargement and gland stalk’s thickening. The etiological diagnosis is still challenging without affecting the management strategy. Corticosteroids have widely been used but a close follow-up without any treatment has also been approved. Case Description: In this report, seven patients with hypophysitis have been collected over a period of 6 years. The average age of our patients was 32.1 years ± 11.8 with a female predominance (71.4%). Panhypopituitarism was objective in 42.9% of cases, a combined deficiency of the hypothalamic-pituitary thyroid, adrenal and gonadal axes in 28.6% of cases. A central diabetes insipidus was noted in 42.9% of the patients. Idiopathic hypophysitis was the most common etiology. The use of long course corticosteroids was required in 28.6% when compressive signs were reported. Conclusion: Hypophysitis remains a rare disease with nonspecific clinical and radiological patterns. Autoimmune origin seems to be the most frequent etiology. No guidelines have been established for hypophysitis management and the evolution is still unpredictable.

Distinct Signaling Functions of Rap1 Isoforms in NO Release From Endothelium

Small GTPase Rap1 plays a prominent role in endothelial cell (EC) homeostasis by promoting NO release. Endothelial deletion of the two highly homologous Rap1 isoforms, Rap1A and Rap1B, leads to endothelial dysfunction ex vivo and hypertension in vivo. Mechanistically, we showed that Rap1B promotes NO release in response to shear flow by promoting mechanosensing complex formation involving VEGFR2 and Akt activation. However, the specific contribution of the Rap1A isoform to NO release and the underlying molecular mechanisms through which the two Rap1 isoforms control endothelial function are unknown. Here, we demonstrate that endothelial dysfunction resulting from knockout of both Rap1A and Rap1B isoforms is ameliorated by exogenous L-Arg administration to rescue NO-dependent vasorelaxation and blood pressure. We confirmed that Rap1B is rapidly activated in response to agonists that trigger eNOS activation, and its deletion in ECs attenuates eNOS activation, as detected by decreased Ser1177 phosphorylation. Somewhat surprising was the finding that EC deletion of Rap1A does not lead to impaired agonist-induced vasorelaxation ex vivo. Mechanistically, the deletion of Rap1A led to elevated eNOS phosphorylation both at the inhibitory, T495, and the activating Ser1177 residues. These findings indicate that the two Rap1 isoforms act via distinct signaling pathways: while Rap1B directly positively regulates eNOS activation, Rap1A prevents negative regulation of eNOS. Notably, the combined deficiency of Rap1A and Rap1B has a severe effect on eNOS activity and NO release with an in vivo impact on endothelial function and vascular homeostasis.

Vitamin C, A, E, B2 and β-carotene status of patients with gastrointestinal diseases

Deficiency of vitamins is a risk factor for the development of various diseases of the gastrointestinal tract (GIT), and, on the contrary, diseases serve as the cause of the deficiency of these micronutrients. Data on the actual vitamin status of gastrointestinal patients are necessary to develop measures for its improvement.Material and methods. The blood serum level of vitamins C, A, E, B2 and β-carotene in 29 patients (10 men and 19 women) 22–80 years old with gastrointestinal diseases has been determined. The first group consisted of 14 patients with irritable bowel syndrome (IBS). The second group included patients with gastrointestinal diseases of various etiologies.Results. There was no significant difference in vitamins C, A, E, B2 and β-carotene sufficiency in patients with IBS and those with other gastrointestinal diseases. The characteristic features of the vitamin status of patients in both groups were the absence of individuals optimally provided with all vitamins, and a rather high frequency of occurrence (27.6%) of multiple deficiency of 3 vitamins and β-carotene. When the evaluation using 3 indicators at the same time (absolute concentration of vitamins C, E and their molar ratio) was carried out, only two patients in each group were optimally provided with vitamins C and E, and only three of them were optimally provided with β-carotene. Four patients in each group were adequately provided with all the vitamins studied. A combined deficiency of 3 micronutrients (any two vitamins and β-carotene) was found in two patients; combined deficiency of two vitamins or one vitamin and β-carotene was noted in 24.1% of the examined.Conclusion. A purposeful development of vitamin complexes with effective doses for gastrointestinal patients is necessary.

ADAM10 and ADAM17 regulate EGFR, c-Met and TNF RI signalling in liver regeneration and fibrosis

ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in inhibited EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development. Furthermore, we show that while ablation of ADAM17 resulted in decreased shedding of TNF RI, ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.

Interdependent Iron and Phosphorus Availability Controls Photosynthesis Through Retrograde Signaling

Iron deficiency hampers photosynthesis and is associated with chlorosis. We recently showed that iron deficiency-induced chlorosis depends on phosphorus availability. How plants integrate these cues to control chlorophyll accumulation is unknown. Here, we show that iron limitation downregulates photosynthesis genes in a phosphorus-dependent manner. Using transcriptomics and genome-wide association analysis, we identify two genes, a chloroplastic ascorbate transporter (PHT4;4) and a nuclear transcription factor (bZIP58), which prevent the downregulation of photosynthesis genes leading to the stay-green phenotype under iron-phosphorus deficiency. Joint limitation of these nutrients induces ascorbate accumulation by activating expression of an ascorbate biosynthesis gene, VTC4, which requires bZIP58. Exogenous ascorbate prevents iron deficiency-induced chlorosis in vtc4 mutants, but not in bzip58 or pht4;4. Our study demonstrates chloroplastic ascorbate transport is essential for preventing the downregulation of photosynthesis genes under iron-phosphorus combined deficiency. These findings uncover a molecular pathway coordinating chloroplast-nucleus communication to adapt photosynthesis to nutrient availability.

ADAM10 and ADAM17 in Liver Regeneration and Fibrosis: Regulation of EGFR, c-Met and TNF RI Signalling

ADAM10 and ADAM17 are proteases that affect multiple signalling pathways by releasing molecules from the cell surface. As their substrate specificities partially overlaps, we investigated their concurrent role in liver regeneration and fibrosis, using three liver-specific deficient mouse lines: ADAM10- and ADAM17-deficient lines, and a line deficient for both proteases. In the model of partial hepatectomy, double deficient mice exhibited decreased AKT phosphorylation, decreased release of EGFR activating factors and lower shedding of HGF receptor c-Met. Thus, simultaneous ablation of ADAM10 and ADAM17 resulted in impaired EGFR signalling, while HGF/c-Met signalling pathway was enhanced. In contrast, antagonistic effects of ADAM10 and ADAM17 were observed in the model of chronic CCl4 intoxication. While ADAM10-deficient mice develop more severe fibrosis manifested by high ALT, AST, ALP and higher collagen deposition, combined deficiency of ADAM10 and ADAM17 surprisingly results in comparable degree of liver damage as in control littermates. Therefore, ADAM17 deficiency is not protective in fibrosis development per se, but can ameliorate the damaging effect of ADAM10 deficiency on liver fibrosis development and results in decreased shedding of TNF RI, while ADAM10 deficiency leads to increased levels of soluble TNF RI in serum. In conclusion, hepatocyte-derived ADAM10 and ADAM17 are important regulators of growth receptor signalling and TNF RI release, and pathological roles of these proteases are dependent on the cellular context.

Underpinning wheat physiological and molecular responses to co-occurring iron and phosphate deficiency stress

ABSTRACTIron (Fe) and phosphate (P) are essential mineral nutrients for plant growth and development. While it is known that Fe and P pathways interacts within plants however, our understanding of the molecular mechanisms regulating nutrient interaction during plant vegetative and reproductive stages remains largely unknown. Herein, we provide a comprehensive physiological and molecular analysis of hexaploid wheat response to single P/Fe and combined Fe and P deficiency. Our data showed that wheat primary root growth was inhibited in response to –Fe, and remarkably rescued by co-occurring deficiencies of Fe and P. Transcriptome analysis revealed drastic and distinct molecular rearrangements to adapt the single and combined nutrient stress with dominance of Fe responsive cis-regulatory elements. Gene-based clustering and root-specific transcriptome expression analysis identify several important unique components induced in response to combined stress –Fe–P, including UDP-glycosyltransferases and cytochrome-P450 and glutathione metabolism. These data are consistent with our metabolome data, which further reveals specific metabolite accumulation in –Fe–P those include amino-isobutyric acid, arabinonic acid and aconitic acid. Finally, at reproductive stage alleviations of the negative effect of Fe was also observed in –Fe–P (i.e. spikelet development). Collectively, the data obtained is essential for designing new strategies to improve resilience of crops to cope with the limited nutrients in soils.HighlightHexaploid wheat showed distinct physiological and molecular changes during single and combined deficiency of iron and phosphate. Alleviations of the negative effect of - Fe was observed in –Fe–P combined deficiency in the root phenotype and spike development.