ABSTRACT
BACKGROUND: The impact of chronic moderate and profound hyponatremia on neurocognitive performance, motor skills, and mood stability has not been investigated systematically so far, and results regarding mild to moderate hyponatremia are inconsistent. Furthermore, it is not known whether treatment has an effect on outcome in these patients. METHODS: A total of 130 hospitalized patients with confirmed euvolemic hyponatremia (<130 mEq/L) were subjected to a test battery (Mini-Mental State Examination, DemTect, Trail-Making Tests A and B, Beck Depression Inventory, Timed-up-and-go Test) before and after treatment; additionally, 50 normonatremic group-matched patients served as reference group. RESULTS: The scores of all tested domains were significantly worse in the hyponatremia group (median serum sodium [Na+] 122 (119-126) mEq/L) as compared to the reference group (P <0.001), and the odds of obtaining a pathological test result increased markedly with more profound hyponatremic states (odds ratios between 5.0 and 21.8 in the group with Na+ <120 mEq/L compared to reference group). Inversely, treatment led to a significant amelioration of all test results with medium to large effect sizes. Linear regression models revealed the increment of Na+ as an important predictor of test outcome. CONCLUSION: We demonstrate a clear association between lower levels of Na+ beyond mild hyponatremia and impairment of neurocognitive and motor performance as well as mood disorders. Our analysis further suggests a causal role of hyponatremia in this context. However, there are apparent differences between the distinct tested domains warranting further investigations.
Subject(s)
Affect , Cognition , Depression/psychology , Hyponatremia/physiopathology , Physical Functional Performance , Aged , Case-Control Studies , Female , Hospitalization , Humans , Hyponatremia/psychology , Logistic Models , Male , Mental Status and Dementia Tests , Middle Aged , Severity of Illness Index , Trail Making TestABSTRACT
Lymphomas arising from NK or γδ-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n=51), γδ-T-cell lymphomas (n=43) and their cell lines (n=9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of γδ-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.
Subject(s)
Gene Expression Regulation, Neoplastic , Killer Cells, Natural/cytology , Lymphoma, T-Cell/metabolism , STAT3 Transcription Factor/genetics , STAT5 Transcription Factor/genetics , T-Lymphocyte Subsets/cytology , Binding Sites , HEK293 Cells , Histidine/chemistry , Humans , Interleukin-2/metabolism , Janus Kinase 1/metabolism , Mutation , Phosphotyrosine/chemistry , Protein Structure, Tertiary , Receptors, Antigen, T-Cell, gamma-delta/metabolismABSTRACT
Infants born to diabetic mothers have elevated cord blood leptin levels. The aim of this study was to investigate whether the situation persists at the 2nd postnatal day, taking the fasting and satiety states into account and the influence of fetal exposure to hyperinsulinemia, which are proven important contributing factors to plasma leptin levels. Twenty infants born to mothers with gestational diabetes (Group I) and 20 controls (Group II) were included in the study. Groups were similar for sex and anthropometric measurements. Group I had higher leptin concentrations compared to Group II in fasting and satiety states (p < 0.01). Fasting state leptin levels were significantly lower than seen in satiety in both groups (p < 0.01). There was a positive and significant correlation between leptin concentrations and body mass index of infants. Leptin concentrations were positively correlated with plasma insulin levels in Group I. These findings suggest that plasma leptin levels are high in both fasting and satiety states on the 2nd postnatal day in infants born to mothers with gestational diabetes. The possible mechanism underlying this condition is fetal exposure to hyperinsulinemia due to hyperglycemia. The uniqueness of this report are that fasting and satiety states were taken into account and that the data was collected from the samples taken on the 2nd postnatal day, thus reflecting the exact milieu of the infant excluding the effects of the mother and the placenta.