AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome.

Down syndrome (DS) is associated with increased susceptibility to infections, auto-immunity, immunodeficiency and haematological malignancies. The exact underlying immunological pathophysiology is still unclear. The immunophenotype and clinical characteristics of DS resemble those of Activated PI3K Delta Syndrome (APDS), in which the PI3K/AKT/mTOR pathway is overactivated. We hypothesized that T cell exhaustion and the hyperactivation of the AKT signalling pathway is also present in immune cells of children with DS. In this observational non-interventional cohort study we collected blood samples of children with DS (n=22) and healthy age-matched controls (n=21) for flowcytometric immunophenotyping, phospho-flow AKT analysis and exhaustion analysis of T cells. The median age was 5 years (range 1-12y). Total T and NK cells were similar for both groups, but absolute values and transitional B cells, naive memory B cells and naive CD4+ and CD8+ T cells were lower in DS. pAKT and AKT were increased for CD3+ and CD4+ T cells and CD20+ B cells in children with DS. Total AKT was also increased in CD8+ T cells. Children with DS showed increased expression of inhibitory markers Programmed cell dealth-1 (PD-1), CD244 and CD160 on CD8+ T cells and increased PD-1 and CD244+ expression on CD4+ T cells, suggesting T cell exhaustion. Children with DS show increased pAKT and AKT and increased T cell exhaustion, which might contribute to their increased susceptibility to infections, auto immunity and haematological malignancies.

Interventions with Music in PECTus excavatum treatment (IMPECT trial): a study protocol for a randomised controlled trial investigating the clinical effects of perioperative music interventions.

INTRODUCTION: Pectus excavatum repair is associated with substantial postoperative pain, despite the use of epidural analgesia and other analgesic regimens. Perioperative recorded music interventions have been shown to alleviate pain and anxiety in adults, but evidence for children and adolescents is still lacking. This study protocol describes a randomised controlled trial that evaluates the effects of recorded music interventions on postoperative pain relief in children and adolescents after pectus excavatum repair. METHODS: A multicentre randomised controlled trial was set up comparing the effects of perioperative recorded music interventions in addition to standard care with those of standard care only in patients undergoing a Nuss procedure for pectus excavatum repair. One hundred and seventy subjects (12-18 years of age) will be included in three centres in the Netherlands. Patient inclusion has started in November 2018, and is ongoing. The primary outcome is self-reported perceived pain measured on the visual analogue scale. Secondary outcomes are anxiety level, analgesics consumption, vital parameters such as heart rate, blood pressure and respiratory rate, length of hospital stay, postoperative complications, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Centre Rotterdam, The Netherlands, has approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBER: NL6863.

Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review.

OBJECTIVE: To review the effects of non-oral administration of postmenopausal hormone therapy (HT) on risk markers for atherosclerotic and venous thromboembolic disease.Non-oral postmenopausal HT appears not to increase venous thromboembolic risk, whereas the effect on coronary heart disease risk is less clear. DESIGN: Systematic review of literature obtained from MEDLINE, EMBASE, and CENTRAL databases from 1980 until and including April 2006. Terms for "postmenopausal hormone therapy" and for "non-oral administration" were combined in the search. SETTING: Randomized clinical trials. PATIENT(S): Postmenopausal women, both healthy and with established cardiovascular disease or specified cardiovascular risk factors INTERVENTION(S): Non-oral HT (e.g., transdermal or intranasal) compared with oral HT or no treatment/placebo. MAIN OUTCOME MEASURE(S): Lipoprotein(a), homocysteine, C-reactive protein (CRP), cell adhesion molecules, markers of endothelial dysfunction, coagulation, and fibrinolysis. RESULT(S): Seventy-two studies investigating either transdermal or intranasal administration were included. For non-oral HT, decreases in lipoprotein(a), cell adhesion molecules, and factor VII generally were significant, resistance to activated protein C (APCr) was slightly increased, and other markers including CRP and homocysteine did not change. Compared with oral HT, changes in CRP and APCr were smaller, changes in cell adhesion molecules and some fibrinolytic parameters tended to be smaller, whereas changes in other factors including lipoprotein(a) and homocysteine did not differ. CONCLUSION(S): Potentially unfavorable changes seen with oral HT on two important markers, CRP and APCr, are substantially smaller with non-oral HT. Non-oral HT has minor effects on the other cardiovascular risk markers studied. Therefore, compared with oral HT, non-oral HT appears be safer with respect to atherosclerotic and venous thromboembolic disease risk.

Comparative effects of a contraceptive vaginal ring delivering a nonandrogenic progestin and continuous ethinyl estradiol and a combined oral contraceptive containing levonorgestrel on hemostasis variables.

OBJECTIVE: This study aimed to compare the effects on hemostasis variables of a contraceptive vaginal ring with those of an oral contraceptive. STUDY DESIGN: Twenty-three and 22 healthy premenopausal women were randomized to the contraceptive vaginal ring (150 microg Nestorone and 15 microg ethinyl estradiol) or Stediril 30 during 3 cycles. Analysis of covariance was performed with baseline values as covariate. RESULTS: The contraceptive vaginal ring changed most hemostasis variables similarly but raised (95% confidence intervals of percent treatment differences) Factor VIIt (28% to 49%), extrinsic activated protein C resistance (14% to 65%), and sex hormone-binding globulin (117% to 210%) and lowered Protein S (-32% to -16%) and the global activated partial thromboplastin time-based activated protein C resistance (-12% to -2%) more than the oral contraceptive. CONCLUSION: The contraceptive vaginal ring affected some measured hemostasis variables and sex hormone-binding globulin differently from the oral contraceptive, most likely because of difference in androgenicity of the progestins. The results suggest that the contraindications for oral contraceptive use would also apply to the tested contraceptive vaginal ring.