CD4(+) T cells play a critical role in mediating hypertension in response to placental ischemia

Similar to preeclamptic women, hypertension in the chronic Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia (RUPP) is associated with increased CD4+ T cells, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). We examined the effect inhibition of T cell co-stimulation in RUPP rats treated with (A) (abatacept, 250 mg/kg, infused i.v. at gestation day 13), on hypertension and sFlt-1, TNF-alpha and AT1-AA. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+2 mmHg in Normal Pregnant (NP) to 123 +/- 3 mmHg in RUPP control rats. This response was attenuated by Abatacept, MAP was 104 +/- 2 mmHg in RUPP +/- A, and 96 +/- 2 mmHg NP +/- A. Percent circulating CD4+ T cells were 66 +/- 3% in RUPPs compared to 55 +/- 3% NP rats (p<0.04) but were normalized in RUPP +/- A rats (54 +/- 3%). The twofold increase in TNF alpha seen in RUPPs (277 +/- 47 pg/ml) was decreased to 80 +/- 18 pg/ml in RUPP+A. Placental sFlt-1 was reduced 70 % to 151 +/- 28 in RUPP +/- A compared 488 +/- 61 pg/ml in RUPP (p<0.001). AT1-AA decreased from 20 +/- 0.8 bpm in control RUPP to 6 +/- 0.7 bpm in RUPP +/- A. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (123 +/- 5 mmHg) and RUPP athymic nude rats (123 +/- 7 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that CD4+ Tcells in response to placental ischemia play an important role in the pathophysiology of hypertension associated with preeclampsia

Onasemnogene abeparvovec preserves bulbar function in infants with presymptomatic spinal muscular atrophy: a post-hoc analysis of the SPR1NT trial

Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function

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Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

A Comparison of Stimulus Set Size on Tact Training for Children with Autism Spectrum Disorder

Previous studies on skill acquisition have taught targets in stimulus sets composed of different numbers of stimuli. Although the rationale for selection of a stimulus set size is not clear, the number of target stimuli trained within a set is a treatment decision for which there is limited empirical support. The current investigation compared the efficiency of tact training in 4 stimulus set sizes, each of which included 12 stimuli grouped into (a) 4 sets of 3 stimuli, (b) 3 sets of 4 stimuli, (c) 2 sets of 6 stimuli, and (d) 1 set of 12 stimuli. Results of all 4 participants with autism spectrum disorder show tact training with larger (i.e., 6 and 12) stimulus set sizes was more efficient than training with smaller (i.e., 3 and 4) stimulus set sizes

RNA interference therapeutics targeting angiotensinogen ameliorate preeclamptic phenotype in rodent models

Preeclampsia, with the hallmark features of new-onset hypertension and proteinuria after 20 weeks of gestation, is a major cause of fetal and maternal morbidity and mortality. Studies have demonstrated a role for the renin-angiotensin system (RAS) in its pathogenesis; however, small-molecule RAS blockers are contraindicated because of fetal toxicity. We evaluated whether siRNA targeting maternal hepatic angiotensinogen (Agt) could ameliorate symptoms of preeclampsia without adverse placental or fetal effects in 2 rodent models. The first model used a cross of females expressing human Agt with males expressing human renin, resulting in upregulation of the circulating and uteroplacental RAS. The second model induced ischemia/reperfusion injury and subsequent local and systemic inflammation by surgically reducing placental blood flow midgestation (reduced uterine perfusion pressure [RUPP]). These models featured hypertension, proteinuria, and fetal growth restriction, with altered biomarkers. siRNA treatment ameliorated the preeclamptic phenotype in both models, reduced blood pressure, and improved intrauterine growth restriction, with no observed deleterious effects on the fetus. Treatment also improved the angiogenic balance and proteinuria in the transgenic model, and it reduced angiotensin receptor activating antibodies in both. Thus, an RNAi therapeutic targeting Agt ameliorated the clinical sequelae and improved fetal outcomes in 2 rodent models of preeclampsia

Placental CD4(+) T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia

AIM: Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4(+) T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4(+) T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4(+) T cells from normal pregnant (NP) women. However, the role of PE CD4(+) T cells to cause AT1-AA as a mechanism of hypertension is not known. Our goal was to determine if PE CD4(+) T cells stimulate AT1-AA in pregnant nude-athymic rats. METHODS: CD4(+) T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4(+) T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4(+) T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained. RESULTS: MAP [114 ± 1 mmHg (n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4(+) T cells compared to NP nude + NP CD4(+) T cells [98 ± 2 mmHg (n = 7, P < 0.05) and 1.3 ± 0.9 bpm (n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4(+) T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4(+) T cells. CONCLUSIONS: These results show that placental CD4(+) T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy

Surface and bulk contribution to Cu(111) quantum efficiency

The quantum efficiency (QE) of Cu(111) is measured for different impinging light angles with photon energies just above the work function. We observe that the vectorial photoelectric effect, an enhancement of the QE due to illumination with light with an electric vector perpendicular to the sample surface, is stronger in the more surface sensitive regime. This can be explained by a contribution to photoemission due to the variation in the electromagnetic potential at the surface. The contributions of bulk and surface electrons can then be determined