The impact of in utero transfusions on perinatal outcomes in patients with alpha thalassemia major: the UCSF registry.

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

Selective Deletion of the Mechanistic Target of Rapamycin From the Renal Collecting Duct Principal Cell in Mice Down-Regulates the Epithelial Sodium Channel.

The mechanistic target of rapamycin (mTOR), a serine-threonine-specific kinase, is a cellular energy sensor, integrating growth factor and nutrient signaling. In the collecting duct (CD) of the kidney, the epithelial sodium channel (ENaC) essential in the determination of final urine Na+ losses, has been demonstrated to be upregulated by mTOR, using cell culture and mTOR inhibition in ex vivo preparations. We tested whether CD-principal cell (PC) targeted deletion of mTOR using Cre-lox recombination would affect whole-body sodium homeostasis, blood pressure, and ENaC regulation in mice. Male and female CD-PC mTOR knockout (KO) mice and wild-type (WT) littermates (Cre-negative) were generated using aquaporin-2 (AQP2) promoter to drive Cre-recombinase. Under basal conditions, KO mice showed a reduced (∼30%) natriuretic response to benzamil (ENaC) antagonist, suggesting reduced in vivo ENaC activity. WT and KO mice were fed normal sodium (NS, 0.45% Na+) or a very low Na+ (LS, <0.02%) diet for 7-days. Switching from NS to LS resulted in significantly higher urine sodium losses (relative to WT) in the KO with adaptation occurring by day 2. Blood pressures were modestly (∼5-10 mm Hg) but significantly lower in KO mice under both diets. Western blotting showed KO mice had 20-40% reduced protein levels of all three subunits of ENaC under LS or NS diet. Immunohistochemistry (IHC) of kidney showed enhanced apical-vs.-cellular localization of all three subunits with LS, but a reduction in this ratio for γ-ENaC in the KO. Furthermore, the KO kidneys showed increased ubiquitination of α-ENaC and reduced phosphorylation of the serum and glucocorticoid regulated kinase, type 1 [serum glucocorticoid regulated kinase (SGK1)] on serine 422 (mTOR phosphorylation site). Taken together this suggests enhanced degradation as a consequence of reduced mTOR kinase activity and downstream upregulation of ubiquitination may have accounted for the reduction at least in α-ENaC. Overall, our data support a role for mTOR in ENaC activity likely via regulation of SGK1, ubiquitination, ENaC channel turnover and apical membrane residency. These data support a role for mTOR in the collecting duct in the maintenance of body sodium homeostasis.

Transient exposure to environmentally realistic concentrations of di-(2-ethylhexyl)-phthalate during sensitive windows of development impaired larval survival and reproduction success in Japanese medaka.

Di-(2-ethylhexyl) phthalate (DEHP) is a well-known endocrine disruptor and it is ubiquitously distributed in the environment. However, very few studies have investigated the effects of short-term exposure to environmentally realistic concentrations of DEHP during early developmental stages and its chronic effects. This study monitored the long-term effects of transient exposure to DEHP in early life stages (F0 generation) and its subsequent fertilization success in F1 generation using Japanese medaka, Oryzias latipes, as model organism. Embryos (4 h post-fertilization, 4 hpf) of Japanese medaka were exposed to 0.001 ppb, 0.1 ppb, or 10 ppb DEHP for 21 days and returned to control water (without DEHP) for maturation (4 months old). At day 9 of the exposure study, mortality was significantly increased in medaka embryos (before hatching) treated with 0.001 ppb and 10 ppb DEHP. Continual exposure of young hatchlings for an additional 12 days (a total of 21 days of exposure) resulted in a significant increase in mortality in fish exposed to 0.001 ppb, 0.1 and 10 ppb DEHP. Significant reduction in egg production was observed in adult female medaka (4 months old) with prior exposure to 0.1 ppb and 10 ppb DEHP for 21 days during early development. Fertilization and hatching success were also significantly reduced in breeding pairs with prior exposure to 0.001 ppb, 0.1 ppb and 10 ppb DEHP during early life stage. Histological analysis of adult male gonads revealed a significant decline in mature sperm count accompanied by an increase in interstitial space in fish exposed to 0.1 ppb and 10 ppb DEHP during early development. Likewise, the amount of vitellogenic (mature) oocytes observed in the ovaries of adult female with transient exposure to 0.1 ppb and 10 ppb DEHP was significantly reduced when compared with the solvent control group. Our data suggest that transient exposure to ultra low concentrations of DEHP during sensitive time windows of development results in irreversible reproductive impairment which may impact fish populations negatively.

A rare cause of postpartum chest pain.

We report the case of a 45-year-old postpartum female at low risk for coronary artery disease (CAD) who presented with chest pain, a normal electrocardiogram (ECG) and elevation of serial troponin-T levels. Coronary angiography revealed dissection of the first obtuse marginal branch of the left circumflex coronary artery. The patient was treated medically and discharged home safely. Spontaneous coronary artery dissection (SCAD) is a rare condition. In the absence of CAD, it is seen most frequently in young females during the peripartum period. Insult from the hemodynamic stresses during pregnancy and labor combined with the underlying pregnancy related arterial wall changes is the proposed mechanism of dissection in this setting. The normal ECG in the presence of an acute myocardial infarction (AMI) in this case also demonstrates the occasional electrically silent ECG that can occur during acute compromise of the left circumflex coronary artery.

The effect of membrane sweeping on prelabor rupture of membranes: a randomized controlled trial.

OBJECTIVE: To estimate if membrane sweeping increases the rate of prelabor rupture of membranes. METHODS: This randomized trial of term, uncomplicated pregnancies included 300 patients. Patients were randomly assigned into sweep or no-sweep groups, with patients and delivering providers blinded to group allocation. Only the examining provider in the clinic was unblinded to group allocation. Membranes were then swept or not swept at each weekly visit from 38 weeks of gestation onward, depending on the randomization. Data collected included parity, cervix examination at each visit, estimated gestational age at delivery, rupture of membranes, and maternal or fetal complications. RESULTS: A total of 162 patients were randomly assigned to the membrane sweep group and 138 to the no-sweep group. There was no difference in baseline characteristics or obstetric and neonatal outcomes between the groups. The average gestational age at delivery and induction rate were not different. The overall prelabor rupture of membranes rate was not significantly higher in the membrane sweep group (12% compared with 7%) (P=.19); however, patients with a cervix more than 1 cm dilated at time of membrane sweeping were more likely to have prelabor rupture of membranes if they were in the membrane sweep group (9.1% compared with 0%; relative risk 1.10, 95% confidence interval 1.03-1.18). CONCLUSION: No benefit in gestational age at delivery or reduction of postmaturity occurred from membrane sweeping. Although the overall prelabor rupture of membranes rates were similar, patients with membrane sweeping occurring at more than 1 cm cervical dilation may be at increased risk of prelabor rupture of membranes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00294242. LEVEL OF EVIDENCE: I.

Inhibition of nuclear factor kappaB by phenolic antioxidants: interplay between antioxidant signaling and inflammatory cytokine expression.

Phenolic antioxidants inhibit the induction of inflammatory cytokines by inflammatory stimuli. Here, we analyzed the mechanism by which the antioxidants inhibit LPS-induced expression of tumor necrosis factor alpha (TNFalpha) in macrophages. Hydroquinone and tert-butyl hydroquinone, prototypes of phenolic antioxidants, block lipopolysaccharide (LPS)-induced transcription of TNFalpha and a nuclear factor (NF)-kappaB-mediated reporter gene expression, suggesting NF-kappaB as a target in the inhibition. Analyses of the NF-kappaB activation pathway revealed that the antioxidants do not inhibit LPS-induced activation of the IkappaB kinase activity, degradation of IkappaBalpha, or translocation of activated NF-kappaB into the nucleus, but they do block the formation of NF-kappaB/DNA binding complexes. In vitro experiments showed that the antioxidants do not directly interfere with DNA binding of NF-kappaB. Structure-activity analyses suggest that inhibition of NF-kappaB function involves the redox cycling property of the antioxidants. These findings implicate a redox-sensitive factor important for the binding of NF-kappaB to its DNA recognition sequence as a target molecule in the inhibition of NF-kappaB function and inflammatory cytokine expression by phenolic antioxidants.