A single dose of dietary nitrate supplementation protects against endothelial ischemia-reperfusion injury in early postmenopausal women.

The onset of menopause and accompanying changes to ovarian hormones often precedes endothelial dysfunction in women. In particular, accelerated impairments in macrovascular and microvascular function coincide with the loss of estrogen, as does impaired endothelial responses to ischemia-reperfusion (IR) injury. In healthy, early postmenopausal women (n = 12; 3.9 ± 1.5 years since menopause) we tested the hypothesis that acute dietary nitrate (NO3-) supplementation would improve endothelial function and attenuate the magnitude of endothelial dysfunction following whole-arm IR in comparison with placebo. In this randomized, double-blind, placebo-controlled, crossover study we tested participants before and after NO3--rich (BRnitrate) and NO3--depleted (BRplacebo) beetroot juice (BR) consumption, as well as following IR injury, and 15 min after IR to assess recovery. Analyses with repeated-measures general linear models revealed a condition × time interaction for brachial artery flow-mediated dilation (FMD; P = 0.04), and no interaction effect was found for the near-infrared spectroscopy-derived reperfusion slope (P = 0.86). Follow-up analysis showed a significant decline in FMD following IR injury with BRplacebo in comparison with all other timepoints (all, P < 0.05), while this decline was not present with BRnitrate (all, P > 0.05). Our findings demonstrate that a single dose of dietary NO3- minimizes IR-induced macrovascular endothelial dysfunction in healthy, early postmenopausal women, but does not improve resting macrovascular and microvascular function. Trial registration number: NCT03644472. Novelty: In healthy, early postmenopausal women, a single dose of NO3--rich BR can protect against IR-induced endothelial dysfunction. This protection may be due to nitric oxide bioactivity during IR rather than improved endothelial function prior to the IR protocol per se.

Photon Transport in a Bose-Hubbard Chain of Superconducting Artificial Atoms.

We demonstrate nonequilibrium steady-state photon transport through a chain of five coupled artificial atoms simulating the driven-dissipative Bose-Hubbard model. Using transmission spectroscopy, we show that the system retains many-particle coherence despite being coupled strongly to two open spaces. We find that cross-Kerr interaction between system states allows high-contrast spectroscopic visualization of the emergent energy bands. For vanishing disorder, we observe the transition of the system from the linear to nonlinear regime of photon blockade in excellent agreement with the input-output theory. Finally, we show how controllable disorder introduced to the system suppresses nonlocal photon transmission. We argue that proposed architecture may be applied to analog simulation of many-body Floquet dynamics with even larger arrays of artificial atoms paving an alternative way towards quantum supremacy.

Sensitivity enhancement of plasmonic grating in the local field.

A plasmonic grating consisting of parallel gold or silver nanowires on the glass substrate is an excellent sensor for refractive index measurement of a gas or liquid medium. We suggest measuring the local field in a gap between the wires to increase the sensitivity. The local electric field contains more information on the environment since it includes the evanescent waves. Calculation by the boundary element method confirms a substantial improvement of sensitivity owing to a sharp cusp-like gap resonance in the angular dependence. The local field measurement under the frustration of total internal reflection has promising prospects for the development of modern biomedical and chemical sensors.

Mesoscopic Stoner Instability in Open Quantum Dots: Suppression of Coleman-Weinberg Mechanism by Electron Tunneling.

The mesoscopic Stoner instability is an intriguing manifestation of symmetry breaking in isolated metallic quantum dots, underlined by the competition between single-particle energy and Heisenberg exchange interaction. Here we study this phenomenon in the presence of tunnel coupling to a reservoir. We analyze the spin susceptibility of electrons on the quantum dot for different values of couplings and temperature. Our results indicate the existence of a "quantum phase transition" at a critical value of the tunneling coupling, which is determined by the Stoner-enhanced exchange interaction. This quantum phase transition is a manifestation of the suppression of the Coleman-Weinberg mechanism of symmetry breaking, induced by coupling to the reservoir.

Effect of oocyte donor stimulation on recipient outcomes: data from a US national donor oocyte bank.

STUDY QUESTION: How does ovarian stimulation in an oocyte donor affect the IVF cycle and obstetric outcomes in recipients? SUMMARY ANSWER: Higher donor oocyte yields may affect the proportion of usable embryos but do not affect live birth delivery rate or obstetric outcomes in oocyte recipients. WHAT IS KNOWN ALREADY: In autologous oocyte fresh IVF cycles, the highest live birth delivery rates occur when ~15-25 oocytes are retrieved, with a decline thereafter, perhaps due to the hormone milieu, with super-physiologic estrogen levels. There are scant data in donor oocyte cycles, wherein the oocyte environment is separated from the uterine environment. STUDY DESIGN, SIZE, DURATION: This was a retrospective cohort study from 2008 to 2015 of 350 oocyte donors who underwent a total of 553 ovarian stimulations and oocyte retrievals. The oocytes were vitrified and then distributed to 989 recipients who had 1745 embryo transfers. The primary outcome was live birth delivery rate, defined as the number of deliveries that resulted in at least one live birth per embryo transfer cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included oocyte donors and recipients at a donor oocyte bank, in collaboration with an academic reproductive endocrinology division. Donors with polycystic ovary syndrome and recipients who used gestational carriers were excluded. The donors all underwent conventional ovarian stimulation using antagonist protocols. None of the embryos underwent pre-implantation genetic testing. The average (mean) number of embryos transferred to recipients was 1.4 (range 1-3). MAIN RESULTS AND THE ROLE OF CHANCE: Per ovarian stimulation cycle, the median number of oocytes retrieved was 30 (range: 9-95). Among the 1745 embryo transfer cycles, 856 of the cycles resulted in a live birth (49.1%). There were no associations between donor oocyte yield and probability of live birth, adjusting for donor age, BMI, race/ethnicity and retrieval year. The results were similar when analyzing by mature oocytes. Although donors with more oocytes retrieved had a higher number of developed embryos overall, there was a relatively lower percentage of usable embryos per oocyte warmed following fertilization and culture. In our model for the average donor in the data set, holding all variables constant, for each additional five oocytes retrieved, there was a 4% (95% CI 1%, 7%) lower odds of fertilization and 5% (95% CI 2%, 7%) lower odds of having a usable embryo per oocyte warmed. There were no associations between donor oocyte yield and risk of preterm delivery (<37 weeks gestation) and low birthweight (<2500 g) among singleton infants. LIMITATIONS, REASONS FOR CAUTION: Ovarian stimulation was exclusively performed in oocyte donors. This was a retrospective study design, and we were therefore unable to ensure proportional exposure groups. These findings may not generalizable to older or less healthy women who may be vitrifying oocytes for planned fertility delay. There remain significant risks to aggressive ovarian stimulation, including ovarian hyperstimulation. In addition, long-term health outcomes of extreme ovarian stimulation are lacking. Lastly, we did not collect progesterone levels and are unable to evaluate the impact of rising progesterone on outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Live birth delivery rates remain high with varying amounts of oocytes retrieved in this donor oocyte model. In a vitrified oocyte bank setting, where oocytes are typically sent as a limited number cohort, recipients are not affected by oocyte yields. STUDY FUNDING/COMPETING INTEREST(S): Additional REDCap grant support at Emory was provided through UL1 TR000424. Dr. Audrey Gaskins was supported in part by a career development award from the NIEHS (R00ES026648).

Moderating effects of the valence of social interaction on the dysfunctional consequences of perseverative cognition: an ecological study in major depression and social anxiety disorder.

BACKGROUND AND OBJECTIVES: Major depression disorder (MDD) and social anxiety disorder (SAD) are characterized by the use of perseverative cognition (PC) as a dysfunctional coping strategy. We sought to investigate the dysfunctional physiological and psychological consequences of PC and how the valence of social interactions moderates such consequences in these psychopathological conditions. DESIGN/METHODS: The study combined 24-hour heart rate variability (HRV) and ecological momentary assessments in 48 individuals with MDD, SAD, and sex-matched controls. RESULTS: In all participants, PC was associated with mood worsening and reduced ability of the parasympathetic nervous system, mainly the vagus, to inhibit sympathetic arousal (i.e., reduced HRV). Individuals with SAD had the highest frequency of daily PC, while those with MDD reported that PC interfered more with their ongoing activities. In SAD, daily PC was associated with significantly lower HRV after negative social interactions. Individuals with MDD reported higher levels of sadness during PC irrespective of the valence of the preceding social interaction but higher levels of anxiety and efforts to inhibit PC following positive interactions. CONCLUSIONS: Results highlight the need to account for important moderators like the valence of social interaction when looking at the physiological consequences of maladaptive emotion regulation strategies.

Factors associated with depression and anxiety in children with intellectual disabilities.

BACKGROUND: Individuals with intellectual disabilities (ID) are at increased risk for depression and anxiety disorders; however, there is a paucity of research that pertains to associative factors for these mental health disorders in this population. The objective of this investigation was to determine factors associated with depression and anxiety problems in children with ID. METHODS: Children 6-17 years with ID (n = 423; 63% male) from the 2016 National Survey of Children's Health were included in this cross-sectional study. Outcome measures included depression and anxiety problems. Predictor variables included sociodemographics, ID severity, co-morbid conditions (autism spectrum disorders, epilepsy, cerebral palsy, Down syndrome and attention-deficit/hyperactivity disorder), physical factors (i.e. physical activity, sleep duration and pain) and social factors (e.g. participation in activities and bully victimisation). Multivariable logistic regression was performed to determine the association between all factors and depression and/or anxiety problems among children with ID. RESULTS: The prevalence of depression and/or anxiety problems was 35.4%. After adjusting for sociodemographics, Hispanic race was associated with lower odds [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.8] of depression and/or anxiety problems. After adjusting for race, co-morbid conditions, and physical and social factors, autism spectrum disorders (OR, 4.4; 95% CI, 1.1-10.1), Down syndrome (OR, 0.2; 95% CI, 0.1-0.8), attention-deficit/hyperactivity disorder (OR, 5.9; 95% CI, 2.5-14.3), pain (OR, 7.0; 95% CI, 2.9-17.1) and bully victimisation (OR 2.3; 95% CI, 1.0-5.3) were each associated with depression and/or anxiety problems. CONCLUSIONS: The present study identified both treatable and modifiable, as well as unmodifiable, factors associated with depression and/or anxiety problems in children with ID.

Asymmetries in reciprocal baroreflex mechanisms and chronic pain severity: Focusing on irritable bowel syndrome.

BACKGROUND: Objective measures of pain severity remain ill defined, although its accurate measurement is critical. Reciprocal baroreflex mechanisms of blood pressure (BP) control were found to impact differently on pain regulation, and thus their asymmetry was hypothesized to also connect to chronic pain duration and severity. METHODS: Seventy-eight female patients with irritable bowel syndrome (IBS) and 27 healthy women were assessed for IBS severity and chronicity, negative affect, and various measures of resting autonomic function including BP, heart rate and its variability (HRV), baroreceptor-sensitivity to activations and inhibitions, gains of brady- and tachy-cardiac baro-responses, gains of BP falls/rises, and BP start points for these spontaneous baroreflexes. KEY RESULTS: IBS directly and indirectly (through increased negative affect) was associated with asymmetry between baroreceptor activations/inhibitions compared to symmetrical baroreflex reciprocity in the healthy women. In the IBS group, independently of specific IBS symptoms, pain chronicity was associated with (i) decreased BP falls coupled with either (a) decreased tachycardia associated with lower disease severity (earlier "pain resilience" mechanism), or (b) decreased bradycardia associated with higher disease severity (later "pain decompensation" mechanism), or (ii) increased BP start point for baroreceptor activations coupled with either (a) BP increase (delayed "pain adaptation" mechanism) or (b) affect-related HRV decrease (delayed "pain aggravation" mechanism). CONCLUSION AND INFERENCES: We anticipate the findings to be a starting point for validating these autonomic metrics of pain suffering and pain coping mechanisms in other chronic pain syndromes to suggest them as biomarkers of its severity and duration for profiling and correct management of chronic pain patients.

Is a stepdown unit safe for patients with mild traumatic intracranial hemorrhages?

PURPOSE: Traumatic brain injuries (TBIs) are a major source of disability in the United States. The ideal unit in the hospital for patients with mild traumatic intracranial hemorrhages (ICHs) has not been elucidated. We sought to investigate whether patients treated in the surgical stepdown area had worse outcomes than those treated in the surgical ICU. METHODS: We compared patients with ICHs and a Glasgow Coma Scale (GCS) upon admission of 14 or 15 who went to the ICU to those who went to the stepdown area from April 2014 to November 2016. We compared age, gender, Injury Severity Score (ISS), admission GCS (14 or 15), operative intervention, discharge destination, hospital length of stay (HLOS), mortality, and cost between these two groups. RESULTS: Patients admitted to the ICU had a significantly longer HLOS. Admission costs for patients admitted to ICU were also significantly higher than their stepdown area counterparts. This was true for both total charges (p = 0.0001) and for net revenue (p = 0.002) (Table 2). There was no statistically significant difference in mortality, operative intervention, or discharge destination. CONCLUSION: A surgical stepdown unit can be a safe disposition for patients with mild traumatic ICHs and represents an effective use of hospital resources.

Effects of imperfect angular adjustment on plasmonic force.

The attractive plasmonic force between two metallic walls due to electromagnetic wave in the slit has been studied earlier for parallel plates and normal incidence. In present paper the effects of imperfectly adjusted plates and laser beam are analyzed. The change of force for non-parallel plates is shown to be of the first order in angle when the wedge is oriented along wave propagation and of the second order for the transverse case. Beam inclination decreases the force due to an antisymmetric mode excited in the slit.

Magnetic character of holmium atom adsorbed on platinum surface.

We address a recent controversy concerning the magnetic state of holmium adatom on platinum surface. Within a combination of the density functional theory (DFT) with the exact diagonalization (ED) of Anderson impurity model, the 〈J z 〉 = 0 paramagnetic ground state |J = 8, J z = ±8〉 is found. In an external magnetic field, this state is transformed to a spin-polarized state with 〈J z 〉 ≈ 6.7. We emphasize the role of 5d-4f interorbital exchange polarization in modification of the 4f shell energy spectrum.

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage.

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4-, 8-, and 13-fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1-, 1.5-, and 1.7-fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2-fold).

Method for computing the optimal signal distribution and channel capacity.

An iterative method for computing the channel capacity of both discrete and continuous input, continuous output channels is proposed. The efficiency of new method is demonstrated in comparison with the classical Blahut - Arimoto algorithm for several known channels. Moreover, we also present a hybrid method combining advantages of both the Blahut - Arimoto algorithm and our iterative approach. The new method is especially efficient for the channels with a priory unknown discrete input alphabet.

Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer.

In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen-ERα-induced cell proliferation. In ERα-containing cancer cells, the estrogen, 17ß-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα(+) breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.

The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.

BACKGROUND: Bile acid diarrhoea is a common cause of chronic diarrhoea, occurring as a primary condition or secondary to ileal disease or resection. Many patients have reduced levels of the ileal hormone fibroblast growth factor 19 (FGF19), an inhibitory regulator of hepatic bile acid synthesis, secreted in response to farnesoid X receptor (FXR) activation. AIM: To investigate whether obeticholic acid, a potent FXR agonist, could increase FGF19 in patients with bile acid diarrhoea, and produce clinical benefits. METHODS: After a 2 week run-in when bile acid sequestrants were discontinued, patients with previously diagnosed primary bile acid diarrhoea (n = 10), secondary bile acid diarrhoea (n = 10) or idiopathic chronic diarrhoea (n = 8), received oral obeticholic acid 25 mg daily for 2 weeks. Serum FGF19, total bile acids and 7α-OH-4-cholesten-3-one (C4) were measured, symptoms recorded and a diarrhoea index calculated. RESULTS: In primary bile acid diarrhoea, obeticholic acid increased median fasting FGF19 (133-237 pg/mL, P = 0.007) and significantly reduced fasting C4 and bile acid responses. Improvements occurred in median stool frequency (-24% after 2 weeks treatment, P = 0.03), stool form (-14%, P = 0.05) and diarrhoea index (-34%, P = 0.005). In the secondary bile acid diarrhoea group, significant clinical improvements were found predominantly in patients with shorter ileal resections. Symptoms of abdominal pain and urgency improved. FGF19 and bile acids changed in the control group, without significant clinical improvement. Total and LDL-cholesterol increased and triglycerides decreased. Obeticholic acid treatment was well tolerated. CONCLUSIONS: This proof-of-concept study indicates that obeticholic acid stimulates FGF19, reduces bile acid synthesis and produces clinical benefits in bile acid diarrhoea. FXR agonists have therapeutic potential in chronic diarrhoea. EudraCT 2011-003777-28; Clinical Trials: NCT01585025.

Negative surveillance endoscopy occurs frequently in patients with short-segment non-dysplastic Barrett's esophagus.

Surveillance endoscopy of non-dysplastic Barrett's esophagus (NDBE) that fails to detect intestinal metaplasia (IM), or negative surveillance, is known to occur in clinical practice, although the frequency and possible outcomes in a large cohort in clinical practice is not well described. The goals of this study were to define frequency in which negative surveillance occurs and endoscopic outcomes in a screening cohort of short segment NDBE. A retrospective cohort (n = 184) of patients newly diagnosed with short segment NDBE at an outpatient academic tertiary care center between 2003 and 2011 were reviewed. Only those with one or more surveillance endoscopies were included to define a frequency of negative surveillance. Included patients were further assessed if they had two or more surveillance endoscopies and were classified into groups as sampling error or negative IM on consecutive surveillances based on the results of their surveillance endoscopies. The frequency of a negative surveillance endoscopy in all short-segment NDBE patients was 19.66% (92 endoscopic exams were negative for IM of 468 total surveillance exams). A negative surveillance endoscopy occurred in 40.76% (n = 75) patients. Sampling error occurred in 44.12% and negative IM on consecutive surveillance endoscopies in 55.88% of those with ≥ 2 surveillance endoscopies and an initially negative surveillance exam. The frequency of negative IM on consecutive surveillances was 19.00% of all patients who had two surveillance endoscopies. When the index diagnostic Barrett's esophagus segment length was < 1 cm, 32.14% (18/56) of all patients (with ≥ 2 surveillance endoscopies) had negative IM on consecutive surveillance endoscopies. Negative surveillance occurs frequently in short-segment NDBE. When an initial negative surveillance endoscopy occurs, it may be due to either a sampling error or lack of detectable IM on surveillance exam. When a <1 cm segment of NDBE is diagnosed, a significant proportion of patients may go on to have continuously undetected IM on consecutive surveillance endoscopic exams without intervention.

Acute postoperative pain relief with immediate-release tapentadol: randomized, double-blind, placebo-controlled study conducted in South Korea.

OBJECTIVE: To broaden the ethnic groups in which tapentadol IR is evaluated for treating acute postoperative pain to include Asians. METHODS: In this phase 3, multicenter, double-blind, randomized study, 352 Korean adults with moderate-to-severe pain following hallux valgus surgery received tapentadol IR 50 or 75 mg or placebo orally every 4-6 hours for 72 hours. Patients requesting other (rescue) analgesics during this period were discontinued for lack of efficacy. The primary endpoint, sum of pain intensity difference (SPID) over 48 hours, was evaluated based on the difference between tapentadol IR and placebo in least squares (LS) mean change from baseline using analysis of covariance (ANCOVA). Secondary endpoints included the time to first rescue medication use and the distribution of responder rates. RESULTS: A treatment effect, favoring tapentadol IR, was observed for SPID48 (p < 0.001 for both doses vs. placebo, ANCOVA). The between-group difference (vs. placebo) in LS means of SPID48 was 76.4 (95% CI: 51.0, 101.7) for tapentadol IR 50 mg and 90.6 (95% CI: 65.1, 116.1) for tapentadol IR 75 mg. Time to first rescue medication use was delayed for tapentadol IR (p < 0.001 for both doses vs. placebo; log-rank test). The distribution of responders at 12, 24, 48, and 72 hours favored tapentadol IR (p ≤ 0.001 for both doses vs. placebo; Cochran-Mantel-Haenszel test). Dizziness, nausea, and vomiting were each reported in ≥ 10% tapentadol-treated patients and at an incidence ≥ 2-fold higher vs. placebo. The study findings may be limited by study drug dosing every 4 to 6 hours and frequent monitoring during treatment, neither of which mimic pain treatment in clinical practice. However, any potential bias based on this systematic monitoring of patients would be mitigated by the randomized, double-blind nature of the study, with all treatment groups similarly affected by such biases, if any. CONCLUSIONS: Tapentadol IR reduced acute pain intensity, significantly more than placebo, after orthopedic surgery in Korean patients. CLINICAL TRIAL REGISTRATION: NCT01516008.

Mechanisms of hemolysis-associated platelet activation.

BACKGROUND: Intravascular hemolysis occurs after blood transfusion, in hemolytic anemias, and in other conditions, and is associated with hypercoagulable states. Hemolysis has been shown to potently activate platelets in vitro and in vivo, and several mechanisms have been suggested to account for this, including: (i) direct activation by hemoglobin (Hb); (ii) increase in reactive oxygen species (ROS); (iii) scavenging of nitric oxide (NO) by released Hb; and (iv) release of intraerythrocytic ADP. OBJECTIVE: To elucidate the mechanism of hemolysis-mediated platelet activation. METHODS: We used flow cytometry to detect PAC-1 binding to activated platelets for in vitro experiments, and a Siemens' Advia 120 hematology system to assess platelet aggregation by using platelet counts from in vivo experiments in a rodent model. RESULTS: We found that Hb did not directly activate platelets. However, ADP bound to Hb could cause platelet activation. Furthermore, platelet activation caused by shearing of red blood cells (RBCs) was reduced in the presence of apyrase, which metabolizes ADP to AMP. The use of ROS scavengers did not affect platelet activation. We also found that cell-free Hb enhanced platelet activation by abrogating the inhibitory effect of NO on platelet activation. In vivo infusions of ADP and purified (ADP-free) Hb, as well as hemolysate, resulted in platelet aggregation, as shown by decreased platelet counts. CONCLUSION: Two primary mechanisms account for RBC hemolysis-associated platelet activation: ADP release, which activates platelets; and cell-free Hb release, which enhances platelet activation by lowering NO bioavailability.

Packed red blood cell transfusion is an independent risk factor for necrotizing enterocolitis in premature infants.

OBJECTIVE: To determine whether a temporal association exists between antecedent packed red blood cell (PRBC) transfusions and necrotizing enterocolitis (NEC) in premature infants. STUDY DESIGN: This case-control study included inborn infants from a single center who developed NEC during a 2-year period. For every NEC infant, two matched controls from the same period were chosen based on gestational age and birth weight. Transfusion-related NEC was defined as antecedent PRBC transfusion within 48 h prior to the onset of any symptoms attributable to NEC. Bivariate analyses were used to compare baseline characteristics of all infants. To determine the raw odds ratio for the presence of exposure (transfusion) versus outcome (NEC), the hospital course (ages 6 to 63 days) of all study infants was divided into 48-h epochs; occurrence of transfusion and NEC was noted within each epoch. Generalized estimating equations were used to estimate the adjusted odds for developing NEC within an epoch with and without antecedent transfusion, controlling chronological age within infant as well as for gestational age, gender, feeding status in prior 48-h epoch and indicators of disease severity. RESULT: There were 3652 48-h epochs and 557 transfusions among 49 NEC infants and 97 controls; 17 infants had transfusion-related NEC, yielding a raw odds ratio of 3.01 (P<0.001). The adjusted odds ratios were 2.97 (P=0.003) for transfusion and 2.76 (P=0.05) for feeding status in the prior 48-h epoch. Infants who were being fed in the 48-h period prior to transfusion were more than eight times more likely to develop NEC than infants who were neither fed nor transfused. CONCLUSION: Antecedent PRBC transfusion appears to be an independent risk factor for developing NEC during the subsequent 48-h period.

Stress and neurodevelopmental processes in the emergence of psychosis.

The notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored.