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To investigate the therapeutic potential and underlying mechanisms of exogenous nicotinamide adenine dinucleotide+ on postresuscitation myocardial and neurologic dysfunction in a rat model of cardiac arrest.Thirty-eight rats were randomized into three groups: 1) Sham, 2) Control, and 3) NAD. Except for the sham group, untreated ventricular fibrillation for 6 minutes followed by cardiopulmonary resuscitation was performed in the control and NAD groups. Nicotinamide adenine dinucleotide+ (20 mg/kg) was IV administered at the onset of return of spontaneous circulation.University-affiliated research laboratory.Sprague-Dawley rats.Nicotinamide adenine dinucleotide+.Hemodynamic and myocardial function were measured at baseline and within 4 hours following return of spontaneous circulation. Survival analysis and Neurologic Deficit Score were performed up to 72 hours after return of spontaneous circulation. Adenosine triphosphate (adenosine triphosphate) level was measured in both brain and heart tissue. Mitochondrial respiratory chain function, acetylation level, and expression of Sirtuin3 and NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9 (NDUFA9) in isolated mitochondrial protein from both brain and heart tissue were evaluated at 4 hours following return of spontaneous circulation. The results demonstrated that nicotinamide adenine dinucleotide+ treatment improved mean arterial pressure (at 1 hr following return of spontaneous circulation, 94.69 ± 4.25 mm Hg vs 89.57 ± 7.71 mm Hg; p0.05), ejection fraction (at 1 hr following return of spontaneous circulation, 62.67% ± 6.71% vs 52.96% ± 9.37%; p0.05), Neurologic Deficit Score (at 24 hr following return of spontaneous circulation, 449.50 ± 82.58 vs 339.50 ± 90.66; p0.05), and survival rate compared with that of the control group. The adenosine triphosphate level and complex I respiratory were significantly restored in the NAD group compared with those of the control group. In addition, nicotinamide adenine dinucleotide+ treatment activated the Sirtuin3 pathway, down-regulating acetylated-NDUFA9 in the isolated mitochondria protein.Exogenous nicotinamide adenine dinucleotide+ treatment attenuated postresuscitation myocardial and neurologic dysfunction. The responsible mechanisms may involve the preservation of mitochondrial complex I respiratory capacity and adenosine triphosphate production, which involves the Sirtuin3-NDUFA9 deacetylation.

Blocking ferroptosis reduces ischemia-reperfusion injury in some pathological contexts. However, there is no evidence that ferroptosis contributes to post-resuscitation myocardial dysfunction (PRMD). Here, we evaluated the therapeutic performance of ferroptosis inhibitors (UAMC-3203 or/and Deferoxamine) on the PRMD in a rat model of cardiac arrest and surveyed the changes of essential ferroptosis markers in the myocardium. Remarkably, all treatments reduce the severity of cardiac dysfunction and microcirculation hypoperfusion after resuscitation compared with control. Consistently, we observe that the ferroptosis marker Glutathione peroxidase 4, 4-hydroxynonenal and non-heme iron altered (1 ± 0.060 vs. 0.021 ± 0.016, 1 ± 0.145 vs. 3.338 ± 0.221, 52.010 ± 3.587 ug/g vs. 70.500 ± 3.158 ug/g, all P 0.05) in the myocardium after resuscitation. These changes were significantly suppressed by UAMC-3203 [(0.187 ± 0.043, 2.848 ± 0.169, all P 0.05), (72.43 ± 4.920 ug/g, P 0.05)], or Deferoxamine (0.203 ± 0.025, 2.683 ± 0.273, 55.95 ± 2.497 ug/g, all P 0.05). Briefly, UAMC-3203 or/and Deferoxamine improve post-resuscitation myocardial dysfunction and provide evidence of ferroptosis involvement, suggesting that ferroptosis inhibitors could potentially provide an innovative therapeutic approach for mitigating the myocardial damage caused by cardiopulmonary resuscitation.

Cardiac arrest (CA) remains a major public health issue. Inflammatory responses with overproduction of interleukin-1β regulated by NLRP3 inflammasome activation play a crucial role in cerebral ischemia/reperfusion injury. We investigated the effects of the selective NLRP3-inflammasome inhibitor MCC950 on post-resuscitation cerebral function and neurologic outcome in a rat model of cardiac arrest. Thirty-six male rats were randomized into the MCC950 group, the control group, or the sham group (N = 12 of each group). Each group was divided into a 6 h non-survival subgroup (N = 6) and a 24 h survival subgroup (N = 6). Ventricular fibrillation (VF) was electrically induced and untreated for 6 min, followed by 8 min of precordial compressions and mechanical ventilation. Resuscitation was attempted with a 4J defibrillation. Either MCC950 (10 mg/kg) or vehicle was injected intraperitoneally immediately after the return of spontaneous circulation (ROSC). Rats in the sham group underwent the same surgical procedures without VF and CPR. Brain edema, cerebral microcirculation, plasma interleukin Iβ (IL-1β), and neuron-specific enolase (NSE) concentration were measured at 6 h post-ROSC of non-survival subgroups, while 24 h survival rate, neurological deficits were measured at 24 h post-ROSC of survival subgroups. Post-resuscitation brain edema was significantly reduced in animals treated with MCC950 (p

Background To investigate the therapeutic potential of combined therapy with polyethylene glycol‐20k (PEG‐20k) and MCC950 on post‐resuscitation myocardial function in a rat model of cardiac arrest. Methods and Results Thirty rats were randomized into 5 groups: Sham, Control, PEG‐20k, MCC950, PEG‐20k+ MCC950. Except for sham, animals were subjected to 6 minutes of ventricular fibrillation followed by 8 minutes cardiopulmonary resuscitation. Two milliliters PEG‐20k was administered by intravenous injection coincident with the start of cardiopulmonary resuscitation; MCC950 (10 mg/kg), a highly selective NLRP3 inflammasome inhibitor, was delivered immediately after restoration of spontaneous circulation. Myocardial function, sublingual microcirculation, mitochondrial function, plasma cardiac troponin I, and interleukin‐1β, expression of proteins in SIRT1 (sirtuin 1)/PGC‐1α (peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha) and NLRP3 (the NOD‐like receptor family protein 3) inflammasome pathways were evaluated. Following cardiopulmonary resuscitation, myocardial function was compromised with a significantly decreased cardiac output, ejection fraction, and increased myocardial performance index, cardiac troponin I. Sublingual microcirculation was disturbed with impaired perfused vessel density and microvascular flow index. Cardiac arrest reduced mitochondrial routine respiration, Complex I‐linked respiration, respiratory control rates and oxidative phosphorylation coupling efficiency. PEG‐20k or MCC950 alone restored mitochondrial respiratory function, restituted sublingual microcirculation, and preserved myocardial function, whereas a combination of PEG‐20k and MCC950 further improved these aspects. PEG‐20k restored the expression of SIRT1 and PGC‐1α, and blunted activation of NLRP3 inflammasomes. MCC950 suppressed expression of cleaved‐caspase‐1/pro‐caspase‐1, ASC (apoptosis‐associated speck‐like protein), GSDMD [gasdermin d], and interleukin‐1β. Conclusions Combined therapy with PEG‐20k and MCC950 is superior to either therapy alone for preserving post‐resuscitated myocardial function, restituting sublingual microcirculation at restoration of spontaneous circulation at 6 hours. The responsible mechanisms involve upregulated expression of SIRT1/PGC1‐α in tandem with inhibition of NLRP3 inflammasomes.

Accumulating evidence demonstrated that administration of ω-3 polyunsaturated fatty acid (ω-3 PUFA) or ascorbic acid (AA) following cardiac arrest (CA) improves survival. Therefore, we investigate the effects of ω-3 PUFA combined with AA on myocardial function after CA and cardiopulmonary resuscitation (CPR) in a rat model. Thirty male rats were randomized into 5 groups: (1) sham; (2) control; (3) ω-3 PUFA; (4) AA; (5) ω-3 PUFA + AA. Ventricular fibrillation (VF) was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Infusion of drug or vehicle occurred at the start of CPR. Myocardial function and sublingual microcirculation were measured at baseline and after return of spontaneous circulation (ROSC). Heart tissues and blood were collected 6 h after ROSC. Myocardial function and sublingual microcirculation improvements were seen with ω-3 PUFA or AA compared to control after ROSC (p < 0.05). ω-3 PUFA + AA shows a better myocardial function than ω-3 PUFA or AA (p < 0.05). ω-3 PUFA or AA decreases pro-inflammatory cytokines, cTnI, myocardium malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) modified proteins compared to control (p < 0.05). ω-3 PUFA and AA combined have lower MDA and 4-HNE modified proteins than alone (p < 0.05). ω-3 PUFA or AA treatment reduces the severity of post-resuscitation myocardial dysfunction, improves sublingual microcirculation, decreases lipid peroxidation and systemic inflammation in the early phase of recovery following CA and resuscitation. A combination of ω-3 PUFA and AA treatment confers an additive effect in suppressing lipid peroxidation and improving myocardial function.

Introduction: Previous studies have demonstrated that ferroptosis, a newly defined iron-dependent cell death, mediates ischemia/reperfusion induced cardiomyopathy. However, it is unclear whether ferroptosis plays a role in post-resuscitation myocardial dysfunction (PRMD). This study investigated the effects of UAMC-3203, a novel analog of ferroptosis specific inhibitors, on myocardial function after cardiopulmonary resuscitation (CPR). Hypothesis: Administration of UAMC-3203 during CPR alleviates PRMD in a rat model of cardiac arrest (CA) and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450-550g were randomized into 3 groups: 1) Sham, 2) Control, and 3) UAMC-3203 (5mg/kg, IP at start of precordial compression). Ventricular fibrillation (VF) was induced and continued for 6min. CPR was then initiated for 8min, after which defibrillation was attempted. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 15min, 1h, 3h and 6h respectively after return of spontaneous circulation (ROSC). Results: A significant reduction in cardiac function was observed after resuscitation. At 15 minutes after ROSC, ultrasound showed no difference in cardiac function between UAMC and control. However, at 1, 3, and 6 h after ROSC, UAMC significantly improved myocardial function (p Conclusion: A ferroptosis-specific inhibitor, UAMC-3203, alleviated PRMD significantly in a rat of model of CA and CPR. Further study is needed to determine the benefit of this agent in larger animals and potential safety in humans before it can be tested in clinical resuscitation.

Introduction: Massive systemic inflammation is a primary cause of myocardial dysfunction following cardiac arrest (CA) and resuscitation (CPR). We investigated the effects of ω-3 polyunsaturated fatty acids (ω-3 PUFA) on systemic inflammation and myocardial function after CA and CPR. Hypothesis: Administration of ω-3 PUFA at the start of CPR will alleviate post CPR inflammation and improve cardiac function in a rat model of CA and CPR. Methods: 18 male Sprague-Dawley rats weighing between 450g-550g were randomized into three groups: Sham, Control, and ω-3 PUFA. Ventricular fibrillation (VF) was induced and untreated for 6 min. 4J defibrillation was attempted after 8 min of CPR. Saline placebo or ω-3 PUFA (5mL/kg) was infused at the start of CPR and continued for 4h. Ejection fraction (EF), cardiac output (CO) and myocardial performance index (MPI) were measured by echocardiography at baseline, 1, 3 and 6h after return of spontaneous circulation (ROSC). Inflammatory cytokines (IL-6 and TNF-α) and cardiac biomarker (cTnI) levels in plasma were detected at baseline and 6 hrs after ROSC. Results: A decrease in EF and CO and an increase in MPI occurred after resuscitation. Significant improvement was noted in ω-3 PUFA compared to control animals (p Conclusion: Administration of ω-3 PUFA attenuates post-resuscitation systemic inflammation and improves myocardial function in a rat model of CA and CPR.

Background The association between Free Sugars intake and non-communicable diseases such as obesity and dental caries is well documented and several countries are taking measures to reduce sugars intakes. Public Health England (PHE) instigated a range of approaches to reduce sugars, including a national health marketing campaign (Sugar Smart). The campaign aimed to raise awareness of the amount of sugars in foods and drinks and to encourage parents to reduce their children’s intake. The aim of this study was to determine whether the campaign was effective in altering dietary behaviour, by assessing any impact of the campaign on sugars intake among children aged 5–11 years. Parental perceptions of the campaign and barriers to reducing sugars intake were also explored. Methods Parents of 873 children aged 5–11 years, identified from an existing PHE database, were invited to take part. Dietary information was collected online using Intake24 before, during, and at 1, 10 and 12 months following the campaign. Change in sugars intake was assessed using mixed effects linear regression models. One-to-one telephone interviews were conducted with a purposive sample of parents to explore perceptions of the campaign and identify barriers and facilitators to reducing children’s sugars intake. Results Completion rates for dietary assessment ranged from 61 to 72% across the follow up time points. Qualitative telephone interviews were conducted with 20 parents. Total sugars intake decreased on average by ~ 6.2 g/day (SD 43.8) at peak campaign and the percentage of energy from total sugars significantly decreased immediately and 1 year post campaign. The percentage of energy from Free Sugars significantly decreased across all time points with the exception of the long term follow up at 12-months post campaign. The percentage of energy intake from total fat increased. Parents expressed a willingness to reduce sugars intakes, however, identified barriers including time constraints, the normalisation of sugary treats, and confusing information. Conclusions A health marketing campaign had a positive impact in reducing sugars intake but reductions in sugars were not sustained. Parents want to reduce their child’s sugars intake but societal barriers and confusion over which sources of sugars to avoid hamper efforts to change.

Background Epinephrine increases the rate of return of spontaneous circulation. However, it increases severity of postresuscitation myocardial and cerebral dysfunction and reduces duration of survival. We investigated the effects of aortic infused polyethylene glycol, 20 000 molecular weight ( PEG ‐20k) during cardiopulmonary resuscitation on coronary perfusion pressure, postresuscitation myocardial and cerebral function, and duration of survival in a rat model of cardiac arrest. Methods and Results Twenty‐four male rats were randomized into 4 groups: (1) PEG ‐20k, (2) epinephrine, (3) saline control–intravenous, and (4) saline control–intra‐aortic. Cardiopulmonary resuscitation was initiated after 6 minutes of untreated ventricular fibrillation. In PEG ‐20k and Saline‐A, either PEG ‐20k (10% weight/volume in 10% estimated blood volume infused over 3 minutes) or saline was administered intra‐aortically after 4 minutes of precordial compression. In epinephrine and placebo groups, either epinephrine (20 μg/kg) or saline placebo was administered intravenously after 4 minutes of precordial compression. Resuscitation was attempted after 8 minutes of cardiopulmonary resuscitation. Sublingual microcirculation was measured at baseline and 1, 3, and 5 hours after return of spontaneous circulation. Myocardial function was measured at baseline and 2, 4, and 6 hours after return of spontaneous circulation. Neurologic deficit scores were recorded at 24, 48, and 72 hours after return of spontaneous circulation. Aortic infusion of PEG ‐20k increased coronary perfusion pressure to the same extent as epinephrine. Postresuscitation sublingual microcirculation, myocardial and cerebral function, and duration of survival were improved in PEG ‐20k ( P P Conclusions Aortic infusion of PEG ‐20k during cardiopulmonary resuscitation increases coronary perfusion pressure to the same extent as epinephrine, improves postresuscitation myocardial and cerebral function, and increases duration of survival in a rat model of cardiac arrest.

The physiology and physiopathology process of mitochondrial function following cardiac arrest remains poorly understood. We aimed to assess mitochondrial respiratory function on the heart and brain homogenates from cardiac arrest rats. The expression level of SIRT1/PGC-1α pathway was measured by immunoblotting. 30 rats were assigned to the CA group and the sham group. Rats of CA were subjected to 6 min of untreated ventricular fibrillation (VF) followed by 8 min of cardiopulmonary resuscitation (CPR). Mitochondrial respiratory function was compromised following CA and I/R injury, as indicated by CIL (451.46 ± 71.48 vs. 909.91 ± 5.51 pmol/min*mg for the heart and 464.14 ± 8.22 vs. 570.53 ± 56.33 pmol/min*mg for the brain), CI (564.04 ± 64.34 vs. 2729.52 ± 347.39 pmol/min*mg for the heart and 726.07 ± 85.78 vs. 1762.82 ± 262.04 pmol/min*mg for the brain), RCR (1.88 ± 0.46 vs. 3.57 ± 0.38 for the heart and 2.05 ± 0.19 vs. 3.49 ± 0.19, for the brain) and OXPHOS coupling efficiency (0.45 ± 0.11 vs. 0.72 ± 0.03 for the heart and 0.52 ± 0.05 vs. 0.71 ± 0.01 for the brain). However, routine respiration was lower in the heart and comparable in the brain after CA. CIV did not change in the heart but was enhanced in the brain. Furthermore, both SIRT1 and PGC-1α were downregulated concurrently in the heart and brain. The mitochondrial respiratory function was compromised following CA and I/R injury, and the major affected respiratory state is complex I-linked respiration. Furthermore, the heart and the brain respond differently to the global I/R injury after CA in mitochondrial respiratory function. Inhibition of the SIRT1/PGC-1α pathway may be a major contributor to the impaired mitochondrial respiratory function.

Brain mitochondria are more sensitive to global ischemia compared to heart mitochondria. Complex I in the electron transport chain (ETC) is sensitive to ischemic injury and is a major control point of the rate of ADP stimulated oxygen consumption. The purpose of this study was to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest. Animals were randomized into 4 groups (n = 6): 1) Sham 2) VF 3) VF+CPR 4) ROSC 1hr. Ventricular Fibrillation (VF) was induced through a guide wire advanced from the right jugular vein into the ventricle and untreated for 8 min. Resuscitation was attempted with a 4J defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Brain mitochondria and cardiac mitochondrial subpopulations were isolated. Calcium retention capacity was measured to assess susceptibility to mitochondrial permeability transition pore opening. ADP stimulated oxygen consumption and ETC activity assays were performed. Brain mitochondria are far more sensitive to injury during cardiac arrest and resuscitation compared to cardiac mitochondria. Complex I is highly sensitive to injury in brain mitochondria. With markedly decreased calcium retention capacity, mitochondria contribute to cerebral reperfusion injury. Therapeutic preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurologic function.

Background Soluble receptor for advanced glycation end-products (sRAGE), a soluble isoform of the RAGE receptor, is elevated in lungs from patients with acute conditions such as acute respiratory distress syndrome and bronchiolitis. This study investigated whether sRAGE is present in ventilated infants. Methods Tracheal aspirates from the first week or the fifth week of life were obtained from intubated very low birth weight subjects and analyzed by Western blot. Immunohistochemistry analysis for sRAGE was performed on paraffin-embedded lung autopsy slides from 19 other infants. Results The sRAGE band densities were similar among the seven infants who fully recovered, eight who developed bronchopulmonary dysplasia (BPD), and 5 who died (analysis of variance p = 0.797) but was higher at 4 weeks, p = 0.0324. There was minimal sRAGE staining in the autopsied lungs from previable infants (20–21 weeks) or from those who were not ventilated or had mild lung disease. In contrast, substantial staining was present in two of three with BPD, and those who received high ventilatory support. Conclusion sRAGE is present in ventilated infants. Levels are generally higher in those who receive prolonged or vigorous mechanical ventilation. Since sRAGE may have roles in inflammation and cell adherence, its role in the development of BPD may warrant study.

Introduction: Neurologic and myocardial dysfunction after successful resuscitation is prominent and mitochondrial dysfunction is predicted to be a key determinant of poor outcomes. Mitochondria contribute a critical role as effectors and targets of reperfusion injury. However, the onset and severity of mitochondrial dysfunction during cardiac arrest (CA) is not fully understood. The present study was done to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest and cardiopulmonary resuscitation (CPR). Hypothesis: Mitochondrial injury is more severe in the brain compared to the heart during and following cardiac arrest and CPR. Methods: Sprague-Dawley rats weighing between 450 - 550 g were randomized into 4 groups (n=6): 1) sham (surgery, no ventricular fibrillation (VF) or CPR), 2) VF (VF 8 mins, no CPR); 3) VF and CPR (VF 8 mins and CPR 8 mins, no defibrillation); ROSC 1 h (VF 8 mins, CPR 8 mins, defibrillation, and observe 1 h after ROSC). VF was induced through a guide wire advanced from the right jugular vein into the right ventricle. Brain and heart mitochondria were extracted by differential centrifugation and used to measure oxidative phosphorylation and calcium retention capacity (CRC). Results: Compared with sham, brain mitochondrial CRC in VF, VF+CPR and ROSC 1 h were decreased (110±11 vs. 70±13, 62±24, 50±6 nmol Ca 2+ /mg protein, p2+ /mg protein). Brain mitochondrial oxidative phosphorylation with complex I substrate glutamate in VF, VF+CPR and ROSC 1 h were all decreased compared to sham (127 + 8 vs 92±17, 84±12, and 92±15, p Conclusions: Mitochondria in the brain are more sensitive to injury during CA and CPR compared to heart mitochondria. With markedly decreased CRC, mitochondria are likely to contribute to cerebral reperfusion injury during CPR and ROSC. Preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurological function.

Introduction: Epinephrine is the primary drug given during cardiopulmonary resuscitation (CPR), when given early, to reverse cardiac arrest (CA) by stimulation of α-adrenergic receptors in vascular smooth muscle. This increases coronary perfusion pressure (CPP) and increases rate of return of spontaneous circulation (ROSC). However, the use of epinephrine is not associated with a significant difference in long-term survival or favorable neurologic outcome when given late after arrest onset. In the present study, we compared the effects of aortic injection of polyethylene glycol-20k (PEG-20k) vs. epinephrine during CPR on CPP and postresuscitation myocardial and cerebral function in a rat model of CA. Hypothesis: Aortic injection of PEG-20k during CPR will increase CPP to the same extent as epinephrine without adversely affecting post-resuscitation myocardial and cerebral function. Methods: Twenty four male Sprague-Dawley rats weighing between 450-550 g were randomized into four groups: 1) PEG-20k 2) epinephrine 3) saline placebo 4) saline-intra-aorta (IA). Eight minutes of CPR was initiated after 6 minutes of untreated ventricular fibrillation. PEG-20k IA (10% est. total blood volume [1.8ml]), saline IA, saline IV or epinephrine IV (20ug/kg) was given after 4 minutes of CPR by continuous infusion over 3 minutes. CPP was recorded continuously and resuscitation was attempted with 4 Joule defibrillation. Myocardial function was measured at baseline, 2, 4, and 6 hours after ROSC by echocardiography and neurologic deficit scores (NDS) were recorded at 24, 48, and 72 hours after ROSC. Results: In both saline groups, CPP did not change. However, aortic injection of PEG-20k increased CPP significantly to the same extent as epinephrine (Fig 1). Post-resuscitation ejection fraction was significantly greater in PEG-20k compared to epinephrine (64 + 1 vs 45 + 3, p+ 50 vs 450 + 50, p

Introduction: NLRP3 inflammasome mediated pyroptosis has been demonstrated to increase myocardial and cerebral ischemia/reperfusion injury. MCC950 is a newly developed highly selective inhibitor of the NLRP3 inflammasome. Hypothesis: MCC950 administered following resuscitation will reduce the severity of post-resuscitation myocardial and cerebral dysfunction and improve duration of survival in a rat model of CPR. Methods: 15 male Sprague-Dawley rats weighting between 450-550 g were randomized into three groups: 1) MCC950 2) Control 3) Sham. Ventricular fibrillation (VF) was induced and untreated for 6 min. CPR was then initiated and continued for 8 min. Resuscitation was attempted with a 4 J defibrillation. Either MCC950 (10mg/kg) or vehicle was administered intraperitoneal (IP) in line with cardiac injury animal studies immediately after return of spontaneous circulation (ROSC). Sham underwent the same surgical procedure without VF and CPR. Sublingual microcirculation was measured at baseline (BL), 3, 6 and 48 hrs after ROSC. Ejection fraction (EF) was measured at BL, 1, 3, 6 and 48 hrs after ROSC. Neurologic Deficit Score (NDS) was recorded at 48 hrs after resuscitation. Results: Post-resuscitation ejection fraction and perfused sublingual vessel density were greater in MCC950 compared to control (p Conclusion: Administration of MCC950 following ROSC mitigates post-resuscitation myocardial and cerebral dysfunction, improves sublingual microcirculation and duration of survival in a rat model of CPR.

Introduction: Gasdermin D (GSDMD), a previously unknown protein, serves as a key effector in pyroptosis and its inhibition has protective effects during cerebral ischemia and reperfusion. Necrosulfonamide (NSA) specifically blocks the mixed lineage kinase domain-like pseudo kinase (MLKL), which directly binds to GSDMD preventing pyroptotic cell death and interleukin-1 (IL-1) release. In this study, we investigated the effects of NSA on survival and neurological function after cardiac arrest and resuscitation. Hypothesis: Administration of NSA following cardiopulmonary resuscitation (CPR) will improve survival and neurological function in a rat model of cardiac arrest. Methods: Twelve male Sprague-Dawley rats weighting between 450-550g were utilized. Ventricular fibrillation was induced and untreated for 6 min followed by defibrillation after 8 min of CPR. Animals were then randomized into two groups: NSA and control. NSA (10mg/kg) or vehicle was administered 5 minutes after restoration of spontaneous circulation (ROSC) by intraperitoneal injection. Duration of survival and neurological deficit scores were recorded at 24, 48, and 72 hours after ROSC. Results: All animals were resuscitated successfully. Duration of survival was significantly longer in the NSA group compared to control (p Conclusion: Administration of NSA after ROSC improves post-resuscitation survival and neurological function in a rat model of cardiac arrest.

Introduction: Cerebral ischemia-reperfusion injury produces inflammation and cerebral microcirculatory dysfunction after cardiopulmonary resuscitation (CPR). Melatonin (N-acetyl-5-methoxytryptamine) has both anti-inflammatory and anti-oxidative properties. In this study, we investigated the effects of melatonin on inflammation and cerebral microcirculation after cardiopulmonary resuscitation in a rat model of cardiac arrest. Hypothesis: Melatonin decreases the systemic inflammatory response after cardiopulmonary resuscitation and will preserve cerebral microcirculation in a rat model of cardiac arrest. Method: Eighteen male Sprague Dawley rats weighing between 450-550 g were randomized into three groups: 1) sham: no ventricular fibrillation (VF) and CPR; 2) CPR control: untreated VF for 6 min followed by 8 min CPR; 3) CPR+melatonin: untreated VF for 6 min followed by 8 min CPR. Melatonin (10 mg/kg) was administered intraperitoneal (IP) in line with hypoxia-ischemia animal studies after return of spontaneous circulation (ROSC). Serum TNF- α, IL-1 β and cerebral microcirculation were measured at baseline and 6 h following ROSC. Result: Serum TNF-α and IL-1β were significantly lower in the CPR+melatonin group at 6h after ROSC compared to CPR controls ( p p Conclusion: In a rat model of cardiac arrest, melatonin reduced systemic inflammation and preserved cerebral microcirculation following resuscitation.

Online self-reported 24-h dietary recall systems promise increased feasibility of dietary assessment. Comparison against interviewer-led recalls established their convergent validity; however, reliability and criterion-validity information is lacking. The validity of energy intakes (EI) reported using Intake24, an online 24-h recall system, was assessed against concurrent measurement of total energy expenditure (TEE) using doubly labelled water in ninety-eight UK adults (40–65 years). Accuracy and precision of EI were assessed using correlation and Bland–Altman analysis. Test–retest reliability of energy and nutrient intakes was assessed using data from three further UK studies where participants (11–88 years) completed Intake24 at least four times; reliability was assessed using intra-class correlations (ICC). Compared with TEE, participants under-reported EI by 25 % (95 % limits of agreement −73 % to +68 %) in the first recall, 22 % (−61 % to +41 %) for average of first two, and 25 % (−60 % to +28 %) for first three recalls. Correlations between EI and TEE were 0·31 (first), 0·47 (first two) and 0·39 (first three recalls), respectively. ICC for a single recall was 0·35 for EI and ranged from 0·31 for Fe to 0·43 for non-milk extrinsic sugars (NMES). Considering pairs of recalls (first two v. third and fourth recalls), ICC was 0·52 for EI and ranged from 0·37 for fat to 0·63 for NMES. EI reported with Intake24 was moderately correlated with objectively measured TEE and underestimated on average to the same extent as seen with interviewer-led 24-h recalls and estimated weight food diaries. Online 24-h recall systems may offer low-cost, low-burden alternatives for collecting dietary information.

BackgroundNausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are more severe and the most severe form of NVP – hyperemesis gravidarum (HG) – affects 0.3–1.0% of pregnant women. There is no widely accepted point at which NVP becomes HG.ObjectivesThis study aimed to determine the relative clinical effectiveness and cost-effectiveness of treatments for NVP and HG.Data sourcesMEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, PsycINFO, Commonwealth Agricultural Bureaux (CAB) Abstracts, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, British Nursing Index, Science Citation Index, Social Sciences Citation Index, Scopus, Conference Proceedings Index, NHS Economic Evaluation Database, Health Economic Evaluations Database, China National Knowledge Infrastructure, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from inception to September 2014. References from studies and literature reviews identified were also examined.Obstetric Medicinewas hand-searched, as were websites of relevant organisations. Costs came from NHS sources.Review methodsA systematic review of randomised and non-randomised controlled trials (RCTs) for effectiveness, and population-based case series for adverse events and fetal outcomes. Treatments: vitamins B6 and B12, ginger, acupressure/acupuncture, hypnotherapy, antiemetics, dopamine antagonists, 5-hydroxytryptamine receptor antagonists, intravenous (i.v.) fluids, corticosteroids, enteral and parenteral feeding or other novel treatment. Two reviewers extracted data and quality assessed studies. Results were narratively synthesised; planned meta-analysis was not possible due to heterogeneity and incomplete reporting. A simple economic evaluation considered the implied values of treatments.ResultsSeventy-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder (n = 20) it was unclear. The non-randomised studies (n = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo (n = 12); steroid versus usual treatment (n = 7); ginger versus placebo (n = 6); ginger versus vitamin B6 (n = 6); and vitamin B6 versus placebo (n = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin®[Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices.LimitationsThe main limitations were the quantity and quality of the data available.ConclusionThere was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and larger trials of the main therapies considered within the UK NHS are needed.Study registrationThis study is registered as PROSPERO CRD42013006642.FundingThe National Institute for Health Research Health Technology Assessment programme.

Background Epinephrine administered during cardiopulmonary resuscitation (CPR) is associated with severe post‐resuscitation myocardial dysfunction. We previously demonstrated that therapeutic hypothermia reduced the severity of post‐resuscitation myocardial dysfunction caused by epinephrine; however, the relationship between myocardial adrenoceptor expression and myocardial protective effects by hypothermia remains unclear. Methods and Results Rats weighing between 450 and 550 g were randomized into 5 groups: (1) normothermic placebo, (2) normothermic epinephrine, (3) hypothermic placebo, (4) hypothermic epinephrine, and (5) sham (not subject to cardiac arrest and resuscitation). Ventricular fibrillation was induced and untreated for 8 minutes for all other groups. Hypothermia was initiated coincident with the start of CPR and maintained at 33±0.2°C for 4 hours. Placebo or epinephrine was administered 5 minutes after the start of CPR and 3 minutes before defibrillation. Post‐resuscitation ejection fraction was measured hourly for 4 hours then hearts were harvested. Epinephrine increased coronary perfusion pressure during CPR (27±6 mm Hg versus 21±2 mm Hg P cAMP doubled in the normothermic epinephrine group (655.06±447.63 μmol/L) compared with the hypothermic epinephrine group (302.51±97.98 μmol/L; P 1 ‐adrenoceptor expression decreased with normothermia cardiac arrest but not with hypothermia regardless of epinephrine. Conclusions Epinephrine, administered during normothermic CPR , increased the severity of post‐resuscitation myocardial dysfunction. This adverse effect was inhibited by intra‐arrest hypothermia resuscitation. Declined cAMP with more preserved β 1 ‐adrenoceptors in hypothermia‐resuscitated myocardium is associated with improved post‐resuscitated myocardial function in vivo.

Microcirculation is the motor of sepsis. In the present study, we investigated whether microcirculatory alterations occur prior to changes of systemic hemodynamics in a rat model of cecum ligation and puncture (CLP)-induced sepsis. We further investigated renal microcirculatory changes during sepsis and compared those with buccal microcirculation. Twelve male Sprague-Dawley rats were randomized into a sham control group (n = 6) and a CLP group (n = 6). Perfused microvessel density (PVD) and microvascular flow index (MFI) were evaluated using sidestream dark field (SDF) video microscopy at baseline, 60, 120, 180, 240, 300, and 360 minutes following CLP. A semiquantitative score was calculated for vessels of < 20 um, primarily representing the capillaries. Hemodynamic measurements such as cardiac output (CO), aortic pressure (AP), heart rate (HR), end tidal CO2 (ETCO2), blood pH, and lactate were measured simultaneously. The serum cytokine Interleukin 6 (IL-6) was measured at baseline, 120, 240, and 360 minutes. In the CLP group, Buccal PVD and MFI were reduced at 180 minutes (p < 0.05 vs. baseline); Renal PVD and MFI were reduced at 180 minutes (p < 0.05 vs. baseline), but MAP and CO did not change until 300 minutes after CLP. In the rat model of peritonitis-induced sepsis, microcirculatory alterations of both peripheral mucosa and kidney occurred earlier than global hemodynamics. Monitoring the microcirculation may provide a means of early detection of circulatory failure during sepsis. The changes of renal microcirculation correlate with that of buccal during sepsis and septic shock.

Dietary assessment has come under much criticism of late to the extent that it has been questioned whether self-reported methods of dietary assessment are worth doing at all. Widespread under-reporting of energy intake, limitations due to memory, changes to intake due to the burden of recording and social desirability bias all impact significantly on the accuracy of the dietary information collected. Under-reporting of energy intakes has long been recognized as a problem in dietary research with doubly labeled water measures of energy expenditure uncovering significant under-reporting of energy intakes across different populations and different dietary assessment methods. In this review we focus on dietary assessment with children with particular attention on the 24-hour dietary recall method. We look at the level of under-reporting of energy intakes and how this tends to change with age, gender and body mass index. We discuss potential alternatives to self-reported (or proxy-reported) dietary assessment methods with children, such as biomarkers, and how these do not enable the collection of information important to public health nutrition such as the cooking method, the mixture of foods eaten together or the context in which the food is consumed. We conclude that despite all of the challenges and flaws, the data collected using self-reported dietary assessment methods are extremely valuable. Research into dietary assessment methodology has resulted in significant increases in our understanding of the limitations of self-reported methods and progressive improvements in the accuracy of the data collected. Hence, future investment in dietary surveillance and in improving self-reported methods of intake can make vital contributions to our understanding of dietary intakes and are thus warranted.

SUMMARY Background Patients on haemodialysis (HD) have greater iron needs than the normal population. In 2004, the Caring for Australasians with Renal Impairment (CARI) group audited six Australian renal centres and found considerable variability in achievement of iron and haemoglobin targets. Objectives The aim of this study was to determine whether intravenous iron guidelines and evidence translate into good clinical outcomes for patients on HD. Design and Measurement Data were extracted from the Renal Anaemia Management database for the period of 2007–2009. These data were compared with the target levels described in the CARI guidelines. Results Most patients were not achieving recommended haemoglobin, ferritin or transferrin saturation levels. Australian Aboriginal and Torres Strait Islander people were less likely to achieve targets. Conclusions Iron guidelines are not translating into good clinical practice for patients on HD. This situation may be improved by updating the CARI guidelines (as has recently been carried out for haemoglobin targets), introduction of more consistent dosing protocols across hospitals and greater assessment of safe levels of cumulative iron and ferritin.

SUMMARY Background Indigenous Australians have significantly higher rates of end-stage renal disease and worse health outcomes than non-indigenous Australians. Objectives We investigated whether the effect of inflammation on C-reactive protein (CRP) and ferritin levels is being overlooked in indigenous patients with chronic kidney disease. Design Data for 23,000 patients were extracted from the Renal Anaemia Management database for the period November 1999 to October 2010. Measurement Haemoglobin, ferritin, transferrin saturation and CRP levels for indigenous and non-indigenous Australians were compared with target levels given in the Caring for Australians with Renal Impairment (CARI) guidelines. Results Compared with non-indigenous patients, indigenous Australians had higher median CRP and mean ferritin levels, lower mean haemoglobin level and were less likely to meet CARI targets. Conclusion The effect of inflammation on laboratory parameters should be considered particularly when treating indigenous Australians.

Importance Nausea and vomiting affects approximately 85% of pregnant women. The most severe form, hyperemesis gravidarum, affects up to 3% of women and can have significant adverse physical and psychological sequelae.Objective To summarize current evidence on effective treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum.Evidence Review Databases were searched to June 8, 2016. Relevant websites and bibliographies were also searched. Titles and abstracts were assessed independently by 2 reviewers. Results were narratively synthesized; planned meta-analysis was not possible because of heterogeneity and incomplete reporting of findings.Findings Seventy-eight studies (n = 8930 participants) were included: 67 randomized clinical trials (RCTs) and 11 nonrandomized studies. Evidence from 35 RCTs at low risk of bias indicated that ginger, vitamin B6, antihistamines, metoclopramide (for mild symptoms), pyridoxine-doxylamine, and ondansetron (for moderate symptoms) were associated with improved symptoms compared with placebo. One RCT (n = 86) reported greater improvements in moderate symptoms following psychotherapy (change in Rhodes score [range, 0 {no symptoms} to 40 {worst possible symptoms}], 18.76 [SD, 5.48] to 7.06 [SD, 5.79] for intervention vs 19.18 [SD, 5.63] to 12.81 [SD, 6.88] for comparator [P

This study compared strength, dexterity, and the muscle activation of individuals with rheumatoid arthritis (RA) when different splints were worn. Five persons with RA were observed in four splint conditions (none, static, hinged, spiral) during grip, pinch, and dexterity tests by recording muscle activity of eight muscles in the upper extremity using electromyography (EMG). Statistically significant differences were found in clinical tests when hinged (p0.001) and spiral splints (p=0.02) were worn. Grip strength decreased when hinged splints were worn, whereas two-point pinch increased and dexterity improved on the Nine-Hole Peg Test with the spiral splint. Although no significant EMG differences were found during different splint conditions, wrist muscles were recruited more for grip, and shoulder muscles were used most during pinch and dexterity tests. Individuals with RA who wore splints had decreased grip when wearing hinged splints, but improved pinch and dexterity were found when the spiral splint was worn. Increased use of proximal shoulder muscles was observed during pinch and dexterity tests with and without splints.

BACKGROUND: While the efficacy and effectiveness of brief interventions for alcohol (ABI) have been demonstrated in primary care, there is weaker evidence in other settings and reviews do not consider differences in content. We conducted a systematic review to measure the effect of ABIs on alcohol consumption and how it differs by the setting, practitioner group and content of intervention. METHODS: We searched MEDLINE, EMBASE, PsycINFO; CINAHL, Social Science Citation Index, Cochrane Library and Global Health up to January 2015 for randomised controlled trials that measured effectiveness of ABIs on alcohol consumption. We grouped outcomes into measures of quantity and frequency indices. We used multilevel meta-analysis to estimate pooled effect sizes and tested for the effect of moderators through a multiparameter Wald test. Stratified analysis of a subset of quantity and frequency outcomes was conducted as a sensitivity check. RESULTS: 52 trials were included contributing data on 29 891 individuals. ABIs reduced the quantity of alcohol consumed by 0.15 SDs. While neither the setting nor content appeared to significantly moderate intervention effectiveness, the provider did in some analyses. Interventions delivered by nurses had the most effect in reducing quantity (d=-0.23, 95% CI (-0.33 to -0.13)) but not frequency of alcohol consumption. All content groups had statistically significant mean effects, brief advice was the most effective in reducing quantity consumed (d=-0.20, 95% CI (-0.30 to -0.09)). Effects were maintained in the stratified sensitivity analysis at the first and last assessment time. CONCLUSIONS: ABIs play a small but significant role in reducing alcohol consumption. Findings show the positive role of nurses in delivering interventions. The lack of evidence on the impact of content of intervention reinforces advice that services should select the ABI tool that best suits their needs.

Quantitative studies of neural graft development require: (1) a cell label which is both preferential for neurons and can be measured in terms of specific labeling; (2) a serial reconstruction method for identifying labeled cells in a three-dimensional pattern in the host; and (3) measurements of cell dispersion which indicate the specificity of cell movement in the host. We have used 5' bromodeoxyuridine (BrdU) as a nuclear marker of transplanted fetal hippocampal cells, performing daily injections into the donor to label the majority of cells in the hippocampus between Gestation Days 15 and 19. After harvesting, the BrdU-labeled hippocampal cell suspensions were either cultured or grafted into normal adult hippocampus. The labeling index of these fetal hippocampal cells was calculated to be 90% in both smears of cell suspensions and 48-h cultures and these were predominantly (77%) neurons by immunostains. Quantitative studies of potential toxicity of the BrdU in culture also revealed no differences in neurite development or survival, compared to unlabeled cells. The survival and migration of grafted cells were quantitatively evaluated by three-dimensional serial reconstruction of host brain sections. Absolute graft cell survival (cells recovered/cells injected) varied according to location: grafts in close proximity to the ventricle and white matter tracts (corpus callosum or fimbria) showed improved survival (20 and 25%, respectively) compared to grafts localized entirely within the (normal) hippocampus (only 9% survival). Although the grafts expanded considerably from the initial injection site, the graft cell dispersion appeared nonspecific. Thus, this format of quantitative graft assessment indicates that under normal (nonlesioned) host conditions the location of the grafts critically influenced graft development and there was minimal specific migration of grafted cells into cell body regions.

Effects of fetal hippocampal transplants were evaluated following a prolonged intraventricular excitotoxic lesion (1.0 mg of N-methyl-D-aspartate over two weeks infusion) in F344 rats. The septum and ipsilateral hippocampus (CA1 and dentate regions) showed extensive cell loss, decreased acquisition of spatial memory was observed and a decrease in AChE positive fiber innervation to the hippocampus was noted following the lesion. Fetal hippocampal transplants into the posterior lateral ventricle resulted in moderate graft survival and physiological analysis of graft-host interconnection in vitro demonstrated evoked field potentials. However, the transplants did not lead to significant improvement in behavior, possibly due to poor synaptic integration of the intraventricular transplants into the host hippocampus. The prolonged intraventricular NMDA lesion may be helpful to understand a mixed lesion model of both septal areas and hippocampus and also as a background lesion in which to assess the connectivity and development of various types of neural grafts.

The purpose of this study was to measure dexterity in children aged 4-19 years using the Nine-hole Peg Test. Four hundred and six children were tested with their dominant hand and then their nondominant hand. A commercial version of the Nine-hole Peg Test was used. An analysis of variance showed a main effect for age, gender, and hand dominance. Speed of dexterity improved with age. In all age groups, females performed faster than males. Participants performed faster with the dominant hand than the nondominant hand. The normative data collected provide information for comparing scores to children with different diagnostic categories to screen for fine motor difficulties.

F344 rats of various ages (2-3 months, 15-16 months, and 24-25 months) were tested on a spatial memory task. The 15- and 24-month-old rat groups showed impaired acquisition and retention of the memory task, compared to the young animals. Extracellular field potential recordings in the CA1 region were subsequently performed in vitro, using hippocampal slices from both these tested rats and similar but untested F344 young and aged rats. Findings included: a) a positive correlation between baseline dendritic EPSP slope values and retention scores across age groups; b) a more rapid decay of both somatic and dendritic short-term potentiation in aged slices; c) decreased somatic but not dendritic long-term potentiation overall in aged slices, regardless of bath Mg2+ level; and d) decreased paired-pulse facilitation in slices from aged rats bathed in 4.0 mM Mg2+ media compared to young controls. These findings suggest an age-related alteration in both presynaptic and postsynaptic potentiation mechanisms, which may relate to the poor spatial memory acquisition and retention in the aged rats. These age-related differences point to substantial changes in neuronal signal processing capabilities and local circuit function in the hippocampus as a function of aging.