Commitment to inclusion: The importance of collaboration in gender equity work.

Despite decades of faculty professional development programs created to prepare women for leadership, gender inequities persist in salary, promotion, and leadership roles. Indeed, men still earn more than women, are more likely than women to hold the rank of professor, and hold the vast majority of positions of power in academic medicine. Institutions demonstrate commitment to their faculty's growth by investing resources, including creating faculty development programs. These programs are essential to help prepare women to lead and navigate the highly matrixed, complex systems of academic medicine. However, data still show that women persistently lag behind men in their career advancement and salary. Clearly, training women to adapt to existing structures and norms alone is not sufficient. To effectively generate organizational change, leaders with power and resources must commit to gender equity. This article describes several efforts by the Office of Faculty in the Johns Hopkins University School of Medicine to broaden inclusivity in collaborative work for gender equity. The authors are women and men leaders in the Office of Faculty, which is within the Johns Hopkins University School of Medicine dean's office and includes Women in Science and Medicine. Here, we discuss potential methods to advance gender equity using inclusivity based on our institutional experience and on the findings of other studies. Ongoing data collection to evaluate programmatic outcomes in the Johns Hopkins University School of Medicine will be reported in the future.

Proteasome localization and activity in pig brain and in vivo small molecule screening for activators.

Introduction: Loss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology. Methods: Using pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes. Results: By Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm < nucleus). Some PSMB5 immunoreactivity was colocalized with mitochondrial (voltage-gated anion channel and cyclophilin D) and cell death (Aven) proteins in the neuronal soma and neuropil in the neocortex of pig and human brains. In the nucleus, PSMB5 immunoreactivity was diffuse, particulate, and clustered, including perinucleolar decorations. By fluorogenic assay, proteasome chymotrypsin-like activities (CTL) in crude tissue soluble fractions were generally similar within eight different pig brain regions. Proteasome CTL activity in the hippocampus was correlated with activity in nasal mucosa biopsies. In pilot analyses of subcellular fractions of pig cerebral cortex, proteasome CTL activity was highest in the cytosol and then ~50% lower in nuclear fractions; ~15-20% of total CTL activity was in pure mitochondrial fractions. With in-gel activity assay, 26S-singly and -doubly capped proteasomes were the dominant forms in the pig cerebral cortex. With a novel in situ histochemical activity assay, MG132-inhibitable proteasome CTL activity was localized to the neuropil, as a mosaic, and to cell bodies, nuclei, and centrosome-like perinuclear satellites. In piglets treated intravenously with pyrazolone derivative and chlorpromazine over 24 h, brain proteasome CTL activity was modestly increased. Discussion: This study shows that the proteasome in the pig brain has relative regional uniformity, prominent nuclear and perinuclear presence with catalytic activity, a mitochondrial association with activity, 26S-single cap dominance, and indications from small molecule systemic administration of pyrazolone derivative and chlorpromazine that brain proteasome function appears safely activable.

Staying Virtual: A Survey Study of the Virtual Lecture Experience in Academic Medicine.

BACKGROUND: Increasing clinical demands can adversely impact academic advancement, including the ability to deliver lectures and disseminate scholarly work. The virtual lecture platform became mainstream during the height of the coronavirus-19 pandemic. Lessons learned from this period may offer insight into supporting academic productivity among physicians who must balance multiple demands, including high clinical workloads and family care responsibilities. We evaluated perceptions on delivering virtual lectures to determine whether virtual venues merit continuation beyond the pandemic's initial phase and whether these perceptions differ by gender and rank. METHODS: In a survey study, faculty who spoke in 1 of 3 virtual lecture programs in the Departments of Anesthesiology and Critical Care Medicine, Otolaryngology, and Radiology at a university hospital in 2020 to 2022 were queried about their experience. Speakers' motivations to lecture virtually and the perceived advantages and disadvantages of virtual and in-person lectures were analyzed using descriptive statistics and qualitative analyses. RESULTS: Seventy-two of 95 (76%) faculty members responded (40% women, 38% men, and 22% gender undisclosed). Virtual lectures supported the speakers "a lot" to "extremely" with the following goals: enhancing one's reputation and credibility (76%), networking (70%), receiving feedback (63%), and advancing prospects for promotion (59%). Virtual programs also increased the speakers' sense of accomplishment (70%) and professional optimism (61%) by at least "a lot," including instructors and assistant professors who previously had difficulty obtaining invitations to speak outside their institution. Many respondents had declined prior invitations to speak in-person due to clinical workload (66%) and family care responsibilities (58%). Previous opportunities to lecture in-person were also refused due to finances (39%), teaching (26%), and research (19%) requirements, personal medical conditions or disabilities (9%), and religious obligations (5%). Promotion was a stronger motivating factor to lecture virtually for instructors and assistant professors than for associate and full professors. By contrast, disseminating work and ideas was a stronger motivator for associate and full professors. Associate and full professors also reported greater improvement in work-related well-being than earlier career faculty from the virtual lecture experience. Very few differences were found by gender. CONCLUSIONS: Virtual lecture programs support faculty who might not otherwise have the opportunity to lecture in-person due to multiple constraints. To increase the dissemination of scholarly work and expand opportunities to all faculty, virtual lectures should continue even as in-person venues are reestablished.

Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2-7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

Perioperative Management of Pediatric Patients with Moyamoya Arteriopathy.

Pediatric patients with moyamoya arteriopathy are at high risk for developing new onset transient or permanent neurologic deficits secondary to cerebral hypoperfusion, particularly in the perioperative period. It is therefore essential to carefully manage these patients in a multidisciplinary, coordinated effort to reduce the risk of new permanent neurologic deficits. However, little has been published on perioperative management of pediatric patients with moyamoya, particularly in the early postoperative period during intensive care unit admission. Our pediatric neurocritical care team sought to create a multidisciplinary periprocedural evidence- and consensus-based care pathway for high-risk pediatric patients with moyamoya arteriopathy undergoing anesthesia for any reason to decrease the incidence of periprocedural stroke or transient ischemic attack (TIA). We reviewed the literature to identify risk factors associated with perioperative stroke or TIA among patients with moyamoya and to gather data supporting specific perioperative management strategies. A multidisciplinary team from pediatric anesthesia, neurocritical care, nursing, child life, neurosurgery, interventional neuroradiology, neurology, and hematology created a care pathway for children with moyamoya undergoing anesthesia, classifying them as either high or standard risk, and applying an individualized perioperative management plan to high-risk patients. The incidence of neurologic sequelae before and after pathway implementation will be compared in future studies.

Rapid, selective and homogeneous brain cooling with transnasal flow of ambient air for pediatric resuscitation.

Neurologic outcome from out-of-hospital pediatric cardiac arrest remains poor. Although therapeutic hypothermia has been attempted in this patient population, a beneficial effect has yet to be demonstrated, possibly because of the delay in achieving target temperature. To minimize this delay, we developed a simple technique of transnasal cooling. Air at ambient temperature is passed through standard nasal cannula with an open mouth to produce evaporative cooling of the nasal passages. We evaluated efficacy of brain cooling with different airflows in different size piglets. Brain temperature decreased by 3°C within 25 minutes with nasal airflow rates of 16, 32, and 16 L/min in 1.8-, 4-, and 15-kg piglets, respectively, whereas rectal temperature lagged brain temperature. No substantial spatial temperature gradients were seen along the neuroaxis, suggesting that heat transfer is via blood convection. The evaporative cooling did not reduce nasal turbinate blood flow or sagittal sinus oxygenation. The rapid and selective brain cooling indicates a high humidifying capacity of the nasal turbinates is present early in life. Because of its simplicity, portability, and low cost, transnasal cooling potentially could be deployed in the field for early initiation of brain cooling prior to maintenance with standard surface cooling after pediatric cardiac arrest.

Fetal factors disrupt placental and maternal iron homeostasis in murine ß-thalassemia.

Pregnancy rates in ß-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human ß-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia. We hypothesized that disordered iron metabolism in pregnant Th3/+ mice would negatively affect their unborn offspring. The experimental design included these groups: wild-type (WT) dams carrying WT fetuses (WT1); WT dams carrying WT and Th3/+ fetuses (WT2); Th3/+ dams carrying WT and Th3/+ fetuses (Th3/+); and age-matched, nonpregnant adult females. Serum hepcidin was low, and mobilization of splenic and hepatic storage iron was enhanced in all 3 groups of experimental dams. Intestinal 59Fe absorption was lower in Th3/+ dams (as compared with WT1/2 dams) but splenic 59Fe uptake was higher. Th3/+ dams had hyperferremia, which led to fetal and placenta iron loading, fetal growth restriction, and placentomegaly. Notably, Th3/+ dams loaded Th3/+ and WT fetuses, with the latter situation more closely mirroring human circumstances when mothers with thalassemia have relatively unaffected (thalassemia trait) offspring. Iron-related oxidative stress likely contributed to fetal growth impairment; enhanced placental erythropoiesis is a probable cause of placental enlargement. Moreover, high fetal liver iron transactivated Hamp; fetal hepcidin downregulated placental ferroportin expression, limiting placental iron flux and thus mitigating fetal iron loading. Whether gestational iron loading occurs in human thalassemic pregnancy, when blood transfusion can further elevate serum iron, is worth consideration.

Evaluating the Women's Empowerment and Leadership Initiative: Supporting mentorship, career satisfaction, and well-being among pediatric anesthesiologists.

The Society for Pediatric Anesthesia launched the Women's Empowerment and Leadership Initiative (WELI) in 2018 to empower highly productive women pediatric anesthesiologists to achieve equity, promotion, and leadership. WELI is focused on six career development domains: promotion and leadership, networking, conceptualization and completion of projects, mentoring, career satisfaction, and sense of well-being. We sought feedback about whether WELI supported members' career development by surveys emailed in November 2020 (baseline), May 2021 (6 months), and January 2022 (14 months). Program feedback was quantitatively evaluated by the Likert scale questions and qualitatively evaluated by extracting themes from free-text question responses. The response rates were 60.5% (92 of 152) for the baseline, 51% (82 of 161) for the 6-month, and 52% (96 of 185) for the 14-month surveys. Five main themes were identified from the free-text responses in the 6- and 14-month surveys. Members reported that WELI helped them create meaningful connections through networking, obtain new career opportunities, find tools and projects that supported their career advancement and promotion, build the confidence to try new things beyond their comfort zone, and achieve better work-life integration. Frustration with the inability to connect in-person during the coronavirus-19 pandemic was highlighted. Advisors further stated that WELI helped them improve their mentorship skills and gave them insight into early career faculty issues. Relative to the baseline survey, protégés reported greater contributions from WELI at 6 months in helping them clarify their priorities, increase their sense of achievement, and get promoted. These benefits persisted through 14 months. Advisors reported a steady increase in forming new meaningful relationships and finding new collaborators through WELI over time. All the members reported that their self-rated mentoring abilities improved at 6 months with sustained improvement at 14 months. Thus, programs such as WELI can assist women anesthesiologists and foster gender equity in career development, promotion, and leadership.

Plasma Biomarkers of Evolving Encephalopathy and Brain Injury in Neonates with Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: The objective of the study was to evaluate the relationship between a panel of candidate plasma biomarkers and (1) death or severe brain injury on magnetic resonance imaging (MRI) and (2) dysfunctional cerebral pressure autoregulation as a measure of evolving encephalopathy. STUDY DESIGN: Neonates with moderate-to-severe hypoxic-ischemic encephalopathy (HIE) at 2 level IV neonatal intensive care units were enrolled into this observational study. Patients were treated with therapeutic hypothermia (TH) and monitored with continuous blood pressure monitoring and near-infrared spectroscopy. Cerebral pressure autoregulation was measured by the hemoglobin volume phase (HVP) index; a higher HVP index indicates poorer autoregulation. Serial blood samples were collected during TH and assayed for Tau, glial fibrillary acidic protein, and neurogranin. MRIs were assessed using National Institutes of Child Health and Human Development scores. The relationships between the candidate biomarkers and (1) death or severe brain injury on MRI (defined as a National Institutes of Child Health and Human Development score of ≥ 2B) and (2) autoregulation were evaluated using bivariate and adjusted logistic regression models. RESULTS: Sixty-two patients were included. Elevated Tau levels on days 2-3 of TH were associated with death or severe injury on MRI (aOR: 1.06, 95% CI: 1.03-1.09; aOR: 1.04, 95% CI: 1.01-1.06, respectively). Higher Tau was also associated with poorer autoregulation (higher HVP index) on the same day (P = .022). CONCLUSIONS: Elevated plasma levels of Tau are associated with death or severe brain injury by MRI and dysfunctional cerebral autoregulation in neonates with HIE. Larger-scale validation of Tau as a biomarker of brain injury in neonates with HIE is warranted.

Bacterially Converted Oat Active Ingredients Enhances Antioxidative and Anti-UVB Photoaging Activities.

Oat (Avena sativa L.) is one of the most widely consumed cereal grains worldwide and is considered as an important cereal crop with high nutritional value and potential health benefits. With different bacterial strains, fermented oat extracts were examined for the antioxidant and antiaging effects on the skin after optimization of extraction conditions. Fermented oats contained high avenanthramides, and its function was investigated on matrix metalloproteinase-1 and collagen expression with human dermal fibroblast cells. After fractionation, butanol layers showed the highest avenanthramides contents. Therefore, the microbial fermentation of oats enhances the quality and content of functional ingredients of oats, which provide natural dietary supplements, antioxidants, and antiaging agents.

Lowering n-6/n-3 Ratio as an Important Dietary Intervention to Prevent LPS-Inducible Dyslipidemia and Hepatic Abnormalities in ob/ob Mice.

Obesity is closely associated with low-grade chronic and systemic inflammation and dyslipidemia, and the consumption of omega-3 polyunsaturated fatty acids (n-3 PUFAs) may modulate obesity-related disorders, such as inflammation and dyslipidemia. An emerging research question is to understand the dietary intervention strategy that is more important regarding n-3 PUFA consumption: (1) a lower ratio of n-6/n-3 PUFAs or (2) a higher amount of n-3 PUFAs consumption. To understand the desirable dietary intervention method of n-3 PUFAs consumption, we replaced lard from the experimental diets with either perilla oil (PO) or corn oil (CO) to have identical n-3 amounts in the experimental diets. PO had a lower n-6/n-3 ratio, whereas CO contained higher amounts of PUFAs; it inherently contained relatively lower n-3 but higher n-6 PUFAs than PO. After the 12-week dietary intervention in ob/ob mice, dyslipidemia was observed in the normal chow and CO-fed ob/ob mice; however, PO feeding increased the high density lipoprotein-cholesterol (HDL-C) level; further, not only did the HDL-C level increase, the low density lipoprotein-cholesterol (LDL-C) and triglyceride (TG) levels also decreased significantly after lipopolysaccharide (LPS) injection. Consequently, extra TG accumulated in the liver and white adipose tissue (WAT) of normal chow- or CO-fed ob/ob mice after LPS injection; however, PO consumption decreased serum TG accumulation in the liver and WAT. PUFAs replacement attenuated systemic inflammation induced by LPS injection by increasing anti-inflammatory cytokines but inhibiting pro-inflammatory cytokine production in the serum and WAT. PO further decreased hepatic inflammation and fibrosis in comparison with the ND and CO. Hepatic functional biomarkers (aspartate aminotransferase (AST) and alanine transaminase (ALT) levels) were also remarkably decreased in the PO group. In LPS-challenged ob/ob mice, PO and CO decreased adipocyte size and adipokine secretion, with a reduction in phosphorylation of MAPKs compared to the ND group. In addition, LPS-inducible endoplasmic reticulum (ER) and oxidative stress decreased with consumption of PUFAs. Taken together, PUFAs from PO and CO play a role in regulating obesity-related disorders. Moreover, PO, which possesses a lower ratio of n-6/n-3 PUFAs, remarkably alleviated metabolic dysfunction in LPS-induced ob/ob mice. Therefore, an interventional trial considering the ratio of n-6/n-3 PUFAs may be desirable for modulating metabolic complications, such as inflammatory responses and ER stress in the circulation, liver, and/or WAT.

Partial Replacement of High-Fat Diet with Beef Tallow Attenuates Dyslipidemia and Endoplasmic Reticulum Stress in db/db Mice.

High-fat diet (HFD) consumption is closely associated with an increased risk of metabolic syndromes (MetS), such as obesity, type 2 diabetes, and cardiovascular diseases (CVDs). Therefore, the consumption of alternative and functional fatty acids to replace saturated fatty acids and/or trans-fatty acids with polyunsaturated fatty acids has become an important dietary strategy for the prevention of MetS. Consumption of omega-3 fatty acids (n-3) reduces various physiological complications, including CVDs, nonalcoholic fatty liver disease, and insulin resistance, related to inflammatory responses. In this study, we investigated the partial replacement effects of HFD with beef tallow (BT) on dyslipidemia and endoplasmic reticulum (ER) stress in male db/db mice. The animals were grouped to one of four dietary intervention groups (n = 16 per group): (1) normal diet, (2) HFD, (3) HFD partially replaced with regular beef tallow (HFD+BT1), or (4) HFD partially replaced with beef tallow containing a relatively reduced omega-6 fatty acid (n-6)/n-3 ratio (HFD+BT2) than HFD+BT1. After 6 weeks of dietary intervention, 1 mg/kg of phosphate-buffered saline or tunicamycin (TM) was injected intraperitoneally. HFD+BT2 significantly suppressed the serum total cholesterol and non-high-density lipoprotein cholesterol levels more than HFD and HFD+BT1, and triglyceride levels in the epididymal adipose tissue (EAT) were remarkably decreased. Mice that received HFD+BT2 had elevated protein expressions of phospho-AMP-activated protein kinase (p-AMPK). Moreover, HFD+BT2 effectively inhibited ER stress in the liver and EAT. Consistent with our hypothesis, HFD+BT2 remarkably alleviated dyslipidemia and TM-inducible ER stress, while activating p-AMPK.

Comparison of different metrics of cerebral autoregulation in association with major morbidity and mortality after cardiac surgery.

BACKGROUND: Cardiac surgery studies have established the clinical relevance of personalised arterial blood pressure management based on cerebral autoregulation. However, variabilities exist in autoregulation evaluation. We compared the association of several cerebral autoregulation metrics, calculated using different methods, with outcomes after cardiac surgery. METHODS: Autoregulation was measured during cardiac surgery in 240 patients. Mean flow index and cerebral oximetry index were calculated as Pearson's correlations between mean arterial pressure (MAP) and transcranial Doppler blood flow velocity or near-infrared spectroscopy signals. The lower limit of autoregulation and optimal mean arterial pressure were identified using mean flow index and cerebral oximetry index. Regression models were used to examine associations of area under curve and duration of mean arterial pressure below thresholds with stroke, acute kidney injury (AKI), and major morbidity and mortality. RESULTS: Both mean flow index and cerebral oximetry index identified the cerebral lower limit of autoregulation below which MAP was associated with a higher incidence of AKI and major morbidity and mortality. Based on magnitude and significance of the estimates in adjusted models, the area under curve of MAP < lower limit of autoregulation had the strongest association with AKI and major morbidity and mortality. The odds ratio for area under the curve of MAP < lower limit of autoregulation was 1.05 (95% confidence interval, 1.01-1.09), meaning every 1 mm Hg h increase of area under the curve was associated with an average increase in the odds of AKI by 5%. CONCLUSIONS: For cardiac surgery patients, area under curve of MAP < lower limit of autoregulation using mean flow index or cerebral oximetry index had the strongest association with AKI and major morbidity and mortality. Trials are necessary to evaluate this target for MAP management.

The neurosurgical management of Severe Hemophilia A and Moyamoya (SHAM): challenges, strategies, and literature review.

INTRODUCTION: Severe Hemophilia A and Moyamoya arteriopathy (SHAM syndrome) is a rare genetic disorder caused by deletion of portions of the cytogenic band Xq28. A case of SHAM syndrome requiring bilateral cerebral revascularization is described with an emphasis on perioperative management. CASE REPORT: A 5-year-old boy with severe hemophilia A complicated by factor VIII inhibition presented with right-sided weakness. Imaging revealed multiple strokes and vascular changes consistent with Moyamoya disease. The patient underwent two-staged indirect cerebral bypass revascularizations, first on the left side and several months later on the right. Perioperative management required balancing the administration of agents to prevent coagulopathy and perioperative hemorrhage while mitigating the risk of thromboembolic events associated with bypass surgery. Despite a multidisciplinary effort by the neurosurgery, hematology, critical care, and anesthesiology teams, the post-operative course after both surgeries was complicated by stroke. Fortunately, the patient recovered rapidly to his preoperative functional baseline. CONCLUSION: We describe a rare case of SHAM syndrome in a pediatric patient who required bilateral revascularizations and discuss strategies for managing the perioperative risk of hemorrhage and stroke. We also review existing literature on SHAM syndrome.

Partial Replacement of Dietary Fat with Krill Oil or Coconut Oil Alleviates Dyslipidemia by Partly Modulating Lipid Metabolism in Lipopolysaccharide-Injected Rats on a High-Fat Diet.

This study investigated the effects of partial replacement of dietary fat with krill oil (KO) or coconut oil (CO) on dyslipidemia and lipid metabolism in rats fed with a high-fat diet (HFD). Sprague Dawley rats were divided into three groups as follows: HFD, HFD + KO, and HFD + CO. The rats were fed each diet for 10 weeks and then intraperitoneally injected with phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (1 mg/kg). The KO- and CO-fed rats exhibited lower levels of serum lipids and aspartate aminotransferases than those of the HFD-fed rats. Rats fed with HFD + KO displayed significantly lower hepatic histological scores and hepatic triglyceride (TG) content than rats fed with HFD. The KO supplementation also downregulated the adipogenic gene expression in the liver. When treated with LPS, the HFD + KO and HFD + CO groups reduced the adipocyte size in the epididymal white adipose tissues (EAT) relative to the HFD group. These results suggest that KO and CO could improve lipid metabolism dysfunction.

Four AAs increase DMT1 abundance in duodenal brush-border membrane vesicles and enhance iron absorption in iron-deprived mice.

Iron-deficiency anemia is common worldwide and typically treated by oral iron supplementation. Excess enteral iron, however, may cause pathological outcomes. Developing new repletion approaches is thus warranted. Previous experimentation revealed that select amino acids (AAs) induce trafficking of transporters onto the enterocyte brush-border membrane (BBM) and enhance electrolyte absorption/secretion. Here, we hypothesized that certain AAs would increase the abundance of the main intestinal iron importer, divalent metal-ion transporter 1 (DMT1), on the BBM of duodenal enterocytes, thus stimulating iron absorption. Accordingly, all 20 AAs were screened using an ex vivo duodenal loop/DMT1 western blotting approach. Four AAs (Asp, Gln, Glu, and Gly) were selected for further experimentation and combined into a new formulation. The 4 AAs stimulated 59Fe transport in mouse duodenal epithelial sheets in Ussing chambers (∼4-fold; P < .05). In iron-deprived mice, oral intragastric administration of the 4 AA formulation increased DMT1 protein abundance on the enterocyte BBM by ∼1.5-fold (P < .05). The 4 AAs also enhanced in vivo 59Fe absorption by ∼2-fold (P < .05), even when ∼26 µg of cold iron was included in the transport solution (equal to a human dose of ∼73 mg). Further experimentation using DMT1int/int mice showed that intestinal DMT1 was required for induction of iron transport by the 4 AAs. Select AAs thus enhance iron absorption by inducing DMT1 trafficking onto the apical membrane of duodenal enterocytes. We speculate that further refinement of this new 4 AA formulation will ultimately allow iron repletion at lower effective doses (thus mitigating negative side effects of excess enteral iron).

The Utility of Cerebral Autoregulation Indices in Detecting Severe Brain Injury Varies by Cooling Treatment Phase in Neonates with Hypoxic-Ischemic Encephalopathy.

Identifying the hemodynamic range that best supports cerebral perfusion using near infrared spectroscopy (NIRS) autoregulation monitoring is a potential physiologic marker for neonatal hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia. However, an optimal autoregulation monitoring algorithm has not been identified for neonatal clinical medicine. We tested whether the hemoglobin volume phase (HVP), hemoglobin volume (HVx), and pressure passivity index (PPI) identify changes in autoregulation that are associated with brain injury on MRI or death. The HVP measures the phase difference between a NIRS metric of cerebral blood volume, the total hemoglobin (THb), and mean arterial blood pressure (MAP) at the frequency of maximum coherence. The HVx is the correlation coefficient between MAP and THb. The PPI is the percentage of coherent MAP-DHb (difference between oxygenated and deoxygenated hemoglobin, a marker of cerebral blood flow) epochs in a chosen time period. Neonates cooled for HIE were prospectively enrolled in an observational study in two neonatal intensive care units. In analyses adjusted for study site and encephalopathy level, all indices detected relationships between poor autoregulation in the first 6 h after rewarming with a higher injury score on MRI. Only HVx and PPI during hypothermia and the PPI during rewarming identified autoregulatory dysfunction associated with a poor outcome independent of study site and encephalopathy level. Our findings suggest that the accuracy of mathematical autoregulation algorithms in detecting the risk of brain injury or death may depend on temperature and postnatal age. Extending autoregulation monitoring beyond the standard 72 h of therapeutic hypothermia may serve as a method to provide personalized care by assessing the need for and efficacy of future therapies after the hypothermia treatment phase.

Depletion of Zinc Causes Osteoblast Apoptosis with Elevation of Leptin Secretion and Phosphorylation of JAK2/STAT3.

Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 µM (Low Zn) or 15 µM (High Zn) of ZnCl2 containing 5 µM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.

Use of an end-tidal carbon dioxide-guided algorithm during cardiopulmonary resuscitation improves short-term survival in paediatric swine.

AIM: To evaluate an algorithm that uses an end-tidal carbon dioxide (ETCO2) target of ≥ 30 torr to guide specific changes in chest compression rate and epinephrine administration during cardiopulmonary resuscitation (CPR) in paediatric swine. METHODS: Swine underwent asphyxial cardiac arrest followed by resuscitation with either standard or ETCO2-guided algorithm CPR. The standard group received chest compressions at a rate of 100/min and epinephrine every 4 min during advanced life support consistent with the American Heart Association paediatric resuscitation guidelines. In the ETCO2-guided algorithm group, chest compression rate was increased by 10 compressions/min for every minute that the ETCO2 was < 30 torr, and the epinephrine administration interval was decreased to every 2 min if the ETCO2 remained < 30 torr. Short-term survival and physiologic data during active resuscitation were compared. RESULTS: Short-term survival was significantly greater in the ETCO2-guided algorithm CPR group than in the standard CPR group (16/28 [57.1%] versus 4/28 [14.3%]; p = 0.002). Additionally, the algorithm group had higher predicted mean ETCO2, chest compression rate, diastolic and mean arterial pressure, and myocardial perfusion pressure throughout resuscitation. Swine in the algorithm group also exhibited significantly greater improvement in diastolic and mean arterial pressure and cerebral perfusion pressure after the first dose of epinephrine than did those in the standard group. Incidence of resuscitation-related injuries was similar in the two groups. CONCLUSIONS: Use of a resuscitation algorithm with stepwise guidance for changes in the chest compression rate and epinephrine administration interval based on a goal ETCO2 level improved survival and intra-arrest hemodynamics in this porcine cardiac arrest model.