Transradial Renal Angioplasty and Stent Placement for Systemic Hypertension Caused by Severe Unilateral Renovascular Stenosis.

Percutaneous transluminal angioplasty and stent placement for renovascular hypertension is a recognized albeit seldom used therapy. We present a case of severe renovascular hypertension, due to renal artery atherosclerosis, treated successfully with stent placement via the radial artery access approach.

Air-Evacuation-Relevant Hypobaria Following Traumatic Brain Injury Plus Hemorrhagic Shock in Rats Increases Mortality and Injury to the Gut, Lungs, and Kidneys.

ABSTRACT: Rats exposed to hypobaria equivalent to what occurs during aeromedical evacuation within a few days after isolated traumatic brain injury exhibit greater neurologic injury than those remaining at sea level. Moreover, administration of excessive supplemental O2 during hypobaria further exacerbates brain injury. This study tested the hypothesis that exposure of rats to hypobaria following controlled cortical impact (CCI)-induced brain injury plus mild hemorrhagic shock worsens multiple organ inflammation and associated mortality. In this study, at 24 h after CCI plus hemorrhagic shock, rats were exposed to either normobaria (sea level) or hypobaria (=8,000 ft altitude) for 6 h under normoxic or hyperoxic conditions. Injured rats exhibited mortality ranging from 30% for those maintained under normobaria and normoxia to 60% for those exposed to 6 h under hypobaric and hyperoxia. Lung histopathology and neutrophil infiltration at 2 days postinjury were exacerbated by hypobaria and hyperoxia. Gut and kidney inflammation at 30 days postinjury were also worsened by hypobaric hyperoxia. In conclusion, exposure of rats after brain injury and hemorrhagic shock to hypobaria or hyperoxia results in increased mortality. Based on gut, lung, and kidney histopathology at 2 to 30 days postinjury, increased mortality is consistent with multi-organ inflammation. These findings support epidemiological studies indicating that increasing aircraft cabin pressures to 4,000 ft altitude (compared with standard 8,000 ft) and limiting excessive oxygen administration will decrease critical complications during and following aeromedical transport.

Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration.

Mitochondria are both a primary source of reactive oxygen species (ROS) and a sensitive target of oxidative stress; damage to mitochondria can result in bioenergetic dysfunction and both necrotic and apoptotic cell death. These relationships between mitochondria and cell death are particularly strong in both acute and chronic neurodegenerative disorders. ROS levels are affected by both the production of superoxide and its toxic metabolites and by antioxidant defense mechanisms. Mitochondrial antioxidant activities include superoxide dismutase 2, glutathione peroxidase and reductase, and intramitochondrial glutathione. When intracellular conditions disrupt the homeostatic balance between ROS production and detoxification, a net increase in ROS and an oxidized shift in cellular redox state ensues. Cells respond to this imbalance by increasing the expression of genes that code for proteins that protect against oxidative stress and inhibit cytotoxic oxidation of proteins, DNA, and lipids. If, however, the genomic response to mitochondrial oxidative stress is insufficient to maintain homeostasis, mitochondrial bioenergetic dysfunction and release of pro-apoptotic mitochondrial proteins into the cytosol initiate a variety of cell death pathways, ultimately resulting in potentially lethal damage to vital organs, including the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a translational activating protein that enters the nucleus in response to oxidative stress, resulting in increased expression of numerous cytoprotective genes, including genes coding for mitochondrial and non-mitochondrial antioxidant proteins. Many experimental and some FDA-approved drugs promote this process. Since mitochondria are targets of ROS, it follows that protection against mitochondrial oxidative stress by the Nrf2 pathway of gene expression contributes to neuroprotection by these drugs. This document reviews the evidence that Nrf2 activation increases mitochondrial antioxidants, thereby protecting mitochondria from dysfunction and protecting neural cells from damage and death. New experimental results are provided demonstrating that post-ischemic administration of the Nrf2 activator sulforaphane protects against hippocampal neuronal death and neurologic injury in a clinically-relevant animal model of cardiac arrest and resuscitation.

Acne vulgaris and risk of depression and anxiety: A meta-analytic review.

BACKGROUND: Several studies have shown an association of acne vulgaris with depression and anxiety, but a quantitative review has not yet been conducted. OBJECTIVE: We sought to conduct a systematic review and meta-analysis that elucidates the association of acne vulgaris with depression and anxiety. METHODS: A systematic review and meta-analysis of literature published before October 1, 2019 from the PubMed, PsycINFO, MEDLINE, and Cochrane databases was conducted. We used a metaanalytic approach to perform a random effects analysis comparing individuals with and without acne. Subgroup analyses between studies included age, study setting, and geographic region. RESULTS: Forty-two studies were included. We found a significant association of acne vulgaris with depression (r = 0.22 [95% confidence interval 0.17-0.26, P < .00001]) and anxiety (r = 0.25 [95% confidence interval 0.19-0.31, P < .00001]). Subgroup analyses and comparisons showed moderating influences based on factors including age, study setting, and geographic region. LIMITATIONS: Inconsistency between publications regarding acne and outcome ascertainment, data reporting, and studies with no control group posed considerable barriers to synthesizing all available published literature. CONCLUSIONS: Because of an increased risk for depression and anxiety, clinicians should pursue aggressive treatment of acne and consider psychiatric screening or referrals.

Clinical Characteristics of Pediatric Patients With Carbon Monoxide Poisoning.

OBJECTIVES: Carbon monoxide (CO) poisoning is a common and deadly form of poisoning that is often treated with hyperbaric oxygen. The characteristics of children exposed to CO and then treated with hyperbaric oxygen have not been delineated. The purpose of this study was to describe the clinical characteristics of children treated with hyperbaric oxygen therapy for CO poisoning at a regional hyperbaric referral center. METHODS: The study is based on a retrospective review of data extracted from the medical records of children (age <19 years) who were referred to our center for hyperbaric oxygen therapy for CO poisoning between 2008 and 2013. Inferential analyses were used to compare demographic characteristics, serum carboxyhemoglobin (COHb) levels, and presenting symptoms. RESULTS: Forty-seven children met our study criteria. Their mean age was 8.9 years, and their mean COHb level was 14.3% (range, 3.4%-30.1%). Severity of symptoms did not correlate with serum COHb levels; however, neurologic symptoms at presentation were more common in patients with a COHb level greater than 25%. There was a correlation between increasing age and higher COHb levels and between COHb and lactate levels. CONCLUSIONS: Our retrospective review of patients' records showed no correlation of serum COHb levels with symptoms on presentation; however, a correlation was found between increasing age and COHb level as well as lactate level and COHb level.

Reduced perineuronal net expression in Fmr1 KO mice auditory cortex and amygdala is linked to impaired fear-associated memory.

Fragile X Syndrome (FXS) is a leading cause of heritable intellectual disability and autism. Humans with FXS show anxiety, sensory hypersensitivity and impaired learning. The mechanisms of learning impairments can be studied in the mouse model of FXS, the Fmr1 KO mouse, using tone-associated fear memory paradigms. Our previous study reported impaired development of parvalbumin (PV) positive interneurons and perineuronal nets (PNN) in the auditory cortex of Fmr1 KO mice. A recent study suggested PNN dynamics in the auditory cortex following tone-shock association is necessary for fear expression. Together these data suggest that abnormal PNN regulation may underlie tone-fear association learning deficits in Fmr1 KO mice. We tested this hypothesis by quantifying PV and PNN expression in the amygdala, hippocampus and auditory cortex of Fmr1 KO mice following fear conditioning. We found impaired tone-associated memory formation in Fmr1 KO mice. This was paralleled by impaired learning-associated regulation of PNNs in the superficial layers of auditory cortex in Fmr1 KO mice. PV cell density decreased in the auditory cortex in response to fear conditioning in both WT and Fmr1 KO mice. Learning-induced increase of PV expression in the CA3 hippocampus was only observed in WT mice. We also found reduced PNN density in the amygdala and auditory cortex of Fmr1 KO mice in all conditions, as well as reduced PNN intensity in CA2 hippocampus. There was a positive correlation between tone-associated memory and PNN density in the amygdala and auditory cortex, consistent with a tone-association deficit. Altogether our studies suggest a link between impaired PV and PNN regulation within specific regions of the fear conditioning circuit and impaired tone memory formation in Fmr1 KO mice.

Oximetry-Guided normoxic resuscitation following canine cardiac arrest reduces cerebellar Purkinje neuronal damage.

BACKGROUND: Animal studies indicate that maintaining physiologic O2 levels (normoxia) immediately after restoration of spontaneous circulation (ROSC) from cardiac arrest (CA) results in less hippocampal neuronal death compared to animals ventilated with 100% O2. This study tested the hypothesis that beneficial effects of avoiding hyperoxia following CA are apparent in the cerebellum and therefore not limited to one brain region. METHODS: Adult beagles were anesthetized and mechanically ventilated. Ventricular fibrillation CA was induced by electrical myocardial stimulation and cessation of ventilation. Ten min later, dogs were ventilated with 100% O2 and resuscitated using 3 min of open chest CPR followed by defibrillation. Dogs were ventilated for 1 h with either 100% O2 or with O2 titrated rapidly to maintain hemoglobin O2 saturation at 94-96%. FiO2 was adjusted in both groups between one and 24 h post-arrest to maintain normoxic PaO2 of 80-120 mm Hg. Following 24 h critical care, dogs were euthanized and cerebellum analyzed for histochemical measures of neuronal damage and inflammation. RESULTS AND CONCLUSIONS: Hyperoxic resuscitation increased the number of injured Purkinje cells by 278% and the number of activated microglia/macrophages by 18% compared to normoxic resuscitation. These results indicate that normoxic resuscitation promotes favorable histopathologic outcomes in the cerebellum (in addition to hippocampus) following CA/ROSC. These findings emphasize the importance of avoiding unnecessary hyperoxia following CA/ROSC.

ADRA2B deletion variant and enhanced cognitive processing of emotional information: A meta-analytical review.

This meta-analytical review examines whether a deletion variant in ADRA2B, a gene that encodes α2B adrenoceptor in the regulation of norepinephrine availability, influences cognitive processing of emotional information in human observers. Using a multilevel modeling approach, this meta-analysis of 16 published studies with a total of 2752 participants showed that ADRA2B deletion variant was significantly associated with enhanced perceptual and cognitive task performance for emotional stimuli. In contrast, this genetic effect did not manifest in overall task performance when non-emotional content was used. Furthermore, various study-level factors, such as targeted cognitive processes (memory vs. attention/perception) and task procedures (recall vs. recognition), could moderate the size of this genetic effect. Overall, with increased statistical power and standardized analytical procedures, this meta-analysis has established the contributions of ADRA2B to the interactions between emotion and cognition, adding to the growing literature on individual differences in attention, perception, and memory for emotional information in the general population.

Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria.

At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.

Aeromedical evacuation-relevant hypobaria worsens axonal and neurologic injury in rats after underbody blast-induced hyperacceleration.

BACKGROUND: Occupants of military vehicles targeted by explosive devices often suffer from traumatic brain injury (TBI) and are typically transported by the aeromedical evacuation (AE) system to a military medical center within a few days. This study tested the hypothesis that exposure of rats to AE-relevant hypobaria worsens cerebral axonal injury and neurologic impairment caused by underbody blasts. METHODS: Anesthetized adult male rats were secured within cylinders attached to a metal plate, simulating the hull of an armored vehicle. An explosive located under the plate was detonated, resulting in a peak vertical acceleration force on the plate and occupant rats of 100G. Rats remained under normobaria or were exposed to hypobaria equal to 8,000 feet in an altitude chamber for 6 hours, starting at 6 hours to 6 days after blast. At 7 days, rats were tested for vestibulomotor function using the balance beam walking task and euthanized by perfusion. The brains were then analyzed for axonal fiber injury. RESULTS: The number of internal capsule silver-stained axonal fibers was greater in animals exposed to 100G blast than in shams. Animals exposed to hypobaria starting at 6 hours to 6 days after blast exhibited more silver-stained fibers than those not exposed to hypobaria. Rats exposed to 100% oxygen (O2) during hypobaria at 24 hours postblast displayed greater silver staining and more balance beam foot-faults, in comparison with rats exposed to hypobaria under 21% O2. CONCLUSION: Exposure of rats to blast-induced acceleration of 100G increases cerebral axonal injury, which is significantly exacerbated by exposure to hypobaria as early as 6 hours and as late as 6 days postblast. Rats exposed to underbody blasts and then to hypobaria under 100% O2 exhibit increased axonal damage and impaired motor function compared to those subjected to blast and hypobaria under 21% O2. These findings raise concern about the effects of AE-related hypobaria on TBI victims, the timing of AE after TBI, and whether these effects can be mitigated by supplemental oxygen.

Inhaler syncope.

Syncope can result from certain activities that trigger an exaggerated physiological response in susceptible individuals; examples include cough, laugh, and micturition syncope. We report a novel cause for syncope, that due to reflex bradycardia and asystole produced by the use of asthma inhalers. We discuss the possible mechanisms for this effect and briefly review other breathing-related causes of bradycardia.

Carbon monoxide and ST-elevation myocardial infarction: case reports.

We describe two cases of myocardial infarction with ST-segment elevation on electrocardiogram associated with carbon monoxide (CO) poisoning, a condition rarely reported in the literature. The first was a 62-year-old woman who experienced chest pain in the emergency department (ED) while being assessed for exposure to carbon monoxide in her home. The second was an 80-year-old man who fainted at home and was found to have ST elevation during the ED workup. After hospitalization, he returned home and soon thereafter had difficulty walking and speaking. The responding paramedics detected a very high CO level in the home. Both patients received hyperbaric oxygen therapy within the first several hours of presentation. For this combination of conditions, it is difficult to derive evidence-based management recommendations, given the paucity of cases reported to date. We conclude that rapid consultation with interventional cardiology and consideration of angioplasty or stenting are appropriate, especially when electrocardiographic findings and echocardiography point to a specific coronary distribution. Hyperbaric oxygen therapy might have a role in the treatment, based on its effects on myocardial ischemia and injury in other models.

Simulated Aeromedical Evacuation Exacerbates Experimental Brain Injury.

Aeromedical evacuation, an important component in the care of many patients with traumatic brain injury (TBI), particularly in war zones, exposes them to prolonged periods of hypobaria. The effects of such exposure on pathophysiological changes and outcome after TBI are largely unexplored. The objective of this study was to investigate whether prolonged hypobaria in rats subjected to TBI alters behavioral and histological outcomes. Adult male Sprague-Dawley rats underwent fluid percussion induced injury at 1.5-1.9 atmospheres of pressure. The effects of hypobaric exposure (6 h duration; equivalent to 0.75 atmospheres) at 6, 24, and 72 h, or 7 days after TBI were evaluated with regard to sensorimotor, cognitive, and histological changes. Additional groups were evaluated to determine the effects of two hypobaric exposures after TBI, representing primary simulated aeromedical evacuation (6 h duration at 24 h after injury) and secondary evacuation (10 h duration at 72 h after injury), as well as the effects of 100% inspired oxygen concentrations during simulated evacuation. Hypobaric exposure up to 7 days after injury significantly worsened cognitive deficits, hippocampal neuronal loss, and microglial/astrocyte activation in comparison with injured controls not exposed to hypobaria. Hyperoxia during hypobaric exposure or two exposures to prolonged hypobaric conditions further exacerbated spatial memory deficits. These findings indicate that exposure to prolonged hypobaria up to 7 days after TBI, even while maintaining physiological oxygen concentration, worsens long-term cognitive function and neuroinflammation. Multiple exposures or use of 100% oxygen further exacerbates these pathophysiological effects.

Clinical Utility and Lifespan Profiling of Neurological Soft Signs in Schizophrenia Spectrum Disorders.

Neurological soft signs (NSSs) bear the promise for early detection of schizophrenia spectrum disorders. Nonetheless, the sensitivity and specificity of NSSs in the psychosis continuum remains a topic of controversy. It is also unknown how NSSs reveal neurodevelopmental abnormality in schizophrenia. We investigated the effect sizes of NSSs in differentiating individuals with schizophrenia spectrum disorders from individuals with other psychiatric conditions and from covariate-matched healthy subjects. We also investigated the partitioned age-related variations of NSSs in both schizophrenia and healthy individuals. NSSs were assessed by the abridged version of the Cambridge Neurological Inventory (CNI) in 3105 participants, consisting of healthy individuals (n=1577), unaffected first-degree relatives of schizophrenia patients (n= 155), individuals with schizotypal personality disorder (n= 256), schizophrenia patients (n= 738), and other psychiatric patients (n= 379). Exact matching and propensity score matching procedures were performed to control for covariates. Multiple regression was used to partition age-related variations. Individuals along the schizophrenia continuum showed elevated levels of NSSs, with moderate effect sizes, in contrast to other psychiatric patients who had minimal NSSs, as well as matched healthy controls. Furthermore, the age-and-NSS relationship in schizophrenia patients was represented by a flat but overall elevated pattern, in contrast to a U-shaped pattern in healthy individuals. In sum, NSSs capture a moderate portion of psychosis proneness with reasonable specificity. Lifespan profiling reveals an abnormal developmental trajectory of NSSs in schizophrenia patients, which supports the endophenotype hypothesis of NSSs by associating it with the neurodevelopmental model of schizophrenia.

Reflections on the origins of meta-analysis.

In this interview, we discuss my early uses of meta-analytic procedures, first to combine p-values and then to combine effect sizes as well. My interest in quantifying the magnitude and the statistical significance of the effect of interpersonal expectations probably grew out of the following: (1) a long-held interest in the concept of replication and (2) a series of controversies over the very existence of any effect of interpersonal expectations held, for example, by psychological experimenters, classroom teachers, and leaders of various organizations.

Hyperoxic resuscitation improves survival but worsens neurologic outcome in a rat polytrauma model of traumatic brain injury plus hemorrhagic shock.

BACKGROUND: Many traumatic brain injury (TBI) patients experience additional injuries, including those that result in hemorrhagic shock (HS). Interactions between HS and TBI can include reduced brain O2 delivery, resulting in partial cerebral ischemia and worse neurologic outcome. This study tested the hypothesis that inspiration of 100% O2 during resuscitation following TBI and HS improves survival, reduces brain lesion volume, and improves neurologic outcome compared with resuscitation in the absence of supplemental O2. METHODS: The adult male rat polytrauma model consisted of controlled cortical impact-induced TBI followed by 30 minutes of HS (mean arterial pressure, 35-40 mm Hg) induced by blood withdrawal. The HS phase was followed by a 1-hour "prehospital" Hextend fluid resuscitation phase and then a 1-hour "hospital phase" when shed blood was reinfused. Rats were randomized on the day of surgery to three groups with 10 per group: sham, polytrauma normoxic, and polytrauma hyperoxic. Normoxic animals inspired room air, and hyperoxic animals inspired 100% O2 during both resuscitation phases. Neurobehavioral tests were conducted weekly until the rats were perfused with fixative at 30 days after injury. Brain sections were stained with Fluoro Jade B and used for quantification of contusion, penumbral, and healthy cortical volumes. RESULTS: Survival was greater following hyperoxic compared with normoxic resuscitation. Composite neuroscores obtained at 2 weeks to 4 weeks following hyperoxic resuscitation were lower than those of shams. Balance beam foot faults measured at 2 weeks after injury were greater following hyperoxic resuscitation compared with normoxic resuscitation and those of shams. There was no significant difference in cerebrocortical pathology between the normoxic and hyperoxic polytrauma groups. CONCLUSION: The survival of rats following controlled cortical impact plus HS was greater following hyperoxic resuscitation. In contrast, neurologic outcomes were better following normoxic resuscitation.