A Double-Edged Sword Role for Ubiquitin-Proteasome System in Brain Stem Cardiovascular Regulation During Experimental Brain Death

BACKGROUND: Brain stem cardiovascular regulatory dysfunction during brain death is underpinned by an upregulation of nitric oxide synthase II (NOS II) in rostral ventrolateral medulla (RVLM), the origin of a life-and-death signal detected from blood pressure of comatose patients that disappears before brain death ensues. Furthermore, the ubiquitin-proteasome system (UPS) may be involved in the synthesis and degradation of NOS II. We assessed the hypothesis that the UPS participates in brain stem cardiovascular regulation during brain death by engaging in both synthesis and degradation of NOS II in RVLM. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of brain death using Sprague-Dawley rats, pretreatment by microinjection into the bilateral RVLM of proteasome inhibitors (lactacystin or proteasome inhibitor II) antagonized the hypotension and reduction in the life-and-death signal elicited by intravenous administration of Escherichia coli lipopolysaccharide (LPS). On the other hand, pretreatment with an inhibitor of ubiquitin-recycling (ubiquitin aldehyde) or ubiquitin C-terminal hydrolase isozyme L1 (UCH-L1) potentiated the elicited hypotension and blunted the prevalence of the life-and-death signal. Real-time polymerase chain reaction, Western blot, electrophoresis mobility shift assay, chromatin immunoprecipitation and co-immunoprecipitation experiments further showed that the proteasome inhibitors antagonized the augmented nuclear presence of NF-κB or binding between NF-κB and nos II promoter and blunted the reduced cytosolic presence of phosphorylated IκB. The already impeded NOS II protein expression by proteasome inhibitor II was further reduced after gene-knockdown of NF-κB in RVLM. In animals pretreated with UCH-L1 inhibitor and died before significant increase in nos II mRNA occurred, NOS II protein expression in RVLM was considerably elevated. CONCLUSIONS/SIGNIFICANCE: We conclude that UPS participates in the defunct and maintained brain stem cardiovascular regulation during experimental brain death by engaging in both synthesis and degradation of NOS II at RVLM. Our results provide information on new therapeutic initiatives against this fatal eventuality

Acu-TENS and Postexercise Expiratory Flow Volume in Healthy Subjects

Transcutaneous Electrical Nerve Stimulation over acupoints (Acu-TENS) facilitates recovery of resting heart rate after treadmill exercise in healthy subjects. Its effect on postexercise respiratory indices has not been reported. This study investigates the effect of Acu-TENS on forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in healthy subjects after a submaximal exercise. Eleven male subjects were invited to the laboratory twice, two weeks apart, to receive in random order either Acu-TENS or Placebo-TENS (no electrical output from the TENS unit) over bilateral Lieque (LU7) and Dingchuan (EX-B1) for 45 minutes, before undergoing exercise following the Bruce protocol. Exercise duration, rate of perceived exertion (RPE), and peak heart rate (PHR) were recorded. Between-group FEV1 and FVC, before, immediately after, at 15, 30, and 45minutes postexercise, were compared. While no between-group differences in PHR, RPE, and FVC were found, Acu-TENS was associated with a longer exercise duration (0.9 min (P = .026)) and a higher percentage increase in FEV1 at 15 and 45 minutes postexercise (3.3 ± 3.7% (P = .013) and 5.1 ± 7.5% (P = .047), resp.) compared to Placebo-TENS. We concluded that Acu-TENS was associated with a higher postexercise FEV1 and a prolongation of submaximal exercise

Theory-based behavioral change interventions to improve periodontal health

Periodontal disease is a significant global health burden affecting half of the world's population. Given that plaque and inflammation control are essential to the attainment of periodontal health, recent trends in preventive dentistry have focused on the use of behavioral models to understand patient psychology and promote self-care and treatment compliance. In addition to their uses in classifying, explaining and predicting oral hygiene practices, behavioral models have been adopted in the design of oral hygiene interventions from individual to population levels. Despite the growing focus on behavioral modification in dentistry, the currently available evidence in the field of periodontology is scarce, and interventions have primarily measured changes in patient beliefs or performance in oral hygiene behaviors. Few studies have measured their impact on clinical outcomes, such as plaque levels, gingival bleeding and periodontal pocket reduction, which serve as indicators of the patient's disease status and quality of oral self-care. The present narrative review aims to summarize selected literature on the use of behavioral models to improve periodontal outcomes. A search was performed on existing behavioral models used to guide dental interventions to identify their use in interventions measuring periodontal parameters. The main models were identified and subsequently grouped by their underlying theoretical area of focus: patient beliefs (health belief model and cognitive behavioral principles); stages of readiness to change (precaution adoption process model and transtheoretical model); planning behavioral change (health action process approach model, theory of planned behavior and client self-care commitment model); and self-monitoring (self-regulation theory). Key constructs of each model and the findings of associated interventions were described. The COM-B model, a newer behavioral change system that has been increasingly used to guide interventions and policy changes, is discussed with reference to its use in oral health settings. Within the limitations of the available evidence, interventions addressing patient beliefs, motivation, intention and self-regulation could lead to improved outcomes in periodontal health. Direct comparisons between interventions could not be made due to differences in protocol design, research populations and follow-up periods. The conclusions of this review assist clinicians with implementing psychological interventions for oral hygiene promotion and highlight the need for additional studies on the clinical effects of behavioral model-based interventions

GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

Genomic Reconstruction of an Uncultured Hydrothermal Vent Gammaproteobacterial Methanotroph (Family Methylothermaceae) Indicates Multiple Adaptations to Oxygen Limitation

Hydrothermal vents are an important contributor to marine biogeochemistry, producing large volumes of reduced fluids, gasses, and metals and housing unique, productive microbial and animal communities fueled by chemosynthesis. Methane is a common constituent of hydrothermal vent fluid and is frequently consumed at vent sites by methanotrophic bacteria that serve to control escape of this greenhouse gas into the atmosphere. Despite their ecological and geochemical importance, little is known about the ecophysiology of uncultured hydrothermal vent-associated methanotrophic bacteria. Using metagenomic binning techniques, we recovered and analyzed a near-complete genome from a novel gammaproteobacterial methanotroph (B42) associated with a white smoker chimney in the Southern Lau basin. B42 was the dominant methanotroph in the community, at ∼80x coverage, with only four others detected in the metagenome, all on low coverage contigs (7x–12x). Phylogenetic placement of B42 showed it is a member of the Methylothermaceae, a family currently represented by only one sequenced genome. Metabolic inferences based on the presence of known pathways in the genome showed that B42 possesses a branched respiratory chain with A- and B-family heme copper oxidases, cytochrome bd oxidase and a partial denitrification pathway. These genes could allow B42 to respire over a wide range of oxygen concentrations within the highly dynamic vent environment. Phylogenies of the denitrification genes revealed they are the result of separate horizontal gene transfer from other Proteobacteria and suggest that denitrification is a selective advantage in conditions where extremely low oxygen concentrations require all oxygen to be used for methane activation

Brain Stem Death as the Vital Determinant for Resumption of Spontaneous Circulation after Cardiac Arrest in Rats

BACKGROUND:Spontaneous circulation returns to less than half of adult cardiac arrest victims who received in-hospital resuscitation. One clue for this disheartening outcome arises from the prognosis that asystole invariably takes place, after a time lag, on diagnosis of brain stem death. The designation of brain stem death as the point of no return further suggests that permanent impairment of the brain stem cardiovascular regulatory machinery precedes death. It follows that a crucial determinant for successful revival of an arrested heart is that spontaneous circulation must resume before brain stem death commences. Here, we evaluated the hypothesis that maintained functional integrity of the rostral ventrolateral medulla (RVLM), a neural substrate that is intimately related to brain stem death and central circulatory regulation, holds the key to the vital time-window between cardiac arrest and resumption of spontaneous circulation. METHODOLOGY/PRINCIPAL FINDINGS:An animal model of brain stem death employing the pesticide mevinphos as the experimental insult in Sprague-Dawley rats was used. Intravenous administration of lethal doses of mevinphos elicited an abrupt cardiac arrest, accompanied by elevated systemic arterial pressure and anoxia, augmented neuronal excitability and enhanced microvascular perfusion in RVLM. This period represents the vital time-window between cardiac arrest and resumption of spontaneous circulation in our experimental model. Animals with restored spontaneous circulation exhibited maintained neuronal functionality in RVLM beyond this critical time-window, alongside resumption of baseline tissue oxygen and enhancement of local blood flow. Intriguingly, animals that subsequently died manifested sustained anoxia, diminished local blood flow, depressed mitochondrial electron transport activities and reduced ATP production, leading to necrotic cell death in RVLM. That amelioration of mitochondrial dysfunction and bioenergetic failure in RVLM by coenzyme Q10, the mobile electron carrier in mitochondrial respiratory chain, or oxygenation restored spontaneous circulation further established a causal relationship between functionality of RVLM and resumed spontaneous circulation after cardiac arrest. CONCLUSIONS/SIGNIFICANCE:We conclude that whereas necrotic cell death because of bioenergetic failure triggered by anoxia in RVLM, which precipitates brain stem death, negates resuscitation of an arrested heart, maintained functional integrity of this neural substrate holds the key to resumption of spontaneous circulation after cardiac arrest in rats

Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients - a longitudinal observational study

<p>Abstract</p> <p>Background</p> <p>The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes.</p> <p>Methods</p> <p>This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrolment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005.</p> <p>Results</p> <p>Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment.</p> <p>Conclusion</p> <p>In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.</p

Pitch perception and production in congenital amusia: evidence from Cantonese speakers

This study investigated pitch perception and production in speech and music in individuals with congenital amusia (a disorder of musical pitch processing) who are native speakers of Cantonese, a tone language with a highly complex tonal system. Sixteen Cantonese-speaking congenital amusics and 16 controls performed a set of lexical tone perception, production, singing, and psychophysical pitch threshold tasks. Their tone production accuracy and singing proficiency were subsequently judged by independent listeners, and subjected to acoustic analyses. Relative to controls, amusics showed impaired discrimination of lexical tones in both speech and non-speech conditions. They also received lower ratings for singing proficiency, producing larger pitch interval deviations and making more pitch interval errors compared to controls. Demonstrating higher pitch direction identification thresholds than controls for both speech syllables and piano tones, amusics nevertheless produced native lexical tones with comparable pitch heights/contours and intelligibility as controls. Significant correlations were found between pitch threshold and lexical tone perception, music perception and production, but not between lexical tone perception and production for amusics. These findings provide further evidence that congenital amusia is domain-general language-independent pitch-processing deficit that is associated with severely impaired music perception and production, mildly impaired speech perception, and largely intact speech production

Brain-Derived Neurotrophic Factor Ameliorates Brain Stem Cardiovascular Dysregulation during Experimental Temporal Lobe Status Epilepticus

Background: Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20–30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action. Methodology/Principal Findings: In a clinically relevant experimental model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47 phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist (losartan) blunted significantly the augmented superoxide anion or phosphorylated p47 phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdn