Seasonal variation in ambulatory blood pressure control in patients on clinic blood pressure-guided antihypertensive treatment.

BACKGROUND: We investigated seasonal variation in ambulatory blood pressure control in hypertensive patients on clinic blood pressure-guided antihypertensive treatment. METHODS: The study participants were hypertensive patients enrolled in an 8-week therapeutic study. Antihypertensive treatment was initiated with long-acting dihydropyridine calcium channel blockers amlodipine 5 mg/day or the gastrointestinal therapeutic system (GITS) formulation of nifedipine 30 mg/day, with the possible up-titration to amlodipine 10 mg/day or nifedipine-GITS 60 mg/day at 4 weeks of follow-up. RESULTS: The proportion of up-titration to higher dosages of antihypertensive drugs at 4 weeks of follow-up was higher in patients who commenced treatment in autumn/winter ( n  = 302) than those who commenced treatment in spring/summer ( n  = 199, 24.5 vs. 12.0%, P  < 0.001). The control rate of clinic blood pressure, however, was lower in autumn/winter than in spring/summer at 4 (56.7 vs. 70.7%, P  = 0.003) and 8 weeks of follow-up (52.5 vs. 74.9%, P  < 0.001). At 8 weeks, patients who commenced treatment in autumn/winter, compared with those who commenced treatment in spring/summer, had a significantly ( P ≤0.03) smaller daytime (mean between-season difference -3.2/-2.8 mmHg) but greater nighttime SBP/DBP reduction (3.6/1.6 mmHg). Accordingly, at 8 weeks, the prevalence of nondippers was significantly ( P  < 0.001) higher in spring/summer than in autumn/winter for both SBP (54.8 vs. 30.0%) and DBP (53.4 vs. 28.8%). CONCLUSION: Clinic blood pressure-guided antihypertensive treatment requires a higher dosage of medication in cold than warm seasons, which may have led to over- and under-treatment of nighttime blood pressure, respectively.

Alcohol Consumption and Antihypertensive Treatment Effect in Male Patients With Hypertension.

BACKGROUND: Alcohol consumption is a proven risk factor of hypertension. In the present analysis, we investigated the use of antihypertensive medications and blood pressure control in male alcohol drinkers and non-drinkers with hypertension (systolic/diastolic blood pressure 160-199/100-119 mm Hg). METHODS: The study participants were patients enrolled in a 12-week therapeutic study and treated with the irbesartan/hydrochlorothiazide combination 150/12.5 mg once daily, with the possible up-titration to 300/12.5 mg/day and 300/25 mg/day at 4 and 8 weeks of follow-up, respectively, for blood pressure control of <140/90 mm Hg or <130/80 mm Hg in patients with diabetes mellitus. Alcohol consumption was classified as non-drinkers and drinkers. RESULTS: The 68 alcohol drinkers and 168 non-drinkers had similar systolic/diastolic blood pressure at baseline (160.8 ±â€…12.1/99.8 ±â€…8.6 vs. 161.8 ±â€…11.0/99.2 ±â€…8.6, P ≥ 0.55) and other characteristics except for current smoking (80.9% vs. 47.6%, P < 0.0001). In patients who completed the 12-week follow-up (n = 215), the use of higher dosages of antihypertensive drugs was similar at 4 weeks of follow-up in drinkers and non-drinkers (10.6% vs. 12.4%, P = 0.70), but increased to a significantly higher proportion in drinkers than non-drinkers at 12 weeks of follow-up (54.7% vs. 36.6%, P = 0.01). The control rate of hypertension tended to be lower in alcohol drinkers, compared with non-drinkers, at 4 weeks of follow-up (45.6% vs. 58.9%, P = 0.06), but became similar at 12 weeks of follow-up (51.5% vs. 54.8%, P = 0.65). CONCLUSION: Alcohol drinkers compared with non-drinkers required a higher dosage of antihypertensive drug treatment to achieve similar blood pressure control. CLINICAL TRIAL REGISTRY NUMBER: NCT00670566 at www.clinicaltrials.gov.

Wnt signaling in synaptogenesis of Alzheimer's disease.

Alzheimer's disease (AD), recognized as the leading cause of dementia, occupies a prominent position on the list of significant neurodegenerative disorders, representing a significant global health concern with far-reaching implications at both individual and societal levels. The primary symptom of Alzheimer's disease is a decrease in synaptic potency along with synaptic connection loss. Synapses, which act as important linkages between neuronal units within the cerebral region, are critical in signal transduction processes essential to orchestrating cognitive tasks. Synaptic connections act as critical interconnections between neuronal cells inside the cerebral environment, facilitating critical signal transduction processes required for cognitive functions. The confluence of axonal and dendritic filopodial extensions culminates in the creation of intercellular connections, coordinated by various signals and molecular mechanisms. The progression of synaptic maturation and plasticity is a critical determinant in maintaining mental well-being, and abnormalities in these processes have been linked to the development of neurodegenerative diseases. Wnt signaling pathways are important to the orchestration of synapse development. This review examines the complicated interplay between Wnt signaling and dendritic filopodia, including an examination of the regulatory complexities and molecular machinations involved in synaptogenesis progression. Then, these findings are contextualized within the context of AD pathology, allowing for the consideration of prospective therapeutic approaches based on the findings and development of novel avenues for future scientific research.

Current and recent cigarette smoking in relation to cardiovascular and non-cardiovascular mortality in an elderly male Chinese population.

OBJECTIVE: To investigate the association between current and former smoking and the risk of mortality in elderly Chinese men. METHODS: Our study participants were elderly (≥ 60 years) men recruited in a suburban town of Shanghai. Cigarette smoking status was categorized as never smoking, remote (cessation > 5 years) and recent former smoking (cessation ≤ 5 years), and light-to-moderate (≤ 20 cigarettes/day) and heavy current smoking (> 20 cigarettes/day). Cox proportional hazards models and restricted cubic splines were used to examine the associations of interest. RESULTS: The 1568 participants had a mean age of 68.6 ± 7.1 years. Of all participants, 311 were never smokers, 201 were remote former smokers, 133 were recent former smokers, 783 were light-to-moderate current smokers and 140 were heavy current smokers. During a median follow-up of 7.9 years, all-cause, cardiovascular and non-cardiovascular deaths occurred in 267, 106 and 161 participants, respectively. Heavy current smokers had the highest risk of all-cause and non-cardiovascular mortality, with an adjusted hazard ratio (HR) of 2.30 (95% CI: 1.34-4.07) and 3.98 (95% CI: 2.03-7.83) versus never smokers, respectively. Recent former smokers also had a higher risk of all-cause (HR = 1.62, 95% CI: 1.04-2.52) and non-cardiovascular mortality (HR = 2.40, 95% CI: 1.32-4.37) than never smokers. Cox regression restricted cubic spline models showed the highest risk of all-cause and non-cardiovascular mortality within 5 years of smoking cessation and decline thereafter. Further subgroup analyses showed interaction between smoking status and pulse rate (≥ 70 beats/min vs. < 70 beats/min) in relation to the risk of all-cause and non-cardiovascular mortality, with a higher risk in current versus never smokers in those participants with a pulse rate below 70 beats/min. CONCLUSIONS: Cigarette smoking in elderly Chinese confers significant risks of mortality, especially when recent former smoking is considered together with current smoking.

Brain region-specific synaptic function of FUS underlies the FTLD-linked behavioural disinhibition.

Synaptic dysfunction is one of the earliest pathological processes that contribute to the development of many neurological disorders, including Alzheimer's disease and frontotemporal lobar degeneration. However, the synaptic function of many disease-causative genes and their contribution to the pathogenesis of the related diseases remain unclear. In this study, we investigated the synaptic role of fused in sarcoma, an RNA-binding protein linked to frontotemporal lobar degeneration and amyotrophic lateral sclerosis, and its potential pathological role in frontotemporal lobar degeneration using pyramidal neuron-specific conditional knockout mice (FuscKO). We found that FUS regulates the expression of many genes associated with synaptic function in a hippocampal subregion-specific manner, concomitant with the frontotemporal lobar degeneration-linked behavioural disinhibition. Electrophysiological study and molecular pathway analyses further reveal that fused in sarcoma differentially regulates synaptic and neuronal properties in the ventral hippocampus and medial prefrontal cortex, respectively. Moreover, fused in sarcoma selectively modulates the ventral hippocampus-prefrontal cortex projection, which is known to mediate the anxiety-like behaviour. Our findings unveil the brain region- and synapse-specific role of fused in sarcoma, whose impairment might lead to the emotional symptoms associated with frontotemporal lobar degeneration.

Multisystem inflammatory syndrome (MIS-C) with SARS-CoV-2 omicron variant BA.2.38 in a four-year-old Chinese girl: A case report.

We report a severe COVID-19 complicated with MIS-C in a girl treated by the author in China, and discuss the current research status and progress in the diagnosis and therapy of MIS-C in children. The patient was a 4-year-old child previously healthy who was referred to the hospital with a complaint of fever, finally, Multisystem inflammatory syndrome was diagnosed with COVID-19.

Hyperthyroidism Presenting with Coronary Vasospasm.

Hyperthyroidism is associated with a number of heart diseases, and it may aggravate previous cardiac problems or cause new ones, such as hyperthyroid cardiopathy. Cases of hyperthyroidism presenting with coronary vasospasm are rarely reported. Herein, we present a case of a 54-year male patient with recurrent left chest pain for 2 months. Coronary angiography showed no obvious coronary artery stenosis, and coronary vasospasm was suspected. After admission, the patient's thyroid function and TSH-receptor antibody (TRAb) were abnormal. However, there was no obvious palpitation, hyperhidrosis, or weight loss, and the diagnosis of Graves' disease was rendered, which seemed to be the cause of coronary vasospasm. The patient did not experience chest pain after treatment with methimazole. Patients with coronary vasospasm should be investigated for the possibility of hyperthyroidism. Key Words: Hyperthyroidism, Chest pain, Coronary angiography, Coronary vasospasm.

Z-DNA/RNA Binding Protein 1 Senses Mitochondrial DNA to Induce Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like-Driven Necroptosis in Developmental Sevoflurane Neurotoxicity.

Developmental sevoflurane exposure leads to widespread neuronal cell death known as sevoflurane-induced neurotoxicity (SIN). Receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL)-driven necroptosis plays an important role in cell fate. Previous research has shown that inhibition of RIPK1 activity alone did not attenuate SIN. Since RIPK3/MLKL signaling could also be activated by Z-DNA/RNA binding protein 1 (ZBP1), the present study was designed to investigate whether ZBP1-mediated and RIPK3/MLKL-driven necroptosis is involved in SIN through in vitro and in vivo experiments. We found that sevoflurane priming triggers neuronal cell death and LDH release in a time-dependent manner. The expression levels of RIPK1, RIPK3, ZBP1 and membrane phosphorylated MLKL were also dramatically enhanced in SIN. Intriguingly, knockdown of RIPK3, but not RIPK1, abolished MLKL-mediated neuronal necroptosis in SIN. Additionally, inhibition of RIPK3-mediated necroptosis with GSK'872, rather than inhibition of apoptosis with zVAD, significantly ameliorated SIN. Further investigation showed that sevoflurane treatment causes mitochondrial DNA (mtDNA) release into the cytosol. Accordingly, ZBP1 senses cytosolic mtDNA and consequently activates RIPK3/MLKL signaling. This conclusion was reinforced by the evidence that knockdown of ZBP1 or depleting mtDNA with ethidium bromide remarkably improved SIN. Finally, the administration of the RIPK3 inhibitor GSK'872 relieved sevoflurane-induced spatial and emotional disorders without influence on locomotor activity. Altogether, these results illustrate that ZBP1 senses cytosolic mtDNA to induce RIPK3/MLKL-driven necroptosis in SIN. Elucidating the role of necroptosis in SIN will provide new insights into understanding the mechanism of anesthetic exposure in the developing brain.

The function of FUS in neurodevelopment revealed by the brain and spinal cord organoids.

The precise control of proliferation and differentiation of neural progenitors is crucial for the development of the central nervous system. Fused in sarcoma (FUS) is an RNA-binding protein pathogenetically linked to Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) disease, yet the function of FUS on neurodevelopment is remained to be defined. Here we report a pivotal role of FUS in regulating the human cortical brain and spinal cord development via the human iPSCs-derived organoids. We found that depletion of FUS via CRISPR/CAS9 leads to an enhancement of neural proliferation and differentiation in cortical brain-organoids, but intriguingly an impairment of these phenotypes in spinal cord-organoids. In addition, FUS binds to the mRNA of a Trk tyrosine kinase receptor of neurotrophin-3 (Ntrk3) and regulates the expression of the different isoforms of Ntrk3 in a tissue-specific manner. Finally, alleviated Ntrk3 level via shRNA rescued the effects of FUS-knockout on the development of the brain- and spinal cord-organoids, suggesting that Ntrk3 is involved in FUS-regulated organoids developmental changes. Our findings uncovered the role of FUS in the neurodevelopment of the human CNS.

Serum metabolomic characterization of PLA2G6-associated dystonia-parkinsonism: A case-control biomarker study.

Introduction: Phospholipase A2 Group VI (PLA2G6), encoding calcium-independent phospholipase A2, has been isolated as the gene responsible for an autosomal recessive form of early-onset Parkinson's disease (namely, PARK14). Compared to idiopathic Parkinson's disease (iPD), PARK14 has several atypical clinical features. PARK14 has an earlier age at onset and is more likely to develop levodopa-induced dyskinesia. In iPD, serum metabolomics has observed alterations in several metabolic pathways that are related to disease status and clinical manifestations. This study aims to describe the serum metabolomics features of patients with PARK14. Design: This case-control biomarker study tested nine patients diagnosed with PARK14. Eight age and sex-matched healthy subjects were recruited as controls. To evaluate the influence of single heterozygous mutation, we enrolled eight healthy one-degree family members of patients with PARK14, two patients diagnosed with early-onset Parkinson's disease (EOPD) who had only a single heterozygous PLA2G6 mutation, and one patient with EOPD without any known pathogenic mutation. Methods: The diagnosis of PARK14 was made according to the diagnostic criteria for Parkinson's disease (PD) and confirmed by genetic testing. To study the serum metabolic features, we analyzed participants' serum using UHPLC-QTOF/MS analysis, a well-established technology. Results: We quantified 50 compounds of metabolites from the serum of all the study subjects. Metabolites alterations in serum had good predictive accuracy for PARK14 diagnosis (AUC 0.903) and advanced stage in PARK14 (AUC 0.944). Of the 24 metabolites that changed significantly in patients' serum, eight related to lipid metabolism. Oleic acid and xanthine were associated with MMSE scores. Xanthine, L-histidine, and phenol correlated with UPDRS-III scores. Oleic acid and 1-oleoyl-L-alpha-lysophosphatidic acid could also predict the subclass of the more advanced stage in the PLA2G6 Group in ROC models. Conclusion: The significantly altered metabolites can be used to differentiate PLA2G6 pathogenic mutations and predict disease severity. Patients with PLA2G6 mutations had elevated lipid compounds in C18:1 and C16:0 groups. The alteration of lipid metabolism might be the key intermediate process in PLA2G6-related disease that needs further investigation.

[Effect of nape cluster acupuncture on swallowing function and respiratory function in patients with post-stroke dysphagia].

OBJECTIVE: To observe the effect of nape cluster acupuncture on swallowing function and respiratory function in patients with post-stroke dysphagia, and to explore its relationship to cerebral arterial flow and neurotrophic factors. METHODS: A total of 120 patients with post-stroke dysphagia were randomized into an observation group and a control group, 60 patients in each one. The conventional swallowing rehabilitation therapy and respiratory function training were adopted in the control group. On the basis of treatment in the control group, nape cluster acupuncture was applied at Fengchi (GB 20), Tianzhu (BL 10), Wangu (GB 12), Lianquan (CV 23), Panglianquan (Extra), once a day; pricking blood was applied at Jinjin (EX-HN 12) and Yuye (EX-HN 13), once every 2 days. Both groups were treated for 2 weeks. The therapeutic efficacy was compared between the two groups, and the swallowing function (scores of Kubota water swallowing test, standardized swallowing assessment [SSA] and video fluoroscopic swallowing study [VFSS]), the respiratory function indexes (forced vital capacity [FVC], maximal voluntary ventilation [MVV] and maximal expiratory time), the bilateral cerebral arterial hemodynamics parameters (systolic peak velocity [Vs], mean flow velocity [Vm] and vascular resistance index [RI]) and the serology indexes (brain-derived neurotrophic factor [BDNF], nerve growth factor [NGF] and insulin-like growth factors-1 [IGF-1]) before and after treatment were observed in the both groups. RESULTS: The total effective rate was 80.0% (48/60) in the observation group, which was superior to 60.0% (36/60) in the control group (P<0.05). After treatment, the scores of Kubota water swallowing test and SSA in the observation group were lower than the control group (P<0.05), the VFSS score, FVC, MVV and maximal expiratory time were higher than the control group (P<0.05). After treatment, the Vs and Vm of bilateral cerebral artery and serum levels of BDNF, NGF and IGF-1 in the observation group were higher than the control group (P<0.05), the RI of bilateral cerebral artery was lower than the control group (P<0.05). CONCLUSION: On the basis of the conventional rehabilitation training, nape cluster acupuncture can effectively improve the swallowing function and respiratory function in patients with post-stroke dysphagia, its mechanism may be related to the improvement of cerebral hemodynamics and the regulation of neurotrophic factors.

Protected quantum coherence by gain and loss in a noisy quantum kicked rotor.

We study the effects of non-Hermiticity on quantum coherence via a noisy quantum kicked rotor (NQKR). The random noise comes from the fluctuations in kick amplitude at each time. The non-Hermitian driving indicates the imaginary kicking potential, representing the environment-induced atom gain and loss. In the absence of gain and loss, the random noise destroys quantum coherence manifesting dynamical localization, which leads to classical diffusion. Interestingly, in the presence of non-Hermitian kicking potential, the occurrence of dynamical localization is highly sensitive to the gain and loss, manifesting the restoration of quantum coherence. Using the inverse participation ratio arguments, we numerically obtain a phase diagram of the classical diffusion and dynamical localization on the parameter plane of noise amplitude and non-Hermitian driving strength. With the help of analysis on the corresponding quasieigenstates, we achieve insight into dynamical localization, and uncover that the origin of the localization is interference between multiple quasi-eigenstates of the quantum kicked rotor. We further propose an experimental scheme to realize the NQKR in a dissipative cold atomic gas, which paves the way for future experimental investigation of an NQKR and its anomalous non-Hermitian properties.

Long noncoding RNA BS-DRL1 modulates the DNA damage response and genome stability by interacting with HMGB1 in neurons.

Long noncoding RNAs (lncRNAs) are known to regulate DNA damage response (DDR) and genome stability in proliferative cells. However, it remains unknown whether lncRNAs are involved in these vital biological processes in post-mitotic neurons. Here, we report and characterize a lncRNA, termed Brain Specific DNA-damage Related lncRNA1 (BS-DRL1), in the central nervous system. BS-DRL1 is a brain-specific lncRNA and depletion of BS-DRL1 in neurons leads to impaired DDR upon etoposide treatment in vitro. Mechanistically, BS-DRL1 interacts with HMGB1, a chromatin protein that is important for genome stability, and is essential for the assembly of HMGB1 on chromatin. BS-DRL1 mediated DDR exhibits cell-type specificity in the cortex and cerebellum in gamma-irradiated mice and BS-DRL1 knockout mice show impaired motor function and concomitant purkinje cell degeneration. Our study extends the understanding of lncRNAs in DDR and genome stability and implies a protective role of lncRNA against neurodegeneration.

Stepwise neoadjuvant chemoradiotherapy in the management of mid-low locally advanced rectal cancer.

BACKGROUND: This study aimed to compare the treatment response, complications and prognosis in mid-low locally advanced rectal cancer (LARC) patients who underwent stepwise neoadjuvant chemoradiotherapy (SCRT) or traditional neoadjuvant chemoradiotherapy (CRT). METHODS: The medical records of patients with mid-low rectal cancer who underwent SCRT or CRT were retrospectively analyzed. Differences in the treatment response, pathologic complete response (pCR), R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation, defunctioning stoma, treatment-emergent adverse events (TEAEs), overall survival (OS) and disease-free survival (DFS) between patients who underwent SCRT and CRT were compared. RESULTS: A total of 430 medical records were investigated, including 194 patients in the SCRT group and 236 patients in the CRT group. There was no significant difference in the rates of treatment response, pCR, R0 resection, local recurrence, anastomotic leakage, presacral infection, anal preservation or TEAEs between the two groups. However, the rate of defunctioning stoma in the SCRT group was significantly lower than that in the CRT group (20.1% vs. 44.1%, respectively, P < 0.01). Moreover, the median OS time of the SCRT and CRT groups was 44.0 and 50.5 months, respectively (P = 0.17). The median DFS time of the SCRT and CRT groups was 41.0 and 46.8 months, respectively (P = 0.32). CONCLUSION: Compared with the CRT group, the SCRT group had a similar treatment response, local control and long-term prognosis, and more importantly, a portion of the patients in the SCRT group were exempted from excessive radiation.

[Analysis on regional homogeneity of resting brain during balance acupuncture-induced analgesic effect in migraine patients without aura].

OBJECTIVE: To observe the relationship between the analgesic effect of balance acupuncture and functional changes in brain in patients with migraine without aura. METHODS: A total of 40 cases of migraine without aura were equally randomized into a headache-acupoint group and a sham-acupoint group. When acupuncture given, a filiform needle was inserted into the headache-acupoint (the midpoint of the depression region anterior to the juncture of the first and second metatarsal bones on the dorsum of the foot) or the sham point (the midpoint of the depression region anterior to the juncture site between the 3rd and 4th metatarsal joints of the dorsum of the foot) about 25-40 mm deep and manipulated for a while till the patient experienced feelings of electric shock and numbness, then withdrawn immediately. The treatment was conducted once daily for 4 weeks. The visual analogue scale (VAS) was used to evaluate the severity of pain, and the regional homogeneity (ReHo) analysis of resting state functional magnetic resonance imaging (fMRI) was used to assess changes of the spontaneous brain activity. RESULTS: After acupuncture, the analgesic effect of headache-acupoint was better than that of the sham-acupoint in both intervention stage and the follow-up stage (P< 0.05), and was also stronger in the intervention stage than in the follow-up stage (P<0.05). There was no significant difference in the analgesic effect between the intervention stage and the follow-up stage in the sham-acupoint group (P>0.05). Compared with pre-intervention, 4-weeks' intervention at the headache-acupoint showed an increase of ReHo values in the anterior cingulate gyrus, anterior central gyrus, superior orbital frontal gyrus, insula, inferior lobule, left anterior cingulate gyrus, ventral lateral nucleus and ventral posteromedial nucleus of the thalamus, pontine nucleus, cerebellar tonsils and orbital frontal inferior gyrus of the brain (P<0.05), and a decrease of ReHo values in the right brain bridge, central posterior gyrus, posterior cingulate gyrus, left central anterior gyrus, posterolateral nucleus of thalamus, and hippocampus (P<0.05), separately. In the sham-acupoint group, the ReHo value was increased in the right tongue gyrus, the left anterior lobe, the anterior cingulate gyrus and the lower occipital gyrus of the brain (P<0.05), and reduced in the left ventral posterolateral nucleus of the thalamus, separately (P<0.05). CONCLUSION: Balance acupuncture stimulation of headache acupoint has an analgesic effect in migraine patients without aura, which may be related to its effect in regulating resting state brain function of the limbic-system-dominated multiple brain regions.

The Neuronal Activation of Deep Cerebellar Nuclei Is Essential for Environmental Enrichment-Induced Post-Stroke Motor Recovery.

The level of cerebellar activity in stroke patients has been shown to correlate with the extent of functional recovery. We reasoned that the cerebellum may be an important player in post-stroke rehabilitation. Because the neurons in the deep cerebellar nuclei (DCN) represent virtually all of the output from the cerebellum, in this study, using environmental enrichment (EE) to promote rehabilitation, we investigated the influence of the optogenetic neuronal modulation of DCN on EE-induced rehabilitation. We found that neuronal inhibition of the DCN almost completely blocked motor recovery in EE treated mice, but the stroke mice with neuronal activation of the DCN achieved a similar recovery level as those in the EE treated group. No difference was observed in anxiety-like behavior. Moreover, Htr2a in the DCN, the gene encoding 5-HT2A receptor, was shown to be a hub gene in the protein-protein interaction network identified using RNA-seq. This indicated that 5-HT2A receptor-mediated signaling may be responsible for DCN-dependent functional improvement in EE. We further verified this using the 5-HT2A receptor antagonist, MDL100907, to inhibit the function of 5-HT2A receptor in the DCN. This treatment resulted in impaired recovery in EE treated mice, who performed at a level as poor as the stroke-only group. Thus, this work contributes to an understanding of the importance of the DCN activation in EE-induced post-stroke rehabilitation. Attempts to clarify the mechanism of 5-HT2A receptor-mediated signaling in the DCN may also lead to the creation of a pharmacological mimetic of the benefits of EE-induced rehabilitation.

Effects of intraoperative PEEP on postoperative pulmonary complications in patients undergoing robot-assisted laparoscopic radical resection for bladder cancer or prostate cancer: study protocol for a randomized controlled trial.

BACKGROUND: There are increasing studies showing that the use of a lung-protective ventilation strategy has a lung protection effect in patients undergoing abdominal surgery; however, the appropriate positive end-expiratory pressure (PEEP) has not yet defined. Adopting a suitable PEEP may prevent postoperative pulmonary complications. Robot-assisted laparoscopic surgery is the newest and most minimally invasive treatment for bladder cancer or prostate cancer. It is also necessary to consider the effects of Trendelenburg position with pneumoperitoneum on airway pressure and pulmonary function. The role of PEEP during the intraoperative period in preventing postoperative pulmonary complications for robot-assisted laparoscopic surgery is not clearly defined. METHODS/DESIGN: A total of 208 patients undergoing robot-assisted laparoscopic radical resection for bladder cancer or prostate cancer will be enrolled and then randomly assigned to a standard PEEP (6-8 cm H2O) group and a low PEEP (≤2 cm H2O) group. Both groups will receive an inspired oxygen fraction of 0.50 and a tidal volume of 8 mL/kg ideal body weight. Standard perioperative fluid management standardization and analgesic treatments will be applied in both groups. The primary endpoint is postoperative pulmonary complications within 7 days after surgery. Secondary endpoints are the modified clinical pulmonary infection score, postoperative extrapulmonary complications, postoperative surgical complications, intensive care unit length of stay, hospital length of stay, and 30-day mortality. DISCUSSION: This trial aimed to assess the effects of low tidal volumes combined with intraoperative PEEP ventilation strategy on postoperative pulmonary complications in patients undergoing robot-assisted laparoscopic radical resection for bladder cancer or prostate cancer. TRIAL REGISTRATION: ID: ChiCTR1800019867 . Registered on December 2, 2018.

Optimization of brain metabolism using metabolic-targeted therapeutic hypothermia can reduce mortality from traumatic brain injury.

BACKGROUND: Therapeutic hypothermia is widely used to treat traumatic brain injuries (TBIs). However, determining the best hypothermia therapy strategy remains a challenge. We hypothesized that reducing the metabolic rate, rather than reaching a fixed body temperature, would be an appropriate target because optimizing metabolic conditions especially the brain metabolic environment may enhance neurologic protection. A pilot single-blind randomized controlled trial was designed to test this hypothesis, and a nested metabolomics study was conducted to explore the mechanics thereof. METHODS: Severe TBI patients (Glasgow Coma Scale score, 3-8) were randomly divided into the metabolic-targeted hypothermia treatment (MTHT) group, 50% to 60% rest metabolic ratio as the hypothermia therapy target, and the body temperature-targeted hypothermia treatment (BTHT) control group, hypothermia therapy target of 32°C to 35°C body temperature. Brain and circulatory metabolic pool blood samples were collected at baseline and on days 1, 3, and 7 during the hypothermia treatment, which were selected randomly from a subgroup of MTHT and BTHT groups. The primary outcome was mortality. Using H nuclear magnetic resonance technology, we tracked and located the disturbances of metabolic networks. RESULTS: Eighty-eight severe TBI patients were recruited and analyzed from December 2013 to December 2014, 44 each were assigned in the MTHT and BTHT groups (median age, 42 years; 69.32% men; mean Glasgow Coma Scale score, 6.17 ± 1.02). The mortality was significantly lower in the MTHT than the BTHT group (15.91% vs. 34.09%; p = 0.049). From these, eight cases of MTHT and six cases from BTHT group were enrolled for metabolomics analysis, which showed a significant difference between the brain and circulatory metabolic patterns in MTHT group on day 7 based on the model parameters and scores plots. Finally, metabolites representing potential neuroprotective monitoring parameters for hypothermia treatment were identified through H nuclear magnetic resonance metabolomics. CONCLUSION: MTHT can significantly reduce the mortality of severe TBI patients. Metabolomics research showed that this strategy could effectively improve brain metabolism, suggesting that reducing the metabolic rate to 50% to 60% should be set as the hypothermia therapy target. LEVEL OF EVIDENCE: Therapeutic study, Level I.

Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling.

It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors contributed to the relief of sevoflurane neurotoxicity, and the ERK1/2 MAPK signaling may be involved in this process.