Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Sniffing oxytocin: Nose to brain or nose to blood?

In recent years ample studies have reported that intranasal administration of the neuropeptide oxytocin can facilitate social motivation and cognition in healthy and clinical populations. However, it is still unclear how effects are mediated since intranasally administered oxytocin can both directly enter the brain (nose to brain) and increase peripheral vascular concentrations (nose to blood). The relative functional contributions of these routes are not established and have received insufficient attention in the field. The current study used vasoconstrictor pretreatment to prevent intranasal oxytocin (24 IU) from increasing peripheral concentrations and measured effects on both resting-state neural (electroencephalography) and physiological responses (electrocardiogram, electrogastrogram and skin conductance). Results demonstrated that intranasal oxytocin alone produced robust and widespread increases of delta-beta cross-frequency coupling (CFC) from 30 min post-treatment but did not influence peripheral physiological measures. As predicted, vasoconstrictor pretreatment greatly reduced the normal increase in peripheral oxytocin concentrations and, importantly, abolished the majority of intranasal oxytocin effects on delta-beta CFC. Furthermore, time-dependent positive correlations were found between increases in plasma oxytocin concentrations and corresponding increases in delta-beta CFC following oxytocin treatment alone. Our findings suggest a critical role of peripheral vasculature-mediated routes on neural effects of exogenous oxytocin administration with important translational implications for its use as an intervention in psychiatric disorders.

Acetate Ions Facilitated Immobilization of Highly Dispersed Transition Metal Oxide Nanoclusters in Mesoporous Silica.

The immobilization of tiny active species within inert mesoporous silica imparts a range of functions, enhancing their applicability. A significant obstacle is the spontaneous migration and aggregation of these species within the mesopores, which threaten their uniform distribution. To address this, we propose a postmodification method that involves grafting transition metal oxide nanoclusters into silica mesopores via interfacial condensation, catalyzed by acetate ions. Specifically, CuO nanoclusters, in the form of oligomeric [O1-x-Cu2-(OH) 2x]n2+, have a strong interaction with the silica framework. This interaction inhibits their growth and prevents mesopore blockage. Theoretical calculation results reveal that the acetate ion promotes proton transfer among various hydroxy species, lowering the free energy and thereby facilitating the formation of Cu-O-Si bonds. This technique has also been successfully applied to the encapsulation of four other types of transition metal oxide nanoclusters. Our encapsulation strategy effectively addresses the challenge of dispersing transition metal oxides in mesoporous silica, offering a straightforward and widely applicable method for enhancing the functionality of mesoporous materials.

Application of Independent Component Analysis and Nelder-Mead Particle Swarm Optimization Algorithm in Non-Contact Blood Pressure Estimation.

In recent years, hypertension has become one of the leading causes of illness and death worldwide. Changes in lifestyle among the population have led to an increasing prevalence of hypertension. This study proposes a non-contact blood pressure estimation method that allows patients to conveniently monitor their blood pressure values. By utilizing a webcam to track facial features and the region of interest (ROI) for obtaining forehead images, independent component analysis (ICA) is employed to eliminate artifact signals. Subsequently, physiological parameters are calculated using the principle of optical wave reflection. The Nelder-Mead (NM) simplex method is combined with the particle swarm optimization (PSO) algorithm to optimize the empirical parameters, thus enhancing computational efficiency and accurately determining the optimal solution for blood pressure estimation. The influences of light intensity and camera distance on the experimental results are also discussed. Furthermore, the measurement time is only 10 s. The superior accuracy and efficiency of the proposed methodology are demonstrated by comparing them with those in other published literature.

[Effect and mechanism of free total rhubarb anthraquinones on pyroptosis of J774A.1 macrophages].

In this study, J774A.1 macrophages stimulated by lipopolysaccharide(LPS) and adenosine triphosphate(ATP) were used to establish an in vitro model of pyroptosis, and the intervention mechanism of free total rhubarb anthraquinones(FTRAs) on pyroptosis was investigated. J774A.1 macrophages were cultured in vitro, and the experiment was assigned to the control group and groups with different concentrations of LPS(0.25, 0.5, and 1 µg·mL~(-1)) and ATP(1.25, 2.5, and 5 mmol·L~(-1)). An in vitro model of macrophage pyroptosis was established by detecting cell viability through CCK-8, propidium iodide(PI) apoptotic cell staining, lactate dehydrogenase(LDH), interleukin(IL)-18, and tumor necrosis factor(TNF)-α release. Then, J774A.1 macrophages were randomly divided into six groups: blank control group, LPS+ATP group, high-dose FTRA group, and low, medium, and high-dose FTRA pre-protection group. The phenotypic characteristics and key indicators of pyroptosis were detected as the basis for evaluating the effect of FTRAs on pyroptosis induced by LPS and ATP. Western blot and RT-PCR were used to detect the expression levels of protein and mRNA related to the pyroptosis pathway in caspase-1/11 and elucidate the molecular mechanism of the anti-pyroptosis effect. The results showed that the stimulation condition of 0.50 µg·mL~(-1) LPS+5.00 mmol·L~(-1) ATP was the most effective in the in vitro model of macrophage pyroptosis. FTRAs pre-protected cells for 24 h and then can increase cell viability under pyroptosis conditions, alleviate cell damage, lower the positive rate of PI staining, and reduce the release of LDH, IL-18, and TNF-α. FTRAs were able to significantly inhibit the activation of GSDMD proteins and significantly down-regulate the protein expression of the pyroptosis pathway signature molecules, TLR4, NLRP3, cleaved-caspase-1, and cleaved-caspase-11, but they had no significant effect on ASC proteins. FTRAs were also able to significantly inhibit the mRNA expression of caspase-1, caspase-11, and GSDMD. These results indicate that FTRAs have an inhibitory effect on the pyroptosis model induced by LPS and ATP and play an anti-pyroptosis effect by regulating classical and non-classical pyroptosis signaling pathways and reducing the production of inflammatory cytokines.

Prospective role of 3ßHSD1 in prostate cancer precision medicine.

BACKGROUND: Prostate cancer is addicted to androgens. The steroidogenic enzyme 3ß-hydroxysteroid dehydrogenase 1 (3ßHSD1) recognizes pregnenolone, dehydroepiandrosterone (DHEA), and steroidal medicine abiraterone as substrates to accelerate disease progression. METHODS: References for this review were identified through searches of PubMed with the search terms "prostate cancer", "HSD3B1", and "3bHSD1" from 1990 until June, 2022. RESULTS: Genotype of 3ßHSD1 has been reported to correlate with tumor aggressiveness of advanced prostate cancer in multiple clinical scenarios. The ethnic differences and limitations of using 3ßHSD1 genotype as a prognostic biomarker have been discussed here. The activity of 3ßHSD1 increases in patients treated with abiraterone and enzalutamide, giving rise to treatment resistance. Further elucidation of 3ßHSD1 regulatory mechanisms will shed light on more approaches for disease intervention. We also review the recent advance on 3ßHSD1 inhibitors and targeting 3ßHSD1 for prostate cancer management. Novel 3ßHSD1 inhibitors will be needed to provide additional options for prostate cancer management. CONCLUSION: 3ßHSD1 is both a predictive biomarker and a promising therapeutic target for prostate cancer.

Interactive effect of increased high sensitive C-reactive protein and dyslipidemia on cardiovascular diseases: a 12-year prospective cohort study.

BACKGROUND: Dyslipidemia and inflammation are significant factors for the onset of cardiovascular diseases (CVD); however, studies regarding their interactions on the risk of CVD are scarce. This study aimed to assess the interaction of dyslipidemia and high-sensitivity C-reactive protein (hs-CRP) on CVD. METHODS: This prospective cohort enrolled 4,128 adults at baseline in 2009 and followed them up until May 2022 for collecting CVD events. Cox-proportional hazard regression analysis estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of the associations of increased hs-CRP (≥ 1 mg/L) and dyslipidemia with CVD. The additive interactions were explored using the relative excess risk of interaction (RERI) and the multiplicative interactions were assessed with HRs (95% CI) while the multiplicative interactions were assessed by the HRs (95% CI) of interaction terms. RESULTS: The HRs of the association between increased hs-CRP and CVD were 1.42 (95% CI: 1.14-1.79) and 1.17 (95% CI: 0.89-1.53) among subjects with normal lipid levels and subjects with dyslipidemia, respectively. Stratified analyses by hs-CRP levels showed that among participants with normal hs-CRP (< 1 mg/L), TC ≥ 240 mg/dL, LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, ApoB < 0.7 g/L, and LDL/HDL-C ≥ 2.02 were associated with CVD [HRs (95%CIs): 1.75 (1.21-2.54), 2.16 (1.37-3.41), 1.95 (1.29-2.97), 1.37 (1.01-1.67), and 1.30 (1.00-1.69), all P < 0.05, respectively]. While in the population with increased hs-CRP, only ApoAI > 2.10 g/L had a significant association with CVD [HR (95% CI): 1.69 (1.14-2.51)]. Interaction analyses showed that increased hs-CRP had multiplicative and additive interactions with LDL-C ≥ 160 mg/dL and non-HDL-C ≥ 190 mg/dL on the risk of CVD [HRs (95%CIs): 0.309 (0.153-0.621), and 0.505 (0.295-0.866); RERIs (95%CIs): -1.704 (-3.430-0.021 and - 0.694 (-1.476-0.089), respectively, all P < 0.05]. CONCLUSION: Overall our findings indicate negative interactions between abnormal blood lipid levels and hs-CRP on the risk of CVD. Further large-scale cohort studies with trajectories measurement of lipids and hs-CRP might verify our results as well explore the biological mechanism behind that interaction.

Revealing an initiation inhibition of RCA and its application in nucleic acid detection.

Rolling circle amplification is a widely used biosensing technique. Although various secondary structures have been employed in RCA, their effects on RCA efficiency have seldom been reported. Here, we find that stems in circular templates can strongly inhibit RCA, and the primer-stem distance is responsible for the inhibition. Based on the results, we propose an initiation inhibition mechanism and present a design principle for a general RCA assay. Inspired by this mechanism, we further propose a new nucleic acid detection method. The results verify that this method can increase RCA detection sensitivity according to the target recycling principle. Besides DNA detection, it can also achieve single mismatch discrimination of miRNA detection after optimization. This method also shows convenient visualization detection. The initiation inhibition of RCA could be helpful for RCA applications as promising detection techniques.

Targeting presynaptic H3 heteroreceptor in nucleus accumbens to improve anxiety and obsessive-compulsive-like behaviors.

Anxiety commonly co-occurs with obsessive-compulsive disorder (OCD). Both of them are closely related to stress. However, the shared neurobiological substrates and therapeutic targets remain unclear. Here we report an amelioration of both anxiety and OCD via the histamine presynaptic H3 heteroreceptor on glutamatergic afferent terminals from the prelimbic prefrontal cortex (PrL) to the nucleus accumbens (NAc) core, a vital node in the limbic loop. The NAc core receives direct hypothalamic histaminergic projections, and optogenetic activation of hypothalamic NAc core histaminergic afferents selectively suppresses glutamatergic rather than GABAergic synaptic transmission in the NAc core via the H3 receptor and thus produces an anxiolytic effect and improves anxiety- and obsessive-compulsive-like behaviors induced by restraint stress. Although the H3 receptor is expressed in glutamatergic afferent terminals from the PrL, basolateral amygdala (BLA), and ventral hippocampus (vHipp), rather than the thalamus, only the PrL- and not BLA- and vHipp-NAc core glutamatergic pathways among the glutamatergic afferent inputs to the NAc core is responsible for co-occurrence of anxiety- and obsessive-compulsive-like behaviors. Furthermore, activation of the H3 receptor ameliorates anxiety and obsessive-compulsive-like behaviors induced by optogenetic excitation of the PrL-NAc glutamatergic afferents. These results demonstrate a common mechanism regulating anxiety- and obsessive-compulsive-like behaviors and provide insight into the clinical treatment strategy for OCD with comorbid anxiety by targeting the histamine H3 receptor in the NAc core.

Oral Administration of Oxytocin, Like Intranasal Administration, Decreases Top-Down Social Attention.

BACKGROUND: The neuropeptide oxytocin (OXT) modulates social cognition by increasing attention to social cues and may have therapeutic potential for impaired social attention in conditions such as autism spectrum disorder. Intranasal administration of OXT is widely used to examine the drug's functional effects in both adults and children and is assumed to enter the brain directly via this route. However, OXT can also influence brain function through increased blood concentrations, and we have recently shown that orally (lingual) administered OXT also modulates neural responses to emotional faces and may be better tolerated for therapeutic use. Here, we examine whether 24 IU OXT administered orally can facilitate social attention. METHODS: In a randomized, placebo-controlled pharmacologic study, we used a validated emotional antisaccade eye-tracking paradigm to explore the effects of oral OXT on bottom-up and top-down attention processing in 80 healthy male participants. RESULTS: Our findings showed that in terms of top-down attention, oral OXT increased errors for both social (angry, fearful, happy, sad, and neutral emotion faces) and nonsocial stimuli (oval shapes) in the antisaccade condition but increased response latencies only in the social condition. It also significantly reduced post-task state anxiety, but this reduction was not correlated with task performance. A comparison with our previous intranasal OXT study using the same task revealed that both routes have a similar effect on increasing antisaccade errors and response latencies and on reducing state anxiety. CONCLUSIONS: Overall, our findings suggest that oral administration of OXT produces similar effects on top-down social attention control and anxiety to intranasal administration and may therefore have therapeutic utility.

Ineffective esophageal motility in Chicago Classification version 4.0 better predicts abnormal acid exposure.

BACKGROUND: The updated Chicago Classification version 4.0 (CCv4.0) establishes a more stringent criteria to diagnose ineffective esophageal motility (IEM). This study aims to investigate the clinical significance of IEM in CCv4.0 in the context of gastroesophageal reflux disease (GERD). METHODS: A retrospective study was conducted among suspected GERD patients who had heartburn and/or regurgitation as their chief complaints and completed esophageal function tests in our center from 2017 to 2019. Patients were further grouped as "CCv3.0 IEM" and normal motility according to Chicago Classification version 3.0 (CCv3.0), and as "CCv4.0 IEM" and normal motility according to CCv4.0. The clinical characteristics, high-resolution manometry, esophageal reflux monitoring, and proton pump inhibitor (PPI) efficacy were compared between different groups. Multivariate analyses were performed to identify esophageal motility parameters associated with reflux burden and symptom outcome. RESULTS: Of 172 subjects included, 93 patients were identified as CCv3.0 IEM, 69 as CCv4.0 IEM. IEM in either version was concomitant with elevated acid burden and impaired esophageal clearance as compared to normal motility in corresponding diagnostic criteria, while the only presence of IEM in CCv4.0 was predictive to abnormal acid exposure (AET > 6%: OR = 2.66, 95% CI [1.27-5.56], p < 0.01). The presence of "CCv3.0 IEM" and low EGJ-CI (EGJ-CI < 39.1 mmHg·cm) had no added value in predicting increased reflux burden. No interaction effect was found between the presence of IEM and a weakened EGJ. None of the manometric variables was capable of predicting PPI response. CONCLUSIONS: Stringent criteria of IEM in CCv4.0 can better predict abnormal acid exposure as compared to CCv3.0.

Segregating domain-general from emotional context-specific inhibitory control systems - ventral striatum and orbitofrontal cortex serve as emotion-cognition integration hubs.

Inhibitory control hierarchically regulates cognitive and emotional systems in the service of adaptive goal-directed behavior across changing task demands and environments. While previous studies convergently determined the contribution of prefrontal-striatal systems to general inhibitory control, findings on the specific circuits that mediate emotional context-specific impact on inhibitory control remained inconclusive. Against this background we combined an evaluated emotional Go/No Go task with fMRI in a large cohort of subjects (N=250) to segregate brain systems and circuits that mediate domain-general from emotion-specific inhibitory control. Particularly during a positive emotional context, behavioral results showed a lower accuracy for No Go trials and a faster response time for Go trials. While the dorsal striatum and lateral frontal regions were involved in inhibitory control irrespective of emotional context, activity in the ventral striatum (VS) and medial orbitofrontal cortex (mOFC) varied as a function of emotional context. On the voxel-wise whole-brain network level, limbic and striatal systems generally exhibited highest changes in global brain connectivity during inhibitory control, while global brain connectivity of the left mOFC was less decreased during emotional contexts. Functional connectivity analyses moreover revealed that negative coupling between the VS with inferior frontal gyrus (IFG)/insula and mOFC varied as a function of emotional context. Together these findings indicate separable domain- general as well as emotional context-specific inhibitory brain systems which specifically encompass the VS and its connections with frontal regions.

Apolipoprotein C1 stimulates the malignant process of renal cell carcinoma via the Wnt3a signaling.

BACKGROUND: Renal cell carcinoma (RCC) is a clinically common tumor in the urinary system, showing an upward trend of both incidence and mortality. Apolipoprotein C1 (APOC1) has been identified as a vital regulator in tumor progression. This study aims to uncover the biological function of APOC1 in RCC process and the underlying mechanism. METHODS: Differential levels of APOC1 in RCC samples and normal tissues in a downloaded TCGA profile and clinical samples collected in our center were detected by quantitative reverse transcription PCR (qRT-PCR). The prognostic value of APOC1 in RCC was assessed by depicting Kaplan-Meier survival curves. After intervening APOC1 level by transfection of sh-APOC1 or oe-APOC1, changes in phenotypes of RCC cells were examined through CCK-8, colony formation, Transwell assay and flow cytometry. Subsequently, protein levels of EMT-related genes influenced by APOC1 were determined by Western blot. The involvement of the Wnt3a signaling in APOC1-regulated malignant process of RCC was then examined through a series of rescue experiments. Finally, a RCC xenograft model was generated in nude mice, aiming to further clarify the in vivo function of APOC1 in RCC process. RESULTS: APOC1 was upregulated in RCC samples. Notably, its level was correlated to overall survival of RCC patients, displaying a certain prognostic value. APOC1 was able to stimulate proliferative, migratory and invasive abilities in RCC cells. The Wnt3a signaling was identified to be involved in APOC1-mediated RCC process. Notably, Wnt3a was able to reverse the regulatory effects of APOC1 on RCC cell phenotypes. In vivo knockdown of APOC1 in xenografted nude mice slowed down the growth of RCC. CONCLUSIONS: APOC1 stimulates the malignant process of RCC via targeting the Wnt3a signaling.

Genetic factors involved in delayed methotrexate elimination in children with acute lymphoblastic leukemia.

BACKGROUND: Delayed excretion of methotrexate can lead to life-threatening toxicity that may result in treatment cessation, irreversible organ damage, and death. Various factors have been demonstrated to influence the pharmacokinetic process of methotrexate, including genetic and nongenetic factors. METHODS: We investigated the genetic factors primarily related to the metabolic pathway of methotrexate in children with acute lymphoblastic leukemia with delayed elimination, defined as C44-48h ≥ 1.0µmol/L in this study. A total of 196 patients (delayed excretion group: 98; normal excretion group: 98) who received CCCG-ALL-2015 protocol after propensity score-matched analysis were included in the study. Twenty-eight target single-nucleotide polymorphisms (SNPs) were analyzed by multiplex polymerase chain reaction and sequencing, and 25 SNPs were finally included in the study. RESULTS: The genotype distribution of SLCO1B1 rs2306283 SNP was different between the delayed and normal excretion groups. SLCO1B1 rs2306283 AA carriers had a significantly lower methotrexate C44-48h /D ratio than GG carriers in both groups. Furthermore, compared with the normal excretion group, SLCO1B1 rs2306283 AG and GG were risk factors for developing oral mucositis (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.11-4.08; P < .001), hepatotoxicity (OR: 2.12; 95% CI: 1.26-3.56; P < .001), and myelosuppression (OR: 1.21; 95% CI: 1.04-1.41; P = .005) in delayed excretion group. CONCLUSIONS: The results from this study indicate the potential role of SLCO1B1 rs2306283 as a pharmacogenomic marker to guide and optimize methotrexate treatment for delayed elimination in children with acute lymphoblastic leukemia.

Endoscopic acanthosis nigricans appearance: A novel specific marker for diagnosis of low-grade intraepithelial neoplasia.

BACKGROUND AND AIM: At present, there is no recognized diagnostic criteria for gastric low-grade intraepithelial neoplasia (LGIN). The purpose of this study was to determine whether an "endoscopic acanthosis nigricans appearance (EANA)" could be a useful endoscopic marker for distinguishing LGIN lesions from peripheral non-neoplastic tissues. METHODS: A retrospective study was conducted on 638 cases of suspected superficial lesions with endoscopic images from white light endoscopy and magnifying endoscopy combined with narrow band imaging. According to the pathological results of accurate biopsies, those lesions were divided into three groups: a control group, an LGIN group, and an early gastric cancer (EGC) group. RESULTS: According to the presence of EANAs, the sensitivity, specificity, positive predictive value, and negative predictive value for differentiating between the LGIN and control groups were 24.8%, 97.3%, 78.3%, and 76.6%, respectively. The sensitivity (84.1%) and negative predictive value (92.4%) were significantly improved by combining EANA with types IV-VI pit pattern. The intervening part and mean gray value of glands, representing microsurface features and microvascular variation, were significantly larger or higher in EANA lesions than in the surrounding non-neoplastic mucosa. LGIN with EANA was more likely to be present in lesions of type 0-IIa. In addition, the prevalence of EANAs in EGC was 16.7%. CONCLUSION: An EANA could be used as an auxiliary indicator for a diagnosis of LGIN in suspected lesions. It could also play a potential assistive role in the diagnosis of EGC lesions.

A new exploration of white globe appearance (WGA) in ulcerative lesions.

AIM: White globe appearance (WGA), a small white lesion with a globular shape that can be clearly visualized by magnifying endoscopy with narrow-band imaging (ME-NBI), was reported to be a reliable marker of early gastric cancer (EGC). However, we found that this endoscopic presentation could also be seen in non-cancerous tissues, especially in ulcerative lesions. This study aimed to further investigate the diagnostic value of WGA in differentiating non-cancerous lesions from EGC in ulcer-type cases. MATERIALS AND METHODS: We retrospectively reviewed 54 cases of EGC and 155 cases of non-cancerous lesions in this study, all of which had endoscopic imaging data of ME-NBI scanning and pathological data of biopsy or resected specimens. The correlation of the prevalence of WGA and ulcerative lesions, as well as the characteristics of WGA between the 2 groups were analyzed in this study. RESULTS: WGA was more common in ulcerative lesions (27.6 %, 21/76) than in non-ulcerative lesions (3.8 %, 5/133) (p < 0.001) in our study. In the ulcerative cases, no significant difference in prevalence of WGA was observed between EGC and non-cancerous lesions (p = 0.532). Compared with WGA in EGC, WGA in non-cancerous lesions tended to show the characteristic of tree-branch-like vessels on globular shape (p < 0.001). CONCLUSIONS: WGA is more likely to occur in ulcerative lesions, and the presence of WGA alone cannot distinguish EGC from non-cancerous lesions in ulcer-type cases. In WGA-positive tissue, tree-branch-like vessels of globular shape may provide a certain clinical value in diagnosis of non-cancerous lesions or EGC.

Association of high sensitive C-reactive protein with coronary heart disease: a Mendelian randomization study.

OBJECTIVES: Whether high sensitivity C-reactive protein (hs-CRP) has a causal effect on coronary heart disease (CHD) is unclear. This study investigated the causal effect of hs-CRP on CHD risk using Mendelian Randomization (MR) analysis. METHODS: A total of 3802 subjects were recruited in the follow-up study. Linear regression model was used to evaluate the relationship between CRP polymorphisms and hs-CRP. Survival receiver operator characteristic curve method was used to explore the cut-off of hs-CRP on CHD incidence. Cox regression model was applied to detect the association of hs-CRP with CHD by calculating the hazard ratio (HR) and 95% confidence interval (CI). Rs1205 and rs876537 in CRP were selected as instrumental variables in MR analysis. RESULTS: During a median follow-up time of 5.01 years, 98 CHD incidence was identified (47.03/104 person-years). Hs-CRP was significantly increased among rs1205 and rs876537 genotypes with r values of 0.064 and 0.066, respectively. Hs-CRP 1.08 mg/L was identified as the cut-off value with a maximum value of sensitivity and specificity on prediction of CHD. Participants with ≥1.08 mg/L of hs-CRP has a higher risk of CHD incidence than that of participants with < 1.08 mg/L, the adjusted HR (95% CI) was 1.69 (1.11-2.60) with a P value of 0.016. No significant casual association was observed between hs-CRP and CHD with a P value of 0.777. CONCLUSIONS: The association between hs-CRP and CHD is unlikely to be causal, hs-CRP might be a predictor for incidence of CHD in general population.

Facilitation of spinal α-motoneuron excitability by histamine and the underlying ionic mechanisms.

Spinal α-motoneurons directly innervate skeletal muscles and function as the final common path for movement and behavior. The processes that determine the excitability of motoneurons are critical for the execution of motor behavior. In fact, it has been noted that spinal motoneurons receive various neuromodulatory inputs, especially monoaminergic one. However, the roles of histamine and hypothalamic histaminergic innervation on spinal motoneurons and the underlying ionic mechanisms are still largely unknown. In the present study, by using the method of intracellular recording on rat spinal slices, we found that activation of either H1 or H2 receptor potentiated repetitive firing behavior and increased the excitability of spinal α-motoneurons. Both of blockage of K+ channels and activation of Na+-Ca2+ exchangers were involved in the H1 receptor-mediated excitation on spinal motoneurons, whereas the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were responsible for the H2 receptor-mediated excitation. The results suggest that, through switching functional status of ion channels and exchangers coupled to histamine receptors, histamine effectively biases the excitability of the spinal α-motoneurons. In this way, the hypothalamospinal histaminergic innervation may directly modulate final motor outputs and actively regulate spinal motor reflexes and motor execution.