Values of prognostic nutritional index for predicting Kawasaki disease: a systematic review and meta-analysis.

Objective: This systematic review and meta-analysis aimed to evaluate the relationship between the prognostic nutritional index (PNI) and intravenous immunoglobulin (IVIG) resistance and coronary artery lesion (CAL) in Kawasaki disease (KD). Methods: The relevant literature was searched on PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar up to August 5, 2023. A pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC) were calculated to assess the predicted values of PNI in KD patients with IVIG resistance and CAL. Results: A total of 8 articles containing 10 studies involving 7,047 participants were included. The pooled results revealed a pooled sensitivity of 0.44 (0.25-0.65), a pooled specificity of 0.87 (0.73-0.94), a pooled PLR of 3.4 (2.0-5.9), a pooled NLR of 0.65 (0.48-0.87), a pooled DOR of 5.26 (2.76-10.02), and a pooled AUC of 0.75 (0.71-0.78) in the diagnosis of KD with CAL. The pooled results suggested that a pooled sensitivity was 0.69 (0.60-0.77), specificity was 0.76 (0.69-0.82), PLR was 2.9 (2.1-4.1), NLR was 0.40 (0.29-0.56), DOR was 7.27 (3.89-13.59), and AUC was 0.79 (0.75-0.82) in the diagnosis of KD with IVIG resistance. The combined results revealed the pooled sensitivity was 0.63 (0.58-0.67), specificity was 0.82 (0.80-0.83), PLR was 3.09 (1.06-8.98), NLR was 0.38 (0.07-2.02), DOR was 8.23 (0.81-83.16) in differentiating KD from febrile patients. These findings demonstrated low sensitivity and relatively high specificity of PNI for KD, KD-CAL, and IVIG-resistant KD. Conclusion: In conclusion, this study was the first systematic review and meta-analysis of the diagnostic value of PNI in KD with IVIG resistance and CAL. The results suggested that PNI could be used as biomarkers for distinguish KD, KD with CAL, and KD with IVIG resistance.

Hierarchical rhythmic propagation of corticothalamic interactions for consciousness: A computational study.

Clarifying the mechanisms of loss and recovery of consciousness in the brain is a major challenge in neuroscience, and research on the spatiotemporal organization of rhythms at the brain region scale at different levels of consciousness remains scarce. By applying computational neuroscience, an extended corticothalamic network model was developed in this study to simulate the altered states of consciousness induced by different concentration levels of propofol. The cortex area containing oscillation spread from posterior to anterior in four successive time stages, defining four groups of brain regions. A quantitative analysis showed that hierarchical rhythm propagation was mainly due to heterogeneity in the inter-brain region connections. These results indicate that the proposed model is an anatomically data-driven testbed and a simulation platform with millisecond resolution. It facilitates understanding of activity coordination across multiple areas of the conscious brain and the mechanisms of action of anesthetics in terms of brain regions.

Association of noncoding RNAs with Kawasaki disease: A meta-analysis based on the current evidences.

BACKGROUND: In recent years, many studies have focused on the relationship between noncoding RNAs (ncRNAs) and Kawasaki disease (KD). Studies have indicated that ncRNAs are associated with the occurrence and development of KD. Thus, we performed a systematic review and meta-analysis to investigate the diagnostic value of ncRNAs in KD patients. METHODS: We searched the PubMed, Web of Science, Embase and Cochrane Library, China National Knowledge Infrastructure, VIP, China Biology Medicine disc databases, and Wanfang databases until August 25, 2023 and screened all eligible studies focusing on the diagnostic performance of ncRNAs in KD patients. RESULTS: In total, 535 articles were found, and 28 articles were included in this systematic review and meta-analysis. The calculated area under the curve value was 0.880 (95% confidence intervals, 0.840-0.900). The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.790, 0.830, 4.610, and 0.260, respectively. The pooled diagnostic odds ratio was 17.890 (95% confidence intervals, 13.110-24.420), indicating a relatively good diagnostic performance of the ncRNAs for detecting KD. In addition, the diagnostic value of micro RNAs in KD was better than that of long noncoding RNAs and circular noncoding RNAs. A subgroup analysis by specimen indicated a better diagnostic value of ncRNAs in plasma and platelet than serum. The diagnostic accuracy of ncRNAs was better in febrile controls than in healthy control groups, indicating a relatively good accuracy in distinguishing KD patients from febrile diseases. CONCLUSIONS: This systematic review and meta-analysis demonstrated that ncRNAs could be used as novel biomarkers for detecting KD. More studies should be conducted in the future to verify the diagnostic values of ncRNAs in KD.

Diagnostic significance of noncoding RNAs in kawasaki disease: A systematic review and meta-analysis.

Objective: Kawasaki disease (KD) is a systemic vasculitis disease, and early effective intervention would reduce the occurrence of coronary artery lesions (CALs). Recently, many scholars have been committed to studying the relationship between noncoding RNAs and KD. This systematic review aimed to analyze the diagnostic value of noncoding RNAs(ncRNAs) in distinguishing different KD status. Methods: We searched for the literature about diagnostic values of ncRNAs in KD in CNKI, VIP, Wanfang, China Biomedical Literature Database as well as PubMed, Web of Science, Embase, and Cochrane Library up to April 15, 2022. All included studies were further analyzed using STATA 12.0, Meta-disc 1.4 and RevMan 5.4 software. Results: A total of six studies investigating the diagnostic performance of ncRNAs in differentiating KD-CAL (n = 101) from KD-NCAL patients (n = 123) were included in this this meta-analysis. The calculated area under the curve(AUC) was 0.83 (0.80-0.86). Four studies on the diagnostic performance of ncRNAs in differentiating acute KD patients (n = 139) from convalescent KD patients (n = 109) were included. The calculated AUC was 0.87 (0.84-0.90). Four studies focused on the diagnostic performance of ncRNAs combined with other laboratory indexes in KD by assessing 137 KD patients and 152 febrile controls. The calculated AUC was 0.90 (0.87-0.92). Four studies assessed the diagnostic performance of ncRNAs in differentiating intravenous immunoglobulin (IVIG)-resistant KD patients from IVIG-responsive KD patients. The calculated AUC was 0.9135 ± 0.0307. These results indicated that ncRNAs have a good diagnostic efficacy in KD. Conclusions: This meta-analysis showed that ncRNAs have potential as a biomarker for distinguishing different KD status. However, since limited studies were included in this meta-analysis, larger and well-designed diagnostic studies should be conducted to validate these results. Systematic Review Registration: INPLASY.COM, identifier: doi: 10.37766/inplasy2022.10.0035.

Comparison Between Human and Rodent Neurons for Persistent Activity Performance: A Biologically Plausible Computational Investigation.

Elucidating the multi-scale detailed differences between the human brain and other brains will help shed light on what makes us unique as a species. Computational models help link biochemical and anatomical properties to cognitive functions and predict key properties of the cortex. Here, we present a detailed human neocortex network, with all human neuron parameters derived from the newest Allen Brain human brain cell database. Compared with that of rodents, the human neural network maintains more complete and accurate information under the same graphic input. Unique membrane properties in human neocortical neurons enhance the human brain's capacity for signal processing.

Synthesis and Biological Evaluation of Novel Triazine Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors.

Enhancing neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) function can alleviate cognitive deficits. Here, we report the design, synthesis, and evaluation of N-(4-(trifluoromethoxy)phenyl)-1,3,5-triazin-2-amine derivatives 8-10 as a series of novel α7 nAChR positive allosteric modulators (PAMs). The representative compound 10e functions as a type I PAM with an EC50 of 3.0 µM and approximately 38-fold enhancement of α7 current in the presence of agonist acetylcholine (100 µM). It specifically enhances α7 current with high selectivity. Compound 10e shows good pharmacokinetic property in mice. Intraperitoneal injection of 10e (3 mg/kg) exhibits sufficient blood-brain barrier penetration in mice. Furthermore, 10e can also rescue the auditory gating deficit in mice with schizophrenia-like behavior. Molecular docking of 10e with homopentameric α7 nAChR reveals a new mode of action. These results support the potential of 10e for treatment for schizophrenia and Alzheimer's disease.

Computational Investigation of Contributions from Different Subtypes of Interneurons in Prefrontal Cortex for Information Maintenance.

Interneurons play crucial roles in neocortex associated with high-level cognitive functions; however, the specific division of labor is still under investigation. Interneurons are exceptionally diverse in their morphological appearance and functional properties. In this study, we modify a prefrontal multicolumn circuit in which five subtypes of inhibitory interneurons play distinct roles in the maintenance of transient information. These interneurons are classified according to the extending range of axonal projections. Our work simplifies the division of labor between different types of interneurons for the maintenance of information and the principle of functional redundancy of the brain from the perspective of computational modeling. This model presents a framework to understand the cooperation between different interneurons in a recurrent cortical circuit.

Discovery of fused heterocyclic carboxamide derivatives as novel α7-nAChR agonists: Synthesis, preliminary SAR and biological evaluation.

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher Emax than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a, which showed EC50 of 1.88 µM and Emax of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4ß2 and α3ß4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists.

Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice.

A series of novel thiazolo[4,5- d]pyrimidin-7(6 H)-ones (3aa-3eq) were designed, synthesized, and evaluated as the type I positive allosteric modulators of human α7 nAChR expressed in Xenopus ooctyes by a two-electrode voltage clamp. The structure-activity relationship analysis identified the compound 3ea as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 µM) and an EC50 = 1.26 µM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT3A, NMDA, and GABAA receptors. Compound 3ea showed an elimination half-life of 10.8 ± 1.5 h for 3 mg/kg, i.v., and 7.4 ± 1.1 h for 60 mg/kg, i.g. in rat. It also exhibited sufficient blood-brain barrier penetration with no significant effect on hERG channel. Most importantly, compound 3ea dose-dependently (0.1-1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1ß3γ2 and α5ß3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

The current agonists and positive allosteric modulators of α7 nAChR for CNS indications in clinical trials.

The alpha-7 nicotinic acetylcholine receptor (α7 nAChR), consisting of homomeric α7 subunits, is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Enhancement of α7 nAChR function is considered to be a potential therapeutic strategy aiming at ameliorating cognitive deficits of neuropsychiatric disorders such as Alzheimer's disease (AD) and schizophrenia. Currently, a number of α7 nAChR modulators have been reported and several of them have advanced into clinical trials. In this brief review, we outline recent progress made in understanding the role of the α7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of α7 nAChR modulators used in clinical trials.

[Relationship between vitamin D deficiency and early-onset neonatal sepsis].

OBJECTIVE: To evaluate the effect of vitamin D level on early-onset sepsis (EOS) in neonates. METHODS: Seventy-eight full-term neonates with EOS were used as the research group (EOS group). sixty healthy full-term neonates without clinical and/or laboratory features related to infections were used as the control group. Blood samples of the neonates and their mothers in both groups were collected within 72 hours of delivery to determine 25-hydroxyvitamin D(25-OHD) levels. The rate of vitamin D deficiency in the neonates and the level of 25-OHD supplemented to their mothers during pregnancy were compared between the two groups. RESULTS: There was a significant positive correlation between the serum level of 25-OHD of the mothers and that of the neonates in both groups (EOS group: r=0.797, P<0.01; control group: r=0.929, P<0.01). The neonates and their mothers in the EOS group had significantly lower 25-OHD levels than those in the control group (P<0.01). The rate of vitamin D deficiency among the neonates in the EOS group was significantly higher than that of the control group (P<0.01). The level of vitamin D supplemented to the mothers during the last 3 months of pregnancy in the EOS group was significantly lower than that in the control group (P<0.01). CONCLUSIONS: Low serum level of 25-OHD is associated with the development of early-onset sepsis in full-term neonates.

[Multicenter prospective epidemiological studies on Haemophilus influenzae infection among hospitalized children with lower respiratory tract infections].

OBJECTIVE: To understand epidemiological characteristics of Haemophilus influenzae (Hi) infection in hospitalized children with lower respiratory tract infection (LRTI) in west Sichuan China. METHOD: The multicenter prospective cross-sectional design was used; four hospitals in west Sichuan China were chosen as research field, sputum bacterial culture was done and biological typing, PCR identification and drug sensitivity test of Hi epidemic strains were carried out among 0-17y hospitalized patients with LRTI in four hospitals located in west Sichuan China. RESULT: Totally 5 748 cases with LRTI in four hospitals were investigated in west Sichuan from Nov. 2013 to April 2014 and the rate of sputum culture was 46.96% (2,699/5 748). The total pathogenic bacteria positive rate of sputum culture was 43.53% (1,175/2 699), and 279 Haemophilus influenzae (Hi) strain in 272 cases were isolated, the Hi positive rate was 10.08% (272/2 699). All the strains (100%) were non-typeable Haemophilus influenzae (NTHi ) indentified by PCR. The main biotype of 279 strains was type Ⅰ with 39.07% (109/279) and type Ⅳ with 50.90% (142/279) ; 272 cases were enrolled in this survey, 12.50% (34/272) had broncheolitis, the rest of lower respiratory infection was 87.50 % (238/272), and 2.57% (7/272) was neonatal pneumonia, 2.21%(6/272)was pneumonia complicated with sepsis; in four hospitals the overall positive rate of Hi in inpatients with lower respiratory infection was 10.21%, 28.96%, 4.80%, 10.21% (χ(2) = 112.561, P = 0.000) and the positive rate of Hi inpatients with broncheolitis was 11.92%, 20.93%, 4.76%, and 66.67% (Fisher exact probability P = 0.001), with the rest lower respiratory infection was 9.96%, 30.90%, 4.81%, 9.85% (χ(2) =108.876, P = 0.000); 2.87% (8/279) bacterial strains of ß-lactamase-nonproducing-ampicillin-intermediary (BLNAI) distributed in four hospitals, and 1.79% (5/279) bacterial strains of ß-lactamase-nonproducing-ampicillin-resistant (BLNAR), 0.72% (2/279) bacterial strains of ß-lactamase-positive amoxicillin-clavulanate-resistance (BLPACR) were found in two hospitals respectively. CONCLUSION: All the Hi isolated from sputum were non-typeable among 0-17y inpatients with LRTI and the main biotype were type Ⅰ and type Ⅳ in west Sichuan China. Much attention should be paid to BLNAR and BLPACR strains found in the west Sichuan region.

[The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold].

Alpha7 nicotinic acetylcholine receptor（α7 nAChR） is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships（SAR）. All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16 c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60 ± 0.19 µmol·L-1 and maximum effect (Emax) of 69.0% ± 2.8% compared with 3 mmol·L-1 ACh. Compound 17 b with 8-cyclopropyl substitution shows an increased Emax of 81.1% ± 9.3% with EC50 at 2.74 ± 0.74 µmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.

A cascade amplification strategy based on rolling circle amplification and hydroxylamine amplified gold nanoparticles enables chemiluminescence detection of adenosine triphosphate.

A highly sensitive and selective chemiluminescent (CL) biosensor for adenosine triphosphate (ATP) was developed by taking advantage of the ATP-dependent enzymatic reaction (ATP-DER), the powerful signal amplification capability of rolling circle amplification (RCA), and hydroxylamine-amplified gold nanoparticles (Au NPs). The strategy relies on the ability of ATP, a cofactor of T4 DNA ligase, to trigger the ligation-RCA reaction. In the presence of ATP, the T4 DNA ligase catalyzes the ligation reaction between the two ends of the padlock probe, producing a closed circular DNA template that initiates the RCA reaction with phi29 DNA polymerase and dNTP. Therein, many complementary copies of the circular template can be generated. The ATP-DER is eventually converted into a detectable CL signal after a series of processes, including gold probe hybridization, hydroxylamine amplification, and oxidative gold metal dissolution coupled with a simple and sensitive luminol CL reaction. The CL signal is directly proportional to the ATP level. The results showed that the detection limit of the assay is 100 pM of ATP, which compares favorably with those of other ATP detection techniques. In addition, by taking advantage of ATP-DER, the proposed CL sensing system exhibits extraordinary specificity towards ATP and could distinguish the target molecule ATP from its analogues. The proposed method provides a new and versatile platform for the design of novel DNA ligation reaction-based CL sensing systems for other cofactors. This novel ATP-DER based CL sensing system may find wide applications in clinical diagnosis as well as in environmental and biomedical fields.