Diabetic kidney disease treatment: new perspectives.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage kidney disease worldwide, as the obesity epidemic and the burden of diabetes continue to rise globally. In general, guideline management of patients with DKD recommends lifestyle modifications, blood pressure and glycemic control, and dyslipidemia treatment along with other cardiovascular disease risk reduction measures. The inhibition of the renin-angiotensin system (RAS) using an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker remains the foundational therapy for DKD. In type 2 diabetes (T2D), significant advances in therapeutics, including the sodium-glucose cotransporter-2 inhibitors (SGLT2i), the glucagon-like peptide-1 receptor agonists (GLP-1 RA), and the nonsteroidal mineralocorticoid receptor agonist (MRA) finerenone, have dramatically expanded the armamentarium for treating DKD and its cardiovascular complications. Initiating, optimizing, and sustaining evidence-based pharmacological therapy using a therapeutic combination of RAS inhibitor + SGLT2i/GLP-1 RA + nonsteroidal MRA + statin is likely to significantly improve outcomes for T2D with DKD. Research into potential novel therapeutic targets for DKD remains particularly active and brings much anticipation and optimism to this field.

Application of Bayesian network and regression method in treatment cost prediction.

Charging according to disease is an important way to effectively promote the reform of medical insurance mechanism, reasonably allocate medical resources and reduce the burden of patients, and it is also an important direction of medical development at home and abroad. The cost forecast of single disease can not only find the potential influence and driving factors, but also estimate the active cost, and tell the management and reasonable allocation of medical resources. In this paper, a method of Bayesian network combined with regression analysis is proposed to predict the cost of treatment based on the patient's electronic medical record when the amount of data is small. Firstly, a set of text-based medical record data conversion method is established, and in the clustering method, the missing value interpolation is carried out by weighted method according to the distance, which completes the data preparation and processing for the realization of data prediction. Then, aiming at the problem of low prediction accuracy of traditional regression model, this paper establishes a prediction model combined with local weight regression method after Bayesian network interpretation and classification of patients' treatment process. Finally, the model is verified with the medical record data provided by the hospital, and the results show that the model has higher prediction accuracy.

cGMP signaling pathway that modulates NF-κB activation in innate immune responses.

The nuclear factor-kappa B (NF-κB) pathway is an evolutionarily conserved signaling pathway that plays a central role in immune responses and inflammation. Here, we show that Drosophila NF-κB signaling is activated via a pathway in parallel with the Toll receptor by receptor-type guanylate cyclase, Gyc76C. Gyc76C produces cyclic guanosine monophosphate (cGMP) and modulates NF-κB signaling through the downstream Tollreceptor components dMyd88, Pelle, Tube, and Dif/Dorsal (NF-κB). The cGMP signaling pathway comprises a membrane-localized cGMP-dependent protein kinase (cGK) called DG2 and protein phosphatase 2A (PP2A) and is crucial for host survival against Gram-positive bacterial infections in Drosophila. A membrane-bound cGK, PRKG2, also modulates NF-κB activation via PP2A in human cells, indicating that modulation of NF-κB activation in innate immunity by the cGMP signaling pathway is evolutionarily conserved.

Clinical and EEG characteristics analysis of autoimmune encephalitis in children with positive and negative anti-N-methyl- D-aspartate receptor antibodies.

BACKGROUND: Autoimmune encephalitis is complex and varied, but it is a curable disease. However, the diagnosis and treatment of children with Autoimmune encephalitis remains challenging. Therefore, we conducted this study to analyze the clinical features, electroencephalogram (EEG) characteristics, treatment and prognosis of autoimmune encephalitis in children with negative and positive anti-N-methyl-D-aspartate receptor (NMDAR) antibody. METHODS: From January 2015 to January 2017, 28 child patients with autoimmune encephalitis were hospitalized in the Neural Ward of the Children's Medical Center, Qilu Hospital of Shandong University. Inclusion criteria were based on the diagnostic criteria for autoimmune encephalitis published in Lancet Neurology in 2016. The clinical, EEG and imaging data were summarized. The clinical features, treatment regimen, follow-up and prognosis were also analyzed. RESULTS: Among these 28 child patients, 10 patients had positive anti-NMDAR antibody, while 18 patients had negative anti-NMDAR antibody. The clinical manifestations, EEG findings and seizures were similar (P>0.05) between these two groups. All 28 child patients were treated with methylprednisolone shock and human immunoglobulin. The response to immunotherapy was similar between these two groups (P>0.05). CONCLUSIONS: The clinical manifestation of autoimmune encephalitis is complex and varied, but it is a curable disease. Immunotherapy should be considered as soon as possible, with or without autoantibodies. Most of the child patients had a good prognosis, while some of them had the sequelae of epilepsy, mild mental symptoms, and dyskinesia. It is necessary to improve the understanding of autoimmune encephalitis with/without positive antibodies, and make diagnosis and treatment as soon as possible, in order to improve the prognosis.

Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults.

The Drosophila Toll pathway plays important roles in innate immune responses against Gram-positive bacteria and fungi. To identify previously uncharacterized components of this pathway, we performed comparative, ex vivo, genome-wide RNA interference screening. In four screens, we overexpressed the Toll adaptor protein dMyd88, the downstream kinase Pelle, or the nuclear factor κB (NF-κB) homolog Dif, or we knocked down Cactus, the Drosophila homolog of mammalian inhibitor of NF-κB. On the basis of these screens, we identified the E3 ubiquitin ligase Sherpa as being necessary for the activation of Toll signaling. A loss-of-function sherpa mutant fly exhibited compromised production of antimicrobial peptides and enhanced susceptibility to infection by Gram-positive bacteria. In cultured cells, Sherpa mediated ubiquitylation of dMyd88 and Sherpa itself, and Sherpa and Drosophila SUMO (small ubiquitin-like modifier) were required for the proper membrane localization of an adaptor complex containing dMyd88. These findings highlight a role for Sherpa in Drosophila host defense and suggest the SUMOylation-mediated regulation of dMyd88 functions in Toll innate immune signaling.

Ex vivo genome-wide RNAi screening of the Drosophila Toll signaling pathway elicited by a larva-derived tissue extract.

Damage-associated molecular patterns (DAMPs), so-called "danger signals," play important roles in host defense and pathophysiology in mammals and insects. In Drosophila, the Toll pathway confers damage responses during bacterial infection and improper cell-fate control. However, the intrinsic ligands and signaling mechanisms that potentiate innate immune responses remain unknown. Here, we demonstrate that a Drosophila larva-derived tissue extract strongly elicits Toll pathway activation via the Toll receptor. Using this extract, we performed ex vivo genome-wide RNAi screening in Drosophila cultured cells, and identified several signaling factors that are required for host defense and antimicrobial-peptide expression in Drosophila adults. These results suggest that our larva-derived tissue extract contains active ingredients that mediate Toll pathway activation, and the screening data will shed light on the mechanisms of damage-related Toll pathway signaling in Drosophila.

Fluorescent sensing of pyrophosphate anion in synovial fluid based on DNA-attached magnetic nanoparticles.

In this work, a new fluorescent method for sensitive detection of pyrophosphate anion (P2O7(4-), PPi) in the synovial fluid was developed using fluorophore labeled single-stranded DNA-attached Fe3O4 NPs. The sensing approach is based on the strong affinity of PPi to Fe3O4 NPs and highly efficient fluorescent quenching ability of Fe3O4 NPs for fluorophore labeled single-stranded DNA. In the presence of PPi, the fluorescence would enhance dramatically due to desorption of fluorophore labeled single-stranded DNA from the surface of Fe3O4 NPs, which allowed the analysis of PPi in a very simple manner. The proposed sensing system allows for the sensitive determination of PPi in the range of 2.0 × 10(-7)-4 × 10(-6)M with a detection limit of 76 nM. Importantly, the protocol exhibits excellent selectivity for the determination of PPi over other phosphate-containing compounds. The method was successfully applied to the determination of PPi in the synovial fluid, which suggests our proposed method has great potential for diagnostic purposes.

[Influence of ketogenic diet on the clinical effects and electroencephalogram features in 31 children with pharmacoresistant epileptic encephalopathy].

OBJECTIVE: To investigate the effect of ketogenic diet (KD) on the clinical and electroencephalogram features in children with pharmacoresistant epileptic encephalopathy. METHOD: Thirty-one children (19 boys, 12 girls) aged 7 months to 7 years (mean 2 years 5 month) with epilepsy refractory to conventional antiepileptic drugs (AEDs) were included in this study. In addition to their original AED treatment, the children were assigned to different ketogenic diets based on their age. The prospective electro-clinical assessment was performed prior to the KD and then one week, one month and again 3 months after the initiation of therapy, respectively. RESULT: The reduction of seizure frequency in 52%, 68% and 71% of all patients exceeded 50% one week, one month and three months after KD treatment respectively. KD is particularly effective in myoclonic astatic epilepsy (MAE; Doose Syndrome) and West syndrome with 100% and 81.25% of the patients having a greater than 50% seizure reduction, respectively. After 3 months of KD treatment, more than 2/3 patients experienced a reduction in interictal epileptiform discharges (IEDs) and improvement in EEG background. CONCLUSION: The clinical and electroencephalographic improvement confirms that KD is beneficial in children with refractory epilepsy.

Stable label-free fluorescent sensing of biothiols based on ThT direct inducing conformation-specific G-quadruplex.

In this work, a new, label-free, turn-on fluorescent sensor for biothiols detection based on ThT direct inducing conformation-specific G-quadruplex is developed. The sensing approach is based on a conformational switch of oligonucleotide controlled by Hg(2+) and a commercially available water-soluble fluorescent dye, Thioflavin T (ThT). A noticeable fluorescence light-up in ThT on binding to the G-quadruplex grants the sensor excellent sensitivity. The specific quadruplex conformation induced directly by ThT and pronounced structural selectivity of ThT for G-quadruplexes could generate more stable luminescence and make sure high specificity in complex biological samples. The present assay allows for the selective determination of cysteine and glutathione in the range of 2.0 × 10(-8)-2.5 × 10(-6)M and 3.0 × 10(-8)-2.0 × 10(-6)M with a detection limit of 8.4 nM and 13.9 nM respectively. The diagnostic capability and potential in practical applications of this method have been demonstrated by detecting biothiols in human blood serum.

Enhanced luminescence of photosensitizer-based mesoporous silica nanocomposites via energy transfer from conjugated polymer.

A unique assembly approach was developed to fabricate conjugated polymer and photosensitizer-doped mesoporous silica nanoparticles with effective Förster resonance energy transfer (FRET) from poly[(9,9-di(3,30-N,N0-trimethylammonium)-propylfluorenyl-2,7-diyl)-alt-co-(1,4-phenylene)] (PFP) to porphyrin-based photosensitizers (PSs). PFP and silica nanoparticles form a complex through electrostatic interactions, and efficient energy transfer from PFP to porphyrin-based PSs occurs upon irradiation. This approach is stable, effective, and diversified. PS-doped mesoporous silica nanoparticles showed three- to four-fold enhanced emission with the excitation of the maximum absorption wavelength of PS in the presence of PFP in comparison to the case without PFP. Doping fluorescence dyes into the nonporous core and adjusting the content of PS conjugated with the shell can endow the silica nanoparticles with a combinational optical signal of dyes and PS. These silica nanoparticles exhibit further improved performance on the basis of enhanced energy transfer offered by light-harvesting conjugated polymers.

A sensitive and selective near-infrared fluorescent probe for mercuric ions and its biological imaging applications.

A new mercury(II) near-infrared region fluorescent probe 3,9-dithia-6-monoazaundecane-tricarbocyanine has been designed and synthesized. It consists of two functional moieties: the tricarbocyanine performs as the near-infrared region fluorophore, and the 3,9-dithia-6-monoazaundecane acts as the selected binding site for metal ions. The near-IR excitation and emission profiles of the probe can minimize cell and tissue damage and avoid native fluorescence from natural cellular species. It exhibits fluorescence increase upon the binding of the Hg(2+) based on the inhibition of the photoinduced electron transfer quenching mechanism. Excellent sensitivity and selectivity for mercuric ions are observed with this probe. The value of the system is demonstrated by its use in monitoring the real-time uptake of Hg(2+) within HepG2 cells and five day old zebrafish. The synthesis and remarkable properties of it help to extend the development of metal ions fluorescent probes for biological applications.

Poor correlation between coronary artery calcification and obstructive coronary artery disease in an end-stage renal disease patient.

Vascular calcification is highly prevalent and often severe in patients with chronic kidney disease. Arterial calcification in patients with chronic kidney disease can result from the deposition of mineral along the intimal layer of arteries in conjunction with atheromatous plaques or from calcium deposition in the medial wall of arteries, also known as Monckeberg's sclerosis. Whether coronary artery calcium scores as measured by electron beam computed tomography correlate with occlusive atherosclerotic disease in the dialysis population is uncertain. Here we report a case of an asymptomatic patient with diabetes mellitus and end-stage renal disease undergoing maintenance hemodialysis, who was found to have extremely elevated coronary artery calcium scores on electron beam computed tomography, but varied degrees of atherosclerotic plaque in her coronary arteries on coronary angiography. This suggests that in addition to the calcification anticipated in a remodeled intima, a proportion of the calcification is also likely to be in the arterial media. Thus, this case demonstrates that even an extremely high coronary calcium score may not be a satisfactory surrogate marker for obstructive atherosclerosis in elderly diabetic dialysis patients.

Supramolecular interaction of ethylenediamine linked beta-cyclodextrin dimer and berberine hydrochloride by spectrofluorimetry and its analytical application.

The supramolecular interaction of beta-cyclodextrin dimer with berberine hydrochloride was studied in aqueous KH2PO4-H3PO4 buffer solution of pH 2.00 at room temperature by spectrofluorimetry. The apparent association constant of the complex was 1.53 x 10(4) L mol(-1). Based on the significant enhancement of fluorescence intensity of supramolecular sandwich complexes, a spectrofluorimetric method with high sensitivity and selectivity was developed for the determination of berberine hydrochloride in aqueous solution in presence of ethylenediamine linked beta-CD dimer. The linear range of the method was 12.8-1.00 x 10(4 )ng mL(-1) with the detection limit 3.6 ng mL(-1). There was no interference from the normally used in tablets and serum constituents. The proposed method was successfully applied to the determination of berberine hydrochloride in tablets and serum. And then it has a promising potential in therapeutic drug monitoring, pharmacokinetics and clinical application.

Synthesis of ethylenediamine linked beta-cyclodextrin dimer and its analytical application for tranilast determination by spectrofluorimetry.

A synthesis of beta-cyclodextrin (beta-CD) dimer, containing two beta-CD moieties that are linked through their sides by ethylenediamine, was presented. The dimer was characterized by means of IR, (1)H NMR, (13)C NMR, and elemental analysis. The inclusion complexation behavior of beta-cyclodextrin dimer with tranilast was studied in an aqueous KH(2)PO(4)-citric acid buffer solution of pH 2.00 at room temperature by spectrofluorimetry. Based on the significant enhancement of fluorescence intensity of tranilast, a spectrofluorimetric method with high sensitivity and selectivity was developed for the determination of tranilast in bulk aqueous solution in the presence of ethylenediamine beta-CD dimer. The apparent association constant of the complex was 8.39 x 10(3) L mol(-1), and the linear range was 10.8-1.40 x 10(4) ng mL(-1) with the detection limit 3.2 ng mL(-1). There was no interference from the excipients normally used in tablets and serum constituents. The proposed method was successfully applied to the determination of tranilast in serum.