Chemical profiling of Zhi-Ke-Bao pills and its potential mechanism against cough by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and network pharmacology.

Zhi-Ke-Bao pills (ZKB), a traditional Chinese medicine preparation composed of 13 herbs, is generally used to treat cough caused by external wind cold, phlegm, etc in clinical applications, and it plays a core role in relieving cough caused by COVID-19 and influenza in China. Till now, the understanding of its chemical constituents was dramatically limited due to its chemical complexity, restricting its clinical application or development. In this work, a developed ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF MS) method, a targeted and non-targeted strategy and network pharmacology were used to comprehensively characterize the chemical compositions in ZKB and predict its mechanism against cough. A total of 164 compounds (148 targeted compounds and 16 non-targeted ones) were identified or tentatively characterized in ZKB, including 65 flavonoids, 25 alkaloids, 19 organic acids, 41 saponins, 9 coumarins, 2 phenylpropanoids, 2 anthraquinones, and 1 other types. Among them, 37 compounds were unambiguously identified by comparison to reference standards. Meanwhile, the fragmentation behaviors of five main chemical structure types were also summarized. 309 targets and two core signaling pathways of ZKB against cough were predicted by network pharmacology, including MAPK and PI3K-Akt signaling pathways. It was the first time to characterize the chemical compounds of ZKB and reveal its potential mechanism against cough, providing the material basis for further quality control or pharmacodynamic evaluation of ZKB.

Multi-omics and chemical profiling approaches to understand the material foundation and pharmacological mechanism of sophorae tonkinensis radix et rhizome-induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sophorae tonkinensis Radix et Rhizoma (STR) is an extensively applied traditional Chinese medicine (TCM) in southwest China. However, its clinical application is relatively limited due to its hepatotoxicity effects. AIM OF THE STUDY: To understand the material foundation and liver injury mechanism of STR. MATERIALS AND METHODS: Chemical compositions in STR and its prototypes in mice were profiled by ultra-performance liquid chromatography coupled quadrupole-time of flight mass spectrometry (UPLC-Q/TOF MS). STR-induced liver injury (SILI) was comprehensively evaluated by STR-treated mice mode. The histopathologic and biochemical analyses were performed to evaluate liver injury levels. Subsequently, network pharmacology and multi-omics were used to analyze the potential mechanism of SILI in vivo. And the target genes were further verified by Western blot. RESULTS: A total of 152 compounds were identified or tentatively characterized in STR, including 29 alkaloids, 21 organic acids, 75 flavonoids, 1 quinone, and 26 other types. Among them, 19 components were presented in STR-medicated serum. The histopathologic and biochemical analysis revealed that hepatic injury occurred after 4 weeks of intragastric administration of STR. Network pharmacology analysis revealed that IL6, TNF, STAT3, etc. were the main core targets, and the bile secretion might play a key role in SILI. The metabolic pathways such as taurine and hypotaurine metabolism, purine metabolism, and vitamin B6 metabolism were identified in the STR exposed groups. Among them, taurine, hypotaurine, hypoxanthine, pyridoxal, and 4-pyridoxate were selected based on their high impact value and potential biological function in the process of liver injury post STR treatment. CONCLUSIONS: The mechanism and material foundation of SILI were revealed and profiled by a multi-omics strategy combined with network pharmacology and chemical profiling. Meanwhile, new insights were taken into understand the pathological mechanism of SILI.

The phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity of Forsythiae Fructus: An updated systematic review.

Forsythiae Fructus (FF), the dried fruit of F. suspensa, is commonly used to treat fever, inflammation, etc in China or other Asian countries. FF is usually used as the core herb in traditional Chinese medicine preparations for the treatment of influenza, such as Shuang-huang-lian oral liquid and Yin-qiao powder, etc. Since the wide application and core role of FF, its research progress was summarized in terms of traditional uses, phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity. Meanwhile, the anti-influenza substances and mechanism of FF were emphasized. Till now, a total of 290 chemical components are identified in F. suspensa, and among them, 248 components were isolated and identified from FF, including 42 phenylethanoid glycosides, 48 lignans, 59 terpenoids, 14 flavonoids, 3 steroids, 24 cyclohexyl ethanol derivatives, 14 alkaloids, 26 organic acids, and 18 other types. FF and their pure compounds have the pharmacological activities of anti-virus, anti-inflammation, anti-oxidant, anti-bacteria, anti-tumor, neuroprotection, hepatoprotection, etc. Inhibition of TLR7, RIG-I, MAVS, NF-κB, MyD88 signaling pathway were the reported anti-influenza mechanisms of FF and phenylethanoid glycosides and lignans are the main active groups. However, the bioavailability of phenylethanoid glycosides and lignans of FF in vivo was low, which needed to be improved. Simultaneously, the un-elucidated compounds and anti-influenza substances of FF strongly needed to be explored. The current quality control of FF was only about forsythoside A and phillyrin, more active components should be taken into consideration. Moreover, there are no reports of toxicity of FF yet, but the toxicity of FF should be not neglected in clinical applications.

A review of the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology of Abri Herba (Ji-Gu-Cao).

Abri Herba (AH, known as 'Ji-Gu-Cao' in China) has a long-term medicinal history of treating cholecystitis, acute and chronic hepatitis and non-alcoholic fatty liver (NAFL) in China or other Asian countries. This review aimed to provide a comprehensive analysis of AH in terms of ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology. The information involved in the study was collected from a variety of electronic resources, and >100 scientific studies have been used since 1962. Until now, 95 chemical compounds have been isolated and identified from AH and the seeds of Abrus cantoniensis Hance (ACH), including 47 terpenoids, 26 flavonoids and 4 alkaloids. The pharmacological activities of AH extracts and their pure compounds have been explored in the aspects of anti-hyperlipidaemia, hepatoprotection, anti-tumour, anti-viral, anti-bacterial, anti-inflammatory and analgesic, immunomodulation, antioxidant and others. The pharmacokinetics and excretion kinetics of AH in vivo and 15 traditional and clinical prescriptions containing AH have been sorted out, and the potential therapeutic mechanism and drug metabolism pattern were also summarised. The pods of ACH are toxic, with a median lethal dose (LD50) of 10.01 ± 2.90 g/kg (i.g.) in mice. Interestingly, the toxicity of ACH's pods and seeds decreased after boiling. However, the toxicity mechanism of pods of ACH is unclear, limiting its clinical application. Clinical trials in the future should be used to explore its safety. Meanwhile, as one of the relevant pharmacological activities, the effects and mechanism of AH on anti-hyperlipidaemia and hepatoprotection should be further studied, which is of great significance for understanding its mechanism of action in the treatment of NAFL disease and improving its clinical application.

The comparative analysis of Lonicerae Japonicae Flos and Lonicerae Flos: A systematical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae Japonicae Flos (LJF) and Lonicerae Flos (LF) were once used as the same herb in China, but they were distinguished by Chinese Pharmacopoeia in 2005 in terms of their medicinal history, plant morphology, medicinal properties and chemical constituents. However, their functions, flavor, and meridian tropism are the same according to the Chinese pharmacopoeia 2020 edition, making researchers and customers confused. AIM OF THE REVIEW: This review aimed to provide a comparative analysis of LJF and LF in order to provide a rational application in future research. MATERIALS AND METHODS: The information was gathered from China National Knowledge Infrastructure (CNKI), SciFinder, Google Scholar, PubMed, Web of Science, and Chinese Masters and Doctoral Dissertations (all chosen articles were reviewed attentively from 1980.1 to 2023.8). RESULTS: Till now, 507 chemical compounds have been isolated and identified in LJF, while 223 ones (79 overlapped compounds) are found in LF, including organic acids and derivatives, flavonoids, triterpenoids, iridoids, and essential oil components, etc. In addition, the pharmacological activities of LJF and LF, especially for their anti-influenza efficacy and mechanism, and their difference in terms of pharmacokinetic parameters, toxicology, and clinical applications were also summarized. CONCLUSION: The current work offers comparative information between LJF and LF in terms of botany, traditional uses, phytochemistry, ethnopharmacology, pharmacokinetics, toxicology, and pharmacology, especially their anti-influenza activities. Despite the same clinical applications and similar chemical components in LJF and LF, differentiated components were still existed, resulting in differentiated pharmacological activities and pharmacokinetics parameters. Moreover, the research about anti-influenza mechanism and functional substances of LJF and LF is dramatically limited, restricting their clinical applications. In addition, few studies have investigated the metabolism feature of LF in vivo, which is one of the important bases for revealing the pharmacological mechanism of LF. At the same time, the toxicity of LJF and LF is not fully studied, and the toxic compounds of LJF and LF need to be screened out in order to standardize the drug use and improve their rational applications.

Dissection of the antitumor mechanism of tetrandrine based on metabolite profiling and network pharmacology.

RATIONALE: Tetrandrine, the Q-marker in Stephaniae Tetrandrae Radix, was proven to present an obvious antitumor effect. Until now, the metabolism and antitumor mechanism of tetrandrine have not been fully elucidated. METHODS: The metabolites of tetrandrine in rats were profiled using ultra-high-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential antitumor mechanism of tetrandrine in vivo was predicted using network pharmacology. RESULTS: A total of 30 metabolites were characterized in rats after ingestion of tetrandrine (10 mg/kg), including 0 in plasma, 7 in urine, 11 in feces, 9 in liver, 8 in spleen, 4 in lung, 5 in kidney, 5 in heart, and 4 in brain. This study was the first to show the metabolic processes demethylation, hydroxylation, and carbonylation in tetrandrine. The pharmacology network results showed that tetrandrine and its metabolites could regulate AKT1, TNF, MMP9, MMP2, PAK1, and so on by involving in proteoglycan tumor pathway, PI3K-Akt signaling pathway, tumor pathway, MAPK signaling pathway, and Rap1 signaling pathway. CONCLUSIONS: The metabolism features of tetrandrine and its potential antitumor mechanism were summarized, providing data for further pharmacological validation.

Integrative Analysis of Transcriptomic and Metabolomic Data for Identification of Pathways Related to Matrine-Induced Hepatotoxicity.

Matrine (MT) is a major bioactive compound extracted from Sophorae tonkinensis. However, the clinical application of MT is relatively restricted due to its potentially toxic effects, especially hepatotoxicity. Although MT-induced liver injury has been reported, little is known about the underlying molecular mechanisms. In this study, transcriptomics and metabolomics were applied to investigate the hepatotoxicity of MT in mice. The results indicated that liver injury occurred when the administration of MT (30 or 60 mg/kg, i.g) lasted for 2 weeks, including dramatically increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc. The metabolomic results revealed that steroid biosynthesis, purine metabolism, glutathione metabolism, and pyruvate metabolism were involved in the occurrence and development of MT-induced hepatotoxicity. Further, the transcriptomic data indicated that the downregulation of NSDHL with CYP51, FDFT1, and DHCR7, involved in steroid biosynthesis, resulted in a lower level of cholic acid. Besides, Gstps and Nat8f1 were related to the disorder of glutathione metabolism, and HMGCS1 could be treated as the marker gene of the development of MT-induced hepatotoxicity. In addition, other metabolites, such as taurine, flavin mononucleotide (FMN), and inosine monophosphate (IMP), also made a contribution to the boosting of MT-induced hepatotoxicity. In this work, our results provide clues for the mechanism investigation of MT-induced hepatotoxicity, and several biomarkers (metabolites and genes) closely related to the liver injury caused by MT are also provided. Meanwhile, new insights into the understanding of the development of MT-induced hepatotoxicity or other monomer-induced hepatotoxicity were also provided.

Psychological impact of the COVID-19 epidemic among healthcare workers in paediatric intensive care units in China.

To perform a mental health evaluation and an early psychological intervention for healthcare workers (HCWs) during the coronavirus disease 2019 (COVID-19) epidemic, an online survey was conducted among 3055 HCWs in the paediatric intensive care units (PICUs) of 62 hospitals in China on March 26, 2020, by the Neurology and Sedation Professional Group, Emergency Department, Paediatrics Branch, Chinese Medical Association. The questionnaire was divided into three parts, including general information, the Impact of Event Scale-Revised (IES-R), and the Depression Anxiety Stress Scale-21 (DASS-21). The results show that a total of 970 HCWs (45.99%) were considered to meet the clinical cut-off scores for posttraumatic stress (PTS), and the proportions of participants with mild to extremely severe symptoms of depression, anxiety and stress were 39.69%, 36.46% and 17.12%, respectively. There was no significant difference in the psychological impact among HCWs of different genders. Married HCWs were 1.48 times more likely to have PTS than unmarried HCWs (95% Cl: 1.20-1.82, p <0.001). Compared with junior professional title participants, the PTS-positive rate of HCWs with intermediate professional titles was 1.91 times higher (90% Cl: 1.35-2.70, p<0.01). Those who had been in contact with confirmed COVID-19 cases were 1.40 times (95% Cl: 1.02-1.92, p <0.05) more likely to have PTS than those who did not have contact with COVID-19 cases or did not know the relevant conditions. For depression, the proportion of HCWs with intermediate professional titles was significantly higher, at 1.65 times (90% Cl: 1.17-2.33, p <0.01) that of those with junior professional titles. The depression of HCWs at work during the epidemic was 1.56 times that of HCWs on vacation (95% Cl: 1.03-2.37, p <0.05), and their anxiety was 1.70 times greater (95% Cl: 1.10-2.63, p <0.05). Participants who had been in contact with confirmed COVID-19 cases had more pronounced anxiety, 1.40 times that of those who did not have contact with COVID-19 cases or did not know the relevant conditions (95% Cl: 1.02-1.92, p <0.05). There was no significant correlation between the variables and the positive results of stress symptoms. In total, 45.99%, 39.69%, 36.46% and 17.12% of PICU HCWs were affected by PTS, depression, anxiety and stress, respectively, to varying degree. Married status, intermediate professional titles and exposure history were independent risk factors for PTS. Intermediate professional titles and going to work during the epidemic were independent risk factors for depression, and going to work and exposure history during the epidemic were independent risk factors for anxiety. In the face of public health emergencies, HCWs not only specialize in paediatric intensive care but also, as a high-risk group, must actively take preventive measures and use mitigation strategies.

Talaromyces Marneffei Infection in an HIV-Negative Child with a CARD9 Mutation in China: A Case Report and Review of the Literature.

BACKGROUND: Talaromyces marneffei (T. marneffei) is a thermally dimorphic fungus causing systemic mycosis. Due to the atypical symptoms and diverse imaging findings, T. marneffei-infected patients may be misdiagnosed thus preventing timely antifungal therapy. Moreover, HIV-negative patients with T. marneffei infection may be congenitally immunocompromised because of the mutation of immune-related genes. CASE PRESENTATION: We describe a case of an HIV-negative child who developed disseminated T. marneffei infection in a nonendemic area. Chest CT showed similar imaging changes of miliary pulmonary tuberculosis, while there was no other evidence of tuberculosis infection, and empirical antituberculosis treatment was not effective. Lymphocyte subset analysis showed reduced natural killer cells, and the immunoglobulin profile showed low levels of IgM, C3 and C4. A bone marrow smear revealed T. marneffei infection, and ascites culture also proved T. marneffei infection. Despite antifungal treatment, the child died of multiple organ failure. Two gene mutations in caspase recruitment domain-containing protein 9 (CARD9) were detected, which had not been reported previously in T. marneffei-infected patients. CONCLUSIONS: HIV-negative patients with CARD9 mutations may be potential hosts of T. marneffei. Abnormalities in the immunoglobin profile and lymphocyte subset may provide clues for immunocompromised patients, and further genetic testing is advised to identify gene mutations in HIV-negative patients with T. marneffei infection.

[Research Advances on Clinical Application of Umbilical Cord Blood Transplantation in the Treatment of Hematological Diseases--Review].

Abstract　　Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSCs) for patients who were lack of HLA match related or unrelated donors. Compared with bone marrow and mobilized peripheral blood, UCB has the advantages of easy availability, safety for donors, and low requirement for HLA match between donors and recipients. However, the cell amount in UCB is relatively less, which was associated with increased graft failure, delayed hematologic recovery, immune reconstitution, and higher transplant related mortality after UCB transplantation (UCBT). Double-unit UCB is a straightforward method to augment cell amount in UCB. Compared with single-unit UCBT, double-unit CBT associated with less risk of primary disease relapse and increased incidence rate of graft-versus-host disease (GVHD), but the hematologic recovery and overall survival of recipients were no significantly difference between single and double-unit UCBT. Novel strategies for UCB expansion significantly increased the cell amount in UCB, single-unit expanded UCBT not only increased the sources of UCB, but also decreased the high cost of double-unit UCB. ATG can decrease the risk of graft failure and GVHD rate, but the role of ATG in UCBT is still controversial. Herein, the recent clinical advances on UCBT in the treatment of hematologic diseases are systematically reviewed.

B(C6 F5 )3 /Chiral Phosphoric Acid Catalyzed Ketimine-Ene Reaction of 2-Aryl-3H-indol-3-ones and α-Methylstyrenes.

The enantioselective ketimine-ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine-ene reactions of 2-aryl-3H-indol-3-ones with α-methylstyrenes were achieved by utilizing a B(C6 F5 )3 /chiral phosphoric acid (CPA) catalyst. These ketimine-ene reactions proceed well with low catalyst loading (B(C6 F5 )3 /CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2-allyl-indolin-3-ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C6 F5 )3 significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen-bonding interactions, especially the enhanced N-H⋅⋅⋅O hydrogen-bonding interaction, differentiates the free energy of the transition states of CPA and B(C6 F5 )3 /CPA, thereby inducing the improvement of stereoselectivity.

Comparison of admission serum albumin and hemoglobin as predictors of outcome in children with moderate to severe traumatic brain injury: A retrospective study.

Hypoalbuminemia and anemia are frequent among in patients with traumatic brain injury (TBI). We assess whether serum albumin and hemoglobin at admission can predict outcome in children with moderate to severe TBI.This retrospective study was conducted in a tertiary pediatric hospital between May 2012 and Jun 2018 included children with an admission Glasgow Coma Scale of ≤13.A total of 213 patients were included of whom 45 died in hospital. Multivariate logistic regression showed that hypoalbuminemia (serum albumin <30 g/L) was independently associated with mortality (adjusted odds ratio [OR] = 3.059; 95% confidence interval [CI]: 1.118-8.371; P = .030) in children with moderate to severe TBI, while anemia (hemoglobin <90 g/L) was not independently associated with mortality (adjusted OR = 1.742; 95% CI: 0.617-4.916; P = .295). Serum albumin was significantly superior to hemoglobin (area under the curve [AUC] 0.738 vs AUC 0.689, P < .05) under receiver operating characteristic curve analysis. Hypoalbuminemia was also associated with reduced 14-day ventilation-free days, 14-day intensive care unit (ICU)-free days, and 28-day hospital-free days.Serum albumin at admission was superior to hemoglobin in predicting the mortality in children with moderate to severe TBI and also associated with reduced ventilator-free, ICU-free, and hospital-free days.

The impact of admission serum lactate on children with moderate to severe traumatic brain injury.

BACKGROUND: Lactate is used to evaluate the prognosis of adult patients with trauma. However, the prognostic significance of admission serum lactate in the setting of pediatric traumatic brain injury (TBI) is still unclear. We aim to investigate the impact of admission lactate on the outcome in children with moderate to severe TBI. METHODS: This retrospective study was conducted in a tertiary pediatric hospital between May 2012 and Jun 2018 included children with an admission Glasgow Coma Scale (GCS) of ≤13. Two hundred and thirteen patients were included in the analysis and 45 patients died in hospital. RESULTS: Admission lactate and glucose were significantly higher in non-survivors than those in survivors (P < 0.05). Admission lactate was positively correlated with admission glucose and negatively correlated with GCS in all patients (n = 213), subgroup of isolated TBI (n = 112) and subgroup of GCS ≤ 8 (n = 133), respectively. AUCs of lactate could significantly predict the mortality and were higher than those of glucose in all patients, subgroup of isolated TBI and subgroup of GCS ≤ 8, respectively. Multivariate logistic regression showed that admission lactate (Adjusted OR = 1.189; 95% CI: 1.002-1.410; P = 0.047) was independently associated with mortality, while admission glucose (Adjusted OR = 1.077; 95% CI: 0.978-1.186; P = 0.133) wasn't an independent risk factor of death. Elevated admission lactate (> 2 mmol/L) was associated with death, reduced 14-day ventilation-free days, 14-day ICU-free days and 28-day hospital-free days. CONCLUSIONS: Admission serum lactate can effectively predict the mortality of children with moderate to severe TBI. Elevated admission lactate is associated with death, reduced ventilator-free, ICU-free, and hospital-free days. Admission serum lactate could be used as a prognostic biomarker of mortality in children with moderate to severe TBI.

[Effect of augmented renal clearance on plasma concentration of vancomycin and treatment outcome in children with methicillin-resistant Staphylococcus aureus infection].

OBJECTIVE: To investigate the effect of augmented renal clearance (ARC) on plasma concentration of vancomycin, bacteriological outcome, and clinical outcome in children with methicillin-resistant Staphylococcus aureus (MRSA) infection treated by vancomycin. METHODS: A retrospective analysis was performed for the clinical data of 60 critically ill children who were treated with vancomycin due to MRSA infection from January 2013 to July 2017 and underwent plasma concentration monitoring. According to estimated glomerular filtration rate, these children were divided into an ARC group with 19 children and a normal renal function group with 41 children. The two groups were compared in terms of the use of vancomycin, plasma concentration of vancomycin, and treatment outcome. RESULTS: The children in the ARC group had an age of 1-12 years, and the ARC group had significantly higher body weight and body surface area than the normal renal function group (P<0.05). Compared with the normal renal function group, the ARC group had a significantly lower initial trough concentration of vancomycin and a significantly lower proportion of children who achieved the effective trough concentration of vancomycin (10-20 mg/L) (P<0.05). There were no significant differences in bacteriological outcome and clinical outcome between the two groups (P>0.05), but the ARC group had significantly longer length of stay in the pediatric intensive care unit (PICU) and length of hospital stay than the normal renal function group (P<0.05). CONCLUSIONS: ARC can significantly reduce the trough concentration of vancomycin and prolong the length of PICU stay and the length of hospital stay in children with MRSA infection. Idividualized medication should be administered to children with ARC.

A case report of a teenager with severe hand, foot, and mouth disease with brainstem encephalitis caused by enterovirus 71.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is an acute viral infection occurring mostly in infants and children. Enterovirus 71 (EV71) infection mostly occurs in children < 5 years of age. Severe cases, however, are usually encountered in children under the age of 3 years, and exceedingly rare in teenagers > 14 years and adults. CASE PRESENTATION: We report a rare case of HFMD in a 16-year-old male teenager residing in Chonqing, China. The clinical presentation was typical of HFMD and included vesicular lesions and oral mucosal ulcers, macular and vesicular lesions on palms and soles. He developed severe neurological complications that were suggestive of brainstem encephalitis. EV71 RNA was detected in the patient's faecal samples by reverse transcription-polymerase chain reaction. Specific IgM antibody to EV71 was detected in both serum and cerebrospinal fluid by ELISA. Gamma immunoglobulin therapy at 25 g/day was administered for 2 days, along with methylprednisolone, mannitol, ganglioside, and creatine phosphate sodium. The patient showed neurological improvement and recovered completely in 1 month. CONCLUSIONS: This case indicates that EV71 infection may cause HFMD in teenagers with potentially severe neurological involvement. Clinicians should be aware of the possibility of HFMD occurring in adults and teenagers as prompt treatment could be life-saving in these patients.

Single- Versus Double-Unit Umbilical Cord Blood Transplantation for Hematologic Diseases: A Systematic Review.

Controversial results exist regarding the clinical benefits of single- vs double-unit umbilical cord blood transplantation (UCBT) in patients with hematologic diseases. A systematic review was conducted to evaluate this issue. The PubMed, Embase, and Cochrane Library databases were searched up to May 2018. A total of 25 studies including 6571 recipients were identified. Although double-unit UCB contained higher doses of total nucleated cells and CD34+ cells, it offered no advantages over single-unit UCB in terms of hematologic recovery, including the rate and speed of neutrophil and platelet engraftment. Double-unit UCBT was associated with higher incidences of grades II-IV acute and extensive chronic graft-vs-host disease, accompanied by a lower relapse incidence, which may be attributed to a graft-vs-graft effect induced by double-unit UCB. However, transplant-related mortality, disease-free survival, and overall survival were comparable between single- and double-unit UCBT. Although double-unit UCBT confers no clinical advantages over single-unit UCBT, certain patients, such as those at high risk of relapse, might benefit from double-unit UCBT, a possibility that needs to be clarified in future randomized trials.

Efficacy and safety of mesenchymal stromal cells for the prophylaxis of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials.

A meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the efficacy and safety of mesenchymal stromal cells (MSCs) for the prophylaxis of chronic graft-versus-host disease (cGVHD) in patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Six studies involving 365 patients were included. The pooled results showed that MSCs significantly reduced the incidence of cGVHD (risk ratio [RR] 0.63, 95% confidence interval [CI] 0.46 to 0.86, P = 0.004). Favorable prophylactic effects of MSCs on cGVHD were observed with umbilical cord-derived, high-dose, and late-infusion MSCs, while bone marrow-derived, low-dose, and coinfused MSCs did not confer beneficial prophylactic effects. In addition, MSC infusion did not increase the risk of primary disease relapse and infection (RR 1.02, 95% CI 0.70 to 1.50, P = 0.913; RR 0.89, 95% CI 0.44 to 1.81, P = 0.752; respectively). Moreover, there was an apparent trend toward increased overall survival (OS) in the MSC group compared with that in the control group (RR 1.13, 95% CI 0.98 to 1.29, P = 0.084). In conclusion, this meta-analysis demonstrated that MSC infusion is an effective and safe prophylactic strategy for cGVHD in patients with hematological malignancies undergoing allo-HSCT.

[Association between vasoactive-inotropic score and prognosis in children with septic shock].

OBJECTIVE: To investigate the association between vasoactive-inotropic score (VIS) and prognosis in children with septic shock. METHODS: A total of 117 children with decompensated septic shock who received the treatment with vasoactive agents were enrolled. According to their prognosis, they were divided into death group with 41 children and survival group with 76 children. With the maximum VIS within the first 24 hours (24hVIS max) as the cut-off value (29.5), the children were divided into low VIS group with 78 children and high VIS group with 39 children. The 24hVIS max and the mean VIS within the first 24 hours (24hVIS mean) were calculated for all children. A receiver operating characteristic (ROC) curve analysis was performed for the association between VIS and the prognosis of septic shock. RESULTS: Compared with the survival group, the death group had significantly higher 24hVIS max, 24hVIS mean, PRISM III score, and level of lactate before the use of vasoactive agents and after 24 hours of use (P<0.05). 24hVIS max, 24hVIS mean, PRISM III score, level of lactate before the use of vasoactive agents and after 24 hours of use, and 24-hour pH had a certain value in predicting the prognosis of septic shock, but 24hVIS max had the largest area under the ROC curve. Compared with the low VIS group, the high VIS group had significantly higher number of deaths, PRISM III score, and level of lactate before treatment and after 24 hours of treatment (P<0.05). CONCLUSIONS: VIS is associated with the mortality of children with septic shock, and the severity and mortality of patients increase with the increase in VIS.

Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity.

Clinical Significance and Prognostic Effect of Serum 25-hydroxyvitamin D Concentrations in Critical and Severe Hand, Foot and Mouth Disease.

OBJECTIVE: To examine the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with critical and severe hand, foot and mouth disease (HFMD) and assess the clinical significance and prognostic effect of 25(OH)D concentrations in children with HFMD. METHODS: This is a prospective observational study. The 138 children with HFMD were divided into common (49 cases), severe (52 cases), and critical (37 cases) HFMD groups. Another 59 healthy children undergoing outpatient medical examinations during the same period were chosen as the control group. Serum 25(OH)D concentrations were measured in all the subjects, and each group was subdivided by serum 25(OH)D concentration into 25(OH)D normal (≥30 ng/mL); insufficiency (20-29.9 ng/mL), and deficiency (<20 ng/mL) groups. The pediatric critical illness score (PCIS) was recorded for the critical and severe HFMD group upon admission to the pediatric intensive care unit (PICU). Children with critical and severe HFMD were also monitored for blood lactate (LAC), serum calcium ions (Ca++), D-dimer (DD), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB) levels; the incidences of brainstem encephalitis, neurogenic pulmonary edema, and circulatory failure; and the 14-day mortality rate. RESULTS: Serum 25(OH)D concentrations were generally low in all groups. The critical HFMD group showed a significantly lower serum 25(OH)D mean concentration (20.0 ± 8.4 ng/mL) and a higher proportion of deficiency (18%) compared with the control group (28.1 ± 6.6 ng/mL, 8%), common (29.5 ± 8.1 ng/mL, 10%) and severe (31.9 ± 9.7 ng/mL, 8%) HFMD groups (p < 0.05). In the critical and severe HFMD groups, the 25(OH)D deficiency group had lower PCISs than the 25(OH)D normal and insufficiency groups (p < 0.05); and had higher values than the latter two groups for LAC, LDH, CK-MB and DD; and the incidences of brainstem encephalitis, neurogenic pulmonary edema, circulatory failure, and mortality (p < 0.05). The death group showed significantly lower serum 25(OH)D concentrations and PCISs than the survival group (p < 0.05) and had higher LAC, LDH, CK-MB and DD levels and higher incidences of brainstem encephalitis, neurogenic pulmonary edema, and circulatory failure (p < 0.05). Logistic regression analysis revealed that the serum 25(OH)D concentration was an independent factor that influenced mortality in children with critical and severe HFMD. CONCLUSIONS: In this study, we find the serum 25(OH)D concentrations are substantially reduced in children with critical and severe HFMD and are associated with the severity of HFMD. The serum 25(OH)D concentrations may have clinical value for determining the progression of critical HFMD and predicting the risk of death. Further evidence is needed before it can be stated that 25(OH)D concentrations have clinical value in HMFD diagnosis.