Vitamin D3 improves iminodipropionitrile-induced tic-like behavior in rats through regulation of GDNF/c-Ret signaling activity.

Children with chronic tic disorders (CTD), including Tourette syndrome (TS), have significantly reduced serum 25-hydroxyvitamin D [25(OH)D]. While vitamin D3 supplementation (VDS) may reduce tic symptoms in these children, its mechanism is unclear. The study aim was to investigate the effects and mechanisms of vitamin D deficiency (VDD) and VDS on TS model behavior. Forty 5-week-old male Sprague-Dawley rats were randomly divided into (n = 10 each): control, TS model, TS model with VDD (TS + VDD), or TS model with VDS (TS + VDS; two intramuscular injections of 20,000 IU/200 g) groups. The VDD model was diet-induced (0 IU vitamin D/kg); the TS model was iminodipropionitrile (IDPN)-induced. All groups were tested for behavior, serum and striatal 25(OH)D and dopamine (DA), mRNA expressions of vitamin D receptor (VDR), glial cell line-derived neurotrophic factor (GDNF), protooncogene tyrosine-protein kinase receptor Ret (c-Ret), and DA D1 (DRD1) and D2 (DRD2) receptor genes in the striatum. TS + VDD had higher behavior activity scores throughout, and higher total behavior score at day 21 compared with TS model. In contrast, day 21 TS + VDS stereotyped behavior scores and total scores were lower than TS model. The serum 25(OH)D in TS + VDD was < 20 ng/mL, and lower than control. Striatal DA of TS was lower than control. Compared with TS model, striatal DA of TS + VDD was lower, while in TS + VDS it was higher than TS model. Furthermore, mRNA expression of VDR, GDNF, and c-Ret genes decreased in TS model, and GDNF expression decreased more in TS + VDD, while TS + VDS had higher GDNF and c-Ret expressions. VDD aggravates, and VDS ameliorates tic-like behavior in an IDPN-induced model. VDS may upregulate GDNF/c-Ret signaling activity through VDR, reversing the striatal DA decrease and alleviating tic-like behavior.

Circulating retinol and 25(OH)D contents and their association with symptoms in children with chronic tic disorders.

The present study measured serum levels of vitamin A (VA) and vitamin D (VD) in children with chronic tic disorders (CTD) and investigated their potential association with CTD and comorbidity of attention deficit hyperactivity disorder (ADHD) and the association of their co-insufficiencies or deficiencies with CTD symptoms. A total of 176 children (131 boys and 45 girls, median age of 9 years) with CTD were recruited as the CTD group. During the same period, 154 healthy children were selected as the healthy control (HC) cohort. Circulating retinol and 25-hydroxyvitamin D (25[OH]D) levels were measured for all participants using high-performance liquid chromatography (HPLC) and tandem mass spectrometry. The Yale Global Tic Severity Scale (YGTSS) was employed for the assessment of tic status and CTD impairment. The Swanson, Nolan, and Pelham Rating Scale (SNAP-IV) and the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) were used to evaluate comorbidity symptoms. CTD pediatric participants exhibited markedly diminished circulating retinol and 25(OH)D levels compared to HCs. Moreover, VA and VD deficiencies and their co-insufficiencies/deficiencies were more prevalent in CTD participants than HCs. Circulating 25(OH)D levels were inversely proportional to the YGTSS motor tic scores. YGTSS scores in CTD children with only VA or VD insufficiency or deficiency or with VA and VD co-insufficiency/deficiency did not differ from those in CTD children with normal VA and VD. CTD children with comorbid ADHD displayed reduced circulating retinol and 25(OH)D concentrations and elevated prevalence of VD deficiency compared to CTD participants without comorbid ADHD. Lower serum retinol content was intricately linked to the presence of elevated CTD and comorbid ADHD. VA and VD deficiencies and their co-insufficiencies/deficiencies were markedly enhanced in CTD pediatric participants compared to HCs. Lower VA concentration was linked to the presence of enhanced CTD and comorbid ADHD. Therefore, children with CTD, especially with comorbid ADHD, may be at a higher risk of VA or VD deficiency, which may prompt the clinicians to consider whether blood tests for VA and VD in CTD children would be helpful for clinical care.

Magnesium enhances the graft-versus-tumor effect of donor lymphocytic infusion on hematologic malignancies.

Donor lymphocyte infusion (DLI) cures relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation through the graft-versus-tumor (GVT) effect. Although the important role of magnesium in enhancing immunity has been mentioned in studies, limited clinical data have explored how magnesium affects the efficacy of DLI. Besides, although laboratory data demonstrate that magnesium can enhance CD8+ T cells effector function, whether magnesium regulates the tumor killing effect of peripheral blood mononuclear cells (PBMCs) remains to be explored. Here, for the retrospective study, we collected clinical data of relapsed patients receiving DLI and explored the relationship between different serum magnesium levels and patient outcomes. For in vitro studies, we investigated the effect of magnesium on the cytotoxicity of DLI cells which were PBMCs and preliminarily explored the mechanism. Eighty-one patients were enrolled in this study. It was found that the high post-DLI magnesium level was significantly associated with a higher incidence of complete remission (CR) or partial remission (CR/PR) and a higher possibility of survival. The magnesium level after DLI was an independent risk factor of overall survival. In vitro studies proved that increased magnesium enhanced the cytotoxic function of PBMCs on hematologic malignancies. Besides, magnesium modulated LFA-1 headpiece opening. When blocking the integrin-ligand interaction between LFA-1 and ICAM-1, the regulation effect of magnesium on PBMCs was weakened. Therefore, it was possible that magnesium regulated PBMCs effector function by stimulating LFA-1. These results show that serum magnesium levels affect immunological responses mediated by donor lymphocytes in hematologic malignancies.

Marine Aspergillus: A Treasure Trove of Antimicrobial Compounds.

Secondary metabolites from marine organisms are diverse in structure and function. Marine Aspergillus is an important source of bioactive natural products. We reviewed the structures and antimicrobial activities of compounds isolated from different marine Aspergillus over the past two years (January 2021-March 2023). Ninety-eight compounds derived from Aspergillus species were described. The chemical diversity and antimicrobial activities of these metabolites will provide a large number of promising lead compounds for the development of antimicrobial agents.

Recent Updates on the Antimicrobial Compounds from Marine-Derived Penicillium fungi.

In this review, 72 compounds isolated from marine-derived Penicillium fungi and their antimicrobial activities are reviewed from 2020 to 2023. According to their structures, these compounds can be divided into terpenoids, polyketides, alkaloids and other structural compounds, among which terpenoids and polyketides are relatively large in number. Some compounds have powerful inhibitory effects against different pathogenic bacteria and fungi. This review aims to provide more useful information and enlightenment for further efficient utilization of Penicillium spp. and their secondary metabolites.

Non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level: predictors related to the severity of autism spectrum disorder in Northeast China.

BACKGROUND: The prevalence of autism spectrum disorder (ASD) has increased rapidly in recent years. Environmental factors may play an important role in the pathogenesis of ASD. These factors may include socioeconomic factors, nutritional factors, heavy metal exposure, air pollution, etc. Our aim is to analyze possible environmental factors associated with the severity of ASD. METHODS: All participating children were divided into two groups (mild and moderate/severe) according to the severity of their symptoms, as determined by their Childhood Autism Rating Scale (CARS) scores. The socioeconomic, demographic factors and the nutritional factors that may affect the severity of ASD were included in the logistic regression to analyze whether they were predictors that affected the severity of ASD. RESULTS: Logistic regression showed that caregivers(P = 0.042), maternal education (P = 0.030), gastrointestinal problems (P = 0.041) and a high serum concentration of lead (P = 0.003) were statistically significantly associated with ASD severity. CONCLUSION: Many environmental factors affect the severity of ASD. We concluded that non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level maybe predictors that affected the severity of ASD in northeast China.

Comparative transcriptomic analysis of Stenotrophomonas sp. MNB17 revealed mechanisms of manganese tolerance at different concentrations and the role of histidine biosynthesis in manganese removal.

Bacteria possess protective mechanisms against excess Mn(Ⅱ) to reduce its toxicity. Stenotrophomonas sp. MNB17 showed high Mn(Ⅱ) removal capacity (92.24-99.16 %) by forming Mn-precipitates (MnCO3 and Mn-oxides), whose Mn-oxides content increased with increasing Mn(Ⅱ) concentrations (10-50 mM). Compared with 0 mM Mn(Ⅱ)-stressed cells, transcriptomic analysis identified genes with the same transcriptional trends in 10 mM and 50 mM Mn(Ⅱ)-stressed cells, including genes involved in metal transport, cell envelope homeostasis, and histidine biosynthesis, as well as genes with different transcriptional trends, such as those involved in oxidative stress response, glyoxylate cycle, electron transport, and protein metabolism. The upregulation of histidine biosynthesis and oxidative stress responses were the most prominent features of these metabolisms under Mn(Ⅱ) stress. We confirmed that the increased level of reactive oxygen species was one of the reasons for the increased Mn-oxides formation at high Mn(Ⅱ) concentrations. Metabolite analysis indicated that the enhanced histidine biosynthesis rather than the tricarboxylic acid cycle resulted in an elevated level of α-ketoglutarate, which helped eliminate reactive oxygen species. Consistent with these results, the exogenous addition of histidine significantly reduced the production of reactive oxygen species and Mn-oxides and enhanced the removal of Mn(Ⅱ) as MnCO3. This study is the first to correlate histidine biosynthesis, reactive oxygen species, and Mn-oxides formation at high Mn(Ⅱ) concentrations, providing novel insights into the molecular regulatory mechanisms associated with Mn(Ⅱ) removal in bacteria.

[Effect of Jingfang Granules on carrageenan-induced tail thrombosis in mice based on ERK/p38 MAPK signaling pathway].

The present study explored the anti-inflammatory and anti-thrombotic mechanism of Jingfang Granules on tail thrombosis induced by carrageenan in mice. Thirty-two male ICR mice were randomly divided into a control group, a model group, a Jingfang Granules group, and a positive drug(aspirin) group, with eight mice in each group. The thrombosis model was induced by intraperitoneal injection of carrageenan(45 mg·kg~(-1)) combined with low-temperature stimulation, and the mice were treated with drugs for 7 days before modeling. Twenty-four hours after modeling, blood was detected for four blood coagulation indices in each group. The enzyme-linked immunosorbent assay(ELISA) was used to detect the activity of plasma interleukin-6(IL-6), interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), and other inflammatory factors. The tails of mice in each group were cut off to observe tail lesions and measure the length of the thrombus. The protein expression and phosphorylation level of extracellular signal-regulated kinase 1/2(ERK1/2) and p38 mitogen-activated protein kinase(p38 MAPK) in spleen tissues were detected by Western blot. The results showed that dark red thrombus appeared in the tails of mice in each group. The length of the black part accounted for about 40% of the total tail in the model group. Additionally, the model group showed prolonged prothrombin time(PT), increased fibrinogen(FIB) content, and shortened activated partial thromboplastin time(APTT). Compared with the model group, the groups with drug intervention displayed shortened black parts in the tail and improved four blood coagulation indices(P<0.05). As revealed by ELISA, the expression levels of TNF-α, IL-1ß, and IL-6 in the mouse plasma were significantly up-regulated in the model group, and those in the groups with drug intervention were reduced as compared with the model group(P<0.05). As demonstrated by Western blot, the protein expression and phosphorylation levels of ERK1/2 and p38 MAPK in the spleen tissues were significantly elevated in the model group, while those in the Jingfang Granules group were down-regulated as compared with the model group with a significant difference. Jingfang Granules can inhibit tail thrombosis of mice caused by carrageenan presumedly by inhibiting the activation of ERK1/2 and p38 MAPK signaling pathways.

Risk factors and associations with clinical outcomes of cytomegalovirus reactivation after haploidentical versus matched-sibling unmanipulated PBSCT in patients with hematologic malignancies.

In allogeneic hematopoietic stem cell transplantation recipients, cytomegalovirus (CMV) infection can cause overt CMV-associated disease, which is a main cause of transplantation-associated mortality. CMV infection correlates closely with donor's type. We therefore examined whether risk factors of CMV reactivation and clinical endpoints in patients with hematologic malignancies after allogeneic peripheral blood stem cell transplantation (PBSCT) differed between using matched-sibling donors (MSD-SCT) and haploidentical donors (HID-SCT). In this retrospective cohort study, we enrolled in 200 consecutive patients received an unmanipulated G-CSF-mobilized allogeneic PBSCT. Ninety (45%) patients received MSD-SCT and 110 (55%) received HID-SCT. Quantitative PCR was used for monitoring of CMV reactivation after transplantation. One-year cumulative incidence of CMV DNAemia was 55.0%, ranging from 23.5% in MSD-SCT group to 81.0% in HID-SCT group (p < 0.001). Although univariate analyses showed that non-myeloid malignancies, disease in complete remission status at transplantation, pretreatment with antithymocyte globulin, HLA-haploidentical donors, male donors, previous Epstein-Barr virus DNAemia, and absolute lymphocyte count on day 30 < 0.6 × 109/L were respectively associated with CMV reactivation after transplantation in total cohort of recipients (all p < 0.05), haploidentical donors were found to be the only independent predictor in multivariate analyses (Hazard ratio = 6.4, p < 0.001). Furthermore, univariate analyses revealed that non-myeloid malignancies and previous Epstein-Barr virus DNAemia were respectively associated with CMV reactivation in MSD-SCT recipients, and female was associated with CMV reactivation in HID-SCT recipients (all p < 0.05). In HID-SCT recipients, but not MSD-SCT recipients, previous CMV DNAemia was associated with a lower cumulative incidence of acute graft-versus-host disease (49.2% vs. 72.6%, p < 0.001). CMV DNAemia did not play a role in the relapse rate, but it was strongly associated with an increased risk of non-relapse mortality either in total cohort of recipients (30.5% vs. 13.7%; p = 0.003) or in the HID-SCT subgroup (36.0% vs. 16.7%; p = 0.030). Relapse-free survival and overall survival in total cohort of recipients with CMV DNAemia were both inferior to those without CMV DNAemia (45.3% vs. 57.6% and 54.8% vs. 65.8%, respectively; both p < 0.05). However, in subgroup analysis according to donor's type, neither relapse-free survival nor overall survival was impacted by CMV status (both p > 0.05). This study addressed differences in incidence, risk factors, and associations with clinical outcomes of CMV reactivation after haploidentical versus matched-sibling PBSCT.

[Intelligence structure and clinical features of school-age children with attention deficit hyperactivity disorder and specific learning disorder].

OBJECTIVE: To study the intelligence structure and clinical features of children with attention deficit hyperactivity disorder (ADHD) and specific learning disorder (SLD). METHODS: A retrospective analysis was performed on 88 school-age children with ADHD. According to the presence or absence of SLD, they were divided into two groups: simple ADHD group with 45 children and ADHD+SLD group with 43 children. Intelligence structure and clinical features were compared between the two groups. RESULTS: Compared with the simple ADHD group, the ADHD+SLD group had significantly lower verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full intelligence quotient (FIQ) (P<0.05), significantly lower scores of VIQ factors (including information, similarities, arithmetic, and recitation) (P<0.05), and significantly lower scores of PIQ factors (including picture completion, picture arrangement, block design, and object assembly) (P<0.05). The development of SLD was negatively correlated with FIQ, VIQ, and PIQ. It was also negatively correlated with the scores of intelligence structure factors (including information, similarities, arithmetic, recitation, picture completion, picture arrangement, block design, and object assembly) (P<0.05). CONCLUSIONS: Children with ADHD and SLD have poorer FIQ, VIQ, and PIQ than those with ADHD alone, which mainly manifests as the weak abilities of most intelligence structure factors. It is necessary to pay attention to the management and intervention of SLD in school-age children with ADHD.

[Effect of parental training based on Early Start Denver Model combined with intensive training on children with autism spectrum disorder and its impact on parenting stress].

OBJECTIVE: To explore the effect of parental training based on the Early Start Denver Model (ESDM) combined with intensive training on the treatment outcome of children with autism spectrum disorder (ASD) and its impact on parenting stress. METHODS: Seventy children aged 2-5 years who were diagnosed with ASD were enrolled in the study. They were divided into an ESDM group and a parental training group by the random number table method (n=35 each). The ESDM group received intensive training based on ESDM. In addition to intensive ESDM-based training, parents of the children in the parental training group received ESDM skills training. Both groups were assessed by Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS), Autism Treatment Evaluation Checklist (ATEC) and Parenting Stress Index-Short Form (PSI-SF) before and after the intervention of 3 months. RESULTS: After 3 months of intervention, the total scores of ABC, CARS and ATEC were both significantly decreased in the two groups (P<0.05). There was no significant difference in the total scores of ABC, CARS and ATEC between the two groups before and after intervention (P>0.05). The change between ABC, CARS and ATEC total scores in the two groups had no significant difference (P>0.05). After 3 months of intervention, the total scores of PSI-SF were both significantly decreased in the two groups (P<0.05). The difficult child sub-scale scores in PSI-SF were significantly decreased in the ESDM group (P<0.05). While three sub-scale scores of parent distress, parent-child dysfunctional interaction and difficult child in PSI-SF were significantly decreased in the parental training group (P<0.05). Before and after intervention of 3 months, no significant difference was found in PSI-SF total scores between the two groups. Compared with the ESDM group, the change between PSI-SF total scores and two sub-scales of PSI-SF (parent distress and difficult child) were significantly bigger in the parental training group (P<0.05). CONCLUSIONS: Both the combination of intensive training and parent training based on ESDM and ESDM intensive training alone can improve the core symptoms of children with ASD aged 2-5 years and relieve the parenting stress, however, the former is more effective in relieving parenting stress.

Risk factors and clinical outcomes of Epstein-Barr virus DNAemia and post-transplant lymphoproliferative disorders after haploidentical and matched-sibling PBSCT in patients with hematologic malignancies.

In allogeneic hematopoietic stem cell transplantation recipients, reactivation of Epstein-Barr virus (EBV) can cause post-transplantation lymphoproliferative disorder (PTLD), which may rapidly progress to multiorgan failure and even death. Development of EBV PTLD correlates very closely with use of anti-thymocyte globulin (ATG) and type of transplant. To assess the incidences and clinical features of EBV DNAemia and PTLD in the setting of stem cell transplantation using unmanipulated G-CSF-primed allogeneic peripheral blood stem cells as graft, we performed a retrospective analysis of stem cell transplantation from HLA-matched sibling donors (MSD-SCT, n = 90) or HLA-haploidentical related donors (HID-SCT, n = 110) in patients with hematological malignancies. All of HID-SCT recipients and 27.8% of MSD-SCT recipients received an ATG-containing conditioning regimen. One-year cumulative incidence of EBV DNAemia was 44.1%, ranging from 4.8% in MSD-SCT recipients not using ATG to 20.0% in MSD-SCT recipients using ATG, and 73.7% in HID-SCT recipients. Risk factors for EBV reactivation included use of ATG (p = 0.008), male donor (p = 0.034), and cytomegalovirus DNAemia (p < 0.001). One-year incidence of EBV PTLD was 11.9%, ranging from 1.8% in recipients of MSD-SCT not using ATG to 4.4% in recipients of MSD-SCT using ATG, and 23.5% in recipients of HID-SCT. Risk factors for PTLD after HID-SCT included in fludarabine-containing conditioning regimen (p = 0.010), cytomegalovirus DNAemia (p = 0.036), and patient's age < 40-yr (p = 0.032). Two-year non-relapse mortality was higher for patients with EBV DNAemia than those without EBV DNAemia (35.8% vs. 15.3%, p = 0.002). One-year relapse-free survival and overall survival among patients with PTLD were 40.2% and 44.9%, respectively, as opposed to 63.4% and 68.4% among patients without PTLD (both p < 0.05). In multivariate analyses, EBV DNAemia predicted a lower risk of relapse (p = 0.025), while PTLD was a marginally significant predictor of relapse (p = 0.092). This study identified patients at risk of EBV reactivation and PTLD after unmanipulated allogeneic peripheral blood stem cell transplantation.

Outcomes of myeloablative peripheral blood stem cell transplantation for non-complete remission patients with relapsed/refractory peripheral T cell lymphomas.

There was limited information about the efficacy of myeloablative allogeneic peripheral blood stem cell transplantation (allo-PBSCT) in non-complete remission (non-CR) patients with relapsed/refractory peripheral T cell lymphomas (PTCLs). We conducted a retrospective study of 21 consecutive non-CR patients with relapsed/refractory PTCLs who received myeloablative allo-PBSCT between January 2008 and June 2016. The median follow-up of survivors was 46.5 months (range, 14-105 months). The estimated 3-year relapse rate was 24% (95% CI, 9 to 43%). The 3-year non-relapsed mortality rate was 24% (95% CI, 9 to 44%). Overall, the estimated 3-year overall survival was 47% (95% CI, 25 to 66%). And the estimated 3-year progression-free survival was 46% (95% CI, 24 to 66%). Specifically, eight patients failed to achieve a CR at the first evaluation 3 months after allo-PBSCT and received withdraw of immunosuppression. Five patients also received donor lymphocytes infusions. Five (5/8, 62.5%) patients responded subsequently to these interventions (complete = 4, partial = 1). Overall, ten patients were alive at our last follow-ups, and durable CR were achieved in nine patients without further therapy. Five (50%) of these ten alive patients experienced chronic graft-versus-host disease (GVHD). Our favorable clinical outcomes suggested myeloablative allo-PBSCT was a valid therapeutic option for non-CR patients with relapsed/refractory PTCLs. The sustained CR after immunotherapeutic intervention and high prevalence of chronic GVHD in alive patients provided evidence of graft versus T cell lymphoma effects.

Comparison of the safety and efficacy of prophylactic donor lymphocyte infusion after haploidentical versus matched-sibling PBSCT in very high-risk acute myeloid leukemia.

Donor lymphocyte infusion (DLI) might be used prophylactically to reduce relapse after allogeneic hematopoietic stem cell transplantation for very high-risk leukemia/lymphoma without effective targeted therapy. To compare the safety and efficacy of prophylactic DLI for prevention of relapse after allogeneic peripheral blood stem cell transplantation from haploidentical donors (HID-SCT) and matched-sibling donors (MSD-SCT) in patients with very high-risk acute myeloid leukemia (AML), we performed a retrospective analysis in a cohort of 21 HID-SCT and 13 MSD-SCT recipients, displaying similar baseline characteristics except for donor's gender distribution. Grade 2-4 acute graft-versus-host disease (GVHD) at 100-day post-DLI was higher in HID-SCT group than that in MSD-SCT group (59.5% vs. 30.8%, p = 0.05). The grade 3-4 acute GVHD (17.5% vs. 7.7%), 1-year chronic GVHD (36.6% vs. 33.2%), and severe chronic GVHD (15.3% vs. 27.3%) were not statistically significant different between groups. One-year non-relapse mortality was higher in HID-SCT group than that in MSD-SCT group with marginal significance (27.9% vs. 0.0%, p = 0.061). One-year relapse rate was not statistically significant different between HID-SCT group and MSD-SCT group (21.6% vs. 36.5%, p = 0.543). For HID-SCT recipients, 1-year relapse rate was lower in patients receiving prophylactic DLI than that in a control cohort of eight patients with same very high-risk features but not receiving prophylactic DLI (62.5% vs. 28.3%, p = 0.037). No statistically significant difference was observed in 1-year overall survival (OS, 55.1% vs. 83.9%, p = 0.325) and relapse-free survival (RFS, 50.1% vs. 74.0%, p = 0.419) rates between HID-SCT group and MSD-SCT group. In multivariate analyses, non-remission status prior to transplant, poor-risk gene mutations, and donor's age ≥ 48 years predicted a higher risk of relapse after DLI. Non-remission status prior to transplant predicted inferior OS and RFS. Patient's age ≥ 40 years also predicted an inferior OS. In conclusion, prophylactic DLI was very safe and efficient for reducing relapse in patients with very high-risk AML receiving MSD-SCT. In the recipients of HID-SCT, the application of prophylactic DLI could reduce the risk of relapse, although with a higher incidence of DLI-associated acute GVHD than those of MSD-SCT.

Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies.

Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3+ cells for infusion was 1.8 × 107/kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p = 0.029), disease in non-remission status prior to transplantation (p = 0.005), and donors older than 40 years of age (p = 0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio = 4.079; p = 0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma.

The disruption of verM activates the production of gliocladiosin A and B in Clonostachys rogersoniana.

Gliocladiosin A (1) and B (2), two dipeptides conjugated with macrolides, were identified from a verM disruption mutant of the Cordycep-colonizing fungus Clonostachys rogersoniana. The structures and absolute configurations of 1 and 2 were determined on the basis of spectroscopic data analysis, including MS, NMR, CD and X-ray diffraction. A biogenetic pathway for 1 and 2 was proposed. These two compounds showed moderate antibacterial effects.

Fluctuations in clinical symptoms with changes in serum 25(OH) vitamin D levels in autistic children: Three cases report.

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by complicated interactions between genetic and environmental factors. Clinical trials, including case reports, case-control studies, and a double-blinded randomized clinical study, have suggested that high-dose vitamin D3 regimens may ameliorate the core symptoms of ASD. Vitamin D3 supplementation was effective in about three-quarters of children with ASD. To further investigate the relationship between vitamin D and ASD symptoms in vitamin D-responsive autistic children, changes in symptoms were assessed in three children with ASD who were given vitamin D3 supplementation followed by a long interruption. The core symptoms of ASD were remarkably improved during the vitamin D3 supplementation period when serum 25-hydroxyvitamin D [25(OH)]D levels reached over 40.0 ng/mL. However, symptoms reappeared after the supplementation was stopped, when serum 25(OH)D levels fell below 30.0 ng/mL but were again improved with re-administration of vitamin D3 after the interruption, when serum 25(OH)D levels exceeded 40.0 ng/mL. Overall, these results showed that the core symptoms of ASD fluctuated in severity with changes in serum 25(OH)D levels in children, indicating that maintaining a responsive 25(OH)D level is important for treating ASD. Maintaining a serum 25(OH)D level between 40.0 and 100.0 ng/ml may be optimal for producing therapeutic effects in vitamin D-responsive individuals with ASD.

[Research advances in validity of predictors for extubation outcome in children receiving invasive mechanical ventilation].

The development of invasive mechanical ventilation technology provides effective respiratory support for critically ill children. However, respiratory support is not the end of treatment as the ultimate goal is successful extubation in children. At present, some evaluation indicators before extubation including rapid shallow breathing index, maximal inspiratory pressure, and work of breathing are of high clinical value in predicting adult extubation outcome, but their evidence of evidence-based medicine is not sufficient in the field of pediatric intensive care. This paper reviews the current research on the validity of predictors for extubation outcomes in children. It shows that there is still a lack of indicators with good sensitivity and specificity for assessment before extubation in children. The studies are still in a small-sample size and single-center stage. Therefore, how to optimize evaluation before extubation and improve the success rate of extubation is the direction of joint efforts of doctors in the pediatric intensive care unit and rehabilitation medicine department.

[Clinical effect of vitamin D3 combined with the Early Start Denver Model in the treatment of autism spectrum disorder in toddlers].

OBJECTIVE: To study the clinical effect of vitamin D3 (VitD3) combined with the Early Start Denver Model (ESDM) in the treatment of autism spectrum disorder (ASD) in toddlers. METHODS: A total of 102 toddlers with ASD, aged 1 to 3 years, were enrolled. According to the wishes of their parents, they were divided into conventional rehabilitation, ESDM and ESDM+VitD3 groups. Autism Behavior Checklist (ABC) and Childhood Autism Rating Scale (CARS) were used evaluate behavior problems before treatment and after 3 months of treatment. RESULTS: The conventional rehabilitation group had significant reductions in the total score and the scores on somatic movement and self-care subscales of the ABC scale after 3 months of treatment (P<0.05). After 3 months of treatment, the ESDM group had significant reductions in the total score and the scores on somatic movement, self-care, social interaction and language subscales of the ABC scale (P<0.05), as well as a significant reduction in the total score of the CARS (P<0.05). After 3 months of treatment, the ESDM+VitD3 group had a significant increase in the level of 25(OH)D and significant reductions in the total score and the scores on self-care, sensation, social interaction and language subscales of the ABC scale (P<0.05), as well as a significant reduction in the total score of the CARS (P<0.05). The ESDM group had a significantly greater reduction in the score on social interaction subscale than the conventional rehabilitation group (P<0.05). The ESDM+VitD3 group had a significantly greater reduction in the score on social interaction subscale than the other two groups (P<0.05). CONCLUSIONS: ESDM can effectively improve the clinical symptoms of toddlers with ASD, with a significantly better clinical effect in improving social interaction and somatic movement than conventional rehabilitation. ESDM combined with VitD3 has a significantly better clinical effect in improving social communication skills and may be one of the best strategies for improving the clinical symptoms of toddlers with ASD.

A Myb transcription factor represses conidiation and cephalosporin C production in Acremonium chrysogenum.

Acremonium chrysogenum is the industrial producer of cephalosporin C (CPC). We isolated a mutant (AC554) from a T-DNA inserted mutant library of A. chrysogenum. AC554 exhibited a reduced conidiation and lack of CPC production. In consistent with it, the transcription of cephalosporin biosynthetic genes pcbC and cefEF was significantly decreased in AC554. Thermal asymmetric interlaced polymerase chain reaction (TAIL-PCR) was performed and sequence analysis indicated that a T-DNA was inserted upstream of an open reading frame (ORF) which was designated AcmybA. On the basis of sequence analysis, AcmybA encodes a Myb domain containing transcriptional factor. Observation of red fluorescent protein (RFP) tagged AcMybA showed that AcMybA is naturally located in the nucleus of A. chrysogenum. Transcriptional analysis demonstrated that the AcmybA transcription was increased in AC554. In contrast, the AcmybA deleted mutant (ΔAcmybA) overproduced conidia and CPC. To screen the targets of AcmybA, we sequenced and compared the transcriptome of ΔAcmybA, AC554 and the wild-type strain at different developmental stages. Twelve differentially expressed regulatory genes were identified. Taken together, our results indicate that AcMybA negatively regulates conidiation and CPC production in A. chrysogenum.