Immune checkpoint inhibitor-induced aplastic anaemia: Case series and large-scale pharmacovigilance analysis.

Introduction: Impressive advances in immunotherapy especially immune checkpoint inhibitors have made great progress in treating multiple cancers but can also cause serious even incurable immune-related adverse events, mostly found in colitis, dermatitis, hepatitis, and thyroiditis patients. Rare autoimmune hematologic toxicities have been reported in the literature, but are poorly described. Aplastic anaemia induced by immune checkpoint inhibitors is a life-threatening autoimmune disease; however, only a few cases have been reported in the literature. Objective: To characterize and evaluate Aplastic anaemia associated with different ICI regimens in public database and review the literature. Methods: We described a case series of patients experiencing Aplastic anaemia while on immune checkpoint inhibitors. We also mined the Food and Drug Administration's Adverse Event Reporting System and used reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker algorithms to achieve the data of the suspected adverse events of Aplastic anaemia-induced by immune checkpoint inhibitors between January 2011 and June 2022. Results: Thirteen patients with Aplastic anaemia events while on immune checkpoint inhibitors were included in our case series, and seven of them had a fatal outcome. In FAERS, a total of 38 individual case safety reports (immune checkpoint inhibitors) with different ICI regimens were retrieved, of which 25 (65.79%) were reported as monotherapy and 13 (34.2%) had a fatal outcome. The reporting odds ratio was significant for nivolumab (reporting odds ratio 3.05, 95%CI 1.73-5.38), pembrolizumab (reporting odds ratio 2.33, 95%CI 1.16-4.67), avelumab (reporting odds ratio 12.63, 95%CI 3.15-50.62) and ipilimumab/nivolumab (ROR 2.57, 95%CI 1.15-5.72). Conclusion: There is a significant reporting signal of Aplastic anaemia with several ICI agents. Clinicians should raise awareness and monitor this potentially fatal adverse event.

Modified Huangqi Chifeng decoction inhibits excessive autophagy to protect against Doxorubicin-induced nephrotic syndrome in rats via the PI3K/mTOR signaling pathway.

The aim of the present study was to investigate whether modified Huangqi Chifeng decoction (MHCD) could be an effective treatment against Doxorubicin-induced nephrosis in rats and whether it regulates autophagy via the phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway. A total of 40 male Sprague-Dawley rats were randomly divided into blank, model, telmisartan and MHCD groups. The rat model of nephrosis was induced by intragastric administration of Doxorubicin for 8 weeks. Rats were housed in metabolic cages and urine was collected once every 2 weeks to measure 24-h protein levels. Blood samples were obtained from the abdominal aorta and levels of albumin (ALB), total cholesterol (TCH), triacylglyceride (TG) and serum creatinine (Scr) were assessed. Renal pathological changes were examined using hematoxylin-eosin, Masson's trichome and periodic acid-Schiff staining. Podocytes and autophagosomes were observed using an electron microscope. The expression and distribution of microtubule-associated proteins 1A/1B light chain 3B (LC3), LC3-I, LC3-II, beclin-1, PI3K and mTOR were determined using immunohistochemistry and western blotting. At weeks 6 and 8, 24-h proteinuria significantly decreased in the MHCD group compared with the model group (P<0.05). Compared with the model group, the MHCD group exhibited significantly reduced levels of TG, TCH and Scr, as well as significantly increased ALB levels (P<0.05). MHCD was demonstrated to prevent glomerular and podocyte injury. The number of autophagosomes was significantly decreased and the expression of beclin-1, LC3, LC3-I and LC3-II was inhibited following MHCD treatment compared with the model group (P<0.05). MHCD treatment significantly increased the expression of PI3K and mTOR in Doxorubicin nephrotic rats compared with the model group (P<0.05). In conclusion, MHCD was demonstrated to ameliorate proteinuria and protect against glomerular and podocyte injury by inhibiting excessive autophagy via the PI3K/mTOR signaling pathway.

Sinomenine Hydrochloride Attenuates Renal Fibrosis by Inhibiting Excessive Autophagy Induced by Adriamycin: An Experimental Study.

The objective of this study is to investigate if sinomenine hydrochloride (SIN-HCl) could be effective against adriamycin-induced renal fibrosis by regulating autophagy in a rat model. Forty male Sprague-Dawley (SD) rats were randomly divided into control group, model group, telmisartan group, and SIN-HCl group; rat model was induced by adriamycin; all rats were given intragastric administration for 6 weeks. Urine was collected from rats in metabolic cages to determine 24 h protein level. This was done after intragastric administration for the first two weeks and then once for every two weeks. Renal pathological changes were examined by the staining of HE, Masson, and PASM. Expressions and distributions of fibronectin (FN), laminin (LN), light chain 3 (LC3), and Beclin-1 were observed by immunohistochemistry. SIN-HCl ameliorates proteinuria, meanwhile attenuating the renal pathological changes in adriamycin-induced rats and also attenuating renal fibrosis and excessive autophagy by reducing the expression of FN, LN, LC3, and Beclin-1. SIN-HCl attenuates renal fibrosis by inhibiting excessive autophagy induced by adriamycin and upregulates the basal autophagy.

Noninvasive high-frequency oscillatory ventilation versus nasal continuous positive airway pressure in preterm infants with moderate-severe respiratory distress syndrome: A preliminary report.

OBJECTIVE: The aim of this study was to compare the effect of noninvasive high-frequency oscillatory ventilation (nHFOV) with nasal continuous positive airway pressure (nCPAP) in preterm infants with moderate-severe respiratory distress syndrome (RDS) after surfactant administration via INSURE (intubation, surfactant, extubation) method on the need for invasive mechanical ventilation (IMV). METHODS: A total of 81 infants with a gestational age (GA) of 28-34 weeks were eligible and were randomized to nCPAP (n = 42) or to nHFOV (n = 39). The need for IMV was the primary outcome. The incidence of bronchopulmonary dysplasia (BPD), occurrence of intraventricular hemorrhage (IVH), and air leaks, and mortality were considered as secondary outcomes. RESULT: A total 76 infants finally completed the study. The need for IMV was significantlylower in the nHFOV group compared with the nCPAP group(24.3% vs 56.4%, P < 0.01). The incidence of IVH, air leaks or BPD was similar between the two groups. In addition, the mortality rate was not statistically different. CONCLUSION: In this prospective, randomized controlled study, nHFOV significantly reduced the need for IMV as compared with nCPAP in preterm infants with moderate-severe RDS without increase in adverse effects.

Comparison of the morphine-sparing effect of intraoperative dexmedetomidine with and without loading dose following general anesthesia in multiple-fracture patients: A prospective, randomized, controlled clinical trial.

Intraoperative dexmedetomidine (DEX) with or without loading dose both promote morphine-sparing effect in patient-controlled analgesia on postoperative acute pain. However, the contribution of the loading dose to this effect is largely unknown, especially in long-lasting surgeries. The present study was designed to investigate the role of a loading dose of DEX in this morphine-sparing effect in multiple-fracture patients following general anesthesia.Eighty-six patients scheduled multiple-fracture surgeries under general anesthesia were allocated into 3 groups which were maintained with propofol/remifentanil/Ringer solution (PRR), propofol/remifentanil/DEX with (PRDw), or without (PRDo) DEX loading dose before induction, respectively. Time to first morphine request and 24-hour morphine consumption was monitored. Pain intensity was evaluated with visual analog scale.During the first 24 hours following surgery, patients in the PRDw/o group showed increased time to first request of postoperative morphine and decreased total morphine consumption as compared with PRR patients. There was no significant difference with respect to these parameters between patients from the PRDw and PRDo groups. More patients from the PRDw groups experienced intraoperative bradycardia when compared to those from the PRR or PRDo group.This randomized controlled trial indicates that the morphine-sparing effect of intraoperative DEX was not affected by a loading dose in long-time surgeries.

[Risk factors for excessive bleeding in patients undergoing open heart surgery with cardiopulmonary bypass].

OBJECTIVE: To evaluate the pre- and intraoperative risk factors associated with excessive bleeding during the perioperative period in adult patients undergoing open heart surgery with cardiopulmonary bypass (CPB). METHODS: A total of 1079 consecutive patients undergoing open heart surgery with CPB from January 2001 to May 2010 were included (except for emergency operation). The possible risk factors associated with excessive bleeding were retrospectively analyzed. Patients who received ≥ 7 units of RBC or had a re-operation during which no active bleeding point was found within one day of operation were classified as excessive bleeding. According to the occurrence of excessive bleeding, they were divided into 2 groups: excessive and non-excessive bleeding groups. The possible risk factors associated with excessive bleeding were retrospectively analyzed. Univariate analysis and multivariate Logistic regression analysis were used to examine the relationship between these factors and excessive bleeding. RESULTS: Among them, 120 (11.1%) developed excessive bleeding. Multivariate Logistic analysis indicated that the risk factors for excessive bleeding were age (OR = 4.533, 95%CI 2.624 - 7.831), previous sternotomy (OR = 2.781, 95%CI 1.410 - 5.486), preoperative hematocrit concentration (OR = 0.896, 95%CI 0.861 - 0.932), CPB duration (OR = 2.782, 95%CI 1.791 - 4.322) and type of procedure (OR = 2.292, 95%CI 1.376 - 3.817). CONCLUSION: Age ≥ 65 years, previous sternotomy, preoperative low hematocrit concentration, CPB duration ≥ 120 min and complex operation were the significant predictors for excessive bleeding in patient undergoing open heart surgery with CPB.

Changes of positron emission tomography in newborn infants at different gestational ages, and neonatal hypoxic-ischemic encephalopathy.

Cerebral glucose metabolism was measured by (18)F-fluorodeoxyglucose position emission tomography in infants at different gestational ages and with neonatal hypoxic-ischemic encephalopathy. Thirty-six preterm and term infants at different gestational ages without brain injury were divided into four subgroups: ≤32 weeks (n = 4), 33-34 weeks (n = 5), 35-36 weeks (n = 12), and ≥37 weeks (n = 15). Twenty-four newborn infants with hypoxic-ischemic encephalopathy were divided into three subgroups: mild (n = 13), moderate (n = 7), and severe (n = 4). Cerebral glucose metabolism manifested a trend toward increase, and the structure of cranial (18)F-fluorodeoxyglucose positron emission tomography images became clear with increased gestational age, especially at ≥37 weeks. Uptakes of (18)F-fluorodeoxyglucose in the ≥37-week group were significantly higher than in the ≤32-week group (P < 0.01). Cerebral glucose metabolism changed significantly in neonatal hypoxic-ischemic encephalopathy, and was either unbalanced bilaterally or relatively low at all sites. Moreover, uptakes of (18)F-fluorodeoxyglucose were significantly lower in severe than in mild and medium hypoxic-ischemic encephalopathy (P < 0.05). Cerebral glucose metabolism, as measured by (18)F-fluorodeoxyglucose positron emission tomography, may prove useful for estimating brain development and injury in newborn infants, and its clinical values need further investigation.

[Oral controlled-release oxycodone for uterine cramping pain after cesarean section].

OBJECTIVE: To evaluate whether combined oral oxycodone hydrochloride controlled-release tablets plus paracetamol and tramadol hydrochloride tablets is better than epidural analgesia with respect to uterine cramping pain control and side effects after cesarean section. METHODS: Sixty consecutive patients scheduled for cesarean section from April to May, 2010 were randomized to either patient-controlled epidural analgesia with 0.1% ropivacaine, 0.1 µg/ml sufentanil (for postoperative 48 h) plus injected pethidine on demand (EDA group) or controlled-release oxycodone (2 × 15 mg for 1st postoperative 24 h; 2 × 10 mg for 2nd postoperative 24 h), paracetamol & tramadol hydrochloride tablets (8 × 1 tablet for postoperative 48 h) orally plus pethidine injection on demand (OXY group). Two groups were compared with respects to uterine cramping pain control when the oxytocin infusion (20 U plus 500 ml 5% glucose solution, iv. gtt within 2 h) once per day for postoperative 3 days as determined by the means of a visual analogue scale (VAS), pethidine consumption, side effects and costs. RESULTS: The EDA group experienced significant more pain than the OXY group when the oxytocin infusion was administered (mm) [50.0 (15.0, 72.5) vs 25.0 (0, 40.0), 60.0 (47.5, 72.5) vs 20.0 (0, 30.0), 35.0 (20.0, 50.0) vs 0 (0, 20.0)]. all P < 0.05). Pethidine was used for pain control in 2 patients (150 mg total) of EDA group during the oxytocin infusion whereas none of the OXY group received an injection of pethidine. There was a higher level of maternal satisfaction with a lower analgesic dose in the EDA group (80.9 ± 9.3 vs 90.0 ± 9.8, P < 0.01). The median duration of hospital stay was around 5 days in both groups. CONCLUSION: Postoperative pain control after cesarean section with the above combined regimen is superior to EDA in terms of a lower cost and a higher level of maternal satisfaction.

Brain positron emission tomography in preterm and term newborn infants.

OBJECTIVE: To study the clinical values of positron emission tomography (PET) in preterm and term newborn infants through observing brain glucose metabolism by (18)F-fluorodeoxyglucose ((18)F-FDG) PET. METHOD: To observe the brain (18)F-FDG PET imaging in 9 term and 7 preterm newborn infants in the same condition after administration of 0.1 mCi/kg (18)F-FDG. RESULT: The brain (18)F-FDG PET imaging showed that the uptake of (18)F-FDG was relatively more in the thalamus, and less in the cerebral cortex in preterm and term newborn infants. The uptake of (18)F-FDG of cerebral cortex in preterm infants was less than that in term infants, so the structure of brain (18)F-FDG PET imaging was a little fainter in preterm neonates as compared with that in term newborns. CONCLUSION: (18)F-FDG PET imaging could show different glucose metabolisms of brain in preterm and term infants. Brain (18)F-FDG PET imaging might be a useful tool for estimating the brain function in newborn infants, and its clinical values need further investigation.

[Role of dendritic cells in the pathogenesis of asthma in children].

UNLABELLED: Dendritic cells (DC) are very potent antigen-presenting cells (APC) with a unique ability to activate naive T cells to induce the differentiation of TH1/TH2. Monocytes can develop into DC in the presence of different cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. DCs are thought to play a key role in the initiation and maintenance of T cell immunity to inhaled antigens. While the density of DC within the bronchial mucosa is increased in asthma, there is little information currently available concerning the effects of DC in asthmatic children. OBJECTIVE: To investigate the role of dendritic cells in the pathogenesis of acute attack of asthma in children. METHODS: Thomas' method was adopted. The adherent precursors of DC were isolated from peripheral blood of asthmatic children in acute attack stage and healthy controls. The adherent cells were induced with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-alpha) to DC in vitro. The expression of the surface molecules CD80, CD86, HLA-DR etc. on the DC was examined by fluorescent activated cell sorter (FACS). And the ability to secret IL-10, IL-12 and their potentials to stimulate the proliferative reaction of DC inductive self T- lymphocyte were observed. RESULTS: The results showed that in asthmatic children's acute attack stage, self T- lymphocyte proliferative reaction induced by DC was remarkably increased compared with normal control subjects (P < 0.01). At the same time, the asthmatic children in acute attack stage had remarkably decreased the ability to secret IL-10 compared with normal control subjects (P < 0.01), while the ability to secret IL-12 remarkably decreased compared with normal control subjects (P < 0.01); meanwhile, the HLA-DR and co-stimulating factor CD86(B(7-2)) expressed by DCs remarkably increased in the asthmatic children in acute attack stage compared with normal control subjects (P < 0.01). CONCLUSION: DC possibly plays a vital role in the immunological mechanism of asthma by means of inducing the differentiation of TH1/TH2, that is DC may be the key factor in initiating the airway allergic reaction and the possible mechanism may involve interleukins (especially IL-10 and IL-12, etc.) secreted by DCs.

[Effect of osteopractic total flavone on bone mineral density and bone histomorphometry in ovariectomized rats].

OBJECTIVE: To observe the effect of osteopractic total flavone on bone histomorphometry of osteoporosis model in rath with ovariectomized female rat models. METHOD: The ovariectomy-induced model, bone sliceswith calcium, pigmentation, and Leica Qwin image analysis system were adopted on bone histomorphometry. RESULT: As compared with the model group, the effect of small-dose group and middle-dose group of osteopractic total flavone on TBV% of shankbone increased significantly; the effect of small-dose group and middle-dose group of osteopractic total flavone on TRS% of shankbone reduced significantly and TFS%, AFS%, MAR, BFR of shankbone reduced obviously; the effect of middle-dose group of osteopractic total flavone on OSW and mAR reduced obviously, the effect of small-dose group of osteopractic total flavone on them had the tendency of reducing, but there was no statistical significance. CONCLUSION: The ovariectomized rats having been fed with osteopractic total flavone for 6 months, TBV% increased significantly while TRS%, AFS%, MAR, BFR, OSW, and mAR reduced obviously. It indicates that the therapeutical effect of osteopractic total flavone on ovariectomy-induced osteoporosis model is significant. And the ovariectomy-induced osteoporosis model is a high transformative type of osteoporosis model in which bone absorption is higher than bone formation.

[Activation of nuclear factor kappa B in newborn rats sepsis].

OBJECTIVE: The aim of the study is to explore the effect of NF-kappa B signal pathway in neonatal sepsis so as to provide the experimental base for corresponding clinical treatment of the sepsis, in which NF-kappa B is taken as the target. METHODS: The sepsis model was established in newborn rats by giving Staphylococcus aureus subcutaneously: (1) The electrophoretic mobility shift assay (EMSA) was used to observe the activity of NF-kappa B in the lungs and the livers in newborn rats with Staphylococcus aureus sepsis. (2) Immunohistochemical method was used to observe the activity of NF-kappa B P56 in newborn rats with Staphylococcus aureus sepsis. (3) The anti-oxidant pyrrolidine dithiocarbamate (PDTC) was used to observe its effect on NF-kappa B activities of liver and lungs and on the activity of splenic NF-kappa B P56 in newborn rats with Staphylococcus aureus sepsis. RESULTS: In newborn rats with Staphylococcus aureus sepsis, the NF-kappa B activity in lungs was enhanced at the 1st hour and reached to the peak level at the 3rd hour; then, it was weakened gradually and at the 24th hour faded away. The activity of the liver NF-kappa B was also activated and peaked at the 4th hour; then, it was gradually weakened and at the 24th hour faded away. The positive expression of splenic NF-kappa B P56 began to be intensified at the 1st hour (12.0 +/- 3.7), peaked at the 3rd hour (51.4 +/- 5.9) and showed insignificant differences at the 24th hour (3.4 +/- 1.4) as compared with the sepsis group. PDTC had an inhibitive effect on the activities of liver NF-kappa B and lung NF-kappa B and on the positive expression of splenic NF-kappa B P56 used in the dosage of 50-200 mg/kg. The larger the dosage was used, the more intensified inhibitive effect could be obtained. In the dosage of 200 mg/kg, the inhibitive effect was the most intensified. CONCLUSIONS: (1) In newborn rats with Staphylococcus aureus sepsis, the NF-kappa B of lungs, liver and spleen were activated, and all indicate a peak. (2) The anti-oxidant PDTC can inhibit NF-kappa B activity in a dose-effect fashion in newborn rats with Staphylococcus aureus sepsis.