Comparative Analysis of Short-Term and Long-Term Clinical Efficacy of Mesenchymal Stem Cells from Different Sources in Knee Osteoarthritis: A Network Meta-Analysis.

Background: Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived from different sources in treating OA patients remains unclear. Therefore, this study aimed to explore the differences between the effectiveness and safety of different sources of MSCs. Materials and Methods: For inclusion consideration, we searched trial registries and published databases, including PubMed, Cochrane Library, Embase, and Web of Science databases. Revman (V5.3), STATA (V16.0), and R (V4.0) were utilized for conducting data analysis, while the Cochrane Risk of Bias Tool was employed for assessing the quality of the studies. We derived outcome measures at 6 and 12 months based on the duration of study follow-up, including visual analog scale (VAS) score, WOMAC score, WOMAC pain, WOMAC Functional Limitation, and WOMAC stiffness. The evaluation time for short-term effectiveness is set at 6 months, while 12 months is utilized as the longest follow-up time for most studies to assess long-term effectiveness. Results: The evaluation of literature quality showed that the included studies had excellent methodological quality. A meta-analysis revealed that different sources of MSCs improved knee function and pain more effectively among patients suffering from knee OA (KOA) than controls. The results of the network meta-analysis showed the following: short-term functional improvement (the indexes were evaluated after 6 months of follow-up) (WOMAC total score: bone marrow-derived MSC (BMMSC) vs. adipose-derived MSC (ADMSC) (mean difference (MD) = -20.12, 95% confidence interval (CI) -125.24 to 42.88), umbilical cord-derived MSC (UCMSC) (MD = -7.81, 95% CI -158.13 to 74.99); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.51, 95% CI -7.27 to 4.29), UCMSC (MD = -0.75, 95% CI -9.74 to 6.63); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -12.22, 95% CI -35.05 to 18.86), UCMSC (MD = -9.31, 95% CI -44.26 to 35.27)). Long-term functional improvement (the indexes were evaluated after 12 months of follow-up) (WOMAC total: BMMSC vs. ADMSC (MD = -176.77, 95% CI -757.1 to 378.25), UCMSC (MD = -181.55, 95% CI -937.83 to 541.13); WOMAC stiffness: BMMSC vs. ADMSC (MD = -0.5, 95% CI -26.05 to 18.61), UCMSC (MD = -1.03, 95% CI -30.44 to 21.69); WOMAC functional limitation: BMMSC vs. ADMSC (MD = -5.18, 95% CI -316.72 to 177.1), UCMSC (MD = -8.33, 95% CI -358.78 to 218.76)). Short-term pain relief (the indexes were evaluated after 6 months of follow-up) (VAS score: UCMSC vs. BMMSC (MD = -10.92, 95% CI -31.79 to 12.03), ADMSC (MD = -14.02, 95% CI -36.01 to 9.81), PLMSC (MD = -17.09, 95% CI -46.31 to 13.17); WOMAC pain relief: BMMSC vs. ADMSC (MD = -11.42, 95% CI -39.52 to 11.77), UCMSC (MD = -6.73, 95% CI -47.36 to 29.15)). Long-term pain relief (the indexes were evaluated after 12 months of follow-up) (VAS score: BMMSC vs. UCMSC (MD = -4.33, 95% CI -36.81 to 27.08), ADMSC (MD = -11.43, 95% CI -37.5 to 13.42); WOMAC pain relief: UCMSC vs. ADMSC (MD = 0.23, 95% CI -37.87 to 38.11), BMMSC (MD = 5.89, 95% CI -25.39 to 51.41)). According to the GRADE scoring system, WOMAC, VAS, and AE scores were of low quality. Conclusion: Meta-analysis suggests MSCs can effectively treat KOA by improving pain and knee function compared to control groups. In terms of functional improvement in KOA patients, both short-term (6-month follow-up) and long-term (12-month follow-up) results indicated that while the differences between most treatments were not statistically significant, bone marrow-derived MSCs may have some advantages over other sources of MSCs. Additionally, BM-MSCs and UC-MSCs may offer certain benefits over ADMSCs in terms of pain relief for KOA patients, although the variances between most studies were not statistically significant. Therefore, this study suggests that BM-MSCs may present clinical advantages over other sources of MSCs.

Measles Outbreak in Pediatric Hematology and Oncology Patients in Shanghai, 2015.

BACKGROUND: Despite substantial progress toward measles control are making in China, measles outbreaks in immunocompromised population still pose a challenge to interrupt endemic transmission. This study aimed to investigate the features of measles in pediatric hematology and oncology patients and explore the reasons behind the outbreak. METHODS: We collected demographic, epidemiological, and clinical data of immunocompromised measles children. All suspected measles cases were laboratory-confirmed based on the presence of measles IgM and/or identification of measles RNA. The clinical data were statistically analyzed by t-test for continuous variables and Fisher's exact test for categorical variables. RESULTS: From March 9 to July 25 in 2015, a total of 23 children with malignancies and post hematopoietic stem cell transplantation (post-HSCT) were notified to develop measles in Shanghai. Of these 23 patients with the median age of 5.5 years (range: 11 months-14 years), 20 (87.0%) had received 1-3 doses of measles vaccine previously; all patients had fever with the median fever duration of 8 days; 21 (91.3%) had cough; 18 (78.3%) had rash; 13 (56.5%) had Koplik's spot; 13 (56.5%) had complications including pneumonia and acute liver failure; and five (21.7%) vaccinated patients died from severe pneumonia or acute liver failure. Except the first patient, all patients had hospital visits within 7-21 days before measles onset and 20 patients were likely to be exposed to each other. CONCLUSIONS: The outcome of measles outbreak in previously vaccinated oncology and post-HSCT pediatric patients during chemotherapy and immunosuppressant medication was severe. Complete loss of protective immunity induced by measles vaccine during chemotherapy was the potential reason. Improved infection control practice was critical for the prevention of measles in malignancy patients and transplant recipients.

A novel miR-200b-3p/p38IP pair regulates monocyte/macrophage differentiation.

Monocyte/macrophage differentiation represents a major branch of hematopoiesis and is a central event in the immune response, but the molecular mechanisms underlying are not fully delineated. Here we show that p38 mitogen-activated protein kinase (MAPK) interacting protein (p38IP) is downregulated during monocyte/macrophage differentiation in vitro. Overexpression of p38IP halted monocyte/macrophage differentiation, whereas forward knockdown of p38IP by RNA interference induced G1/S arrest and promoted monocyte differentiation into macrophages and the maturation of macrophages as well. Moreover, we found that miR-200b-3p was upregulated during monocyte/macrophage differentiation and mediated the downregulation of p38IP by binding to the 3' untranslated terminal region of p38IP mRNA. Overexpression of a miR-200b-3p mimic resembled the effect of p38IP knockdown, whereas a miR-200b-3p inhibitor blocked monocyte/macrophage differentiation by enhancing p38IP expression. Further western blotting analysis revealed that p38IP downregulation enhanced the activity of p38 MAPK and the subsequent accumulation of cyclin-dependent kinase inhibitor p21, thus promoting G1/S arrest and monocyte/macrophage differentiation. Moreover, the decline of GCN5 acetyltransferase caused by p38IP downregulation was required but was not sufficient for monocyte/macrophage differentiation. This study demonstrated a new role for p38IP and a novel miR-200b-3p/p38IP pair in the regulation of monocyte/macrophage differentiation.

The p38-interacting protein (p38IP) regulates G2/M progression by promoting α-tubulin acetylation via inhibiting ubiquitination-induced degradation of the acetyltransferase GCN5.

p38-interacting protein (p38IP) is a component of the GCN5 histone acetyltransferase-containing coactivator complex (GCN5-SAGA complex). It remains unclear whether p38IP or GCN5-SAGA is involved in cell cycle regulation. Using RNA interference to knock down p38IP, we observed that cells were arrested at the G2/M phase, exhibiting accumulation of cyclins, shrunken spindles, and hypoacetylation of α-tubulin. Further analysis revealed that knockdown of p38IP led to proteasome-dependent degradation of GCN5. GCN5 associated with and acetylated α-tubulin, and recovering GCN5 protein levels in p38IP knockdown cells by ectopic expression of GCN5 efficiently reversed α-tubulin hypoacetylation and G2/M arrest. During the G2/M transition, the association of α-tubulin with GCN5 increased, and the acetylation of α-tubulin reached a peak. Biochemical analyses demonstrated that the interaction between p38IP and GCN5 depended on the p38IP N terminus (1-381 amino acids) and GCN5 histone acetyltransferase domain and bromodomain. The p38IP N terminus could effectively reverse p38IP depletion-induced GCN5 degradation, thus recovering α-tubulin acetylation and G2/M progression. p38IP-mediated suppression of GCN5 ubiquitination most likely occurs via nuclear sequestration of GCN5. Our data indicate that the GCN5-SAGA complex is required for G2/M progression, mainly because p38IP promotes the acetylation of α-tubulin by preventing the degradation of GCN5, in turn facilitating the formation of the mitotic spindle.

[Randomized controlled multi-center trial for treatment of varicella in pediatric patients with hydrochloride valacyclovir].

OBJECTIVE: To evaluate the efficacy and safety of hydrochloride valacyclovir in treatment of varicella in pediatric patients between April 2006 and March 2007. METHODS: A randomized controlled multi-center clinical trial was conducted in 5 pediatric centers, i.e., Children's Hospital of Fudan University, Children's Hospital of Zhejiang University, Children's Hospital of Nanjing Medical University, Pediatric Department of Tongji Hospital of Tongji Medical College, Huazhong University of Science & Technology and Children's Hospital, Chongqing University of Medical Sciences. Patients who were clinically diagnosed as varicella without any complications and were beyond 3 years of age were enrolled into the study from the out-patient clinics. The subjects were divided into two groups randomly, one was treated with hydrochloride valacyclovir, the other with ribavirin. There were 128 cases in the group treated with hydrochloride valacyclovir and 132 cases in control group treated with ribavirin. The treatment duration of two groups was five days. The clinical efficacy and safety were evaluated after the first day and the fourth day of the treatment and within three days after the end of the treatment. The clinical efficacy was assessed by efficacy index. RESULTS: (1) The efficacy index on the fourth day of the therapy (0.80 +/- 0.24) in the valacyclovir group was significantly higher than that of ribavirin control group (0.59 +/- 0.37) (t = 5.42, P < 0.01). The efficacy index at the end of the treatment (0.86 +/- 0.14) in the hydrochloride valacyclovir group was also significantly higher than that (0.70 +/- 0.30) of the ribavirin control group (t = 5.43, P < 0.01). (2) In the valacyclovir and ribavirin groups, the effective rates on the fourth day of the therapy were 94.53% and 72.7% respectively (chi2) = 22.38, P < 0.01). The effective rates at the end of the therapy were 99.2% and 88.6%, respectively (chi(2) = 12.60, P < 0.01). The rates of cure of the two groups were 33.6% and 25.0% (chi2) = 2.32, P > 0.05). (3) No severe adverse drug reactions were observed in any of the two groups. CONCLUSIONS: The hydrochloride valacyclovir was safe, reliable and convenient in treatment of uncomplicated varicella in children.