Arthroscopic Transplantation of Synovial Stem Cells Improves Clinical Outcomes in Knees With Cartilage Defects

Background

Transplantation of mesenchymal stem cells (MSCs) is one possible strategy to achieve articular cartilage repair. We previously reported that synovial MSCs were highly proliferative and able to undergo chondrogenesis. We also found that placing a suspension of synovial MSCs on a cartilage defect for 10 minutes promoted cartilage repair in rabbit and pig models. However, the in vivo efficacy of this approach has not been tested clinically.

Questions/purposes

We asked whether transplantation of synovial MSCs improves (1) MRI features, (2) histologic features, and (3) clinical evaluation scores in patients with cartilage defects in the knee?

Methods

Patients with a symptomatic single cartilage lesion of the femoral condyle were indicated for inclusion in our study, and between April 2008 and April 2011, 10 patients were enrolled in this study. All patients completed followups of 3 years or more. The average followup period was 52 months (range, 37–80 months). Synovial MSCs were expanded with 10% autologous human serum for 14 days after digestion. For transplantation, the patient was positioned so that the cartilage defect was facing upward, and synovial MSC suspension was placed on the cartilage defect with a syringe under arthroscopic control. The defect with the applied suspension then was held in the upward position for 10 minutes. Five patients underwent concomitant ACL reconstructions, among whom two had meniscus suturing performed simultaneously. For MRI quantification, the cartilage defect was scored from 0 to 5. Second-look arthroscopy was performed for four patients and biopsy specimens were evaluated histologically. Clinical outcome was assessed using the Lysholm score and Tegner Activity Level Scale at final followup. Comparisons of MRI and Lysholm scores before and after treatment for each patient were analyzed using the Wilcoxon signed-rank test.

Results

MRI score (median ± 95% CI) was 1.0 ± 0.3 before and 5.0 ± 0.7 after, and increased after treatment in each patient (p = 0.005). Second-look arthroscopy in four patients showed that the cartilage defect appeared to be qualitatively better in all cases. Histologic analyses showed hyaline cartilage in three patients and fibrous cartilage in one at the deep zone. The Lysholm score (median ± 95% CI) was 76 ± 7 before and 95 ± 3 after, and increased after treatment in each patient (p = 0.005). The Tegner Activity Level Scale did not decrease after treatment in each patient.

Conclusions

For this small initial case series, transplantation of synovial MSCs was effective in terms of MRI score, qualitative histology, and Lysholm score. The use of synovial MSCs has an advantage in that the cells can be prepared at passage 0 in only 14 days. Transplantation of synovial MSCs may be less invasive than mosaicplasty and autologous chondrocyte implantation. To conclusively show the effectiveness of this treatment requires comparative studies, especially with more established arthroscopic procedures, such as marrow stimulation techniques.

Level of Evidence

Level IV, therapeutic study.     

Modifiable factors for the length of life with disability before death: mortality retrospective study in Japan

BACKGROUND: Past studies have measured and described the length of life with disability before death, but there has been no study of the relationship between modifiable lifestyle factors and duration of disability. OBJECTIVE: To examine whether there are modifiable factors influencing the length of life with disability before death. METHODS: The study was designed as a retrospective observation of the deceased who had earlier been enrolled in a prospective cohort study.During the follow-up period (1996-1999), we documented 781 deaths among those who were 70-79 years of age at the baseline survey in 1994 (n=10,216). In 2000, we interviewed family members of the deceased about the duration of the subjects' disability before death (n=655). RESULTS: The median duration of disability before death was approximately 6 months. Both higher Body Mass Index (BMI) and shorter time spent walking were significantly associated with an increased risk of long-term disability (more than 6 months). The odds ratios of long-term disability were 1.3 in those with BMI 20-25 and 2.1 in those with BMI>25, compared with BMI<20. The odds ratios of long-term disability were 1.3 in those walking for 0.5-0.9 h/day and 1.7 in those walking for <0.5 h/day, compared with those walking for >1.0 h/day. These relationships were unchanged after stratification for causes of death. CONCLUSION: Weight control and walking in later life may shorten the length of life with disability before death.     

Status of endothelial dependent vasodilation in patients with hyperuricemia

Hyperuricemia has been associated with an increased risk for cardiovascular disease and increased mortality. However, the biologic mechanisms that link elevated serum uric acid to cardiovascular disease are uncertain. This study tested the hypothesis that elevated serum uric acid is associated with impaired endothelial function in hyperuricemic patients without any overt cardiovascular disease. Seventeen male patients with hyperuricemia (mean age 42+/-4 years) and 9 control subjects (mean age 45+/-5 years) were studied. All subjects were nonsmokers. All patients had never been treated for hyperuricemia, were on no medications, and were free of any other known diseases. Endothelial function was evaluated by flow-mediated dilation measured by ultrasound. Flow-mediated dilation was significantly impaired in patients with hyperuricemia (4.0+/-0.7%) compared with control subjects (6.4+/-0.8%) (p=0.044). Flow-mediated dilation correlated inversely with uric acid levels (r=-0.4, p=0.05). Nitrate-induced dilation was 12.3+/-1.0% in patients with hyperuricemia and 11.8+/-2.3% in control subjects (p=0.82). Impaired endothelial-dependent vasodilation is present in hyperuricemic patients even in the absence of any overt cardiovascular disease. The elevated serum uric acid, per se, may constitute a novel risk factor for endothelial dysfunction.     

Diagnosis and assessment of monkeypox virus (MPXV) infection by quantitative PCR assay: differentiation of Congo Basin and West African MPXV strains

Human monkeypox, an infectious disease caused by monkeypox virus (MPXV), is endemic to western and central Africa. A LightCycler quantitative PCR (LC-qPCR) system was developed for the diagnosis of this disease, targeting the A-type inclusion body gene (ATI gene) of MPXV. One naive monkey was infected with MPXV Zr-599 (Congo Basin strain) and one with MPXV Liberia (West African strain). Another three monkeys were immunized with smallpox vaccine on 0, 3, or 7 days, respectively, before infection with MPXV Zr-599. Peripheral blood cell (PBC) and throat swab (TS) specimens were serially collected. The LC-qPCR was validated for the diagnosis of monkeypox using virus isolation. Sequencing of the partial ATI gene revealed the insertion of a unique 453-nucleotide residue in the West African strains but not in the Congo Basin strains. Specific reverse primers for Congo Basin and West African strains were designed based on the unique sequence insertion. The LC-qPCR detected the MPXV genome, but not those of the other orthopoxviruses tested nor the varicella-zoster virus. Both the sensitivity and specificity of the LC-qPCR were over 90% in comparison to virus isolation when TS specimens were tested. Fourteen of the 15 virus isolation-positive PBC specimens showed positive reactions in the assay. Further, most PBC specimens collected from symptomatic monkeys in the later stage of illness showed positive reactions in the assay but negative reaction in virus isolation. It was possible to differentiate between these two groups with the LC-qPCR. Thus, the newly developed LC-qPCR is a useful and reliable diagnostic tool for MPXV infection.     

Difference in CD22 molecules in human B cells and basophils

OBJECTIVE: CD22 is believed to be restricted to normal and neoplastic B cells. Human basophils were found to express CD22 molecules. Among the antibodies against CD22, Leu14, which recognized the ligand binding domain, reacted to basophils, and B3 and 4KB128, which recognized the amino terminus side and carboxy terminus side of the ligand binding epitope, respectively, did not. To clarify the difference of CD22 antigenicity in human B cells and basophils, we investigated RNA sequence and structures of CD22 molecules. MATERIALS AND METHODS: Purified B cells and basophils were obtained from normal human volunteers by using a MACS magnetic cell sorting system and anti-CD19 and anti-Fc epsilon R1 antibodies, respectively. RT-PCR and sequencing of CD22 mRNA were performed in the exons 3 to 8. Western blotting analysis of CD22 was also performed. RESULTS: The sequence of CD22 mRNA extracted from the basophils was the same as that of B cells in exons 3 to 8 (epitopes recognized by Leu14, B3, and 4KB128 were translated from exons 4 and 5). Reduced CD22 peptide extracted from the basophils reacted to Leu14 as well as B3 and 4KB128, and the molecular size of the reduced and nonreduced products was 130 kDa as expected. CONCLUSION: Disulfide bonds and the resulting 3D conformation of the CD22 molecules may have important roles in the difference of antigenicity of CD22 beta in B cells (CD22 beta 1) and basophils (CD22 beta 2). The difference in molecular structure surrounding the ligand-binding domain of CD22 may imply a specialization of the conformational forms of CD22 according to the ligand isoforms.