Cranial irradiation is widely used in cancer therapy, but it often causes cognitive defects in cancer survivors. Oxidative stress is considered a major cause of tissue injury from irradiation. However, in an earlier study mice deficient in the antioxidant enzyme extracellular superoxide dismutase (EC-SOD KO) showed reduced sensitivity to radiation-induced defects in hippocampal functions. To further dissect the role of EC-SOD in neurogenesis and in response to irradiation, we generated a bigenic EC-SOD mouse model (OE mice) that expressed high levels of EC-SOD in mature neurons in an otherwise EC-SOD-deficient environment. EC-SOD deficiency was associated with reduced progenitor cell proliferation in the subgranular zone of dentate gyrus in KO and OE mice. However, high levels of EC-SOD in the granule cell layer supported normal maturation of newborn neurons in OE mice. Following irradiation, wild-type mice showed reduced hippocampal neurogenesis, reduced dendritic spine densities, and defects in cognitive functions. OE and KO mice, on the other hand, were largely unaffected, and the mice performed normally in neurocognitive tests. Although the resulting hippocampalrelated functions were similar in OE and KO mice following cranial irradiation, molecular analyses suggested that they may be governed by different mechanisms: whereas neurotrophic factors may influence radiation responses in OE mice, dendritic maintenance may be important in the KO environment. Taken together, our data suggest that EC-SOD plays an important role in all stages of hippocampal neurogenesis and its associated cognitive functions, and that highlevel EC-SOD may provide protection against irradiation-related defects in hippocampal functions.

Object Minimally invasive (MI) transforaminal lumbar interbody fusion (TLIF) has been demonstrated in previous studies to offer improvement in pain and function comparable to those provided by the open surgical approach. However, comparative studies in the obese population are scarce, and it is possible that obese patients may respond differently to these two approaches. In this study, the authors compared the clinical benefit of open and MI TLIF in obese patients. Methods The authors conducted a retrospective cohort study based on review of electronic medical records at a single institution. Eligible patients had a body mass index (BMI) ≥ 30 kg/m2, were ≥ 18 years of age, underwent single-level TLIF between 2007 and 2011, and outcome was assessed at a minimum 6 months postoperatively. The authors categorized patients according to surgical approach (open vs MI TLIF). Outcome measures included postoperative improvement in visual analog scale (VAS), Oswestry Disability Index (ODI), estimated blood loss (EBL), and hospital length of stay (LOS). Results A total 74 patients (21 open and 53 MI TLIF) were studied. Groups had similar baseline characteristics. The median BMI was 34.4 kg/m2 (interquartile range 31.6–37.5 kg/m2). The mean follow-up time was 30 months (range 6.5–77 months). The mean improvement in VAS score was 2.8 (95% CI 1.9–3.8) for the open group (n = 21) and 2.4 (95% CI 1.8–3.1) for the MI group (n = 53), which did not significantly differ (unadjusted, p = 0.49; adjusted, p = 0.51). The mean improvement in ODI scores was 13 (95% CI 3–23) for the open group (n = 14) and 15 (95% CI 8–22) for the MI group (n = 45), with no significant difference according to approach (unadjusted, p = 0.82; adjusted, p = 0.68). After stratifying by BMI (< 35 kg/m2 and ≥ 35 kg/m2), there was still no difference in either VAS or ODI improvement between the approaches (both unadjusted and adjusted, p > 0.05). Complications and EBL were greater for the open group than for the MI group (p < 0.05). Conclusions Obese patients experienced clinically and statistically significant improvement in both pain and function after undergoing either open or MI TLIF. Patients achieved similar clinical benefit whether they underwent an open or MI approach. However, patients in the MI group experienced significantly decreased operative blood loss and complications than their counterparts in the open group.

Object Minimally invasive (MI) transforaminal lumbar interbody fusion (TLIF) has proven to be effective in the treatment of spondylolisthesis and degenerative disc disease (DDD). Compared with the traditional open TLIF, the MI procedure has been associated with less blood loss, less postoperative pain, and a shorter hospital stay. However, it is uncertain whether the advantages of an MI TLIF also apply specifically to obese patients. This study was dedicated to evaluating whether obese patients reap the perioperative benefits similar to those seen in patients with normal body mass index (BMI) when undergoing MI TLIF. Methods Obese patients—that is, those with a BMI of at least 30 kg/m2—who had undergone single-level TLIF were retrospectively identified and categorized according to BMI: Class I obesity, BMI 30.0–34.9 kg/m2; Class II obesity, BMI 35.0–39.9 kg/m2; or Class III obesity, BMI ≥ 40.0 kg/m2. In each obesity class, patients were stratified by TLIF approach, that is, open versus MI. Perioperative outcomes, including intraoperative estimated blood loss (EBL), complications (overall, intraoperative, and 30-day postoperative), and hospital length of stay (LOS), were compared. The chi-square test, Fisher exact test, or 2-tailed Student t-test were used when appropriate. Results One hundred twenty-seven patients were included in the final analysis; 49 underwent open TLIF and 78 underwent MI TLIF. Sixty-one patients had Class I obesity (23 open and 38 MI TLIF); 45 patients, Class II (19 open and 26 MI); and 21 patients, Class III (7 open and 14 MI). Overall, mean EBL was 397.2 ml and mean hospital LOS was 3.7 days. Minimally invasive TLIF was associated with significantly less EBL and a shorter hospital stay than open TLIF when all patients were evaluated as a single cohort and within individual obesity classes. Overall, the complication rate was 18.1%. Minimally invasive TLIF was associated with a significantly lower total complication rate (11.5% MI vs 28.6% open) and intraoperative complication rate (3.8% MI vs 16.3% open) as compared with open TLIF. When stratified by obesity class, MI TLIF was still associated with lower rates of total and intraoperative complications. This effect was most profound and statistically significant in patients with Class III obesity (42.9% open vs 7.1% MI). Conclusions Minimally invasive TLIF offers obese patients perioperative benefits similar to those seen in patients with normal BMI who undergo the same procedure. These benefits include less EBL, a shorter hospital stay, and potentially fewer complications compared with open TLIF. Additional large retrospective studies and randomized prospective studies are needed to verify these findings.

BACKGROUND CONTEXT A large percentage of back pain can be attributed to degeneration of the intervertebral disc (IVD). Bone morphogenetic protein-2 (BMP-2) is known to play an important role in chondrogenesis of the IVD. Simvastatin is known to up-regulate expression of BMP-2. Thus, we hypothesized that intradiscal injection of simvastatin in a rat model of degenerative disc disease (DDD) would result in retardation of DDD. PURPOSE To develop a novel conservative treatment for DDD and related discogenic back pain. STUDY DESIGN/SETTING Laboratory investigation. METHODS Disc injury was induced in 272 rats via 21-gauge needle puncture. After 6 weeks, injured discs were treated with simvastatin in a saline or hydrogel carrier. Rats were sacrificed at predetermined time points. Outcome measures assessed were radiologic, histologic, and genetic. Radiologically, the MRI index (number of pixels multiplied by corresponding image densities) was determined. Histologically, disc spaces were read by 3 blinded scorers employing a previously described histological grading scale. Genetically, nuclei pulposi were harvested and polymerase chain reaction was run to determine relative levels of aggrecan, collagen type II, and BMP-2 gene expression. This project was supported by Grant No. R01 AR056649 from NIAMS/NIH. There are no other financial conflicts of interest to report. RESULTS Radiologically, discs treated with 5 mg/mL simvastatin in hydrogel or saline demonstrated MRI indices that were normal through 8 weeks post-treatment, although this was more sustained when delivered in hydrogel. Histologically, discs treated with 5 mg/mL simvastatin in hydrogel demonstrated improved grades in comparison to discs treated at higher doses. Genetically, discs treated with 5 mg/mL of simvastatin in hydrogel demonstrated higher gene expression of aggrecan and collagen type II than control. CONCLUSIONS Degenerate discs treated with 5 mg/mL simvastatin in a hydrogel carrier demonstrated radiographic and histologic features resembling normal, non-injured IVDs. In addition, gene expression of aggrecan and collagen type II (important constituents of the IVD extracellular matrix) was up-regulated in treated discs. Injection of simvastatin into degenerate IVDs may result in retardation of disc degeneration and represents a promising investigational therapy for conservative treatment of DDD.

Mn superoxide dismutase (MnSOD) is an important mitochondrial antioxidant enzyme, and elevated MnSOD levels have been shown to reduce tumor growth in part by suppressing cell proliferation. Studies with fibroblasts have shown that increased MnSOD expression prolongs cell cycle transition time in G1/S and favors entrance into the quiescent state. To determine if the same effect occurs during tissue regeneration in vivo, we used a transgenic mouse system with liver-specific MnSOD expression and a partial hepatectomy paradigm to induce synchronized in vivo cell proliferation during liver regeneration. We show in this experimental system that a 2.6 fold increase in MnSOD activities leads to delayed entry into S phase, as measured by reduction in bromodeoxyuridine (BrdU) incorporation, and decreased expression of proliferative cell nuclear antigen (PCNA). Thus, compared to control mice with baseline MnSOD levels, transgenic mice with increased MnSOD expression in the liver have 23% fewer BrdU positive cells and a marked attenuation of PCNA expression. The increase in MnSOD activity also leads to an increase of the mitochondrial form of thioredoxin (thioredoxin 2), but not of several other peroxidases examined, suggesting the importance of thioredoxin 2 in maintaining redox balance in mitochondria with elevated levels of MnSOD.