Valgus stress radiography following superficial medial collateral ligament reconstruction using a modified LaPrade technique with adjustable loop femoral fixation.

Purpose of this study was to assess postoperative laxity of MCL reconstructions utilizing a modified LaPrade superficial MCL reconstruction. We retrospectively reviewed post-operative valgus stress radiographs in 23 multiligament injured patients who underwent concurrent sMCL and cruciate ligament reconstruction by a single surgeon. Post- operatively, 23 patients underwent valgus stress radiographs that were assessed at a mean of 8.7 months (range: 4-13 months), and mean SSD was 0.64mm ± 0.42mm. Eight patients underwent both pre- and post-operative valgus stress radiographs. Post-operative (0.09mm ± 0.63mm) SSD was found to be significantly reduced compared to pre-operative (2.07mm ± 0.44mm) SSD (mean diff. = 1.98mm, 95% CI = 0.72-3.24, P=0.007). Inter-observer reliability value for medial compartment gap measurement was 0.91 with a 95% confidence interval of 0.34- 0.97. In conclusion, presented technique results in excellent static stability of the knee as measured by valgus stress radiography at a minimum of 6 months postoperative. Level of Evidence: IV.

FTO influences adipogenesis by regulating mitotic clonal expansion.

The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity.

Pharmacological inhibition of FTO.

In 2007, a genome wide association study identified a SNP in intron one of the gene encoding human FTO that was associated with increased body mass index. Homozygous risk allele carriers are on average three kg heavier than those homozygous for the protective allele. FTO is a DNA/RNA demethylase, however, how this function affects body weight, if at all, is unknown. Here we aimed to pharmacologically inhibit FTO to examine the effect of its demethylase function in vitro and in vivo as a first step in evaluating the therapeutic potential of FTO. We showed that IOX3, a known inhibitor of the HIF prolyl hydroxylases, decreased protein expression of FTO (in C2C12 cells) and reduced maximal respiration rate in vitro. However, FTO protein levels were not significantly altered by treatment of mice with IOX3 at 60 mg/kg every two days. This treatment did not affect body weight, or RER, but did significantly reduce bone mineral density and content and alter adipose tissue distribution. Future compounds designed to selectively inhibit FTO's demethylase activity could be therapeutically useful for the treatment of obesity.

The intriguing enhancement of chloroperoxidase mediated one-electron oxidations by azide, a known active-site ligand.

Azide is a well-known inhibitor of heme-enzymes. Herein, we report the counter-intuitive observation that at some concentration regimes, incorporation of azide in the reaction medium enhances chloroperoxidase (CPO, a heme-enzyme) mediated one-electron abstractions from several substrates. A diffusible azidyl radical based mechanism is proposed for explaining the phenomenon. Further, it is projected that the finding could have significant impact on routine in situ or in vitro biochemistry studies involving heme-enzyme systems and azide.

Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects.

Deficiency of the transcription factor Cited2 in mice results in cardiac malformation, adrenal agenesis, neural tube, placental defects and partially penetrant cardiopulmonary laterality defects resulting from an abnormal Nodal->Pitx2c pathway. Here we show that a maternal high-fat diet more than doubles the penetrance of laterality defects and, surprisingly, induces palatal clefting in Cited2-deficient embryos. Both maternal diet and Cited2 deletion reduce embryo weight and kidney and thymus volume. Expression profiling identified 40 embryonic transcripts including Pitx2 that were significantly affected by embryonic genotype-maternal diet interaction. We show that a high-fat diet reduces Pitx2c levels >2-fold in Cited2-deficient embryos. Taken together, these results define a novel interaction between maternal high-fat diet and embryonic Cited2 deficiency that affects Pitx2c expression and results in abnormal laterality. They suggest that appropriate modifications of maternal diet may prevent such defects in humans.