Foxc2 induces Wnt4 and Bmp4 expression during muscle regeneration and osteogenesis.

Proliferation and fusion of myoblasts is a well-orchestrated process occurring during muscle development and regeneration. Although myoblasts are known to originate from muscle satellite cells, the molecular mechanisms that coordinate their commitment toward differentiation are poorly understood. Here, we present a novel role for the transcription factor Forkhead box protein C2 (Foxc2) in regulating proliferation and preventing premature differentiation of activated muscle satellite cells. We demonstrate that Foxc2 expression is upregulated early in activated mouse muscle satellite cells and then diminishes during myogenesis. In undifferentiated C2C12 myoblasts, downregulation of endogenous Foxc2 expression leads to a decrease in proliferation, whereas forced expression of FOXC2 sustains proliferation and prevents differentiation into myotubes. We also show that FOXC2 induces Wnt signaling by direct interaction with the Wnt4 (wingless-type MMTV integration site family member-4) promoter region. The resulting elevated expression of bone morphogenetic protein-4 (Bmp4) and RhoA-GTP proteins inhibits the proper myoblast alignment and fusion required for myotube formation. Interestingly, continuous forced expression of FOXC2 alters the commitment of C2C12 myoblasts toward osteogenic differentiation, which is consistent with FOXC2 expression observed in patients with myositis ossificans, an abnormal bone growth within muscle tissue. In summary, our results suggest that (a) Foxc2 regulates the proliferation of multipotent muscle satellite cells; (b) downregulation of Foxc2 is critical for myogenesis to progress; and (c) sustained Foxc2 expression in myoblast cells suppresses myogenesis and alters their lineage commitment toward osteogenesis by inducing the Wnt4 and Bmp4 signaling pathways.

Short-term electrical stimulation of the lower esophageal sphincter increases sphincter pressure in patients with gastroesophageal reflux disease.

BACKGROUND: Electrical stimulation (ES) of the lower esophageal sphincter (LES) increases resting LES pressure (LESP) in animal models. Our aims were to evaluate the safety of such stimulation in humans, and test the hypothesis that ES increases resting LESP in patients with gastroesophageal reflux disease (GERD). METHODS: A total of 10 subjects (nine female patients, mean age 52.6 years), with symptoms of GERD responsive to PPIs, low resting LES pressure, and abnormal 24-h intraesophageal pH test were enrolled. Those with hiatal hernia >2 cm and/or esophagitis >Los Angeles Grade B were excluded. Bipolar stitch electrodes were placed longitudinally in the LES during an elective laparoscopic cholecystectomy, secured by a clip and exteriorized through the abdominal wall. Following recovery, an external pulse generator delivered two types of stimulation for periods of 30 min: (i) low energy stimulation; pulse width of 200 µs, frequency of 20 Hz and current of 5-15 mA (current was increased up to 15 mA if LESP was less than 15 mmHg), and (ii) high energy stimulation; pulse width of 375 ms, frequency of 6 cpm, and current 5 mA. Resting LESP, amplitude of esophageal contractions and residual LESP in response to swallows were assessed before and after stimulation. Symptoms of chest pain, abdominal pain, and dysphagia were recorded before, during, and after stimulation and 7-days after stimulation. Continuous cardiac monitoring was performed during and after stimulation. KEY RESULTS: All patients were successfully implanted nine subjects received high frequency, low energy, and four subjects received low frequency, high energy stimulation. Both types of stimulation significantly increased resting LESP: from 8.6 mmHg (95% CI 4.1-13.1) to 16.6 mmHg (95% CI 10.8-19.2), P < 0.001 with low energy stimulation and from 9.2 mmHg (95% CI 2.0-16.3) to 16.5 mmHg (95% CI 2.7-30.1), P = 0.03 with high energy stimulation. Neither type of stimulation affected the amplitude of esophageal peristalsis or residual LESP. No subject complained of dysphagia. One subject had retrosternal discomfort with stimulation at 15 mA that was not experienced with stimulation at 13 mA. There were no adverse events or any cardiac rhythm abnormalities with either type of stimulation. CONCLUSIONS & INFERENCES: Short-term stimulation of the LES in patients with GERD significantly increases resting LESP without affecting esophageal peristalsis or LES relaxation. Electrical stimulation of the LES may offer a novel therapy for patients with GERD.

High-sensitivity C-reactive protein and erythrocyte sedimentation rate in systemic lupus erythematosus.

Levels of C-reactive protein (CRP) have been shown to rise in acute illnesses such as infections and some autoimmune diseases, but not in flares of systemic lupus erythematosus (SLE). Our goal was to investigate the high-sensitivity CRP (hsCRP) response to infection versus disease flare in patients with SLE, and to compare this with the erythrocyte sedimentation rate (ESR) response in these patients. We aimed to determine the hsCRP level that distinguishes between infection and flare in SLE, and investigated the correlation between hsCRP and organ involvement in SLE. We reviewed electronic medical records of all patients with SLE admitted to Cedars Sinai Medical Center between 28 August 2001 and 27 April 2008. Patients were divided into three groups based on the reason for hospitalization: (1) lupus flare; (2) active infection; and (3) both lupus flare and active infection. Data were collected on patient demographics, medication use, microbial culture results, organ involvement in lupus flare, ESR and CRP levels. Data were collected on 85 eligible patients, of whom 54 had a lupus flare, 22 had active infection and eight had both. While the ESR levels did not differ significantly between patients with disease flare and active infection, the hsCRP level was significantly lower in the lupus flare group than in the infection group. Most patients in the lupus flare group who had a significantly high hsCRP level had serositis. We found that at a cut-off of above 5 mg/dl, hsCRP level was correlated with infection with a specificity of 80%. At a cut-off of above 6 mg/dl, hsCRP correlated with infection with a specificity of 84%. hsCRP level was found to be significantly higher in patients with pulmonary involvement than without. hsCRP levels are significantly lower in SLE patients with disease flare than in those with active infection. Elevated hsCRP levels can be used as a predictor of active infection in SLE patients with a high specificity. We review the relationship between IL-6 and hsCRP production in lupus patients.