Research Spotlight

Wu, N., F. Meng, T. Zhou, Y. Han, L. Kennedy, J. Venter, H. Francis, S. DeMorrow, P. Onori, P. Invernizzi, F. Bernuzzi, R. Mancinelli, E. Gaudio, A. Franchitto, S. Glaser and G. Alpini (2017). “Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by mir-200b down-regulation.” Faseb j: 2017 Jun [Epub ahead of print].

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Melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in bile-duct-ligated (BDL) rats; however, no information exists in primary sclerosing cholangitis (PSC). Thus, we aimed to determine the therapeutic effects of prolonged dark therapy or melatonin administration on hepatic fibrosis in the Mdr2-/- mouse model of PSC. Melatonin levels, biliary mass, liver fibrosis, angiogenesis and miR-200b expression were evaluated in wild-type and Mdr2-/- mice exposed to darkness or melatonin treatment or in male PSC patient samples and healthy controls. Mdr2-/- mice were also treated with miR-200b inhibitor or control before evaluating biliary mass, liver fibrosis, and angiogenesis. After overexpression of arylalkylamine N-acetyltransferase (AANAT; the enzyme regulating melatonin synthesis) or inhibition of miR-200b in cholangiocytes and hepatic stellate cells in vitro, we evaluated angiogenesis and fibrosis gene expression. After exposure to darkness or administration of melatonin, Mdr2-/- mice show elevated serum melatonin levels and inhibition of biliary mass, along with reduction of liver fibrosis and angiogenesis. miRNA PCR analysis demonstrated that miR-200b expression increased in Mdr2-/- mice and PSC patient samples compared with controls and decreased in Mdr2-/- mice subjected to dark exposure or melatonin treatment. Inhibition of miR-200b in Mdr2-/- ablates biliary proliferation, liver fibrosis, and angiogenesis. In vitro, overexpression of AANAT or inhibition of miR-200b in cholangiocytes and hepatic stellate cells decreased the expression of miR-200b, angiogenesis, and fibrosis genes. Dark therapy or targeting melatonin/miR-200b axis may be important in the management of biliary damage and liver fibrosis in cholangiopathies including PSC.-Wu, N., Meng, F., Zhou, T., Han, Y., Kennedy, L., Venter, J., Francis, H., DeMorrow, S., Onori, P., Invernizzi, P., Bernuzzi, F., Mancinelli, R., Gaudio, E., Franchitto, A., Glaser, S., Alpini G. Prolonged darkness reduces liver fibrosis in a mouse model of primary sclerosing cholangitis by miR-200b down-regulation.

Martin, H. D., A. N. Khoury, R. Schroder, J. Gomez-Hoyos, S. Yeramaneni, M. Reddy and I. James Palmer (2017). “The effects of hip abduction on sciatic nerve biomechanics during terminal hip flexion.” J Hip Preserv Surg 4(2): 178-186.

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Terminal hip flexion contributes to increased strain in peripheral nerves at the level of the hip joint. The effects of hip abduction and femoral version on sciatic nerve biomechanics are not well understood. A decrease in sciatic nerve strain will be observed during terminal hip flexion and hip abduction, independent of femoral version. Six un-embalmed human cadavers were utilized. Three Differential Variable Reluctance Transducers (DVRTs) sensors were placed on the sciatic nerve while the leg was flexed to 70 degrees with a combination of – 10 degrees , 0 degrees , 20 degrees and 40 degrees adduction/abduction. DVRT placement included: (i) under piriformis, (ii) immediately distal to the gemelli/obturator, (iii) four centimeters distal to sensor two. A de-rotational osteotomy to decrease femoral version 10 degrees was performed, and sciatic nerve strain was measured by the same procedure. Data were analyzed with three-way analysis of variance and Bonferroni post-hoc analysis to identify differences in the mean values of sciatic nerve strain between native and decreased version state, hip abduction angle and DVRT sensor location. Significant main effects were observed for femoral version (P = 0.04) and DVRT sensor location (P = 0.01). Sciatic nerve strain decreased during terminal hip flexion and abduction in the decreased version state. An 84.23% decrease in sciatic nerve strain was observed during hip abduction from neutral to 40 degrees in the presence of decreased version at terminal hip flexion. The results obtained from this study confirm the role of decreased femoral version and hip abduction at terminal hip flexion to decrease the strain in the sciatic nerve.

Packer, M. and J. J. V. McMurray (2017). “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.” Lancet 389(10081): 1831-1840.

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The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Karakkattil, P. P. M., E. P. P. Trudelle-Jackson, H. H. D. Brown, P. D. Hammontree and M. D. Okolo (2017). “Outcomes of botulinum toxin type a for equinovarus deformity in patients with cva: A case series.” Physiother Theory Pract 33(5): 410-419.

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BACKGROUND: There is evidence that Botulinum Toxin-A (BTX-A) reduces focal spasticity associated with equinovarus to improve gait in patients poststroke. However, there is little research examining whether gait improvements are maintained after the effectiveness period of BTX-A injections. The purpose of this observational study was to determine whether there was a difference in gait parameters in three patients before BTX-A injection versus four and ten weeks after. CASE SERIES: Three women, ages 63, 60, and 42 postischemic stroke with hemiparesis and equinovarus underwent measurements for: plantar flexor spasticity, ankle dorsiflexion ROM, temporal-spatial gait parameters, and gait endurance. All participants improved in ankle ROM. At week 10, spasticity had returned to initial measurement levels in participants A and C. Base of support and step length symmetry ratios did not improve following injections. Participants A and B, who received physical therapy during the study, showed modest gains in gait endurance and velocity. CONCLUSION: Although BTX-A injections improved spasticity, this improvement did not translate to gait outcomes. Addition of physical therapy interventions appeared to improve gait outcomes in this case series. We suggest future randomized control studies to compare effects of physical therapy alone to BTX-A combined with physical therapy on gait outcomes.

Mehta, R. H., J. D. Leimberger, S. van Diepen, J. Meza, A. Wang, R. Jankowich, R. W. Harrison, D. Hay, S. Fremes, A. Duncan, E. G. Soltesz, J. Luber, S. Park, M. Argenziano, E. Murphy, R. Marcel, D. Kalavrouziotis, D. Nagpal, J. Bozinovski, W. Toller, M. Heringlake, S. G. Goodman, J. H. Levy, R. A. Harrington, K. J. Anstrom and J. H. Alexander (2017). “Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery.” N Engl J Med 376(21): 2032-2042.

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BACKGROUND: Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery. METHODS: In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 mug per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 mug per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5. RESULTS: A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups. CONCLUSIONS: Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass.