The molecular biology and novel treatments of vestibular schwannomas

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4(DCAF1). A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.     

Effects of pomegranate juice consumption on oxidative stress in patients with type 2 diabetes: a single-blind,randomized clinical trial

Increased free radicals production due to hyperglycemia produces oxidative stress in patients with diabetes. Pomegranate juice (PJ) has antioxidant properties. This study was conducted to determine the effects of PJ consumption in oxidative stress in type 2 diabetic patients.

This study was a randomized clinical trial performed on 60, 40–65 years old diabetic patients.

The patients were randomly allocated either to PJ consumption group or control. Patients in PJ group consumed 200?ml of PJ daily for six weeks. Sex distribution and the mean age were not different between two groups. After six weeks intervention, oxidized LDL and anti-oxidized LDL antibodies decreased and total serum antioxidant capacity and arylesterase activity of paraoxonase increased significantly in the PJ-treated group compared to the control group. Our data have shown that six weeks supplementation of PJ could have favorable effects on oxidative stress in patients with type 2 diabetes (T2D).     

Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial

Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 microg of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-microg dose was 0.5% and 0.4% with a 2-microg dose (P>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1; P=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9; P=0.62) with a 1-microg dose, and 0.5 (95% CI: 0.3 to 0.9; P=0. 03) with a 2-microg dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69; P=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69; P<0.001) with a 1-microg dose, and 0.54 (95% CI: 0.35 to 0.83; P=0. 01) with a 2-microg dose (P<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.     

Numerical simulations investigating the regional and overall deposition efficiency of the human nasal cavity

Numerical simulations have been carried out on a model of the right passageway of an anonymous, adult male's nasal cavity, constructed from magnetic resonance imagery (MRI) scans. Steady, laminar, inspiratory flow was assumed to simulate inhalation. Analysis shows smoothly varying streamlines with a peak in velocity magnitude occurring in the nasal valves and a peak in vorticity magnitude immediately posterior. Dilute, uniform concentrations of inertial (1 microm < or = d(ae) < or = 10 microm) particles were released at the nostril and tracked via a Lagrangian tracking algorithm. Deposition efficiency is shown to increase with particle size and flow rate. Preferential deposition is seen in the anterior third of the nasal cavity for large Stokes number particles. An empirical expression for particle deposition is proposed that incorporates particle size, flow rate, and nose anatomy.     

Avoiding Opioids and Their Harmful Side Effects in the Postoperative Patient: Exogenous Opioids,Endogenous Endorphins,Wellness, Mood,and Their Relation to Postoperative Pain

Prescribed opioids are routinely used for many postoperative patients. However, these medications have daunting adverse effects on the body''s innate pain management system - the action of the beta-endorphins. The prescribed opioids not only severely impair the function of the mu-opioid receptors, but also inhibit the release of beta-endorphin. This is unfortunate, because beta-endorphin appears to be a much more potent agonist of the mu-opioid receptor than opioids. In addition, beta-endorphin indirectly elevates dopamine, a neurotransmitter related to feelings of euphoria. Therefore, by prescribing opioids, practitioners may inadvertently prolong and increase the overall intensity of the postoperative patients'' pain as well as herald anhedonia. This article highlights the relationships between prescribed (exogenous) opioids, beta-endorphins, mu-opioid receptors, wellness, mood, and postoperative pain. The role of patient education, opioid alternatives, and additional recommendations regarding pain control in the postoperative patient are also discussed.     

Anti-inflammatory and anti-nociceptive effects of the ethanolic extracts of Alkanna frigida and Alkanna orientalis

Alkanna species are used in Iranian traditional medicine for treatment of rheumatoid arthritis and other inflammatory diseases. This study was designed to evaluate the anti-inflammatory and anti-nociceptive effects of Alkanna frigida and Alkanna orientalis ethanolic extracts via the carrageenan-induced paw edema test and formalin test in rat and mouse, respectively. Ethanolic extracts of plant root were prepared and were injected intraperitoneally 60 min before carrageenan-induced inflammation or formalin-induced nociception at 100, 200 and 400 mg/kg. Anti-inflammatory effects of plants were monitored for 3 h after carrageenan injection and anti-nociceptive effects were evaluated during the first hour after formalin injection. Diclofenac, a well-known anti-inflammatory and anti-nociceptive agent, was used as a positive control. Our results show that, in contrast to Alkanna orientalis, ethanolic extract of Alkanna frigida significantly decreases carrageenan-induced inflammation at 400 mg/kg, especially 3 h after inflammation induction. Both Alkanna frigida and Alkanna orientalis ethanolic extracts possess a remarkable anti-nociceptive effect at each dose (100, 200 and 400 mg/kg) in a dose-dependent manner during the first hour after formalin injection.The present findings provide more evidence for the potential anti-nociceptive effect of Alkanna sp. and the anti-inflammatory effect of Alkanna frigida. It supports their traditional indication in the treatment of pain and inflammatory-related diseases. These useful effects may result from the inhibitory interaction of the plant ethanolic extract with cyclooxygenase-2 enzyme and the subsequent reduction in prostaglandin production.     

Phosphodiesterase inhibitors in inflammatory bowel disease

Inflammatory bowel disease (IBD) is fundamentally a relapsing and remitting disease appearing in forms of ulcerative colitis (UC) or Crohn's disease (CD) with a non-well-known etiology. With the hope to prevent adverse drug events and to increase the efficacy of therapies for IBD, in the recent years, other than new monoclonal antibodies such as infliximab, the novel phosphodiesterase inhibitors (PDEIs) have been introduced. Among PDE4Is, rolipram, OPC-6535, mesopram, roflumilast and tetomilast have shown beneficial effects in experimental colitis. Unfortunately until now, human studies have not been successful in showing significant superiority of PDE4Is in the treatment of IBD. Parallel with discovery of PDE4Is and their anti-inflammatory properties, inhibiting other PDE isoenzymes in immune and proinflammatory cells is on the way. PDE7Is have shown synergistic effect with PDE4Is and they may act similar to PDE3Is in experimental settings. Sildenafil as the PDE5I has shown good effects in experimental colitis by balancing oxidant-antioxidant status. Although the present data about PDE superfamily and their specific roles in gastrointestinal tract is limited but inhibitors of PDE4, PDE5 and PDE7 seem good candidates as the next generation of effective drugs. The synergistic anti-inflammatory effect of PDE4Is and PDE7Is is also important.