Entrapment neuropathy results in different microRNA expression patterns from denervation injury in rats

<p>Abstract</p> <p>Background</p> <p>To compare the microRNA (miRNA) expression profiles in neurons and innervated muscles after sciatic nerve entrapment using a non-constrictive silastic tube, subsequent surgical decompression, and denervation injury.</p> <p>Methods</p> <p>The experimental L4-L6 spinal segments, dorsal root ganglia (DRGs), and soleus muscles from each experimental group (sham control, denervation, entrapment, and decompression) were analyzed using an Agilent rat miRNA array to detect dysregulated miRNAs. In addition, muscle-specific miRNAs (miR-1, -133a, and -206) and selectively upregulated miRNAs were subsequently quantified using real-time reverse transcription-polymerase chain reaction (real-time RT-PCR).</p> <p>Results</p> <p>In the soleus muscles, 37 of the 47 miRNAs (13.4% of the 350 unique miRNAs tested) that were significantly downregulated after 6 months of entrapment neuropathy were also among the 40 miRNAs (11.4% of the 350 unique miRNAs tested) that were downregulated after 3 months of decompression. No miRNA was upregulated in both groups. In contrast, only 3 miRNAs were upregulated and 3 miRNAs were downregulated in the denervated muscle after 6 months. In the DRGs, 6 miRNAs in the entrapment group (miR-9, miR-320, miR-324-3p, miR-672, miR-466b, and miR-144) and 3 miRNAs in the decompression group (miR-9, miR-320, and miR-324-3p) were significantly downregulated. No miRNA was upregulated in both groups. We detected 1 downregulated miRNA (miR-144) and 1 upregulated miRNA (miR-21) after sciatic nerve denervation. We were able to separate the muscle or DRG samples into denervation or entrapment neuropathy by performing unsupervised hierarchal clustering analysis. Regarding the muscle-specific miRNAs, real-time RT-PCR analysis revealed an ~50% decrease in miR-1 and miR-133a expression levels at 3 and 6 months after entrapment, whereas miR-1 and miR-133a levels were unchanged and were decreased after decompression at 1 and 3 months. In contrast, there were no statistical differences in the expression of miR-206 during nerve entrapment and after decompression. The expression of muscle-specific miRNAs in entrapment neuropathy is different from our previous observations in sciatic nerve denervation injury.</p> <p>Conclusions</p> <p>This study revealed the different involvement of miRNAs in neurons and innervated muscles after entrapment neuropathy and denervation injury, and implied that epigenetic regulation is different in these two conditions.</p

BPR1K653, a Novel Aurora Kinase Inhibitor, Exhibits Potent Anti-Proliferative Activity in MDR1 (P-gp170)-Mediated Multidrug-Resistant Cancer Cells

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Sino-Soviet Relations: 1946-1952

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Assessment of shoulder function following scapular free flap.

BACKGROUND: The scapular system free flap has been increasing in popularity to reconstruct short segment mandibular bony defects. It is important to assess donor site morbidities systematically. METHODS: Prospective cohort study using objective measures of range of motion (ROM) and shoulder strength were measured. Subjective disability was evaluated with validated questionnaires-Neck Disability Impairment Index and Shoulder Pain and Disability Index. RESULTS: Twenty-six patients were recruited-19 with scapular tip and 7 with lateral border scapular free flap. Decreased ROM on the operated side was noted for shoulder abduction, shoulder flexion, and external rotation. No significant difference was noted for shoulder extension. Strength was reduced for shoulder flexion, shoulder abduction, and external rotation. Subjective measurements did not indicate significant shoulder function disruption. CONCLUSION: Patients with scapular free flap reconstruction did not experience significant shoulder morbidity. Measures of shoulder ROM and power were objectively affected; however, subjective measures of shoulder disability were not significantly affected

Impact on postpartum hemorrhage of prophylactic administration of oxytocin 10 IU via Uniject™ by peripheral health care providers at home births: design of a community-based cluster-randomized trial.

BACKGROUND: Hemorrhage is the leading direct cause of maternal death globally. While oxytocin is the drug of choice for postpartum hemorrhage prevention, its use has generally been limited to health facilities. This trial assesses the effectiveness, safety, and feasibility of expanding the use of prophylactic intramuscular oxytocin to peripheral health care providers at home births in four predominantly rural districts in central Ghana. METHODS: This study is designed as a community-based cluster-randomized trial in which Community Health Officers are randomized to provide (or not provide) an injection of oxytocin 10 IU via the Uniject™ injection system within one minute of delivery of the baby to women who request their presence at home at the onset of labor. The primary aim is to determine if administration of prophylactic oxytocin via Uniject™ by this cadre will reduce the risk of postpartum hemorrhage by 50 % relative to deliveries which do not receive the prophylactic intervention. Postpartum hemorrhage is examined under three sequential definitions: 1) blood loss ≥500 ml (BL); 2) treatment for bleeding (TX) and/or BL; 3) hospital referral for bleeding and/or TX and/or BL. Secondary outcomes address safety and feasibility of the intervention and include adverse maternal and fetal outcomes and logistical concerns regarding assistance at home births and the storage and handling of oxytocin, respectively. DISCUSSION: Results from this trial will build evidence for the effectiveness of expanding the delivery of this established prophylactic intervention to peripheral settings. Complementary data on safety and logistical issues related to this intervention will assist policymakers in low-income countries in selecting both the best uterotonic and service delivery strategy for postpartum hemorrhage prevention. Results of this trial are expected in mid-2013. The trial is registered at ClinicalTrials.gov: NCT01108289