Effects of A2 Pulley Venting on Bowstringing and Tendon Slack: A Biomechanical Investigation.

BACKGROUND: A2 pulley release is often needed for exposure of the lacerated tendon, retrieval of retracted tendons, placement of core sutures, or to permit full motion and gliding of the repaired and edematous tendon. However, there is no agreement in the literature on the specific quantity of pulley venting that can be performed and recommendations are limited to an undefined "judicious release" of the pulleys when necessary. METHODS: Following a previously developed testing protocols, finger kinematics, tendon excursion, and bowstringing were evaluated on cadaveric hands for venting in increments of 20% of the pulley length. RESULTS: In our study, we found a statistically significant influence of venting on bowstringing, although no difference was found between fingers, and a significant difference in tendon slack, which was variable depending on the finger. Bowstringing started increasing at 20% of A2 venting and peaked at full release. Tendon slack did not start until 40% of A2 venting on the index finger, but started at 20% on the middle, ring, and small fingers. CONCLUSIONS: Venting of the A2 pulley leads to an incremental increase in tendon bowstringing and tendon slack. However, differences in metacarpophalangeal flexion angle were not observed until full A2 pulley release, and only observed in the index finger, and no differences were observed in proximal interphalangeal flexion angles. Therefore, the benefit of releasing the A2 pulley when clinically necessary will likely outweigh the risks of loss of motion or strength.

'Distraction Vaginogenesis': Preliminary Results Using a Novel Method for Vaginal Canal Expansion in Rats.

Vaginal atresia is seen in genetic disorders such as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which can cause significant sexual dysfunction. Current treatments include surgical reconstruction or mechanical dilation of the vaginal canal. Mechanical dilation requires patients to be highly motivated and compliant while surgical reconstruction has high rates of complications. This study evaluated a novel vaginal expansion sleeve (VES) method as an alternative treatment for vaginal atresia. The proprietary cylindrical VES is a spring-like device consisting of polyethylene terephthalate helicoid trusses capped at each end with a fixed diameter resin cap for fixation within tissues. Following the development of the VES and mechanical characterization of the force-length relationships within the device, we deployed the VES in Sprague Dawley rat vaginas anchored with nonabsorbable sutures. We measured the VES length-tension relationships and post-implant vaginal canal expansion ex vivo. Vaginal histology was examined before and after implantation of the VES devices. Testing of 30 mm sleeves without caps resulted in an expansion force of 11.7 ± 3.4 N and 2.0 ± 0.1 N at 50% and 40%, respectively. The implanted 20 mm VES resulted in 5.36 mm ± 1.18 expansion of the vaginal canal, a 32.5 ± 23.6% increase (p = 0.004, Student t test). Histological evaluation of the VES implanted tissue showed a significant thinning of the vaginal wall when the VES was implanted. The novel VES device resulted in a significant expansion of the vaginal canal ex vivo. The VES device represents a unique alternative to traditional mechanical dilation therapy in the treatment of vaginal atresia and represents a useful platform for the mechanical distension of hollow compartments, which avoids reconstructive surgeries and progressive dilator approaches.

Pharmacogenetics of KCNQ channel activation in 2 potassium channelopathy mouse models of epilepsy.

OBJECTIVES: Antiseizure drugs are the leading therapeutic choice for treatment of epilepsy, but their efficacy is limited by pharmacoresistance and the occurrence of unwanted side effects. Here, we examined the therapeutic efficacy of KCNQ channel activation by retigabine in preventing seizures and neurocardiac dysfunction in 2 potassium channelopathy mouse models of epilepsy with differing severity that have been associated with increased risk of sudden unexpected death in epilepsy (SUDEP): the Kcna1-/- model of severe epilepsy and the Kcnq1A340E/A340E model of mild epilepsy. METHODS: A combination of behavioral, seizure threshold, electrophysiologic, and gene expression analyses was used to determine the effects of KCNQ activation in mice. RESULTS: Behaviorally, Kcna1-/- mice exhibited unexpected hyperexcitability instead of the expected sedative-like response. In flurothyl-induced seizure tests, KCNQ activation decreased seizure latency by ≥50% in Kcnq1 strain mice but had no effect in the Kcna1 strain, suggesting the influence of genetic background. However, in simultaneous electroencephalography and electrocardiography recordings, KCNQ activation significantly reduced spontaneous seizure frequency in Kcna1-/- mice by ~60%. In Kcnq1A340E/A340E mice, KCNQ activation produced adverse cardiac effects including profound bradycardia and abnormal increases in heart rate variability and atrioventricular conduction blocks. Analyses of Kcnq2 and Kcnq3 mRNA levels revealed significantly elevated Kcnq2 expression in Kcna1-/- brains, suggesting that drug target alterations may contribute to the altered drug responses. SIGNIFICANCE: This study shows that treatment strategies in channelopathy may have unexpected outcomes and that effective rebalancing of channel defects requires improved understanding of channel interactions at the circuit and tissue levels. The efficacy of KCNQ channel activation and manifestation of adverse effects were greatly affected by genetic background, potentially limiting KCNQ modulation as a way to prevent neurocardiac dysfunction in epilepsy and thereby SUDEP risk. Our data also uncover a potential role for KCNQ2-5 channels in autonomic control of chronotropy.

Scn2a deletion improves survival and brain-heart dynamics in the Kcna1-null mouse model of sudden unexpected death in epilepsy (SUDEP).

People with epilepsy have greatly increased probability of premature mortality due to sudden unexpected death in epilepsy (SUDEP). Identifying which patients are most at risk of SUDEP is hindered by a complex genetic etiology, incomplete understanding of the underlying pathophysiology and lack of prognostic biomarkers. Here we evaluated heterozygous Scn2a gene deletion (Scn2a+/-) as a protective genetic modifier in the Kcna1 knockout mouse (Kcna1-/-) model of SUDEP, while searching for biomarkers of SUDEP risk embedded in electroencephalography (EEG) and electrocardiography (ECG) recordings. The human epilepsy gene Kcna1 encodes voltage-gated Kv1.1 potassium channels that act to dampen neuronal excitability whereas Scn2a encodes voltage-gated Nav1.2 sodium channels important for action potential initiation and conduction. SUDEP-prone Kcna1-/- mice with partial genetic ablation of Nav1.2 channels (i.e. Scn2a+/-; Kcna1-/-) exhibited a two-fold increase in survival. Classical analysis of EEG and ECG recordings separately showed significantly decreased seizure durations in Scn2a+/-; Kcna1-/- mice compared with Kcna1-/- mice, without substantial modification of cardiac abnormalities. Novel analysis of the EEG and ECG together revealed a significant reduction in EEG-ECG association in Kcna1-/- mice compared with wild types, which was partially restored in Scn2a+/-; Kcna1-/- mice. The degree of EEG-ECG association was also proportional to the survival rate of mice across genotypes. These results show that Scn2a gene deletion acts as protective genetic modifier of SUDEP and suggest measures of brain-heart association as potential indices of SUDEP susceptibility.

Gradient Index Microlens Implanted in Prefrontal Cortex of Mouse Does Not Affect Behavioral Test Performance over Time.

Implanted gradient index lenses have extended the reach of standard multiphoton microscopy from the upper layers of the mouse cortex to the lower cortical layers and even subcortical regions. These lenses have the clarity to visualize dynamic activities, such as calcium transients, with subcellular and millisecond resolution and the stability to facilitate repeated imaging over weeks and months. In addition, behavioral tests can be used to correlate performance with observed changes in network function and structure that occur over time. Yet, this raises the questions, does an implanted microlens have an effect on behavioral tests, and if so, what is the extent of the effect? To answer these questions, we compared the performance of three groups of mice in three common behavioral tests. A gradient index lens was implanted in the prefrontal cortex of experimental mice. We compared their performance with mice that had either a cranial window or a sham surgery. Three presurgical and five postsurgical sets of behavioral tests were performed over seven weeks. Behavioral tests included rotarod, foot fault, and Morris water maze. No significant differences were found between the three groups, suggesting that microlens implantation did not affect performance. The results for the current study clear the way for combining behavioral studies with gradient index lens imaging in the prefrontal cortex, and potentially other regions of the mouse brain, to study structural, functional, and behavioral relationships in the brain.

Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines.

Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low-energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC(50) values of 0.396 microm and 0.143 microm, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.