Temporal bone borehole accuracy for cochlear implantation influenced by drilling strategy: an in vitro study

Purpose

Minimally invasive cochlear implantation is a surgical technique which requires drilling a canal from the mastoid surface toward the basal turn of the cochlea. The choice of an appropriate drilling strategy is hypothesized to have significant influence on the achievable targeting accuracy. Therefore, a method is presented to analyze the contribution of the drilling process and drilling tool to the targeting error isolated from other error sources.

Methods

The experimental setup to evaluate the borehole accuracy comprises a drill handpiece attached to a linear slide as well as a highly accurate coordinate measuring machine (CMM). Based on the specific requirements of the minimally invasive cochlear access, three drilling strategies, mainly characterized by different drill tools, are derived. The strategies are evaluated by drilling into synthetic temporal bone substitutes containing air-filled cavities to simulate mastoid cells. Deviations from the desired drill trajectories are determined based on measurements using the CMM.

Results

Using the experimental setup, a total of 144 holes were drilled for accuracy evaluation. Errors resulting from the drilling process depend on the specific geometry of the tool as well as the angle at which the drill contacts the bone surface. Furthermore, there is a risk of the drill bit deflecting due to synthetic mastoid cells.

Conclusions

A single-flute gun drill combined with a pilot drill of the same diameter provided the best results for simulated minimally invasive cochlear implantation, based on an experimental method that may be used for testing further drilling process improvements.     

Shoulder muscle activation and coordination in patients with a massive rotator cuff tear: an electromyographic study

Adaptive muscle activation strategies following a massive rotator cuff tear (MRCT) are inadequately understood, and the relationship among muscles during everyday activities has not been considered. Thirteen healthy subjects comprised the control group, and 11 subjects with a MRCT the patient group. Upper limb function was assessed using the Functional Impairment test‐hand, neck, shoulder, and arm (FIT‐HaNSA). Electromyography (EMG) was recorded from 13 shoulder muscles, comprising five muscle groups, during a shelf‐lifting task. Mean FIT‐HaNSA scores were significantly lower in MRCT patients (p ≤ 0.001), reflecting a severe functional deficit. In MRCT patients, EMG signal amplitude was significantly higher for the biceps brachii‐brachioradialis (p < 0.001), upper trapezius‐serratus anterior (p = 0.025), muscle groups and for the latissimus dorsi (p = 0.010), and teres major (p = 0.007) muscles. No significant differences in the correlation among muscle groups were identified, pointing to an unchanged neuromuscular strategy following a tear. In MRCT patients, a reorganization of muscle activation strategy along the upper limb kinetic chain is aimed at reducing demand on the glenohumeral joint. Increased activation of the latissimus dorsi and teres major muscles is an attempt to compensate for the deficient rotator cuff. Re‐education towards an alternate neuromuscular control strategy appears necessary to restore function. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1140–1146, 2012     

The Epworth Sleepiness Scale: translation and validation study of the Iranian version

Purpose

The main purpose of this study was to assess the reliability and validity of the Iranian version of the Epworth Sleepiness Scale (ESS-IR).

Methods

This was a cross-sectional study of 507 suspicious patients either to obstructive sleep apnea (n?=?466) or narcolepsy (n?=?41) in order to carry out a psychometric evaluation of the ESS-IR by performing reliability, validity, and responsiveness analyses. Reliability of the ESS-IR was assessed by internal consistency and test–retest reliability. Validity of the instrument was assessed using several statistical approaches including construct validity (exploratory factor analysis), discriminant validity, and criterion validity. Responsiveness of the ESS-IR was assessed by comparing the ESS-IR total score before and after 6–9 months of continues positive airway pressure (CPAP) treatment in 16 patients with obstructive sleep apnea (OSA).

Results

The ESS-IR had an acceptable internal consistency and test–retest reliability. Factor analysis in both groups showed a two-factor solution for the ESS-IR, but the first factor showed statistically significant loads in all items. In addition, the ESS-IR discriminated well between patients with and without OSA. There is a fair correlation between the ESS-IR total score and multiple sleep latency test results that is not significant at all. Finally, the ESS-IR was found to be responsive to change where the total score was significantly decreased after CPAP treatment (P?<?0.001).

Conclusion

The findings suggest that the ESS-IR is a reliable and valid measure for evaluating daytime sleepiness and now can be used in research and clinical settings in Iran.     

Enhancing tumor cell response to chemotherapy through nanoparticle-mediated codelivery of siRNA and cisplatin prodrug

Cisplatin and other DNA-damaging chemotherapeutics are widely used to treat a broad spectrum of malignancies. However, their application is limited by both intrinsic and acquired chemoresistance. Most mutations that result from DNA damage are the consequence of error-prone translesion DNA synthesis, which could be responsible for the acquired resistance against DNA-damaging agents. Recent studies have shown that the suppression of crucial gene products (e.g., REV1, REV3L) involved in the error-prone translesion DNA synthesis pathway can sensitize intrinsically resistant tumors to chemotherapy and reduce the frequency of acquired drug resistance of relapsed tumors. In this context, combining conventional DNA-damaging chemotherapy with siRNA-based therapeutics represents a promising strategy for treating patients with malignancies. To this end, we developed a versatile nanoparticle (NP) platform to deliver a cisplatin prodrug and REV1/REV3L-specific siRNAs simultaneously to the same tumor cells. NPs are formulated through self-assembly of a biodegradable poly(lactide-coglycolide)-b-poly(ethylene glycol) diblock copolymer and a self-synthesized cationic lipid. We demonstrated the potency of the siRNA-containing NPs to knock down target genes efficiently both in vitro and in vivo. The therapeutic efficacy of NPs containing both cisplatin prodrug and REV1/REV3L-specific siRNAs was further investigated in vitro and in vivo. Quantitative real-time PCR results showed that the NPs exhibited a significant and sustained suppression of both genes in tumors for up to 3 d after a single dose. Administering these NPs revealed a synergistic effect on tumor inhibition in a human Lymph Node Carcinoma of the Prostate xenograft mouse model that was strikingly more effective than platinum monotherapy.Advances in genomics and cell biology have highlighted the heterogeneity and complexity of cancer. It is generally accepted that cancer is usually the result of a combination of interconnected disease pathways that may not be treated effectively with 1D therapeutic mechanisms (1). The inhibition of a pathway by a single-drug therapy often results in the emergence of drug resistance and tumor relapse, largely because of pathway redundancy, cross-talk, compensatory and neutralizing actions, and antitarget activities that commonly occur with single-drug cancer therapy (2). In some cases, relapse can result in the emergence of phenotypically distinct and possibly more virulent tumors. For example, treatment of prostatic adenocarcinoma with androgen ablation therapies, such as abiraterone or enzalutamide, results in the development of abiraterone or enzalutamide refractory castration-resistant prostate cancer that is phenotypically nonadenocarcinoma and represents a rare and often lethal form of prostate cancer with a neuroendocrine phenotype (3).Platinum agents are among the most widely used cytotoxic agents for cancer therapy. Cisplatin and other DNA adduct-forming chemotherapeutics cause DNA damage as their primary mechanism of cellular cytotoxicity. However, several cellular pathways are activated in response to their interaction with DNA, which include DNA repair pathways that remove the damage and translesion DNA synthesis (TLS) by specialized DNA polymerases that helps the cells tolerate the DNA damage (4, 5). The Rev1/Rev3L/Rev7-dependent error-prone TLS pathway has been shown to play an important role in cisplatin-induced mutations that improve the capacity of tumor cells to either repair or tolerate DNA damage, resulting in acquired chemoresistance (6). Rev1 is a translesion DNA polymerase, while Rev3 is the catalytic subunit of the translesion DNA polymerase Polζ (Rev3L/Rev7). Recent studies using mouse lymphoma and lung cancer models have shown that the suppression of error-prone TLS activity in mammalian cells by knocking down Rev1 or Rev3L can inhibit drug-induced mutagenesis so that relapsed tumors remain sensitive to subsequent treatment (6, 7). It has been suggested that combining conventional chemotherapy with newly emerging siRNA therapeutics could be a promising strategy for improving the efficacy of chemotherapy through additive or synergistic effects (8).Since the discovery of RNAi, synthetic siRNA has emerged as a class of attractive therapeutics for treatment of various diseases, including cancer (9, 10). Given the ability to target and silence nearly any gene of interest, specific siRNA can be constructed to target genes encoding proteins involved in DNA repair and the acquisition of multidrug resistance (6, 11). Naked siRNA cannot readily cross cellular membranes due to its polyanionic and macromolecular characteristics, and it is susceptible to degradation by endogenous enzymes (12). Therefore, considerable efforts have been made to develop safe and effective vehicles to facilitate the delivery of siRNA into cells (13–15). Similarly, the methods by which chemotherapeutics are delivered also have a significant effect on the efficacy (16, 17). Recent research has begun to explore the feasibility of combining chemotherapeutics with siRNA using a variety of nanocarrier platforms (18, 19). One of the earliest efforts using this therapeutic paradigm involved cancer treatment by targeted minicells containing specific siRNA followed by drug-loaded minicells, which efficiently reversed drug resistance in drug-resistant tumors and produced enhanced therapeutic efficacy in inhibiting tumor growth (20). However, to exert optimal synergistic effects, both the drug and siRNA may need to be temporally colocalized in the tumor cells. As a result, nanocarrier platforms that are capable of simultaneously delivering siRNA and anticancer drugs to the same tumor cells are emerging as a promising nanomedicine approach for improved cancer therapy (21, 22).Nanoparticles (NPs) self-assembled from biodegradable PLGA-PEG block copolymers represent a promising class of potential delivery vehicles due to several unique properties: PLGA-PEG copolymers (i) are biocompatible and biodegradable and used in many U.S. Food and Drug Administration-approved products, (ii) are capable of encapsulating small- and macromolecular payloads with a wide range of physiochemical properties, and (iii) can be designed for controlled release through a combination of polymer degradation and drug diffusion (23). Recently, a docetaxel-containing formulation termed BIND-014 (BIND Biosciences), which has been selected from an NP library composed of poly(d,l-lactide), PLGA, and PEG, is currently in phase I clinical trials (24). Another NP system based on PLGA-PEG has been developed by Kolishetti et al. (25) for codelivery of cisplatin and docetaxel, two drugs with different characteristics and metabolic targets, to prostate cancer cells. However, there remains a pressing need to engineer nanocarriers that are capable of delivering combination therapeutics involving siRNA because systemic delivery of siRNA still remains challenging. Herein, we describe an integrated nanodelivery system capable of simultaneously delivering cisplatin prodrug and siRNAs against REV1 and REV3L to enhance chemosensitivity of tumors. PLGA-PEG was formulated with a cationic lipid-like molecule designated as G0-C14 into NPs that comprise three components: an aqueous inner core, a cationic and hydrophobic layer composed of PLGA and G0-C14, and a hydrophilic PEG corona (Fig. 1A). The G0-C14 compound is synthesized with cationic head groups that can efficiently bind siRNA via electrostatic interactions and flexible hydrophobic tails for self-assembly with PLGA-PEG to form Pt(IV)-prodrug encapsulating NPs (Fig. 1A). In this study, we applied a Pt(IV)-prodrug approach previously used in our laboratory to deliver cisplatin (26). In this approach, a unique Pt(IV) precursor compound, c,c,t [Pt(NH₃)₂Cl₂(O₂C(CH₂)₈CH₃)₂] (compound 1; Fig. 1B), was developed to allow the release of cisplatin at a lethal dose upon intracellular reduction. The linear decanoyl chains in compound 1 also enable efficient encapsulation within the hydrophobic layer of NPs and controlled release without compromising either feature (26). We investigated the ability of these polymer/lipid hybrid NPs to down-regulate the expression of target genes as well as to induce diminished resistance and enhanced therapeutic profile both in vitro and in vivo. Using a human Lymph Node Carcinoma of the Prostate (LNCaP) xenograft mouse model of prostate cancer, we further demonstrated that these hybrid NPs containing Pt(IV)-prodrug and REV1/REV3L-specific siRNAs (siREV1, siREV3L) cooperatively suppress tumor growth through synergistic effects.Open in a separate windowFig. 1.(A) Chemical structure of PLGA-PEG/G0-C14 NPs. The particle consists of three components: (i) an outer PEG surface, (ii) a PLGA/G0-C14 layer that plays two roles: (a) acting as a polymer matrix loaded with nonpolar drugs and (b) protecting and promoting siRNA molecule retention inside the NP core and controlling drug release, and (iii) an aqueous inner core containing siRNA. (B) Chemical structure of the hydrophobic platinum(IV) compound 1 and the chemistry by which the active drug cisplatin is released after reduction in the cell. (C) Synthesis of G0-C14 through ring opening of 1,2-epoxytetradecane by ethylenediamine core-PAMAM generation 0 dendrimer. (D) Size distribution of the NPs containing both compound 1 and siRNA determined by dynamic light scattering. (E) Representative transmission EM image of the NPs. (Scale bar, 200 nm.)     

Amlodipine: Can act as an antioxidant in patients with transfusion‐dependent β‐thalassemia? A double‐blind,controlled, crossover trial

Background and AimThis study aimed to assess the antioxidant effects of amlodipine in transfusion‐dependent β‐thalassemia (TDT) patients.MethodsThis crossover trial consisted of two sequences (AP and PA). In the AP sequence, nine cases received amlodipine 5 mg daily (phase I) and then were switched to placebo (phase II). In PA sequence, 10 patients took the placebo (phase I) and were shifted to amlodipine (phase II). The washout period was 2 weeks. The length of each phase was 6 months. Serum malondialdehyde (MDA, μmol/L), carbonyl (protein CO, μM/L), glutathione (GSH, nM/L), and total antioxidant capacity (TAC, μmol FeSO4/L) were measured in the beginning and at the end of phases I and II. The clinical significance was viewed as a minimum change difference of 5% for each outcome between amlodipine and placebo.ResultsSeventeen cases completed the study. According to the baseline MDA values, the adjusted Hedges''s g for MDA was −0.59, 95% confidence interval [CI] −1.26 to 0.08. After controlling the baseline protein CO values, Hedges''s g computed for protein CO was −0.11, 95% CI −0.76 to 0.55. The estimated values of the adjusted Hedges''s g for GSH and TAC were also 0.26, 95% CI −0.40 to 0.91, and 0.42, 95% CI −0.24 to 1.09, respectively. The change difference for MDA was 8.3% (protein CO 2.2%, GSH 3.1%, and TAC 12.9%).ConclusionClinically, amlodipine therapy is an efficacious adjuvant treatment with conventional iron chelators for improving the levels of MDA and TAC in patients with TDT.