Midterm outcomes and quality of life following percutaneous coronary intervention in nonagenarians

The midterm clinical and functional benefits of percutaneous coronary intervention in patients aged ≥90 years have not been clearly defined. From January 2005 to June 2009, 173 patients aged ≥90 years underwent diagnostic cardiac catheterization, of whom 90 underwent percutaneous coronary intervention. There were 45 men (50%) and 45 women (50%), with a mean age of 92 years (range 90 to 101). Of these, 24 patients (27%) presented with ST-segment elevation myocardial infarction, 31 (34%) with non-ST-segment elevation myocardial infarction, 28 (31%) with unstable angina pectoris, and 2 (2%) with stable angina pectoris; 5 patients (6%) were studied for preoperative risk assessment. A total of 127 lesions were successfully treated using 102 drug-eluting stents and 37 bare-metal stents, with a mean of 1.5 stents per patient. Postprocedural complications included renal insufficiency in 5 patients (5.6%), heart failure in 6 patients (6.7%), and cardiogenic shock in 2 patients (2.2%). Seventy-seven patients (85.6%) experienced no postprocedural complications. In-hospital mortality was 7.8%, and actuarial survival was 61.5 ± 5.2% at 24 months and 31.6 ± 6.1% at 48 months. The SF-36 Health Survey was administered at follow-up, and results demonstrated a quality of life similar to that of the general population corrected for age and gender. In conclusion, this study demonstrates that percutaneous coronary intervention in nonagenarians can be accomplished with low mortality and morbidity and excellent midterm results. Moreover, functional improvement in nonagenarians supports enhanced quality of life comparable to that of the general population.     

Graves' ophthalmopathy and gene polymorphisms in interleukin-1α, interleukin-1β, interleukin-1 receptor and interleukin-1 receptor antagonist

Purpose: Interleukin‐1 (IL‐1) is known to have an important role in pathogenesis of Graves' ophthalmopathy (GO). Polymorphisms in IL‐1 gene have been associated with autoimmune reactions. This study aimed to investigate the association of GO with single‐nucleotide polymorphisms (SNPs) in the IL‐1 family (IL‐1α, IL‐1β, IL‐1 receptor [IL‐1R] and IL‐1 receptor antagonist [IL‐1RA]). Methods: A total of 57 patients of Graves' disease without GO, 50 patients with GO and 140 healthy controls were enrolled. Patients were recruited consecutively from the outpatient endocrine clinic of a large university general hospital. Cytokine typing was performed by the polymerase chain reaction with sequence‐specific primers assay. The allele and genotype frequencies of the following polymorphisms were determined: IL‐1α (?889C/T), IL‐1β (?511C/T), IL‐1β (+3962C/T), IL‐1R (Pst‐1 1970C/T) and IL‐1RA (Mspa‐1 11100C/T). Genotype distributions among patients were in Hardy–Weinberg equilibrium for all polymorphisms. Results: Among the five SNPs studied, the frequencies of the T allele and the TT genotype of IL‐1α (?889C/T) were significantly higher among patients with GO than those without GO (odds ratio [OR] = 2.16, 95% confidence interval [CI] = 1.25–3.74; P = 0.006 and 5.67, 95% CI = 1.66–49.34; P = 0.005, respectively). For IL‐1RA (Mspa‐1 11100C/T), the frequencies of the C allele and the CC genotype were significantly higher among patients with GO (OR = 2.31, 95% CI = 1.34–4.00; P = 0.004 and 6.73 95% CI = 1.94–23.36; P = 0.004, respectively; P < 0.01). No significant association was found for other SNPs. Conclusion: This is the first study to show a positive correlation between polymorphisms in the IL‐1α and IL‐1RA genes and susceptibility to GO. These findings promote further research into genetic correlates of GO.     

Uterine contraction pattern as a predictor of the mode of delivery.

OBJECTIVE: To determine whether analysis of the frequency or regularity of uterine contractions can distinguish between women delivering vaginally and women requiring Cesarean section for dystocia. STUDY DESIGN: This was a case-control study. Cases meeting the following criteria were identified: nulliparous women in spontaneous labor, singleton pregnancy, cephalic presentation, 37 to 42 weeks' gestation, Cesarean section for dystocia, a minimum of three analyzable hours of electronically archived cardiotocograph (CTG) prior to onset of the second stage. Cases delivered by Cesarean section for dystocia were each matched with two controls delivering vaginally. The peak of each contraction was visually identified and electronically marked on each CTG trace. A moving average (MTIME) and standard deviation (SDTIME) of five interpeak times were calculated for successive 30-minute periods and plotted against cervical dilatation for each group. RESULTS: Overall, both MTIME and SDTIME fell as labor progressed, with these changes being more marked in the vaginal delivery group. In women requiring oxytocin, the rate of fall of MTIME and SDTIME was significantly greater following oxytocin in the group which subsequently delivered vaginally (slope of MTIME -2.71 pre-oxytocin and -28.95 post-oxytocin, p=0.0004; slope of SDTIME -0.44 and -6.44, p=0.0002). No such change was seen in the Cesarean section group. CONCLUSION: As normal labor progresses, there is a shortening of the intercontraction interval and an increase in contraction regularity. A successful response to oxytocin augmentation may be predicted by the change in contraction pattern following treatment.     

The promising role of monoclonal antibodies for immunotherapy of the HIV-associated cancer,non-Hodgkin lymphoma

Association between HIV/AIDS and some of the cancers such as lymphomais is well known. Relative risk for developing non-Hodgkin lymphoma (NHL) increases 60–200 folds in HIV-infected individuals. Diffuse large B cell lymphoma (DLBCL), primary effusion lymphoma (PEL), Burkitt's lymphoma (BL) and Plasmablastic Lymphoma (PBL) are among the most frequent subtypes. During the last century, scientists found that the immune system could potentially detect and destroy cancer cells. Therefore, they started a new field of study, which is named immunotherapy. There are different immunotherapeutic methods, among which therapeutic antibodies, such as Brentuximabvedotin (Adcetris), Ibritumomabtiuxetan (Zevalin) and rituximab (Rituxan), used for treatment of NHLs showed promising results. In this article, we will review the immunotherapeutic option, monoclonal antibodies, for treatment of HIV-associated NHLs as well as their recent clinical status. We will also discuss the selective monoclonal antibody for each subtype of NHLs.     

The Levels of Brachyspira hyodysenteriae Binding to Porcine Colonic Mucins Differ between Individuals,and Binding Is Increased to Mucins from Infected Pigs with De Novo MUC5AC Synthesis

Brachyspira hyodysenteriae colonizes the pig colon, resulting in mucohemorrhagic diarrhea and growth retardation. Fecal mucus is a characteristic feature of swine dysentery; therefore, we investigated how the mucin environment changes in the colon during infection with B. hyodysenteriae and how these changes affect this bacterium''s interaction with mucins. We isolated and characterized mucins, the main component of mucus, from the colon of experimentally inoculated and control pigs and investigated B. hyodysenteriae binding to these mucins. Fluorescence microscopy revealed a massive mucus induction and disorganized mucus structure in the colon of pigs with swine dysentery. Quantitative PCR (qPCR) and antibody detection demonstrated that the mucus composition of pigs with swine dysentery was characterized by de novo expression of MUC5AC and increased expression of MUC2 in the colon. Mucins from the colon of inoculated and control pigs were isolated by two steps of isopycnic density gradient centrifugation. The mucin densities of control and inoculated pigs were similar, whereas the mucin quantity was 5-fold higher during infection. The level of B. hyodysenteriae binding to mucins differed between pigs, and there was increased binding to soluble mucins isolated from pigs with swine dysentery. The ability of B. hyodysenteriae to bind, measured in relation to the total mucin contents of mucus in sick versus healthy pigs, increased 7-fold during infection. Together, the results indicate that B. hyodysenteriae binds to carbohydrate structures on the mucins as these differ between individuals. Furthermore, B. hyodysenteriae infection induces changes to the mucus niche which substantially increase the amount of B. hyodysenteriae binding sites in the mucus.     

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.     

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.)