Tag Archives: gdc-0980

Small or immature teratomas are

Small or immature teratomas are particularly hard to detect due to the lack of tissues with high secretion levels such as gland-like structures. In line with that, we found one teratoma in our test set for which none of the eight tested biomarkers was positive. Histological characterization showed that this particular teratoma had substantial necrosis in the core, did not contain any gland-like structures, and consisted primarily of undifferentiated cells. Immature teratoma will therefore limit the sensitivity of serum biomarkers for early teratoma detection unless a new sensitive biomarker for undifferentiated gdc-0980 can be found (Ahrlund-Richter and Hendrix, 2014). However, they are likely to be detectable by imaging as this immature teratoma was readily detectable via MRI. Furthermore, screening strategies for regenerative cell therapies should also be able to detect neoplastic growth that might be difficult to detect with serum biomarkers depending on the cell types that are growing. A combination of serum biomarkers and structural imaging should offer a high probability to detect neoplastic growth, as well as immature and mature teratomas. Although detection limits from small-animal studies are difficult to extrapolate to human scale, the larger plasma volume and lower imaging resolution of clinical MRI systems will decrease the sensitivity to detect teratoma. Assuming a similar growth rate for teratomas in humans and a linear decrease in detection sensitivity corresponding to increased plasma volume and decreased image resolution, blood sampling and imaging frequencies could be reduced for humans (Figure S6M). We observed a growth rate of 10 days for the doubling of teratoma volume, which is similar to high growth rates of 11–12 days that have been observed for some human teratomas (Selby et al., 1979). Even with such a high growth rate, it would take several months for a teratoma to reach detection limits in humans as the number of undifferentiated or de-differentiated cells transplanted is likely to be very small. These plasma collection and imaging frequencies would be similar to the sampling strategies employed in clinical trials to assess functional changes following cardiovascular interventions, which should simplify the adaption of such a monitoring strategy to detect neoplastic growth or teratomas.

Experimental Procedures
An expanded Experimental Procedures section is available in the online Supplemental Information.

Author Contributions

The clinical use of cardiac cells derived from embryonic and induced pluripotent stem cells (ESCs and iPSCs) is a promising and potentially patient-tailorable approach to address myocardial disease. ESCs and iPSCs have an unlimited capacity to self-renew and derive cardiovascular cells (Burridge et al., 2012; Zwi et al., 2009). However, guiding pluripotent stem cell differentiation into defined cardiac cell populations is still a major challenge. In contrast to undifferentiated ESCs that form tumors in vivo (Amariglio et al., 2009), cells directed toward the cardiac lineage in vitro can integrate and support heart function when delivered in vivo (Leor et al., 2007; Nsair et al., 2012). Culture protocols for deriving heterogeneous cell populations that resemble the fetal developmental stages of atrial and ventricular cardiomyocytes (CMs) from pluripotent stem cell sources use versatile biological, chemical, and/or physical factors, and to identify the cardiac differentiation states requires laborious analytical procedures based on intracellular markers (Mummery et al., 2012; Schenke-Layland et al., 2008). Patient-specific iPSC-derived CMs offer a new paradigm for disease-modeling-in-a-dish, as well as drug screening and discovery (Matsa et al., 2014); however, it will be imperative to monitor chamber specificity and maturity of the pluripotent cell-derived CMs in real time and preferably marker free. To date, the methods of choice to determine the developmental stage of differentiating pluripotent stem cell-derived CMs include invasive gene and protein expression profiling of harvested cells, or electrophysiological analyses via patch clamp technologies (Karakikes et al., 2014). Cardiac promoters were used to drive expression of the fluorescent reporter gene EGFP to allow identification and sorting of atrial- or ventricular-like CMs differentiated from pluripotent cell sources (Huber et al., 2007). However, such genetic manipulation for the purpose of cell purification is rather laborious, and most of all, it limits the clinical usability of the cells.

br Acknowledgments The support of

The support of Ferdowsi University of Mashhad – Iran (Research and Technology) for this work (code 3/38606, date 13/10/2015) is appreciated.

Textile industry wastewaters have large amounts of diverse dyes, which are generally bio-resistant and consequently conventional biological methods are not effective for their treatment [1]. Moreover, other physical and chemical processes such as coagulation and adsorption merely transfer pollutants to secondary phases, that require more remediation [2]. Hence, utilization of advanced oxidation processes (AOPs) are more appropriate not only to degrade, but also to mineralize various contaminants with no further waste [3]. Among AOPs, the Fenton and ultrasonic processes are easy and efficient treatment techniques that are widely used for the degradation of different contaminates in polluted water sources [4]. Hydroxyl radicals (OH) as a reactive oxygen species (ROS) have the substantial role in AOPs owing to unselective attack to organic pollutants and their degradation intermediates to convert them to harmless compounds like carbon dioxide, water and inorganic mineral salts [5]. They can be produced by the heterogeneous Fenton reaction (Eq. (1)) or from water cleavage under ultrasonic waves (Eq. (2)) via cavitation phenomenon [6].
After directing ultrasonic irradiation into a liquid phase, the cavitation results in generation, growth, and eventually collapse of microbubbles forming high localized pressures and temperatures based on hot spot approach [7]. However, ultrasonic process consumes more gdc-0980 and time in comparison of other methods in AOPs owing to its low degradation rate; thus it can be coupled with other processes such as Fenton process to enhance its performance for water treatment [8]. gdc-0980 Moreover, it should be mentioned that catalyst recycling and also its separation from the treated water restrict the application of homogeneous Fenton process, which can be carried out in acidic medium (pH 3) to prevent from the precipitation of iron. Besides, usage of heterogeneous Fenton process with no requirement for separation of catalyst, performing at milder pHs and low leached iron is another way to reduce these drawbacks [9].
Magnetite [10], goethite [11] and pyrite [12] are used as heterogeneous catalysts in Fenton process in which superficial Fe ions catalyze the generation of OH. The pyrite (FeS2) is the most plentiful and nontoxic metal sulfide in the earth [13]. The application of synthesized pyrite has been studied in water treatment processes including the Fenton and adsorption methods [14,15]. It should be noticed that the heterogeneous Fenton process has some confines compared to the homogeneous one like mass transfer resistance and limited active reaction sites. The effective solutions to overcome these obstacles are usage of nanostructured catalysts and sonication [16]. However, formation of nano-sized compounds by synthesis methods needs expensive and toxic reactants [17].
Plasma is an ionized gas composing of positive and negative ions, electrons and uncharged species, considered as forth state of matter. It is an environmentally-friendly way for formation of various nanostructures for different applications [18]; silent discharge, radio frequency and glow discharge techniques as non-thermal plasma method have been used for development of modified catalysts [19,20]. For instance, the surface area and activity of natural clinoptilolite and synthesized zeolites have been enhanced using plasma treatment [19]. The catalytic performance and stability of the Pd/HZSM-5 catalyst have been improved after plasma modification [21]. The hydrogenation selectivity of acetylene increases by using of the Ar, H2 and O2 atmosphere plasma for treated Pd/TiO2 catalyst [22]. Modified magnetite by oxygen and argon glow discharge plasmas was utilized for degradation of an oxazine dye through catalytic ozonation [23]. Hydrogenation of carbon monoxide has been carried out using plasma-treated Fe2O3/ZSM-5 catalyst with high activity and selectivity prepared by the oxygen and argon glow discharge plasmas [24].

We have developed two unique approaches in an

We have developed two unique approaches in an attempt to solve this issue: (i) reducing the size of our ultrasound contrast agents, and (ii) incorporating vaso-active gases inside our ELIP to facilitate the entry of ELIP into the arterial wall via the vasa vasorum. Unlike other ultrasound contrast agents that are homogeneous in size and distribution and tend to be greater than 3 μm, our ELIP formulations vary in size from <100 nm to several micrometers, with bimodal medians of ∼90 and 800 nm (Kopechek et al. 2011). Smaller sizes allow these contrast agents to penetrate all layers of the vascular bed, including the adventitia via the vasa vasorum. Nitric oxide (NO) is a potent bio-active gas with a wide range of vaso-active properties (Fischer et al. 2004). Although delivery of NO to the arterial wall has several potential benefits, successful NO delivery to targeted tissues is challenging because of the presence of endogenous NO scavengers such as hemoglobin (Tsao et al. 1994), as well as poor tissue retention. Our laboratory has developed techniques for encapsulating NO into our ELIP, thus preventing its sequestration by hemoglobin in the bloodstream (Huang et al. 2009). By encapsulating NO into ELIP, we have also observed retention of NO in cultured endothelial cells (Huang et al. 2009). In animal models, we found that locally released NO from NO-containing ELIP (NO-ELIP) can facilitate the penetration of ICAM-1 antibody-conjugated ELIP into all layers of the arterial wall and improve highlighting of the atheroma (Kee et al. 2014; Kim et al. 2013).

Figure 1 illustrates a representative artery with early/intermediate atheroma and late atheroma. Progression of atheroma development is clearly observed. In Figure 2 are representative VCAM-1-stained images of an uninjured control artery, an early/intermediate atherosclerotic artery and a late atherosclerotic artery. There was expression of VCAM-1 in the neointima and the arterial wall including the adventitia in both early/intermediate and late atheroma. Immunohistochemistry of the gdc-0980 pre-treated with or without NO-ELIP revealed no differences in VCAM staining between the subgroups at baseline.
For the early/intermediate atherosclerotic stage animals, there was little acoustic enhancement with IgG-ELIP treatment compared with baseline (p > 0.05) in both the gray-scale and radiofrequency (RF) data sets (Fig. 3). There was also no difference in highlighting among arteries treated with IgG-ELIP by pre-treatment type (i.e., standard ELIP plus ultrasound, NO-ELIP without ultrasound or NO-ELIP plus ultrasound, p > 0.05) (Figs. 3 and 4). All the subsequent data analyses with IgG-ELIP treatment groups were therefore compiled as one control group.
Anti-VCAM-1-ELIP treatment resulted in enhanced highlighting in atherosclerotic arteries on the IVUS image data compared with IgG-ELIP treatment regardless of the pre-treatment subgroup (p < 0.001) (Fig. 3). However, there was a difference in highlighting observed among the different pre-treatment subgroups with anti-VCAM-1-ELIP treatment. Pre-treatment with standard ELIP plus ultrasound or NO-ELIP without ultrasound caused comparable enhancement of highlighting (12.8 ± 2.1% vs. 13.5 ± 1.3% for gray-scale values, p > 0.05; 27.1 ± 3.2% vs. 32.6 ± 3.1% for RF data, p > 0.05) compared with baseline (p < 0.001 vs. IgG-ELIP) (Figs. 3 and 4). On the other hand, there was a significant increase in acoustic enhancement when arteries were pre-treated with both NO-ELIP and ultrasound activation (21.3 ± 1.5% for gray-scale value, 53.9 ± 3.1% for RF data; p < 0.001 vs. IgG-ELIP, and p < 0.05 vs. pre-treatment with standard ELIP plus ultrasound or NO-ELIP without ultrasound) (Figs. 3 and 4). For the late atherosclerotic animals, similar patterns of acoustic enhancement were observed compared with the early/intermediate atherosclerotic group. IgG-ELIP treatment caused little enhancement of highlighting regardless of pre-treatment type (Fig. 5). Similarly all subsequent data analyses with IgG-ELIP treatment groups for the late atherosclerotic animal model were compiled as one control group. Treatment with anti-VCAM-1-ELIP similarly resulted in enhanced highlighting of the arteries compared with IgG-ELIP treatment (p < 0.001 versus IgG-ELIP) (Fig. 5). However, we noted that the overall improvement in highlighting after anti-VCAM-1-ELIP treatment for the late atherosclerotic stage animals was less than that for the early/intermediate stage animals. For the groups pre-treated with standard ELIP plus ultrasound followed by anti-VCAM-1-ELIP, there was a 7.7 ± 0.8% increase in gray-scale values (vs. 12.8 ± 2.1% for the early/intermediate stage animals, p = 0.014); pre-treatment with NO-ELIP without ultrasound resulted in 10.7 ± 1.0% acoustic enhancement in gray-scale values (vs. 13.5 ± 1.3% for the early/intermediate stage animals, p > 0.05). These differences were further appreciated with RF data. There were increases of 12.1 ± 1.4% and 19.7 ± 1.8% in RF signal values for pre-treatment with standard ELIP plus ultrasound and NO-ELIP without ultrasound, respectively, compared with 27.1 ± 3.2% and 32.6 ± 3.1% in RF data (for the early/intermediate stage animals, p < 0.05 for both). gdc-0980 Similar to the early/intermediate stage animal model, pre-treatment with both NO-ELIP and ultrasound followed by anti-VCAM-1-ELIP resulted in a further increase in highlighting of atheroma (16.1 ± 1.1% and 36.4 ± 2.2%, in gray-scale and RF data respectively, p < 0.001 vs. IgG-ELIP, and p < 0.05 vs. pre-treatment with standard ELIP plus ultrasound or NO-ELIP without ultrasound) (Fig. 5). However, the overall improvement in highlighting after anti-VCAM-1-ELIP treatment with pre-treatment using both NO-ELIP and ultrasound was less in the late atherosclerotic model than i the early/intermediate stage animals (vs. 21.3 ± 1.5% for gray-scale value [p = 0.039] and 53.9 ± 3.1% for RF data [p < 0.01] in the early/intermediate stage animals).

In Hong Kong ketamine was first

In Hong Kong, ketamine was first seized in 1999 and has been on top of the list of commonly abused psychotropic substances since 2001. According to the Hong Kong Central Registry of Drug Abuse Sixty-third Report, which gathered information from various reporting agencies including local law enforcement departments, drug treatment and rehabilitation centers, counseling centers for psychotropic substance abusers, centers for drug counseling of nongovernment organizations, youth outreach teams of nongovernment organizations, and substance abuse clinics under the Hospital Authority, ketamine remained the most popular psychotropic substance being abused from 2004 to 2013, with a peak of > 5000 abusers in 2009 (Fig. 1). When stratified by age, the trend was also similar for young abusers under the age 21 years. The actual number of young ketamine abusers in recent years, however, was not decreasing as it gdc-0980 seemed to be, as more abusers are “hidden ketamine abusers”—51% of abusers younger than 21 years have admitted to have abused ketamine at home or at friend\’s home in 2013, which is a substantial increase from 13% in 2006.
Regarding the proportion of ketamine abusers presenting with lower urinary tract symptoms, a small scale survey conducted by a psychotropic substance rehabilitation center in Hong Kong reported that ∼30% of ketamine abusers had lower urinary tract symptoms.
As for Taiwan, according to the National Bureau of Controlled Drugs, the 2014 International Narcotics Central Report, and local Taiwan Bureau, ketamine abuse has been a growing problem in Taiwan since 2008 and remains to be a popular party drug among teenagers because of its low potential for addiction and absence of criminal penalties for possession of a small amount (< 20 g). China is the source of ∼76% of the ketamine seized or sold in Taiwan. According to China\'s National Narcotics Control Commission 2014 Annual Report on Drug Control in China, ketamine is the second most abused drug in China with seizures of 9.7 metric tons of ketamine in 2013, compared to 4.7 metric tons in 2012.
Management of ketamine uropathy in Hong Kong Chinese population

Understanding the pathophysiology of ketamine cystitis
The exact pathophysiology of ketamine uropathy is still unknown, despite the efforts gdc-0980 made in gathering clinical, biochemical, and histological evidences together with laboratory and animal studies. Our current knowledge is that ketamine or its metabolites, being primarily excreted in urine, induce an initial acute inflammatory reaction of the urothelium, which starts a chain reaction that eventually results in bladder damage, such as epithelium denudation, ulceration, submucosal inflammation, and fibrosis. A recent Taiwan study has revealed elevated serum immunoglobulin E levels in ketamine cystitis patients compared with interstitial cystitis patients, bacterial cystitis patients, and controls. This suggests that hypersensitivity may play an important role in the pathogenesis of ketamine uropathy.

Resources and direction on lowering the burden
In Hong Kong, since the publication of the first report of 10 patients with ketamine cystitis in 2007, the Government of the Hong Kong Special Administrative Region has provided tremendous financial support to antiketamine abuse research on clinical and basic laboratory science, projects on raising community and school awareness, and rehabilitation. Besides, enhanced law enforcement by the Hong Kong Judicial Bureau on drug trafficking of ketamine since 2008 had helped reduce ketamine supply in the territory (Table 1).
One of the clinical projects supported by the Beat Drugs Fund in Hong Kong is a prospective longitudinal study on the outcomes of various treatment modalities under a standardized protocol in patients suffering from ketamine-induced voiding dysfunction. This study concluded that both anti-inflammatory drugs and analgesics could effectively alleviate symptoms of ketamine cystitis. However, abstinence from ketamine usage and the amount of ketamine consumed remained two important factors determining the response to treatment as well as symptom relief.

The bilateral diaphragm is the most

The bilateral gdc-0980 is the most important respiratory muscle. Diaphragmatic dysfunction is an underappreciated cause of respiratory difficulties and may be due to a wide variety of issues, including surgery, trauma, tumor, and infection (1). Several previous studies have evaluated diaphragmatic motion using fluoroscopy 2; 3; 4 ;  5, ultrasound 6 ;  7, magnetic resonance (MR) fluoroscopy (dynamic MR imaging [MRI]) 8; 9; 10; 11 ;  12, and computed tomography (CT) 13; 14; 15 ;  16. However, the data of the previous studies using ultrasound, MR fluoroscopy, or CT were obtained in a supine position 6; 7; 8; 9; 10; 11; 12; 13; 14; 15 ;  16, not in a standing position. Also, while the data of the previous studies using fluoroscopy were obtained in a standing position, the data were assessed under forced breathing 2 ;  3, not under tidal or resting breathing. Thus, diaphragmatic motion in a standing position during tidal breathing remains unclear, even though it is essential for understanding respiratory physiology in our daily life. Furthermore, the evaluation of diaphragmatic motion using fluoroscopy, ultrasound, dynamic MRI, or CT has not been used as a routine examination because of limitations, including high radiation dose, small field of view, low temporal resolution, and/or high cost.

Recently, dynamic chest radiography using a flat panel detector (FPD) system with a large field of view was introduced for clinical use. This technique can provide sequential chest radiographs with high temporal resolution during respiration (17), and the radiation dose is much lower than that of CT. Also, whereas CT and MRI are performed in the supine or prone position, dynamic chest radiology can be performed in a standing or sitting position, which is physiologically relevant. To the best of our knowledge, no detailed study has analyzed diaphragmatic motion during tidal breathing by using dynamic chest radiography.

The purpose of this study was to evaluate diaphragmatic motion during tidal breathing in a standing position in a health screening center cohort using dynamic chest radiography in association with participants\’ demographic characteristics.

Materials and Methods

Study Population

This cross-sectional study was approved by the institutional review board, and all the participants provided written informed consent. From May 2013 to February 2014, consecutive 220 individuals who visited the health screening of our hospital and met the following inclusion criteria for the study were recruited: age greater than 20 years, scheduled for conventional chest radiography, and underwent pulmonary function test. Patients with any of the following criteria were excluded: pregnant (n  =  0), potentially pregnant or lactating (n  =  0), refused to provide informed consent (n  =  22), had incomplete datasets of dynamic chest radiography (n  =  3), had incomplete datasets of pulmonary function tests (n  =  1), could not follow tidal breathing instructions (eg, holding breath or taking a deep breath) (n  =  18), or their diaphragmatic motion could not be analyzed by the software described next (n  =  4). Thus, a total of 172 participants (103 men, 69 women; mean age 56.3 ± 9.8 years; age range 36–85 years) were finally included in the analysis ( Fig 1). The data from 47 participants of this study population were analyzed in a different study (under review). The heights and weights of the participants were measured, and the body mass index (BMI, weight in kilograms divided by height squared in meters) was calculated.

Figure 1. Flow diagram of the study population.Figure optionsDownload full-size imageDownload high-quality image (83 K)Download as PowerPoint slide