Monthly Archives: November 2017

br Conclusions br Acknowledgments br Introduction Malignancies

Conclusions

Acknowledgments

Introduction
Malignancies of the kidney and renal pelvis account for 3% to 5% of all solid adult cancers [1]. Despite the widespread use of abdominal cross-sectional imaging, which has led to a stage buy LY 2109761 with earlier diagnosis of renal tumors, 25% to 30% of patients with renal cell carcinoma (RCC) present with metastatic disease [2–4], and 10% of patients have tumor invasion into the inferior vena cava (IVC) at diagnosis [5–8]. Less than 1% of patients have tumor thrombus extension above the level of the hepatic veins (level III and level IV) [9,10]. Surgical extirpation remains the cornerstone of therapy for patients with RCC who have advanced IVC tumor thrombus extension [11–14]. Even with advanced multidisciplinary management, major complications occur in one-third of patients [15,16]. Surgical management is associated with a 5-year survival rate of 50% in patients with nonmetastatic disease in contemporary series [17–19].
The strongest predictors of long-term survival in patients with high-level tumor thrombi include the presence of distant metastases, regional nodal metastases, and tumor pathologic characteristics including grade and necrosis [17–23]. Patients with level IV thrombus have buy LY 2109761 a greater incidence of postoperative complications when compared with those with level III thrombus; however, tumor thrombus height (level III vs. level IV) has not been shown to be an independent predictor of long-term oncologic outcomes [15,17]. Although pathologic features are the strongest predictors of long-term outcomes, these factors cannot be included in preoperative prognostic models owing to the infrequency of preoperative tissue diagnosis by biopsy in patients with RCC planned for nephrectomy and caval thrombectomy. Martinez-Salamanca et al. [24] reported a postoperative nomogram including pathologic variables for patients with all level thrombi (levels I–IV). Similarly, Nakayama et al. [25] reported on a preoperative prognostic model for patients with RCC who have venous thrombus; however, the study was small and included patients with less-advanced thrombi (levels 0–II). There are currently no preoperative clinical tools to guide patient selection and counseling for surgical therapy specifically in the setting of RCC with suprahepatic tumor thrombus (levels III–IV). Thus, our aim was to develop multivariable models and prognostic nomograms for prediction of survival and major postsurgical complications based on readily available preoperative variables in patients with RCC who have advanced (levels III–IV) tumor thrombus. In addition to providing individualized risk assessment, these models could have utility in the design of future clinical trials of targeted therapies in this setting.

Materials and methods
Institutional review board approval was obtained at all centers. We retrospectively identified all patients (n = 166) treated with nephrectomy and caval thrombectomy for RCC with level III or level IV IVC tumor thrombus between January 1, 2000, and June 30, 2013, at 4 tertiary centers. A total of 34 patients with incomplete data for analysis were excluded. The centers involved were Mayo Clinic Rochester (44 patients), the University of Texas MD Anderson Cancer Center in Houston (44 patients), the University of Texas Southwestern Medical Center at Dallas (25 patients), and the University of Wisconsin Hospital (19 patients). Tumor thrombus level was determined from transesophageal echocardiography or preoperative magnetic resonance imaging. Level III thrombus was defined as thrombus above the hepatic veins but below the diaphragm, and level IV thrombus was defined as thrombus extending above the diaphragm [9,10]. Management including the use of preoperative targeted therapy, preoperative angioembolization, lymphadenectomy, and cardiopulmonary bypass was at the discretion of the surgical team. Follow-up was not standardized but commonly included physical examination, complete serum biochemistry, and computerized tomography or ultrasound every 3 months in the first year and semiannually thereafter.

In many cases somatic mutations

In many cases, somatic mutations are present in clonally expanded cell populations in nonmalignant tissues, detectable at tissue-level resolution. It is reported that current and former smokers had more molecular changes in DNA in the lung compared with nonsmokers [14]. Therefore, we thought that nonmalignant prostate glands may also show mutations or molecular changes in carcinogenic genes owing to smoking. So, we aimed to find out alterations in some of the tumor suppressor genes, and DNA repair genes associated with cigarette smoking in benign glands of the prostate. For this purpose, PTEN, RB, p16INK4a, p53, E-cadherin, CHK2, and MSH2 gene expressions were investigated with immunohistochemical staining.

Materials and methods

Results
Information such as age, serum PSA levels, inflammation on histologic sections, and smoking history are shown in Table 1. There were no statistically significant differences between the nonsmokers and smokers for inflammation (all CIS and single CIS), serum PSA levels, and age (P = 0.74 and 0.69, P = 0.25, and P = 0.68, respectively).

Discussion
Smoking can cause alterations in some genes associated with cancer. In this way, the carcinogenetic process can begin. Tumor suppressor genes are extremely important in the initiation and progression of prostate cancer. Among them, PTEN has become important due to the growing evidence of its role in the pathogenesis of prostate carcinoma. According to a study, combined gnrh agonist of PTEN and p53 in prostate was synergistic causing much more aggressive tumors that arose with decreased latency. Moreover, some authors suggested that the PTEN gene may be involved in the etiology of smoking initiation [8,16,17].
Regulation of cell proliferation is controlled by gradual activation of cyclins and cyclin-dependent kinases. One of the cyclin-dependent kinase inhibitor genes is the p16INK4a. The functional disorder or inactivation of it can lead to the loss of control on cell mitosis [5]. P16INK4a inactivation occurs in many malignancies with long-term exposure to carcinogens [18]. Bhatia et al. [19] showed that suppression of p16INK4a significantly extends normal human prostate epithelial cells lifespan. In the study of Fan et al. [20], p16INK4a expression was low in prostate carcinoma compared with normal prostatic epithelial cells.
P53 mutations appear to be more common in high-grade, metastatic, androgen-independent human prostate carcinoma [21]. Hu and Chen [22] observed that cigarette smoking induces a characteristic gene expression profile involved in cell cycle control and p53 response cascade. In a study, irritation of cytotoxic drugs caused a marked increase in p53 in ex vivo cultures of human prostate tissue [23]. In the present study, expression of p53 was higher in smokers. The primary antibody of p53, which was used in our study detects mutant and wild types of p53. The toxic contents of smoke can mutate p53 gene, and inactivated mutant p53 may accumulate in the cell nucleus. We might have detected this accumulation. In addition, circulating smoke contents can damage the DNA. As an answer to this damage, accumulation of p53 might have occurred for providing DNA repair.
In multivariate analysis, smoking was the main independent factor that had an effect on the immunohistochemical expressions for p53, p16, and PTEN. There were no statistically significant effects for age and inflammation. Age-dependent changes in expression of some genes that are associated with carcinogenesis have been reported in the literature [24]. In addition, there are increasing epidemiological and biological evidence that suggests the role of inflammation in prostate carcinogenesis [25]. It could be expected that there might have been age and inflammation-related changes in the present study. However, no difference was present between smokers and nonsmokers for age and inflammation. This situation might be attributed to the similarity between 2 groups for age and inflammation.

Correspondingly the landscape preferences also

Correspondingly, the landscape preferences also vary with the type and level of nature in a place (Ode et al., 2009). As shown by Simonič (2003) in a study on visual landscape perception, differences in preference not only arise between those general landscape categories (urban vs. nature), but also within the more specific naturalistic landscape type (e.g. picturesque, wild garden, parkland abstract, biotope, etc.). Han (2010) also shows that scenic beauty and preference versus restoration could be distinguished from each other with respect to the types of natural landscapes and the three physical features—complexity, openness, and water features.
Since individuals elaborate information received from their surrounding environment and further response to that information by applying adaption processes accordingly (such as by altering their experiential connection to the nature), the benefits or impacts generated by physical environments on that individuals will also vary. In other words, people\’s wellbeing gained through natural experience may vary in association with the level of nature in a place, as a result of the change in the subtle human–nature interaction in respond to their different preferences with the degree of naturalness. As shown by MacKerron and Mourato (2013) in a study on exploring the relationship between subjective wellbeing (SWB) and exposure to green or natural environments in daily life, the study participants are found to be significantly and substantially happier outdoors in all green or natural habitat types (i.e. marine and coastal margins; freshwater, wetlands and flood plains; mountains, moors and heathland; semi-natural grasslands; enclosed farmland; woodland) than they AP20187 are in urban environments. In their study on investigating the association between environmental parameters and the perceiving AP20187 levels of restorativeness during visits to coastal parks, Hipp and Ogunseitan (2011) found that perceived restorativeness is significantly constrained during high tides, a proxy for sea living rise and beach crowding. Other studies, such as Kjellgren and Buhrkall (2010), and Martens et al. (2011) also pointed out that perceived wellbeing varies with different natural conditions.
Given that naturalness is a powerful factor in preference (Kaplan et al., 1972; Purcell and Lamb, 1984; Lamb and Purcell, 1990; Junker and Buchecker, 2008; Ode et al., 2009; Zheng et al., 2011), and the perceived naturalness is an important dimension of environmental experience (Neff et al., 2000; Williams, 2002; Gobster and Westphal, 2004), studies that strive to explore the relationship between the degree of naturalness and its associated effects on human wellbeing are worth to be conducted. More importantly, Noautonomous controlling elements is of meaningful to understand how such relationship formed within a rapidly urbanized city, where urban natures are relatively more susceptible to the physical and economic changes brought by the ever growing development pressure. Apart from that, a deeper understanding of the different meanings of urban natures will provide a tool to match the urban natural resource management and conservation, as well as promising the ongoing survival of these urban natures for the sake of urban dwellers’ wellbeing.

Methodology

Results and discussions

Conclusion
Past researches have reported positive correlation between environmental preferences and perceived naturalness (Fenton, 1985), and the natural environments have been shown to have significant benefits for human wellbeing (Ulrich, 1984; Kaplan, 1995). Even a positive relationship is observed between natural settings and the likelihood of people undertaking outdoor activities (or recreation) (Neff et al., 2000). By applying a combination of research techniques and analysis, the present study successfully gives an observational support to the potential relation that links together naturalness, experiential connection to nature, and human wellbeing; where naturalness is an important dimension of environmental experience that may benefit to the human wellbeing (in terms of physical, mental, and social) through influencing the human–nature interaction. The findings show that a more ‘natural’ forest tends to serve the public in a more diverse way than the less ‘natural’ forest. A more ‘human-controlled’ forest, on the other hand, tends to serve the public in a more specific way due to the instalment of certain facility which aims to facilitate the forest users for conducting certain activity. Although only three forests were studied and may not be representative to the whole local community, the results were quite informative and inspiring, particularly with regard to people\’s perception on their relationship with the natural environment. It was found that local people tends to assess a forest\’s naturalness through certain forest setting attributes, such as greenery, coherence, wildness, and diversity. Most often, theories on human–nature interaction were initiated and based on the developed countries context, which may not be applicable to a developing country like Malaysia. Thus, insights drawn from this study associated with the local views on nature can be a useful contribution in studying the human–nature interaction.

Our respondents reported that forests are the

Our respondents reported that forests are the most preferred space at the nature end of the continuum, they are very common where people live, and provide many opportunities for free unstructured play. Few studies have been carried out on the forest and nature preferences of children in the Fennoscandian countries (Gundersen and Frivold, 2008), however, the few available studies show that children appreciate wild, dense, and hidden forest more than cultivated and open forest (Grahn, 1991; Rydberg, 1998). Children prefer, to a large extent, to play in nature-like spaces or spaces including natural elements, because it offers a androgen receptor of opportunities for play, activities and for exploration (Fjørtoft, 2001; Zamani, 2016), and place preference studies have shown that children often prefer the freedom of forest spaces without the control of their parents (cf. Moore, 1986; Korpela, 1992; Korpela et al., 2002). There are strong indications that the best nature play environments are minimally designed and maintained, and include loose materials that children can manipulate and use to construct their own environments (Fjørtoft, 2001; Zamani, 2016). For example boreal forests with a high degree of naturalness, including a high diversity of different structural elements (dead wood, old trees, mixed trees etc.) and spatial diversity (gaps, multilayered etc.), may fit with children’s landscape preferences and give many opportunities for play (e.g. Grahn et al., 1997; Rydberg and Falck, 2000). Forests can provide more unstructured environments that provide places where children can alter and manipulate the landscape themselves. These factors should be crucial for the management of nearby nature for children in order to provide an environment that offers a spectrum of play opportunities.
Our data shows that most Norwegian children play in nature once or several times during a year, with or without the supervision of adults. Nature visits may be especially important experiences for those children that rarely access nature. As a contribution to the debate over concerns about children’s reduced nature contact, one should perhaps be more focused on what kind of experiences these sporadic nature visits offer, compared to for example competitive indoor activities at school or home. An important quality of nature experience is that it provides a contrast to common everyday situations for children including time constraints, tasks, organization and adult presence (Burdette and Whitaker, 2005; Skår et al., 2016). Following Øksnes (2010) we should be more aware of the qualities of child\’s play; as it self-directed and spontaneous, and not controlled, disciplined and moderated by adults. If this is acknowledged then it becomes the adult’s task to ensure that such nature play is possible for their children during the few times they access nature. Nature offers unique experiences for children and these especially occur when children have the opportunity to make places their own, through observing and experiencing them without the direction of adults (Burdette and Whitaker, 2005; Stordal et al., 2015; Skar et al., 2016).
Respondents reported that children spent most time in nature during school hours, during weekends and holidays, in their own garden and at the ‘cabin’. School hours were evaluated by the parents to by an important situation for being in nature during scheduled time, and often the trip to school meant children passed through nature areas. As children spend more time in institutions such as schools and in day-care centers, and under adult supervision, this may, for many children, be the only option they have for free unstructured play in nature. For example, regular forest visits have been implemented in some schools in Britain over the past few years through the Forest School approach, and this has shown positive impacts on children in terms of confidence, social skills, language and communication, motivation and concentration, physical skills and knowledge and understanding (O‘Brien and Murray, 2007). The ability to androgen receptor preplan and locate nature play areas where children spend much of their time, at school and in after school care, can create opportunities for children on a regular rather than an occasional basis (Jansson et al., 2014; Mårtensson et al., 2014).

br Discussion By coupling the data inventory resources

Discussion
By coupling the data inventory resources of the City of Cambridge with the efforts of citizen scientists, we have demonstrated that the survival rate of trees in the City of Cambridge is relatively high compared to other reported values (Lawrence et al., 2012; Nowak et al., 2004; Roman and Scatena, 2011). The carbon sequestration estimates calculated using our empirical sequential tree diameter measurements were often lower than the estimates using i-Tree Streets or the Urban Tree Database (UTD) equations, suggesting that the trees we measured grow more slowly than predicted by the other models. Adding additional flexibility into widely used model structures to allow for additional inputs, such as empirically growth rate calculations, could enable more accurate estimates of glut 1 service provisions at the local scale. Although these types of data are not always available, changing the model structure to allow for these types of input (when they are available) could be a useful next step.
Our growth rate estimates were generally lower than the estimates for the Northeast climate zone in i-Tree Streets or the UTD models (McPherson et al., 2016, 2007), as well as the estimates based on empirical data from Bolzano, Italy (Russo et al., 2014), which has a similar climate to our study site. However, our estimates were higher than those of forest trees in the Northeast US (Teck and Hilt, 1991). Because tree growth is influenced not only by climate, but also by site conditions, planting conditions and management strategies, growth rate differences within and among locales are to be expected (McPherson and Peper, 2012).
In our study, growth rates varied by species and tree diameter. Similarly, Lawrence et al. (2012) found that the average mean annual growth increments for trees in Florida increased with DBH for some species and decreased for others (Lawrence et al., 2012). In many temperate forests, individual tree diameter growth tends to follow a sigmoidal pattern over time, such that large, old trees have smaller annual diameter increments than younger trees (Uzoh and Oliver, 2008). These patterns are generated by the increased growth rate allowed through increasing leaf area, which is eventually offset by competition from neighbors (Bebber et al., 2004), increased allocation to reproduction (Thomas, 2011), or the effects of increasing size on water transport (Mencuccini et al., 2005). In an urban setting, aboveground neighborhood competition is unlikely to be an issue (McHale et al., 2009), but we speculate that growth rates could be limited by below-ground factors in the built environment, such as the constriction of root growth, or reduced water availability or oxygen supply (Close et al., 1996).
Although other studies have found higher urban tree survival and growth rates in open areas such as lawns or parks (Iakovoglou et al., 2001; Lawrence et al., 2012; Lu et al., 2010; Quigley, 2004), the amount of permeable surface surrounding tree boles did not influence survival or growth rates in our study. This may result from the limited variation in permeable surface among the trees in our sample, as our dataset was limited to street trees for which over half of the area within a 10m radius of each tree was impervious surface.
Furthermore, light availability did not appear to be a limiting factor for tree survival or growth in our study. Although few studies have investigated the role of the urban light environment in tree growth, Lawrence et al. (2012) found that the growth of certain species increased with tree crown exposure in Florida. In i-Tree Eco, standardized annual growth rate estimates for urban trees are almost twice as large as those of park and forest trees (Nowak et al., 2013), suggesting that light and belowground resources are not often limiting factors in urban settings. Although in some cases very open conditions may create adverse microclimates with increased temperatures and vapor pressure deficits, which may reduce growth rates (Close et al., 1996), we did not observe this effect in our study.

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).
Methods

Results
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).

vascular disrupting agent br Conclusions This study provided the proof of concept

Conclusions
This study provided the proof-of-concept for a combined HIFU and LHM catheter and illustrated the feasibility of its use in vivo for controlled cardiac ablation. It has been found that this catheter-sized device can be made small enough to enter the vasculature and detect induced displacements. More importantly, this device can detect a change in displacements corresponding to a change in tissue properties through the formation of a lesion (thermal coagulation). During ex vivo and in vivo experiments, displacements were estimated and a decrease in the amplitudes of those displacements indicated tissue coagulation. More experiments need to be conducted to enable use of such a device in the clinic; these should cover the formation of larger lesions, a therapy controller that will enable automatic detection of a lesion through an online surgical platform and increased robustness of lesion localization. This study found that a LHM catheter device has the potential to both produce and detect lesions, and provides an ultrasound-based system for cardiac ablation treatment and treatment monitoring.

Acknowledgments

Introduction
Osteoarthritis (OA), the most common of all arthritides, is a heterogeneous disease characterized by synovial joint failure (Hunter et al. 2014). Recent estimates suggest that vascular disrupting agent of the knee affects approximately 250 million people globally (Murray et al. 2013). Although the precise pathologic mechanisms responsible for OA remain unclear, improper functioning of chondrocytes is believed to be pivotal in the pathology of OA via the induction of an imbalance of extracellular matrix (ECM) anabolism and catabolism (Park et al. 2005). Pro-inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO) are believed to alter the balance of ECM degradation and repair (Sellam and Berenbaum 2010). Nitric oxide and prostaglandins often are simultaneously increased in synovial fluid from arthritic patients (Sellam and Berenbaum 2010). PGE2 and NO may influence the synthesis of one another, thereby modulating cellular responses. PGE2 decreases proteoglycans (PG) synthesis and enhances the degradation of both aggrecan and type II collagen (COL II; Attur et al. 2008). Nitric oxide has been proposed as a contributor to the OA pathologic process by (i) inducing synthesis of matrix metalloproteases (Murrell et al. 1995) and depolymerizing hyaluronan (Stefanovic-Racic et al. 1993), (ii) inhibiting PG and collagen synthesis (Lotz 1999) and (iii) inhibiting chondrocyte proliferation and inducing chondrocyte apoptosis (Blanco et al. 1995; Lotz 1999).
Although various management techniques are available for the treatment of OA, there are presently no therapies that modify the onset or progression of OA-induced structural damage (Matthews and Hunter 2011; Zhang et al. 2010). Ultrasound (US) treatment has been used as a non-invasive modality for management of OA over the past 60 y because it relieves pain through thermal and non-thermal modalities (mechanical effects; Ter Haar 1999). Traditional unfocused US technology is beneficial with regard to cartilage metabolism. In basic science studies, US stimulation of cartilage increased expression of COL II or PG (Tien et al. 2008), promoted cartilage healing, induced chondrocyte proliferation (Cook et al. 2001; Wiltink et al. 1995; Korstjens et al. 2008) and enhanced chondrocyte differentiation (Ebisawa et al. 2004). However, unfocused US did not alter apoptosis (Zeng et al. 2012), and a recent study confirmed that stimulation of COL II and PG synthesis by US was not due to increased chondrocyte proliferation (Tien et al. 2008). To date, how US modifies expression of COL II and PG in OA cartilage has not been concluded.
To study these events, appropriate US selection is paramount. Although pressure waves propagated by US transfer mechanical energy into tissue (Gleizal et al. 2006; Reher et al. 1997), energy from unfocused US can diffuse and destroy adjacent structures (Jung et al. 2015). Previous work suggests that focused low-intensity pulsed ultrasound (FLIPUS) improves re-ossification by enhancing cell proliferation in calvarial defect sites in rats (Jung et al. 2015). However, few applications of FLIPUS have been published that describe healing cartilage.

Figure a is a typical ultrasound display during breast

Figure 1a is a typical ultrasound display during breast examination; it TAPI-1 consists of an ultrasound image and the corresponding image annotation. The annotation is used to register the image location with respect to the breast (American College of Radiology [ACR] 2011). Because the follow-up diagnosis, evaluation and treatment are performed on the basis of the stored annotation, it is crucial that the annotations be accurate and complete. The stored annotation is also very important for surgery. For women with large tumors, such as a malignant lesion located across different quadrants, mastectomy is usually recommended (American Cancer Society [ACS] 2014). As illustrated in Figure 1a, there are two parts to the annotation, a graphic pictogram and a textual sequence. In the graphic pictogram, the circle represents the breast region. The irregular part next to the circle represents the arm, which is used to indicate the laterality (left or right) of the breast. The arrow is the probe icon, which represents the probe location. The arrow direction is the probe direction, and the movable arrow can be manipulated by the operator to reflect the current location of the ultrasound image. Most commonly, a trackball on the ultrasound machine is employed to manipulate the position of the probe icon relative to the breast marker region. There are three types of breast marker, as illustrated in Figure 1b. The operator can choose a suitable pictogram to annotate the image according to the image location. The spatial information is also indicated in the textual sequence. In Figure 1a, ‘L’ means it is the left breast, ‘3’ represents the 3 o\’clock radial direction and ‘4’ indicates that it is 4 cm to the nipple.
During breast examination, when one image is useful for diagnosis, a series of complex hand motions need to be performed to annotate the image (Jackson and Chenal TAPI-1 2006; Kuzara and Brown 2006). The operator first freezes the ultrasound image using the freeze button on the ultrasound machine and then the changes the probe icon position according to the estimation. Finally, the textual sequence is typed using the keyboard. In the hospital, patient care and productivity are the main concerns. However, this manual annotation method causes a variety of issues.
One issue arises from the complex manual annotation procedure. The aforementioned actions are repeated for every ultrasound image and are time consuming (Entrekin 2010). The annotation takes more time than the breast scanning procedure, especially for new staff with little experience. In China, the clinical practice guideline recommends that there are two operators in each breast ultrasound examination (Chinese Medical Association 2004). One manipulates the ultrasound machine to scan the breast, and the other records the image and annotates it. This method can effectively decrease examination time, but Multiforked chromosome is obviously a waste of human resources in health care institutions. In addition, the highly repetitive annotation procedure is also fatigue to the operator.
Another problem caused by the manual annotation method is subjective registration of the image location, which is set according to the estimation of the probe location relative to the breast by the operator. Manual estimation depends on the operator\’s training and experience and may lead to inaccurate results or even errors. Furthermore, different operators may annotate images in their own way, which can cause inconsistency in image recording (Brandli 2007). For example, as illustrated in Figure 1a, some operators may type the textual sequence near the breast marker region, whereas others may type it on the ultrasound image. The inconsistent ultrasound images can cause difficulties in follow-up image processing or statistical analysis (Cupples et al. 2004). In addition, as also illustrated in Figure 1a, the 2-D annotation cannot display all spatial information in 3-D space, such as the probe tilt angle. This can also cause problems in downstream evaluation and treatment. On the basis of the incomplete spatial information, different clinicians may make different judgments on the image location in 3-D space.

br Acknowledgments This work is supported by grants from the

Acknowledgments
This work salvinorin supported by grants from the NIH National Institute of Biomedical Imaging and Bioengineering under Award R01 salvinorin EB008998, National Institute of Neurological Disorders and Stroke under Award R21 NS093121, and the Focused Ultrasound Foundation.

Introduction
Acute occlusion of a coronary artery causes elevation of the ST segment on the electrocardiogram, resulting in ST-segment elevation myocardial infarction (STEMI). Current therapy is focused on immediate restoration of flow of the obstructed epicardial coronary artery. This can be achieved with either thrombolytic therapy or primary percutaneous coronary intervention (PCI), the latter being favored in situations where trained personnel and specialized equipment are available (Windecker et al. 2015). Unfortunately, despite successful epicardial reperfusion, myocardial perfusion of the microvasculature is not restored in 5%–50% of cases, resulting in adverse clinical outcomes (Niccoli et al. 2009; Wu et al. 1998; Yellon and Hausenloy 2007). This phenomenon, known as no-reflow or microvascular occlusion (MVO), is of multifactorial origin and is possibly initiated by microvascular thromboembolization (Henriques et al. 2002; Niccoli et al. 2009), as well as intra-myocardial hemorrhage (Kloner et al. 1974; Robbers et al. 2013), but platelet and leukocyte aggregation, inflammation, edema and vasoconstriction all play an important role (Ibáñez et al. 2015). The relatively sudden reperfusion caused by PCI can also lead to cellular lethal reperfusion injury (Betgem et al. 2014). This is most likely caused by a combination of factors including high oxidative stress, intracellular calcium overload, (micro)vascular thrombi and inflammation, but the exact mechanism remains unknown (Fröhlich et al. 2013; Yellon and Hausenloy 2007). Detection and treatment of MVO are currently a focus of scientific research, which has led to mixed results in efficacy (Jaffe et al. 2010; Roos et al. 2014). One potential technique used an attempts to support PCI in the treatment of patients with acute STEMI is called sonolysis and consists of high-mechanical-index (MI) therapeutic ultrasound (US) directed at epicardial and microvascular thrombi to disrupt them and increase microvascular perfusion (Unger et al. 2004). Diagnostic ultrasound has already proven to be a useful tool in clinical cardiology, but normally uses low-mechanical-index US that allows function assessment and myocardial perfusion imaging. Therapeutic US usually consists of high-intensity US, which by itself causes cavitation in fluids and is therefore not suitable for diagnostic imaging. Combining therapeutic US with intravenous microbubbles significantly increases the amount of cavitation (Stride 2009). By using inertial cavitation, a large proportion of cavitating microbubbles release large amounts of energy, resulting in microjetting, among other effects, capable of destroying thrombi (Roos et al. 2014). However, the amount of microbubbles that undergo inertial cavitation is strongly dependent not only on the amplitude of the US, but also on the US frequency and the mechanical properties of the microbubble used (Radhakrishnan et al. 2013).
Increasing the mechanical index (Leeman et al. 2012) and increasing pulse duration (Wu et al. 2014) result in increased thrombus destruction in most but not all studies. Holland et al. (2008) reported that the largest thrombolytic enhancement at 1 MHz was achieved using a 1.0-MPa peak-to-peak pressure amplitude; however, with 120-kHz probes, a frequency that is not used in echocardiography in humans, pressures beyond 0.48 MPa did not result in increased sonothrombolysis (Datta et al. 2006; Holland et al. 2008). The increase in mechanical index and pulse duration might be the reason for the reduction in the amount of tissue plasminogen activator treatment needed to achieve thrombolysis in remote areas (Wu et al. 2015). A recent in vivo study in rats revealed that high-MI, long-pulse-tone therapeutic ultrasound is capable of achieving a reduction in microemboli in the biceps femoris muscle in a thrombotic vascular occlusion model (Pacella et al. 2015). The aim of the present study was to incorporate these pre-clinical results in a clinical scenario and to test the tolerability and feasibility of longer-pulse-duration (20 μs), high-MI (1.3) US with intravenous microbubble infusion for treatment of microvascular disease in acute STEMI patients using novel software that alternates therapeutic high-intensity US and diagnostic low-intensity US. This allows myocardial perfusion imaging to be used as a guide for therapy (theragnostic imaging).

PND-1186 br Conclusions br Acknowledgments br

Conclusions

Acknowledgments

Introduction
Positron emission tomography (PET) is an in vivo nuclear medicine technique producing 3-D images of functional processes. The tracer accumulation, observed as [18F]fluorodeoxyglucose (FDG) uptake, indicates a glucose-avid, hypermetabolic area or suspected tumor (Ansari et al. 2013; Blechacz and Gores 2010; Schöder et al. 2004). FDG-PET plays a pivotal role in the staging, follow-up and assessment of response to treatment for many cancers, influencing consistently the decision making and management of the cancer patient. The standardized uptake value (SUV) represents a simple semiquantitative parameter. It is the ratio of tissue radioactivity concentration to time T and administered dose at the time of injection divided by weight. In many cancers the change in SUV allows early discrimination between responders and non-responders to systemic therapies. However, the widespread use of PET scans results in a number of indeterminate findings, requiring further investigation with morphologic modalities (Luk et al. 2013; Purohit et al. 2014). In particular, “mild positive” PET results raise concern because they PND-1186 warrant further imaging with ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI).

Methods
We evaluated the original CEUS and PET reports and recorded the maximum SUV indicated, whenever available. We categorized indeterminate PET or PET-CT studies into four options. Group A included those cases with no FDG uptake but still requiring further investigation because of the findings on the combined CT images. Group B comprised patients with indeterminate, non-specific PET results (i.e., non-specific FDG uptake with no SUV given). Group C included patients with indeterminate, but specific PET results (well-defined FDG uptake with a defined maximum SUV provided, requiring further investigation). Group D included patients with determinate but still to be investigated PET results (well-defined FDG uptake with a maximum SUV provided, for which the nuclear medicine physician called for further investigation).
The prevalence of a correct CEUS diagnosis in the four different subgroups of patients was compared using the χ2 test. A p value < 0.05 was considered significant for all tests. Statistical analysis was performed using the Statistics Toolbox of MATLAB R2007a (The MathWorks, Natick, MA, USA). Final diagnosis was confirmed by biopsy (8 cases), surgery (7 cases), further cross-sectional imaging with definitive findings (30 cases) and imaging follow-up (25 cases).
Results
Six of 70 cases had a negative PET result, but required additional imaging because of the combined CT findings (Group A). In all of these cases CEUS allowed a definitive, correct diagnosis to be reached. Twenty of the 70 CEUS studies had been performed in patients with indeterminate, non-specific PET findings (Group B). In this subset of patients, CEUS diagnosis was correct in 19 cases and incorrect in one (Table 1). Thirty-four of the CEUS examinations had been carried out in patients with an indeterminate but specific PET or PET-CT result (Group C). CEUS diagnosis was found to be correct in 30 of these cases and incorrect in 4 cases. Ten of the 70 CEUS studies had been performed in patients with a PET or PET-CT result that was determinate but still to be investigated (Group D). CEUS allowed a correct diagnosis to be obtained in 9 such cases, whereas metabolic pathway made an incorrect diagnosis in one subject. There was no difference in the accuracy of CEUS between the three different PET categories (p > 0.5). In the end, based on the final diagnosis, CEUS allowed a correct diagnosis in 64 of 70 cases with indeterminate PET findings. In the remaining 6 cases, the result was found to be incorrect at the retrospective assessment.

Discussion
Contrast-enhanced ultrasound has become, at least for the liver, a standardized imaging modality, with well-defined indications, possibilities and limitations (Catalano et al. 2005, 2011, 2015; Claudon et al. 2013; Quaia et al. 2004; Piscaglia et al. 2012; Sporea et al. 2014). As for US, deeper areas may be hard to explore with CEUS, especially in large patients. However, when the area of interest is sufficiently accessible to the exploration, the diagnostic accuracy of CEUS is comparable to that of MRI and is at least comparable to (if not greater than) that of CT (Quaia et al. 2004, 2014;Seitz et al. 2009, 2010). Although CEUS was originally developed to better assess findings indeterminate at US, the indications for its use have expanded. In our cancer center, CEUS is frequently employed as a simple and quick problem-solving tool in patients with indeterminate or discrepant findings at “heavy machineries” such as CT and MRI. In a 1-y survey we found that 104 of 644 liver CEUS examinations were carried out because of diagnostic doubt at another imaging modality (CT, MRI, PET), and 39 CEUS examinations were performed because of a discrepancy between two imaging modalities (Catalano et al. 2011). Lanka et al. (2007) found that 74% of 1040 consecutive CEUS liver examinations had been ordered by clinicians, in most cases because a previous CT and/or MRI study had yielded an inconclusive result. In a review article, Quaia (2012) emphasized a number of circumstances in which CEUS is of great additional value in patients with uncertain lesion characterization at CT or MR (Quaia 2012). In a study on indeterminate, subcentimetric focal liver lesions seen at CT in the staging or follow-up of cancer patients, we found CEUS very useful in differentiating cystic, solid benign and solid malignant lesions (Laghi et al. 2010). In patients with lymphomatous lesions of the spleen, Picardi et al. (2009) found CEUS more accurate than CT and PET.