Torin 1 ESRD RCC is considered biologically distinct from RCC

ESRD-RCC is considered biologically distinct from RCC in the general population or sporadic RCC. ESRD-RCC is characterized by young patients, predominantly male, frequent multicentric and bilateral occurrence, and non–clear cell carcinoma associated with acquired cystic disease [5,9]. Some recent studies have shown that most ESRD-RCCs are incidental and asymptomatic low-stage, low-grade tumors with favorable prognosis [3,9,10]. The main Torin 1 to explain these findings is that earlier diagnosis by close surveillance could contribute to better prognosis in patients with ESRD-RCC. The efficacy of routine cancer screening is, however, controversial in dialysis patients from a cost-effectiveness perspective because of their poorer survival rates than the general population [27]. An individualized approach based on their cancer risk factors and expected survival is required for cancer screening in these patients. In this context, a worldwide, well-standardized, widely available, and inexpensive biomarker like serum CRP could be a helpful screening tool.
ESRD is a complex condition, where kidney dysfunction is accompanied by numerous metabolic changes affecting almost all organ systems of the human body. A number of factors are involved in the inflammatory process in dialysis patients, including disease-related factors (uremia, comorbidity, oxidative stress, infections, and immunologic factors) as well as dialysis treatment itself (membrane and dialysate biocompatibility) [28]. The association of CRP with all-cause and cardiovascular mortality has been evaluated in dialysis patients [29]. Systemic inflammation is considered to play an important role in the pathogenesis of atherosclerosis and malnutrition resulting in higher cardiovascular disease mortality, which is the most common cause of death in dialysis patients [30].
Other possible limitations include the study׳s retrospective nature and a small sample size that could cause unknown sources of bias in the findings. Another major limitation is the heterogeneity of HD procedures and follow-up methods at various HD clinics, which might be associated with serum CRP levels and the clinical outcome of patients with ESRD-RCC. Rashidi et al. evaluated an association between serum CRP level and HD frequency. The study suggested that increasing dialysis frequency could improve the inflammation and nutrition states, resulting in a decrease in serum CRP levels [30]. In addition, we did not evaluate pathological features such as tumor necrosis and sarcomatoid change in nephrectomy specimens, which may improve the accuracy of survival prediction [17]. Therefore, further external validation, such as a future prospective study in a larger population, is warranted to accurately clarify the prognostic significance of serum CRP levels in patients with ESRD-RCC on HD undergoing nephrectomy.

Conclusions

Acknowledgments

Introduction
Metformin (1,1-dimethylbiguanide hydrochloride) is an oral therapy ubiquitously used to treat type 2 diabetes and prediabetic syndromes. It received Food and Drug Administration approval in 1994 and is well tolerated, with a wide therapeutic Torin 1 window. Recent in vitro and in vivo studies have identified antineoplastic activity of metformin against renal cell carcinoma (RCC) through activation of the adenosine monophosphate–activated protein kinase. (AMPK) pathway. Liu et al. [1] investigated the effect of metformin on 2 RCC cell lines and tumor xenografts and reported that metformin inhibited the proliferation of RCC cell lines in both a dose- and time-dependent manner via AMPK activation. Furthermore, they observed inhibition of RCC cell colony formation and induction of cell cycle arrest in RCC cells treated with metformin, as well as inhibition of growth of RCC xenografts [1]. Additional work has identified the inhibitory effect of metformin on the mammalian target of rapamycin (mTOR) signaling pathway, likewise resulting in suppression of tumor growth [2].

Seizures were an early concern in the development of

Seizures were an early concern in the development of enzalutamide. As an inhibitor of the gamma-aminobutyric acid–gated chloride channel, it caused seizures at supratherapeutic doses in mice as well as in 3 patients from the initial phase I/II study at doses of 360mg/day and higher (above the licensed 160mg/day) [25,34]. Because of this, men with with a history of seizure or a condition that could predispose to seizure, such as PCI-34051 metastases, transient ischemic attack within the past year, and loss of consciousness within the past year, were excluded from the phase III AFFIRM and PREVAIL trials [28,31]. Across these two trials, 5 of the 800 patients enrolled in the post-chemotherapy AFFIRM and 1 of the 872 patients in pre-chemotherapy PREVAIL (overall 6 of 1672, 0.4%) experienced a seizure event. In the trial (PREVAIL) 1 seizure occurred in each of the enzalutamide and placebo arms which is notable since this pre-chemotherapy setting is likely the point in the illness at which the drug will be most commonly prescribed in clinical practice. The FDA label states that “the safety of enzalutamide in patients with predisposing factors for seizures is unknown.” To assess this, a single-arm open-label study is ongoing seizure frequency in men with CRPC on enzalutamide who have risk factor(s) for seizure such as history of prior seizure, cerebrovascular accident/transient ischemic attack, or treated brain metastases (NCT01977651).
Intense efforts are ongoing to determine whether enzalutamide is best used in combination or in sequence with other agents to maximize outcome for the individual patient. One such study is comparing the safety and efficacy of enzalutamide alone with enzalutamide plus abiraterone as first-line therapy for chemotherapy-naïve CRPC in a multicentre Alliance phase III trial that is planning to enroll 1,224 patients and has a primary end point of overall survival (NCT01949337). Trials have also been designed to test whether it is better to continue a drug on which a patient is progressing and add a second drug or whether the first should be discontinued before the second is started. Equally important are trials in earlier disease states (Table 5) including studies combining enzalutamide with radiotherapy (both with and without ADT) for treatment of high-risk localized prostate cancer based on preclinical studies from the Sawyer׳s group showing that AR signaling contributes to activation of DNA-repair pathways, which could increase resistance to radiation therapy (NCT02064582 and NCT02028988) [35]. Studies are also investigating enzalutamide as monotherapy without concomitant androgen lowering therapies: a study in 67 men with treatment-naïve castration-sensitive prostate cancer showed>90% of patients achieving deep and durable PSA level declines [36]. This approach has the potential to avoid many of the adverse events associated with conventional ADT and improve overall quality of life. Enzalutamide is also being compared with bicalutamide as first-line treatment for non-castrate metastatic prostate cancer in combination with ADT (NCT02058706). Finally, the drug has shown activity in triple-negative breast cancer, which has opened up a whole new area of development (NCT01597193 and NCT02007512).

Conclusion

Introduction
Treatment of castration-resistant prostate cancer (CRPC), the second commonest cause of cancer-related mortality in men, has improved significantly in recent years [1]. Abiraterone acetate is 1 of 5 survival-prolonging treatments approved since 2009 for CRPC. Enzalutamide, a small molecule inhibitor of the androgen receptor (AR) and discussed elsewhere in this series, also demonstrated a survival benefit and was approved in 2012 for use in patients with CRPC who have previously received docetaxel treatment [2]. The efficacy of both novel treatments targeting the AR confirmed CRPCs׳ ongoing dependency on the androgen axis. An additional 3 novel therapies now approved for use in CRPC include radium-223 for patients with symptomatic bone-only metastases [3], the vaccine sipuleucel-T [4], and the second-generation taxane chemotherapy cabazitaxel [5]. Nonetheless, drug resistance invariably develops, and CRPC remains an invariably lethal condition.

Results with cycles of higher doses of etoposide

Results with 2 cycles of higher doses of etoposide (2,250mg/m2 per cycle) and carboplatin (2,100mg/m2 per cycle) were reported in 2007 by Einhorn et al. Of 184 patients, 173 received both cycles of HDCT, and 116 (63%) achieved durable remissions with a median follow-up of 4 years. Only 3 (1.6%) patients died of acute treatment-related complications (Table 1). It should be noted that most patients (n = 135, 73%) in this SCH 727965 series were treated in the initial salvage (second line) setting, 70% of whom achieved durable remissions. In addition, patients with late relapse or primary mediastinal nonseminomatous GCTs (PM-NSGCT), factors associated with poor outcome to HDCT/ASCT, were excluded from this study [8]. Nevertheless, these results underscore the improvements in efficacy and reductions in toxicity that can be achieved with modern supportive care, use of HDCT/ASCT earlier in the disease course, improved patient selection, and escalation of etoposide and carboplatin doses.
The addition of a third drug to the carboplatin-etoposide backbone has been evaluated by several groups, with oxazophosphorines (cyclophosphamide and ifosfamide) being the most extensively studied agents. Investigators at Indiana University evaluated the combination of ifosfamide, carboplatin, and etoposide but ended the study prematurely due to nephrotoxicity experienced by 4 of the first 7 patients treated at the lowest dose level [10]. In contrast, in a German SCH 727965 study of ifosfamide, carboplatin, and etoposide, there was no excess renal toxicity among 74 patients with GCT, and encouraging rates of 2-year event-free survival (EFS) (35%) and TRM (3%) were observed [11]. No obvious differences in supportive care or method of administration of ifosfamide explain these disparate observations.
Motzer et al. evaluated 2 cycles of the combination of cyclophosphamide 60 to 150mg/kg with HD carboplatin 1,500mg/m2 and etoposide 1,200mg/m2 (CECy) in 58 patients with refractory GCT, defined as either an incomplete response to first-line cisplatin-based therapy or progression following salvage CDCT. A CR was achieved in 23 (40%) with 17% remaining in remission for more than 2 years, encouraging results given the unfavorable patient population. Renal toxicity (creatinine level>4mg/dl or blood urea nitrogen>75mg/dl) was observed in 10% of patients. In addition, hepatic toxicity (aspartate transaminase or alanine transaminase≥5×the upper limit of normal occurred in 20% of patients and TRM was observed in 12% of patients [7]. A German randomized trial formally tested the efficacy and safety of HD CECy vs. HD CE while simultaneously evaluating the importance of the number of HD cycles (3 vs. 1). Patients were treated with either 3 cycles of conventional-dose etoposide, ifosfamide, and cisplatin (VIP×3) followed by 1 cycle of CECy or VIP×1 followed by 3 sequential cycles of HD CE [12,13]. No statistical difference was observed in progression-free survival (PFS) or overall survival (OS), but TRM was 16% in the single-cycle HD CECy arm as compared with only 4% in the triple cycle CE arm (P<0.01) [12], resulting in premature study closure and a trend toward improved 5-year OS with sequential HD CE×3 (50% vs. 40%, P = 0.057 ) [13]. Paclitaxel is another agent that has been studied as part of HDCT programs. In 2010, the Memorial Sloan Kettering Cancer Center (MSKCC) group reported the results of a phase I/II trial of the TI-CE regimen, which incorporates conventional doses of paclitaxel (200mg/m2) in combination with ifosfamide into the stem cell mobilization portion of the program [9,14,15]. Subsequently, patients receive 3 cycles of HD carboplatin dosed at an area under the curve of 24 in combination with etoposide 1,200mg/m2, both divided over 3 days followed by autologous stem cell reinfusion on day 5 of each cycle. The study included 107 patients who had progressed after at least one line of prior cisplatin-based chemotherapy and had features predicting an unfavorable outcome to salvage CDCT. These features included extragonadal primary tumor site, an incomplete response to first-line chemotherapy, duration of CR or partial response (PR)-negative markers of<6 months, or progression of disease (PD) after prior salvage CDCT. The favorable response rate (CR+PR markers), 5-year PFS, and 5-year OS were 58%, 48% and 52%, respectively, promising results considering the poor prognosis of the patient population. In addition, 5/21 patients with PM-NSGCT and 2/7 with late relapses, 2 cohorts of patients with historically dismal outcomes to HDCT, achieved long-term PFS with TI-CE [9].

Besides various cancers increasing evidence showed that NLR has been

Besides various cancers, increasing evidence showed that NLR has been associated with poor outcomes in other medical conditions, such as diabetes [26] and cardiovascular diseases [27,28]. Our previous study showed that NLR was associated with abnormal SCR7 and lipid metabolism. It means that NLR value was not only affected by solid tumors, but also by different kinds of pathological or physiological conditions.
In a prospective study, hypertension can independently increase the risk of RCC [29]. Inversely, RCC may cause arterial hypertension. Hypertension was resolved after the patients with RCC underwent nephrectomies [19]. Interestingly, NLR value has a positive correlation with blood pressure [18]. In our subgroup analysis, the NLR values were not different between patients with RCC with or without hypertension. But the multivariate analysis showed that NLR were not the independent prognostic factors for RCC disease-free survival in hypertensive subgroup but still serve as the independent prognostic factor in normotensive subgroup. It means that NLR can be used as a predictor of RCC prognosis. But the accuracy was badly affected by hypertension.
Little has been reported about the effect of hypertension on RCC prognosis. Treatment-induced hypertension has been proposed as a potential biomarker of the clinical effect of antiangiogenic agents. Rini et al. [30] found that sunitinib-associated hypertension is associated with improved clinical outcomes without clinically significant increases in hypertension-associated adverse events, supporting its viability as an efficacy biomarker in metastatic RCC. So, the evaluation of the prognosis by NLR and hypertension in the course of postoperative treatment should accord to specific therapeutic scheme. We will focus on this aspect in the future.
Nowadays, based on pTNM stage, clinical researchers has established various scoring systems for tumor prognosis, which were wildly used for establishing the tumor postoperative treatment plans. It is also very important to find prognostic factors at the point before treatment for clinicians to make treatment decisions. Pretreatment CRP and NLR are the most common prognostic factors reported in various tumor types. Gondo et al. [31] reported that NLR may be superior to CRP to predict recurrence in patients with nonmetastatic RCC. Multivariate analysis shows that Clinical T stage was a stable independent predictor for RCC recurrent-free survival in either total subjects or subgroups. Tumor T stage is a tumor-related factor, which may not be interfered by other host physiologic factors. But NLR as a host-related factor can be interfered by many physiologic factors that can trigger immune response in vivo. In venules respect, pTNM stage has the advantage in tumor outcome prognosis compared with NLR. However, as an easily measured, reproducible, and inexpensive marker, NLR still has application value.

Conclusions

We applaud Dr. Droller for sharing an editor’s considerations in publishing industry-sponsored studies . As members of the Global Alliance of Publication Professionals (), we appreciate his emphasis on the need for practical measures, such as objectivity and transparency, rather than draconian methods, such as banning publication of industry-sponsored studies. We wish to build on his review by identifying recent publications, which suggest that corresponding considerations by organizations representing editors and publication professionals have led to new guidelines designed to improve the quality of publishing industry-sponsored studies.
Dr. Droller referred to good publication practice (GPP) for communicating company-sponsored medical research (GPP2) . The recently updated guidelines (GPP3) address concerns about the potential for bias by providing new sections on GPPs, data sharing, and publishing studies that include negative findings. Like GPP2, GPP3 recommends the use of a written agreement to commit authors and sponsors to collaborate in following GPPs. Furthermore, GPP3 recommends disclosure of data to authors and documentation of intellectual contributions by authors, including their comments on sequential drafts from outline to submission . This step-wise approach should reduce the disingenuous practice of presenting authors with a “finished” article that may convey information in a favorable light or that may discourage authors from making the intellectual contributions needed to qualify for authorship.

Senexin B There have been few reports on the relationship between

There have been few reports on the relationship between BMI and prognosis in patients with mRCC receiving targeted therapy. Studies have shown that BMI is not only a risk factor for the occurrence of RCC, but is also closely related to the postoperative prognosis [13–16]. In the present study, we found that the median PFS and OS times of patients with mRCC with a BMI in the normal range (19–30kg/m2) were 13.8 and 39.6 months, respectively, which were both significantly longer than patients with either a slim body type (BMI<19kg/m2) or with obesity (BMI>30kg/m2) (P = 0.011 and P = 0.000, respectively). Generally, slim patients may have significant tumor consumption with poor physical condition and organ function reserve, whereas in obese patients, the heart, liver, lungs, and other Senexin B are overburdened, and have poor compensatory ability during drug treatment. All these factors may cause patients to exhibit resistance to the drug treatment administered, contributing to the overall treatment results. However, Albiges et al. [17] investigated the effect of BMI on treatment outcome in 1,975 patients treated with targeted therapy for mRCC. Overweight/obese (BMI≥25kg/m2) patients had a longer mOS than underweight/normal weight (BMI<25kg/m2) patients (25.6 vs. 17.1mo respectively; P<0.0001). When Senexin B we segregated the patients in the present study into favorable-risk, intermediate-risk, and poor-risk groups according to the MSKCC model (i.e., on the basis of 5 adverse prognostic factors), we found that the mOS times were 46.6, 30.4, and 16.7 months, respectively (P = 0.005), suggesting therefore that the MSKCC model is also applicable to Chinese patients with mRCC receiving VEGFR-targeted TKI therapy.
When we integrated age and BMI into the MSKCC model to set up a 7-factor prognostic model, the mOS time in the favorable-risk, intermediate-risk, and poor-risk groups varied more widely (71.1, 41.6, and 15.3mo, respectively; P = 0.000). It is noteworthy that the mOS for those patients with the best prognosis was more than 70 months. This suggests that management strategy for these patients should focus more on the sustainability and safety profile of the treatment. However, because of the limitation of a relatively small sample of our study, further prospective studies should be conducted to validate these findings.

Conclusion

Acknowledgments

Introduction
Pathologic stage, tumor grade, and performance status are the most established prognostic factors in renal cell carcinoma (RCC) [1]. The question remains whether histological subtype influences risk of recurrence or death in cases of RCC treated with surgical resection. Although early studies evaluating the effect of histological subtype yielded conflicting results [2–6], it is usually accepted that conventional clear cell histology portends a worse prognosis [7].
In 2012, the International Society of Urological Pathology (ISUP) consensus conference proposed 5 new epithelial neoplasias: tubulocystic RCC, acquired cystic disease–associated RCC, clear cell papillary RCC, microphthalmia family translocation RCC, and hereditary leiomyomatosis RCC syndrome–associated tumors [8]. Furthermore, most of the previous studies addressing the effect of the histological subtype of RCC on survival outcomes included patients who underwent radical nephrectomy (RN). However, the role of kidney-sparing surgery has seen great expansion in recent years [9].
In light of these recent developments, it is not well known whether survival outcomes vary according to histological subtype in contemporary patients. A population-based study reported that histological subtype does not confer prognostic value in patients undergoing partial nephrectomy (PN) [10]. Conflicting results have suggested that histological assignment allows better prognostic stratification for advanced and high-grade tumors only [3] or, conversely, for low-stage tumors only [5]. Here, we evaluate the effect of histological subtype on survival following surgical resection of clinically localized RCC in the era of elective PN.

br Discussion The results show that a range of

Discussion
The results show that a range of different measures have been taken on the eight golf courses in terms of increasing perceived accessibility for the public. We found that after golf course establishment, signs of accessibility have been introduced on the golf courses to inform the public that they are welcome to use paths and resting areas on the courses. As an example, Delsjö close to the city of Gothenburg, is a very popular outdoor recreation area with joggers and Ponatinib using the public paths on the golf course between the city and the adjacent nature reserve. Golf courses in rural areas have relatively few non-golfer visitors on the site and the need for resting areas is consequently low. In the urban situation the need is much higher as is the case for Oppegård, Delsjö, Smørum and Korpa. However, only two of them have high number of public resting areas. Even though several measures can be taken to open up for public recreational use, it is an issue of how lay people perceive accessibility. As Koppen and colleagues points out (2014) there is a difference between physical accessibility and cultural, social and socio-psychological accessibility. A landscape can be perceived as accessible to some, but not to others, depending on peoples background. There seem to be a general scepticism to use golf courses for recreation. This scepticism most likely lies in lack of knowledge of what is allowed for and not on golf courses. People are generally afraid to step on private land – which golf courses probably are considered as by most laymen. Similar parallels can be drawn to coastal areas. According to Norwegian law these areas are free to roam but due to lack of knowledge about laws and rights, some people might find it difficult to use these sites (Skar and Vistad, 2013). Other limitations related to use might lie in the experience of a golf course to be an unsafe place. Increasing the amount of information and seeing other non-golfers on the golf courses can increase the feeling of safety and accessibility.

Acknowledgements
We would like to thank STERF for financial support as well as support with the data collection.

Introduction
Living wall systems provide alternative greening systems in which plants are anchored vertically without the need for rooting space in the ground (Koehler, 2008; Francis and Lorimer, 2011; Perini et al., 2011a). The long-term goal of living walls should be to create attractive vegetation systems that are long-lasting, resource efficient, and that contribute to ecosystem services in areas or locations where other types of green systems cannot be installed due to limited ground space. The technology is still under development, and living walls in their current form require substantial resources during installation and maintenance (Perini and Rosasco, 2013). Vertical greening has several benefits, such as noise mitigation (Van Renterghem et al., 2013) and improvements in local air quality (Ottele et al., 2010; Sternberg et al., 2010). Potentially, these vertical systems can also have a role in developing urban agriculture networks (McLain et al., 2012). Living wall systems can thus be used to improve the built environment and how it is experienced as they provide an alternative way of greening dense urban areas. However, only small and local reductions in temperature in urban areas have been reported in globally widespread studies covering a variety of climates (Onishi et al., 2010; Wong et al., 2010; Perini et al., 2011b; Hunter et al., 2014).
Few studies have been carried out on plant species that are suitable for living wall systems. In the Mediterranean area, Myrtus communis, Cistus x purpurescens and Teuchrium x lucydris have been shown to perform well in living wall systems (Devecchi et al., 2013; Larcher et al., 2013). Although these species cannot be expected to perform well in the Scandinavian climate, it has recently been found that a number of perennial plants survive and perform well in living wall systems in the Scandinavian climate (Mårtensson et al., 2014). The use of Edible and evergreen plants would be highly interesting in living wall systems, since edible plants contribute to urban ecosystem services through flowering and the possibility to harvest fruits or leaves, whereas evergreen plants contribute with year-round aesthetics. Both these characteristics have been stressed as important to achieve a marketable system.

Introduction Heat waves such as the ones which occurred in

Introduction
Heat waves, such as the ones which occurred in Eastern Europe in 2010, North America and Australia in 2012, and China in 2013, are expected to have a large impact on human health, well-being and economic burden in the future (IPCC, 2012). Urban areas are particularly vulnerable to such effects given the density of urban populations and the compounding effect of the urban heat island, which will grow with increased population and greater urbanisation (McMichael et al., 2006; Pascal et al., 2006). To inform climate sensitive planning, intra-urban climate conditions at local (102–104m, e.g. a district) and micro-scales (10−1–103m, e.g. a street canyon) need to be predicted for building aromatase inhibitors applications and for estimating outdoor human thermal comfort in cities.
The thermal comfort at the neighbourhood to street level scale is chiefly influenced by urban structures. It varies greatly within short distances due to shadow patterns generated by urban surface geometry and radiative properties related to materials and urban density (Lindberg and Grimmond, 2011a). For the estimation of thermal comfort, micro-scale modelling of mean radiant temperature () is essential (Lindberg et al., 2008; Matzarakis et al., 2010). The , which describes the radiant (short-wave and long-wave) heat exchange between a person and his or her surroundings, is defined as the ‘uniform temperature of an imaginary enclosure in which the radiant heat transfer from the human body equals the radiant heat transfer in the actual non-uniform enclosure’ (ASHRAE, 2001). It is considered to be one of the most important meteorological variables governing the human energy balance and thermal comfort outdoors, especially during clear and calm summer days (Mayer and Höppe, 1987).
Generally, in order to model for the area of interest, the required meteorological variables (short-wave radiation, air temperature, and humidity) are obtained from observations or models. However, they are often not specific for the site (e.g. they are often derived from an airport), or rely on the use of long-term mean variables rather than typical sequences of conditions. When data from other areas are used (Erell and Williamson, 2006; Lindberg et al., 2013), often it is assumed that both areas are exposed to the same regional conditions and land surface effects on the meteorological variables are ignored. As a result, these local-scale land cover and land use characteristics systematically impact the accuracy of calculations. If data are derived from atmospheric numerical simulation, sometimes with coupled urban land surface schemes (Miao et al., 2009; Flagg and Taylor, 2011; Loridan et al., 2013), this requires large computational cost.
Currently, only a few urban land surface models (ULSMs) are set up to rapidly calculate site-specific air temperature within or above the canopy layer (Swaid and Hoffman, 1990; Erell and Williamson, 2006; Bueno et al., 2012; Bueno et al., 2013; Stewart et al., 2013). Of these, only Bueno et al. (2013) and Stewart et al. (2013) take feedback from the land surface to the meso-scale atmosphere into account. Both use the Town Energy Balance (TEB) scheme (Masson, 2000) coupled to different boundary layer models.
In order to investigate daytime human thermal comfort in cities, simple methods to obtain more site-specific input meteorological variables need to be explored. In this study a scheme is developed to provide daytime meteorological variables representative of an urban area for a micro-scale urban radiation model to simulate . A meso-scale slab convective boundary layer (CBL) model is coupled to two local-scale ULSMs (Section 2). Of interest is the ability of the combined model to simulate meteorological variables, accounting for land surface changes, using minimal computer resources (e.g. a personal computer), and simple inputs around meteorology, land surface cover, and initial state conditions. The number of meteorological inputs is reduced compared to those required for the separate models included in the coupled scheme. The coupled models are tested at three sites (suburban, irrigated sod-farm and unirrigated grassland) in Sacramento, CA (Sections 3 and 4). They replicate well the local-scale urban meteorological variables (air temperature and relative humidity) from those measured at rural sites (Section 6). Here the focus application is to obtain , one of most critical components of outdoor human comfort, by calculation with a micro-scale urban radiation model – the SOlar and Long Wave Environmental Irradiance Geometry model (SOLWEIG) (Lindberg et al., 2008; Lindberg and Grimmond, 2011b). SOLWEIG determines three-dimensional radiation fluxes and . To ensure that the coupled model can provide robust input for this application, sensitivity tests are undertaken with SOLWEIG (Section 5.1 and 6). The coupled model scheme developed is applicable to urban climate sensitive planning issues such as the effect of land cover changes on intra urban temperature variations; building energy applications; air quality forecasting; and dispersion modelling.

A third drawback is caused by

A third drawback is caused by beam steering, which affects not only PWI but other beamforming techniques employing oriented beams. As illustrated in Figure 9 (a, b), beam steering causes regions below the lateral side of the transducer to receive less acoustic pressure than those below its center, potentially affecting the SNR of the BSC. In this study, the latter drawback was avoided by excluding lateral zones of each image as the depth scanned was far from the interception limit (corresponding to 10.8 cm for our transducer measuring m = 38 mm). However, for small probes (e.g., arrays of 10 mm in lateral length), the resolution triangle can imply serious biases for BSC estimation, even at a depth as small as 3 cm. A possible approach to counteract this problem may consist of normalizing the sample power spectrum SSA in eqn (2) with a set of windows in the reference medium having the same loss in acoustic calcium channel blocker (i.e., the same position in the ROI). Nevertheless, to have a consistent estimate with the reference medium, it would be necessary to perform sufficient averaging of power spectra. With a static reference phantom, this may be difficult, but it may be possible in the case of flowing blood, as different time frames may be used.
One important aspect of our results is that they were obtained with a clinical scanner providing RF data and, in the case of FI, with the same software employed for patient examination. This provides more evidence of the possibility of integrating spectral tissue characterization methods into clinical practice, even with new beamforming technologies. Historically, the implementation of spectral-based quantitative ultrasound techniques on clinical scanners has been deferred for a few reasons; in particular, the lack of access to RF signals and the absence of a consensus on the methodology of BSC estimation were early problems (Anderson et al. 2010; Madsen et al. 1999; Nam et al. 2011). Today, most of these causes have been overcome. For example, several commercial ultrasound calcium channel blocker scanners provide easy access to RF data (before or after beamforming), thus facilitating the implementation of robust BSC spectral methods. State-of-the-art BSC estimation procedures can be found in recent textbooks (Franceschini and Cloutier 2013; Ghoshal et al. 2013). Another issue delaying acceptance of quantitative spectral methods is the need for calibration of the backscatter signal intensity (Wear et al. 2005). It is common for most laboratories to create their own reference medium, making it difficult to reproduce measurements (e.g., Salles et al. 2014; Wang and Shung 1997; Wear et al. 2005). Calibrated commercial tissue-mimicking phantoms would alleviate this problem (Nam et al. 2012). Other challenges, such as real-time display of parametric images, are still to be overcome; nevertheless, hardware improvements, such as graphic processing units, in addition to experimental validation as discussed here, allow us to be hopeful of a future clinical scanner with spectral characterization capabilities.

Conclusions
Evidence suggesting the use of plane-wave imaging for the estimation of the backscatter coefficient in biological tissues was discussed. BSC estimates obtained with compounded plane-wave images were equivalent to those obtained with single-element transducers and conventional focusing, in both isotropic and anisotropic media. In particular, small differences were observed between effective scatterer radii derived from the two techniques. Additionally, we evidenced in experiments with porcine blood that single-angle PWI images (i.e., before compounding) could be used to assess the anisotropy of flowing erythrocyte aggregates. These results suggest that plane-wave imaging can be used for spectral tissue characterization, particularly in the case of fast-moving tissues.

Acknowledgments

This work was financially supported by Canadian Institutes of Health Research Grant MOP-84358. Mr. Garcia-Duitama was recipient of a Ph.D. scholarship from the Natural Sciences and Engineering Research Council of Canada (Meditis Program of the Institute of Biomedical Engineering of the École Polytechnique and University of Montreal). He also received the Hydro-Québec scholarship award at the University of Montreal.

br Discussion In the present study unfocused shock waves

Discussion
In the present study, unfocused shock waves (i.e., ESWT) were indicated to be an effective therapeutic modality for the treatment of painful, retracting scars of the hands (Kasuya and Tokura 2014; Wang et al. 2011). The effectiveness of ESWT on retractive scarring was evaluated in multiple respects, including clinical appearance of scars, motion function of underlying joints and subjective pain. In particular, scar appearance was assessed by means of the moVSS score, which is based on scar height, pliability, pigmentation and vascularity; functionally valuable changes in hand mobility were evaluated using a ROM scale, and a VAS score was implemented for detecting any improvements in referred pain.
Administration of ESWT resulted in clinically meaningful improvements in height, pliability, pigmentation and vascularity of treated scars as early as at T1 (i.e., after five treatment sessions at a rate of two sessions per wk); these improving trends were maintained to the end of treatment urokinase (i.e., at T2 after 10 treatment sessions), being observed irrespective of whether ESWT had been delivered in association with manual myofascial therapy and/or local treatment with I-Coone system.
As a secondary goal, our study attempted to correlate clinical improvement induced by ESWT with morphologic changes at the histopathologic level (Darby et al. 2014; Frairia and Berta 2012).
Histopathological examination with different histochemical (i.e., hematoxylin-eosin and picrosirius red) and immunohistochemical (fXIIIa, CD31 and CD34) stains showed that treatment of scar tissue with ESWT resulted in a significant increase in dermal fibroblasts, small vessel density, type-I-to-type-III collagen ratio, and number of fXIIIa- and CD34-positive cells.
The results from our study seem to confirm that shock wave treatment is capable of inducing an increase in the number of activated fibroblasts, CD34-positive fibrocytes and fXIIIa-positive dendritic cells; this process is thought to lead to the deposition of new collagen, characterized by thinner collagen fascicles and parallel orientation to the dermo-epidermal junction. Such a process would explain the strong correlation observed between such histologic features and scar macroscopic appearance in treated patients. Additionally, shock wave therapy may be regarded as playing a significant role in the increase in CD31-positive vessel density in the dermis of treated patients, allowing an improved tissue metabolism (Reichenberger et al. 2012).
With regard to skin wounds, Kuo et al. (2009) demonstrated that proper administration of ESWT to wound tissue may be able to reduce the inflammatory response, with consequent reduction in the number of infiltrating leukocytes and oxygen free radical production. It may also promote fibroblasts hyperplasia and dermal neoangiogenesis while reducing the number of apoptotic cells. It has also been shown that, at the skin level, therapy with ESWT may be capable of promoting endothelial reorganization, connective tissue deposition and re-epithelialization; such effects seem to be linked to the release of specific growth factors (such as transforming growth factor β1; Fioramonti et al. 2012; Kuo et al. 2009; Wang et al. 2014).
Additionally, it is currently believed that administration of ESWT to wounded skin leads to an early response with conditioning of sympathetic nerve endings and opening of the capillary bed (wash-out effect), followed by a secondary response occurring after some days from treatment characterized by true neoangiogenesis and extensive cleaning of treated tissues with removal of inflammatory mediators (Fioramonti et al. 2014; Henry and Garner 2003; Kuo et al. 2009; Meirer et al. 2005; Saggini et al. 2008, 2013; Wang et al. 2014). Furthermore, ESWT may also be capable of inducing an analgesic effect; indeed, tissue levels of substance P have been shown to increase within the first 24 h after the cutaneous application of shock waves and progressively decrease in the subsequent 6 wk. It appears that the typical course of perceived pain (i.e., intense after the first application but gradually decreasing after subsequent applications of shock waves) is paralleled at the histologic level by the progressive degeneration of nerve fibers originating from small, ATF3-positive neurons (Maier et al. 2000).

In this pilot study the feasibility

In this pilot study, the feasibility of using FUS to treat rats with EAE by targeting hyperthermia to the cervical buy Embelin nodes was assessed. Targeted hyperthermia through FUS is a minimally invasive therapy (i.e., only ultrasound waves penetrate) that could specifically target the cervical lymph nodes and has the potential to retain long term viability of the cervical lymph nodes while killing lymphocytes or degrading the function of lymphocytes residing in the lymph nodes. Furthermore, in the case of the chronic remitting/relapsing forms of MS, FUS therapy has the potential to be applied repeatedly for each relapse episode.

Materials and Methods

Results
On average the PRS for FUS-treated animals was 1.14 ± 0.48 versus a PRS of 0.33 ± 0.27 for sham-treated animals. These differences were statistically significant (p = 0.037). The relapse rate for the FUS-treated rats was 0.57; the relapse rate for the sham-treated rats was 0.17. These differences were statistically significant. However, the relapse rate for the sham-treated animals was low because only two animals underwent a remittance during the 21-d observation period. The average rat masses at the d of MOG injection were 127 ± 15 g and 127 ± 16 g for the FUS-treated and sham-treated groups, respectively. The average rat masses at the d of euthanasia were 118 ± 20 g and 116 ± 13 g for the FUS-treated and sham-treated groups, respectively. Figure 2 shows the average EAE score for FUS-treated versus sham-treated animals. The sharp remittance in EAE symptoms after the second treatment (day 12) can be observed from Figure 2 for the FUS-treated animals. Temperatures, recorded from the rectal thermometer, were on average 33.7 ± 1.3°C and 33.8 ± 1.3°C before and after treatment, respectively, for sham-treated animals. For FUS-treated rats the average temperatures were 33.2 ± 1.8°C and 36.1 ± 1.7°C before and after treatment, respectively. This indicates that the core temperature was slightly elevated using the FUS therapy.
As can be observed from Figure 2 there was a difference in the progression of the disease after day 8 between sham-treated and FUS-treated (and before any treatments were applied). On average the progression of EAE symptoms was delayed in the shams by about a day. Two of the six sham-treated animals did not show signs of EAE until day 10 post-injection. However, to be consistent with the therapy time applications between all animals, the two sham-treated animals that had delayed EAE symptoms still underwent the sham treatment on days 9 and 12 post-MOG injection.
Table 1 provides information about the maximum EAE score reached for each animal in the study and the day post-injection when remittance of EAE score was observed, if the animal did remit. All but one of the FUS-treated animals underwent remittance during the 21-d post-MOG injection. The single FUS-treated rat (rat 7 of the FUS treatment group) that did not remit during the 21 d only reached an EAE score of one and never progressed beyond an EAE score of one. In the sham treatment group only two animals ever remitted their symptoms over the 21 d.
Figure 3 shows the time progression of the ADI for the sham-treated and FUS-treated rats. The FUS-treated rats had a decrease in the ADI following the last day of therapy (day 12), which recovered at about day 18. For the sham-treated rats, the ADI continued to increase with a short drop at day 19 and recovery at day 20. The ADI was always larger for the sham-treated rats compared to the FUS-treated rats after the day of treatment, indicating a higher disability among the sham-treated animals.

Discussion
Targeted hyperthermia using FUS of the superficial cervical lymph nodes in rats with EAE resulted in a statistically significant improvement in the remittance of EAE. Two treatments using FUS were spaced 3 d apart (days 9 and 12 post-MOG injection) to reduce the load of lymphocytes residing in the cervical lymph nodes. Based on the occurrence of the remittance of the EAE score in FUS-treated rats (Fig. 2), the remittance was closely associated with the timing of the treatments. In the sham-treated animals, remittance, if it occurred, was observed at least 4 d after the last sham treatment. Therefore, the timing of the remittances of EAE also suggests that the EAE remittance was associated with the FUS therapy. Furthermore, the timing of the ADI also suggests a relationship between (or an association between) the remittance to the actual therapy. The ADI was observed to decrease from day 13 and only recovering again at day 18 post-injection in the FUS-treated rats. Whereas in the sham-treated rats, the ADI increased up until day 19 and then recovered by day 20 post-injection.