Furthermore although using response surface methodology RSM to statistically and

Furthermore, although using response surface methodology (RSM) to statistically and mathematically optimize various factors has a long history, it continues to be investigated intensively in various research fields because it can simultaneously consider relevant decision factors in the reaction performance [13–18]. Therefore, considering this research background, the present research investigates the feasibility of electric fields with regard to WAS management. Subsequently, in order to optimize the individual electric field (I-EF) technique, three parameters, the total solid (TS) concentration, applied voltage, and reaction time, were considered using RSM with a Box–Behnken design (BBD). Finally, the combined treatment, which is called electric field-assisted ultrasonication (EF-U) in this study, was optimized to enhance disintegration of WAS, and four parameters were selected: the TS concentration, strength of ultrasonication, applied voltage, and reaction time.

Materials and methods

Results and discussion

In the first stage of this study, the applicability of electric fields for the disintegration of WAS was investigated, and its operational conditions were statistically optimized using RSM with a BBD. The overall results demonstrated that the BBD is a well-matched method for optimizing the electric field conditions. The repeated experiments at optimal conditions recorded a solubilization of 10.26±0.14%, which exhibited high agreement with the predicted response value. Subsequently, the combination of electric field and ultrasonication for disintegration of WAS was statistically optimized using the BBD. The confirmation test showed that the disintegration efficiency of WAS was significantly enhanced (47.28±0.20%) by the EF-U, which corresponded to 98.3% of the predicted value, though this was limited to highly disintegrated WAS when the electric field or ultrasonication was applied individually. We conclude that electric fields are a useful option for the combined treatment of WAS because there is no chemical addition and it is an ep4 receptor effective method.

This work was supported by Grants from the Korea Research Council of Fundamental Science and Technology (Project No. 2N38090) and the KIST Institutional Program (Project No. 2E24562).

Diet rich in fruits and vegetables has been proven to exert a positive effect on preventing the development of a considerable number of chronic diseases such as cancer and cardiovascular diseases. This protective effect has been attributed to the high concentrations of functional compounds [1]. For the effective utilization of ingredients present in consumed foods, gut microflora plays an important role [2]. In this context, prebiotic oligosaccharides are considered to be key compounds. Since the late 1990s and the birth of the prebiotic concept, many scientists have started studying the health properties of prebiotic compounds which resulted in a number of scientific publications describing them in relation to human health [3,4]. The major prebiotic oligosaccharides in the market are fructo-oligosaccharides and galacto-oligosaccharides whose bioactive properties have been evaluated using a range of in vitro and in vivo methods [5–8].
The oligosaccharides are obtained by extraction from natural sources or by chemical or enzymatic synthesis [9–12]. For extraction of low-molecular weight carbohydrates such as oligosaccharides from plant material, the optimal solvent is water [13]. However, water also facilitates interference between carbohydrates and other water-soluble substances such as certain polysaccharides and proteins [14]. Thus, most of the conventional extraction methods for oligosaccharides often use high concentrations of alcohol [15].
The use of ultrasound assisted extraction (UAE) instead of traditional extraction has been increasing and its use has been investigated in the pharmaceutical, chemical and food industries. UAE became a good alternative extraction method when compared to classical extraction methods because of its high efficiency, low energy requirement and low water consumption (no reflux or refrigeration are needed) [16]. The improvement of the extraction process caused by ultrasound is attributed to the disruption of the cell wall, reduction of the particle size and the enhancement of the mass transfer of the cell content to the solvent caused by the collapse of the bubbles produced by cavitation [17]. Therefore, UAE provides increased extraction yield, increased rate of extraction, reduced extraction time and higher processing throughput along with the advantage of usage of reduced temperature and solvent volume which is very advantageous for the extraction of heat labile compounds [18]. The application of UAE in food processing technology is of interest for enhancing extraction of components from plant and animal materials such as phenolic compounds, anthocyanins, aromatic compounds, polysaccharides, oils and functional compounds [19–25]. Among all applications, UAE is nowadays considered as the most feasible and economically profitable large-scale application of ultrasound in the food field [26].

eletriptan Supplier The effect of mechanical index a

The effect of mechanical index (a standard scale of acoustic cavitation), in irradiated group with ultrasound mechanical index of 0.40 showed a significant increase in proliferation spermatogonial stem cells. In 0.51 mechanical index group an increase in proliferation was observed so that comparing to 500 thousand initial cells, it was 2.89±0.07 and 2.17±0.10 respectively in the two groups. The effect of secondary factors i.e. LIUS on the growth and proliferation of spermatogonial stem eletriptan Supplier well have been observed in the cell groups. Mohaghegh [31] similarity studied effect of LIUS on spermatogonial stem cells, the cells were radiated by intensity of 100, 200 and 300mW.m−2 at a frequency of 1MHz, and the results showed that continuous LIUS of 200mW.m−2, causing a significant increase 1.90±0.06 times in the proliferation of the initial cells compared to controls 1.63±0.03 after seven days of cultivation. These results are consistent with the findings of the present study. But in the study of Mohaghegh did not mentioned ultrasound mechanical index. As well as a culture plate don’t set based on the specified distance to ultrasonic transducer and the intensity was selected as optimal intensity only for experimental testing. Jong [41] studied on mesenchymal stem cells derived from human umbilical cord also showed 40kHz (LIUS), intensity less than 25 to 35 watts per square centimeters and periods of 100, 300 or 600s and duty factor 50% improves proliferation of mesenchymal stem cells derived from human umbilical cord.
In the report of British Medical Ultrasound Society [7,42], cavitation threshold is by mechanical index higher than 0.7 as this amount is related to cavitation threshold in the tissue. In recent studies to control the risks of diagnostic and clinical applications of ultrasound, the mechanical index have been introduced for certain organs. In the Kotopulis study [43], to avoid the dangers and harm to the babies lung, mechanical index less than 0.3 and to prevent damage to the intestinal the mechanical index between 0.3 to 0.7 were proposed. At Hlinomazova study [44] the mechanical index of 0.23 for eye applications was introduced in a report of the Food and Drug Administration .According to studies and concerning mechanical index range of cavitation threshold, the mechanical index in water and culture medium are less than 0.7, because the eye tissue and culture medium is made of water -equivalent material. Thus, considering cavitation threshold of different materials and environment and cells are necessary to find effective mechanical index ranges on proliferation for the used frequencies.


Conflict of interest

This study was approved by Faculty of Medical Sciences of Tarbiat Modares University. This work was supported in part by the Iran National Sciences Foundation (INSF).

Camptothecin (CPT) is a quinoline alkaloid obtained from different plant sources such as Nothapodytes nimmoniana[1], Ophirrohiza mungos, Eravatamia heyneana[2] and Mostueabrunonis[3]. CPT was first isolated from Camptotheca acuminata by Wall and Wani in 1960 [4]. CPT showed potent anticancer activity and attracted immense interest worldwide due to its unique mechanism of action of selective inhibition DNA topoisomerase I. CPT has emerged as the most prominent lead for the development of new anticancer drugs [5,6] though by itself is not used clinically due to severe cytotoxic effects and pharmacokinetic problems. Semisynthetic forms, topotecan, and irinotecan approved by United States Food and Drug Administration (USFDA) are currently marketed as most promising anticancer agents worldwide for eletriptan Supplier treating small-cell lung cancer, ovarian cancer, and colorectal cancer [7,8]. Other CPT analogues such as nitrocamptothecin, lurtotecan, exatecan, gimatecan, karenitecan, diflomotecan are currently in different stages of preclinical and clinical trials [9].
Efforts have been directed towards the development of practical and concise total synthesis of CPT and their analogues [9–11]. However, the synthetic routes are not yet suitable for commercial exploitation due to low yield and the high cost of reagents [9]. Till date synthetic route developed by Comins et. al. remains the most promising with overall yield of 12.5% [12,13]. Therefore as of now the natural source is the only source of CPT. Currently, plant species C. acuminata (China) and N. nimmoniana (India) are the convenient sources available for industrial scale extraction and purification. CPT is not localised but distributed in different parts the plants. In the case of N. nimmoniana from Mahabaleshwar region of Maharashtra state in India concentration of CPT reported in different parts are roots (0.68%), stem (0.81%), fruits (1.22%) and leaves (0.1%) [14]. With increasing demand of CPT and its highest occurrence in N. nimmoniana among the possible natural sources, development of efficient extraction of CPT from this plant is an important research project.

Additionally in order to further increase the value

Additionally, in order to further increase the value of biomass, extraction pretreatment is also widely used. Extractives derived from biomass materials are believed to possess high utility value in cosmetics, medicines, and other consumer goods. Nevertheless, traditional extraction technologies such as basic maceration or Soxhlet extraction (SE) are inefficient and time consuming, which stimulates researchers to explore better methods for extraction. Based on previous studies, ultrasonic treatment has been used in a wide range from extractions to purifications [10–12], because it provides a unique physicochemical environment for raw material processing [13]. The application of ultrasound intensifies mass and heat transfer in reactions, and enhances the contact and disengagement of heterogeneous reactants, intermediates and products. It is an interesting potential alternative for enhancing industrial processes in applications such as wood pretreatment [14,15], extraction of natural products [16,17]. Moreover, ultrasound-assisted extraction (UAE) has been investigated by many researchers. Li et al. [18] used 20kHz high-intensity ultrasound to extract oil from soybeans, and Hemwimol et al. [19] found that UAE improved the extraction efficiency of anti-oxidant activity compounds and anthraquinones in Morinda citrifolia. Such studies confirmed that ultrasound was conducive to the extractability of biomass and reduced the time necessary for successful extraction in different samples, but they didn’t provide sufficient discussion on the changes in properties of extracted biomass.
Though biomass contains relatively few extractives, they have an important effect on the material’s thermochemical characteristics [20]. Guo et al. [21] studied the differences in pyrolysis between original biomass and extracted residues and reported that extractives facilitated the formation of acetic MG 149 manufacturer and inhibit the formation of levoglucosan. Wang et al. [22] investigated the influence of extractives on the yield and composition of oil obtained from biomass samples and found that extractives enhanced not only oil yield but also alkane content. Moreover, Mészáros et al. [23] extracted Robinia pseudoacacia with different solvents and investigated the thermal behavior and composition of extractives via TG/MS, Py-GC/MS, and THM-GC/MS.
In summary, despite numerous valuable contributions to the literature on pyrolysis and the utilization of extraction including UAE [24,25], to the best of our knowledge, there remains a lack of information on the influence of ultrasound-assisted extraction on the biomass pyrolysis process – especially for eucalyptus, which is regarded as an attractive potential renewable resource. The benzene-ethanol extractions with and without application of ultrasound were investigated in this study to determine the effects of UAE on the pyrolysis characteristics and kinetic parameters of eucalyptus.

Materials and methods

Results and discussion

In this study, UAE was proved to be a suitable and efficient pretreatment for biomass. The results indicated that UAE exerted significant effects on the pyrolysis of eucalyptus by altering materials chemically and physically. Cavitation caused by ultrasound could enhance the permeability and intensify mass transfer in biomass, which increased the amount of extractives by 139.21% than SE. In TG and kinetic analysis, UAE samples showed a stronger maximum weight loss rate (−22.92%/min) and higher activation energy (206.09kJ/mol) during pyrolysis. As shown in chemical analysis and TG-FTIR results, though the impact was slight, ultrasound treatment did break down some lignocellulose in amorphous regions and increased access to cellulose. Overall, the findings represent novel insight into biomass pyrolysis and may serve as a valuable reference for optimizing the application of UAE for material pretreatment.

One consistently reported trend seen with

One consistently reported trend seen with the obese vs. lean state in dogs, is the increased circulating MCP-1 concentrations in canine obesity. Our study found that obese Labrador retrievers have a thirty percent increase in fasting serum MCP-1 concentrations compared with lean controls. Interestingly, our study also found a significant correlation between MCP-1 concentrations and age, indicating that for every one year increase in age MCP-1 levels increased an average of 3%. In addition to this present study showing elevated MCP-1 concentrations with increasing adiposity, two other studies have indicated a significant decrease in MCP-1 concentrations from an obese to a lean state after weight loss in dogs (Wakshlag et al., 2011; Bastien et al., 2015). This is in contrast to previous research that showed no significant change in MCP-1 after weight loss in pet dogs, however this study reported great variations in concentrations of MCP-1 detected using a different assay format, and surmised it may be related with the assays cross reactivity or sample size of the study (German et al., 2009).


This research was supported by a grant from Hill\’s Pet Care.
Labrador serum collections were part of a larger cohort supported by the Cornell Biobank, NIHR24 GM0829-A1 and R24 GM082910-S1.

The importance of CD8+ T Exendin-3 (9-39) amide in control of lentiviral infection of humans, macaques and cats has been apparent for decades (Flynn et al., 1999; Jeng et al., 1996; Kannagi et al., 1988; Walker et al., 1986). Studies of different CD8+ subset function in innate and adaptive immune responses has indicated that central memory CD8+ T cells are the CD8+ cell subset with the most in vitro viral suppressive activity (Buckheit et al., 2012; Lopez et al., 2011; Mendoza et al., 2012; Ndhlovu et al., 2012).
Historically, large granular lymphocytes (LGLs) have been considered either NK cells or CD3+ cells that participate in antibody-dependent cytotoxicity (Chan et al., 1986). LGLs represent 10–15% of the peripheral blood mononuclear cell (PBMC) population in healthy individuals (Loughran, 1993). This low percentage of LGLs has made detailed analysis difficult and thus, most information about LGLs is derived from studies on patients with LGL leukemia (Alekshun and Sokol, 2007). LGLs have only been anecdotally reported during HIV infection, and have usually been associated with neoplasia (Boveri et al., 2009; Pulik et al., 1997). However, a study of HIV-infected patients reported that LGLs persisted between 6 and 30 months and had a consensus phenotype in PBMC of activated CD8+ T cells expressing CD57. LGLs in these patients represented polyclonal T cells (Smith et al., 2000).
We have previously reported that FIV-infected cats had a LGL lymphocytosis that was temporally associated with neutropenia, increased PBMC-associated FasL mRNA and decreased in PBMC FIV proviral loads (Sprague et al., 2010). We report here that these LGLs correlated with cells that expressed low surface CD8 and FAS, that were polyclonal T cells and that expressed similar intracellular interferon-γ in FIV-infected animals compared to FIV-naive control animals. These cells also expressed decreased surface CD3epsilon (CD3ɛ) levels in FIV-infected animals compared to FIV-naive controls and this decreased expression was upregulated via cytokine rescue. Most interestingly, we found that LGLs arise during acute SIV infection in macaques and are detectable and elevated during HIV infection in humans, documenting the importance and presence of these cells during lentiviral infections in three different species.

Materials and methods


We identified the phenotype of LGLs that arise during acute FIV infection and persist in chronic infection as CD8lo+FAS+ T cells. CD8lo+FAS+ T cells from chronically infected cats had decreased CD3ɛ and similar expression of IFN-γ compared to the same cells from the FIV-naïve counterparts. These cells did not express CD56, were found to be polyclonal T cells, and did not represent a significant source of virus in FIV–infected cats. In addition, we identified LGLs in blood smears of macaques with SIV infection and in humans with HIV infection, demonstrating this cell phenotype is not unique to FIV.

To the best of our knowledge there have been no

To the best of our knowledge, there have been no reports of quail or chicken strains producing eggs with an IgY concentration that is not proportional to the blood IgY concentration, suggesting that the maternal IgY transfer system is a fundamental and basic physiological phenomenon to ensure survival of the offspring. In fact, Grindstaff (2008) reported that growth-suppressive effects of antigen exposure during the development of quail offspring are ameliorated by the presence of maternal antibodies, but in the absence of specific maternal antibodies, the offspring must consume their ability and energy source to protect the antigen. On the other hand, if a quail or chicken strain exists that has a distinctive egg yolk IgY concentration that is not proportional to its blood IgY concentration, the strain would be a useful experimental model for studying the mechanisms underlying maternal IgY transfer in avian species.
The concentration factor of egg yolk IgY against blood IgY provides a clue to the mechanism by which blood IgY is selectively transported into ovarian oocytes. In our previous study, the concentration factor of egg yolk IgY against blood IgY was approx. 1.7 regardless of the chicken strain (Kitaguchi et al., 2008a). The same result was obtained in the present study; the concentration factor of egg yolk IgY against blood IgY was 1.5–1.7 in all quail strains. Vitellogenin, an egg yolk precursor synthesized in the liver, is incorporated into maturing oocytes by vitellogenin/VLDL receptor expressed in the oocyte plasma membrane. The concentration of egg yolk phosvitin, a component of vitellogenin, was nine-fold higher than that of blood phosvitin (Cutting and Roth, 1973). Riboflavin and its binding protein are also incorporated into maturing oocytes by the same vitellogenin/VLDL receptor, and they are concentrated six-fold during blood-to-egg yolk transfer (Mac Lachlan et al., 1994). The concentration factor of quail IgY (1.5–1.7) was considerably lower than those of vitellogenin and riboflavin binding protein. However, the richness of IgY in blood [approx. 10-fold higher against vitellogenin (Roth et al., 1976) and 106-fold higher against riboflavin (Naber, 1993)] should be considered in the interpretation of IgY enrichment in egg yolks.
In our previous study, a single amino SCH727965 substitution of the Tyr363 residue located on the Fc domain to an Ala363 residue seriously damaged the IgY-Fc transport into egg yolks (Takimoto et al., 2013). In addition, the comprehensive substitution of Tyr363 with other amino acids revealed that the residues at Tyr363 needs to be allocated with aromatic amino acids to maintain the IgY-Fc transport ability (Murai et al., 2013). In fact, CHIR-AB1, a member of the leukocyte receptor family found in chicken, did not bind to an IgY mutant with a substitution of Tyr363 residue to Ala363 (Pürzel et al., 2009). However, CHIR-AB1 seems to have limited relevance in the IgY transport into egg yolks because of its scarce gene expression in ovarian follicles (unpubl. data). FcRY is responsible for the transfer of yolk IgY to embryonic circulation. However, relevance of FcRY on maternal blood IgY to the egg yolks is unlikely, because human IgG does not bind to FcRY (West et al., 2004) even though human IgG is transported into egg yolks. In addition, FcRY gene expression is undetectable in the ovarian inner layers (Kitaguchi et al., 2010). Taken the present results and recent reports together, we propose again that unidentified receptor involved in maternal IgY transfer exists in the maturing oocytes in avian species.

This work was supported by a Grant-in-Aid (No. 25450407 to A.M.) from the Japan Society for the Promotion of Science. We are thankful to the National BioResource Project – Chicken and Quail (http://www.agr.nagoya-u.ac.jp/∼NBRP/) for providing quail strains (L, AWE, DB, PS, WE).

Enzootic bovine leukosis (EBL) is the most common, infectious, fatal neoplastic disease of cattle. The etiological agent of EBL is an oncogenic, B-lymphocytotropic, deltaretrovirus, designated BLV (Bovine Leukemia Virus), which infects cattle with diverse clinical outcomes. Most cattle infected by BLV remain clinically silent in an aluekemic state, approximately 30% of infected animals develop a benign polyclonal proliferation of B-cells, called persistent lymphocytosis (PL), and, lastly, lethal lymphoma or lymphosarcoma occurs in less than 5% of infected animals, after a long latency period (Rodríguez et al., 2011; Gillet et al., 2007). Despite a few inconsistencies in some of the studies, the general view emerged as BLV-infected cows were associated with reduced economic value, due to higher susceptibility to infectious diseases, decreased productivity, lower reproductivity and higher culling rate (Trainin and Brenner, 2005) with annual economic losses estimated for $525 million only for US (Bartlett et al., 2014). In EU countries, additional economic losses are due to trade limitations and eradication costs (European Food Safety Authority AHAW Panel, 2015).

Endotoxin tolerance was investigated in several different species and was

Endotoxin tolerance was investigated in several different species and was shown to vary in duration. In vivo endotoxin tolerance lasts approximately 3 weeks in rats and mice (Sanchez-Cantu et al., 1989; Lu et al. 2008). In people, the duration of in vivo endotoxin tolerance is between 2 and 5 weeks (Kox et al., 2011; Rittig et al., 2015). The purpose of the present study was to determine the duration of endotoxin tolerance in horses, in vivo. We hypothesized that horses would develop endotoxin tolerance, exhibiting decreased clinical responses to repeated endotoxin administration and diminished proinflammatory gene purchase HG-9-91-01 and that the tolerance response would last approximately 2–3 weeks, similar to other species.

Materials and methods


The results of this study demonstrated that horses developed endotoxin tolerance that was maintained for at least 7 days, in vivo, but subsided within 14–21 days, which is similar to the duration of endotoxin tolerance in rodents and people (Sanchez-Cantu et al., 1989; Lu et al. 2008; Kox et al., 2011; Rittig et al., 2015). Horses responded systemically to endotoxin, developing fever, tachycardia, tachypnea, and evidence of pain (Allen et al., 1996; Fessler et al., 1989; MacKay et al., 1991; Jacobs et al., 2013; Moore et al., 2007; Nieto et al., 2009; Tadros and Frank, 2012; Toth et al., 2008). Horses also developed leukopenia and neutropenia, followed by rebounding of these circulating white blood cell populations, and significantly increased proinflammatory cytokine gene expression in whole blood following endotoxin exposure as was previously reported (MacKay et al., 1991; Tadros and Frank, 2012) confirming the efficacy of the equine endotoxemia model. The clinical signs associated with the inflammatory response and the gene expression of TNFα were diminished when repeated endotoxin infusion occurred 7days after a previous endotoxin exposure, signifying the development of endotoxin tolerance in these horses (Allen et al., 1996; Tadros and Frank, 2012). Evidence of endotoxin tolerance abated by 14–21 days. When endotoxin was administered to horses 14–21days following the previous endotoxin infusion, clinical signs were similar or even enhanced and there was no significant change in the purchase HG-9-91-01 expression of TNFα compared to measurements taken following the endotoxin treatment 14–21days earlier. These results suggest that in vivo endotoxin tolerance lasted at least 7days in this equine endotoxemia model but not 14–21 days, such that the use of repeated measures designs may be considered with sufficient amounts of time between endotoxin exposures. Additional work is required to determine in vitro and ex vivo endotoxin tolerance intervals which will likely differ and be affected by endotoxin dose, product and duration of endotoxin exposure.
The systemic responses measured in the horses in this study, including fever and tachycardia following endotoxin administration, were consistent with reports of previous equine endotoxemia models (Allen et al., 1996; Fessler et al., 1989; MacKay et al., 1991; Jacobs et al., 2013; Moore et al., 2007; Nieto et al., 2009; Tadros and Frank, 2012; Toth et al., 2008). Shorter duration of fever and degree of tachycardia in endotoxin tolerant horses were previously reported (Allen et al., 1996) and may be associated with the diminished TNFα response or prostaglandin E production (not measured in this study), and lower pain scores. The cause for the elevated respiratory rate at 240 and 300min is unclear, as palindrome occurred after the highest values for pain score and rectal temperature, two events that might induce increased respiratory rates. Metabolic acidosis may have stimulated a compensatory hyperventilation and respiratory alkalosis, however blood gas variables were not assessed in this study. Elevated respiratory rate at 4–8h after endotoxin infusion was previously reported in horses (Allen et al., 1996). Partial pressure of carbon dioxide (CO2) in the blood was not measured in this study so enhanced CO2 production, perhaps caused by increased metabolic activity, may have stimulated the increased respiratory rate, but this remains unknown. The diminished respiratory rate and duration of tachypnea in horses 7days following previous endotoxin administration further supports the development of endotoxin tolerance in these horses. The similar and then enhanced respiratory rate in horses that received endotoxin 14–21days after a previous endotoxin exposure suggests the absence of endotoxin tolerance in horses by 14–21days post endotoxin exposure.

br Comment IMT of the bladder has many monikers including

IMT of the carboxypeptidase has many monikers including inflammatory pseudotumor, inflammatory pseudosarcomatous fibromyxoid tumor, plasma cell granuloma, nodular fasciitis, pseudosarcomatous myofibroblastic tumor, fibromyxoid pseudotumor, and, when seen within 3 months of a surgical procedure, postoperative spindle-cell nodule. Regardless of the nomenclature, the most often clinical presentation of IMTs is painless gross hematuria. More rarely, they can cause local symptoms such as pelvic pain, penile discomfort, or voiding symptoms. Symptoms often lead to radiologic evaluation. IMT can either appear as a well-defined pedunculated mass or as simple bladder wall thickening on ultrasound with variable echogenicity. It can be difficult to characterize these lesions on noncontrast CT. Similarly, on ultrasound, IMTs can appear as polypoid masses or simple bladder wall thickening when able to be visualized at all. Contrasted CT is more revealing and shows an enhancing mass or thickened region of the bladder. magnetic resonance imaging generally shows lesions that are isointense to skeletal muscle with a surrounding enhancing ring consistent with their underlying cellular composition and inflammatory nature, respectively.
After radiologic identification of a bladder mass, tissue diagnosis is normally obtained from cystoscopic biopsy. At a microscopic level, the alternative titles for IMTs are an apt description of the lesion. Spindle-cell myofibroblasts and inflammatory components including prominent plasma cells are the histologic hallmarks. They have features in common with malignant conditions such as leiomyosarcoma, rhabdomyosarcoma, and sarcomatoid carcinoma. They are spindle-cell neoplasms and can have cytologic atypia and an infiltrative growth pattern, but unlike sarcomatous, malignant, spindle-cell neoplasms, there is not prominent mitotic figures, myxoid degeneration, predominance of neutrophils, or extensive necrosis. Immunostaining is positive for vimentin, smooth muscle actin, and occasionally desmin. Frequently (33%-89%), a gene fusion product at chromosome 2p23, ALK-1, is present and differentiates IMTs from sarcomatoid malignancies.
The malignant potential of IMTs is incompletely characterized. IMTs have been known to recur after local excision in 10%-20% of cases, and histologic progression has been reported. A majority of these lesions follow a benign course and do not recur. Despite the concern for malignant potential and invasive growth pattern, series report a predominance of transurethral resection as the initial management strategy. More rarely, patients undergo partial cystectomy and, as an exception, cystectomy with urinary diversion (usually when diagnostic uncertainty exists pertaining to the malignant potential of the lesion). Serial ultrasound evaluation postoperatively and surveillance cystoscopy are prudent after resection. This is especially true when the lesion is resected transurethrally considering the invasive growth pattern of many IMTs.
IMTs have been confused with malignant conditions in the past including rhabdomyosarcoma or leiomyosarcoma based on commonalities in pathologic tissue examination, radiologic appearance, and clinical presentation. Confusion with eosinophilic cystitis, another benign inflammatory bladder tumor has not been reported as problematic in the literature. Microscopic evaluation of eosinophilic cystitis is characterized by a dense inflammatory reaction with eosinophilic prominence unlike in an IMT where eosinophilic infiltrate is scant or absent. In our case, the mucosa overlying the inflammatory lesion was densely infiltrated with eosinophils and there was a paucity of characteristic spindle cells, thus the diagnosis of what appeared to be classic eosinophilic cystitis. This is typically treated with a course of steroids, and in some cases, observation alone is sufficient. In our case, the uncharacteristic lack of response to appropriate medical therapy led to increasing diagnostic uncertainty and ultimately to open resection.

The difficulty in identifying a uniform postoperative pain

The difficulty in identifying a uniform postoperative pain management strategy arises due to the lack of well-conducted comparative trials as well as wide variations in physician and institutional preference. Morrison et al conducted a survey of pediatric urologists on their pain management strategies for various urological procedures. The study was affected by an only 26% response rate, and was characterized by a wide discrepancy in practice. For bilateral open ureteral reimplantation, 54% of urologists would use only local anesthetic, whereas 42% would use an epidural or caudal injection of analgesics. For the laparoscopic orchiopexy, 69% reported using local anesthetic, and only 19% used an epidural or caudal.
Pain is predominantly subjective, precluding empirical analysis when assessing a cohort within a broad age range, as was the case in our study. Older children and younger children sense and express pain very differently. Identifying the source of the pain is also difficult, as pain may be a result of acetylcholine chloride spasms from the stents or catheters in place, or even from the discomfort of being in a hospital bed. The perception of pain also will vary in children of the same age, depending on biological, psychological, and social factors. Although race was not considered as a factor for this study, Sadhasivam et al demonstrated that pain sensitivity may vary by race, as some groups tend to have a lower tolerance for pain. African Americans, for example, had a lower risk of experiencing the negative side effects associated with opioids analgesics, and Caucasian children demonstrated a lower morphine clearance rate. These factors, if considered for a future study, may assist in targeting postoperative pain control more effectively.


The authors report the findings from their retrospective review of pediatric patients who underwent laparoscopic urologic surgery and compared the postoperative course between those who had single-dose intrathecal opioid (ITO) prior to incision and matched them to a cohort who instead had local anesthetic infiltration (LAI) at wound sites. They found no statistically significant difference in postoperative narcotic usage or pain scores between the two groups.
This study was an adjunct to a study published from their institution by Ganesh et al in 2007 displaying the benefits of low-dose ITO, morphine 4-5 mcg/kg, for a variety of pediatric surgeries in 2007. In the previous study of 187 patients, 80% of the patients did not need rescue opioids in the first 8 hours postoperatively and only 52% needed oral rescue analgesics in the first 24 hours. Any potential benefits of spinal opioid must be weighed against the risks and side effects they may cause. Spinal opioids can cause nausea and vomiting, itchiness, urinary retention, and postoperative respiratory depression. The placement of the spinal medication has a risk of postdural puncture headache or nerve injury. In Ganesh\’s study of 187 patients, 3 had unintended dural puncture with the introducer needle, 1 leading to postdural puncture headache and 2 had brief periods of hypoxia.
A major limitation of the LAI vs ITO paper is that there was no standardized protocol for administration of postoperative medication, which makes geographic isolation hard to compare medication totals between these 2 groups with absolute certainty. Despite this possible limitation, the findings are similar with other studies comparing ITO use in laparoscopic, and even some open adult surgeries, to other analgesia regimens (ie, intravenous patient-controlled analgesia use). Although these other studies on ITO use did find a decrease in postoperative opioid use and pain scores in the ITO groups, they found no overall differences in recovery between the 2 groups and that patient satisfaction for pain control was not improved despite initial decrease in postoperative opioid use in the ITO group.

br CT br Conclusion br Conflicts of interest br Sources



Conflicts of interest

Sources of funding

Ketamine has been used as an anesthesia agent since the 1960s and as a “recreational drug” for at least the past 2 decades, particularly in nightclubs, because of its well-known “k-hole effect” and psychological dissociation symptoms. According to a ketamine urinary analysis for drug abusers in Taiwan, the positive results of ketamine doubled in 8 years (15.4% in 2006 and 31.6% in 2015). In 2012, a study in the UK, which used online questionnaires to survey drug use among 3806 participants via the website, showed that the prevalence of ketamine use in the last year was 33.8% and 17% of ketamine users were found to be dependent on the drug. There is a selection bias in this study because the study was promoted by a national dance music magazine and website, and the participants may not represent the normal population. In fact, the real prevalence of ketamine abuse may be underestimated, because the issue of privacy and the illegal status of ketamine make it buy H 89 difficult to evaluate the undiscovered ketamine-abusing population.
By contrast, although the World Health Organization concluded that international control of ketamine is not really necessary, the drug should be kept under close surveillance. The evidence of increasing ketamine abuse due to its low cost, easy availability to adolescents, as well as the relatively lenient penalty for ketamine use demands more stringent laws against the drug. Thus, although ketamine is now classified as a class C drug in Taiwan and many other countries in the world, the demand for reclassifying ketamine as a class B drug is increasing.
Ketamine-induced uropathy (KIU) was first described in 2007 by Shahani et al, with findings of ketamine-associated ulcerative cystitis. Thereafter, multiple cases of KIU were reported, and 20–26.6% of frequent or recent users of ketamine reported experiencing urinary symptoms. In addition, the relationship between the dosage and frequency of drug use and urinary symptoms has been shown, however, it was difficult to correlate. Nevertheless, the diagnosis of KIU remains challenging even today. An increasing number of patients present to urological services for ketamine-associated urinary symptoms. General physicians as well as urologists should be educated about KIU to make patients aware of the disease and prevent them from presenting at a relatively later stage. Women who present with pelvic pain similar to the pains caused by pelvic inflammatory disease, ovarian cyst accident, or pressure symptoms from uterine fibroids may be referred to gynecologists. An awareness of KIU should also be spread. Privacy is another issue of diagnosis challenge because patients tend to hide or deny the illegal use of ketamine.
KIU can involve both the lower and the upper urinary tract, with the lower urinary tract being predominantly affected. The diagnosis of KIU is based on the clinical presentation and a history of ketamine use. KIU investigation is essential, and the aims of investigating KIU are as follows: (1) confirming the diagnosis of KIU; (2) excluding other causes contributing to the symptoms; (3) evaluating the immediate complications and upper urinary tract involvement; and (4) providing long-term surveillance. Among the investigating tools, image modalities such as computed tomography urography (CTU) and rigid cystoscopy are most important. CTU seems to be superior to rigid cystoscopy because CTU is noninvasive and does not require general anesthesia.

Prevalence of ketamine cystitis among a Chinese population
Since the first report of street ketamine-associated cystitis involving 10 young Chinese patients by the authors\’ team from Hong Kong in 2007, more cases of the new clinical syndrome of ketamine cystitis were subsequently reported from other Chinese regions: Taiwan and China. The first case series in mainland China was from Nanfong Hospital, Guangzhou, China in 2008. As for Taiwan, the first reported case series was from Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan in 2009. Extremely low market price and easy accessibility to the drug have made ketamine the drug of choice among young people. Furthermore, cracking down of ketamine trafficking is particularly difficult, as Minichromosome is legally produced and shipped for use in both human and veterinary medicines, which can be easily diverted for illicit purposes. This legal availability may help explain why ketamine came to prominence as a recreational drug in the past number of years.

br Materials and methods br

Materials and methods

Among the 820 patients with PCa, the mean age and PSA level were 66.3 years and 14.24ng/ml, respectively, and 515 patients (62.8%) had clinical T1c stage disease. After RP, 262 extracapsular extensions (ECE), 79 seminal vesicle invasions, and 10 Staurosporine neck invasions were detected, and 360 patients (43.9%) had pathologic disease that was not organ confined. After RP, most patients had pathologic Gleason score 7 (78.7%), whereas 61 patients (7.4%) had pathologic Gleason score 6 and 40 patients (4.9%) had pathologic Gleason score 8.
The genotype frequencies in all patients according to advanced disease, which were not confined to the prostate, were analyzed using a logistic regression model, and the data are shown in a Manhattan plot (Fig. 1). The results from genotyping 242,186 SNPs by exome arrays using blood DNA revealed that 5 SNPs (rs6804162 in chromosome [Chr] 3, rs8055236 in Chr 6, rs56335308 in Chr 8, rs6104 in Chr 18, and rs12618769 in Chr 2) were significantly associated with advanced stage in men who underwent RPs (Table 2). The rs6804162, rs56335308, and rs12618769 SNPs were positively correlated with advanced stage, and the rs8055236 and rs6104 SNPs were negatively associated with advanced stage of PCa. Among patients who had genetic variations that positively associated with a SNP, 62.5% had pathologic T3 stage, which was higher than the average rate of 43.9%.
The multivariate models incorporated variables, such as age, initial serum PSA levels, biopsy Gleason scores, clinical stage, percentage of positive core, and cumulative tumor length in cores, including and excluding the lead SNP variants shown in Table 3. In the preoperative clinical model, to predict pathologic advanced stage, PSA level, biopsy Gleason score, percentage of positive core, and tumor length in cores were significant predictors, and the accuracy level of the clinical model derived from the AUC of receiver operating characteristic was 0.839 (95% CI: 0.806–0.870). When the 5 SNP variants were added to the clinical multivariate model, the resulting clinicogenetic model had more accurate predictive value for identifying pathologic advanced stage (accuracy level: 0.872, 95% CI: 0.819–0.905), with a significantly higher level of accuracy than that of the clinical model (P<0.0001, Fig. 2).
Pathologic stage had been reported to be an important factor in influencing outcomes after RP. An update of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) study showed that extracapsular tumor growth was associated with a 7-fold increase in the risk of death due to PCa, when compared with patients without these lesions (relative risk = 6.92) [9]. Therefore, patients who are at a high risk, as determined by extracapsular tumor extension disease of PCa, have been traditionally treated with a combination of androgen deprivation therapy and radiation therapy [10]. However, PCa is undoubtedly a clinically and pathologically heterogeneous disease [11]. Approximately 13% to 27% of the patients with clinically T3 PCa were actually older than average and had pathologically organ-confined disease at RP [12–16]. From these observations, it appears that an important heterogeneity exists in the outcomes of patients presenting with locally advanced PCa. The need for improved prediction of surgical pathology in these patients is a key step in providing appropriate treatment to patients with PCa [17].
Until now, several predictive models have been introduced. One of the most well-known and used predictive models for staging prediction was developed by Partin et al. in 1997 [18]. Specifically, they reported the first lookup tables for prediction of organ-confined disease (AUC = 67.3%), ECE (AUC = 59.6%), and seminal vesicle invasions (AUC = 79.6%) [19]. Since then, many reports have shown similar results using external and internal validation sets. For example, Blute et al. [20] provided strong evidence that the sensitivity and specificity of the Partin tables for American clinical sites were similar to those that were originally reported. Gamito et al. [21] relied on preoperative characteristics to predict ECE in 4,133 subjects, with an AUC of up to 76%. Ohori et al. [22] proposed a nomogram predicting side-specific ECE Staurosporine in 763 North American patients. The proposed nomogram achieved a final accuracy of 81% in predicting side-specific ECE. Satake et al. [23] recently showed enhanced predictive preoperative model using biopsy parameters, such as positive core percentage, and showed an accuracy level of 0.799. In our analysis, we built the clinical model to include the percentage of positive cores and cumulative tumor length in cores, and we showed that its accuracy value was 0.839. In addition to the clinical factors, we analyzed the genetics of all enrolled patients who underwent RP, and we found a significant genetic variation associated with pathologic advanced stage. When we added this genetic information to the clinical model to identify additional predictive gain, the accuracy of the final clinicogenetic model was 0.872, which was significantly increased.