BDNF s role as a biomarker has

BDNF’s role as a biomarker has not been completely established by the data and results obtained thus far. For example, its specificity to schizophrenia has not been demonstrated; decreased levels of BDNF have also been found in patients with neurodegenerative disorders and other neuropsychiatric ailments. Nevertheless, BDNF’s characterization as a biomarker for the cognitive dimension of schizophrenia appears to be a promising line of investigation, although more study and analysis on this relationship need to be performed (Penadés et al., 2013). Choosing BDNF as an indicator of the cognitive dimension of schizophrenia, while tempting, remains premature.


Role of Funding Sources


Conflict of Interest


Cognitive deficits are a primary characteristic of schizophrenia that significantly impact patient functioning (Bowie et al., 2006; Green et al., 2000). Among other hypotheses, it has been postulated that the primary cognitive alterations in schizophrenia (working memory and executive functions) are due to dysfunction in the frontal lobe, specifically hypodopaminergia in the prefrontal GSK503 (PFC). Dopaminergic tone in the PFC is essential for cognitive functioning. The catechol-O-methyltransferase (COMT) enzyme is vital for the regulation of dopamine levels in the PFC (review: Tunbridge et al., 2006). A functional polymorphism of the COMT gene (rs4680) significantly impacts the dopamine levels in the PFC. The Val allele is associated with greater enzymatic activity and, therefore, with greater dopamine degradation in the synapses of the PFC (Chen et al., 2004; Lachman et al., 1996). This genetic polymorphism, although weakly linked to the risk of a schizophrenia diagnosis (Glatt et al., 2003), is a good candidate for understanding the relationships between dopamine levels in the PFC and cognitive functioning.
Many studies have investigated the link between cognition and the Val158Met COMT polymorphism in both healthy controls and clinical populations with varied results (review: Dickinson and Elvevåg, 2009). One of the first links between the COMT enzyme and executive functions (Egan et al., 2001) has been replicated in other studies (Joober et al., 2002; Mattay et al., 2003; Rosa et al., 2004), yet other groups have been unable to reproduce the results (Diaz-Asper et al., 2008; Ho et al., 2005; Tsai et al., 2003). Other cognitive phenotypes have also been studied including working memory, attentional control, and episodic memories, with both positive (Blasi et al., 2005; Goldberg et al., 2003) and negative results (Bilder et al., 2002; Stefanis et al., 2004).
Many of the studies that explore the association between cognition and the gene that encodes the COMT enzyme use neuropsychological examinations, which are sensitive to differences among clinical groups but do not have the ability to accurately determine differences between genotypes (MacDonald et al., 2007). One strategy that could prove useful in detecting cognitive differences between genotypes is to employ cognitive paradigms that evaluate specific cognitive functions or dysfunction instead of generalized deficits, which could aid in the study of their biological correlates.
Numerous tests have demonstrated the ability to identify specific deficits in cognitive functions dependent on the PFC. Among these tests is the Dot Pattern Expectancy Task (DPX), which evaluates a specific prefrontal cognitive function, context processing. The cognitive construct of context processing resembles the goal maintenance construct and involves cognitive control functions. The deficits in context processing appear to be specific to schizophrenia, detectable in the early stages of the illness, and not significantly affected by antipsychotic treatments (Barch et al., 2003). Various studies have shown context processing deficits to be a stable cognitive feature of schizophrenia (Cohen et al., 1999; Delawalla et al., 2008; Javitt et al., 2000; Jones et al., 2010; MacDonald and Carter, 2003; MacDonald et al., 2003; Stratta et al., 1998). Context processing also appears to be linked to the functioning of the dorsolateral PFC (MacDonald and Carter, 2003) and is thus likely linked to the dopaminergic system (Cohen and Servan-Schreiber, 1992). A link has also been described between context processing and the Val158Met COMT polymorphism in healthy control subjects (Leung et al., 2007; MacDonald et al., 2007). Individuals with the Val/Val genotype (low dopamine availability in the PFC) show selective deficits in goal maintenance in the DPX test.

br Materials and Methods All the male

Materials and Methods
All the 666 male graduates of the College of Dentistry, KSU from the first set of 1982 until 2004 were studied out of the total of 857 male and female graduates. We excluded those who had graduated after 2004 to allow for a minimum of four years for continuing postgraduate education (PGE). The names and the years of the graduation for the graduates were identified from the College published records (Al-Dlaigan et al., 2007).
The questionnaire was designed to include fourteen multiple choices and written survey questions. It consisted of sections covering:

The response rate of (80%) was satisfactory due to the limitations for this GSK503 type of study which required more detailed information about graduates of over 28years ago when the first group graduated from College of Dentistry, King Saud University. We were hoping to cover the entire 666 male graduates from the year 1982 to 2004, but unfortunately there were several limitations, such as getting the contact number for each graduate which was really one of the hardest steps during the study. At times, even when we got the contact numbers, there were either no answers or willingness to give detailed information. Considerable detailed information about the graduates was obtained from the Saudi Dental Society memberships list, the Saudi Commission for Health Specialties and some classmates for each group. The sample covered all the 22 groups with a fair and reasonable representation.
The high percentage (77%) of the sample who obtained PGE leading to gaining either clinical specialty or academic degrees, such as Master’s degree and Doctorate degree was unexpected. Adding the percentage of those who are currently enrolled in PGE (11%) to the percentage of those who completed PGE (77%), meant 89% soon. These results indicate that the large percentage of KSU dental graduates were motivated, enthusiastic and eager to continue studying and are optimistic to obtain a lifelong education. On the different specialties of interest for the current residents, the majority of residents wished to obtain SBARD (37%). This result indicated that the board program was the most preferred higher dental education program, which is in agreement with the study of Ashri et al. (2007). About 24% were wishing to obtain specialty in Orthodontics, which is close to the findings of Drugan et al. (2004) who investigated the current working patterns and future career aspirations of specialist trainees in dentistry.
The dental specialties recognized by American Dental Association at different times beginning in 1947 are oral and maxillofacial surgery, pediatric dentistry, orthodontics and dentofacial orthopedics, prosthodontics, periodontics, oral and maxillofacial pathology (1949), dental public health (1950), endodontics (1963), oral and maxillofacial radiology (1999) as described by Neumann and Nix (2002). It was found Sporozoans prosthodontics and orthodontics were the most preferred among the participants. These findings are in agreement with Ashri et al. (2007) who found that Saudi general practitioners were mostly interested in prosthodontics and orthodontics, respectively. The uncommon specialties attracted those who wanted to work in the academic field, suggesting that interest was not limited to the more popular specialties. It was found that 248 had a Master’s degree, including those who had more than one Master’s degree. The Master’s of Science degree was the common type of degree obtained by the graduates. Leggate and Russell (2002) study reported similar findings among Master’s degree holders among Scottish dentists. The majority of Master’s degree holders in the study obtained their degrees from USA and UK, respectively. This may be due to several factors which encouraged the graduates to study in USA and UK, such as the curriculum of the College of Dentistry, KSU which is close to the American and British dental schools system, the language of study which is English, the interest of the students and the greater chance of acceptance in these two countries. Also for the Doctorate degree, the majority of the graduates obtained their degrees from USA and UK (Table 6). However, Saudi Arabia was the third country from which the students got their Master’s degree. The results showed that our graduates obtained their Master’s degree from 43 Universities in 14 countries, which indicated that the graduates of College of Dentistry at KSU were internationally recognized.

br Roles of M macrophages in DNFB

Roles of M2 macrophages in DNFB-induced CHS
Although proinflammatory roles of M1 macrophages in skin inflammation including CHS have been well documented, the roles of M2 macrophages in CHS remain largely unknown. We therefore performed cell transfer experiments of bone marrow (BM)-derived M1 and M2 macrophages into the sites of CHS to address the roles of M1 and M2 macrophages in CHS. Intradermal injection of BM-derived M2 macrophages significantly exacerbated ear thickness and increased the numbers of CD4+ T cells, CD8+ T cells, neutrophils, and eosinophils in the skin lesion in DNFB-induced CHS. In contrast, intradermal injection of BM-derived M1 macrophages did not significantly exacerbate ear thickness and only modestly increased the numbers of CD4+ T cells, CD8+ T cells, neutrophils, and eosinophils in the skin lesion in DNFB-induced CHS. These findings suggest that M2 macrophages but not M1 macrophages can exacerbate DNFB-induced CHS.
We next investigated the transcriptome of MR+ F4/80+ GSK503 and MR− F4/80+ cells isolated from the skin in DNFB-induced CHS to address the mechanisms underlying M2 macrophage-mediated exacerbation of CHS. RNA-sequencing analysis identified 189 genes that are more than 4-fold higher in MR+ F4/80+ cells than MR− F4/80+ cells. Among them, we picked 11 genes, Ccl8, Pf4, Mmp12, Ccl5, Cpxm1, Ctsk, Cpe, Gdf15, Adamts2, Bmp5, and Bmp2, according to the two categories: “extracellular region” Gene Ontology (GO) cellular component and “cytokine/chemokine” or “proteolytic enzyme” of GO molecular function (Table 2). Owing to the expression profiles available, we focused on matrix metalloproteinase 12 (MMP12), also known as macrophage elastase, among 11 genes as a candidate gene that possibly involves the M2 macrophage-mediated exacerbation of CHS. Consistent with the data of RNA-sequencing analyses, qPCR analyses revealed that MMP12 mRNA was highly expressed in MR+ F4/80+ cells as compared to that in MR− F4/80+ cells in the skin lesion of DNFB-induced CHS. In addition, MMP12 mRNA was highly expressed in BM-derived M2 macrophages as compared to that in BM-derived M1 macrophages. These findings suggest that MMP12 is highly and preferentially expressed in M2 macrophages in the skin lesion in DNFB-induced CHS. Our findings are consistent with a previous report showing that MMP12 is one of the most strongly induced genes in the skin of hapten-induced CHS in rat models.
It has been shown that IL-4-STAT6 signaling induces not only the polarization toward M2 phenotype but also the transcriptional activation of a part of M2 macrophage-specific genes in macrophages. We therefore examined the roles of IL-4-STAT6 signaling in MMP12 expression in BM-derived macrophages and found that IL-4 induced the expression of MMP12 mRNA in BM-derived macrophages of wild-type mice but not of STAT6-deficient mice. In addition, in agreement with the presence of a putative STAT6-binding site in MMP12 promoter, ChIP-qPCR analysis revealed that IL-4 induced STAT6 binding to the promoter region of MMP12 gene. These findings suggest that IL-4 induces MMP12 expression through STAT6-mediated activation of MMP12 promoter in M2 macrophages (Fig. 1).

Roles of M2 macrophage-derived MMP12 in CHS
MMP12 belongs to a family of matrix metalloproteinase (MMPs) that are structurally related extracellular matrix-degrading enzymes. As other MMPs, MMP12 is capable of degrading extracellular matrix components such as elastin and thought to be involved in tissue remodeling process. However, recent studies have raised the possibility that MMP12 is involved in the development of inflammatory responses. For example, it has been shown that cigarette smoke-induced accumulation of neutrophils and macrophages into the lung depends on MMP12.
To determine the roles of MMP12 in CHS, we first examined DNFB-induced CHS in MMP12-deficient mice and littermate wild-type mice. Importantly, MMP12-deficient mice showed reduced ear thickness in DNFB-induced CHS as compared with wild-type mice. Histological analyses revealed that MMP12-deficient mice exhibited less inflammatory change in the skin in DNFB-induced CHS. Flow cytometric analyses of leukocytes isolated from the skin lesion showed that the numbers of CD4+ T cells, CD8+ T cells, neutrophils, M1 macrophages, and M2 macrophages were significantly decreased in MMP12-deficient mice as compared to those in wild-type mice in DNFB-induced CHS. These findings suggest that MMP12 plays critical roles in the induction of DNFB-induced CHS (Fig. 1).

The present study investigated a large selection of indoor

The present study investigated a large selection of indoor air pollutants and TC parameters in ECCs both in summer and winter season. Several significant differences were found for IAQ and TC parameters when compared by season, when indoor parameters were compared with outdoor, when differences between the 22 ECCs or their internal spaces were tested. Although the reliability of p values associated to GSK503 testing is limited – as in this case – by the presence of multiple comparison, these data provide a comprehensive view on the quality of IAQ and TC in this setting, and especially on the relative importance of building characteristics and ECCs daily life activities in determining indoor conditions in the ECCs. Our findings which are in keeping with our project preliminary results (Mendes et al., 2013), provide remarkable information to assess housing structure and function along with lifestyle decisions determinants to IAQ. This research will contribute to the understanding of the health effects due to IAQ variables and their potential to improve the health of our elderly population.



The gas detection is a subject of study more and more tackled in connection with environmental and health safety problems (Yamazoe and Miura, 1994; Zhou et al., 2014; Donga et al., 2010). Whether for the control of industrial emissions (Soldan et al., 2014) or indoor quality air supervision (Suriano et al., 2014; Amodio et al., 2014), the challenge remains to produce detection systems with weak production and use costs, of high performance (sensitive, selective, reliable) and adapted to atmospheric conditions (linked to detection scales fixed by environmental standards). Qualitative and quantitative analysis of gaseous compounds such as VOC, NH3, CO2, CO, O2, O3 or H2 are performed by operating very various sensitive materials (organic materials (Rossignol et al., 2013; Itagaki et al., 2005; Bouvet et al., 2013; Trometer et al., 1992), metal oxides (Korotcenkov, 2014; Jouhannaud et al., 2008; Barsan et al., 2007; Jiménez-Cadena et al., 2007)) and transduction techniques among which we can quote methods based on electrical (Jiménez-Cadena et al., 2007; Airoudj, 2007), optical (Jiménez-Cadena et al., 2007; Airoudj, 2007; Lim et al., 2011), acoustic (Jiménez-Cadena et al., 2007; Airoudj, 2007; Shapira et al., 1976), spectroscopic (Jiménez-Cadena et al., 2007; Airoudj, 2007) or calorimetric (Jiménez-Cadena et al., 2007; Airoudj, 2007) variations.
In any case, the gas sensing mechanism can be described as an adsorption/desorption process. Thus, one of the key element of a gas sensor is its sensitive material. The interaction between a gas and a sensitive material can be depicted according to: chemisorption (Gomri et al., 2005; Calvini and Levi, 2005), physisorption (Levi and Pisoni, 2004; Barochi et al., 2011), or both. In the case of chemisorption, an atomic connection is created by the interaction between the gas and the material, modifying the material characteristics in an irreversible way. To desorb the gas from the material, and thus eliminate formed bounds, an energy supply must be applied to the material through a heating. In the case of a physisorption, the interaction causes disturbances, modifying temporarily the material characteristics. The main interactions involved are Coulomb and Van Der Waals forces. As no atomic bounds are constituted, the modifications of the material characteristics are temporary. The sensitive material does not need any energy supply to regain its initial characteristics.
Most of the commercialized gas sensors are based on conductimetric transduction using non-stoichiometric metal oxides as sensitive materials (Gurlo, 2006). They present a long lifespan with a ppm resolution and response times compatible with environmental standards at low-costs. They are mainly sensitive to redox active species which can accept or give electrons, inducing a variation of the charge carriers density (Jouhannaud et al., 2007). They are also sensitive to species able to modify the mobility of these carriers, and more generally the transport properties in sensitive materials (Jiménez-Cadena et al., 2007).

Here we describe methods that can be used to

Here, we describe methods that can be used to improve the reconstruction based on shape constraints both before and after the actual reconstruction algorithm is applied. Specifically, we introduce a method to implicitly approximate any APT reconstruction by a barycentric coordinate transform [29] based on a 3D mesh that can be used to translate the coordinates of extracted shapes from reconstruction to the detector coordinate space (or ‘detector space’), and to apply both global and local shape constraints from a priori knowledge and/or correlative microscopy. This is closely related to affine transformations, a concept that is widely used in image manipulation (e.g. Adobe Photoshop\’s ‘warp’ tool) and image feature detection [30].
We also present a method to create a boundary for the dataset in both the detector space and reconstruction space. This method is used to compensate for ion trajectory aberrations caused by residual fields in the ion drift region of the GSK503 probe [31,32] and to provide a boundary for the dataset to be used in the creation of analysis models in other feature analyses methods such as the one presented in [33].

Materials and methods
The data in Fig. 2c is from a technically pure Mo sample that contains a grain boundary, acquired on a Cameca LEAP 3000 X HR operating in laser pulsing mode. This instrument is equipped with a reflectron lens to improve mass resolution. The dataset in Figs. 3 and 4 contains a grain boundary, lifted out from a Ni-based superalloy sample (A718 [34]), using the protocol published in [9]. It was acquired on an Imago LEAP 3000 Si atom probe operating in voltage pulsing mode at 40K with a pulse amplitude of 25% of the DC bias voltage (‘pulse fraction’), regulated to trigger a detector event on 1% of the voltage pulses (‘detection rate’). The samples in Fig. 5 were measured in voltage pulsing mode at 40K, with 20% pulse fraction and 2% detection rate, apart from the Si sample, which was measured in the LEAP 4000 X Si in laser pulsing mode at 50K, with a 355nm UV laser at 50 pJ with a spot size of ~2µm, and an evaporation rate of 2%.
All data analysis was carried out by using custom programs in Matlab®, with the exception of the dataset in Fig. 2c, which was reconstructed using Cameca IVAS®. All 3D visualisation was done in Blender 3D (

Results and discussion

Being able to translate models of objects, obtained in an imperfect reconstruction, into detector space, enables an entirely new approach to the calibration of APT reconstructions. The object\’s model is co-reconstructed with the rest of the data, and it\’s shape properties are evaluated and compared to a priori knowledge about the sample or data from correlative methods. This way, the reconstruction can be optimised iteratively.

The authors acknowledge the facilities, and the scientific and technical assistance, of the Australian Microscopy & Microanalysis Research Facility at the University of Sydney. This work was funded by the Australian Research Council. The dataset in Fig. 2 was provided by K. Babinsky and S. Primig, MU Leoben. Ni-superalloy specimens (Figs. 3 and 4) were provided by Mahesh Chaturvedi from The University of Manitoba, Canada. Some of the datasets used for Fig. 5b were provided by T. Sato and A. Breen, University of Sydney. PF would like to thank the Blender Foundation for their effort in making high quality 3D programs available open source.

Determining the electromagnetic field distribution within materials is fundamental to both characterizing and understanding a variety of functional properties [1–6]. Using transmission electron microscopy we can seek to infer the field distribution by measuring the deflection of the probe electron trajectories – or, in more appropriate wave optical terms, to measure the phase shift – resulting from the Coulomb–Lorentz force from the electromagnetic fields in the sample.

Therefore the identification of a specific RPE value associated with

Therefore, the identification of a specific RPE value, associated with the VT (RPEVT), may be an effective strategy to guide cardiorespiratory training intensity, particularly from a public health perspective. Thus, the individuals can regulate exercise intensity (e.g., walking or running speed) based on their own perceptual sense. However, previous studies have shown that there is considerable variability in the RPEVT among adults, ranging from 11 to 14, using Borg\’s scale. In general, these studies analyzed the influence of gender, training level, exercise modality, and exercise protocol, evaluating only people with normal body mass.
Particularly in overweight and obese individuals, the identification of the RPEVT has important implications, because exercise performed above the VT in these groups is associated with greater pain sensatio###http://www.GENS-BIO.COM/images/1-s2.0-S1607551X1630153X-gr1.jpg####n, physical discomfort, and feelings of displeasure than in groups with normal body mass. To date, no study has identified the RPEVT in women with different nutritional status. Thus, the aim of this GSK503 study was to identify and compare the RPEVT in normal body mass, overweight, and obese sedentary women.

The study consisted of three familiarization sessions, followed by a session to evaluate anthropometric measurements, according to the procedures of Gordon et al. and maximal cardiopulmonary fitness. Sessions were separated by at least 48–72 hours. The participants were instructed to abstain from vigorous physical activity, caffeinated products, and alcohol 24 hours before the experimental session. All sessions were conducted with participants wearing athletic apparel and footwear.

The characteristics of the sample are summarized in Table 1. Table 2 shows the results for cardiopulmonary parameters related to the maximal exercise test. The obese group showed lower , at VT, at VT, and %HRmax at the VT than the normal body mass and overweight groups (p < 0.05). There were no differences between the normal body mass and overweight groups (p > 0.05).
Fig. 1 shows the RPEVT during the maximal exercise test in the women with different BMI. There was no difference between groups (p > 0.05): RPE = 12.1 ± 1.4 for normal body mass women; RPE = 12.0 ± 1.6 for overweight women; and RPE = 12.0 ± 1.4 for obese women.

The purpose of this study was to identify a specific RPEVT in sedentary women, and to analyze whether there were differences in RPEVT among normal body mass, overweight, and obese groups. We found that the volunteers perceived the exercise intensity associated with the VT as between light and somewhat hard (Borg RPE = 12), independently of BMI. These results are consistent with previous studies that reported a mean RPE value between 11 and 14 at the VT or lactate threshold in different populations (active men and women, sedentary middle-aged men, young trained men, trained cyclists, and type 2 diabetes individuals).
Several studies have demonstrated the benefits of cardiorespiratory training at exercise intensities of close to or at the VT for physical fitness and health. However, in clinical settings, it is often not possible to acquire expensive equipment to monitor cardiorespiratory exercise intensity (e.g., HR monitor, metabolic measurement equipment). Recent studies have shown that perceived exertion is a valid means of evaluating VT, demonstrating acceptable correlation with VT. As such, this method may be recommended to predict maximal functional capacity in sedentary males, young and middle to older-aged individuals who are active or sedentary, and obese women. In addition, previous investigations have shown the efficacy of exercise training involving exercise intensity using perceptually regulated training at a target RPE. Céline et al. found that a 6-week exercise program involving perceptually regulated training at an individualized RPEVT resulted in a mean improvement in VO2max of 10% in healthy young women. Parfitt et al. found that an 8-week exercise program involving perceptually regulated training at an RPE of 13 on the Borg Scale resulted in mean improvements in , mean arterial pressure, cholesterol, and BMI in sedentary men and women. Furthermore, Scherr et al. in a cohort of 2560 participants, reported a very high competency in the assessment of RPE in relation to metabolic (lactate concentrations) and cardiac (HR) intensity parameters, and found that RPE at LT1 was approximately 11 in all groups. From a public health perspective, exercise intensity perceptually regulated at RPEVT may be an effective strategy to be implemented and disseminated for clinical practice. Based on the current results, perceptually regulated exercise intensity at an RPE of 12 may be a practical, simple, noninvasive, and low-cost method to guide exercise intensity at the VT in sedentary women, regardless of BMI classification. Further longitudinal research is necessary to confirm whether cardiorespiratory benefit can be achieved with exercise programming using RPE-based exercise intensity in normal body mass, overweight, and obese women.

br Our study showed that

Our study showed that the excursion and peak motion speed of the left GSK503 are significantly greater and faster than those of the right. With regard to the excursion, the results of our study are consistent with those of previous reports using fluoroscopy in a standing position 2 ;  3. However, in the previous studies evaluating diaphragmatic motion in the supine position, the asymmetric diaphragmatic motion was not mentioned 7 ;  8. The asymmetric excursion of the bilateral diaphragm may be more apparent in the standing position, but may not be detectable or may disappear in the supine position. Although we cannot explain the reason for the asymmetry in diaphragmatic motion, we speculate that the presence of the liver may limit the excursion of the right diaphragm. Regarding the motion speed, to the best of our knowledge this study is the first to evaluate it. The faster motion speed of the left diaphragm compared to that of the right diaphragm would be related to the greater excursion of the left diaphragm.

We found that higher BMI and higher tidal volume were independently associated with the increased excursions of the bilateral diaphragm by both univariate and multivariate analyses, although the strength of these associations was weak. We cannot explain the exact reason for the correlation between BMI and the excursion of the diaphragm. However, a previous study showed that BMI is associated with peak oxygen consumption (23), and the increased oxygen consumption in an obese participant may affect diaphragmatic movement. Another possible reason is that lower thoracic compliance due to higher BMI may cause increased movement of the diaphragm for compensation. Regarding the correlation between tidal volume and excursion of the diaphragm, given that diaphragmatic muscle serves as the most important respiratory muscle, the result is to be expected. Considering our results, the excursion evaluated by dynamic X-ray phrenicography could potentially predict tidal volume.

Our study has several limitations. First, we included only 172 volunteers, and additional studies on larger participant populations are required to confirm these preliminary findings. Second, we evaluated only the motion of the highest point of the diaphragms for the sake of simplicity, and three-dimensional motion of the diaphragm could not be completely reflected in our results. However, we believe that this simple method would be practical and more easily applicable in a clinical setting.


The time-resolved quantitative analysis of the diaphragms with dynamic X-ray phrenicography is feasible. The average excursions of the diaphragms are 11.0 mm (right) and 14.9 mm (left) during tidal breathing in a standing position in our health screening center cohort. The diaphragmatic motion of the left is significantly larger and faster than that of the right. Higher tidal volume and BMI are associated with increased excursions of the bilateral diaphragm.

AcknowledgmentsThe authors acknowledge the valuable assistance of Hideo Ogata, MD, PhD, Norihisa Motohashi, MD, PhD, Misako Aoki, MD, Yuka Sasaki, MD, PhD, and Hajime Goto, MD, PhD, from the Department of Respiratory Medicine; Yuji Shiraishi, MD, PhD, from the Department of Respiratory Surgery; and Masamitsu Ito, MD, PhD, Atsuko Kurosaki, MD, Yoichi Akiyama, RT, Kenta Amamiya, RT, and Kozo Hanai, RT, PhD, from the Department of Radiology, Fukujuji Hospital, for their important suggestions. The authors also acknowledge the valuable assistance of Alba Cid, MS, for editorial work on the manuscript. Yoshitake Yamada, MD, PhD, is a recipient of a research fellowship from the Uehara Memorial Foundation.

Appendix. Supplementary DataThe following is the supplementary data to this article:
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There is an increasing concern

There is an increasing concern in the possibility that metabolites produced during the degradation of emerging compounds will be more hazardous to either human health or ecosystem than the parent itself. For that, we compared the LC50 for Daphnia sp. (after 48 h) and fish (after 96 h) calculated by ECOSAR packet of EPI-SUITE ( USEPA, 2012), for all metabolites evaluated in this work (Table 6). Both Daphnia sp. and fish were used as proxys of the full ecosystem. In Table 6 we have also included partition coefficients as well as solubility for each GSK503 in order to compare the impact to the environment. Although the presented concentrations of toxicity are referred to the acute toxicity and they are much higher than the environmental concentrations of SMX, they serve as a comparative criterion. Overall, 4-nitro-SMX was the most toxic compound (lowest LC50). The toxicity was associated to the nitroaromatic compounds which are acutely toxic and mutagenic, and many are suspected or established carcinogens (Ju and Parales, 2010). On the other hand, metabolites conserving the isoxazole ring (Product II in Table 3 and 3-amino-5-methylisoxazole) are more toxic when compared to SMX. Contrarily, 4-aminobenzosulfonate and metabolites produced under iron reducing conditions with broken isoxazole ring (Products III and IV in Table 3) are the least toxic of all the compounds studied, and probably they can be mineralized easily (Gao et al., 2010). These results are perfectly correlated with values of logKow and solubility. The highest values of logKow correlated to the highest value of LC50, and at the same time, the highest values of solubility correspond to low risk compounds. High solubility and low values of Kow indicate that all the metabolites will remain mainly in water, with low absorptivity rates into solid phases.
From the combination of reversibility and environmental fate/risk, it seems reasonable to conclude that the most efficient degradation path to remove all presence of SMX from groundwater bodies involves allowing the aquifer to reach iron reducing conditions. We want to stress here that this conclusion is only valid for SMX, and thus a potential intelligent methodology to eliminate a cocktail of emerging organic compound and their metabolites would be to allow the aquifer to reach many different redox states, each one of them being the most efficient one for the degradation of a given molecule. At this point there is a need in the future to investigate many more molecules and even the synergic effect of injecting several compounds together.
In any case, and indistinctly to the redox process, the degradation of SMX is driven by co-metabolism enhanced by the presence of external labile organic carbon. In this way, it might be possible to properly manage the amount of labile organic carbon in the system, thus properly allowing the control (in space and time) of redox zonation for the proper management of EOCs degradation in the subsurface. One real example of this application is the installation of a labile organic carbon layer (compost) on the bottom of an infiltration pond in a managed aquifer recharge facility that enhanced EOCs degradation (Schaffer et?al., 2015, Valhondo et?al., 2014 and Valhondo et?al., 2015). The induced redox zonation by the oxidation of labile organic carbon increased the possibilities of degradation of different emerging compounds, here including sulfamethoxazole.

GSK503 The results of the calibration

The results of the calibration of the GSK503 SMX degradation model are displayed in Table 5. The parameters inferred display a high degree of uncertainty, being larger in the BAR experiment. This is probably due to the lack of measurements regarding one of the metabolites (desamino-SMX), affecting the values of k2, k4 through Equation (2), with such uncertainty propagating to k1 and k3. Furthermore, the correlation matrix displayed by PEST showed that there was no correlation among the parameters (all values were lower than 0.55, results not shown).
Note that despite modeling the same processes in the two experiments, the parameters determined in BAR and NDL are quite different being higher in the former (for example k1 and k2 are two orders of magnitude higher). All but first-order degradation rates (third-order in the nitrosation of the primary amines and second-order in the nitration of the benzene ring) are dependent on initial conditions (Atkins and de Paula, 2011). As the initial conditions were three orders of magnitude different, it is evident that the parameters were not able to be compared. Furthermore, the high concentration of SMX in NDL experiment could represent some type of GSK503 inhibition and could be another reason for such differences. Nevertheless, we did not have enough experimental data to characterize if this existed and if it had any consequence.
Regarding the degradation of SMX under iron-reducing conditions, the best fit was obtained using the automatically calibrated by PEST parameters (see section 3.1.1) and they are listed in Table 5, and the actual fit to data is displayed in Fig. 5. Actually, in the same Figure the fit with an exponential model is also presented, here focused only on early time data, to show the transition in behavior as a function of time. Note that all potential degradation pathways described would be naturally limited by the low amount of organic carbon in the subsoil. Besides this, iron-reducing conditions will only be reached when all the previous redox states were ended. Thus, the amount of organic carbon supplied to the system is key. Once iron reducing conditions were achieved, the degradation of SMX is achieved in hours (Fig. 5).
Fig. 5. Experimental point (from Mohatt et al. (2011)) and modeling results using first-order degradation rate and power law.Figure optionsDownload full-size imageDownload high-quality image (211 K)Download as PowerPoint slide
3.2. Potential extensions to real field site applications
The main reactive path for the degradation of SMX under denitrifying conditions involves the presence of nitrous acid that accumulates associated with the building up (and further decay) of nitrite. Nitrite is a usual transient compound in denitrification processes. Its accumulation can be, traditionally, explained by different reasons: 1) the presence of low levels of oxygen (up to 0.7 mg/l) (Coyne and Tiedje, 1990); 2) the competition between nitrate and nitrite enzymes for a common electron donor (Thomsen et al., 1990); 3) large differences in the maximum reduction rates of nitrate and nitrite reductases (Betlach and Tiedje, 1981); and 4) the choice of carbon source (van Rijn et al., 1996). In addition, the presence of antibiotics is suggested to inhibit the reduction step from nitrate to nitrite (Yan et al., 2013), and thus facilitate nitrite accumulation and nitrous acid formation. Other studies also suggested that a continuous exposition to SMX in large quantities will affect the bacterial denitrifying community (Underwood et al., 2011). Consequently, the presence of 4-nitro-SMX would be quite plausible in natural aqueous environments where nitrate and antibiotics leakage converge, such as rural areas where nitrate and veterinarian antibiotics coexist (García-Galán et al., 2010). As the formation of desamino-SMX will be conditioned to the presence of alcohol which is not always present in organic matter, we expect that in real site applications 4-nitro-SMX will be the dominant metabolite. If we consider that alcohol and, therefore, desamino-SMX are not present, we could assume that SMX would only transition to 4-nitro-SMX.

Other authors also analyzed the suitability of

Other authors also analyzed the suitability of humification indices to evaluate progress in humification. For example Sánchez-Monedero et al. (1999) analyzed 4 different indices, i.e. HR, HI (humification index, HI = (CHA/CTOC) · 100), DP and PHA (percentage of HA, PHA = (CHA/CHS) · 100) to evaluate humification during composting of six kinds of waste (primary aerobic sewage sludge, cotton waste, sorghum bagasse, pine bark, brewery sludge and the organic fraction of selectively collected municipal solid waste) in different mixtures. They showed that, for all mixtures, DP was the most sensitive indicator for evaluation of the humification processes. The values of DP in mature compost were from 1.58 to 3.07-times higher than in the feedstock. Moreover, changes in the value of other indicators were less evident. Similarly, Hsu and Lo (1999) showed a considerable increase in the values of DP during composting of pig manure, from 0.60 in the feedstock to 3.33 after 122 days of composting. Moreover, they GSK503 noted increases in PHA from 16.4 to 47.4. Similar results were obtained by Paredes et al. (2001), although they composted different waste (sewage sludge, industrial waste from orange juice extraction, and cotton gin waste). They found that humification progress was best indicated by increases in DP and PHA. However, they showed that HR and HI generally did not show a clear tendency during the composting process. In contrast, Jouraiphy et al. (2005) noted significant changes in all analyzed indices (HR, HI, PHA and DP) during composting of sewage sludge and green waste mixtures. After 135 days of composting there was an increase in HR from 18.1 to 27.9; HI from 7.4 to 19.2; PHA from 40.9 to 68.9 and DP from 0.69 to 2.21.
It is worth emphasizing that, in the present study, a continuous increase in the values of DP occurred during the entire composting process, whereas the most intense increase in the concentration of HS occurred during the first 3 months of the process (after this time the rate of HS formation was low). As a result, the amount of HS in compost matured for a longer period of time differed only slightly from that matured for a shorter period of time. This means that lengthening the maturation time affects mainly the polymerization of FA to HA, i.e. transformation from one kind of HS to another does not considerably increase the total concentration of humic substances. This small change in total HS concentration has practical significance because it means that it is possible to use compost after 3 months of maturation. This conclusion is supported by the author’;s previous study, which shows that it is possible to use compost after 3 months of maturation for stabilization of metals in contaminated soil (Gusiatin and Kulikowska, 2015). That study examined how the redistribution pattern, metal mobility and stability of Cu and Zn were affected by the maturation time (3, 6 and 12 months) of sewage-sludge compost that was added to the contaminated soil. Although Cu redistribution, bioavailability and stability were favorably affected by compost addition, these results were not affected by lengthening the maturation time of the compost and thus increasing the share of HA in the compost.
4. Conclusions
In the present study, the kinetic constants of OM removal were an order of magnitude higher than the kinetic constants of humification during sewage sludge composting. Organics removal occurred mainly during the first 15 days of composting, whereas humification occurred most intensively during the first 3 months of composting, as indicated by the concentration profiles of OM, HS and HA. Lengthening compost maturation time over 3 months increased HS concentration only slightly but the polymerization of FF to HA took place, as shown by the DP values. The high content of HS (182 mg C/g OM) indicated that the compost could also be used in soil remediation, both as an amendment in stabilization or as a source of HS in soil washing.