The clot digestion value was expressed as the mean clot diameter

The clot digestion value was expressed as the mean clot diameter (cm). The effect of Batroxase on coagulation was evaluated using human plasma (200 μL) incubated with different concentrations of the metalloproteinase (0.1, 0.2, 0.4, 0.8, 1.6 and 2.0 μg/25 μL) at 37 °C. As a control, human plasma (200 μL) was added to 25 μL of CaCl2 PR-171 manufacturer at 0.25 mM, which induced clot formation within 3 min (Selistre et al., 1990). The minimum coagulant dose (MCD) was calculated as the minimum amount of protein that was able to induce plasma clotting in 60 seconds. The fibrinolytic activity was assessed

in Petri plates containing fibrin according to Leitão et al. (2000). Aliquots of 30 μL containing different concentrations of Batroxase (0.5, 1.0, 4.0, 6.0, 8.0, 10, 20 and 40 μg) were added to cavities on the fibrin gel and incubated at 37 °C for 24 h. The fibrinolytic activity was evaluated visually and quantified according to the halo diameter, which was compared to a positive control (plasmin 10 μg) and a negative control (PBS only). The ability Bortezomib solubility dmso of Batroxase to digest fibrinogen was

evaluated using the method published by Edgar and Prentice (1973), with some modifications. A 25 μl aliquot of fibrinogen solution (2.0 mg/mL in 25 mM Tris–HCl pH 7.4) was incubated with several concentrations of Batroxase (0.25, 0.5, 1, 2, 6, 8 and 10 μg in 5 μL 25 mM Tris–HCl pH 7.4) at 37 °C for 90 min. The reaction was stopped with 20 μL of 50 mM Tris–HCl pH 6.8 containing 10% glycerol (v/v), 4% SDS (w/v), 0.05% bromophenol blue (v/v) and 4% β-mercaptoethanol (v/v), followed by heating at 100 °C for 5 min. After reduction and denaturation, the samples were assayed for fibrinogen hydrolysis by 13.5% SDS-PAGE. The fibrinogen digestion kinetics were evaluated by incubating a fixed concentration of Batroxase with fibrinogen for different time intervals (0, 5, 10, 15, 30, 60 and 120 min) at 37 °C. The fibrinogenolytic activity was also tested under different pH values (2.5; 3.0; 4.0; 5.0; 6.0; 7.0; 9.0

and 10.0) and temperature conditions (−80, 17-DMAG (Alvespimycin) HCl −20, 5, 37, 50 and 100 °C). Protease inhibitors (EDTA, EGTA, PMSF) and β-mercaptoethanol were assayed for inhibition of fibrinogen hidrolysis by Batroxase. The GE Life Sciences molecular mass standards were used. Type IV collagen solution (4 μg/μL) was prepared in 10 mM Tris–HCl pH 7.4 containing 10 mM NaCl and incubated with different concentrations of Batroxase. The reaction was stopped by adding 20 μL of 50 mM Tris–HCl pH 6.8 containing 10% glycerol (v/v), 4% SDS (w/v), 0.05% bromophenol blue (v/v) and 4% β-mercaptoethanol (v/v), followed by heating at 100 °C for 5 min. The substrate digestion was analyzed by 7.5% SDS-PAGE. Fibronectin (4 μg/μL) in 10 mM Tris–HCl pH 7.4 and 10 mM NaCl was incubated with Batroxase at a molar ratio of 1:50 enzyme:substrate at 37 °C for 2, 6, 12 and 24 h.


Fig  4 the dendrogram resulted from the cluster analys


Fig. 4 the dendrogram resulted from the cluster analysis of three genotypes broths is shown with three forms of preparation. There is a formation of three groups with highest degree of similarity. The first group is formed by the BAF-CWSW, BAF-COSW, UI-CWS and BAF-CWS broth samples is due to high total phenolic Selleck Sotrastaurin and tannin levels. The second group consisting of UI-COSW, IAP-CWSW, UI-CWSW, IAP-CWSW and IAP-CWS has low levels of total phenolic and tannin compounds. Finally, the third group with broth samples of BAF-CWSW, UI-CWS, BAF-CWS, UI-CWSW and IAP-CWSW, were determinated due to similarities in the phytate content. The contribution of the first two principal components (Fig. 5) represented 85.1% of the total variance, with 58.4% and 26.8%

in the first and second component, respectively. Each genotype showed a distinct behavior, and for the BAF genotype the CWSW and COSW broths were closer, for the UI genotype, the CWS and CWSW broths demonstrated higher similarities, and to IAP genotype the CWS and COSW broths were less discrepant. The variables that had a greater relationship with the first component were the phenolic compounds (−0.972), tannin (−0.834) and phytate (−0.808) while the antioxidant activity variable (−0.955) had the highest correlation with

PI3K Inhibitor Library purchase the second component. In general, cooking with previous soaking showed the highest potential to reduce free radicals in the three analyzed genotypes. It was also detected a negative relation between cooking and losses of total phenolics, tannin and phytate, demonstrating the importance of consumption and use of cooked broth. also Among the cooked beans the preparation that preserved more efficiently their characteristic and their nutrients were the beans cooked without soaking (CWS), except to antioxidant activity variable. In the broths, BAF 55 showed the highest tannin and phenolic compound levels in all preparation forms. For other variables, each broth and genotype reacted differently to cooking. Therefore, more studies with beans and broths may be performed to explain what occurs in the preparation of this food. It is important to remember that the raw food analysis is necessary to know its nutritional value, but beans are supposed to be cooked in order to be consumed and there are interferences such as preparation forms, genotype, broth and soaking water using that can modify significantly the food characteristics as well its nutrients availability for absorption.

used a value of 8, 22 and in African children Hendriksen et al u

used a value of 8, 22 and in African children Hendriksen et al. used a value of 3 (based on in vitro and non-human primate data). 30 Importantly, our main findings were robust to variation of this parameter over Ku-0059436 order most of the range of replication rates

estimated to occur in African children with SM (as shown in Table 4). 29 Furthermore, sequestered-parasite biomass in children with CM in our study was quantitatively similar to that estimated mathematically from parasite clearance curves in Gambian children with CM. 41 In a sensitivity analysis we found that our main conclusions were robust to reasonable variations in model parameters. However, we have made the same assumptions as Dondorp et al., that model parameters are the same for UM and SM, and do not vary during the course of infection. 22 Although data from humans to inform between-group and temporal variations in model parameters is lacking, recent data from Plasmodium berghei ANKA infection in mice suggests that the sequestration rate and the clearance rate of sequestered-parasites may be dynamic throughout the course of an infection, 42 making this an important area for future study. It is also important to consider potential sources of bias in our study which might influence our results. Antibodies against PfHRP2 might cause under-estimation of sequestered biomass

in SM relative to UM cases, but young Gambian children (who are most likely to have SM) are the least likely to have antibodies to P. falciparum antigens. 43 Prior antimalarial treatment and polyclonal infections might cause deviation from the basic assumptions of the model, 22 but we selleck chemicals llc found no evidence of any interaction between age, prior antimalarial treatment, or clonality of infection, with severity and sequestered-parasite burden. Differences in parasite multiplication rate between UM and SM cases might be a source of bias. 22 However, parasite multiplication rate is thought to be reduced at high parasite densities, 44 which we observed predominantly in

SM cases; using the same multiplication rate for UM and SM is thus expected to lead to over- rather than under-estimation of the total parasite biomass in children with SM. Other causes of illness may mimic the clinical features of SM in children with incidental parasitaemia and lead to Masitinib (AB1010) misclassification. One postmortem study showed that 23% of clinically defined fatal cases of CM had an alternative cause of death, 21 but there are no comparable data for other SM syndromes or for survivors of SM. By comparison our study was conducted in a relatively low transmission setting 43 (which reduces the likelihood of incidental parasitaemia), 45 used a relatively high cut-off peripheral parasitaemia for inclusion (which improves the specificity of diagnosis of malaria), 45 and we found no evidence of bacterial co-infection, the most likely alternative or confounding cause of severe illness, using specific PCR for the two most common bacterial pathogens.

However, Aea-HP-1 did not activate the mosquito SP/MIP receptor i

However, Aea-HP-1 did not activate the mosquito SP/MIP receptor in a well-established in vitro assay for receptor activity. Aea-HP-1 appears to have a role in changing the behavior of female A. aegypti after a blood-meal. Females refrain from host-seeking

in two phases; within 1 h after a blood-meal [23] and a second phase starting 30 h post-blood-meal which continues until oviposition and the start of another gonadotrophic cycle. MG-132 manufacturer The first loss of interest in a host is triggered by distension of the abdomen [24] and the later sustained response to the blood-meal appears to involve the release of Aea-HP-1-like material into the hemolymph at around 24 h after the meal from either neurosecretory or midgut endocrine cells

[4]. Changes in host-seeking behavior MDV3100 in response to a blood-meal are strongly influenced by the size of the meal and whether the female has mated [21]. Gravid females are more likely to desist from seeking a host if they have been inseminated [18], [23], [24], [26] and [27]. Lavoipierre showed that biting by gravid virgin A. aegypti females with developing öocytes (fifth stage) was rapidly and completely inhibited by mating and that this effect lasted for around 4–5 h, suggesting the existence of a fast acting inhibitory factor [27]. Implantation of MAGs or injection of a MAG homogenate into virgin gravid females results in inhibition of host-seeking and feeding, suggesting that substances made in the MAG and presumably Abiraterone datasheet present in seminal fluid are involved in changing female behavior toward the host [13] and [18]. The ability of the male to influence inseminated gravid females in this way is possibly an adaptation that helps to minimize risks from defensive actions of a host (see [21]).

Gravid females who have not yet mated might benefit from maintaining host-seeking behavior because in the natural environment sexually competent males are also attracted to the host, thus increasing the chances of mating success [15]. Our discovery that high concentrations of Aea-HP-1 are found in the MAG and that the peptide is transferred to the female suggests a mechanism by which the male can influence the behavior of the female either by activating sensory neurons in the female reproductive tract or by elevating Aea-HP-1 levels in the hemolymph. We thank the Royal Society (UK) for the award of a Joint Research Grant (REI and Y-JK) and Defra and the Chemicals Regulation Directorate, Health and Safety Executive, UK (NA). We also thank Yeu-Kyung Yoon (Gwangju Institute of Science and Technology) for technical assistance and Jaroslaw Krzywinski (Liverpool School of Tropical Medicine) for advice and supplying mosquitoes. The Wellcome Trust are gratefully acknowledged for supporting the bio-imaging facility and the maintenance of the mosquito colony at the University of Leeds (Grants 065321/ZO1/Z and 075513/Z/04/Z).

We identified isoform-specific effects on MFS, RFS, and OS, with

We identified isoform-specific effects on MFS, RFS, and OS, with low levels of CXCL12-α, -β and -γ significantly correlated with worse MFS and RFS. Most notably, we note that low levels of CXCL12-δ associated with worse OS and showed the same trend for RFS and MFS, despite the fact that CXCL12-δ expression does not correlate with expression of the other isoforms. This relationship is robust and persists even after taking into account CXCL12, CXCR4, and CXCR7 expression selleck chemicals in multi-gene analysis, indicating the independent prognostic significance of CXCL12-δ. These data provide the first evidence that

CXCL12-δ is expressed in human cancer and correlate with a patient outcome. Expression levels of CXCL12 in breast cancer cell lines generally selleck chemical mirror conclusions from the clinical samples that lower levels of CXCL12 correlate with worse prognosis. We found that breast cancer cell lines without metastatic potential (in mouse models) had higher levels of CXCL12 expression than cell lines that metastasize more widely. Studies of CXCL12 in breast cancer focus on secretion of this chemokine by stromal cells in primary and metastatic sites, frequently overlooking effects of CXCL12 produced by cancer cells.

However, epigenetic silencing of the CXCL12 promoter has been reported in breast cancer cells with greater metastatic potential, and re-expressing CXCL12 limits metastatic disease in mouse xenograft models [25]. Our analysis of cell lines may inform likely sources of various CXCL12 isoforms in tumor microenvironments. Breast cancer cells express CXCL12-α, -β, and -γ with very minimal expression of δ, which could indicate that stromal cells are the predominant source of the δ isoform in primary breast cancers. We also note that CXCL12-γ is higher than α and β in our panel of breast cancer cell lines, which is opposite the pattern in primary tumors. Differences between data Phosphoribosylglycinamide formyltransferase from cell lines versus tumors may reflect dynamic regulation of CXCL12 isoforms in vivo, greater contributions of stromal cells to overall expression of CXCL12-α and -β in breast tumors, or simply genomic changes as the original

cancer samples were transformed into immortalized cell lines. In addition, CXCL12 levels within the tumor microenvironment may be affected by posttranslational modification, such as cleavage by CD26 or matrix-metalloproteinase-2 [50] and [51]. Isoform-specific differences in expression and breast cancer outcomes suggest distinct functions of individual splice variants of CXCL12 on disease progression. Recent studies have begun to identify unique biochemical properties of CXCL12 isoforms, particularly α, β, and γ. While all isoforms share the same core structure, CXCL12-β, -γ, -δ, -ε, and -φ differ by inclusion of exons that add 4, 40, 51, 1, or 11 additional amino acids, respectively, to the carboxy terminus of the molecule [24].

Despite the recent decrease in total catch compared with 10 years

Despite the recent decrease in total catch compared with 10 years ago, fish exports have increased constantly; this

increase seems to occur at the expense of local consumption and has caused significant increases in fish prices in local markets [44]. Artisanal fishing accounts for well over 90% of the total production [27]. The key fisheries resources, shown in Table 1, include pelagic fishery for tuna and tuna-like species and demersal fishery for fish, cuttlefish, shrimp, and lobster. Tuna and tuna-like species and cuttlefish are prevalent in the Gulf of Aden and the Arabian Sea, whereas demersal fish are more abundant in the Red Sea. Key pelagic species include yellowfin tuna, longtail tuna, little tuna, narrow-barred Spanish mackerel, Indian mackerel, anchovy, and sharks; key demersal fish species include emperors, groupers, snappers, and jacks [27] and [32]. Despite selleck products the lack of comprehensive EPZ5676 in vitro stock assessment studies and reliable catch statistics, it is believed that most fish stocks, except small pelagic species for which there is no market demand, are either fully exploited or overexploited [37]; interviews with fishermen and

different stakeholders confirm these beliefs. Cuttlefish (Sepia pharaonis) has been harvested since 1967 by industrial fleets in the Gulf of Aden and the Arabian Sea region. The intensive trawling on their spawning aggregations has led to overfishing and a major decline of the fishery by 1982–1983 with reported annual landings falling from around 9000 to 1500 t. Landings of the rock lobster (Panulirus homarus) virtually collapsed to near zero in the late 1990s from peaks of around 400 t in the early part of the decade. This collapse was attributed to the widespread use of nets rather than traps to capture lobsters [37]. Large-scale harvest of sea cucumbers started in 2003 with the advent of air compressors, which facilitated diving; this process

led, a few years later, to the collapse of the fishery [45]. Many important demersal fish stocks and some pelagic species, such as Indian Inositol monophosphatase 1 mackerel [41], narrow-barred Spanish mackerel, and sharks [40] and [46], have experienced severe overfishing and their production levels have been beyond the maximum sustainable yields. The lack of FMPs, widespread IUU fishing, uncontrolled growth of fishing effort, and weak compliance and enforcement arrangements have led to significant economic losses associated with the suboptimal use of the resources, which has in turn resulted from weak and ineffective governance and subsequent overfishing. Small-scale fishermen typically use two types of fishing boats: small fiberglass boats called huris, 7–16 m long, with outboard engines and 2–6 crew members, and larger wooden boats called sambuks, 10–20 m long, with inboard or outboard engines and with a crew from 10 up to 25 or more [4] and [27]. Huris were traditionally used for single day trips in inshore waters, within 40 km of the shore [4].

All statistical analyses were conducted using the JMP (version 9

All statistical analyses were conducted using the JMP (version 9.0.2) software program for Windows (SAS Institute Inc, Cary, NC). All statistical tests were two-sided, and P < 0.05 was considered to be statistically significant. A total of 268 patients with NSCLC were enrolled in this study. The characteristics of these 268 patients are summarized

in Table 1. All the patients were Asian (Japanese, Korean, or Chinese), their median age was 68 years (range: 31–87 years), and they included 76 women and 192 GSK-3 inhibitor men. One hundred and ninety-four patients had a history of smoking whereas the remaining 74 patients had never smoked. The numbers of patients with squamous cell carcinoma, adenocarcinoma, and other carcinomas were 63, 195,

and 10, respectively. The ECOG PS was 0–2 in 210 patients and 3–4 in 58 patients. Fifteen patients had stage IIIb disease, whereas 253 patients had stage IV disease. Two hundred and twenty-seven patients had received at least 1 regimen of systemic chemotherapy, whereas 41 patients FDA approval PARP inhibitor had received best supportive care alone. Specifically, a history of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment was reported in 107 patients, whereas the remaining 161 patients had not received EGFR-TKI treatment. To evaluate the hematological indices of patients with NSCLC, a comparator group of 134 age- and sex-matched patients was randomly selected from among patients with COPD or bronchial asthma. The data from the 2 groups are summarized in Table 2. There were no significant differences in age and sex between the 2 groups. The MPV, platelet distribution width

(PDW), and platelet large cell ratio (P-LCR) were significantly lower in the patients with NSCLC than in the comparator group. In contrast, the PC, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), white blood cell count WBC), and CRP level were significantly elevated in the patients with NSCLC than in the comparator group. Red blood cell distribution width (RDW) did not differ significantly between the groups. Interestingly, the MPV/PC ratio was also significantly decreased in the patients with NSCLC. We calculated the cutoff value for the MPV/PC ratio using ROC curve oxyclozanide analysis. A cutoff value of 0.408730 was found to be an identifier value for patients with advanced NSCLC, with a sensitivity of 74.6% and specificity of 74.6% (area under the curve [AUC], 0.72492). We divided the patients with NSCLC into 2 groups according to the cutoff value for the MPV/PC ratio of 0.408730. The characteristics of the 2 groups are summarized in Table 1. There were no significant differences in age, sex, PS, clinical stage, smoking history, or histological typing proportions between the 2 groups. We also reanalyzed the MPV, PC, and MPV/PC ratio in 3 groups: NSCLC patients with a low MPV/PC ratio; those with a high MPV/PC ratio; and the comparator group (Fig. 1).

14 Although differences in tooth shape among mammalian


14 Although differences in tooth shape among mammalian

taxa have lead to the establishment of distinct categories of dental wear, principles adopted are similar and rely on standardization of criteria by the researcher. In odontocete cetaceans, homodonty and absence of cusps or other morphological features facilitates and simplifies the standardization of categories by using the estimated percentage of tooth loss.26 In our study, superficial wear was frequent in all species of dolphins with exception of the Clymene dolphin S. clymene and false killer whale P. crassidens. However, besides having small sample sizes, sampled specimens of both species were most likely adults due to their body length (see Table 1), a factor that could explain higher frequencies of moderate and severe wear in these species. For most of the other species analysed, although general prevalence of wear was this website high, wear was mostly superficial and affected enamel and outer dentine. This observation is consistent with the limited role of dolphin teeth in food processing and modified occlusion Belnacasan solubility dmso resulting in interdigitation contact. 35 It is expected that the natural progression of wear will generate moderately to severely worn teeth. While superficial wear would have limited or negligible

implications for the fitness of individuals, moderate and severe wear could have the potential to expose the pulp cavity and lead to tissue necrosis and increase the susceptibility to infections. 30 and 41 In general, the occurrence of dental wear is related to progression of age.9, 11, 19, 20 and 23 In S. guianensis, Ramos et al. 24 observed that the height of the tooth crown and the height of the tooth itself were negatively related to the age of specimens,

due to the higher prevalence of Dichloromethane dehalogenase wear. Using the total body length (TBL) of individuals as a proxy to estimate age, we observed that our sample of S. guianensis did not follow the same trend established by Ramos et al. For our specimens, superficial wear was frequent even in bigger and potentially older animals. The weak association between indexes of wear and body size of specimens of D. capensis, L. hosei and S. guianensis suggests that, at least in these species, dental wear is common among all body sizes and age ranges and it is not influenced by growth and ageing processes. It would be expected that in those cases, interdigitation contact of upper and lower teeth played a more important role in generating dental wear than abrasion due to tooth use. Besides, allometric growth of teeth and body should also be taken into consideration. It means that different body parts may grow at varying rates during lifetime and could explain the weak association between dental wear and body size in these species. S. frontalis and T.

MVHP and SSA/P have overlapping morphologic features and distinct

MVHP and SSA/P have overlapping morphologic features and distinction between these polyp types in routine practice may be difficult or impossible, particularly when the polyps are small or when dealing with biopsies

rather than excised lesions. While SSA/Ps are well known to harbor the somatic BRAF V600E mutation, this molecular alteration is also present in a significant proportion of MVHPs [23], [24], [25] and [26] The presence of overlapping morphology with SSA/P and molecular alterations, including the somatic BRAF V600E mutation, raised the possibility of MVHP to have the ability to progress to more advanced lesions of the serrated pathway [25], [27] and [2]. In addition to mutations in the BRAF gene, lesions of the serrated pathway are also characterized by high frequency of MSI and CIMP [28], [29] and [30]. Our gene expression this website analysis has identified 744 genes that were differentially expressed between MVHP and SSA/P stratified

by BRAF V600E mutation status (adjusted P < .05, fold change ≥ ± 2), providing convincing evidence that these polyp types are most likely derived from distinct molecular pathways, which is consistent with other published reports [9], [11], [12], [13] and [31]. Several studies have attempted to identify biomarkers of SSA/P to develop a diagnostic tool to assist the pathologist to correctly diagnose this polyp type or to expand our knowledge on biology

and underlying molecular events involved in malignant transformation of these lesions [8], [9] and [10]. A recently CT99021 published study that employed microarray gene expression profiling with RT-PCR validation on a similar number of MVHPs and SSA/Ps revealed a strong association of the annexin A10 gene with SSA/P but not with MVHP making it a potential biomarker of SSA/P [10]. Mapping of the most differentially expressed genes in the same study onto 12 core cancer signaling pathways Tacrolimus (FK506) demonstrated a significant up-regulation of the CLDN1 gene in SSA/P. Interestingly, both genes were in the top six of the most differentially expressed genes in our study (sixth and first, respectively). The fact that CLDN1 was found to be upregulated in SSA/P in our microarray and not in the previous work may reflect the stratification of our polyps based on BRAF mutation status and/or sampling differences as our samples were obtained with assistance of a laser capture microscope. Interestingly, the same study demonstrated overexpression of a trefoil factor family gene, TFF2, in SSA/P and not in MVHP. These results and our previous observation of overexpression of the TFF1 gene in SSAs indicate the likely involvement of trefoil factor family genes in serrated pathway neoplasia [9].

Prespecified exploratory outcomes included the proportion of pati

Prespecified exploratory outcomes included the proportion of patients in the overall population who had a CDAI-100 response at week 6 and proportions of patients in the overall and TNF antagonist–failure populations who had a CDAI-100 response at week 10, as well as changes from baseline to weeks 6 and

10 in CRP concentration (among patients with increased baseline CRP concentration [>2.87 mg/L]) and from baseline to week 6 in fecal calprotectin level. To summarize efficacy in important subgroups and further clarify primary and secondary BMS-354825 solubility dmso outcomes, additional prespecified exploratory analyses were performed, including clinical remission and CDAI-100 response at weeks 6 and 10 and remission at both Akt inhibitor weeks 6 and 10 in patients who were naive to TNF antagonist therapy and remission at weeks 6 and 10 and CDAI-100 response at week 6 in subgroups defined by concomitant corticosteroid or immunosuppressive use. Adverse events,

serious adverse events (SAEs), standard clinical laboratory test results, and vital signs were evaluated. Consistent with all vedolizumab clinical studies conducted since 2006, the development of new neurologic signs and symptoms potentially consistent with PML was monitored in a risk minimization program27 featuring standardized questionnaires and Etoposide cell line a stepwise diagnostic algorithm overseen by an independent committee of PML experts.

The committee adjudicated potential cases and provided further guidance for the investigator and study sponsor in situations of clinical uncertainty. Blood samples for pharmacokinetic evaluation were collected postdose at week 0, predose and postdose at week 6, and at any time during the study visit at week 10 and any unscheduled disease exacerbation -related visit. Blood samples for anti–vedolizumab antibody assessment were collected predose at weeks 0, 6, 10, and 22, and during any unscheduled disease exacerbation–related visit. All efficacy analyses were performed for patients from intention-to-treat populations who had received any amount of blinded study drug; missing efficacy data were considered therapy failure. The safety population was defined as all patients who received any amount of study drug. Populations for pharmacokinetic analyses were defined as all patients who received 1 or more doses of study drug and underwent sufficient blood sampling for pharmacokinetic evaluation.