Molecular docking and geographical information systems as tools to assess the potential impact of veterinary medicines on non-target organisms and the environment

Veterinary medicines (VMs) from agricultural industry can enter the environment in a number of ways. This includes direct exposure through aquaculture, accidental spillage and disposal, and indirect entry by leaching from manure or runoff after treatment. Many compounds used in animal treatments have ecotoxic properties that may have chronic or sometimes lethal effects when they come into contact with non-target organisms. VMs enter the environment in mixtures, potentially having additive effects. Traditional ecotoxicology tests are used to determine the lethal and sometimes reproductive effects on freshwater and terrestrial organisms. However, organisms used in ecotoxicology tests can be unrepresentative of the populations that are likely to be exposed to the compound in the environment. Most often the tests are on single compound toxicity but mixture effects may be significant and should be included in ecotoxicology testing. This work investigates the use, measured environmental concentrations (MECs) and potential impact of sea lice treatments on salmon farms in Scotland. Alternative methods for ecotoxicology testing including mixture toxicity, and the use of in silico techniques to predict the chronic impact of VMs on different species of aquatic organisms were also investigated. The Scottish Environmental Protection Agency (SEPA) provided information on the use of five sea lice treatments from 2008-2011 on Scottish salmon farms. This information was combined with the recently available data on sediment MECs for the years 2009-2012 provided by SEPA using ArcGIS 10.1. In depth analysis of this data showed that from a total of 55 sites, 30 sites had a MEC higher than the maximum allowable concentration (MAC) as set out by SEPA for emamectin benzoate and 7 sites had a higher MEC than MAC for teflubenzuron. A number of sites that were up to 16 km away from the nearest salmon farm reported as using either emamectin benzoate or teflubenzuron measured positive for the two treatments. There was no relationship between current direction and the distribution of the sea lice treatments, nor was there any evidence for alternative sources of the compounds e.g. land treatments. The sites that had MECs higher than the MAC could pose a risk to non-target organisms and disrupt the species dynamics of the area. There was evidence that some marine protected sites might be at risk of exposure to these compounds. To complement this work, effects on acute mixture toxicity of the 5 sea lice treatments, plus one major metabolite 3-phenoxybenzoic acid (3PBA), were measured using an assay using the bioluminescent bacteria Aliivibrio fischeri. When exposed to the 5 sea lice treatments and 3PBA A. fischeri showed a response to 3PBA, emamectin benzoate and azamethiphos as well as combinations of the three. In order to establish any additive effect of the sea lice treatments, the efficacy of two mixture prediction equations, concentration addition (CA) and independent action ii(IA) were tested using the results from single compound dose response curves. In this instance IA was the more effective prediction method with a linear regression confidence interval of 82.6% compared with 22.6% of CA. In silico molecular docking was carried out to predict the chronic effects of 15 VMs (including the five used as sea lice control). Molecular docking has been proposed as an alternative screening method for the chronic effects of large animal treatments on non-target organisms. Oestrogen receptor alpha (ERα) of 7 non-target bony fish and the African clawed frog Xenopus laevis were modelled using SwissModel. These models were then ‘docked’ to oestradiol, the synthetic oestrogen ethinylestradiol, two known xenoestrogens dichlorodiphenyltrichloroethane (DDT) and bisphenol A (BPA), the antioestrogen breast cancer treatment tamoxifen and 15 VMs using Auto Dock 4. Based on the results of this work, four VMs were identified as being possible xenoestrogens or anti-oestrogens; these were cypermethrin, deltamethrin, fenbendazole and teflubenzuron. Further investigation, using in vitro assays, into these four VMs has been suggested as future work. A modified recombinant yeast oestrogen screen (YES) was attempted using the cDNA of the ERα of the zebrafish Danio rerio and the rainbow trout Oncorhynchus mykiss. Due to time and difficulties in cloning protocols this work was unable to be completed. Use of such in vitro assays would allow for further investigation of the highlighted VMs into their oestrogenic potential. In conclusion, VMs used as sea lice treatments, such as teflubenzuron and emamectin benzoate may be more persistent and have a wider range in the environment than previously thought. Mixtures of sea lice treatments have been found to persist together in the environment, and effects of these mixtures on the bacteria A. fischeri can be predicted using the IA equation. Finally, molecular docking may be a suitable tool to predict chronic endocrine disrupting effects and identify varying degrees of impact on the ERα of nine species of aquatic organisms.

Attenuation of monocyte chemotaxis--a novel anti-inflammatory mechanism of action for the cardio-protective hormone B-type natriuretic peptide

B-type natriuretic peptide (BNP) is a prognostic and diagnostic marker for heart failure (HF). An anti-inflammatory, cardio-protective role for BNP was proposed. In cardiovascular diseases including pressure overload-induced HF, perivascular inflammation and cardiac fibrosis are, in part, mediated by monocyte chemoattractant protein (MCP)1-driven monocyte migration. We aimed to determine the role of BNP in monocyte motility to MCP1. A functional BNP receptor, natriuretic peptide receptor-A (NPRA) was identified in human monocytes. BNP treatment inhibited MCP1-induced THP1 (monocytic leukemia cells) and primary monocyte chemotaxis (70 and 50 %, respectively). BNP did not interfere with MCP1 receptor expression or with calcium. BNP inhibited activation of the cytoskeletal protein RhoA in MCP1-stimulated THP1 (70 %). Finally, BNP failed to inhibit MCP1-directed motility of monocytes from patients with hypertension (n = 10) and HF (n = 6) suggesting attenuation of this anti-inflammatory mechanism in chronic heart disease. We provide novel evidence for a direct role of BNP/NPRA in opposing human monocyte migration and support a role for BNP as a cardio-protective hormone up-regulated as part of an adaptive compensatory response to combat excess inflammation.

Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:
Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.
METHODS:
A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.
RESULTS:
Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.
CONCLUSIONS:
In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis.

SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF WALKING EXERCISE IN CHRONIC MUSCULOSKELETAL PAIN

SYSTEMATIC REVIEW AND META-ANALYSIS: EFFECTS OF WALKING EXERCISE IN CHRONIC MUSCULOSKELETAL PAIN O'Connor S.R.1, Tully M.A.2, Ryan B.3, Baxter D.G.3, Bradley J.M.1, McDonough S.M.11University of Ulster, Health & Rehabilitation Sciences Research Institute, Newtownabbey, United Kingdom, 2Queen's University, UKCRC Centre of Excellence for Public Health (NI), Belfast, United Kingdom, 3University of Otago, Centre for Physiotherapy Research, Dunedin, New ZealandPurpose: To examine the effects of walking exercise on pain and self-reported function in adults with chronic musculoskeletal pain.Relevance: Chronic musculoskeletal pain is a major cause of morbidity, exerting a substantial influence on long-term health status and overall quality of life. Current treatment recommendations advocate various aerobic exercise interventions for such conditions. Walking may represent an ideal form of exercise due to its relatively low impact. However, there is currently limited evidence for its effectiveness.Participants: Not applicable.Methods: A comprehensive search strategy was undertaken by two independent reviewers according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) and the recommendations of the Cochrane Musculoskeletal Review Group. Six electronic databases (Medline, CINAHL, PsychINFO, PEDro, Sport DISCUS and the Cochrane Central Register of Controlled Trials) were searched for relevant papers published up to January 2010 using MeSH terms. All randomised or non-randomised studies published in full were considered for inclusion. Studies were required to include adults aged 18 years or over with a diagnosis of chronic low back pain, osteoarthritis or fibromyalgia. Studies were excluded if they involved peri-operative or post-operative interventions or did not include a comparative, non exercise or non-walking exercise control group. The U.S. Preventative Services Task Force system was used to assess methodological quality. Data for pain and self-reported function were extracted and converted to a score out of 100.Analysis: Data were pooled and analyzed using RevMan (v.5.0.24). Statistical heterogeneity was assessed using the X2 and I2 test statistics. A random effects model was used to calculate the mean differences and 95% CIs. Data were analyzed by length of final follow-up which was categorized as short (≤8 weeks post randomisation), mid (2-12 months) or long-term (>12 months).Results: A total of 4324 articles were identified and twenty studies (1852 participants) meeting the inclusion criteria were included in the review. Overall, studies were judged to be of at least fair methodological quality. The most common sources of likely bias were identified as lack of concealed allocation and failure to adequately address incomplete data. Data from 12 studies were suitable for meta-analysis. Walking led to reductions in pain at short (<8 weeks post randomisation) (-8.44 [-14.54, -2.33]) and mid-term (>8 weeks - 12 month) follow-up (-9.28 [-16.34, -2.22]). No effect was observed for long-term (>12 month) data (-2.49 [-7.62, 2.65]). For function, between group differences were observed for short (-11.57 [-16.06, -7.08]) and mid-term data (-13.26 [-16.91, -9.62]). A smaller effect was also observed at long-term follow-up (-5.60 [-7.70, -3.50]).Conclusions: Walking interventions were associated with statistically significant improvements in pain and function at short and mid-term follow-up. Long-term data were limited but indicated that these effects do not appear to be maintained beyond twelve months.Implications: Walking may be an effective form of exercise for individuals with chronic musculoskeletal pain. However, further research is required which examines longer term follow-up and dose-response issues in this population.Key-words: 1. Walking exercise 2. Musculoskeletal pain 3. Systematic reviewFunding acknowledgements: Department of Employment and Learning, Northern Ireland.Ethics approval: Not applicable.

Tyrosine kinase inhibitor insensitivity of non-cycling CD34+ human acute myeloid leukaemia cells with FMS-like tyrosine kinase 3 mutations.

The efficacy of tyrosine kinase (TK) inhibitors on non-cycling acute myeloid leukaemia (AML) cells, previously shown to have potent tumourigenic potential, is unknown. This pilot study describes the first attempt to characterize non-cycling cells from a small series of human FMS-like tyrosine kinase 3 (FLT3) mutation positive samples. CD34+ AML cells from patients with FLT3 mutation positive AML were cultured on murine stroma. In expansion cultures, non-cycling cells were found to retain CD34+ expression in contrast to dividing cells. Leukaemic gene rearrangements could be detected in non-cycling cells, indicating their leukaemic origin. Significantly, the FLT3-internal tandem duplication (ITD) mutation was found in the non-cycling fraction of four out of five cases. Exposure to the FLT3-directed inhibitor TKI258 clearly inhibited the growth of AML CD34+ cells in short-term cultures and colony-forming unit assays. Crucially, non-cycling cells were not eradicated, with the exception of one case, which exhibited exquisite sensitivity to the compound. Moreover, in longer-term cultures, TKI258-treated non-cycling cells showed no growth impairment compared to treatment-naive non-cycling cells. These findings suggest that non-cycling cells in AML may constitute a disease reservoir that is resistant to TK inhibition. Further studies with a larger sample size and other inhibitors are warranted.

Growth inhibition by tyrosine kinase inhibitors in mesothelioma cell lines.

Clinical outcome following chemotherapy for malignant pleural mesothelioma is poor and improvements are needed. This preclinical study investigates the effect of five tyrosine kinase inhibitors (PTK787, ZD6474, ZD1839, SU6668 and SU11248) on the growth of three mesothelioma cell lines (NCI H226, NCI H28 and MSTO 211H), the presence of growth factor receptors and inhibition of their downstream signalling pathways. GI50 values were determined: ZD6474 and SU11248, mainly VEGFR2 inhibitors, gave the lowest GI50 across all cell lines (3.5-6.9 microM) whereas ZD1839 gave a GI50 in this range only in H28 cells. All cell lines were positive for EGFR, but only H226 cells were positive for VEGFR2 by Western blotting. ZD6474 and ZD1839 inhibited EGF-induced phosphorylation of EGFR, AKT and ERK, whereas VEGF-induced phosphorylation of VEGFR2 was completely inhibited with 0.1 microM SU11248. VEGFR2 was detected in tumour samples by immunohistochemistry. VEGFR2 tyrosine kinase inhibitors warrant further investigation in mesothelioma.

New statin use and left ventricular structure: estimating long-term associations in the Multi-Ethnic Study of Atherosclerosis (MESA)

Thesis (Master's)--University of Washington, 2016-08

Hindfoot Kinematics of Healthy Subjects Using Lateral Wedge Insoles in a Biplane Fluoroscopy System

Thesis (Master's)--University of Washington, 2016-08

Role of active and passive recovery in adaptations to high intensity training

It has been established that Wingate-based high-intensity training (HIT) consisting of 4 to 6 x 30-s all-out sprints interspersed with 4-min recovery is an effective training paradigm. Despite the increased utilisation of Wingate-based HIT to bring about training adaptations, the majority of previous studies have been conducted over a relatively short timeframe (2 to 6 weeks). However, activity during recovery period, intervention duration or sprint length have been overlooked. In study 1, the dose response of recovery intensity on performance during typical Wingate-based HIT (4 x 30-s cycle all-out sprints separated by 4-min recovery) was examined and active recovery (cycling at 20 to 40% of V̇O2peak) has been shown to improve sprint performance with successive sprints by 6 to 12% compared to passive recovery (remained still), while increasing aerobic contribution to sprint performance by ~15%. In the following study, 5 to 7% greater endurance performance adaptations were achieved with active recovery (40%V̇O2peak) following 2 weeks of Wingate-based HIT. In the final study, shorter sprint protocol (4 to 6 x 15-s sprints interspersed with 2 min of recovery) has been shown to be as effective as typical 30-s Wingate-based HIT in improving cardiorespiratory function and endurance performance over 9 weeks with the improvements in V̇O2peak being completed within 3 weeks, whereas exercise capacity (time to exhaustion) being increased throughout 9 weeks. In conclusion, the studies demonstrate that active recovery at 40% V̇O2peak significantly enhances endurance adaptations to HIT. Further, the duration of the sprint does not seem to be a driving factor in the magnitude of change with 15 sec sprints providing similar adaptations to 30 sec sprints. Taken together, this suggests that the arrangement of recovery mode should be considered to ensure maximal adaptation to HIT, and the practicality of the training would be enhanced via the reduction in sprint duration without diminishing overall training adaptations.

Efeito de fatores ambientais e tolerância a herbicidas em três espécies de plantas daninhas da família Rubiaceae

The strong selection pressure exerted by intensive use of glyphosate in cultivated areas has selected populations of the Rubiaceae weed species Borreria latifolia (Aubl.) K.Shum. (broadleaf buttonweed), Galianthe chodatiana (Standl.) E.L. Cabral (galiante) and Richardia brasiliensis Gomes (Brazilian pusley) with differential sensitivity to this herbicide in the South region of Brazil. The control of these weeds with herbicides is troublesome and signals the need to incorporate management practices of ruderal flora and crops, more sustainable and that results in more efficient control for long-term. Therefore, it is very important to expand the information about their biology and management. This study aimed: (a) select efficient methods to overcome dormancy of B. latifolia and G. chodatiana and determine how they influence the kinetics of seeds germination; (b) analyze the effects of temperature, irradiance, pH, aluminum and salinity on seed germination and initial growth of the B. latifolia, G. chodatiana e R. brasiliensis seedlings; (c) evaluate tolerance to glyphosate levels in biotypes of B. latifolia, G. chodatiana e R. brasiliensis through dose-response curves and compare two methods to evaluate herbicidal control; (d) and evaluated the effectiveness of alternative herbicides in pre-emergence and in early and late post-emergence of the three species. The treatment with KNO3 2%/3h + gibberellic acid 400 ppm resulted in higher percentage of G. chodatiana seed germination. This treatment and also the dry heat (60°C/30 min) + KNO3 2%/3h were more effective in overcoming dormancy of B. latifolia. G. chodatiana and R. brasiliensis tolerate lower temperatures during the germination process, while B. latifolia tolerate higher temperatures. B. latifolia and R. brasiliensis are positive photoblastic while G. chodatiana is indifferent to the photoperiod. B. latifolia shows higher germination and early development in pH 3, while G. chodatiana and R. brasiliensis prefer pH range between 5 and 7. B. latifolia and G. chodatiana were more tolerant to the aluminum during the germination process than R. brasiliensis. Low salt levels were sufficient to reduce the seed germination of the three species. Some biotypes of B. latifolia and R. brasiliensis showed medium-high glyphosate tolerance, not being controlled by higher doses than recommended. The G. chodatiana specie was not controlled with the highest dose used, showing a high glyphosate tolerance. The sulfentrazone, s-metolachlor and saflufenacil herbicides sprayed in pre-emergence showed high efficacy both on B. latifolia and R. brasiliensis, while chlorimuron-ethyl and diclosulan were effective only on R. brasiliensis. In early post-emergence the fomesafen, lactofem and flumioxazin herbicides efficiently controlled plants of all species, while bentazon showed high efficacy only on B. latifolia. Noteworthy the susceptibility of the G. chodatiana specie for applications in early post-emergence, because the control effectiveness and the number of effective herbicides are reduced with increasing the plant age. Many treatments with tank mix or sequencial applications with glyphosate, were effective in controlling B. latifolia and R. brasiliensis plants in advanced stage of development.

Status of resistance to phosphine in insect pests of stored products in Vietnam

In response to numerous reports of failures to control insect pests of stored products with phosphine in Vietnam, a national survey for resistance to this key fumigant was undertaken in 2009–2011. Data from a more limited survey undertaken by the authors in 2002 in northern Vietnam are also presented. Samples collected in the 2002 survey (Sitophilus oryzae, n=8; Tribolium castaneum, n=8) were tested using a full dose- response assay, while for the 2009–11 survey, F1 generations were tested for resistance with two discriminating dosages of phosphine to detect frequency of weak and strong resistance phenotypes. Compared with a susceptible reference strain, in 2002, resistance to phosphine was indicated in six T. castaneum samples but only two of S. oryzae. Resistance factor, however, did not exceed 2.8-fold in T. castaneum and 1.7 in S. oryzae indicating relatively low frequency and weak expression of resistance. In 2009–11 survey, 176 samples were collected from a range of food and feed storages along the supply chain and from all major regions of Vietnam (125 sites). Rhyzopertha dominica and S. oryzae were the most common species found infesting stored commodities. Resistance was detected at high frequency in all the species. Weak and strong resistance phenotype frequencies were, respectively: Cryptolestes ferrugineus (37 and 58%, n=19), R. dominica (1.5 and 97%, n=65), S. oryzae (34 and 59%, n=82) and T. castaneum (70 and 30%, n=10). Strong resistance phenotype was detected in all the major regions and all parts of the supply chain but frequency was the highest in central storages and animal feed establishments. The increase in frequency and strength of resistance to phosphine in the eight years between the two surveys has been rapid and dramatic. The survey demonstrates the threat of resistance to grain protection in Vietnam and highlights the need for training of fumigators, and the development and adoption of phosphine resistance management tactics nationally.

Responses to various protein and energy supplements by steers fed low-quality tropical hay. 2. Effect of stage of maturity of steers

Dose response curves to various supplements were established in two pen-feeding experiments (Exp1 and Exp2) with Bos indicus crossbred steers of two age groups (Young, 10–12 months; Old, 33–36 months) fed low-quality tropical grass hays ad libitum. Diets included supplements based on (Exp1) cottonseed meal (CSM; intake (as fed) 0–10 g/kg liveweight (W).day) and a barley mix (Bar; 0–20 g/kg W.day) and (Exp2) a molasses mix (MUP) and a Bar mix, both fed at 0–20 g/kg W.day. Urea was provided with the Bar mixes and urea/copra meal with the MUP mix. Growth rates of Young steers increased linearly with Bar and MUP supplements but asymptotically with CSM whereas those of Old steers increased asymptotically with all supplement types. With supplement intake expressed on a liveweight basis (g/kg W.day), responses were greater for both steer age groups with CSM compared with Bar (Young, P < 0.001; Old, P < 0.01) and Bar compared with MUP treatments (Young, P < 0.01; Old, P < 0.05). Furthermore, Old steers outperformed their Young counterparts with both CSM (P < 0.05) and Bar (P < 0.001) supplements fed in Exp1 and with Bar and MUP supplements (P < 0.01) fed in Exp2. When supplement intake was expressed in absolute terms (kg/day), growth responses were not different between age groups for different supplements except that Old steers had a higher daily W gain on Bar than their Young counterparts (P < 0.05). Intake of hay (W-corrected) was higher for Young compared with Old steers without supplement but was variably reduced for both steer groups with increasing supplement intake. The results of these experiments have implications for supplement formulation for steers at different stages of maturity grazing low-quality forages.

Herança genética e marcadores moleculares associados à resistência de Euphorbia heterophylla L. aos herbicidas inibidores da ALS e PROTOX

This study aimed to assess the genetic inheritance, determine the better DNA isolation protocol for this species and to identify molecular markers associated with the Wild Poinsettia (Euphorbia heterophylla L.) resistance ALS- and PROTOX- inhibiting herbicides and. The genetic inheritance of resistance was determined from crosses between E. heterophylla biotypes susceptible (S) and resistant (R), backcrosses and F2 generation. The complete dominance of resistance was confirmed with dose response curves. Ten adjusted methods for DNA isolation described in the literature were tested. The specific primers for ALS and PROTOX genes were designed from the consensus DNA sequence of these genes, obtained by aligning the gene sequences of the species Manihot esculenta and Ricinus communis L. Additionally, it was assessed the transferability of twenty SSR (simple sequence repeat) markers designed for Manihot esculenta, because among the species of Euphorbiaceae with more developed SSRs markers, because it is the closest relative phylogenetic species of E. heterophylla. Regarding genetic inheritance, the frequencies observed in the F1, F2, RCs and RCr did not differ significantly from the expected frequencies for a trait controlled by two dominant genes for multiple resistance and a single dominant gene for simple resistance to ALS- and PROTOX-inhibiting herbicides. The similar levels of resistance to dosage up to 2000 g i.a. ha-1 of fomesafen and dosage up to 800 g i.a. ha-1 of imazethapyr observed in F1 (heterozygous) and homozygous R biotype confirm the complete dominance of resistance to PROTOX- and ALS-inhibiting herbicides, respectively. The 0.2%BME protocol allowed the isolation of 7,083 ng μL-1 DNA, significantly (P=0.05) higher than other methods. Co-isolation of phenolic compounds was observed in FENOL and 3%BME+TB methods, but the addition of polyvinylpyrrolidone (PVP40) in the protocol extraction buffer 3%BME+TA solved this problem. The primers designed for ALS and PROTOX genes amplified but not showed no visible polymorphism in agarose gel between the S and R biotypes of E. heterophylla. Regarding the SSR transferability, ten markers were transferred to E. heterophylla, however, these six primers showed polymorphism among S and R biotypes.

Neutrophil Chemotaxis in Multiple Chemoattractant Gradients

Chemotaxis, the phenomenon in which cells move in response to extracellular chemical gradients, plays a prominent role in the mammalian immune response. During this process, a number of chemical signals, called chemoattractants, are produced at or proximal to sites of infection and diffuse into the surrounding tissue. Immune cells sense these chemoattractants and move in the direction where their concentration is greatest, thereby locating the source of attractants and their associated targets. Leading the assault against new infections is a specialized class of leukocytes (white blood cells) known as neutrophils, which normally circulate in the bloodstream. Upon activation, these cells emigrate out of the vasculature and navigate through interstitial tissues toward target sites. There they phagocytose bacteria and release a number of proteases and reactive oxygen intermediates with antimicrobial activity. Neutrophils recruited by infected tissue in vivo are likely confronted by complex chemical environments consisting of a number of different chemoattractant species. These signals may include end target chemicals produced in the vicinity of the infectious agents, and endogenous chemicals released by local host tissues during the inflammatory response. To successfully locate their pathogenic targets within these chemically diverse and heterogeneous settings, activated neutrophils must be capable of distinguishing between the different signals and employing some sort of logic to prioritize among them. This ability to simultaneously process and interpret mulitple signals is thought to be essential for efficient navigation of the cells to target areas. In particular, aberrant cell signaling and defects in this functionality are known to contribute to medical conditions such as chronic inflammation, asthma and rheumatoid arthritis. To elucidate the biomolecular mechanisms underlying the neutrophil response to different chemoattractants, a number of efforts have been made toward understanding how cells respond to different combinations of chemicals. Most notably, recent investigations have shown that in the presence of both end target and endogenous chemoattractant variants, the cells migrate preferentially toward the former type, even in very low relative concentrations of the latter. Interestingly, however, when the cells are exposed to two different endogenous chemical species, they exhibit a combinatorial response in which distant sources are favored over proximal sources. Some additional results also suggest that cells located between two endogenous chemoattractant sources will respond to the vectorial sum of the combined gradients. In the long run, this peculiar behavior could result in oscillatory cell trajectories between the two sources. To further explore the significance of these and other observations, particularly in the context of physiological conditions, we introduce in this work a simplified phenomenological model of neutrophil chemotaxis. In particular, this model incorporates a trait commonly known as directional persistence - the tendency for migrating neutrophils to continue moving in the same direction (much like momentum) - while also accounting for the dose-response characteristics of cells to different chemical species. Simulations based on this model suggest that the efficiency of cell migration in complex chemical environments depends significantly on the degree of directional persistence. In particular, with appropriate values for this parameter, cells can improve their odds of locating end targets by drifting through a network of attractant sources in a loosely-guided fashion. This corroborates the prediction that neutrophils randomly migrate from one chemoattractant source to the next while searching for their end targets. These cells may thus use persistence as a general mechanism to avoid being trapped near sources of endogenous chemoattractants - the mathematical analogue of local maxima in a global optimization problem. Moreover, this general foraging strategy may apply to other biological processes involving multiple signals and long-range navigation.