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1.  Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation 
Cancer research  2013;74(1):374-386.
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to breast cancer growth, progression and therapeutic resistance. Due to the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan (HA) within the extracellular matrix (ECM) and that blocking HA synthesis decreases proliferation, migration and therapeutic resistance. Furthermore, FGFR-mediated HA accumulation requires activation of the signal transducer and activator of transcription 3 (STAT3) pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent HA synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and HA levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and HA synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a pro-tumorigenic microenvironment.
doi:10.1158/0008-5472.CAN-13-2469
PMCID: PMC3933218  PMID: 24197137
2.  Experimentally Induced Blood-Stage Plasmodium vivax Infection in Healthy Volunteers 
The Journal of Infectious Diseases  2013;208(10):1688-1694.
Background. Major impediments to development of vaccines and drugs for Plasmodium vivax malaria are the inability to culture this species and the extreme difficulty in undertaking clinical research by experimental infection.
Methods. A parasite bank was collected from a 49-year-old woman with P. vivax infection, characterized, and used in an experimental infection study.
Results. The donor made a full recovery from malaria after collection of a parasite bank, which tested negative for agents screened for in blood donations. DNA sequence analysis of the isolate indicated that it was clonal. Two subjects inoculated with the isolate became polymerase chain reaction positive on days 8 and 9, with onset of symptoms and positive blood smears on day 14, when they were treated with artemether-lumefantrine, with rapid clinical and parasitologic response. Transcripts of the parasite gene pvs25 that is expressed in gametocytes, the life cycle stage infectious to mosquitoes, were first detected on days 11 and 12.
Conclusions. This experimental system results in in vivo parasite growth, probably infectious to mosquitoes. It offers the opportunity to undertake studies previously impossible in P. vivax that will facilitate a better understanding of the pathology of vivax malaria and development of antimalarial drugs and vaccines.
Trial Registration. ANZCTR: 12612001096842.
doi:10.1093/infdis/jit394
PMCID: PMC3888148  PMID: 23908484
Plasmodium vivax; malaria; experimental infection
3.  Assessment of Anthelmintic Efficacy of Mebendazole in School Children in Six Countries Where Soil-Transmitted Helminths Are Endemic 
Background
Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking. However, they are urgently needed to ensure detection of reduced efficacies that are predicted to occur due to growing drug pressure. Here, using a standardized methodology, we assessed the FECR rate of a single oral dose of mebendazole (MEB; 500 mg) against STHs in six trials in school children in different locations around the world. Our results are compared with those previously obtained for similarly conducted trials of a single oral dose of albendazole (ALB; 400 mg).
Methodology
The efficacy of MEB, as assessed by FECR, was determined in six trials involving 5,830 school children in Brazil, Cambodia, Cameroon, Ethiopia, United Republic of Tanzania, and Vietnam. The efficacy of MEB was compared to that of ALB as previously assessed in 8,841 school children in India and all the above-mentioned study sites, using identical methodologies.
Principal Findings
The estimated FECR rate [95% confidence interval] of MEB was highest for A. lumbricoides (97.6% [95.8; 99.5]), followed by hookworm (79.6% [71.0; 88.3]). For T. trichiura, the estimated FECR rate was 63.1% [51.6; 74.6]. Compared to MEB, ALB was significantly more efficacious against hookworm (96.2% [91.1; 100], p<0.001) and only marginally, although significantly, better against A. lumbricoides infections (99.9% [99.0; 100], p = 0.012), but equally efficacious for T. trichiura infections (64.5% [44.4; 84.7], p = 0.906).
Conclusions/Significance
A minimum FECR rate of 95% for A. lumbricoides, 70% for hookworm, and 50% for T. trichiura is expected in MEB-dependent PC programs. Lower FECR results may indicate the development of potential drug resistance.
Author Summary
Soil-transmitted helminths (STHs; roundworms, whipworms, and hookworms) infect millions of children in sub-tropical and tropical countries, resulting in malnutrition, growth stunting, intellectual retardation, and cognitive deficits. To fight against STH, large-scale deworming programs are implemented in which anthelmintic drugs (either albendazole (ALB) or mebendazole (MEB)) are administered. Currently, these large-scale programs are intensifying, highlighting the need to closely monitor the efficacy of anthelmintic drugs to detect changes in drug efficacy that may arise through the evolution of anthelmintic drug resistance in the parasites. We have previously defined the minimum expected efficacy of ALB based on the fecal egg count reduction (FECR) rate, but these reference values are lacking for MEB. Therefore, we therefore evaluated the FECR rate of MEB against STHs in six STH endemic countries. In addition, we compared the results of the FECR rate for MEB with those we obtained previously for ALB. The results confirm that MEB treatment was highly efficacious against roundworms, and to a lesser extend against hookworms, but not against whipworms. Compared to ALB, MEB is less efficacious against hookworm, but equally efficacious against roundworms and whipworms. Based on this study we propose the minimum expected FECR rate for MEB-dependent large-scale deworming programs.
doi:10.1371/journal.pntd.0003204
PMCID: PMC4191962  PMID: 25299391
4.  Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues 
BioMed Research International  2014;2014:103923.
Tumors and wounds share many similarities including loss of tissue architecture, cell polarity and cell differentiation, aberrant extracellular matrix (ECM) remodeling (Ballard et al., 2006) increased inflammation, angiogenesis, and elevated cell migration and proliferation. Whereas these changes are transient in repairing wounds, tumors do not regain tissue architecture but rather their continued progression is fueled in part by loss of normal tissue structure. As a result tumors are often described as wounds that do not heal. The ECM component hyaluronan (HA) and its receptor RHAMM have both been implicated in wound repair and tumor progression. This review highlights the similarities and differences in their roles during these processes and proposes that RHAMM-regulated wound repair functions may contribute to “cancerization” of the tumor microenvironment.
doi:10.1155/2014/103923
PMCID: PMC4137499  PMID: 25157350
5.  Multi-modal MRI of mild traumatic brain injury 
NeuroImage : Clinical  2014;7:87-97.
Multi-modal magnetic resonance imaging (MRI) that included high resolution structural imaging, diffusion tensor imaging (DTI), magnetization transfer ratio (MTR) imaging, and magnetic resonance spectroscopic imaging (MRSI) were performed in mild traumatic brain injury (mTBI) patients with negative computed tomographic scans and in an orthopedic-injured (OI) group without concomitant injury to the brain. The OI group served as a comparison group for mTBI. MRI scans were performed both in the acute phase of injury (~24 h) and at follow-up (~90 days). DTI data was analyzed using tract based spatial statistics (TBSS). Global and regional atrophies were calculated using tensor-based morphometry (TBM). MTR values were calculated using the standard method. MRSI was analyzed using LC Model. At the initial scan, the mean diffusivity (MD) was significantly higher in the mTBI cohort relative to the comparison group in several white matter (WM) regions that included internal capsule, external capsule, superior corona radiata, anterior corona radiata, posterior corona radiata, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, forceps major and forceps minor of the corpus callosum, superior longitudinal fasciculus, and corticospinal tract in the right hemisphere. TBSS analysis failed to detect significant differences in any DTI measures between the initial and follow-up scans either in the mTBI or OI group. No significant differences were found in MRSI, MTR or morphometry between the mTBI and OI cohorts either at the initial or follow-up scans with or without family wise error (FWE) correction. Our study suggests that a number of WM tracts are affected in mTBI in the acute phase of injury and that these changes disappear by 90 days. This study also suggests that none of the MRI-modalities used in this study, with the exception of DTI, is sensitive in detecting changes in the acute phase of mTBI.
doi:10.1016/j.nicl.2014.07.010
PMCID: PMC4299969  PMID: 25610770
Mild traumatic brain injury; Orthopedic injury; Magnetic resonance imaging; Diffusion tensor imaging; Magnetic resonance spectroscopic imaging; Magnetization transfer ratio; Tensor based morphometry; acr, anterior region of corona radiata; alic, anterior limb of internal capsule; cc, corpus callosum; cs, centrum semiovale; cst, corticospinal tract; ec, external capsule; ic, internal capsule; ifo, inferior fronto-occipital fasciculus; ilf, inferior longitudinal fasciculus; pcr, posterior region of corona radiata; plic, posterior limb of internal capsule; scr, superior region of corona radiata; sfo, superior fronto-occipital fasciculus; slf, superior longitudinal fasciculus; sfg, superior frontal gyrus; mfg, superior frontal gyrus; jlc, juxtapositional lobule cortex; cg, cingulate gyrus; pcg, paracingulate gyrus
6.  Plasmodium falciparum parasites lacking histidine-rich protein 2 and 3: a review and recommendations for accurate reporting 
Malaria Journal  2014;13:283.
Malaria rapid diagnostic tests (RDTs) play a critical role in malaria case management, surveillance and case investigations. Test performance is largely determined by design and quality characteristics, such as detection sensitivity, specificity, and thermal stability. However, parasite characteristics such as variable or absent expression of antigens targeted by RDTs can also affect RDT performance. Plasmodium falciparum parasites lacking the PfHRP2 protein, the most common target antigen for detection of P. falciparum, have been reported in some regions. Therefore, accurately mapping the presence and prevalence of P. falciparum parasites lacking pfhrp2 would be an important step so that RDTs targeting alternative antigens, or microscopy, can be preferentially selected for use in such regions. Herein the available evidence and molecular basis for identifying malaria parasites lacking PfHRP2 is reviewed, and a set of recommended procedures to apply for future investigations for parasites lacking PfHRP2, is proposed.
doi:10.1186/1475-2875-13-283
PMCID: PMC4115471  PMID: 25052298
7.  Production and characterization of specific monoclonal antibodies binding the Plasmodium falciparum diagnostic biomarker, histidine-rich protein 2 
Malaria Journal  2014;13:277.
Background
Early and accurate diagnosis of Plasmodium falciparum infection is important for providing appropriate treatment to patients with malaria. However, technical limitations of currently available diagnostic tests limit their use in control programs. One possible explanation for the vulnerability of current antibodies used in RDTs is their propensity to degrade at high ambient temperatures. Isolation of new antibodies with better thermal stability represents an appealing approach to improve the performance of RDTs.
Methods
In this study, phage display technology was deployed to isolate novel binders by screening a human naïve scFv antibody library against recombinant Plasmodium falciparum histidine rich protein 2 (rPfHRP2). The isolated scFv clones were reformatted to whole IgG and the recombinant mAbs were produced in a mammalian CHO cell expression system. To verify the biological activity of these purified recombinant mAbs, range of functional assays were characterized.
Results
Two unique clones (D2 and F9) were isolated after five rounds of biopanning. The reformatted and expressed antibodies demonstrated high binding specificity to malaria recombinant PfHRP2 and native proteins. When 5 μg/mL of mAbs applied, mAb C1-13 had the highest sensitivity, with an OD value of 1, the detection achieved 5 ng/mL of rPfHRP2, followed by mAbs D2 and F9 at 10 ng/mL and 100 ng/mL of rPfHRP2, respectively. Although the sensitivity of mAbs D2 and F9 was lower than the control, these recombinant human mAbs have shown better stability compared to mouse mAb C1-13 at various temperatures in DSC and blot assays. In view of epitope mapping, the predominant motif of rPfHRP2 recognized by mAb D2 was AHHAADAHHA, whereas mAb F9 was one amino acid shorter, resulting in AHHAADAHH. mAb F9 had the strongest binding affinity to rPfHRP2 protein, with a KD value of 4.27 × 10−11 M, followed by control mAb C1-13 at 1.03 × 10−10 M and mAb D2 at 3.05 × 10−10 M.
Conclusions
Overall, the performance of these mAbs showed comparability to currently available PfHRP2-specific mouse mAb C1-13. The stability of these novel binders indicate that they merit further work to evaluate their utility in the development of new generation point of care diagnosis of malaria.
doi:10.1186/1475-2875-13-277
PMCID: PMC4120728  PMID: 25037150
8.  Purification, crystallization and preliminary X-ray diffraction analysis of a hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT) from Coffea canephora involved in chlorogenic acid biosynthesis 
A hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase involved in chlorogenic acid biosynthesis in C. canephora was crystallized using the vapour-diffusion method. A diffraction data set was collected to 3.0 Å resolution on the microfocus beamline (ID23-2) at ESRF and a structure solution was obtained using molecular replacement.
Chlorogenic acids (CGAs) are a group of soluble phenolic compounds that are produced by a variety of plants, including Coffea canephora (robusta coffee). The last step in CGA biosynthesis is generally catalysed by a specific hydroxycinnamoyl-CoA quinate hydroxycinnamoyltransferase (HQT), but it can also be catalysed by the more widely distributed hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT). Here, the cloning and overexpression of HCT from C. canephora in Escherichia coli as well as its purification and crystallization are presented. Crystals were obtained by the sitting-drop technique at 293 K and X-ray diffraction data were collected on the microfocus beamline ID23-2 at the ESRF. The HCT crystals diffracted to better than 3.0 Å resolution, belonged to space group P42212 with unit-cell parameters a = b = 116.1, c = 158.9 Å and contained two molecules in the asymmetric unit. The structure was solved by molecular replacement and is currently under refinement. Such structural data are needed to decipher the molecular basis of the substrate specifities of this key enzyme, which belongs to the large plant acyl-CoA-dependent BAHD acyltransferase superfamily.
doi:10.1107/S1744309112019082
PMCID: PMC3388932  PMID: 22750875
Coffea canephora; phenylpropanoid-biosynthesis pathway; chlorogenic acids; plant acyl-CoA-dependent acyltransferase superfamily; hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase; molecular replacement
9.  Nanomedicine for prion disease treatment 
Prion  2013;7(3):198-202.
Despite their devastating impact, no effective therapeutic yet exists for prion diseases at the symptomatic stage in humans or animals. Progress is hampered by the difficulty in identifying compounds that affect PrPSc and the necessity of any potential therapeutic to gain access to the CNS. Synthetic polymers known as dendrimers are a particularly promising candidate in this area. Studies with cell culture models of prion disease and prion infected brain homogenate have demonstrated that numerous species of dendrimers eliminate PrPSc in a dose and time dependent fashion and specific glycodendrimers are capable of crossing the CNS. However, despite their potential a number of important questions remained unanswered such as what makes an effective dendrimer and how dendrimers eliminate prions intracellularly. In a number of recent studies we have tackled these questions and revealed for the first time that a specific dendrimer can inhibit the intracellular conversion of PrPC to PrPSc and that a high density of surface reactive groups is a necessity for dendrimers in vitro anti-prion activity. Understanding how a therapeutic works is a vital component in maximising its activity and these studies therefore represent a significant development in the race to find effective treatments for prion diseases.
doi:10.4161/pri.24431
PMCID: PMC3783103  PMID: 23764833
prion; dendrimer; therapeutic; scrapie cell assay; neurodegeneration; PrP N-terminal; amyloid; nanomedicine
10.  Updating Memory after Mild Traumatic Brain Injury and Orthopedic Injuries 
Journal of Neurotrauma  2013;30(8):618-624.
Abstract
Few studies have examined the trajectory of recovery of executive function (EF) after mild TBI (mTBI). Therefore, consensus has not been reached on the incidence and extent of EF impairment after mTBI. The present study investigated trajectory of change in executive memory over 3 months after mTBI on 59 right-handed participants with mTBI, as defined by Centers for Disease Control criteria, ages 14–30 years, recruited within 96 hours post-injury and tested <1 week (baseline), 1 month, and 3 months after injury. Also included were 58 participants with orthopedic injury (OI) and 27 typically developing (TD) non-injured participants with similar age, socioeconomic status, sex, and ethnicity. MRI data were acquired at baseline and 3 months. Although criteria included a normal CT scan, lesions were detected by MRI in 19 mTBI patients. Participants completed the KeepTrack task, a verbal recall task placing demands on goal maintenance, semantic memory, and memory updating. Scores reflected items recalled and semantic categories maintained. The mTBI group was divided into two groups: high (score ≥12) or low (score <12) symptoms based on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ). Mixed model analyses revealed the trajectory of change in mTBI patients (high and low RPQ), OI patients, and TD subjects were similar over time (although the TD group differed from other groups at baseline), suggesting no recovery from mTBI up to 90 days. For categories maintained, differences in trajectory of recovery were discovered, with the OI comparison group surprisingly performing similar to those in the mTBI group with high RPQ symptoms, and different from low RPQ and the TD groups, bringing up questions about utility of OIs as a comparison group for mTBI. Patients with frontal lesions (on MRI) were also found to perform worse than those without lesions, a pattern that became more pronounced with time.
doi:10.1089/neu.2012.2392
PMCID: PMC3638547  PMID: 23227898
cognition; executive function, mild traumatic brain injury; memory
12.  Evaluation of protein biomarkers of prostate cancer aggressiveness 
BMC Cancer  2014;14:244.
Background
Prognostic multibiomarker signatures in prostate cancer (PCa) may improve patient management and provide a bridge for developing novel therapeutics and imaging methods. Our objective was to evaluate the association between expression of 33 candidate protein biomarkers and time to biochemical failure (BF) after prostatectomy.
Methods
PCa tissue microarrays were constructed representing 160 patients for whom clinicopathologic features and follow-up data after surgery were available. Immunohistochemistry for each of 33 proteins was quantified using automated digital pathology techniques. Relationships between clinicopathologic features, staining intensity, and time to BF were assessed. Predictive modeling using multiple imputed datasets was performed to identify the top biomarker candidates.
Results
In univariate analyses, lymph node positivity, surgical margin positivity, non-localized tumor, age at prostatectomy, and biomarkers CCND1, HMMR, IGF1, MKI67, SIAH2, and SMAD4 in malignant epithelium were significantly associated with time to BF. HMMR, IGF1, and SMAD4 remained significantly associated with BF after adjusting for clinicopathologic features while additional associations were observed for HOXC6 and MAP4K4 following adjustment. In multibiomarker predictive models, 3 proteins including HMMR, SIAH2, and SMAD4 were consistently represented among the top 2, 3, 4, and 5 most predictive biomarkers, and a signature comprised of these proteins best predicted BF at 3 and 5 years.
Conclusions
This study provides rationale for investigation of HMMR, HOXC6, IGF1, MAP4K4, SIAH2, and SMAD4 as biomarkers of PCa aggressiveness in larger cohorts.
doi:10.1186/1471-2407-14-244
PMCID: PMC4101830  PMID: 24708576
Prostate cancer; Aggressiveness; Biomarker; Signature
13.  Thromboelastography in Patients with Acute Ischemic Stroke 
Background
Thromboelastography (TEG) measures the dynamics of coagulation. There are limited data about TEG in acute ischemic stroke other than a single study from 1974 suggesting that acute ischemic stroke patients are hypercoagulable. There have been no studies of TEG in the thrombolytic era despite its potential usefulness as a measure of clot lysis. This study was designed to provide initial TEG data in stroke patients before and after tissue plasminogen activator (tPA) therapy, and to provide the necessary preliminary data for further study of TEG’s ability to identify clot subtype and predict response to tPA therapy.
Methods
All acute ischemic stroke patients presenting between 11/2009 and 2/2011 eligible for tPA therapy were screened and 56 enrolled. Blood was drawn before (52 patients) and 10 minutes after tPA bolus (30 patients). Demographics, vitals, labs, 24hr National Institutes of Health Stroke Scale (NIHSS) and computed tomography (CT) scan results were collected. Patients were compared to normal controls.
Results
Acute ischemic stroke patients had shorter R (4.8±1.5 vs 6.0 ±1.7 min, p =0.0004), greater a-Angle (65.0±7.6 vs 61.5 ± 5.9°, p =0.01), and shorter K (1.7 ±0.7 vs 2.1 ±0.7 min, p =0.002) indicating faster clotting. Additionally, a subset formed clots with stronger platelet-fibrin matrices. Treatment with tPA resulted in reduction in all indices of clot strength (LY30=0(0–0.4) vs 94.4 (15.2–95.3) p<0.0001), however there was considerable variability in response.
Conclusions
TEG demonstrates that many acute ischemic stroke patients are hypercoaguable. TEG values reflect variable clot subtype and response to tPA. Further study based on these data will determine if TEG is useful for measuring the dynamic aspects of clot formation and monitoring lytic therapy.
doi:10.1111/j.1747-4949.2012.00919.x
PMCID: PMC3535538  PMID: 23017088
cerebral infarction; ischaemic stroke; thrombolysis; stroke; tPA; haemocoagulation
15.  Limb Lengthening and Reconstruction Society AIM Index Reliably Assesses Lower Limb Deformity 
Background
Although several systems exist for classifying specific limb deformities, there currently are no validated rating scales for evaluating the complexity of general lower limb deformities. Accurate assessment of the complexity of a limb deformity is essential for successful treatment. A committee of the Limb Lengthening and Reconstruction Society (LLRS) therefore developed the LLRS AIM Index to quantify the severity of a broad range of lower extremity deformities in seven domains.
Questions/Purposes
We addressed two questions: (1) Does the LLRS AIM Index show construct validity by correlating with rankings of case complexity? (2) Does the LLRS AIM Index show sufficient interrater and intrarater reliabilities?
Methods
We had eight surgeons evaluate 10 fictionalized patients with various lower limb deformities. First, they ranked the cases from simplest to most complex, and then they rated the cases using the LLRS AIM Index. Two or more weeks later, they rated the cases again. We assessed reliability using the Kendall’s W test.
Results
Raters were consistent in their rankings of case complexity (W = 0.33). Patient rankings also correlated with both sets of LLRS AIM ratings (r2 = 0.25; r2 = 0.23). The LLRS AIM Index showed interrater reliability with an intraclass correlation (ICC) of 0.97 for Trial 1 and 0.98 for Trial 2 and intrarater reliability with an ICC of 0.94. The LLRS AIM Index ratings also were highly consistent between the attending surgeons and surgeons-in-training (ICC = 0.91).
Conclusions
Our preliminarily observations suggest that the LLRS AIM Index reliably classifies the complexity of lower limb deformities in and between observers.
Electronic supplementary material
The online version of this article (doi:10.1007/s11999-012-2609-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11999-012-2609-8
PMCID: PMC3549163  PMID: 23054511
16.  AN EMERGENCY DEPARTMENT THAWED PLASMA PROTOCOL IS ASSOCIATED WITH REDCUTION IN BLOOD COMPONENT UTILIZATION AND IMPROVED SURVIVAL IN SEVERELY INJURED PATIENTS 
JAMA surgery  2013;148(2):170-175.
Objectives
To expedite delivery and transfusion of plasma through implementation of an emergency department (TP-ED) protocol.
Design
Retrospective cohort study
Setting
ACS-verified level 1 trauma center
Patients
Protocol was initiated February 2010, placing four units of AB plasma in the ED. All trauma patients admitted eight months before (TP-BB) and after implementing the TP-ED protocol. Patients were included if they received at least one unit of RBC and one unit of plasma in the first six hours after ED admission.
Main Outcome Measures
Primary outcome was time to first unit of plasma. Secondary outcomes included 24-hour blood use and 24-hour and 30-day mortality.
Results
294 patients met study criteria (130 TP-BB, 164 TP-ED). While demographics were similar, TP-ED patients had greater anatomic injury (median ISS 18 vs. 25, p=0.018) and more physiological disturbances (median w-RTS 6.81 vs. 3.83, p=0.008). TP-ED had shorter time to first plasma transfusion (83 min vs. 42 min, p<0.001). TP-ED was associated with a reduction in 24-hour transfusion of RBC (p=0.036), plasma (p=0.044), and platelets (p<0.001). Logistic regression identified TP-ED as an independent predictor of decreased 30-day mortality (OR 0.43, 95% C.I. 0.194–0.956, p=0.038).
Conclusions
We demonstrated that implementation of a ED-TP protocol expedites transfusion of plasma to severely injured patients. This approach is associated with a reduction in overall blood product use and a 60% decreased odds in 30-day mortality.
doi:10.1001/jamasurgery.2013.414
PMCID: PMC3800103  PMID: 23426594
plasma; thawed; transfusion and trauma
18.  Antibody Responses to Sarcoptes scabiei Apolipoprotein in a Porcine Model: Relevance to Immunodiagnosis of Recent Infection 
PLoS ONE  2013;8(6):e65354.
No commercial immunodiagnostic tests for human scabies are currently available, and existing animal tests are not sufficiently sensitive. The recombinant Sarcoptes scabiei apolipoprotein antigen Sar s 14.3 is a promising immunodiagnostic, eliciting high levels of IgE and IgG in infected people. Limited data are available regarding the temporal development of antibodies to Sar s 14.3, an issue of relevance in terms of immunodiagnosis. We utilised a porcine model to prospectively compare specific antibody responses to a primary infestation by ELISA, to Sar s 14.3 and to S. scabiei whole mite antigen extract (WMA). Differences in the antibody profile between antigens were apparent, with Sar s 14.3 responses detected earlier, and declining significantly after peak infestation compared to WMA. Both antigens resulted in >90% diagnostic sensitivity from weeks 8–16 post infestation. These data provide important information on the temporal development of humoral immune responses in scabies and further supports the development of recombinant antigen based immunodiagnostic tests for recent scabies infestations.
doi:10.1371/journal.pone.0065354
PMCID: PMC3675102  PMID: 23762351
19.  Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report 
Malaria Journal  2013;12:112.
The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.
doi:10.1186/1475-2875-12-112
PMCID: PMC3616837  PMID: 23537118
Malaria; Vivax; Falciparum; 8-aminoquinolines; Primaquine; Tafenoquine; G6PD; Deficiency; Diagnostic tests
20.  Functional Reinnervation of the Canine Bladder after Spinal Root Transection and Immediate Somatic Nerve Transfer 
Journal of neurotrauma  2008;25(3):214-224.
This study was performed to determine whether nerve transfer immediately after spinal root transection would lead to bladder reinnervation in a canine model. In one animal, the left T12 intercostal nerve was mobilized, cut and attached to the severed ends of sacral roots inducing bladder contraction using a graft from the T11 intercostal nerve. On the right side and bilaterally in two other dogs, coccygeal roots innervating tail musculature were cut and attached to the severed bladder sacral roots (coccygeal nerve transfer [CG NT]). In four other dogs, bladder sacral roots were transected in the vertebral column, and the genitofemoral nerve was transferred within the abdomen to the pelvic nerve (genitofemoral nerve transfer [GF NT]). After 14 months for CG NT and 4.5 months for GF NT, electrical stimulation of the pelvic nerve induced bladder pressure and urethral fluid flow on the intercostal nerve transfer side, in each of the five CG NT sites and bilaterally in three of the four GF NT animals. Reinnervation was further shown by retrograde labeling of spinal cord neurons following fluorogold injections into the bladder wall and by histological examination of the root/nerve suture sites. In all CG NT animals, labeled neuronal cell bodies were located in ventral horns in lamina IX of coccygeal cord segments. In the three GF NT animals in which pelvic nerve stimulation induced bladder contraction, abundant labeled cell bodies were observed in lamina IX and lateral zona intermedia of upper lumbar cord. These results clearly demonstrate that bladder reinnervation can be accomplished by immediate nerve transfer of intercostal nerves or coccygeal spinal roots to severed bladder sacral roots, or by transfer of peripheral genitofemoral nerves (L1,2 origin) to pelvic nerves.
doi:10.1089/neu.2007.0328
PMCID: PMC3604734  PMID: 18352835
animal studies; axonal injury; neuroplasticity; peripheral nerve injury; regeneration
21.  SPLUNC1 Regulates Cell Progression and Apoptosis through the miR-141-PTEN/p27 Pathway, but Is Hindered by LMP1 
PLoS ONE  2013;8(3):e56929.
Little is known about the role of the host defensive protein short palate, lung and nasal epithelium clone 1 (SPLUNC1) in the carcinogenesis of nasopharyngeal carcinoma (NPC). Here we report that SPLUNC1 plays a role at a very early stage of NPC carcinogenesis. SPLUNC1 regulates NPC cell proliferation, differentiation and apoptosis through miR-141, which in turn regulates PTEN and p27 expression. This signaling axis is negatively regulated by the EBV-coded gene LMP1. Therefore we propose that SPLUNC1 suppresses NPC tumor formation and its inhibition by LMP1 provides a route for NPC tumorigenesis.
doi:10.1371/journal.pone.0056929
PMCID: PMC3589440  PMID: 23472073
22.  An Experimental Test of Insect-Mediated Colonisation of Damaged Pinus radiata Trees by Sapstain Fungi 
PLoS ONE  2013;8(2):e55692.
Vector-pathogen dynamics play a central role in understanding tree health and forest dynamics. There is substantial evidence that bark beetles act as spore vectors for many species of fungi that cause ‘sapstain’ discolouration of damaged trees and timber. However, the direct quantitative link between vector-mediated spore dispersal and subsequent sapstain colonisation of wood is not fully understood. Here, we used caged versus uncaged experimental logs to test whether the exclusion of bark beetles quantitatively alters the distribution and intensity of sapstain fungal spread within damaged trees. Using generalised linear mixed models, we tested the effect of bark beetle exclusion on sapstain intensity within and among cut logs at two plantation forest sites. Overall, sapstain was found on all logs regardless of caging treatment, indicating that sapstain colonisation can occur (to some degree) without arthropod vectors, probably via wind, rain-splash and, potentially, latent endophytic development. This was supported by the dominance of Diplodia pinea in fungal isolations taken from trees felled at the site, as this fungal species is known to disperse independently of bark beetles. However, the intensity of sapstain within and among experimental logs was significantly greater in uncaged than in caged logs, where beetle colonisation was significantly greater. This appeared to be driven by a significant within-log association between the intensity of staining and the intensity of beetle, and other arthropod, tunnelling and feeding activities. Taken together, these results strongly suggest that the dominant mechanism underlying the role of bark beetles in sapstain development in this study system is not vector-mediated spore dispersal, per se, but rather the facilitation of spore entry and hyphal development through tunnelling and feeding activities. We discuss the implications of these findings for forest management and the effective salvage-harvest of trees damaged by stochastic climate events such as storm and fire damage.
doi:10.1371/journal.pone.0055692
PMCID: PMC3566001  PMID: 23405198
23.  Neglected Tropical Diseases of Oceania: Review of Their Prevalence, Distribution, and Opportunities for Control 
Among Oceania's population of 35 million people, the greatest number living in poverty currently live in Papua New Guinea (PNG), Fiji, Vanuatu, and the Solomon Islands. These impoverished populations are at high risk for selected NTDs, including Necator americanus hookworm infection, strongyloidiasis, lymphatic filariasis (LF), balantidiasis, yaws, trachoma, leprosy, and scabies, in addition to outbreaks of dengue and other arboviral infections including Japanese encephalitis virus infection. PNG stands out for having the largest number of cases and highest prevalence for most of these NTDs. However, Australia's Aboriginal population also suffers from a range of significant NTDs. Through the Pacific Programme to Eliminate Lymphatic Filariasis, enormous strides have been made in eliminating LF in Oceania through programs of mass drug administration (MDA), although LF remains widespread in PNG. There are opportunities to scale up MDA for PNG's major NTDs, which could be accomplished through an integrated package that combines albendazole, ivermectin, diethylcarbamazine, and azithromycin, in a program of national control. Australia's Aboriginal population may benefit from appropriately integrated MDA into primary health care systems. Several emerging viral NTDs remain important threats to the region.
doi:10.1371/journal.pntd.0001755
PMCID: PMC3561157  PMID: 23383349
24.  Anti-Prion Drug mPPIg5 Inhibits PrPC Conversion to PrPSc 
PLoS ONE  2013;8(1):e55282.
Prion diseases, also known as transmissible spongiform encephalopathies, are a group of fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans. The ‘protein only hypothesis’ advocates that PrPSc, an abnormal isoform of the cellular protein PrPC, is the main and possibly sole component of prion infectious agents. Currently, no effective therapy exists for these diseases at the symptomatic phase for either humans or animals, though a number of compounds have demonstrated the ability to eliminate PrPSc in cell culture models. Of particular interest are synthetic polymers known as dendrimers which possess the unique ability to eliminate PrPSc in both an intracellular and in vitro setting. The efficacy and mode of action of the novel anti-prion dendrimer mPPIg5 was investigated through the creation of a number of innovative bio-assays based upon the scrapie cell assay. These assays were used to demonstrate that mPPIg5 is a highly effective anti-prion drug which acts, at least in part, through the inhibition of PrPC to PrPSc conversion. Understanding how a drug works is a vital component in maximising its performance. By establishing the efficacy and method of action of mPPIg5, this study will help determine which drugs are most likely to enhance this effect and also aid the design of dendrimers with anti-prion capabilities for the future.
doi:10.1371/journal.pone.0055282
PMCID: PMC3557256  PMID: 23383136
25.  Elimination of Manganese(II,III) Oxidation in Pseudomonas putida GB-1 by a Double Knockout of Two Putative Multicopper Oxidase Genes 
Bacterial manganese(II) oxidation impacts the redox cycling of Mn, other elements, and compounds in the environment; therefore, it is important to understand the mechanisms of and enzymes responsible for Mn(II) oxidation. In several Mn(II)-oxidizing organisms, the identified Mn(II) oxidase belongs to either the multicopper oxidase (MCO) or the heme peroxidase family of proteins. However, the identity of the oxidase in Pseudomonas putida GB-1 has long remained unknown. To identify the P. putida GB-1 oxidase, we searched its genome and found several homologues of known or suspected Mn(II) oxidase-encoding genes (mnxG, mofA, moxA, and mopA). To narrow this list, we assumed that the Mn(II) oxidase gene would be conserved among Mn(II)-oxidizing pseudomonads but not in nonoxidizers and performed a genome comparison to 11 Pseudomonas species. We further assumed that the oxidase gene would be regulated by MnxR, a transcription factor required for Mn(II) oxidation. Two loci met all these criteria: PputGB1_2447, which encodes an MCO homologous to MnxG, and PputGB1_2665, which encodes an MCO with very low homology to MofA. In-frame deletions of each locus resulted in strains that retained some ability to oxidize Mn(II) or Mn(III); loss of oxidation was attained only upon deletion of both genes. These results suggest that PputGB1_2447 and PputGB1_2665 encode two MCOs that are independently capable of oxidizing both Mn(II) and Mn(III). The purpose of this redundancy is unclear; however, differences in oxidation phenotype for the single mutants suggest specialization in function for the two enzymes.
doi:10.1128/AEM.01850-12
PMCID: PMC3536112  PMID: 23124227

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