Assessing risk of major adverse cardiac events among patients with chest pain and cocaine use using the HEART score.

INTRODUCTION: Chest pain (CP), a common presentation in the emergency department (ED) setting, is associated with significant morbidity and mortality if emergency clinicians miss the diagnosis of acute coronary syndrome (ACS). The HEART (History, Electrocardiogram, Age, Risk Factors, Troponin) score had been validated for risk-stratification patients who are at high risk for ACS and major adverse cardiac events (MACE). However, the use of cocaine as a risk factor of the HEART score was controversial. We hypothesized that patients with cocaine-positive (COP) would not be associated with higher risk of 30-day MACE than cocaine-negative (CON) patients. METHODS: This retrospective study included adult patients who presented to 13 EDs of a University's Medical System between August 7, 2017 to August 19, 2021. Patients who had CP and prospectively calculated HEART scores and urine toxicology tests as part of their clinical evaluation were eligible. Areas Under The Receiver Operating Curve (AUROC) were calculated for the performance of HEART score and 30-day MACE for each group. RESULTS: This study analyzed 46,210 patients' charts, 663 (1.4%) were COP patients. Mean age was statistically similar between groups but there were fewer females in the COP group (26.2% vs 53.2%, p < 0.001). Mean (+/- SD) HEART score was 3.7 (1.4) comparing to 3.1 (1.8, p < 0.001) between COP vs CON groups, respectively. Although more COP patients (54%) had moderate HEART scores (4-6) vs. CON group (35.2%, p < 0.001), rates of 30-day MACE were 1.1% for both groups. HEART score's AUROC was 0.72 for COP and 0.78 for CON groups. AUROC for the Risk Factor among COP patients, which includes cocaine, was poor (0.54). CONCLUSION: This study, which utilized prospective calculated HEART scores, demonstrated that overall performance of the HEART score was reasonable. Specifically, our analysis showed that the rate of 30-day MACE was not affected by cocaine use as a risk factor. We would recommend clinicians to consider the HEART score for this patient group.

Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy.

Metastatic melanoma, a deadly form of skin cancer, often develops resistance to the BRAF inhibitor drug vemurafenib, highlighting the need for understanding the underlying mechanisms of resistance and exploring potential therapeutic strategies targeting integrins and TGF-ß signalling. In this study, the role of integrins and TGF-ß signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. In this study, it was found that the transcription of PAI1 and p21 was induced by acquired vemurafenib resistance, and ITGA5 levels were increased as a result of this resistance. The transcription of ITGA5 was mediated by the TGF-ß pathway in the development of vemurafenib resistance. A synergistic effect on the proliferation of vemurafenib-resistant melanoma cells was observed with the combination therapy of vemurafenib and cilengitide. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-ß signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.

Patterns, Predictors, and Intercenter Variability in Empiric Gram-Negative Antibiotic Use Across 928 United States Hospitals.

BACKGROUND: Empiric antibiotic use among hospitalized adults in the United States (US) is largely undescribed. Identifying factors associated with broad-spectrum empiric therapy may inform antibiotic stewardship interventions and facilitate benchmarking. METHODS: We performed a retrospective cohort study of adults discharged in 2019 from 928 hospitals in the Premier Healthcare Database. "Empiric" gram-negative antibiotics were defined by administration before day 3 of hospitalization. Multivariable logistic regression models with random effects by hospital were used to evaluate associations between patient and hospital characteristics and empiric receipt of broad-spectrum, compared to narrow-spectrum, gram-negative antibiotics. RESULTS: Of 8 017 740 hospitalized adults, 2 928 657 (37%) received empiric gram-negative antibiotics. Among 1 781 306 who received broad-spectrum therapy, 30% did not have a common infectious syndrome present on admission (pneumonia, urinary tract infection, sepsis, or bacteremia), surgery, or an intensive care unit stay in the empiric window. Holding other factors constant, males were 22% more likely (adjusted odds ratio [aOR], 1.22 [95% confidence interval, 1.22-1.23]), and all non-White racial groups 6%-13% less likely (aOR range, 0.87-0.94), to receive broad-spectrum therapy. There were significant prescribing differences by region, with the highest adjusted odds of broad-spectrum therapy in the US West South Central division. Even after model adjustment, there remained substantial interhospital variability: Among patients receiving empiric therapy, the probability of receiving broad-spectrum antibiotics varied as much as 34+ percentage points due solely to the admitting hospital (95% interval of probabilities: 43%-77%). CONCLUSIONS: Empiric gram-negative antibiotic use is highly variable across US regions, and there is high, unexplained interhospital variability. Sex and racial disparities in the receipt of broad-spectrum therapy warrant further investigation.

Prediction of blood pressure variability during thrombectomy using supervised machine learning and outcomes of patients with ischemic stroke from large vessel occlusion.

Mechanical thrombectomy (MT) is the standard of care for patients with acute ischemic stroke from large vessel occlusion (AIS-LVO). The association of blood pressure variability (BPV) during MT and outcomes are unknown. We leveraged a supervised machine learning algorithm to predict patient characteristics that are associated with BPV indices. We performed a retrospective review of our comprehensive stroke center's registry of all adult patients undergoing MT between 01/01/2016 and 12/31/2019. The primary outcome was poor functional independence, defined as 90-day modified Rankin Scale (mRS) ≥ 3. We used probit analysis and multivariate logistic regressions to evaluate the association of patients' clinical factors and outcomes. We applied a machine learning algorithm (random forest, RF) to determine predictive factors for the different BPV indices during MT. Evaluation was performed with root-mean-square error (RMSE) and normalized-RMSE (nRMSE) metrics. We analyzed 375 patients with mean age (± standard deviation [SD]) of 65 (15) years. There were 234 (62%) patients with mRS ≥ 3. Univariate probit analysis demonstrated that BPV during MT was associated with poor functional independence. Multivariable logistic regression showed that age, admission National Institutes of Health Stroke Scale (NIHSS), mechanical ventilation, and thrombolysis in cerebral infarction (TICI) score (OR 0.42, 95% CI 0.17-0.98, P = 0.044) were significantly associated with outcome. RF analysis identified that the interval from last-known-well time-to-groin puncture, age, and mechanical ventilation were among important factors significantly associated with BPV. BPV during MT was associated with functional outcome in univariate probit analysis but not in multivariable regression analysis, however, NIHSS and TICI score were. RF algorithm identified risk factors influencing patients' BPV during MT. While awaiting further studies' results, clinicians should still monitor and avoid high BPV during thrombectomy while triaging AIS-LVO candidates quickly to MT.

Clinically relevant adverse cardiovascular events in intermediate heart score patients admitted to the hospital following a negative emergency department evaluation.

STUDY HYPOTHESIS: Study objective: To estimate the frequency of clinically relevant adverse cardiac events (CRACE) in patients admitted to the hospital for chest pain with an intermediate HEART score (4, 5, 6), non-diagnostic EKG, and a negative initial troponin. METHODS: We conducted a retrospective analysis of all patients admitted to the University of Maryland Medical Center (UMMC) from May 2016 to May 2019 with an intermediate HEART score (4, 5, or 6), a non-diagnostic EKG, and a negative initial troponin. Our primary outcome was the rate of inpatient clinically relevant adverse cardiac events (CRACE), composite of life-threatening dysrhythmia, inpatient STEMI, cardiac or respiratory arrest, and all-cause mortality during hospitalization. RESULTS: A total of 1118 patients met our inclusion criteria, 6 of whom had CRACE. Overall the rate of CRACE was 0.5% (95% CI, 0.2-1.2%). Six patients (0.5%, 95% CI, 0.2%-1.2%) experienced inpatient NSTEMIs, 212 patients (19%, 95% CI, 17-21%) underwent provocative testing during their inpatient stay, 5 patients received a stent or CABG, and 5 patients had false positive non-invasive testing and underwent a negative cardiac catheterization. CONCLUSIONS: In this cohort of admitted patients with a documented intermediate-risk HEART score, nonischemic EKG, and negative initial troponin, the occurrence of CRACE during the index hospitalization was 0.5%.

The use of venous Doppler to predict adverse kidney events in a general ICU cohort.

BACKGROUND: Changes in Doppler flow patterns of hepatic veins (HV), portal vein (PV) and intra-renal veins (RV) reflect right atrial pressure and venous congestion; the feasibility of obtaining these assessments and the clinical relevance of the findings is unknown in a general ICU population. This study compares the morphology of HV, PV and RV waveform abnormalities in prediction of major adverse kidney events at 30 days (MAKE30) in critically ill patients. STUDY DESIGN AND METHODS: We conducted a prospective observational study enrolling adult patients within 24 h of admission to the ICU. Patients underwent an ultrasound evaluation of the HV, PV and RV. We compared the rate of MAKE-30 events in patients with and without venous flow abnormalities in the hepatic, portal and intra-renal veins. The HV was considered abnormal if S to D wave reversal was present. The PV was considered abnormal if the portal pulsatility index (PPI) was greater than 30%. We also examined PPI as a continuous variable to assess whether small changes in portal vein flow was a clinically important marker of venous congestion. RESULTS: From January 2019 to June 2019, we enrolled 114 patients. HV abnormalities demonstrate an odds ratio of 4.0 (95% CI 1.4-11.2). PV as a dichotomous outcome is associated with an increased odds ratio of MAKE-30 but fails to reach statistical significance (OR 2.3 95% CI 0.87-5.96), but when examined as a continuous variable it demonstrates an odds ratio of 1.03 (95% CI 1.00-1.06). RV Doppler flow abnormalities are not associated with an increase in the rate of MAKE-30 INTERPRETATION: Obtaining hepatic, portal and renal venous Doppler assessments in critically ill ICU patients are feasible. Abnormalities in hepatic and portal venous Doppler are associated with an increase in MAKE-30. Further research is needed to determine if venous Doppler assessments can be useful measures in assessing right-sided venous congestion in critically ill patients.

National Early Warning Score Is Modestly Predictive of Care Escalation after Emergency Department-to-Floor Admission.

BACKGROUND: Decompensation on the medical floor is associated with increased in-hospital mortality. OBJECTIVE: Our aim was to determine the accuracy of the National Early Warning Score (NEWS) in predicting early, unplanned escalation of care in patients admitted to the hospital from the emergency department (ED) compared to the Shock Index (SI) and the quick Sepsis-Related Organ Failure Assessment (qSOFA) score. METHODS: We conducted a retrospective cohort study of patients admitted directly from the ED to monitored or unmonitored beds (November 9, 2015 to April 30, 2018) in 3 hospitals. Interhospital transfers were excluded. Patient data, vital status, and bed assignment were extracted from the electronic medical record. Scores were calculated using the last set of vital signs prior to leaving the ED. Primary endpoint was in-hospital death or placement in an intermediate or intensive care unit within 24 h of admission from the ED. Scores were compared using the area under the receiver operating curve (AUROC). RESULTS: Of 46,018 ED admissions during the study window, 39,491 (85.8%) had complete data, of which 3.7% underwent escalation in level of care within 24 h of admission. NEWS outperformed (AUROC 0.69; 95% confidence interval [CI] 0.68-0.69) qSOFA (AUROC 0.63; 95% CI 0.62-0.63; p < 0.001) and SI (AUROC 0.60; 95% CI 0.60-0.61; p < 0.001) at predicting unplanned escalations or death at 24 h. CONCLUSIONS: This multicenter study found NEWS was superior to the qSOFA score and SI in predicting early, unplanned escalation of care for ED patients admitted to a general medical-surgical floor.

New insights into the cellular mechanisms of plant growth at elevated atmospheric carbon dioxide concentrations.

Rising atmospheric carbon dioxide concentration ([CO2 ]) significantly influences plant growth, development, and biomass. Increased photosynthesis rate, together with lower stomatal conductance, has been identified as the key factors that stimulate plant growth at elevated [CO2 ] (e[CO2 ]). However, variations in photosynthesis and stomatal conductance alone cannot fully explain the dynamic changes in plant growth. Stimulation of photosynthesis at e[CO2 ] is always associated with post-photosynthetic secondary metabolic processes that include carbon and nitrogen metabolism, cell cycle functions, and hormonal regulation. Most studies have focused on photosynthesis and stomatal conductance in response to e[CO2 ], despite the emerging evidence of e[CO2 ]'s role in moderating secondary metabolism in plants. In this review, we briefly discuss the effects of e[CO2 ] on photosynthesis and stomatal conductance and then focus on the changes in other cellular mechanisms and growth processes at e[CO2 ] in relation to plant growth and development. Finally, knowledge gaps in understanding plant growth responses to e[CO2 ] have been identified with the aim of improving crop productivity under a CO2 rich atmosphere.

Exploring and Exploiting Acceptor Preferences of the Human Polysialyltransferases as a Basis for an Inhibitor Screen.

α2,8-Linked polysialic acid (polySia) is an oncofoetal antigen with high abundance during embryonic development. It reappears in malignant tumours of neuroendocrine origin. Two polysialyltransferases (polySTs) ST8SiaII and IV are responsible for polySia biosynthesis. During development, both enzymes are essential to control polySia expression. However, in tumours ST8SiaII is the prevalent enzyme. Consequently, ST8SiaII is an attractive target for novel cancer therapeutics. A major challenge is the high structural and functional conservation of ST8SiaII and -IV. An assay system that enables differential testing of ST8SiaII and -IV would be of high value to search for specific inhibitors. Here we exploited the different modes of acceptor recognition and elongation for this purpose. With DMB-DP3 and DMB-DP12 (fluorescently labelled sialic acid oligomers with a degree of polymerisation of 3 and 12, respectively) we identified stark differences between the two enzymes. The new acceptors enabled the simple comparative testing of the polyST initial transfer rate for a series of CMP-activated and N-substituted sialic acid derivatives. Of these derivatives, the non-transferable CMP-Neu5Cyclo was found to be a new, competitive ST8SiaII inhibitor.

Rare Pyrenophora teres Hybridization Events Revealed by Development of Sequence-Specific PCR Markers.

Pyrenophora teres f. teres and P. teres f. maculata cause net form and spot form, respectively, of net blotch on barley (Hordeum vulgare). The two forms reproduce sexually, producing hybrids with genetic and pathogenic variability. Phenotypic identification of hybrids is challenging because lesions induced by hybrids on host plants resemble lesions induced by either P. teres f. teres or P. teres f. maculata. In this study, 12 sequence-specific polymerase chain reaction markers were developed based on expressed regions spread across the genome. The primers were validated using 210 P. teres isolates, 2 putative field hybrids (WAC10721 and SNB172), 50 laboratory-produced hybrids, and 7 isolates collected from barley grass (H. leporinum). The sequence-specific markers confirmed isolate WAC10721 as a hybrid. Only four P. teres f. teres markers amplified on DNA of barley grass isolates. Amplified fragment length polymorphism markers suggested that P. teres barley grass isolates are genetically different from P. teres barley isolates and that the second putative hybrid (SNB172) is a barley grass isolate. We developed a suite of markers which clearly distinguish the two forms of P. teres and enable unambiguous identification of hybrids.

Assessment of Fusarium pseudograminearum and F. culmorum Biomass in Seedlings of Potential Host Cereal Species.

Fusarium crown rot is a major disease of wheat and barley worldwide, with the most frequently isolated causal agents being Fusarium pseudograminearum and F. culmorum. This study has successfully designed a quantitative polymerase chain reaction assay that is specific for F. culmorum, which has been used in conjunction with a previously established F. pseudograminearum-specific assay to compare the location and extent of infection by each fungus across a range of potential hosts, including six winter and three summer cereal species. All common winter cereals, excluding oat, demonstrated a similar range of visual and fungal biomass results when inoculated with either F. pseudograminearum or F. culmorum. Oat exhibited the lowest visual disease ratings and fungal biomass values of the winter cereals, while the sorghum, maize, and rice cultivars returned the lowest values overall. The ranking of host species according to visual discoloration was strongly correlated for both pathogens. Visual reactions to F. pseudograminearum were greater than those caused by F. culmorum in all potential hosts trialed; however, fungal biomass results only indicated this trend for barley. These results demonstrate significant variation in the ability of these pathogens to colonize the range of cereal species examined and also suggest differences between the pathogens in their patterns of host colonization.

Colonization of Durum Wheat (Triticum turgidum L. var. durum) Culms Exhibiting Premature Senescence (Dead Heads) Associated with Fusarium pseudograminearum Crown Rot.

Fusarium crown rot is a significant disease of durum wheat (Triticum turgidum L. var. durum), which exhibits high levels of disease susceptibility. The most extreme symptom of crown rot is a prematurely senescing culm that typically fails to set grain. Individual crown rot-affected durum wheat plants displaying both nonsenescent and prematurely senescent culms were harvested to compare visual discoloration, Fusarium pseudograminearum biomass, and vascular colonization in culm sections sampled at three different heights above the crown. Field samples of EGA Bellaroi were collected at Wellcamp, QLD, in 2011, 2012, 2013, and 2014, and of Hyperno at Narrabri, NSW, in 2014. Prematurely senescent culms exhibited greater visual discoloration, F. pseudograminearum biomass, and vascular colonization than nonsenescent culms in each year they were examined. The extent of these differences varied between environments and timing of collection in each year. Vascular colonization initially occurred in xylem vessels and spread into phloem tissues as disease severity increased. The increased presence of hyphae in vascular bundles of prematurely senescing culms provides strong evidence for the hypothesis that restriction of water and nutrient movement in a diseased culm is a key factor in crown rot severity.

An optimised assay for quantitative, high-throughput analysis of polysialyltransferase activity.

The polysialyltransferases are biologically important glycosyltransferase enzymes responsible for the biosynthesis of polysialic acid, a carbohydrate polymer that plays a critical role in the progression of several diseases, notably cancer. Having improved the chemical synthesis and purification of the fluorescently-labelled DMB-DP3 acceptor, we report optimisation and validation of a highly sensitive cell-free high-throughput HPLC-based assay for assessment of human polysialyltransferase activity.

Histopathological Assessment of Fusarium pseudograminearum Colonization of Cereal Culms During Crown Rot Infections.

Histopathological assessment of the crown rot pathogen Fusarium pseudograminearum was performed using fluorescence microscopy of culm tissues of six cereal genotypes grown in inoculated field conditions. Tissue samples were collected at 10, 16, and 22 weeks after planting (WAP). Colonization of culm tissues was initiated through epidermal penetration, most distinctly through stomatal apertures, and progressed into the parenchymatous hypoderm, which exhibited the discoloration used as the basis for visual assessment of disease. Hyphae spread from the culm base vertically through the tissues, initially via the hypoderm and pith cavity. Colonization of sclerified cells occurred later in the disease process. Both xylem and phloem tissues became colonized by 16 WAP in all host genotypes, with colonization being less extensive in the more resistant genotypes. Culms displaying dead head symptoms revealed dense colonization in at least the first three internodes, with frequent xylem vessel and phloem cell occlusions. Paired living culms from the same plants exhibited less extensive colonization. These observations have revealed the ability of F. pseudograminearum to colonize all cell types of nodal and internodal sections, including vascular tissues, across all host genotypes. This study is the first detailed examination of the pattern of F. pseudograminearum colonization in adult hosts and indicates a potential vascular mechanism by which the effects of crown rot are produced.

A multi-center validation of the electronic health record admission source and discharge location fields against the clinical notes for identifying inpatients with long-term care facility exposure.

Identifying long-term care facility (LTCF)-exposed inpatients is important for infection control research and practice, but ascertaining LTCF exposure is challenging. Across a large validation study, electronic health record data fields identified 76% of LTCF-exposed patients compared to manual chart review. OBJECTIVE: Residence or recent stay in a long-term care facility (LTCF) is an important risk factor for antibiotic-resistant bacterial colonization. However, absent dedicated intake questionnaires or resource-intensive chart review, ascertaining LTCF exposure in inpatients is challenging. We aimed to validate the electronic health record (EHR) admission and discharge location fields against the clinical notes for identifying LTCF-exposed inpatients. METHODS: We conducted a retrospective study of 1020 randomly sampled adult admissions between 2016 and 2021 across 12 University of Maryland Medical System hospitals. Using study-developed guidelines, we categorized the following data for LTCF exposure: each admission's history & physical (H&P) note, each admission's EHR-extracted "Admission Source," and (3) the EHR-extracted admission and discharge locations for previous admissions (≤90 days). We estimated sensitivities, with 95% CIs, of H&P notes and of EHR admission/discharge location fields for detecting "current" and "any recent" (≤90 days, including current) LTCF exposure. RESULTS: For detecting current LTCF exposure, the sensitivity of the index admission's EHR-extracted "Admission Source" was 46% (95% CI: 35%­58%) and of the H&P note was 92% (83%­97%). For detecting any recent LTCF exposure, the sensitivity of "Admission Source" across the index and previous admissions was 32% (24%­41%), "Discharge Location" across previous admission(s) was 57% (47%­66%), and of the H&P note was 68% (59%­76%). The combined sensitivity of admission source and discharge location for detecting any recent LTCF exposure was 76% (67%­83%). CONCLUSIONS: The EHR-obtained admission source and discharge location fields identified 76% of LTCF-exposed patients compared to chart review but disproportionately missed currently exposed patients.

Antibiotic Use and Respiratory Viral PCR Testing Among Pediatric Patients With Nosocomial Fever.

Objective Pediatric patients admitted to the hospital often develop fevers during their inpatient stay, and many children are empirically started on antibiotics. The utility of respiratory viral panel (RVP) polymerase chain reaction (PCR) testing in the evaluation of nosocomial fevers in admitted patients is unclear. We sought to evaluate whether RVP testing is associated with the use of antibiotics among inpatient pediatric patients. Patients and methods We conducted a retrospective chart review of children admitted from November 2015 to June 2018. We included all patients who developed fever 48 hours or more after admission to the hospital and who were not already receiving treatment for a presumed infection (on antibiotics). Results Among 671 patients, there were 833 inpatient febrile episodes. The mean age of children was 6.3 years old, and 57.1% were boys. Out of 99 RVP samples analyzed, 22 were positive (22.2%). Antibiotics were started in 27.8% while 33.5% of patients were already on antibiotics. On multivariate logistic regression, having an RVP sent was significantly associated with increased initiation of antibiotics (aOR 95% CI 1.18-14.18, p=0.03). Furthermore, those with a positive RVP had a shorter course of antibiotics compared to those with a negative RVP (mean 6.8 vs 11.3 days, p=0.019). Conclusions Children with positive RVP had decreased antibiotic exposure compared to those with negative RVP results. RVP testing may be used to promote antibiotic stewardship among hospitalized children.

Assessing risk of major adverse cardiac event among COVID-19 patients using HEART score.

Coronavirus disease 2019 (COVID-19) is known to be associated with cardiovascular complications, but whether the current validated HEART score for chest pain is still applicable for these patients is unknown. This study aims to identify the impact and association of COVID-19 co-infection in patients presenting with chest pain and a calculated HEART score to the emergency departments (ED) with 30-day of major adverse cardiac event (MACE). This is a multicenter, retrospective observational study that included adult (age ≥ 18 years) patients visiting 13 different EDs with chest pain and evaluated using a HEART score. The primary outcome was the percentage of 30-day MACE, which included acute myocardial infarction, emergency percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), or death among patients who presented with chest pain and had COVID-19 co-infection. The sensitivity and specificity of the HEART score among COVID-19 co-infection for MACE were assessed by the receiver operating curve (ROC). We analyzed records of 46,210 eligible patients, in which 327 (0.7%) patients were identified as infected with COVID-19. Patients with COVID-19 had higher mean total HEART score of 3.3 (1.7), compared to patients who did not have COVID-19 (3.1, SD 1.8, P = 0.048). The rate of MACE was similar between both groups. There were only 2 (0.6%) COVID-19 patients who had MACE, compared to 504 (1.1%) patients in control group. Total HEART score was associated with an area under the ROC (AUROC) of 0.99, while the control group's was 0.78. History was associated with high AUROC in both COVID-19 (0.74) and control groups (0.76). Older age in COVID-19 had higher AUROC (0.89) than control patients (0.63). Among patients presenting to the ED with chest pain and having COVID-19 infection, HEART score had predictive capability for MACE, similar to patients without COVID-19 infection. Further studies with more COVID-19 patients are still necessary to confirm our observation.

Synthesis and Biological Evaluation of Cyclobutane-Based ß3 Integrin Antagonists: A Novel Approach to Targeting Integrins for Cancer Therapy.

The Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the ß3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvß3 and αIIbß3 are important anticancer targets, most integrin antagonists developed to target the ß3 integrins are highly selective for αvß3 or αIIbß3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic ß3 integrin antagonist. These new antagonists combine a high activity against αvß3 with a moderate affinity for αIIbß3, providing the first evidence for a new approach to integrin targeting in cancer.

Chemical signals of elephant musth: temporal aspects of microbially-mediated modifications.

Mature male African (Loxodonta africana) and Asian (Elephas maximus) elephants exhibit periodic episodes of musth, a state in which serum androgens are elevated, food intake typically decreases, aggressiveness often increases, and breeding success is enhanced. Urine is a common source of chemical signals in a variety of mammals. Elephants in musth dribble urine almost continuously for lengthy periods, suggesting that the chemicals in their urine may reveal their physiological condition to conspecifics. We investigated the volatile urinary chemicals in captive male elephants using automated solid phase dynamic extraction (SPDE) and gas chromatography-mass spectrometry (GC-MS). We found higher levels of alkan-2-ones, alkan-2-ols, and some aromatic compounds in urine from males in musth than in urine from non-musth males or from females. Levels of ketones and alcohols increased as the urine aged, likely due to microbial metabolism of fatty acids. Protein-derived aromatic metabolites also increased in abundance after urination, likely due to microbial hydrolysis of hydrophilic conjugates. We suggest that microbes may play an important role in timed release of urinary semiochemicals during elephant musth.

Assessment of Infection by Fusarium pseudograminearum in Wheat Seedling Tissues Using Quantitative PCR and a Visual Discoloration Scale.

Assessment among cereal genotypes of relative seedling resistance to the crown rot pathogen Fusarium pseudograminearum has been primarily based on visual discoloration of the leaf sheaths. This study is the first to investigate the relationship between the widely used visual rating of seedling leaf sheath discoloration and the degree of colonization of these tissues by the pathogen, based on quantitative polymerase chain reaction (qPCR) of fungal DNA using primers specific for the translation elongation factor α sequence. Fourteen-day-old seedlings of four hard white spring wheat genotypes which differ in their degree of resistance to the pathogen, based on the expression of visible symptoms, were inoculated using a droplet method and assessed weekly from 7 to 35 days after inoculation (dai) for both discoloration and fungal DNA content per unit of tissue weight. Both visual assessment of disease symptoms and qPCR of fungal biomass indicated significant differences between the partially resistant and susceptible wheat genotypes from 14 dai. Visual discoloration of leaf sheath tissues was strongly correlated with fungal biomass estimated by qPCR in all four genotypes; however, this correlation became weaker with increasing time after inoculation. Significant correlations between these parameters were indicated at 14, 21, and 28 dai whereas, by 35 dai, the correlation was not significant. Evaluation of plants at 14 dai provided a rapid test which gave clear discrimination between lines for both parameters and was the time point of closest correlation between fungal colonization and disease symptoms. Symptom expression at all times following inoculation was accompanied by tissue infection, and at no time was symptomless infection observed under this screening environment. These qPCR results confirm that visual assessments of disease symptoms reflect the extent of tissue colonization by the pathogen in recently colonized tissues and confirm the validity of visual assessments for disease rating in high-throughput screening of breeding materials.