A methodical exploration of imaging modalities from dataset to detection through machine learning paradigms in prominent lung disease diagnosis: a review.

BACKGROUND: Lung diseases, both infectious and non-infectious, are the most prevalent cause of mortality overall in the world. Medical research has identified pneumonia, lung cancer, and Corona Virus Disease 2019 (COVID-19) as prominent lung diseases prioritized over others. Imaging modalities, including X-rays, computer tomography (CT) scans, magnetic resonance imaging (MRIs), positron emission tomography (PET) scans, and others, are primarily employed in medical assessments because they provide computed data that can be utilized as input datasets for computer-assisted diagnostic systems. Imaging datasets are used to develop and evaluate machine learning (ML) methods to analyze and predict prominent lung diseases. OBJECTIVE: This review analyzes ML paradigms, imaging modalities' utilization, and recent developments for prominent lung diseases. Furthermore, the research also explores various datasets available publically that are being used for prominent lung diseases. METHODS: The well-known databases of academic studies that have been subjected to peer review, namely ScienceDirect, arXiv, IEEE Xplore, MDPI, and many more, were used for the search of relevant articles. Applied keywords and combinations used to search procedures with primary considerations for review, such as pneumonia, lung cancer, COVID-19, various imaging modalities, ML, convolutional neural networks (CNNs), transfer learning, and ensemble learning. RESULTS: This research finding indicates that X-ray datasets are preferred for detecting pneumonia, while CT scan datasets are predominantly favored for detecting lung cancer. Furthermore, in COVID-19 detection, X-ray datasets are prioritized over CT scan datasets. The analysis reveals that X-rays and CT scans have surpassed all other imaging techniques. It has been observed that using CNNs yields a high degree of accuracy and practicability in identifying prominent lung diseases. Transfer learning and ensemble learning are complementary techniques to CNNs to facilitate analysis. Furthermore, accuracy is the most favored metric for assessment.

Structural insights into the substrate specificity of the endonuclease activity of the influenza virus cap-snatching mechanism.

The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. The anti-influenza drug baloxavir is highly effective, but is associated with resistance mutations that threaten its clinical efficacy. The endonuclease resides within the N-terminal domain of the PA subunit (PAN) of the influenza RNA dependent RNA polymerase, and we report here complexes of PAN with RNA and DNA oligonucleotides to understand its specificity and the structural basis of baloxavir resistance mutations. The RNA and DNA oligonucleotides bind within the substrate binding groove of PAN in a similar fashion, explaining the ability of the enzyme to cleave both substrates. The individual nucleotides occupy adjacent conserved pockets that flank the two-metal active site. However, the 2' OH of the RNA ribose moieties engage in additional interactions that appear to optimize the binding and cleavage efficiency for the natural substrate. The major baloxavir resistance mutation at position 38 is at the core of the substrate binding site, but structural studies and modeling suggest that it maintains the necessary virus fitness via compensating interactions with RNA. These studies will facilitate the development of new influenza therapeutics that spatially match the substrate and are less likely to elicit resistance mutations.

Is developmental rate polymorphism constant? Influence of temperature on the occurrence and constancy of slow and fast development in Zygogramma bicolorata Pallister (Coleoptera: Chrysomelidae).

Temperature plays an important role in different biological activities of organisms. The relationship between temperature and insect development has long been recognized as an important environmental parameter in modeling insect population dynamics. Although few studies have investigated the existence of developmental rate polymorphism within a cohort, the role of abiotic and biotic factors on such developmental variation has so far been meagerly investigated. The present study was designed to investigate the effect of thermal extremes on the developmental rate polymorphism and its influence on reproductive potential of Parthenium beetle, Zygogramma bicolorata Pallister (Coleoptera: Chrysomelidae). The study will also be helpful in solving hitherto whether the existence of slow and fast developers within a cohort has a purely genetic basis or this developmental polymorphism is presided by environmental factors. Our result reveals a clear bimodal pattern of distribution with two peaks at each temperature (20, 25, 27, 30 and 35 °C) where the first peak represents the fast developers and second peak represents the slow developers. Both developmental variants took the longest duration for development at 20 °C followed by 25, 27, 30 °C and minimum at 35 °C. More fast developers were found at higher temperatures. Slow developing individuals were heavier than the fast developing individuals regardless of rearing temperature. Slow developers have higher reproductive success in terms of fecundity and egg viability than the fast developers. The results of this study denote the constancy of the developmental rate polymorphism within a cohort and the possibility that this polymorphism was owing to the exogenous cues inclined differential rates of mortality.

miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing.

BACKGROUND: Genetic alterations in multiple cell signaling pathways are involved in the molecular pathogenesis of thyroid cancer. Oncogene mutation testing and gene-expression profiling are routinely used for the preoperative risk management of adult thyroid nodules. In this study, we evaluated the potential value of miRNA biomarkers for the classification of pediatric thyroid lesions. PROCEDURE: Double-blind case-control study with 113 resected pediatric lesions: 66 malignant and 47 benign. Quantitative and qualitative molecular data generated with a 10-miRNA expression panel (ThyraMIR) and a next-generation sequencing oncogene panel (ThyGeNEXT) were compared with clinicopathological parameters. RESULTS: miRNAs were differentially expressed in benign versus malignant tumors with distinct expression patterns in different histopathology categories. The 10-miRNA classifier identified 39 (59%) malignant lesions with 100% specificity. A positive classifier score was associated with lymph node metastasis, extrathyroidal extension and intrathyroidal spread. Genetic alterations associated with increased risk for malignancy were detected in 35 (53%) malignant cases, 20 positive for point mutations in BRAF, HRAS, KRAS, NRAS, PIK3CA, or TERT and 15 positive for gene rearrangements involving ALK, NTRK3, PPARG, or RET. The 10-miRNA classifier correctly identified 11 mutation-negative malignant cases. The performance of the combined molecular test was 70% sensitivity and 96% specificity with an area under the curve of 0.924. CONCLUSIONS: These data suggest that the regulatory miRNA pathways underlying thyroid tumorigenesis are similar in adults and children. miRNA expression can identify malignant lesions with high specificity, augment the diagnostic yield of mutation testing, and improve the molecular classification of pediatric thyroid nodules.

Colchicine Binding Site Agent DJ95 Overcomes Drug Resistance and Exhibits Antitumor Efficacy.

Interfering with microtubule dynamics is a well-established strategy in cancer treatment; however, many microtubule-targeting agents are associated with drug resistance and adverse effects. Substantial evidence points to ATP-binding cassette (ABC) transporters as critical players in the development of resistance. Herein, we demonstrate the efficacy of DJ95 (2-(1H-indol-6-yl)-4-(3,4,5-trimethoxyphenyl)-1H-imidazo[4,5-c]pyridine), a novel tubulin inhibitor, in a variety of cancer cell lines, including malignant melanomas, drug-selected resistant cell lines, specific ABC transporter-overexpressing cell lines, and the National Cancer Institute 60 cell line panel. DJ95 treatment inhibited cancer cell migration, caused morphologic changes to the microtubule network foundation, and severely disrupted mitotic spindle formation of mitotic cells. The high-resolution crystal structure of DJ95 in complex with tubulin protein and the detailed molecular interactions confirmed its direct binding to the colchicine site. In vitro pharmacological screening of DJ95 using SafetyScreen44 (Eurofins Cerep-Panlabs) revealed no significant off-target interactions, and pharmacokinetic analysis showed that DJ95 was maintained at therapeutically relevant plasma concentrations for up to 24 hours in mice. In an A375 xenograft model in nude mice, DJ95 inhibited tumor growth and disrupted tumor vasculature in xenograft tumors. These results demonstrate that DJ95 is potent against a variety of cell lines, demonstrated greater potency to ABC transporter-overexpressing cell lines than existing tubulin inhibitors, directly targets the colchicine binding domain, exhibits significant antitumor efficacy, and demonstrates vascular-disrupting properties. Collectively, these data suggest that DJ95 has great potential as a cancer therapeutic, particularly for multidrug resistance phenotypes, and warrants further development. SIGNIFICANCE STATEMENT: Paclitaxel is a widely used tubulin inhibitor for cancer therapy, but its clinical efficacy is often limited by the development of multidrug resistance. In this study, we reported the preclinical characterization of a new tubulin inhibitor DJ95, and demonstrated its abilities to overcome paclitaxel resistance, disrupt tumor vasculature, and exhibit significant antitumor efficacy.

Cerebral Artery Vasospasm Detection Using Transcranial Doppler Signal Analysis.

OBJECTIVES: Silent cerebral artery vasospasm in aneurysmal subarachnoid hemorrhage causes serious complications such as cerebral ischemia and death. A transcranial Doppler (TCD) ultrasound system is a noninvasive device that can effectively detect cerebral artery vasospasm as soon as it sets in, even before and in the absence of clinical deterioration. Continuous or even daily TCD monitoring is challenging because of the operator expertise and certification required in the form of a trained sonographer and interpretive experience required in the form of an additionally trained and certified physician to perform these studies. This barrier exists because of a lack of automation for detection (without human intervention) of cerebral artery vasospasm using TCD ultrasound. To overcome this barrier, we present an algorithm that automates detection of cerebral artery vasospasm. METHODS: We extracted features such as the energy, energy entropy, zero-crossing rate, spectral centroid, spectral speed, spectral entropy, spectral flux, spectral roll-off, harmonic ratio, chroma, and Mel frequency cepstral coefficients for signal classification. Then we applied principal component analysis to reduce the data dimensionality. RESULTS: All of the chosen features were used for training a decision-tree classifier. The algorithm had high accuracy for cerebral artery vasospasm detection, with overall sensitivity of 87.5% and specificity of 89.74%. CONCLUSIONS: The algorithm has the potential for development into a continuous cerebral artery vasospasm monitor.

Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor.

The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains.

Prediction of Delayed Cerebral Ischemia with Cerebral Angiography: A Meta-Analysis.

OBJECT: Cerebral catheter angiography is the gold standard for diagnosing cerebral artery vasospasm (vasospasm) in aneurysmal subarachnoid hemorrhage (SAH). We have previously published a meta-analysis of prediction of delayed cerebral ischemia (DCI) from transcranial Doppler (TCD) evidence of vasospasm. Analogous data relating to prediction of DCI have not been previously collated for cerebral angiography nor reconciled against TCD. METHODS: We searched PUBMED, the Cochrane database, and clinicaltrials.gov for studies that used cerebral angiography for diagnosis of vasospasm and evaluated DCI in patients with SAH. We performed a random-effects meta-analysis of prediction of DCI with cerebral angiography, reconciling its accuracy against that of TCD. We also report quality of evidence for the value of cerebral angiography and TCD in SAH based on pooled data from our meta-analyses. RESULTS: A total of 15 studies (n = 5463) were included in the meta-analysis. Sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of cerebral angiography for prediction of DCI are 57, 68, 32, and 90%. These metrics for TCD, based on our previous meta-analysis, are 90, 71, 57, and 92%. We report that test accuracy estimates are "moderate" for TCD and "low" for angiography based on pooled data from our meta-analyses. CONCLUSION: TCD evidence of vasospasm is a better predictor of DCI than angiographic vasospasm. Future comparative effectiveness studies can better define the value of these diagnostic tools in patients with SAH.

An Amino Acid in the Stalk Domain of N1 Neuraminidase Is Critical for Enzymatic Activity.

Neuraminidase (NA) is a sialidase expressed on the surface of influenza A viruses that releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. It is a homotetramer, with each monomer consisting of a transmembrane region, a stalk, and a globular head with sialidase activity. We recently characterized two swine viruses of the pandemic H1N1 lineage, A/swine/Virginia/1814-1/2012 (pH1N1low-1) and A/swine/Virginia/1814-2/2012 (pH1N1low-2), with almost undetectable NA enzymatic activity compared to that of the highly homologous A/swine/Pennsylvania/2436/2012 (pH1N1-1) and A/swine/Minnesota/2499/2012 (pH1N1-2) viruses. pH1N1-1 transmitted to aerosol contact ferrets, but pH1N1low-1 did not. The aim of this study was to identify the molecular determinants associated with low NA activity as potential markers of aerosol transmission. We identified the shared unique substitutions M19V, A232V, D248N, and I436V (N1 numbering) in pH1N1low-1 and pH1N1low-2. pH1N1low-1 also had the unique Y66D substitution in the stalk domain, where 66Y was highly conserved in N1 NAs. Restoration of 66Y was critical for the NA activity of pH1N1low-1 NA, although 19M or 248D in conjunction with 66Y was required to recover the level of activity to that of pH1N1 viruses. Studies of NA stability and molecular modeling revealed that 66Y likely stabilized the NA homotetramer. Therefore, 66Y in the stalk domain of N1 NA was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity. IMPORTANCE: Neuraminidase (NA) is a sialidase that is one of the major surface glycoproteins of influenza A viruses and the target for the influenza drugs oseltamivir and zanamivir. NA is important as it releases progeny viruses from the surface of infected cells and prevents viruses becoming trapped in mucus. Mutations in the globular head domain that decrease enzymatic activity but confer resistance to NA inhibitors have been characterized; however, the importance of specific mutations in the stalk domain is unknown. We identified 66Y (N1 numbering), a highly conserved amino acid that was critical for the stability of the NA tetramer and, subsequently, for NA enzymatic activity.

Retinal Microvascular Abnormalities as Surrogate Markers of Cerebrovascular Ischemic Disease: A Meta-Analysis.

BACKGROUND: To determine the predictive value of retinal microvascular abnormalities for cerebrovascular ischemic diseases (CVDs), we aimed to investigate the quantitative association between retinal microvascular changes and CVD subcategories: white matter hyperintensities (WMHIs), lacunar infarcts (LIs), and cerebral infarctions (CIs). METHODS: Using Meta-analyses Of Observational Studies in Epidemiology guidelines, we searched 6 databases through September 2016 for studies evaluating the linkage between retinal microvascular abnormalities and WMHI, and LI and CI. Studies were included if they reported odds ratios (ORs) and 95% confidence intervals or raw patient level data (that were computed into ORs). Unadjusted and vascular risk-factor adjusted ORs were pooled into meta-analysis using DerSimonian Laird random effects model. Study quality and dissemination biases were assessed and integrated. RESULTS: From 24,444 search-identified records, 28 prospective studies encompassing 56,379 patients were eligible for the meta-analysis. After vascular risk-factor adjustment, focal arteriolar narrowing was associated with WMHI (OR, 1.24 [1.01-1.79]), LI (OR, 1.77 [1.14-2.74]), and CI (OR, 1.75 [1.14-2.69]). Venular dilation was associated with LI (OR, 1.46 [1.10-1.93]), and retinal hemorrhages with WMHI (OR, 2.23 [1.34-3.70]). Any retinopathy exhibited significant association with CI (OR, 1.96 [1.65-2.50]). Heterogeneity was significant (I2>50%) for all syntheses except retinal hemorrhages and WMHI, and retinopathy and CI (I2=0 ⋅ 0%). Associations remained significant after adjustments for quality and publication bias. CONCLUSIONS: We found the most significant association between retinal hemorrhages and WMHI. Focal arteriolar narrowing and retinopathy predicted CVD subtypes after risk-factor adjustment, suggesting that features different than traditional vascular risk factors, are involved in CVD pathophysiology.

Amyloid-Beta-Related Angiitis with Distinctive Neuro-Ophthalmologic Features.

Amyloid beta-related angiitis (ABRA) is a subtype of cerebral amyloid angiopathy-related inflammation, with distinctive pathology and prognosis compared with cerebral amyloid angiopathy (CAA). On a spectrum of increasing severity, ABRA is considered to be in-between the less aggressive inflammatory-CAA and the more severe primary central nervous system (CNS) angiitis. Whereas retinal pathological changes were described in subjects with primary or secondary CNS angiitis, and non-inflammatory CAA, bilateral posterior pole superficial and peripapillary retinal hemorrhages have not been reported as initial signs in patients with pathology-confirmed ABRA, accompanying neurological spells and characteristic neuroimaging findings.

Trends in Transcranial Doppler Monitoring in Aneurysmal Subarachnoid Hemorrhage: A 10-Year Analysis of the Nationwide Inpatient Sample.

BACKGROUND: Transcranial Doppler (TCD) is endorsed by national guidelines for use in aneurysmal subarachnoid hemorrhage (aSAH) for surveillance of cerebral vasospasm (CV). However, nationwide data on utilization of TCD for CV detection and monitoring in aSAH are lacking. METHODS: Analysis of nationwide trends in TCD prevalence was performed using Nationwide Inpatient Sample (NIS) data from 2002 to 2011. Raw counts were converted into weighted counts, which were used to generate national estimates. Teaching hospitals were examined separately for TCD utilization rates. All analyses accounted for the complex sampling design and sample discharge weights of the NIS, following Healthcare Cost and Utilization Project-NIS recommendations. The objective was to estimate the proportion of patients with aSAH receiving TCD monitoring using the NIS. RESULTS: Between 2002 and 2011, a total of 256,089 patients were discharged with a diagnosis of aSAH, of which 3850 underwent TCD monitoring. aSAH accounted for an average of 67.1 discharges per 100,000 annually (95% confidence interval [CI] 61.3-72.8). Of these, 1.5% (95% CI 0.4-2.6) underwent TCD examination. In teaching hospitals, aSAH accounted for an average of 108.5 discharges per 100,000 biennially (95% CI, 96.2-120.8), of which 2% (95% CI 1.0-4.0) underwent TCD examination. TCD utilization increased from <1% during the 2002-2005 period to ≥1.5% during the 2006-2011 period (odds ratio 2.3, 95% CI 1.0-5.7), an increase also seen in teaching hospitals. CONCLUSIONS: TCD is underused nationally in the care of aSAH. Whereas the prevalence of TCD is low in teaching hospitals, it is nearly nonexistent in nonteaching hospitals.

Unique Determinants of Neuraminidase Inhibitor Resistance among N3, N7, and N9 Avian Influenza Viruses.

UNLABELLED: Human infections with avian influenza viruses are a serious public health concern. The neuraminidase (NA) inhibitors (NAIs) are the frontline anti-influenza drugs and are the major option for treatment of newly emerging influenza. Therefore, it is essential to identify the molecular markers of NAI resistance among specific NA subtypes of avian influenza viruses to help guide clinical management. NAI-resistant substitutions in NA subtypes other than N1 and N2 have been poorly studied. Here, we identified NA amino acid substitutions associated with NAI resistance among influenza viruses of N3, N7, and N9 subtypes which have been associated with zoonotic transmission. We applied random mutagenesis and generated recombinant influenza viruses carrying single or double NA substitution(s) with seven internal genes from A/Puerto Rico/8/1934 (H1N1) virus. In a fluorescence-based NA inhibition assay, we identified three categories of NA substitutions associated with reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir): (i) novel subtype-specific substitutions in or near the enzyme catalytic site (R152W, A246T, and D293N, N2 numbering), (ii) subtype-independent substitutions (E119G/V and/or D and R292K), and (iii) substitutions previously reported in other subtypes (Q136K, I222M, and E276D). Our data show that although some markers of resistance are present across NA subtypes, other subtype-specific markers can only be determined empirically. IMPORTANCE: The number of humans infected with avian influenza viruses is increasing, raising concerns of the emergence of avian influenza viruses resistant to neuraminidase (NA) inhibitors (NAIs). Since most studies have focused on NAI-resistance in human influenza viruses, we investigated the molecular changes in NA that could confer NAI resistance in avian viruses grown in immortalized monolayer cells, especially those of the N3, N7, and N9 subtypes, which have caused human infections. We identified not only numerous NAI-resistant substitutions previously reported in other NA subtypes but also several novel changes conferring reduced susceptibility to NAIs, which are subtype specific. The findings indicate that some resistance markers are common across NA subtypes, but other markers need to be determined empirically for each subtype. The study also implies that antiviral surveillance monitoring could play a critical role in the clinical management of influenza virus infection and an essential component of pandemic preparedness.

Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure-activity relationship and a pharmacophore model.

Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. The structure-activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values.

Defining the ischemic penumbra using magnetic resonance oxygen metabolic index.

BACKGROUND AND PURPOSE: Penumbral biomarkers promise to individualize treatment windows in acute ischemic stroke. We used a novel magnetic resonance imaging approach that measures oxygen metabolic index (OMI), a parameter closely related to positron emission tomography-derived cerebral metabolic rate of oxygen utilization (CMRO2), to derive a pair of ischemic thresholds: (1) an irreversible-injury threshold that differentiates ischemic core from penumbra and (2) a reversible-injury threshold that differentiates penumbra from tissue not-at-risk for infarction. METHODS: Forty patients with acute ischemic stroke underwent magnetic resonance imaging at 3 time points after stroke onset: <4.5 hours (for OMI threshold derivation), 6 hours (to determine reperfusion status), and 1 month (for infarct probability determination). A dynamic susceptibility contrast method measured cerebral blood flow, and an asymmetrical spin echo sequence measured oxygen extraction fraction, to derive OMI (OMI=cerebral blood flow×oxygen extraction fraction). Putative ischemic threshold pairs were iteratively tested using a computation-intensive method to derive infarct probabilities in 3 tissue groups defined by the thresholds (core, penumbra, and not-at-risk tissue). An optimal threshold pair was chosen based on its ability to predict infarction in the core, reperfusion-dependent survival in the penumbra, and survival in not-at-risk tissue. The predictive abilities of the thresholds were then tested within the same cohort using a 10-fold cross-validation method. RESULTS: The optimal OMI ischemic thresholds were found to be 0.28 and 0.42 of normal values in the contralateral hemisphere. Using the 10-fold cross-validation method, median infarct probabilities were 90.6% for core, 89.7% for nonreperfused penumbra, 9.95% for reperfused penumbra, and 6.28% for not-at-risk tissue. CONCLUSIONS: OMI thresholds, derived using voxel-based, reperfusion-dependent infarct probabilities, delineated the ischemic penumbra with high predictive ability. These thresholds will require confirmation in an independent patient sample.

Vasospasm Surveillance With Transcranial Doppler Sonography in Subarachnoid Hemorrhage.

The use of transcranial Doppler monitoring for the diagnosis of vasospasm in subarachnoid hemorrhage is backed by national guidelines. However, it remains poorly used across neurologic intensive care units in the United States. This current practice article uses 2 clinical vignettes to illustrate the simplicity and logic behind routine daily surveillance of vasospasm with transcranial Doppler sonography in patients with subarachnoid hemorrhage, in preference to other modalities.

The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the microbial folate biosynthetic pathway. This pathway has proven to be an excellent target for antimicrobial development, but widespread resistance to common therapeutics including the sulfa drugs has stimulated interest in HPPK as an alternative target in the pathway. A screen of a pterin-biased compound set identified several HPPK inhibitors that contain an aryl substituted 8-thioguanine scaffold, and structural analyses showed that these compounds engage the HPPK pterin-binding pocket and an induced cryptic pocket. A preliminary structure activity relationship profile was developed from biophysical and biochemical characterizations of derivative molecules. Also, a similarity search identified additional scaffolds that bind more tightly within the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid elaboration into novel lead antimicrobial agents.

Intravenous fibrinolysis eligibility: a survey of stroke clinicians' practice patterns and review of the literature.

BACKGROUND: The indications and contraindications for intravenous (IV) recombinant tissue plasminogen activator (rtPA) use in ischemic stroke can be confusing to the practicing neurologist. Here we seek to describe practice patterns regarding decision-making among US stroke clinicians. METHODS: Stroke clinicians (attending and fellow) from the 8 National Institutes of Health SPOTRIAS (Specialized Programs of Translational Research in Acute Stroke) centers were asked to complete a survey ahead of the 2012 SPOTRIAS Investigators' meeting. RESULTS: A total of 51 surveys were collected (71% response rate). Most of the responders were attending physicians (68%). Only 18% of clinicians reported strictly adhering to current American Heart Association guidelines for treatment within 3 hours from symptom onset; this increased to 51% for the European Cooperative Acute Stroke Study (ECASS) III criteria in the 3 to 4.5 hours time frame. All clinicians treat eligible patients in the 3 to 4.5 hours time frame. The great majority will recommend rtPA in the following scenarios: (1) elderly individuals irrespective of age (97%); (2) severe stroke irrespective of National Institutes of Health Stroke Scale (NIHSS) (95%); or (3) suspected stroke with seizures at symptom onset (91%). None recommended rtPA in the setting of an international normalized ratio >1.7. Most clinicians defined mild strokes as an exclusion based on the perceived disability of the deficit (80%) rather than on a specific NIHSS threshold. CONCLUSIONS: Most surveyed stroke clinicians seem to find that the current IV rtPA eligibility criteria for the 3-hour time frame too restrictive. All would recommend rtPA to eligible patients in the 3 to 4.5 hours time frame despite the absence of an U.S. Food and Drug Administration (FDA)-approved indication.

Serotonin-Salt-Stress Model-Induced Cell Growth via Promoting an Antioxidant System and Secondary Metabolites in Capsicum annuum Cell Suspension Culture.

Capsicum annuum contains potential therapeutic capsaicinoids, and various stress factors influence plant productivity. Serotonin is an indoleamine involved in signaling several stress response mechanisms in plants. However, the influence of serotonin on cell growth and the accumulation of secondary metabolites, mainly capsaicinoids production, is not yet clearly defined under salt stress. In this study, we optimized chili cell suspension cultures to maximize biomass, capsaicinoids, and phenolic compounds production using response surface methodology with two variables (serotonin and NaCl) of different concentrations in culture media supplemented with 2,4-dichlorophenoxyacetic acid and Kinetin. The results revealed a significant increase in biomass (14.3 g/L FW), capsaicin (0.93 µg/g FW), and dihydrocapsaicin content (0.32 µg/g FW) in chili cell suspension cultures compared with the control. Among all the phenolic compounds, chlorogenic acid was enhanced (17.4 µg/g FW), compared to control cultures. Serotonin exhibited stress mitigation effects and boosted antioxidant potential in chili suspension cultures. The present results illustrated that the optimized conditions can be used in scale-up studies of capsaicinoids production through the bioreactor.

Comparative Evaluation of Oral Health Status and Treatment Needs of Children With Autism Spectrum Disorder: A Cross-Sectional Study.

INTRODUCTION:  Oral health care is essential yet challenging in children with autism spectrum disorder (ASD) due to their impaired emotional and behavioral stability, lack of communication skills, and inability to perform daily home hygiene routines properly. The present study was planned with the aim of assessing the Oral Health Status and Treatment Needs of children with ASD in comparison with children without any systemic disease. METHODS: A total of 160 children, in the age group of 5-14 years, divided equally into two groups, i.e., Group A (children with ASD) and Group B (children without any systemic disease), were assessed for Dental caries, Oral Hygiene Status, and Treatment Needs. The behavior of children in each group, during oral examination, was also assessed and recorded. Student t test and Chi square test were used for quantitative and qualitative analysis, respectively. RESULTS: The mean age of participating children was 7.96±2.43 years with a male predominance (male to female ratio - 1.58:1). Children with ASD displayed more negative behavior with 15% showing definitely negative behavior, 21.2% negative behavior on Frankl's Behavior Rating scale; the statistically lower prevalence of dental caries (Group A - mean decayed, missing and filled primary teeth (dmft): 1.7±3.2, mean decayed, missing and filled permanent teeth (DMFT): 0.19±0.71; Group B - mean DMFT: 5.44±4.88, mean DMFT: 1.01±1.51; p=0.0001), better oral hygiene (Group A - 18.8% showed good Simplified Oral Hygiene Index Score (OHI-S), 56.2% showed fair OHI-S; Group B - 6.2% showed good OHI-S and 46.3% showed fair OHI-S) and lower treatment needs compared to children without any systemic disease. CONCLUSION:  Children with ASD showed better oral health and lower treatment needs. This suggests that introducing oral hygiene care and diet modifications in daily routine can significantly improve the Oral Health Status in children with ASD.