Clostridioides difficile ribotype 106: A systematic review of the antimicrobial susceptibility, genetics, and clinical outcomes of this common worldwide strain.

Clostridioides difficile typing is invaluable for the investigation of both institution-specific outbreaks as well as national surveillance. While the epidemic ribotype 027 (RT027) has received a significant amount of resources and attention, ribotype 106 (RT106) has become more prevalent throughout the past decade. The purpose of this systematic review was to comprehensively summarize the genetic determinants, antimicrobial susceptibility, epidemiology, and clinical outcomes of infection caused by RT106. A total of 68 articles published between 1999 and 2019 were identified as relevant to this review. Although initially identified in the United Kingdom in 1999, RT106 is now found worldwide and became the most prevalent strain in the United States in 2016. Current data indicate that RT106 harbors the tcdA and tcdB genes, lacks binary toxin genes, and does not contain any deletions in the tcdC gene, which differentiates it from other epidemic strains, including ribotypes 027 and 078. Interestingly, RT106 produces more spores than other strains, including RT027. Overall, RT106 is highly resistant to erythromycin, clindamycin, fluoroquinolones, and third-generation cephalosporins. However, the MIC90 in most studies are one to two fold dilutions below the epidemiologic cut-off values of metronidazole and vancomycin, suggesting both are acceptable treatment options from an in vitro perspective. The few clinical outcomes studies available concluded that RT106 causes less severe disease than RT027, but patients were significantly more likely to experience multiple CDI relapses when infected with a RT106 strain. Specific areas warranting future study include potential survival advantages provided by genetic elements as well as a more robust investigation of clinical outcomes associated with RT106.

Engineering the Mucus Barrier.

Mucus selectively controls the transport of molecules, particulate matter, and microorganisms to the underlying epithelial layer. It may be desirable to weaken the mucus barrier to enable effective delivery of drug carriers. Alternatively, the mucus barrier can be strengthened to prevent epithelial interaction with pathogenic microbes or other exogenous materials. The dynamic mucus layer can undergo changes in structure (e.g., pore size) and/or composition (e.g., protein concentrations, mucin glycosylation) in response to stimuli that occur naturally or are purposely administered, thus altering its barrier function. This review outlines mechanisms by which mucus provides a selective barrier and methods to engineer the mucus layer from the perspective of strengthening or weakening its barrier properties. In addition, we discuss strategic design of drug carriers and dosing formulation properties for efficient delivery across the mucus barrier.

Decoding the dynamic representation of musical pitch from human brain activity.

In music, the perception of pitch is governed largely by its tonal function given the preceding harmonic structure of the music. While behavioral research has advanced our understanding of the perceptual representation of musical pitch, relatively little is known about its representational structure in the brain. Using Magnetoencephalography (MEG), we recorded evoked neural responses to different tones presented within a tonal context. Multivariate Pattern Analysis (MVPA) was applied to "decode" the stimulus that listeners heard based on the underlying neural activity. We then characterized the structure of the brain's representation using decoding accuracy as a proxy for representational distance, and compared this structure to several well established perceptual and acoustic models. The observed neural representation was best accounted for by a model based on the Standard Tonal Hierarchy, whereby differences in the neural encoding of musical pitches correspond to their differences in perceived stability. By confirming that perceptual differences honor those in the underlying neuronal population coding, our results provide a crucial link in understanding the cognitive foundations of musical pitch across psychological and neural domains.

Spatiotemporal Co-occurrence of Flanders and West Nile Viruses Within Culex Populations in Shelby County, Tennessee.

West Nile virus (WNV) and Flanders virus (FLAV) can cocirculate in Culex mosquitoes in parts of North America. A large dataset of mosquito pools tested for WNV and FLAV was queried to understand the spatiotemporal relationship between these two viruses in Shelby County, TN. We found strong evidence of global clustering (i.e., spatial autocorrelation) and overlapping of local clustering (i.e., Hot Spots based on Getis Ord Gi*) of maximum likelihood estimates (MLE) of infection rates (IR) during 2008-2013. Temporally, FLAV emerges and peaks on average 10.2 wk prior to WNV based on IR. Higher levels of WNV IR were detected within 3,000 m of FLAV-positive pool buffers than outside these buffers.

An injectable acoustic transmitter for juvenile salmon.

Salmon recovery and the potential detrimental effects of dams on fish have been attracting national attention due to the environmental and economic implications. In recent years acoustic telemetry has been the primary method for studying salmon passage. However, the size of the existing transmitters limits the minimum size of fish that can be studied, introducing a bias to the study results. We developed the first acoustic fish transmitter that can be implanted by injection instead of surgery. The new injectable transmitter lasts four times longer and weighs 30% less than other transmitters. Because the new transmitter costs significantly less to use and may substantially reduce adverse effects of implantation and tag burden, it will allow for study of migration behavior and survival of species and sizes of fish that have never been studied before. The new technology will lead to critical information needed for salmon recovery and the development of fish-friendly hydroelectric systems.

Design and implementation of a new autonomous sensor fish to support advanced hydropower development.

Acceleration in development of additional conventional hydropower requires tools and methods to perform laboratory and in-field validation of turbine performance and fish passage claims. The new-generation Sensor Fish has been developed with more capabilities to accommodate a wider range of users over a broader range of turbine designs and operating environments. It provides in situ measurements of three-dimensional (3D) linear accelerations, 3D rotational velocities, 3D orientation, pressure, and temperature at a sampling frequency of 2048 Hz. It also has an automatic floatation system and built-in radio-frequency transmitter for recovery. The relative errors of the pressure, acceleration, and rotational velocity were within ±2%, ±5%, and ±5%, respectively. The accuracy of orientation was within ±4° and accuracy of temperature was ±2 °C. The new-generation Sensor Fish is becoming a major technology and being deployed for evaluating the conditions for fish passage of turbines or other hydraulic structures in both the United States and several other countries.

Spinal meningeal oligodendrogliomatosis in two boxer dogs.

Two Boxer dogs developed progressive ataxia in association with a neoplastic infiltration of the spinal leptomeninges. In the first dog, the leptomeningeal neoplasm encompassed the entire cord and the ventral aspect of the brainstem and extended bilaterally into the piriform lobes. In the second, the neoplasm surrounded the C1-C3 segments of the spinal cord and the brainstem without involvement of the brain or spinal cord parenchyma. In both dogs, the neoplastic cells had variably distinct cell borders, clear to eosinophilic cytoplasm, and a round to ovoid hyperchromatic nucleus. Neoplastic cells were immunopositive for Olig2 and doublecortin in both dogs and for vimentin in one dog but were immunonegative for glial fibrillary acidic protein, S-100, CD34, E-cadherin, cytokeratin, CD3, and CD20. The morphological and immunohistochemical features of the neoplastic cells were consistent with an oligodendrocyte lineage. This hitherto poorly recognized neoplasm in dogs is analogous to human leptomeningeal oligodendrogliomatosis.

Effect of acetaminophen and fluvastatin on post-dose symptoms following infusion of zoledronic acid.

UNLABELLED: A randomized, double-blind, placebo-controlled study assessed the efficacy of acetaminophen or fluvastatin in preventing post-dose symptoms (increases in body temperature or use of rescue medication) following a single infusion of the intravenous (IV) bisphosphonate zoledronic acid (ZOL). Acetaminophen, but not fluvastatin, significantly reduced the incidence and severity of post-dose symptoms. INTRODUCTION: Transient symptoms including myalgia and pyrexia have been reported post-infusion of IV bisphosphonates, typically starting the day after infusion and resolving within several days. The cause is unknown but may be related to transient cytokine elevations. Statins' potential to block release of these cytokines has been hypothesized. This study was aimed to evaluate efficacy of acetaminophen and fluvastatin in preventing/reducing post-dose symptoms following ZOL 5 mg infusion. METHODS: Randomized, double-blind, placebo-controlled study of efficacy of acetaminophen or fluvastatin in preventing increases in body temperature or use of rescue medication (ibuprofen) following a single ZOL infusion. Bisphosphonate-naive postmenopausal women with low bone mass (N = 793) were randomized into three treatment groups and given 650 mg acetaminophen or 80 mg fluvastatin or placebo 45 min before ZOL infusion. The acetaminophen group continued taking 650 mg acetaminophen every 6 h over the next 3 days, and the other two groups took matching placebo according to the same schedule. Subjects recorded body temperature, symptoms in a diary. Inflammatory cytokines and C-reactive protein (CRP) were measured at baseline, 24, and 72 h in a study subset. RESULTS: Acetaminophen four times/day significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion. Single-dose fluvastatin 80 mg prior to ZOL infusion did not prevent/reduce post-dose symptoms. Cytokine levels increased by 24 h and returned towards baseline by 72 h, similar to the pattern for post-infusion symptoms. CRP levels increased from baseline to 72 h. CONCLUSIONS: Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion.

Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells.

AIMS/HYPOTHESIS: Glucokinase (GK), an enzyme that phosphorylates glucose to form glucose 6-phosphate, serves as the glucose sensor that regulates insulin secretion in beta cells. GK activators (GKAs) activate GK via binding to an allosteric site of the enzyme. GKAs increase glucose-stimulated insulin secretion and decrease blood glucose levels. Using the differentiated beta cell line INS-1, we investigated the role of GKAs in promoting beta cell growth and survival and preventing beta cell apoptosis induced by chronic exposure to high levels of glucose. METHODS: Proliferation was assessed using BrdU incorporation. Apoptosis was measured using caspase-3 activity. Immunoblot analysis was used to detect protein levels and the degree of phosphorylation. RESULTS: The GK agonists GKA50 and LY2121260 increased both cell replication and cell numbers when tested at basal levels of glucose (3 mmol/l) in INS-1 cells. GKAs promoted INS-1 cell proliferation via upregulation of insulin receptor substrate-2 and subsequent activation of protein kinase B phosphorylation. GKA50 also prevented the INS-1 cell apoptosis that was induced by chronic high glucose conditions, probably via an increase in GK protein levels and normalisation of the apoptotic protein BCL2-associated agonist of cell death (BAD) and its phosphorylation. As a result of the reduction in cell apoptosis, GKA50 prevented cell loss and maintained glucose-stimulated insulin secretion. In addition, the anti-apoptotic activity of GKA50 was significantly abrogated by other GKAs that do not inhibit apoptosis, suggesting that direct binding of GKA50 to GK is essential for its anti-apoptotic effect. CONCLUSION/INTERPRETATION: Our results suggest novel roles of GKAs in promoting beta cell growth and preventing chronic-hyperglycaemia-induced beta cell apoptosis. Thus, GKAs may provide novel therapeutics that increase beta cell mass to maintain euglycaemia in diabetes.

Role of C-type lectins in mycobacterial infections.

Worldwide clinical cases due to multi drug- and extensively drug-resistant strains of Mycobacterium tuberculosis (M.tb) are increasing making the need for new therapies more critical than ever. A major obstacle for designing new drugs to treat mycobacterial infections is our limited knowledge of the interface between the bacillus (especially M.tb) and its host. The pulmonary innate immune system plays a key role in the recognition of microbes entering via the respiratory route. Although the specificity of this system is broad and based on the recognition of pathogen-associated molecular patterns (PAMPs), it is uniquely regulated to limit inflammation and thereby prevent damage to the gas-exchanging alveoli. Pulmonary surfactant proteins A and D (SP-A and SP-D) are collagenous, soluble, C-type (Ca(2+)-dependent) lectins (named collectins) of the lung innate immune system that are secreted into the alveoli by resident type II alveolar epithelial cells and distal bronchiolar Clara cells. The related collectin in serum, mannose-binding lectin/protein (MBL or MBP), provides first-line defense against several microbes. Phagocytes represent the first cellular defense in the alveoli and their surface is rich in C-type lectin pattern recognition receptors (PRRs), including the mannose receptor (MR), dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) and DC-associated C-type lectin-1 (Dectin-1). This review will discuss the important roles of the cell-associated C-type lectin PRRs and soluble collectins in the innate immune response to mycobacterial infections, and will present the current state of knowledge regarding the potential uses of these C-type lectins in therapy against infections, focusing on M.tb.

Effects of sucromalt on postprandial responses in human subjects.

BACKGROUND/OBJECTIVE: To compare postprandial responses elicited by sucromalt, a nutritive sweetener produced by treating a blend of sucrose and corn syrup with an enzyme from Leuconostoc mesenteroides, with those after 42% of high-fructose corn syrup (HFCS), and to see if the reduced responses after sucromalt could be accounted for by carbohydrate malabsorption. SUBJECT AND METHODS: Three experiments were performed in separate groups of normal subjects studied after overnight fasts using double-blind, randomized, cross-over designs. HFCS was used as the control because it contained a similar amount of fructose as sucromalt. Experiment 1 (n = 10): plasma glucose and insulin were measured after 50 g sucromalt and 50 g HFCS. Experiment 2 (n = 10): metabolic profiles were measured after 80 g HFCS, 80 g sucromalt or 56 g fructose/glucose blend plus 24 g inulin. Experiment 3 (n = 20): the glycaemic indices of sucromalt and HFCS were determined. RESULTS: Mean glucose and insulin responses after sucromalt were 66 and 62%, respectively, of those after HFCS (P < 0.05). The inulin treatment, used to mimic the effects of carbohydrate malabsorption, elicited higher breath hydrogen (H2), lower glucose and insulin responses, and a significantly earlier rise in serum free fatty acids (FFA) than those of HFCS (all P < 0.05). Sucromalt elicited no rise in breath H2, and delayed falls in glucose and insulin, and a delayed rebound of FFA compared to HFCS (all P < 0.05). CONCLUSIONS: The reduced glucose and insulin responses elicited by sucromalt are not explained by malabsorption and are more likely related to differences in either rate of digestion and absorption or postabsorptive handling by body.

The combined presence of obsessive compulsive behaviors in males and females with eating disorders account for longer lengths of stay and more severe eating disorder symptoms.

The goal of this study was to analyze the impact of obsessive compulsive behaviors (OCB) in eating disorder males and females admitted for residential treatment in terms of length of stay and severity of symptoms. Patients (N=384) were separated into four groups based on gender and the score obtained for the Maudsley Obsessive-Compulsive Inventory at admission. The instrument used to assess severity of eating disorder symptoms was the Eating Disorder Inventory (EDI-2) at admission and discharge. The results showed that the presence of comorbid OCB in eating disordered males and females account for longer length of stay (LOS) and an increased severity of eating disorder symptoms. Clinically, these findings point to the need for development of more targeted residential programs that are equipped for and adept at treating the comorbid eating disorder/OCB patient population.

Lipoprotein risk factors for cardiovascular disease in patients with type 2 diabetes mellitus treated with oral antihyperglycaemic agents.

AIMS: To compare lipoprotein risk factors for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM) treated with a sulphonylurea (SU) compound only, metformin (MET) only, or combined SU + MET. METHODS: The study population consisted of 62 patients with type 2 DM, whose antihyperglycaemic treatment program had been stable for at least 3 months, divided into three groups: 26 patients in the SU group, 17 patients in the MET group and 19 patients in the SU + MET group. None of the patients were taking lipid-lowering drugs. Fasting venous blood samples were taken to measure concentrations of glucose, total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and remnant lipoprotein-cholesterol (RLP-C) as well as for determination of LDL particle diameter. RESULTS: The three groups were similar in terms of age, gender, body mass index and fasting plasma glucose concentrations. Total cholesterol concentrations were significantly lower (p < 0.05 for trend) in those treated with SU + MET as compared with the other two groups. However, there were no significant differences between the three groups in their plasma concentrations of TG, LDL-C, HDL-C or RLP-C; furthermore, the proportion of individuals within each treatment group with small LDL particle diameter was also not different. CONCLUSIONS: The lipoprotein profile of patients with type 2 DM, matched for level of fasting hyperglycaemia, was similar irrespective of treatment with SU alone, MET alone or SU + MET. Thus, we could not identify any changes in lipoprotein metabolism that could account for differences in risk of CVD as a function of treatment.

Evaluation of the toxicity of concentrated barley beta-glucan in a 28-day feeding study in Wistar rats.

Beta-glucans are water-soluble cell-wall polysaccharides consisting of (1-->3,1-->4)-linked beta-D-glucopyranosyl monomers that comprise a considerable proportion of soluble fiber from certain grains including oats and barley. Consumption of foods containing beta-glucan or beta-glucan-enriched fractions prepared from these grains lower serum cholesterol concentrations in humans and in animal models of hypercholesterolemia. The present study was conducted to evaluate the toxicity of beta-glucan-enriched soluble fiber from barley in Wistar rats on dietary administration at concentrations of 0.7, 3.5 and 7% beta-glucan for 28 days. There were no adverse effects on general condition and behavior, growth, feed and water consumption, feed conversion efficiency, red blood cell and clotting potential parameters, clinical chemistry values, and organ weights. Necropsy and histopathology findings revealed no treatment-related changes in any organ evaluated. A dose-dependent increase in full and empty cecum weight was observed. This is a common physiological response of rodents to high amounts of poorly digestible, fermentable carbohydrates, and was of no toxicological concern. The only finding of possible biological relevance was an increase in the number of circulating lymphocytes observed in males. However, the increase was not dose-dependent and was not observed in females. Results of this study demonstrated that consumption of concentrated barley beta-glucan was not associated with any obvious signs of toxicity in Wistar rats even following consumption of large quantities.

Direct cell adhesion to the angiopoietins mediated by integrins.

Genetic ablation of angiopoietin-1 (Ang-1) or of its cognate receptor, Tie2, disrupts angiogenesis in mouse embryos. The endothelial cells in growing blood vessels of Ang-1 knockout mice have a rounded appearance and are poorly associated with one another and their underlying basement membranes (Dumont, D. J., Gradwohl, G., Fong, G. H., Puri, M. C., Gertsenstein, M., Auerbach, A., and Breitman, M. L. (1994) Genes Dev. 8, 1897--1909; Sato, T. N., Tozawa, Y., Deutsch, U., Wolburg-Buchholz, K., Fujiwara, Y., Gendron-Maguire, M., Gridley, T., Wolburg, H., Risau, W., and Qin, Y. (1995) Nature 376, 70--74; Suri, C., Jones, P. F., Patan, S., Bartunkova, S., Maisonpierre, P. C., Davis, S., Sato, T. N., and Yancopoulos, G. D. (1996) Cell 87, 1171--1180). It is therefore possible that Ang-1 regulates endothelial cell adhesion. In this study we asked whether Ang-1 might act as a direct substrate for cell adhesion. Human umbilical vein endothelial cells (HUVECs) plated for a brief period on different substrates were found to adhere and spread well on Ang-1. Similar results were seen on angiopoietin-2 (Ang-2)-coated surfaces, although cells did not spread well on Ang-2. Ang-1, but not Ang-2, supported HUVEC migration, and this was independent of growth factor activity. When the same experiments were done with fibroblasts that either lacked, or stably expressed, Tie2, results similar to those with HUVECs were seen, suggesting that adhesion to the angiopoietins was independent of Tie2 and not limited to endothelial cells. Interestingly, when integrin-blocking agents were included in these assays, adhesion to either angiopoietin was significantly reduced. Moreover, Chinese hamster ovary-B2 cells lacking the alpha(5) integrin subunit did not adhere to Ang-1, but they did adhere to Ang-2. Stable expression of the human alpha(5) integrin subunit in these cells rescued adhesion to Ang-1 and promoted an increase in adhesion to Ang-2. We also found that Ang-1 and Ang-2 bind rather selectively to vitronectin. These results suggest that, beyond their role in modulating Tie2 signaling, Ang-1 and Ang-2 can directly support cell adhesion mediated by integrins.

Mutations in the gene encoding lecithin retinol acyltransferase are associated with early-onset severe retinal dystrophy.

The chromophore of the visual pigments, 11-cis retinal, is derived from vitamin A (all-trans retinol) through a series of reactions that take place in retinal pigment epithelium (RPE); (ref. 1). The first of these reactions is catalyzed by lecithin retinol acyltransferase (LRAT); (ref. 2). We screened 267 retinal dystrophy patients for mutations in LRAT and identified disease-associated mutations (S175R and 396delAA) in three individuals with severe, early-onset disease. We showed that the S175R mutant has no acyltransferase activity in transfected COS-7 cells. Our findings highlight the importance of genetic defects in vitamin A metabolism as causes of retinal dystrophies and extend prospects for retinoid replacement therapy in this group of diseases.

Studies using structural analogs and inbred strain differences to support a role for quinone methide metabolites of butylated hydroxytoluene (BHT) in mouse lung tumor promotion.

Chronic treatment of BALB and GRS mice with BHT (2,6-di-tert-butyl-4-methylphenol) following a single urethane injection increases lung tumor multiplicity, but this does not occur in CXB4 mice. Previous data suggest that promotion requires the conversion of BHT to a tert-butyl-hydroxylated metabolite (BHTOH) in lung and the subsequent oxidation of this species to an electrophilic quinone methide. To obtain additional evidence for the importance of quinone methide formation, structural analogs that form less reactive quinone methides were tested and found to lack promoting activity in BHT-responsive mice. The possibility that promotion-unresponsive strains are unable to form BHTOH was tested by substituting this compound for BHT in the promotion protocol using CXB4 mice. No promotion occurred, and in-vitro work demonstrated that CXB4 mice are, in fact, capable of producing BHTOH and its quinone methide, albeit in smaller quantities. Incubations with BALB lung microsomes and radiolabeled substrates confirmed that more covalent binding to protein occurs with BHTOH than with BHT and, in addition, BHTOH quinone methide is considerably more toxic to mouse lung epithelial cells than BHT quinone methide. These data are consistent with the hypothesis that a two-step oxidation process, i.e. hydroxylation and quinone methide formation, is required for the promotion of mouse lung tumors by BHT.

Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy.

Isotretinoin (13-cis retinoic acid) is frequently prescribed for severe acne [Peck, G. L., Olsen, T. G., Yoder, F. W., Strauss, J. S., Downing, D. T., Pandya, M., Butkus, D. & Arnaud-Battandier, J. (1979) N. Engl. J. Med. 300, 329-333] but can impair night vision [Fraunfelder, F. T., LaBraico, J. M. & Meyer, S. M. (1985) Am. J. Ophthalmol. 100, 534-537] shortly after the beginning of therapy [Shulman, S. R. (1989) Am. J. Public Health 79, 1565-1568]. As rod photoreceptors are responsible for night vision, we administered isotretinoin to rats to learn whether night blindness resulted from rod cell death or from rod functional impairment. High-dose isotretinoin was given daily for 2 months and produced systemic toxicity, but this caused no histological loss of rod photoreceptors, and rod-driven electroretinogram amplitudes were normal after prolonged dark adaptation. Additional studies showed, however, that even a single dose of isotretinoin slowed the recovery of rod signaling after exposure to an intense bleaching light, and that rhodopsin regeneration was markedly slowed. When only a single dose was given, rod function recovered to normal within several days. Rods and cones both showed slow recovery from bleach after isotretinoin in rats and in mice. HPLC analysis of ocular retinoids after isotretinoin and an intense bleach showed decreased levels of rhodopsin chromophore, 11-cis retinal, and the accumulation of the biosynthetic intermediates, 11-cis and all-trans retinyl esters. Isotretinoin was also found to protect rat photoreceptors from light-induced damage, suggesting that strategies of altering retinoid cycling may have therapeutic implications for some forms of retinal and macular degeneration.

Novel antihyperglycemic terpenoid-quinones from Pycnanthus angolensis.

Two new compounds, pycnanthuquinone A (1) and pycnanthuquinone B (2), were isolated from leaves and stems of the African plant, Pycnanthus angolensis (Welw.) Warb (Myristicaceae), by bioassay-guided fractionation of an ethanolic extract using a diabetic mouse model. Pycnanthuquinones A and B are the first representatives of a novel terpenoid-type quinone skeleton, and both compounds possess significant antihyperglycemic activity.