bluuebunny/crossref_metadata_2025_split huggingface dataset:
Site‐specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity
Authors: Gong Nian , Ma Ai‐Niu , Zhang Li‐Jie , Luo Xiao‐Su , Zhang Yin‐Hui , Xu Michael , Wang Yong‐Xiang 
Published: January 2011

BACKGROUND AND PURPOSEExenatide is a 39‐amino‐acid peptide widely used to manage type 2 diabetes mellitus. However, it has a short plasma half‐life and requires a twice daily injection regime. To overcome these drawbacks we used maleimide‐polyethylene glycol to induce site‐specific PEGylation.EXPERIMENTAL APPROACHThe analogue PB‐105 (ExC39) was produced by replacing cysteine at position 39 of exenatide to provide a free thiol group. PB‐105 showed the same glucoregulatory activity as exenatide in mice. Site‐specific PEGylation of PB‐105 was performed to produce PB‐110 (ExC39PEG5kDa), PB‐106 (ExC39PEG20kDa), PB‐107 (ExC39PEG30kDa) and PB‐108 (ExC39PEG40kDa). Their effects on intracellular cAMP, acute glucoregulatory activity and pharmacokinetic profile were compared in mice and rats.KEY RESULTSPEGylation shifted the concentration–response curve of PB‐105 to the right in a parallel, polyethylene glycol mass‐dependent manner but with an inflexion point of at least 20 kDa. The activities of PB‐107 and PB‐108 but not PB‐106 were reduced by 90% and 99%. PEGylation affected in vivo glucoregulatory activity in the same ‘Inflexion‐Shift’ fashion at least at 20 kDa, but linearly increased plasma duration and systemic exposure without inflexion. PB‐106 had a plasma t1/2 approximately 10‐fold that of PB‐105, and exhibited superior glucoregulatory activity compared with PB‐105 in normal and diabetic mice.CONCLUSIONS AND IMPLICATIONSSite‐specific PEGylation of exenatide with a permanent amide linkage affects its activity in a new type of ‘Inflexion‐Shift’ fashion. PB‐106 is a putative new analogue for treating diabetes; it possesses no loss of in vitro activity, prolonged plasma duration and superior, improved in vivo glucoregulatory activity compared with exenatide.
Prevalence and cause of methylisothiazolinone contact allergy
Authors: Lundov Michael D. , Thyssen Jacob P. , Zachariae Claus , Johansen Jeanne D. 
Published: January 2011

Background: Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) has been one of the most frequent sensitizers since the 1980s. In 2005, the use of MI alone was approved for the preservation of cosmetic and household products in the EU. Before that, MI was used in industrial products, and the first cases of isolated MI contact allergy were published. Objectives: To present the prevalence and causes of MI contact allergy. Materials and methods: Patch test results from 2536 dermatitis patients tested with MI at Gentofte University Hospital between May 2006 and February 2010 were analysed. A retrospective investigation of medical records from MI‐allergic patients was performed to reveal the causes of their MI contact allergy. Results: Of patch‐tested patients, 1.5% had MI contact allergy. It was associated with occupational dermatitis, hand eczema and age above 40 years. Exposure to MI in cosmetic products was found in 12 (32%) cases, and exposure to MI in occupational products was found in 11 (30%) cases; 5 of the 11 were painters. Conclusions: The prevalence of MI contact allergy is already at the same level as that of other sensitizing preservatives, which have been on the market for several years, but no rising trend was identified. MI contact allergy was associated with both occupational and consumer products.
Salivary IgA in minor‐gland saliva of children, adolescents, and young adults
Authors: Sonesson Mikael , Hamberg Kristina , Wallengren Marie‐Louise Lundin , Matsson Lars , Ericson Dan 
Published: January 2011

Sonesson M, Hamberg K, Lundin Wallengren M‐L, Matsson L, Ericson D. Salivary IgA in minor‐gland saliva of children, adolescents, and young adults. Eur J Oral Sci 2011; 119: 15–20. © 2011 Eur J Oral Sci According to previous studies, minor glands produce about 35% of the total salivary immunoglobulin A (salivary IgA). The age‐dependent increase in whole‐saliva salivary IgA concentrations has been studied extensively, but we found no published reports comparing the minor‐gland saliva concentrations of salivary IgA in children, adolescents, and adults. In this study we measured the concentration of salivary IgA in saliva from the labial and the buccal minor glands of children, adolescents, and adults. Three age groups donated saliva for analysis: 3‐yr‐old children, 14‐yr‐old adolescents, and 20‐ to 25‐yr‐old adults. Minor‐gland saliva was collected on filter paper and unstimulated whole saliva was collected by draining into a tube, and the salivary IgA concentration was determined by ELISA. The salivary IgA concentration in labial saliva was significantly lower among 3‐yr‐old children (0.037 mg 100 ml−1, SD = 0.035) than among 14‐yr‐old adolescents (0.126 mg 100 ml−1, SD = 0.128) and adults (0.128 mg 100 ml−1, SD = 0.13). The 3‐yr‐old children also had significantly lower whole‐saliva salivary IgA values compared with the other age groups (0.09 mg 100 ml−1, SD = 0.091; 0.179 mg 100 ml−1, SD = 0.149; and 0.170 mg 100 ml−1, SD = 0.099, respectively). This increase in salivary IgA concentrations with age might reflect a developing immune response in the growing child.
Oncogenetics of melanoma: basis for molecular diagnostics and therapy
Authors: Held Laura , Eigentler Thomas K. , Meier Friedegund , Held Marko , Röcken Martin , Garbe Claus , Bauer Jürgen 
Published: January 2011

SummaryOur understanding of oncogenetics and of the molecular mechanisms involved in melanoma development and signaling has dramatically changed in recent years. Today, melanomas are also classified based on molecular alterations. Emerging molecular therapies are targeted against specific mutations in melanoma. An example of targeted therapies is the successful treatment of KIT‐mutant melanoma with the kinase inhibitor imatinib. Highly selective BRAF‐inhibitors are likewise under clinical development and show encouraging clinical responses. An increasing number of targeted drugs will emerge in the coming years, based on molecular diagnostics and classification. The present article reviews signaling pathways in melanocytes and alterations in melanoma that are a prerequisite to understanding modern cancer therapies in melanoma.
Effect of position on oxygen saturation and requirement in convalescent preterm infants
Authors: Elder Dawn E , Campbell Angela J , Galletly Duncan 
Published: January 2011

AbstractAims:  To document the effect of position on oxygen saturation and changes in oxygen requirement in convalescent preterm infants.Methods:  Twelve infants born ≥24 and ≤32 weeks gestation, extubated and without congenital anomaly were studied using nap polysomnography in prone and supine, twice weekly until discharge. Mean oxygen saturation (SpO2), minimum SpO2, mean minimum SpO2 and time with SpO2 < 90% were measured in active sleep.Results:  Eight male and four female infants [median gestation 28 (24–31) weeks and median birthweight 1059 (715–1840) g] had 39 studies. For 21 of 39 studies, the infant was on respiratory support. Four infants had chronic lung disease (CLD). SpO2 varied with postmenstrual age (PMA) (p = 0.003) but not with position (p = 0.36), and PMA did not influence the effect of position on SpO2 (p = 0.19). SpO2 was lower for those with CLD (p < 0.0001) and those on respiratory support (p < 0.001), but there was no effect of position (p = 0.97 and p = 0.67, respectively). From 36 weeks PMA, a change to supine did not increase oxygen requirement.Conclusion:  In preterm infants, PMA and residual respiratory disease have greater effects on oxygenation than position. A supine sleep position is not disadvantageous for preterm infants at discharge.
Acute pancreatitis in children
Authors: Chang Yi‐Jung , Chao Hsun‐Chin , Kong Man‐Shan , Hsia Shao‐Hsuan , Lai Ming‐Wei , Yan Dah‐Chin 
Published: January 2011

AbstractAim:  To identify clinical, laboratory, and imaging characteristics associated with severe acute pancreatitis in children.Methods:  This was a retrospective study of children under 18 years of age with acute pancreatitis between September 1993 and August 2008. Severity of pancreatitis was graded according to established criteria. Clinical, laboratory and radiological data for mild and severe pancreatitis were collected for analysis.Results:  There were 180 cases of pancreatitis; 51 (28.3%) met criteria for severe disease. Severe pancreatitis was most commonly associated with systemic disease (22 of 51; 43.1%) and trauma (13 of 51; 25.4%). Patients with severe pancreatitis had significantly higher body weight, higher frequency of dyspnoea and pleural effusion, and lower serum calcium and albumin levels. Ten patients with systemic disease died; four of them had systemic lupus erythematosus (SLE). Computed tomography (CT) was more accurate than ultrasound in evaluation of the severity of pancreatitis.Conclusions:  Acute pancreatitis in children is associated with significant morbidity and mortality. The severity of paediatric pancreatitis may be influenced by aetiology. CT is recommended for evaluation of severity of pancreatitis.
Mapping gradients of community composition with nearest‐neighbour imputation: extending plot data for landscape analysis
Authors: Ohmann Janet L. , Gregory Matthew J. , Henderson Emilie B. , Roberts Heather M. 
Published: January 2011

AbstractQuestion:How can nearest‐neighbour (NN) imputation be used to develop maps of multiple species and plant communities?Location:Western and central Oregon, USA, but methods are applicable anywhere.Methods:We demonstrate NN imputation by mapping woody plant communities for >100 000 km2of diverse forests and woodlands. Species abundances on ∼25 000 plots were related to spatial predictors (rasters) describing climate, topography, soil and geographic location using constrained ordination (CCA). Species data from the nearest plot in multi‐dimensional CCA space were imputed to each map pixel. Maps of multiple individual species and community types were constructed from the single imputed surface. We computed a variety of diagnostics to characterize different qualities of the imputed (mapped) community data.Results:Community composition gradients were strongly associated with climate and elevation, and less so with topography and soil. Accuracy of the imputation model for presence/absence of 150 species varied widely (kappa 0.00 to 0.80). Omission error rates were higher than commission rates due to low species prevalence, and areal representation of species was only slightly inflated. A map of 78 community types was 41% correct and 78% fuzzy correct. Errors of omission and commission were balanced, and areal representation of both rare and abundant communities was accurate. Map accuracy may be lower for some species than with other methods, but areal representation of species and communities across large landscapes is preserved. Because imputed vegetation surfaces are developed for all species simultaneously, map units contain suites of species known to co‐occur in nature. Maps of individual species, and of community types derived from them, will be internally consistent at map locations.Conclusions:NN imputation is a useful modelling approach where maps of multiple species and plant communities are needed, such as in natural resource management and conservation planning or models that project landscape change under alternative disturbance or climate scenarios. More research is needed to evaluate other ordination methods for NN imputation of plant communities.
Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1
Authors: Mahalingam Alamelu , Simmons Adam P. , Ugaonkar Shweta R. , Watson Karen M. , Dezzutti Charlene S. , Rohan Lisa C. , Buckheit Robert W. , Kiser Patrick F. 
Published: January 2011

ABSTRACT

Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels—3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation—for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months.
In vitro
release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The
in vitro
and
ex vivo
safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In an
in vitro
HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 μg/ml for gel in culture media, which corresponds to ∼0.001 μM IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in
in vivo
models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.
Process Analysis of Variables for Standardization of Antifungal Susceptibility Testing of Nonfermentative Yeasts
Authors: Zaragoza Oscar , Mesa-Arango Ana C. , Gómez-López Alicia , Bernal-Martínez Leticia , Rodríguez-Tudela Juan Luis , Cuenca-Estrella Manuel 
Published: January 2011

ABSTRACT

Nonfermentative yeasts, such as
Cryptococcus
spp., have emerged as fungal pathogens during the last few years. However, standard methods to measure their antifungal susceptibility (antifungal susceptibility testing [AST]) are not completely reliable due to the impaired growth of these yeasts in standard media. In this work, we have compared the growth kinetics and the antifungal susceptibilities of representative species of nonfermentative yeasts such as
Cryptococcus neoformans
,
Cryptococcus gattii
,
Cryptococcus albidus
,
Rhodotorula
spp.,
Yarrowia lipolytica
,
Geotrichum
spp., and
Trichosporon
spp. The effect of the growth medium (RPMI medium versus yeast nitrogen base [YNB]), glucose concentration (0.2% versus 2%), nitrogen source (ammonium sulfate), temperature (30°C versus 35°C), shaking, and inoculum size (10
3
, 10
4
, and 10
5
cells) were analyzed. The growth rate, lag phase, and maximum optical density were obtained from each growth experiment, and after multivariate analysis, YNB-based media demonstrated a significant improvement in the growth of yeasts. Shaking, an inoculum size of 10
5
CFU/ml, and incubation at 30°C also improved the growth kinetics of organisms. Supplementation with ammonium sulfate and with 2% glucose did not have any effect on growth. We also tested the antifungal susceptibilities of all the isolates by the reference methods of the CLSI and EUCAST, the EUCAST method with shaking, YNB under static conditions, and YNB with shaking. MIC values obtained under different conditions showed high percentages of agreement and significant correlation coefficient values between them. MIC value determinations according to CLSI and EUCAST standards were rather complicated, since more than half of isolates tested showed a limited growth index, hampering endpoint determinations. We conclude that AST conditions including YNB as an assay medium, agitation of the plates, reading after 48 h of incubation, an inoculum size of 10
5
CFU/ml, and incubation at 30°C made MIC determinations easier without an overestimation of MIC values.
Virulence Inhibition by Zinc in Shiga-Toxigenic
Escherichia coli
Authors: Crane John K. , Byrd Isaac Wyatt , Boedeker Edgar C. 
Published: January 2011

ABSTRACT

Previously, our laboratories reported that zinc inhibited expression of several important virulence factors in enteropathogenic
Escherichia coli
(EPEC) and reduced EPEC-induced intestinal damage
in vivo
. Since EPEC is genetically related to Shiga-toxigenic
E. coli
(STEC), we wondered whether the beneficial effects of zinc extended to STEC as well. Treatment options for STEC infection are very limited, since antibiotics tend to exacerbate disease via enhanced toxin production, so a safe intervention for this infection would be welcome. In this study, we report that in STEC strains zinc inhibits adherence to cultured cells as well as expression of EHEC secreted protein A (EspA). In addition, zinc inhibits the expression of Shiga toxin (Stx) at both the protein and the RNA level. Zinc inhibits basal and antibiotic-induced Stx production and inhibits both Stx1 and Stx2 by ≥90% at a concentration of 0.4 mM zinc. Rabbit EPEC strains were selected for acquisition of Stx-encoding bacteriophages, and these rabbit STEC strains (designated RDEC-H19A and E22-stx2) were used to test the effects of zinc
in vivo
in ligated rabbit intestinal loops.
In vivo
, zinc reduced fluid secretion into loops, inhibited mucosal adherence, reduced the amount of toxin in the loops, and reduced STEC-induced histological damage (villus blunting). Zinc has beneficial inhibitory effects against STEC strains that parallel those observed in EPEC. In addition, zinc strongly inhibits Stx expression; since Stx is responsible for the extraintestinal effects of STEC infection, such as hemolytic-uremic syndrome (HUS), zinc might be capable of preventing severe sequelae of STEC infection.
HIV-1/Mycobacterium tuberculosisCoinfection Immunology: How Does HIV-1 Exacerbate Tuberculosis?
Authors: Diedrich Collin R. , Flynn JoAnne L. 
Published: January 2011

ABSTRACTHuman immunodeficiency virus type 1 (HIV) andMycobacterium tuberculosishave become intertwined over the past few decades in a “syndemic” that exacerbates the morbidity and mortality associated with each pathogen alone. The severity of the coinfection has been extensively examined in clinical studies. The extrapolation of peripheral evidence from clinical studies has increased our basic understanding of how HIV increases susceptibility to TB. These studies have resulted in multiple hypotheses of how HIV exacerbates TB pathology through the manipulation of granulomas. Granulomas can be located in many tissues, most prominently the lungs and associated lymph nodes, and are made up of multiple immune cells that can actively containM. tuberculosis. Granuloma-based research involving both animal models and clinical studies is needed to confirm these hypotheses, which will further our understanding of this coinfection and may lead to better treatment options. This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments.
Toll-Like Receptor 5 Stimulation Protects Mice from Acute
Clostridium difficile
Colitis
Authors: Jarchum Irene , Liu Mingyu , Lipuma Lauren , Pamer Eric G. 
Published: January 2011

ABSTRACT

Clostridium difficile
is a spore-forming bacterium that infects the lower intestinal tract of humans and is the most common known cause of diarrhea among hospitalized patients.
Clostridium difficile
colitis is mediated by toxins and develops during or following antibiotic administration. We have used a murine model of
C. difficile
infection, which reproduces the major features of the human disease, to study the effect of innate immune activation on resistance to
C. difficile
infection. We found that administration of purified
Salmonella
-derived flagellin, a Toll-like receptor 5 (TLR5) agonist, protects mice from
C. difficile
colitis by delaying
C. difficile
growth and toxin production in the colon and cecum. TLR5 stimulation significantly improves pathological changes in the cecum and colon of
C. difficile
-infected mice and reduces epithelial cell loss. Flagellin treatment reduces epithelial apoptosis in the large intestine, thereby protecting the integrity of the intestinal epithelial barrier during
C. difficile
infection. We demonstrate that restoring intestinal innate immune tone by TLR stimulation in antibiotic-treated mice ameliorates intestinal inflammation and prevents death from
C. difficile
colitis, potentially providing an approach to prevent
C. difficile
-induced pathology.
Maternal Microbe-Specific Modulation of Inflammatory Response in Extremely Low-Gestational-Age Newborns
Authors: Fichorova Raina N. , Onderdonk Andrew B. , Yamamoto Hidemi , Delaney Mary L. , DuBois Andrea M. , Allred Elizabeth , Leviton Alan 
Published: January 2011

ABSTRACTThe fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes.PrevotellaandGardnerellaspecies, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins.Lactobacilluswas associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and thatLactobacillusmay suppress these responses.IMPORTANCEDespite improved intensive care, preterm and especially extremely low-gestation-age neonates continue to be at a considerably increased risk of morbidity, mortality, and developmental problems. The fetal inflammatory response appears to contribute to the onset of preterm labor, fetal injury, and complications, underlying lifetime health challenges facing these children. This study provides evidence that bacterial colonization of the very preterm placenta is associated with distinct microorganism-specific inflammatory protein profiles in the newborn blood specimens. We also provide evidence thatLactobacillusreduces inflammatory responses in newborns. Our data support the concept that targeting of placental colonization by specific drugs or probiotics during early pregnancy holds promise for preventing not only preterm birth but also subsequent and long-lasting, inflammation-provoked late sequelae.