bluuebunny/crossref_metadata_2025 huggingface dataset:
Interleukin‐ 28B: a prognostic marker in interferon based therapy of chronic HCV patients of the Pakistan with variable treatment response
Authors: Resham Saleha , Manzoor Sobia , Imran Muhammad , Saalim Muhammad , Naseem Sidrah , Azam Sikandar
Published: July 2015

Unfortunately Pakistan carries one of the world's highest burdens of chronic hepatitis along with mortality due to liver failure and hepatocellular carcinoma. Scientists after extensive research have come up with this outcome that host genetics play a vital role in dictating the type of treatment response produced by the patients. In 2009, a genome wide association study (GWAS) revealed that genetic variants in close proximity to the IL28B (IFNL3) gene predicted greater likelihood of achieving sustained virological response (SVR) following treatment with pegylated IFN‐alpha (peg INF‐α) and ribavirin. IL28B (rs12979860 and rs8099917) single nucleotide polymorphisms (SNPs) have been recently found among the Pakistani population associated with response to chronic HCV infection INF‐α + ribavirin therapy. Therefore, this study was aimed to investigate the IL‐28B protein levels in the HCV infected patients. The findings showed that the serum IL28B protein level was higher in HCV infected patients as compared to healthy controls (7.743 ± 1.519 pg/mL versus 1.600 ± 0.06054 [mean ± SEM], p < 0.05). When the chronic hepatitis C (CHC) patients were further categorized into SVR and NR (non‐responders) on the basis of treatment outcomes, the mean IL28B protein level was higher in NRs (15.54 ± 3.609) than SVRs (4.259 ± 0.3405). Thus, there was a significant correlation between IL28B protein level in varied treatment response (p < 0.05). However, the findings can lead us to propose that IL28B could be used as a prognostic marker. It can help the clinicians to take better pre‐informed decisions whether to take combinational therapy of peg IFN ± ribavirin or not. This will in turn prove beneficial for the patient by saving patients’ health, treatment cost and undesirable treatment side effects.
Hepatitis E virus in patients with decompensated chronic liver disease: a prospective UK/French study
Authors: Blasco‐Perrin H. , Madden R. G. , Stanley A. , Crossan C. , Hunter J. G. , Vine L. , Lane K. , Devooght‐Johnson N. , Mclaughlin C. , Petrik J. , Stableforth B. , Hussaini H. , Phillips M. , Mansuy J. M. , Forrest E. , Izopet J. , Blatchford O. , Scobie L. , Peron J. M. , Dalton H. R.
Published: July 2015

Background

In developed countries, hepatitis E is a porcine zoonosis caused by hepatitis E virus (HEV) genotype 3. In developing countries, hepatitis E is mainly caused by genotype 1, and causes increased mortality in patients with pre‐existing chronic liver disease (CLD).

Aim

To determine the role of HEV in patients with decompensated CLD.

Methods

Prospective HEV testing of 343 patients with decompensated CLD at three UK centres and Toulouse France, with follow‐up for 6 months or death. IgG seroprevalence was compared with 911 controls.

Results

11/343 patients (3.2%) had acute hepatitis E infection, and three died. There were no differences in mortality (27% vs. 26%, OR 1.1, 95% CI 0.28–4.1), age (P = 0.9), bilirubin (P = 0.5), alanine aminotransferase (P = 0.06) albumin (P = 0.5) or international normalised ratio (P = 0.6) in patients with and without hepatitis E infection. Five cases were polymerase chain reaction (PCR) positive (genotype 3). Hepatitis E was more common in Toulouse (7.9%) compared to the UK cohort (1.2%, P = 0.003). HEV IgG seroprevalence was higher in Toulouse (OR 17, 95% CI 9.2–30) and Truro (OR 2.5, 95% CI 1.4–4.6) than in Glasgow, but lower in cases, compared to controls (OR 0.59, 95% CI 0.41–0.86).

Conclusions

Hepatitis E occurs in a minority of patients with decompensated chronic liver disease. The mortality is no different to the mortality in patients without hepatitis E infection. The diagnosis can only be established by a combination of serology and PCR, the yield and utility of which vary by geographical location.
Pb and Sr Isotopes and the Provenance of the Painting Materials of Cornelius Krieghoff in 19th‐Century Canada
Authors: Stevenson R. K. , Moffatt E. A. , Corbeil M.‐C. , Poirier A.
Published: July 2015

Radiogenic lead and strontium isotope data are presented for lead‐ and calcium carbonate/barium sulphate‐containing paint and ground samples from 15 paintings, executed between 1844 and 1871, by 19th‐century Canadian artist Cornelius Krieghoff. Like many artists of this era, Krieghoff used lead‐based pigments such as lead white, chrome yellow and Naples yellow, and extenders such as calcium carbonate and barium sulphate. The lead isotope analyses of the majority of these pigments are consistent with the isotopic compositions of lead mined from European lead deposits in England and/or Germany. However, three samples from Krieghoff's early career yield lead isotope compositions that are much more radiogenic than European sources. The lead isotope compositions of these three samples are consistent with the addition of a more radiogenic lead component that is similar to the lead derived from North American lead deposits in Missouri and Illinois (Mississippi Valley Pb–Zn type deposits). The strontium isotope compositions of the extenders suggest that the raw materials for calcium carbonate or barium sulphate extenders were largely derived from Palaeozoic to modern‐day marine environments. This study shows that pigments manufactured from North American lead were being incorporated into Canadian paintings as early as 1844.
Characterization of a Historical Cannonball from the Fortress of San Juan De Ulúa Exposed to a Marine Environment
Authors: Hernandez M. , Hernandez‐Escampa M. , Abreu C. , Uruchurtu J. , Bethencourt M. , Covelo A.
Published: July 2015

Metallurgical analyses and chemical characterizations were carried out on historical cannonballs from the Fortress of San Juan de Ulúa, Veracruz, México. Cannonballs dating from the 18th and 19th centuries share metallurgical characteristics similar to those of material coming from a shipment of ammunition found in the wreck of a sunken French ship from the battle of Trafalgar. The analyses show that the base material is grey cast iron with a carbon equivalent of 4.94 and a ferritic–perlitic matrix, in which the high phosphorus content has led to the formation of iron phosphide compounds in conjunction with a homogeneous distribution of carbon graphite flakes of Type C. In addition, corrosion products from samples revealed the presence of various crystalline iron compounds (X‐ray diffraction), mostly highly chlorinated iron compounds identified as akaganeite. X‐ray fluorescence identified various characteristics of the corrosion products as a function of the sampling depth. FT–IR spectroscopy revealed that the main difference between the corrosion products (internal and external) is determined by the number of organic species. Differential scanning calorimetry corroborated that these corrosion products are thermally stable compounds at elevated temperatures.
14C and Maya Long Count Dates: Using Bayesian Modelling to Develop Robust Site Chronologies
Authors: Aldana Y V. G.
Published: July 2015

Bayesian statistics has now demonstrated its strong utility in archaeology, specifically through software that conditions radiocarbon data. Only recently has this technology been applied within Maya archaeology, however, in part because the Maya calendar provides a much greater resolution in dating archaeological events than is possible with radiocarbon data. The Long Count in particular allows for the assignment of some events relative to each other, accurate to the day. In this paper, a new approach is presented to incorporate robust records of both in the same Bayesian analysis through the OxCal software. The results do call for a reconsideration of the earliest radiocarbon studies in the Maya area from the 1960s, as well as the latest attempts to corroborate the currently popular calendar correlation known as the GMT. This new study demonstrates the value of the approach and corroborates the 1σ accuracy of the GMT, while at the same time opening up the possibility of revision by 20 or more years.
Ochre Provenance and Procurement Strategies During The Middle Stone Age at Diepkloof Rock Shelter, South Africa
Authors: Dayet L. , Le Bourdonnec F.‐X. , Daniel F. , Porraz G. , Texier P.‐J.
Published: July 2015

Usually referred to in archaeological contexts simply as ‘ochre’, ferruginous rocks were commonly used during the Middle Stone Age (MSA) in South Africa. While ochre use by early modern humans has often been interpreted as reflecting complex behaviours, related procurement strategies and selection criteria remain poorly documented. Eight ochre sources from the surroundings of Diepkloof rock shelter in South Africa and 28 ochre pieces from the site's MSA levels were studied by XRD, ICP–OES and ICP–MS. Mineralogical and geochemical data demonstrate that ochre was both locally procured and transported to the site from more distant sources. Here, we investigate the reasons underlying the choice of particular local and non‐local ochre sources exploited at Diepkloof, emphasizing differences in their physico‐chemical properties. Regardless of the motivations behind ochre selection, our data shed new light on the behavioural complexity of MSA societies and suggest that ochre procurement strategies may be independent of subsistence concerns.
Physiological roles of the angiogenic factors during posthatching development period and adults in the quail lung
Authors: Sağsöz Hakan , Liman Narin , Alan Emel
Published: July 2015

The bronchus and vasculature form an intrinsic functional component of the avian lung, and its growth must be tightly regulated and coordinated by lung epithelial and endothelial development. Vascular endothelial growth inhibitor (VEGI), vascular endothelial growth factor (VEGF) and its receptors (flk1/KDR, flt1/fms, flt4) are required for epithelial and endothelial cell survival and apoptosis. Especially, VEGF and its receptors are critical for the development of the lung and serve as a maintenance factor during adult life. To determine the function of VEGI, VEGF and its receptors in the posthatching lung development, we revealed its expression and localization using by immunohistochemical procedure. VEGI, VEGF and its receptors were observed in the structural components of the bronchi, atria and air capillaries, as well as in the pulmonary blood vessels throughout the posthatching development period. On the other hand, immunostaining for VEGI, VEGF and its receptors was faintly detected in the glands of the secondary bronchi. Furthermore, it was determined that the secondary bronchial and atrial muscles did not display VEGF immunoreactions. Our results showed that VEGF and its receptors (flt1/fms, flk1/KDR and flt4) and VEGI were expressed at varying intensity by different cell groups. Therefore, they are also required for the development of the lung component during posthatching period.
Episodic foresight and schizophrenia
Authors: Lyons Amanda D. , Henry Julie D. , Rendell Peter G. , Robinson Gail , Suddendorf Thomas
Published: July 2015

Objective

People with schizophrenia have difficulty engaging in specific future‐directed thoughts and behaviours, such as generating phenomenological characteristics of future events (a component of episodic foresight), and executing directed preparatory behaviours (a component of prospective memory). However, it remains unclear whether they also exhibit difficulties using episodic foresight to appropriately guide future‐directed behaviours.

Method

People with schizophrenia and non‐clinical controls were administered a behavioural measure that met strict criteria for assessing episodic foresight. In keeping with our focus on the functional application of foresight, this measure required participants to identify a problem, self‐generate a resolution, and execute the appropriate future‐directed intention.

Results

Relative to controls, people with schizophrenia were less likely to spontaneously acquire items that would later allow a problem to be solved, and were also less likely to subsequently use these items to solve the problems. There was no interaction between group and task, indicating that these two components of foresight were disrupted to an equivalent degree. In the clinical (but not the control) group, item acquisition and item use were correlated with general cognitive capacity. No significant associations with clinical variables emerged.

Conclusion

The capacity to apply episodic foresight in a functionally adaptive way is disrupted in schizophrenia and may at least partially reflect broader cognitive dysfunction. Future work is now needed to clarify the implications of these difficulties in everyday life, as well as how these difficulties might be remediated.

Practitioner points

People with schizophrenia have known difficulties with episodic foresight, and it now appears that those difficulties extend to the performance of foresightful preparatory behaviours.

Because preparatory behaviours are central to routine and adaptive planning, difficulties with episodic foresight may contribute to or be a result of some of the functional difficulties experienced by people with schizophrenia.

Further research is needed to determine whether interventions might be developed for people with reduced episodic foresight.

Interventions may include the use of remedial tools that support and encourage the performance of foresightful behaviour, or cognitive training programs that actively improve the ability and propensity to exercise foresight independently.
Accurate, inaccurate, or biased teacher expectations: Do Dutch teachers differ in their expectations at the end of primary education?
Authors: Timmermans Anneke C. , Kuyper Hans , van der Werf Greetje
Published: July 2015

Background

In several tracked educational systems, realizing optimal placements in classes in the first year of secondary education depends on the accuracy of teacher expectations.

Aims

The aim of this study was to investigate between‐teacher differences in their expectations regarding the academic aptitude of their students.

Sample

The sample consisted of 500 teachers (classes) who provided their expectations of 7,550 students in the final grade of Dutch primary education.

Methods

We analysed the extent to which teachers differed in their expectations and in what contexts their expectations were biased, using multilevel random slope models.

Results

Multilevel analysis showed teacher expectation bias to be related to gender and socio‐ethnic background of students. The differences among teachers in expectations for Turkish, Moroccan, and other foreign students with low‐educated parents were larger than the average teacher expectation bias for these groups in the sample. When student characteristics were controlled for, we found that the teachers in our sample had higher expectations for students in high‐performing classes or classes with only a small proportion of students from low‐SES families. Teacher expectation bias for demographic groups, however, was found to be independent of the class population.

Conclusions

The results indicate the importance of the teacher and the necessity of using multilevel models when investigating the complex nature of between‐teacher differences in expectations of student performance.
Botulinum toxin (OnabotulinumtoxinA) in the male non‐neurogenic overactive bladder: clinical and quality of life outcomes
Authors: Habashy David , Losco Giovanni , Tse Vincent , Collins Ruth , Chan Lewis
Published: July 2015

Objective

To assess the efficacy of OnabotulinumtoxinA (BTXA) injections in men with drug‐refractory non‐neurogenic overactive bladder (NNOAB).

Patients and Methods

A total of 43 men received BTXA injections for NNOAB from 2004 to 2012. Patient Global Impression of Improvement (PGI‐I) score was obtained. For men with wet NNOAB, change in number of pads per day was also assessed.

Results

Forty‐three men with a mean age of 69 (range 37–85) received at least one injection. Of the 43 men, 20 (47%) had prior prostate surgery: 11 had radical prostatectomy (RP) and nine had transurethral resection of prostate (TURP). Overall, average PGI‐I score was 2.7. Comparing PGI‐I score in men who had prior prostate surgery with men who have not: 2.6 ± 0.5 vs 2.8 ± 0.5 respectively (average ± 95% CI), P = 0.6. Comparing PGI‐I score in men who had previous TURP with men who had previous RP: PGI‐I score: 3.3 ± 0.8 vs 2.0 ± 0.5 respectively, P < 0.05. Men who had RP experienced a reduction in pad use (from 3.5 ± 1.7 to 1.6 ± 0.9 pads/day, P < 0.05) while this was not the case amongst men who had TURP (from 1.7 ± 1.5 to 1.4 ± 1.5 pads/day, P = 0.4).

Conclusion

Overall, BTXA injection in men with drug‐refractory NNOAB does provide a symptomatic benefit. Amongst men who have had prior prostate surgery, men who have had RP experience a greater benefit than men who have had TURP, both in regards to PGI‐I score and pad use.
Fen ecosystem responses to water‐level fluctuations during the early and middle Holocene in central Europe: a case study from Wilczków, Poland
Authors: Płóciennik Mateusz , Kruk Andrzej , Forysiak Jacek , Pawłowski Dominik , Mianowicz Kamila , Elias Scott , Borówka Ryszard K. , Kloss Marek , Obremska Milena , Coope Russell , Krąpiec Marek , Kittel Piotr , Żurek Sławomir
Published: July 2015

This paper presents a palaeoenvironmental reconstruction of the Wilczków fen (central Poland). The fen developed in an inactive valley at the onset of the Holocene (~11 ka BP) and peat accumulation lasted until 5.7 ka BP. Multi‐proxy reconstructions were made on the basis of palaeobotanical, cladoceran, chironomid, beetle and geochemical analyses. A Kohonen self‐organizing map (SOM, unsupervised artificial neural network) of the biotic sequence distinguished four stages of fen history. Stage X1 (11.0–10.7 ka BP) was relatively wet and cool. Organic matter started to accumulate but the habitat conditions remained unstable. Moss, sedge and fern communities then developed. Sedimentary changes reveal an intensive groundwater supply at that time. Numerous and diverse chironomid and cladoceran subfossils indicate nearly permanent aquatic conditions. During stage Y1 (10.6–9.2 ka BP) conditions were dry and the upper peat layer desiccated. Cladocera nearly disappeared whereas chironomids were represented by semi‐terrestrial and predatory (Tanypodinae) species. Conditions started to be more reducing. All the remaining samples belonged to the interweaving stages X2 and Y2. Stage Y2 (mostly 9.1–7.3 and 6.0–5.7 ka BP) was also dry but humidity increased towards the top. Oxidizing conditions occurred and the pH became more alkaline, favouring Cladium mariscus. The basin received mostly allochthonous matter input at that time. Stage X2 (mostly 6.8–6.1 ka BP) was humid and warm. The groundwater supply remained low but there was an increase in precipitation, changing local conditions to ombrotrophic. Species‐rich chironomid and cladoceran communities were associated with temporary pools. Finally, conditions returned to those characteristic of stage Y2. The presented reconstruction documents long‐term abiotic and biotic changes determined by water supply, including groundwater outflow, which have rarely been detected at a multi‐proxy scale. We show that inactivated valley fens are sensitive to climate‐driven hydrological fluctuations. Kohonen neural networks appear to be a promising method for analysing variability in multi‐proxy data.
The expanding role of immunopharmacology: IUPHAR Review 16
Authors: Tiligada Ekaterini , Ishii Masaru , Riccardi Carlo , Spedding Michael , Simon Hans‐Uwe , Teixeira Mauro Martins , Landys Chovel Cuervo Mario , Holgate Stephen T , Levi‐Schaffer Francesca
Published: July 2015

Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research have made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen‐specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non‐typical immune system‐driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar (http://iuphar.us/index.php/sections‐subcoms/immunopharmacology) is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR, http://iuphar.us/). ImmuPhar provides a unique international expert‐lead platform that aims to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.
The D1CT‐7 mouse model of Tourette syndrome displays sensorimotor gating deficits in response to spatial confinement
Authors: Godar Sean C , Mosher Laura J , Strathman Hunter J , Gochi Andrea M , Jones Cori M , Fowler Stephen C , Bortolato Marco
Published: July 2015

Background and Purpose

The D1CT‐7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic‐like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT‐7 mice to two critical components of TS pathophysiology: the exacerbation of tic‐like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics.

Experimental Approach

D1CT‐7 and wild‐type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic‐like behaviours and other spontaneous responses were measured. SC‐exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS‐related behaviours, including open‐field locomotion, novel object exploration and social interaction and compared with non‐confined counterparts.

Key Results

SC produced a marked increase in corticosterone concentrations in both D1CT‐7 and WT mice. In D1CT‐7, but not WT mice, SC exacerbated tic‐like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT‐7 mice. Both tic‐like behaviours and PPI impairments in SC‐exposed D1CT‐7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism.

Conclusions and Implications

These findings collectively support the translational and construct validity of D1CT‐7 mice with respect to TS.

Linked Articles

This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc
Alterations in perivascular innervation function in mesenteric arteries from offspring of diabetic rats
Authors: de Queiroz D B , Sastre E , Caracuel L , Callejo M , Xavier F E , Blanco‐Rivero J , Balfagón G
Published: July 2015

Background and Purpose

We have reported that exposure to a diabetic intrauterine environment during pregnancy increases blood pressure in adult offspring, but the mechanisms involved are not completely understood. This study was designed to analyse a possible role of perivascular sympathetic and nitrergic innervation in the superior mesenteric artery (SMA) in this effect.

Experimental Approach

Diabetes was induced in pregnant Wistar rats by a single injection of streptozotocin. Endothelium‐denuded vascular rings from the offspring of control (O‐CR) and diabetic rats (O‐DR) were used. Vasomotor responses to electrical field stimulation (EFS), NA and the NO donor DEA‐NO were studied. The expressions of neuronal NOS (nNOS) and phospho‐nNOS (P‐nNOS) and release of NA, ATP and NO were determined. Sympathetic and nitrergic nerve densities were analysed by immunofluorescence.

Key Results

Blood pressure was higher in O‐DR animals. EFS‐induced vasoconstriction was greater in O‐DR animals. This response was decreased by phentolamine more in O‐DR animals than their controls. L‐NAME increased EFS‐induced vasoconstriction more strongly in O‐DR than in O‐CR segments. Vasomotor responses to NA or DEA‐NO were not modified. NA, ATP and NO release was increased in segments from O‐DR. nNOS expression was not modified, whereas P‐nNOS expression was increased in O‐DR. Sympathetic and nitrergic nerve densities were similar in both experimental groups.

Conclusions and Implications

The activity of sympathetic and nitrergic innervation is increased in SMA from O‐DR animals. The net effect is an increase in EFS‐induced contractions in these animals. These effects may contribute to the increased blood pressure observed in the offspring of diabetic rats.
Down‐regulation of IL‐8 by high‐dose vitamin D is specific to hyperinflammatory macrophages and involves mechanisms beyond up‐regulation of DUSP1
Authors: Dauletbaev N , Herscovitch K , Das M , Chen H , Bernier J , Matouk E , Bérubé J , Rousseau S , Lands L C
Published: July 2015

Background and Purpose

There is current interest in vitamin D as a potential anti‐inflammatory treatment for chronic inflammatory lung disease, including cystic fibrosis (CF). Vitamin D transcriptionally up‐regulates the anti‐inflammatory gene DUSP1, which partly controls production of the inflammatory chemokine IL‐8. IL‐8 is overabundant in CF airways, potentially due to hyperinflammatory responses of CF macrophages. We tested the ability of vitamin D metabolites to down‐regulate IL‐8 production in CF macrophages.

Experimental Approach

CF and healthy monocyte‐derived macrophages (MDM) were treated with two vitamin D metabolites, 25‐hydroxyvitamin D3 (25OHD3) and 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3), or paricalcitol, synthetic analogue of 1,25(OH)2D3. 25OHD3 was tested at doses of 25–150 nM, whereas 1,25(OH)2D3 and paricalcitol at doses of up to 100 nM. IL‐8 was stimulated by bacterial virulence factors. As potential anti‐inflammatory mechanism of vitamin D metabolites, we assessed up‐regulation of DUSP1.

Key Results

MDM from patients with CF and some healthy donors showed excessive production of stimulated IL‐8, highlighting their hyperinflammatory phenotype. Vitamin D metabolites down‐regulated stimulated IL‐8 only in those hyperinflammatory MDM, and only when used at high doses (>100 nM for 25OHD3, or >1 nM for 1,25(OH)2D3 and paricalcitol). The magnitude of IL‐8 down‐regulation by vitamin D metabolites or paricalcitol was moderate (∼30% vs. >70% by low‐dose dexamethasone). Transcriptional up‐regulation of DUSP1 by vitamin D metabolites was seen in all tested MDM, regardless of IL‐8 down‐regulation.

Conclusions and Implications

Vitamin D metabolites and their analogues moderately down‐regulate IL‐8 in hyperinflammatory macrophages, including those from CF. This down‐regulation appears to go through DUSP1‐independent mechanisms.
Tectonic and oceanographic control of sedimentary patterns in a small oceanic basin: Dove Basin (Scotia Sea, Antarctica)
Authors: Pérez Lara F. , Maldonado Andrés , Hernández‐Molina Francisco Javier , Lodolo Emanuele , Bohoyo Fernando , Galindo‐Zaldívar Jesús
Published: July 2015

Dove Basin, a small oceanic domain located within the southern Scotia Sea, evidences a complex tectonic evolution linked to the development of the Scotia Arc. The basin also straddles the junction between the main Southern Ocean water masses: the Antarctic Circumpolar Current (ACC), the Southeast Pacific Deep Water (SPDW) and the Weddell Sea Deep Water (WSDW). Analysis of multichannel seismic reflection profiles, together with swath bathymetry data, reveals the main structure and sediment distribution of the basin, allowing a reconstruction of the tectonostratigraphic evolution of the basin and assessment of the main bottom water flows that influenced its depositional development. Sediment dispersed in the basin was largely influenced by gravity‐driven transport from adjacent continental margins, later modified by deep bottom currents. Sediments derived from melting icebergs and extensive ice sheets also contributed to a fraction of the basin deposits. We identify four stages in the basin evolution which – based on regional age assumptions – took place during the early Miocene, middle Miocene, late Miocene–early Pliocene and late Pliocene–Quaternary. The onsets of the ACC flow in Dove Basin during the early Miocene, the WSDW flow during the middle Miocene, and the SPDW during the late Miocene were influenced by tectonic events that facilitated the opening of new oceanic gateways in the region. The analysis of Dove Basin reveals that tectonics is a primary factor influencing its sedimentary stacking patterns, the structural development of new oceanic gateways permitting the inception of deep‐water flows that have since controlled the sedimentary processes.
How Should Ecologists Define Sampling Effort? The Potential of Procrustes Analysis for Studying Variation in Community Composition
Authors: Saito Victor S. , Fonseca‐Gessner Alaide A. , Siqueira Tadeu
Published: July 2015

Appropriate sampling effort is crucial for ecologists. Procrustes analysis can be used to tackle this question by quantifying the match between subsamples and the complete dataset. We used stream macroinvertebrates to show how sampling design can be optimized by reducing the number of subsamples and increasing the number of sites.
A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T‐cell leukemia/lymphoma
Authors: Ishitsuka Kenji , Utsunomiya Atae , Katsuya Hiroo , Takeuchi Shogo , Takatsuka Yoshifusa , Hidaka Michihiro , Sakai Tatsunori , Yoshimitsu Makoto , Ishida Takashi , Tamura Kazuo
Published: July 2015

Adult T‐cell leukemia/lymphoma (ATL) is a malignancy of peripheral T‐lymphocytes with a poor prognosis. This multicenter, two‐stage, single‐arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression‐free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17‐31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression‐free survival (PFS) was 38 (95% CI; 18–106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.
STX11 functions as a novel tumor suppressor gene in peripheral T‐cell lymphomas
Authors: Yoshida Noriaki , Tsuzuki Shinobu , Karube Kennosuke , Takahara Taishi , Suguro Miyuki , Miyoshi Hiroaki , Nishikori Momoko , Shimoyama Masanori , Tsukasaki Kunihiro , Ohshima Koichi , Seto Masao
Published: July 2015

Peripheral T‐cell lymphomas (PTCL) are a heterogeneous group of non‐Hodgkin lymphomas with poor prognosis. Their molecular pathogenesis has not been entirely elucidated. We previously showed that 6q24 is one of the most frequently deleted regions in primary thyroid T‐cell lymphoma. In this study, we extended the analysis to other subtypes of PTCL and performed functional assays to identify the causative genes of PTCL that are located on 6q24. Genomic loss of 6q24 was observed in 14 of 232 (6%) PTCL cases. The genomic loss regions identified at 6q24 always involved only two known genes, STX11 and UTRN. The expression of STX11, but not UTRN, was substantially lower in PTCL than in normal T‐cells. STX11 sequence analysis revealed mutations in two cases (one clinical sample and one T‐cell line). We further analyzed the function of STX11 in 14 cell lines belonging to different lineages. STX11 expression only suppressed the proliferation of T‐cell lines bearing genomic alterations at the STX11 locus. Interestingly, expression of a novel STX11 mutant (p.Arg78Cys) did not exert suppressive effects on the induced cell lines, suggesting that this mutant is a loss‐of‐function mutation. In addition, STX11‐altered PTCL not otherwise specified cases were characterized by the presence of hemophagocytic syndrome (67% vs 8%, P = 0.04). They also tended to have a poor prognosis compared with those without STX11 alteration. These results suggest that STX11 plays an important role in the pathogenesis of PTCL and they may contribute to the future development of new drugs for the treatment of PTCL.
Design, Synthesis and Molecular Docking Studies of Novel Indole–Pyrimidine Hybrids as Tubulin Polymerization Inhibitors
Authors: Hu Meng‐Jin , Zhang Bei , Yang Hai‐Kui , Liu Yang , Chen Yu‐Rong , Ma Tian‐Zhu , Lu Ling , You Wen‐Wei , Zhao Pei‐Liang
Published: July 2015

A series of novel hybrids of indole–pyrimidine‐containing piperazine moiety were designed, synthesized and evaluated for their antiproliferative and tubulin polymerization inhibitory activities. The results indicated that most of these compounds possessed significant cytotoxic potency against four cancer cell lines, HT‐29, A549, MDA‐MB‐231 and MCF‐7. Particularly, the most promising compound 34 showed more potent and broad‐spectrum cytotoxic activities with the IC50 values ranged from 5.01 to 14.36 μm against A549, MDA‐MB‐231 and MCF‐7 cell lines. Meanwhile, 34 also displayed the most potent tubulin polymerization inhibitory activity with IC50 value of 11.2 μm. Furthermore, molecular docking analysis demonstrated 34 interacts and binds efficiently with the tubulin protein at the colchicine‐binding site. It was worth noting that the compound did not affect the normal human embryonic kidney cells, HEK‐293. These results suggest that this novel class of indole–pyrimidine hybrids may have potential to be developed as new a class of tubulin polymerization inhibitors.
Severe congenital malformations, family functioning and parents' separation/divorce: a longitudinal study
Authors: Brenner M. , Côté S. M. , Boivin M. , Tremblay R. E.
Published: July 2015

Background

We aim to explore the association of a severe congenital malformation (SCM) with postnatal family functioning and parents' separation/divorce and to examine if this association might be moderated by birth order of the child and parental level of education. SCM refers to malformations that, without medical intervention, cause handicap or death.

Methods

Using the Quebec Longitudinal Study of Child Development, an ongoing population‐based birth cohort study initiated in 1998, we compared 1675 families of children with and without a SCM to identify if having a child with a SCM was associated with maternal perception of family functioning. We examined if an SCM was associated with parents' separation and examined parents' education level and birth order of the children to evaluate whether these factors had any moderating effect on the results.

Results

There were no significant differences in family functioning between families with and without a SCM child at 5 and 17 months. At 5 months, family functioning was significantly better (P = 0.03) for families with a SCM firstborn child than for families with a SCM child that is not firstborn. For parental separation, no significant differences were observed at 5 and 29 months and 4 years. No significant moderating effects were observed for birth order and parental education on parental separation.

Conclusions

Families of children with a SCM do not appear to be at higher risk of family dysfunction within the first 17 months after birth nor of parental separation within the first 4 years after birth. Family functioning tends to be worst in families where the child with SCM is the second or subsequent child born.
Development of Inductive Generalization
Authors: Fisher Anna V.
Published: July 2015

Inductive generalization (i.e., making generalizations from instances) is ubiquitous in human cognition. In the developmental literature, researchers have proposed two theoretical accounts of this important process: a naïve theory account and a similarity‐based account. However, neither of these theoretical accounts explains marked developmental changes in inductive generalization with familiar categories that have been documented in prior research. In this article, I describe briefly a revised version of the similarity‐based account of inductive generalization that can explain individual variability as well as developmental change in inductive generalization with familiar categories. I also highlight several unresolved issues in the study of development of inductive generalization.
Oral mucosal lesions’ impact on oral health‐related quality of life in preschool children
Authors: de Oliveira Luísa Jardim Corrêa , Torriani Dione Dias , Correa Marcos Britto , Peres Marco Aurélio , Peres Karen Glazer , Matijasevich Alicia , dos Santos Iná da Silva , Barros Aluisio J.D. , Demarco Flávio Fernando , Tarquinio Sandra Beatriz Chaves
Published: July 2015

Objectives

The aim of this study was to assess the prevalence of oral mucosal lesions and their impact on oral health‐related quality of life (OHRQoL) in children aged 5 years.

Methods

A sample of 1118 children from Pelotas’ birth cohort, born in 2004 (response rate of 85.8%), were selected to participate in the study. Data were collected using a questionnaire applied to mothers and from the oral examinations of the children. OML were identified by type, site, and size. Early Childhood Oral Health Impact Scale (ECOHIS) was used to assess caregivers’ perception on children's OHRQoL. Descriptive, bivariate, and multivariate Poisson regression analyses were carried out, considering the impact on OHRQoL (total ECOHIS score) as the outcome.

Results

The prevalence of the OML was 30.1% (95% CI 27.5–32.9). Ulcers were the more prevalent type of lesion (29.4%), and the most affected site was the gums (31.0%). In bivariate analysis, there was a positive association between the presence of OML and OHRQoL impact measured by the following: mean overall score of ECOHIS (P < 0.001); extent (P < 0.001); prevalence (P = 0.030); and intensity (P = 0.010). After adjustments for sociodemographic and oral health variables, children with OML presented higher impact on OHRQoL [rate ratio (RR) 1.38 95% CI 1.11; 1.72] comparing with their counterparts. Analyzing specific domains, children with OML also presented higher impact on children symptoms (RR 1.46 95% CI 1.20; 1.66) and family functional (RR 3.14 95% CI 1.59; 6.22) domains.

Conclusion

Almost one‐third of children presented with oral mucosal lesions, and these lesions impaired children's oral health‐related quality of life.
Pathogenesis of drug allergy – current concepts and recent insights
Authors: Schnyder B. , Brockow K.
Published: July 2015

Drug hypersensitivity reactions (DHRs) may be caused by immunologic and non‐immunologic mechanisms. According to the World Allergy Organization, drug allergy (DA) encompasses the subgroup of immunologic DHRs which are mediated either by specific antibodies or specific T lymphocytes. Due to the immunologic memory, DA reactions bear an increased risk for dramatically enhanced reactions on re‐exposure. Some current concepts of DA were described decades ago. Drug allergies to soluble macromolecular protein drugs such as biopharmaceuticals are predominantly T cell‐dependent drug‐specific antibody responses leading to IgE‐or IgG‐mediated allergy. However, most drugs are too small to be directly recognized by specific B and T cells. Immune reactions to low‐molecular drugs have been explained by the hapten model: a hapten drug can bind covalently to soluble autologous proteins (e.g. serum albumin). Resulting compounds may then be recognized by matching B cell receptors (BCRs) and induce a specific T cell‐dependent IgE‐or IgG‐antibody production. Drug haptens may bind to extra‐ or intracellular proteins, which are processed and presented by various professional antigen‐presenting cells (APCs). Depending on the APC, they may induce not only specific antibody production, but also non‐immediate T cell‐mediated DA. More recently, a supplementary effector mechanism for non‐immediate DA to low‐molecular drugs has been described, namely the pharmacological interaction of native low‐molecular drugs with immune receptors (p‐i‐concept). Low‐molecular drugs may directly and reversibly attach to immune receptors. These non‐covalent interactions may modify the affinity between autologous major histocompatibility complex (MHC), presented peptides and specifically primed T cell receptors (TCRs) and thereby stimulate T cells. A special type of p‐i‐reaction has been recently described between the antiviral drug abacavir and the F pocket of HLA‐B*57:01. This interaction causes an alteration of the MHC‐presented self‐peptide repertoire and may consecutively lead to a kind of auto‐reactivity. Such types of reactions can explain the strong MHC‐HLA associations which have been found for some T cell‐mediated DHRs.
T regulatory cell phenotypes in peripheral blood and bronchoalveolar lavage from non‐asthmatic and asthmatic subjects
Authors: Baatjes A. J. , Smith S. G. , Watson R. , Howie K. , Murphy D. , Larché M. , Denburg J. A. , Inman M. D. , O'Byrne P. M.
Published: July 2015

Background

An unresolved issue in T regulatory cells' cell biology is the lack of consensus on phenotypic markers that accurately define the natural Treg (nTreg) population.

Objectives

To examine nTreg frequency and functional capacity in healthy controls and their frequency in asthmatic subjects using three different phenotypic strategies. We hypothesized that phenotypically different nTreg are quantitatively and functionally different.

Methods

Thirty‐four healthy, non‐asthmatic and 17 asthmatic subjects were studied. Three nTreg phenotypes were defined as follows: nTreg1 (CD4+CD25+Foxp3+), nTreg2 (CD4+CD25+CD127lowFoxp3+), and nTreg3 (CD4+CD25highFoxp3+). The flow cytometric determination of nTreg frequency in peripheral blood (PB) and bronchoalveolar lavage (BAL) was performed using fluorescently labelled antibodies. Peripheral blood nTreg functional capacity was assessed using a CFSE‐based suppression assay.

Results

There was a significantly lower frequency of PB nTreg3 compared to nTreg2 and nTreg1 (P < 0.05). Both nTreg2 and nTreg3 had a significantly greater suppressive capacity than nTreg1 at T responder (Tresp) to nTreg ratios of 16 : 1 up to 1 : 1 (P < 0.01). Asthmatics exhibited a significantly lower PB nTreg3 and nTreg1 frequency than healthy controls (P < 0.05). There were no differences between healthy controls and asthmatic subjects when comparing BAL nTreg frequency.

Conclusions and Clinical Relevance

Phenotypically different nTreg subsets are quantitatively and functionally different and are variably observed in asthma. The CD4+CD25highFoxp3+ phenotype was the least frequent, but demonstrated the greatest suppression, and was significantly lower in PB of asthmatic subjects. Consequently, it is imperative that nTreg phenotypes be clearly defined and that the interpretation of their frequency and function be phenotype specific.
Epstein–Barr virus-specific CD8+ T lymphocytes from diffuse large B cell lymphoma patients are functionally impaired
Authors: Cárdenas D , Vélez G , Orfao A , Herrera M V , Solano J , Olaya M , Uribe A M , Saavedra C , Duarte M , Rodríguez M , López M , Fiorentino S , Quijano S
Published: July 2015

Epstein–Barr virus (EBV) is a persistent virus with oncogenic capacity that has been implicated in the development of aggressive B cell lymphomas, primarily in immunosuppressed individuals, although it can be present in immunocompetent individuals. Changes in the function and clonal diversity of T lymphocytes might be implied by viral persistence and lymphoma development. The aim of the present study was to evaluate the frequency, phenotype, function and clonotypical distribution of EBV-specific T cells after peripheral blood stimulation with a virus lysate in newly diagnosed patients with diffuse large B cell lymphoma (DLBCL) aged more than 50 years without prior histories of clinical immunosuppression compared with healthy controls. Our results showed impaired EBV-specific immune responses among DLBCL patients that were associated primarily with decreased numbers of central and effector memory CD8+ T lymphocytes. In contrast to healthy controls, only a minority of the patients showed CD4+/tumour necrosis factor (TNF)-α+ T cells expressing T cell receptor (TCR)-Vβ17 and CD8+/TNF-α+ T cells with TCR-Vβ5·2, Vβ9 and Vβ18 in response to EBV. Notably, the production of TNF-α was undetectable among TCR-Vβ5·3+, Vβ11+, Vβ12+, Vβ16+ and Vβ23+ CD8+ T cells. In addition, we observed decreased numbers of CD4+/TNF-α+ and CD8+/TNF-α+, CD8+/interleukin (IL)-2+ and CD8+/TNF-α+/IL-2+ T lymphocytes in the absence of T cells capable of producing TNF-α, IL-2 and IFN-γ after EBV stimulation simultaneously. Moreover, DLBCL patients displayed higher IL-10 levels both under baseline conditions and after EBV stimulation. These findings were also observed in patients with positive EBV viral loads. Prospective studies including a large number of patients are needed to confirm these findings.
Neuron–microglia interactions in neuroinflammation
Authors: Mizuno Tetsuya
Published: July 2015

Neuron–microglia interactions play pivotal roles in the development and maintenance of the central nervous system. Microglia promote synaptic pruning in the developing brain and survey neuronal activity in the mature brain. Neurons regulate microglial function through the production of various cytokines and chemokines. In central nervous system diseases, including neurodegenerative diseases, demyelinating disease and brain ischemia, neuroinflammation induced by activated microglia contributes to the disruption of beneficial neuron–microglia interactions. Activated microglia exert neurotoxicity by producing pro‐inflammatory cytokines, glutamate and reactive oxygen species. Damaged neurons release soluble factors known as “eat me” signals, which enhance microglial phagocytosis and inflammatory response. However, damaged neurons also suppress microglial activation through the induction of anti‐inflammatory cytokines and chemokines, thereby reducing neuroinflammation. Here, the roles of neurons and microglia in neuroinflammation in Alzheimer's disease are reviewed.