bluuebunny/crossref_metadata_2025 huggingface dataset:
Somatostatin receptor positron emission tomography/computed tomography imaging in Merkel cell carcinoma
Authors: Sollini M. , Taralli S. , Milella M. , Erba P.A. , Rubagotti S. , Fraternali A. , Roncali M. , Moscarella E. , Perotti G. , Rufini V. , Versari A.
Published: October 2015

Background

Merkel cell carcinoma (MCC) is an uncommon aggressive primary cutaneous carcinoma with neuroendocrine differentiation. However, literature data about the use of somatostatin receptor positron emission tomography/computed tomography (PET/CT) imaging in MCC are limited and its role is not clearly stated.

Objective

To investigate the role of PET/CT using somatostatin analogues radiolabelled with gallium‐68 in patients with MCC.

Methods

All patients affected by MCC who performed a somatostatin receptor PET/CT imaging from October 2007 to May 2014 were retrospectively analysed. The diagnostic performances of PET/CT were evaluated on a patient‐based analysis and compared to final diagnosis (histology = 3 or clinical/radiological follow‐up = 20).

Results

We evaluated 23 consecutive MCC patients [18 men; median age 71 years (range 47–87)]. Primary tumour was located in ear (1/23), cheek (3/23), arm (2/23), hand (1/23), back (1/23), anal canal (1/23), gluteus (4/23), thigh (3/23) and popliteal fossa (1/23). In 6/23 patients, the site of primary tumour was unknown. PET/CT was performed to detect primary tumour site (4/23) or to stage (8/23) or re‐stage (11/23) patients. PET/CT resulted positive in 14/23 patients and according to the final diagnosis was defined true positive, true negative, false positive (FP) and false negative in 11/23, 8/23, 3/23 and 1/23 cases respectively. FP PET/CT results were due to unspecific liver uptake, post‐surgical inflammation and pancreatic neuroendocrine tumour. PET/CT was unable to detect primary tumour site in all patients with unknown primary MCC. Sensitivity, specificity and diagnostic accuracy of PET/CT were 92%, 73% and 83% respectively.

Conclusions

In our experience, somatostatin receptor PET/CT imaging resulted useful in patients with MCC and presented high diagnostic performances with a significant impact in disease management although in patients with unknown primary MCC, it was unable to identify the primary tumour site.
How to Use the American Geriatrics Society 2015 Beers Criteria—A Guide for Patients, Clinicians, Health Systems, and Payors
Authors: Steinman Michael A. , Beizer Judith L. , DuBeau Catherine E. , Laird Rosemary D. , Lundebjerg Nancy E. , Mulhausen Paul
Published: October 2015

The Beers Criteria are a valuable tool for clinical care and quality improvement but may be misinterpreted and implemented in ways that cause unintended harms. This article describes the intended role of the 2015 American Geriatrics Society (AGS) Beers Criteria and provides guidance on how patients, clinicians, health systems, and payors should use them. A key theme underlying these recommendations is to use common sense and clinical judgment in applying the 2015 AGS Beers Criteria and to remain mindful of nuances in the criteria. The criteria serve as a “warning light” to identify medications that have an unfavorable balance of benefits and harms in many older adults, particularly when compared with pharmacological and nonpharmacological alternatives. However, there are situations in which use of medications included in the criteria can be appropriate. As such, the 2015 AGS Beers Criteria work best not only when they identify potentially inappropriate medications, but also when they educate clinicians and patients about the reasons those medications are included and the situations in which their use may be more or less problematic. The criteria are designed to support, rather than supplant, good clinical judgment.
Domestic Yttrium Consumption Trends in Japan
Authors: Seo Yuna , Morimoto Shinichirou
Published: October 2015

Yttrium tends to occur in the same ore deposits as the lanthanides and exhibits similar chemical properties as rare earth elements. Yttrium sources are typically concentrated in China, and there are concerns about supply security. Yttrium is used in small, but essential, quantities in a variety of advanced industrial sectors, for example, in phosphors, advanced ceramics, optical glasses, and batteries. In terms of resource security, it is important to verify the domestic yttrium consumption trends. In order to characterize the domestic yttrium consumption trends in Japan, we tracked the historical yttrium consumption patterns from 2001 to 2011 by applying the bottom‐up approach and illustrated the recent domestic yttrium flow by using a substance flow analysis. The results showed that the total yttrium consumption has remained steady over 10 years, from 1,124 tonnes (t) in 2001 to 967 t in 2011. Recent consumption in 2011 was driven primarily by the use of yttrium in fluorescent lamps (462 t), nickel metal hydride batteries (185 t), and optic glasses (149 t).
Determination of kainate receptor subunit ratios in mouse brain using novel chimeric protein standards
Authors: Watanabe‐Iida Izumi , Konno Kohtarou , Akashi Kaori , Abe Manabu , Natsume Rie , Watanabe Masahiko , Sakimura Kenji
Published: October 2015

Kainate‐type glutamate receptors (KARs) are tetrameric channels assembled from GluK1‐5. GluK1‐3 are low‐affinity subunits that form homomeric and heteromeric KARs, while GluK4 and GluK5 are high‐affinity subunits that require co‐assembly with GluK1‐3 for functional expression. Although the subunit composition is thought to be highly heterogeneous in the brain, the distribution of KAR subunits at the protein level and their relative abundance in given regions of the brain remain largely unknown. In the present study, we titrated C‐terminal antibodies to each KAR subunit using chimeric GluA2‐GluK fusion proteins, and measured their relative abundance in the P2 and post‐synaptic density (PSD) fractions of the adult mouse hippocampus and cerebellum. Analytical western blots showed that GluK2 and GluK3 were the major KAR subunits, with additional expression of GluK5 in the hippocampus and cerebellum. In both regions, GluK4 was very low and GluK1 was below the detection threshold. The relative amount of low‐affinity subunits (GluK2 plus GluK3) was several times higher than that of high‐affinity subunits (GluK4 plus GluK5) in both regions. Of note, the highest ratio of high‐affinity subunits to low‐affinity subunits was found in the hippocampal PSD fraction (0.32), suggesting that heteromeric receptors consisting of high‐ and low‐affinity subunits highly accumulate at hippocampal synapses. In comparison, this ratio was decreased to 0.15 in the cerebellar PSD fraction, suggesting that KARs consisting of low‐affinity subunits are more prevalent in the cerebellum. Therefore, low‐affinity KAR subunits are predominant in the brain, with distinct subunit combinations between the hippocampus and cerebellum.

image

Kainate receptors, an unconventional member of the iGluR receptor family, have a tetrameric structure assembled from low‐affinity (GluK1‐3) and high‐affinity (GluK4 and GluK5) subunits. We used a simple but novel procedure to measure the relative abundance of both low‐ and high‐affinity subunits. This method revealed that the relative amount of GluK2 plus GluK3 subunits was several times higher than that of GluK4 plus GluK5 subunits, in both the hippocampus and cerebellum.
Direct anti‐inflammatory effects of angiotensin‐(1–7) on microglia
Authors: Liu Meng , Shi Peng , Sumners Colin
Published: October 2015

Much evidence indicates that pro‐inflammatory effects of the renin–angiotensin system within the hypothalamus, including microglial activation and production of pro‐inflammatory cytokines, play a role in chronic neurogenic hypertension. Our objective here was to examine whether angiotensin‐(1–7) [Ang‐(1–7)], a protective component of the renin–angiotensin system, exerts direct actions at microglia to counteract these pro‐inflammatory effects. Mas, the Ang‐(1–7) receptor, was shown to be present on cultured hypothalamic microglia. Treatment of these cells with Ang‐(1–7) (100–1000 nM, 3–12 h) elicited significant decreases in basal levels of mRNAs for the pro‐inflammatory cytokines interleukin‐1β (IL‐1β) and tumor‐necrosis factor α (TNFα) and of the microglia‐macrophage marker CD11b, and increases in basal levels of the anti‐inflammatory cytokine interleukin‐10. Incubation of microglial cultures with (pro)renin (PRO) (10–50 nM; 6 h) elicited significant increases in mRNAs for IL‐1β, TNFα and CD11b. The effects of PRO (10 nM) on IL‐1β and TNFα mRNAs, and TNFα protein, were significantly attenuated by co‐treatment with Ang‐(1–7) (100 nM). Lastly, these actions of Ang‐(1–7) were abolished by the Mas antagonist A‐779, and were associated with reductions in NF‐κB subunit expression. Collectively, these data provide the first evidence that Ang‐(1–7) can exert direct effects at microglia to lower baseline and counteract PRO‐induced increases in pro‐inflammatory cytokines.

image

Renin‐Angiotensin system mediated microglial activation and pro‐inflammatory cytokine production within the hypothalamus are components of the chronic neuroinflammation associated with ‘neurogenic’ hypertension. We demonstrated that angiotension‐(1–7) acting via its receptor Mas on hypothalamic microglia lessens baseline and (pro)renin‐induced increases in pro‐inflammatory cytokine production by these cells. This is the first evidence that angiotensin‐(1–7) has direct anti‐inflammatory effects via microglia.
Gingival crevicular fluid interleukin‐8 and lipoxin A4 levels of smokers and nonsmokers with different periodontal status: a cross‐sectional study
Authors: Lütfioğlu M. , Aydoğdu A. , Sakallioğlu E. E. , Alaçam H. , Pamuk F.
Published: October 2015

Background and Objective

Smoking is an important risk factor for periodontal disease and effects the pathogenesis of the disease. This study evaluated the impact of smoking on gingival crevicular fluid interleukin‐8 (IL‐8) and lipoxin A4 (LxA4) levels in patients with and without periodontal disease.

Material and Methods

A total of 122 participants were grouped as follows: smokers with generalized aggressive periodontitis (S‐GAgP, n = 15); smokers with chronic periodontitis (S‐CP, n = 17); smokers with gingivitis (SG, n = 15); smokers classified as periodontally healthy (SH, n = 15); nonsmokers with generalized aggressive periodontitis (N‐GAgP, n = 15); nonsmokers with chronic periodontitis (N‐CP, n = 15); nonsmokers with gingivitis (NG, n = 15); and nonsmokers classified as periodontally healthy (NH, n = 15). Gingival index, plaque index, probing pocket depth and clinical attachment level were recorded. Gingival crevicular fluid IL‐8 and LxA4 levels were analyzed by ELISA.

Results

Gingival crevicular fluid IL‐8 levels varied among groups, as follows: S‐GAgP>S‐CP>SG>SH and N‐GAgP>N‐CP>NG>NH. The gingival crevicular fluid IL‐8 levels were significantly higher in the S‐GAgP group compared with the N‐GAgP group and in the S‐CP group compared with the N‐CP group (p < 0.05); differences between the SG and NG and the SH and NH groups were not statistically significant (p > 0.05). Gingival crevicular fluid LxA4 levels also varied among groups, but in an inverse direction when compared with the IL‐8 levels, as follows: S‐GAgP<S‐CP<SG and N‐GAgP<N‐CP<NG. (The gingival crevicular fluid LxA4 levels in SH and NH groups were below the limits of detection.) The gingival crevicular fluid LxA4 levels were significantly lower in the S‐GAgP group than in the N‐GAgP group and in the S‐CP group than in the N‐CP group (p < 0.05); differences between the SG and NG groups were not statistically significant (p > 0.05).

Conclusion

The study findings suggest that the observed increases in gingival crevicular fluid IL‐8 levels and decreases in gingival crevicular fluid LxA4 levels reflect changes in immune and inflammatory responses that occur as a result of smoking.
Functional analysis of three topoisomerases that regulate DNA supercoiling levels in Chlamydia
Authors: Orillard Emilie , Tan Ming
Published: October 2015

Chlamydia is a medically important bacterium that infects eukaryotic cells. Temporal expression of chlamydial genes during the intracellular infection is proposed to be regulated by changes in DNA supercoiling levels. To understand how chlamydial supercoiling levels are regulated, we purified and analyzed three putative Chlamydia trachomatis topoisomerases. As predicted by sequence homology, CT189/190 are the two subunits of DNA gyrase, whereas CT643 is a topoisomerase I. CT660/661 have been predicted to form a second DNA gyrase, but the reconstitute holoenzyme decatenated and relaxed DNA, indicating that the proteins are subunits of topoisomerase IV. Promoter analysis showed that each topoisomerase is transcribed from its own operon by the major chlamydial RNA polymerase. Surprisingly, all three topoisomerase promoters had higher activity from a more supercoiled DNA template. This supercoiling‐responsivesness is consistent with negative feedback control of topoisomerase I and topoisomerase IV expression, which is typical of other bacteria. However, activation of the chlamydial gyrase promoter by increased supercoiling is unorthodox compared with the relaxation‐induced transcription of gyrase in other bacteria. We present a model in which supercoiling levels during the intracellular chlamydial developmental cycle are regulated by unusual positive feedback control of the gyrase promoter and the temporal expression of three topoisomerases.
Development of disease‐resistant rice by pathogen‐responsive expression of WRKY45
Authors: Goto Shingo , Sasakura‐Shimoda Fuyuko , Yamazaki Muneo , Hayashi Nagao , Suetsugu Mai , Ochiai Hirokazu , Takatsuji Hiroshi
Published: October 2015

WRKY45 is an important transcription factor in the salicylic acid signalling pathway in rice that mediates chemical‐induced resistance against multiple pathogens. Its constitutive overexpression confers extremely strong resistance against Magnaporthe oryzae and Xanthomonas oryzae pv. oryzae to rice, but has adverse effects on agronomic traits. Here, a new strategy to confer rice with strong disease resistance without any negative effects on agronomic traits was established by expressing WRKY45 under the control of pathogen‐responsive promoters in combination with a translational enhancer derived from a 5′‐untranslated region (UTR) of rice alcohol dehydrogenase (ADH). Rice promoters that responded to M. oryzae and X. oryzae pv. oryzae infections within 24 h were identified, and 2‐kb upstream sequences from nine of them were isolated, fused to WRKY45 cDNA with or without the ADH 5′‐UTR, and introduced into rice. Although pathogen‐responsive promoters alone failed to confer effective disease resistance, the use of the ADH 5′‐UTR in combination with them, in particular the PR1b and GST promoters, enhanced disease resistance. Field trials showed that overall, PR1b promoter‐driven (with ADH 5′‐UTR) lines performed the best and one had agronomic traits comparable to control untransformed rice. Thus, expressing WRKY45 under the control of the PR1b promoter with the ADH 5′‐UTR is an excellent strategy to develop disease‐resistant rice, and the line established could serve as a mother line for breeding disease‐resistant rice.
Parvovirus B19–Associated Microvesicular Eruption
Authors: Martín José M. , Beteta Gerardo , Allende Andrea , Jordá Esperanza
Published: October 2015

We report on a 3‐year‐old girl with a microvesicular generalized rash in whom primary infection by parvovirus B19 was demonstrated by seroconversion. To our knowledge, this is the first instance of an eruption arising from parvovirus B19 with this peculiar clinical pattern.
Transepidermal Water Loss in Neonates: Baseline Values Using a Closed‐Chamber System
Authors: Mathanda Teena R. , M. Bhat Ramesh , Hegde Pavan , Anand Shivaraja
Published: October 2015

Background

Transepidermal water loss (TEWL) is the normal, constitutive loss of water vapor from the skin in the absence of sweat gland activity. It is regarded as one of the most important parameters for characterizing skin barrier function, and the values are dependent on multiple variables. The objective of this study was to evaluate TEWL in neonates using a closed‐ chamber system, and determine if there is a variation of TEWL with the mode of delivery, pre‐term birth, low birthweight or phototherapy.

Methods

This prospective study was conducted in 104 healthy neonates, 30 neonates in the Neonatal Intensive Care Unit (NICU) and 40 adults using a noninvasive, closed‐ chamber system (VapoMeter™).

Results

A statistically significant difference in TEWL was noted between newborns and adults. No remarkable difference in TEWL was seen between boys or men and girls or women or those born via normal vaginal birth and caesarean section, but TEWL was significantly higher in preterm and low birthweight neonates. Significantly higher TEWL was noted from the antecubital fossa of the neonates who received phototherapy when compared with six other sites.

Conclusions

The closed‐ chamber system is an acceptable alternative to the more widely used open‐chamber system. The higher mean TEWL in neonates suggests that the epidermal barrier is still adapting to extrauterine life, making newborn skin more sensitive and requiring appropriate, age adapted care.
Moral Societal Renewal or Getting the Country Back to Work: Welfare State Culture as a Resource and a Constraint for Policy Discourse
Authors: König Pascal D.
Published: October 2015

This article deals with welfare culture as an ideational constraint for governments’ use of normative ideas and justifications in their policy communication. The analysis is based on a focused comparison of reforms related to the labor market that were passed by the governments under David Cameron (the United Kingdom), Mariano Rajoy (Spain), and Enda Kenny (Ireland). The cases were chosen because of their similar broader context while the welfare regimes and cultures differ between the countries. Based on key speeches by the heads of governments and the responsible ministers, a qualitative content analysis extracts justifications in their communication. As the analysis shows, the three cases differ in both the extent and the content of normative justifications in a way that is in line with the differences in the welfare cultures. Furthermore, the findings from the Irish government suggest that party ideology adds to the welfare culture in shaping a government's policy communication.

Related Articles

Delshad, Ashlie B. 2013. “.” Politics & Policy 41 (): 213‐240. http://onlinelibrary.wiley.com/doi/10.1111/polp.12009/abstract

Shanahan, Elizabeth A.,
McBeth, Mark K., and
Hathaway, Paul L. 2011. “.” Politics & Policy 39 (): 373‐400. http://onlinelibrary.wiley.com/doi/10.1111/j.1747-1346.2011.00295.x/abstract
Air Pollution, Neighbourhood Socioeconomic Factors, and Neural Tube Defects in the San Joaquin Valley of California
Authors: Padula Amy M. , Yang Wei , Carmichael Suzan L. , Tager Ira B. , Lurmann Frederick , Hammond S. Katharine , Shaw Gary M.
Published: October 2015

Background

Environmental pollutants and neighbourhood socioeconomic factors have been associated with neural tube defects, but the potential impact of interaction between ambient air pollution and neighbourhood socioeconomic factors on the risks of neural tube defects is not well understood.

Methods

We used data from the California Center of the National Birth Defects Study and the Children's Health and Air Pollution Study to investigate whether associations between air pollutant exposure in early gestation and neural tube defects were modified by neighbourhood socioeconomic factors in the San Joaquin Valley of California, 1997–2006. There were 5 pollutant exposures, 3 outcomes, and 9 neighbourhood socioeconomic factors included for a total of 135 investigated associations. Estimates were adjusted for maternal race‐ethnicity, education, and multivitamin use.

Results

We present below odds ratios (ORs) that exclude 1 and a chi‐square test of homogeneity P‐value of <0.05. We observed increased odds of spina bifida comparing the highest to lowest quartile of particulate matter <10 μm (PM10) among those living in a neighbourhood with: (i) median household income of less than $30 000 per year [OR 5.1, 95% confidence interval (CI) 1.7, 15.3]; (ii) more than 20% living below the federal poverty level (OR 2.6, 95% CI 1.1, 6.0); and (iii) more than 30% with less than or equal to a high school education (OR 3.2, 95% CI 1.4, 7.4). The ORs were not statistically significant among those higher socioeconomic status (SES) neighbourhoods.

Conclusions

Our results demonstrate effect modification by neighbourhood socioeconomic factors in the association of particulate matter and neural tube defects in California.
Can the Consumption Capital Asset Pricing Model Account for Traders' Expected Currency Returns?
Authors: Stillwagon Josh R.
Published: October 2015

This study uses survey data on traders' exchange rate forecasts to test whether their expected excess returns are related to the covariance between the exchange rate and consumption; as predicted by the consumption capital asset pricing model (CCAPM). The covariance is measured through the novel use of rolling windows of the realized covariance (both forward and backward looking) and testing is conducted with the cointegratedVAR. The model is able to account for expected returns with more plausible degrees of risk aversion, but only when using sufficiently long, backward‐looking measures of the covariance. This suggests that market participants assess risk, in part, based upon the pro‐cyclicality of returns, and infer it from experience in the recent past. There is also evidence that inclusion of the real exchange rate improves the plausibility of the estimates and the model fit.
Sclerostin, TNF‐alpha and Interleukin‐18 Correlate and are Together with Klotho Related to Other Growth Factors and Cytokines in Haemodialysis Patients
Authors: Almroth G. , Lönn J. , Uhlin F. , Brudin L. , Andersson B. , Hahn‐Zoric M.
Published: October 2015

Patients with chronic renal failure are known to have renal osteodystrophy (bone disease) and increased calcification of vessels. A new marker of bone disease, sclerostin, the two pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐alpha) and interleukin‐18 (IL‐18), and the fibroblast growth factor‐23 (FGF‐23) receptor‐associated marker Klotho were tested in 84 haemodialysis (HD) patients and in healthy controls. The patients had significantly higher levels of the three former markers than of the controls while Klotho was significantly higher in the controls. Low level, but significant, correlations were observed in the patient group when the levels of these four markers were compared to each other and to those of 5 cytokines and growth factors tested earlier; high‐sensitive CRP (hsCRP), interleukin‐6 (IL‐6), hepatocyte growth factor (HGF), fibroblast growth factor‐23 (FGF‐23) and soluble urokinase plasminogen activator (suPAR). Ln sclerostin correlated positively to Ln hsTNF‐alpha, Ln HGF and Ln suPAR. Ln hsTNF‐alpha correlated positively to Ln sclerostin, Ln hsCRP, Ln IL‐6, Ln FGF‐23, Ln suPAR and Ln IL‐18. Ln IL‐18 correlated positively to Ln suPAR and Ln TNF‐alpha. Ln Klotho correlated negatively to Ln hsCRP but did not correlate to Ln FGF‐23. The markers studied here may be involved in the calcification of vessels seen in HD patients due to a combination of inflammation and bone disease. The mechanisms are still not fully known but may be of importance for future therapeutic possibilities in this group of patients.
Under Pressure: Individual Differences in Children's Suggestibility in Response to Intense Social Influence
Authors: Uhl Elizabeth R. , Camilletti Catherine R. , Scullin Matthew H. , Wood James M.
Published: October 2015

Prior research on the relation between children's suggestibility and verbal skills has yielded mixed results. This study examined children's suggestibility in a high social pressure context in conjunction with individual differences in verbal ability and social understanding. Sixty‐nine children were read a story by a classroom visitor. One week later children were asked suggestive questions about the visit and pressured to respond ‘yes’. One week after the first interview, children were re‐asked the same questions, this time with no pressure. Children's suggestibility in response to social pressure was found to be significantly and negatively correlated with receptive vocabulary knowledge, but not with social understanding, the ability to understand and interpret social interactions. In addition, suggestibility scores exhibited a distinctly bimodal distribution, with many children acquiescing to all pressured suggestions, many children acquiescing to no suggestions, and few children falling between these two extremes.
Coincidence of late‐onset cytomegalovirus‐induced myositis and gastritis in a pediatric renal transplant recipient
Authors: Baek H.S. , Choe B.H. , Kim H.‐K. , Huh S. , Cho M.H.
Published: October 2015

An 8‐year‐old girl with a renal transplant was admitted for myalgia and muscle weakness in both legs over the previous 2 weeks. She also had fever and intermittent epigastric pain. Based on these clinical manifestations, and laboratory and histopathological findings, the diagnosis was coincidence of late‐onset cytomegalovirus (CMV)‐induced myositis and gastritis in an immunocompromised child with a renal transplant. After administration of intravenous ganciclovir for 3 weeks, her symptoms resolved, with normalization of abnormal muscle enzymes, including lactate dehydrogenase, creatine kinase, aspartate aminotransferase, and the disappearance of CMV viremia.
Bronchoscopy can be done safely in patients with thrombocytopenia
Authors: Nandagopal Lakshminarayanan , Veeraputhiran Muthu , Jain Tania , Soubani Ayman O. , Schiffer Charles A.
Published: October 2015

BACKGROUND

Prophylactic platelet (PLT) transfusions are often administered to patients before bronchoscopy or bronchoalveolar lavage (BAL) to prevent bleeding. There is a paucity of data to validate this approach, with a commonly suggested PLT transfusion threshold of fewer than 50 × 109/L, largely based on expert opinion. We conducted a retrospective study on the incidence of bleeding complications in patients with thrombocytopenia undergoing bronchoscopy.

STUDY DESIGN AND METHODS

We identified 150 consecutive patients with PLT counts of not more than 100 × 109/L who underwent bronchoscopy and/or BAL from January 2009 to May 2014 at our institution. The British Thoracic Society (BTS) guidelines were used to categorize bleeding associated with bronchoscopy.

RESULTS

Infection (40%) was the primary indication for bronchoscopy with BAL. Fifty‐eight of 89 (65%) patients with baseline PLT counts of not more than 50 × 109/L received prophylactic transfusions compared to 8% of those with PLT counts of more than 50 × 109/L. The PLT count did not increase to more than 50 × 109/L in many patients who received transfusions. Seventy‐two patients had counts of less than 50 × 109/L at the time of bronchoscopy, with 15 patients having counts of less than 20 × 109/L. Only one patient with a PLT count of 61 × 109/L had bleeding that required continuous suctioning but then resolved spontaneously (termed “mild bleeding” by BTS criteria). Bloody lavage that resolved spontaneously without continuous suctioning (termed “no bleeding” by the BTS criteria) was observed in nine (6%) patients.

CONCLUSION

The very low incidence of bleeding complications from bronchoscopy with or without BAL even in patients with PLT counts of not more than 30 × 109/L (no episodes of clinically significant bleeding in 35 patients) demonstrates that bronchoscopy can be done safely in patients with severe thrombocytopenia.
Assessment of nucleic acid modification induced by amotosalen and ultraviolet A light treatment of platelets and plasma using real‐time polymerase chain reaction amplification of variable length fragments of mitochondrial DNA
Authors: Bakkour Sonia , Chafets Daniel M. , Wen Li , Dupuis Kent , Castro Grace , Green Jennifer M. , Stassinopoulos Adonis , Busch Michael P. , Lee Tzong‐Hae
Published: October 2015

BACKGROUND

Pathogen inactivation methods are increasingly used to reduce the risk of infections after transfusion of blood products. Photochemical treatment (PCT) of platelets (PLTs) and plasma with amotosalen and ultraviolet A (UVA) light inactivates pathogens and white blood cells through formation of adducts between amotosalen and nucleic acid that block replication, transcription, and translation. The same adducts block the amplification of nucleic acids using polymerase chain reaction (PCR) in a manner that correlates with the number of adducts formed, providing a direct quality control (QC). Current QC measures for PCT rely on indirect methods that measure the delivered UVA dose or percent residual amotosalen after illumination, rather than directly measuring nucleic acid modification.

STUDY DESIGN AND METHODS

Endogenous mitochondrial DNA (mtDNA), which is detectable in PLT and plasma units, was chosen as a target for the quantification of photochemically induced modifications. DNA was extracted from untreated or amotosalen and UVA–treated PLTs or plasma, and mtDNA fragments of variable lengths were quantified using a real‐time PCR inhibition assay.

RESULTS

PCT induced increasing real‐time PCR inhibition of mtDNA amplification for larger amplicon sizes. Amplification was unaffected by treatment with amotosalen or UVA alone, whereas up to 3 log inhibition was observed after PCT. Blinded PCR testing of a panel of 110 samples each, from PLT or plasma components prepared for routine use within a blood center, allowed 100% discrimination between untreated and treated units.

CONCLUSION

Our initial findings indicate that an adequately sensitive, quantitative real‐time PCR inhibition assay targeting mtDNA could provide a valuable tool to confirm and monitor PCT.
Preoperative use of platelets in a 6‐year‐old with acute appendicitis and a myosin heavy chain 9–related disorder: a case report and review of literature
Authors: Eichel Yekaterina , Tormos Lee Marie , Squires Jerry E.
Published: October 2015

BACKGROUND

Mutations of nonmuscle myosin heavy chain 9 (MYH9) gene are an autosomal dominant cause of inherited thrombocytopenia in children. MYH9 spectrum disorders include May‐Hegglin anomaly and Sebastian, Fechtner, and Epstein syndromes. Patients with these disorders often present with macroplatelets and thrombocytopenia and have a mild bleeding tendency; extrahematologic manifestations (nephropathy, deafness, and cataracts) correlate with specific mutations. No definitive guidelines exist for preoperative prophylactic platelet (PLT) transfusion in these patients.

STUDY DESIGN AND METHODS

This was a case study and literature review.

RESULTS

A 6‐year‐old male presented with appendicitis. Review of records revealed that he and his siblings had thrombocytopenia; polymerase chain reaction amplification with DNA sequence analysis showed a variation in the MYH9 gene previously reported as a known cause of MYH9‐related disorders. Involvement of other organ systems was not found on initial work‐up. The patient's PLT count on admission was 20 × 109/L. The degree of thrombocytopenia prompted transfusion of apheresis PLTs and he had good response (73 × 109/L). After infusion he developed hives, rash, itching, and nausea, which resolved after administration of epinephrine and hydrocortisone. Transfusion reaction work‐up was negative and symptoms were interpreted as an allergic reaction. The appendectomy was uneventful.

CONCLUSION

This patient's PLT count was within guidelines to warrant transfusion; however, some patients with MYH9 mutations have counts above the transfusion threshold. To the authors’ knowledge, there are no set guidelines for preoperative prophylaxis in a patient with an MYH9 deficiency. The management of the bleeding diathesis in these patients, especially in the setting of invasive procedures, is uncertain.
How do I implement an automated screen for high‐titer ABO antibody as an inventory management tool for ABO plasma–incompatible platelets?
Authors: Fontaine Magali J. , Webster Jan , Gomez Samantha , Pham Tho D. , Goodnough Lawrence T. , Galel Susan A.
Published: October 2015

BACKGROUND

Plasma volume reduction (PVR) may reduce the risk of hemolysis associated with transfusion of plateletpheresis blood products (PLTs) containing ABO‐incompatible plasma. But PVR may delay PLT issue. In collaboration with our blood donor center we evaluated an automated screen of PLT for high‐titer ABO antibody and to apply PVR to high‐titer PLTs.

STUDY DESIGN AND METHODS

At the donor center, plasma from PLT donors was tested using an automated microplate system (PK7300, Beckman). PK settings were set for a detection cutoff equivalent to 1 in 256 using a manual tube method. The donors associated with high‐titer PLTs were characterized by sex and age. In the transfusion service, the number of PVR procedures was evaluated before and after implementation of the high‐titer screen.

RESULTS

During validation, 157 of 1008 PLT units (15%) were positive by the automated method versus 121 (12%) by manual method. After implementation, 2112 of 15,240 PLT units were high‐titer, with higher frequency in donations from females versus males (18% vs. 12%, p < 0.0001). The PLT PVR rate was reduced by 50%.

CONCLUSION

Implementation of an automated method to screen PLTs for high‐titer ABO antibody at the donor center improves the inventory management of PLTs containing ABO‐incompatible plasma at the hospital transfusion service.
Dynamic Control of Radiative Surface Properties With Origami-Inspired Design
Authors: Mulford Rydge B. , Jones Matthew R. , Iverson Brian D.
Published: October 2015

Thermal management systems for space equipment commonly use static solutions that do not adapt to environmental changes. Dynamic control of radiative surface properties is one way to respond to environmental changes and to increase the capabilities of spacecraft thermal management systems. This paper documents an investigation of the extent to which origami-inspired surfaces may be used to control the apparent absorptivity of a reflective material. Models relating the apparent absorptivity of a radiation shield to time-dependent surface temperatures are presented. Results show that the apparent absorptivity increases with increasing fold density and indicate that origami-inspired designs may be used to control the apparent radiative properties of surfaces in thermal management systems.
Thermally annealed iron thin film on an alumina barrier layer by ToF-SIMS
Authors: Kanyal Supriya S. , Jensen David S. , Zhu Zihua , Linford Matthew R.
Published: October 2015

The authors report the positive and negative ion time-of-flight secondary ion mass spectrometry spectra obtained with Bi32+ primary ions at 50 keV of an Fe film annealed in hydrogen at 750 °C to form Fe nanoparticles. This surface had been exposed to the air; it had previously been shown by x-ray photoemission spectroscopy to be entirely oxidized. The strongest signal in the positive ion spectrum corresponded to Fe+, with FexOyHz+ species also present. A substantial Al+ signal was observed due to exposure of the underlying alumina substrate. The negative ion spectrum showed O−, OH−, and AlO−.
Model‐based geometric calibration for medical x‐ray systems
Authors: van der Maas Rick , de Jager Bram , Steinbuch Maarten , Dries Johan
Published: October 2015

Purpose:

Currently applied calibration approaches lead to satisfying 3D roadmapping overlay and 3D reconstruction accuracies; however, the required calibration times are extensive. The aim of this paper is the introduction of a novel model‐based approach for geometric system calibrations, leading to a significant reduction of calibration times.

Methods:

By using physical insight into the system, a physical model is derived which can be exploited to predict geometric calibrations parameters. Model‐parameters are estimated using a limited set of phantom‐based measurement data. Effectively, the calibration procedure is recast to a parameter identification experiment.

Results:

The potential of the proposed approach is illustrated by virtue of a benchmark object, successful reconstruction of a clinical phantom, and comparison to phantom‐based accuracies.

Conclusions:

Accurate models are required to achieve the desired accuracies. Based on the results in this work, the approach seems to be feasible for practical applications; however, to achieve all the desired specifications, future research should focus on enhanced modeling techniques.
Neutrino oscillations honored
Authors: Cho Adrian
Published: October 2015

Observations by Japanese and Canadian teams proved ghostly particles can change identity and have mass.
Beyond the “Mendel-Fisher controversy”
Authors: Radick Gregory
Published: October 2015

Worries about fraudulent data should give way to broader critiques of Mendel's legacy
Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes
Authors: Rostislavleva Ksenia , Soler Nicolas , Ohashi Yohei , Zhang Lufei , Pardon Els , Burke John E. , Masson Glenn R. , Johnson Chris , Steyaert Jan , Ktistakis Nicholas T. , Williams Roger L.
Published: October 2015

Opening up Vps34 protein complexes

During intracellular membrane trafficking, large protein complexes regulate and adapt the activity of signal transducer enzymes such as the class III phosphatidylinositol 3-kinase Vps34. These large enzyme complexes are present in all eukaryotic cells, having widespread importance in neurodegeneration, aging, and cancer; however, a structural understanding has been lacking. Rostislavleva
et al.
provide atomic-resolution insights into the structures of the Vps34-containing protein complexes required for autophagy, endocytic sorting, and cytokinesis. The V-shaped complexes can undergo opening motions, which allows them to adapt to and phosphorylate membranes.

Science
, this issue p.
10.1126/science.aac7365
Membrane traffic en route to cancer
Authors: Ferguson Shawn M.
Published: October 2015

The spatial organization of internal membranes influences receptor signaling and disease

[Also see Report by

Wheeler
et al.

]
The odds of immunotherapy success
Authors: Gubin Matthew M. , Schreiber Robert D.
Published: October 2015

Mutation load correlates with the response of melanomas to immunotherapy

[Also see Report by

Van Allen
et al.

]
Resolution of Chlamydia trachomatis Infection Is Associated with a Distinct T Cell Response Profile
Authors: Picard Michele D. , Bodmer Jean-Luc , Gierahn Todd M. , Lee Alexander , Price Jessica , Cohane Kenya , Clemens Veronica , DeVault Victoria L. , Gurok Galina , Kohberger Robert , Higgins Darren E. , Siber George R. , Flechtner Jessica Baker , Geisler William M.
Published: October 2015

Chlamydia trachomatis
is the causative agent of the most frequently reported bacterial sexually transmitted infection, the total burden of which is underestimated due to the asymptomatic nature of the infection. Untreated
C. trachomatis
infections can cause significant morbidities, including pelvic inflammatory disease and tubal factor infertility (TFI). The human immune response against
C. trachomatis
, an obligate intracellular bacterium, is poorly characterized but is thought to rely on cell-mediated immunity, with CD4
+
and CD8
+
T cells implicated in protection. In this report, we present immune profiling data of subjects enrolled in a multicenter study of
C. trachomatis
genital infection. CD4
+
and CD8
+
T cells from subjects grouped into disease-specific cohorts were screened using a
C. trachomatis
proteomic library to identify the antigen specificities of recall T cell responses after natural exposure by measuring interferon gamma (IFN-γ) levels. We identified specific T cell responses associated with the resolution of infection, including unique antigens identified in subjects who spontaneously cleared infection and different antigens associated with
C. trachomatis
-related sequelae, such as TFI. These data suggest that novel and unique
C. trachomatis
T cell antigens identified in individuals with effective immune responses can be considered as targets for vaccine development, and by excluding antigens associated with deleterious sequelae, immune-mediated pathologies may be circumvented.
Performance of an Early Infant Diagnostic Test, AmpliSens DNA-HIV-FRT, Using Dried Blood Spots Collected from Children Born to Human Immunodeficiency Virus-Infected Mothers in Ukraine
Authors: Chang Joy , Tarasova Tetyana , Shanmugam Vedapuri , Azarskova Marianna , Nguyen Shon , Hurlston Mackenzie , Sabatier Jennifer , Zhang Guoqing , Osmanov Saladin , Ellenberger Dennis , Yang Chunfu , Vitek Charles , Liulchuk Maria , Nizova Natalya
Published: October 2015

An accurate accessible test for early infant diagnosis (EID) is crucial for identifying HIV-infected infants and linking them to treatment. To improve EID services in Ukraine, dried blood spot (DBS) samples obtained from 237 HIV-exposed children (≤18 months of age) in six regions in Ukraine in 2012 to 2013 were tested with the AmpliSens DNA-HIV-FRT assay, the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 Qual test, and the Abbott RealTime HIV-1 Qualitative assay. In comparison with the paired whole-blood results generated from AmpliSens testing at the oblast HIV reference laboratories in Ukraine, the sensitivity was 0.99 (95% confidence interval [CI], 0.95 to 1.00) for the AmpliSens and Roche CAP/CTM Qual assays and 0.96 (95% CI, 0.90 to 0.98) for the Abbott Qualitative assay. The specificity was 1.00 (95% CI, 0.97 to 1.00) for the AmpliSens and Abbott Qualitative assays and 0.99 (95% CI, 0.96 to 1.00) for the Roche CAP/CTM Qual assay. McNemar analysis indicated that the proportions of positive results for the tests were not significantly different (
P
> 0.05). Cohen's kappa (0.97 to 0.99) indicated almost perfect agreement among the three tests. These results indicated that the AmpliSens DBS and whole-blood tests performed equally well and were comparable to the two commercially available EID tests. More importantly, the performance characteristics of the AmpliSens DBS test meets the World Health Organization EID test requirements; implementing AmpliSens DBS testing might improve EID services in resource-limited settings.
Characterizing the Murine Leukemia Virus Envelope Glycoprotein Membrane-Spanning Domain for Its Roles in Interface Alignment and Fusogenicity
Authors: Salamango Daniel J. , Johnson Marc C.
Published: October 2015

The membrane-proximal region of murine leukemia virus envelope (Env) is a critical modulator of its functionality. We have previously shown that the insertion of one amino acid (+1 leucine) within the membrane-spanning domain (MSD) abolished protein functionality in infectivity assays. However, functionality could be restored to this +1 leucine mutant by either inserting two additional amino acids (+3 leucine) or by deleting the cytoplasmic tail domain (CTD) in the +1 leucine background. We inferred that the ectodomain and CTD have protein interfaces that have to be in alignment for Env to be functional. Here, we made single residue deletions to the Env mutant with the +1 leucine insertion to restore the interface alignment (gain of functionality) and therefore define the boundaries of the two interfaces. We identified the glycine-proline pairs near the N terminus (positions 147 and 148) and the C terminus (positions 159 and 160) of the MSD as being the boundaries of the two interfaces. Deletions between these pairs restored function, but deletions outside of them did not. In addition, the vast majority of the single residue deletions regained function if the CTD was deleted. The exceptions were four hydroxyl-containing amino acid residues (T139, T140, S143, and T144) that reside in the ectodomain interface and the proline at position 148, which were all indispensable for functionality. We hypothesize that the hydroxyl-containing residues at positions T139 and S143 could be a driving force for stabilizing the ectodomain interface through formation of a hydrogen-bonding network.

IMPORTANCE
The membrane-proximal external region (MPER) and membrane-spanning domains (MSDs) of viral glycoproteins have been shown to be critical for regulating glycoprotein fusogenicity. However, the roles of these two domains are poorly understood. We report here that point deletions and insertions within the MPER or MSD result in functionally inactive proteins. However, when the C-terminal tail domain (CTD) is deleted, the majority of the proteins remain functional. The only residues that were found to be critical for function regardless of the CTD were four hydroxyl-containing amino acids located at the C terminus of the MPER (T139 and T140) and at the N terminus of the MSD (S143 and T144) and a proline near the beginning of the MSD (P148). We demonstrate that hydrogen-bonding at positions T139 and S143 is critical for protein function. Our findings provide novel insights into the role of the MPER in regulating fusogenic activity of viral glycoproteins.
Bispecific Antibodies Targeting Different Epitopes on the HIV-1 Envelope Exhibit Broad and Potent Neutralization
Authors: Asokan M. , Rudicell R. S. , Louder M. , McKee K. , O'Dell S. , Stewart-Jones G. , Wang K. , Xu L. , Chen X. , Choe M. , Chuang G. , Georgiev I. S. , Joyce M. G. , Kirys T. , Ko S. , Pegu A. , Shi W. , Todd J. P. , Yang Z. , Bailer R. T. , Rao S. , Kwong P. D. , Nabel G. J. , Mascola J. R.
Published: October 2015

The potency and breadth of the recently isolated neutralizing human monoclonal antibodies to HIV-1 have stimulated interest in their use to prevent or to treat HIV-1 infection. Due to the antigenically diverse nature of the HIV-1 envelope (Env), no single antibody is highly active against all viral strains. While the physical combination of two broadly neutralizing antibodies (bNAbs) can improve coverage against the majority of viruses, the clinical-grade manufacturing and testing of two independent antibody products are time and resource intensive. In this study, we constructed bispecific immunoglobulins (IgGs) composed of independent antigen-binding fragments with a common Fc region. We developed four different bispecific IgG variants that included antibodies targeting four major sites of HIV-1 neutralization. We show that these bispecific IgGs display features of both antibody specificities and, in some cases, display improved coverage over the individual parental antibodies. All four bispecific IgGs neutralized 94% to 97% of antigenically diverse viruses in a panel of 206 HIV-1 strains. Among the bispecific IgGs tested, VRC07 × PG9-16 displayed the most favorable neutralization profile. It was superior in breadth to either of the individual antibodies, neutralizing 97% of viruses with a median 50% inhibitory concentration (IC
50
) of 0.055 μg/ml. This bispecific IgG also demonstrated
in vivo
pharmacokinetic parameters comparable to those of the parental bNAbs when administered to rhesus macaques. These results suggest that IgG-based bispecific antibodies are promising candidates for the prevention and treatment of HIV-1 infection in humans.

IMPORTANCE
To prevent or treat HIV-1 infection, antibodies must potently neutralize nearly all strains of HIV-1. Thus, the physical combination of two or more antibodies may be needed to broaden neutralization coverage and diminish the possibility of viral resistance. A bispecific antibody that has two different antibody binding arms could potentially display neutralization characteristics better than those of any single parental antibody. Here we show that bispecific antibodies contain the binding specificities of the two parental antibodies and that a single bispecific antibody can neutralize 97% of viral strains with a high overall potency. These findings support the use of bispecific antibodies for the prevention or treatment of HIV-1 infection.