Tremelimumab-associated tumor regression following after initial progression: two case reports.
The human IgG2 monoclonal antibody tremelimumab is an immune checkpoint inhibitor that blocks cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). The therapeutic response of anti-CTLA-4 monoclonal antibodies possess unique kinetics, in that antitumor responses are often observed after initial short-term disease progression, in some cases as long as 6-12 months after anti-CTLA-4 treatment initiation. Here, we report two cases: one of bile duct cancer and the other of squamous cell carcinoma of unknown primary, both of which demonstrated initial rapid disease progression followed by dramatic tumor shrinkage after one or two doses of tremelimumab, without any immune-related adverse events. This delayed, yet dramatic antitumor response suggests that tremelimumab may hold promise in the treatment of solid tumors.


Genomic Amplifications Cause False Positives in CRISPR Screens.
In CRISPR-based screens for essential genes, Munoz and colleagues and Aguirre and colleagues show that gene-independent targeting of genomic amplifications in human cancer cell lines reduces proliferation or survival. The correlation between CRISPR target site copy number and lethality demonstrates the need for scrutiny and complementary approaches to rule out off-target effects and false positives in CRISPR screens. Cancer Discov; 6(8); 824-6. ©2016 AACR.See related article by Munoz et al., p. 900See related article by Aguirre et al., p. 914.


Clinicopathological Significance of BRAFV600E Mutation in Colorectal Cancer: An Updated Meta-Analysis.
Background and Aims: Numerous studies have identified BRAFV600E mutation as a predictive factor of anti-EGFR antibodies in colorectal cancer (CRC). However, the association between BRAFV600E mutation and clinicopathological features remains unclear. Therefore, we aimed to conduct an updated and comprehensive meta-analysis to evaluate the above issues. Methods: We performed a systematic literature search from PubMed, Web of Science, Embase, and PMC database examining the association between BRAFV600E mutation and clinicopathological features in CRC patients. Odds ratio with 95% confidence interval were used to estimate the effects of BRAFV600E mutation on each clinicopathological parameter with fixed-effect model or random-effect model. Results: Sixty-one studies published, including 32407 CRC patients from multiple countries, were included in the meta-analysis. The overall BRAFV600E mutation rate was 11.38%, and BRAFV600E mutation was positively related to high disease stage (OR=0.81; 95% CI=0.72-0.92; P=0.001), high T stage (OR=0.51; 95% CI=0.40-0.65; P<0.00001), proximal colon (OR=4.76; 95% CI=3.81-5.96; P<0.00001) or right colon (OR=5.15; 95% CI=4.35-6.10, P<0.00001) tumor location, poor tumor differentiation (OR=0.27; 95% CI=0.21-0.34; P<0.00001), mucinous histology (OR=2.97; 95% CI=2.37-3.72; P<0.00001), K-ras-wild type (OR=0.04; 95% CI=0.02-0.07; P<0.00001), TP53-wild type (OR=0.50; 95% CI=0.31-0.78; P=0.003), deficient DNA mismatch repair (OR=2.93; 95% CI=1.78-4.82; P<0.00001), high microsatellite instability (OR=11.15; 95% CI=8.51-14.61; P<0.00001) and high CpG island methylator phenotype (OR=0.04; 95% CI=0.03-0.08; P<0.00001). Conclusions: Our updated meta-analysis demonstrated that BRAFV600E mutation was related to poor prognosis of CRC and associated with the distinct molecular phenotypes.


A Mixed Learning Technology Approach for Continuing Medical Education.
Distance learning technologies have been used for many years to provide CME to rural physicians. The purpose of this study was to evaluate the utility and acceptability of a mixed learning technology approach for providing distance CME. The approach combined audio teleconferencing instruction with a Web-based learning system enabling the live presentation and archiving of instructional material and media, asynchronous computer conferencing discussions, and access to supplemental online learning resources. The study population was comprised of physicians and nurse practitioners who participated in audio teleconference sessions, but did not access the Web-based learning system (nonusers); learners who participated in audio teleconferences and accessed the Web-based system (online users); and faculty. The evaluation focused upon faculty and learners' experiences and perceptions of the mixed learning technology approach; the level of usage; and the effectiveness of the approach in fostering non-mandatory, computer-mediated discussions. The users of the Web-based learning system were satisfied with its features, ease of use, and the ability to access online CME instructional material. Learners who accessed the system reported a higher level of computer skill and comfort than those who did not, and the majority of these users accessed the system at times other than the live audio teleconference sessions. The greatest use of the system appeared to be for self-directed learning. The success of a mixed learning technology approach is dependent on Internet connectivity and computer access; learners and faculty having time to access and use the Web; comfort with computers; and faculty development in the area of Web-based teaching.


Triple Fixed-Combination Bimatoprost/Brimonidine/Timolol in Glaucoma and Ocular Hypertension in India: A Multicenter, Open-Label, Phase 3 Study.
To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a triple fixed-combination of bimatoprost, brimonidine, and timolol (TFC) in patients with glaucoma or ocular hypertension (OHT) treated with fixed-combination or unfixed brimonidine and timolol therapy (dual-combination therapy). In this multicenter, open-label, phase 3 study, patients who received 4-8 weeks of dual-combination therapy twice daily and had an IOP >18 and <34 mmHg in at least one eye were switched (at baseline) to treatment with TFC twice daily for 12 weeks. At Weeks 4, 8, and 12 on TFC, IOP was assessed at Hours 0, 2, and 8. Primary efficacy variable: mean diurnal IOP change from baseline in the study eye at Week 12 (modified intent-to-treat [mITT] population). Sensitivity (per-protocol [PP] population) and subgroup (≤65 vs >65 years) analyses were performed. Safety, including adverse events (AEs), was assessed at each visit. Of 126 patients enrolled, 121 and 103 formed the mITT/safety and PP populations, including 109 (90.1%) and 94 (91.3%) who completed the study, respectively. In the mITT/safety population, mean age was 58.6 years. Patients had open-angle glaucoma (51.2%), angle-closure glaucoma with patent iridotomy (36.4%), and/or OHT (13.2%). At Week 12, the mean diurnal change in IOP from dual combination-treated baseline was statistically significant (P<0.001) with TFC in the mITT (-3.98 mmHg) and PP (-4.22 mmHg) populations. Results were similar at all visits, regardless of the age subgroup. The most frequent treatment-related AEs were conjunctival hyperemia (14.0%) and dry eye (4.1%); 5.8% of the patients discontinued treatment due to ocular AEs. TFC offers a beneficial therapeutic alternative for patients with glaucoma or OHT whose IOP is not sufficiently controlled with dual-combination therapy. Safety and efficacy findings support those of published studies of TFC in primary open-angle glaucoma and OHT, despite differences in study designs.


Neonatal parechovirus infection mimicking a surgical abdomen.
Human parechovirus-3 (PeVA3) infection is a common cause of febrile illness in young infants and the spectrum of clinical presentation is broad. We describe a term infant who presented with marked abdominal distension and anorexia, concerning for an acute surgical abdomen. Evaluation revealed that the infant had PeVA3 infection. This case highlights the importance of recognising severe abdominal distension and discomfort as a clinical presentation associated with PeV and the potential utility of rapid testing for PeV.


Challenging the notion of a thematic preference in young children.
Many researchers have argued that early cognitive development is characterized by a conceptual preference for thematic over taxonomic relations. However, more recent research indicates that infants and toddlers may not favor thematic relations. To resolve this discrepancy, the conceptual preferences of children ranging from 2 to 4 years of age were examined, using a forced-choice task including a target (e.g., a carrot), a thematic alternative (e.g., a rabbit), and a taxonomic alternative (e.g., a tomato). The effects of age, experimenter's instructions, hierarchical level (basic vs. superordinate), and stimulus medium (pictures vs. objects) were examined systematically. Children revealed no pervasive preference for either thematic or taxonomic relations. This challenges the notion of a developmental shift in conceptual preferences and suggests a more continuous trajectory in early conceptual development.


Spatial Patterns in Rydberg Excitations from Logarithmic Pair Interactions.
The collective excitations in ensembles of dissipative, laser driven ultracold atoms exhibit crystal-like patterns, a many-body effect of the Rydberg blockade mechanism. These crystalline structures are revealed in an experiment from a postselection of configurations with fixed numbers of excitations. Here, we show that these subensembles can be well represented by ensembles of effective particles that interact via logarithmic pair potentials. This allows one to study the emergent patterns with a small number of effective particles to determine the phases of Rydberg crystals and to systematically study contributions from N-body terms.


Percutaneous sclerotherapy for varicocele embolization.
Varicocele is a common cause of male infertility and can be treated surgically or by angiographic occlusion of the internal spermatic (testicular) vein. The treatment of clinical as well as subclinical varicoceles has been reported to improve sperm parameters. Varicocele also can cause scrotal pain and discomfort. We treated 89 patients using percutaneous sclerotherapy on an outpatient basis. Our technique proved to be simple and effective and was associated with low morbidity. At follow-up only three failures occurred.


Postpartum depression in a military sample.
Postpartum depression (PPD) affects nearly 1 in 8 mothers and has many negative implications. Studies show particular risk factors are linked with PPD. There are nearly 200,000 women serving in the U.S. Armed Forces, but little is known regarding PPD and active duty (AD) mothers. This study examined rates and risk factors for AD mothers and found that 19.5% were positive for PPD symptoms. Ten significant psychosocial factors were associated with PPD, including low self-esteem, prenatal anxiety, prenatal depression, history of previous depression, social support, poor marital satisfaction, life stress, child care stress, difficult infant temperament, and maternity blues. This study has implications for prevention, identification, and treatment of AD military women with PPD.


Structural organization of the perivascular astrocyte endfeet and their relationship with the endothelial glucose transporter: a confocal microscopy study.
Despite the increasing evidence for a prominent role played by the perivascular endfeet of astrocytes in the functional metabolic coupling between astrocytes and neurons, a clear picture of their spatial organization is still lacking. To examine the three-dimensional structure of the astrocyte endfeet and their relationships with the endothelial cells, coronal rat brain sections immunolabeled for the two astroglial markers [glial fibrillary acidic protein (GFAP)/S-100beta] and the endothelial glucose transporter (GLUT1) were analyzed under the confocal microscope. Double immunolabeling of GFAP and S-100beta showed numerous well-defined astrocytes sending one or more endfeet to the vasculature. Examination of GFAP immunolabeling at higher magnification showed that these endfeet consist of well-defined rosette-like structures lying on the vessel wall. Double immunostaining of GFAP and GLUT1 showed that the endothelial cells were the main targets of these repeated geometrical units formed by the astrocyte endfeet. When three-dimensional images were reconstructed, obvious privileged anatomical relationships were observed between endfeet and individual endothelial cells. These anatomical data provide strong support for the involvement of astrocytes in cerebral metabolic coupling. The finger-like appearance of astrocyte endfeet could allow direct metabolic exchanges between intracerebral vessels and non-glial elements such as nerve terminals.


Yeast xrs2 binds DNA and helps target rad50 and mre11 to DNA ends.
Saccharomyces cerevisiae Rad50, Mre11, and Xrs2 proteins are involved in homologous recombination, non-homologous end-joining, DNA damage checkpoint signaling, and telomere maintenance. These proteins form a stable complex that has nuclease, DNA binding, and DNA end recognition activities. Of the components of the Rad50.Mre11.Xrs2 complex, Xrs2 is the least characterized. The available evidence is consistent with the idea that Xrs2 recruits other protein factors in reactions that pertain to the biological functions of the Rad50.Mre11.Xrs2 complex. Here we present biochemical evidence that Xrs2 has an associated DNA-binding activity that is specific for DNA structures. We also define the contributions of Xrs2 to the activities of the Rad50.Mre11.Xrs2 complex. Importantly, we demonstrate that Xrs2 is critical for targeting of Rad50 and Mre11 to DNA ends. Thus, Xrs2 likely plays a direct role in the engagement of DNA substrates by the Rad50. Mre11.Xrs2 complex in various biological processes.


Red Cell Distribution Width is Associated with Future Incidence of Abdominal Aortic Aneurysm in a Population-Based Cohort Study.
Red cell distribution width (RDW) has been suggested to have a predictive potential for several cardiovascular diseases, but its association with abdominal aortic aneurysm (AAA) is unknown. We examined whether RDW is associated with the risk of AAA among 27,260 individuals from the population-based Malmö Diet and Cancer Study cohort. Data of baseline characteristics were collected during 1991-1996. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for AAA across quartiles of RDW. During a median follow-up of 21.7 years, 491 subjects developed AAA. After adjustment for other confounding factors, participants in the highest quartile of RDW experienced 61% increased risk of AAA as compared to those with the lowest quartile (HR = 1.61, CI = 1.20, 2.12). RDW showed similar relationship with severe (i.e. ruptured or surgically repaired) AAA or non-severe AAA (adjusted HR 1.58 and 1.60, respectively). The observed association between RDW and AAA risk was significant in current smokers (adjusted HR = 1.68, CI = 1.18, 2.38) but not in former smokers (adjusted HR = 1.13, CI = 0.72, 1.79), or never-smokers (adjusted HR = 1.77, CI = 0.74, 4.22). Elevated RDW is associated with increased future incidence of AAA, however the causal and pathophysiological mechanisms remain to be explored.


Enhancement of Neuromuscular Activity by Natural Specimens and Cultured Mycelia of Cordyceps sinensis in Mice.
The present study was aimed to evaluate the effect of natural specimen and laboratory cultured mycelia of Cordyceps sinensis on neuromuscular activity in mice. The powder of natural specimen and laboratory cultured Cordyceps sinensis was orally administered at the dose rate of 100, 300 and 500 mg/kg for 30 days. Natural specimen and in vitro propagated Cordyceps sinensis showed significant (P<0.05) enhancement in neuromuscular endurance and antidepressant activity at 300 and 500 mg/kg as compared to the control group. However, the fungus did not proved to be as effective as fluoxetine in exhibiting antidepressant action. Muscular endurance was determined on a Rota rod apparatus while antidepressant (mood elevating) activity was measured on a photoactometer in Swiss albino mice. The effects produced by both natural specimens and laboratory cultured Cordyceps sinensis were comparable and showed almost equal potency.


Bridging advanced myeloma patients to subsequent treatments and clinical trials with classical chemotherapy and stem cell support.
Rapidly progressing relapsed/refractory multiple myeloma (RRMM) patients with compromised marrow have limited treatment options. Thus, non-myeloablative chemotherapy with a stem cell boost (SCB) may provide disease control and hematopoietic improvement as bridge to subsequent therapies. We identified 96 patients who received a SCB between January 2011 and December 2019 at the Mount Sinai Hospital. Patients had a median age of 64 years, received a median of 7 prior lines of therapy and 68 and 42% were triple-class and penta-drug refractory, respectively. Chemotherapy included melphalan (MEL) (n = 16), melphalan + carmustine (BCNU/MEL) (n = 52) or a variant of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) (n = 28). Median time to neutrophil recovery was 10 days and was significantly lower with DCEP (8 days) compared to MEL and BCNU/MEL (10-11 days) (p = 0.0047). Time to progression, progression-free survival and overall survival were 3.19, 2.7 and 8.38 months, respectively. The BCNU/MEL group had the highest response rate of 85% (p = 0.05), clinical benefit rate of 94% (p = 0.0014), progression-free survival of 3.3 months (p = 0.4) and overall survival of 8.7 months (p = 0.5). Sixty-six patients (69%) were bridged to new lines of therapy, including clinical trials. Non-myeloablative chemotherapy with SCB provides rapid disease control and marrow recovery with potential to receive further therapy.


[Consumption of antidepressants in Chile from 1992 to 2004].
Data from the Ministry of Health show that in Chile in 2004, 17% of the population had some form of depression, and mood disorders are the tenth cause of disability-adjusted life years (DALY) loss. To determine consumption of antidepressants (ADs) in Chile from 1992 to 2004. National sales data were obtained from the company IMS Health Chile and converted into defined daily doses (DDDs) per 1,000 inhabitants per day. Available ADs were classified in four pharmacological groups (i.e., serotonin-norepinephrine reuptake inhibitors, SNRLs; selective-serotonin reuptake inhibitors, SSRLs; tricyclic antidepressants, TCAs; and others). Total economic burden of ADs utilization and cost per DDDs were also calculated. Trends over time were analyzed using Pearson-R2. Total ADs consumption in Chile measured by DDDs per 1,000 inhabitants per day (DHD) increased linearly (y =0.901x + 1.9129; R2 =0.9296; p <0.001) from 2.5 in 1992 to 11.7 in 2004 (total growth of 470.2%). SSRLs were the drug class with higher consumption, and fluoxetine the most commonly consumed antidepressant. SSRLs were the drugs that dominated the market representing 79% of the total drug consumption throughout the years. Total economic burden of ADs in Chile (total cost of DDDs consumed) increased from US$65.4 million in 2001 to US$74.6 million in 2004 (14% increase). Average cost per DDD of all AD increased linearly, however not significantly from US$ 0.94 in 2001 to US$ 1.04 in 2004 (y =0.0362x + 0.8784; R2 =0.7382; p =0,262). DDDs per 1,000 inhabitants per day increased linearly over 470% from 1992-2004. SSRLs were the most commonly consumed drugs in Chile. Future research should evaluate the cost-effectiveness of antidepressants in Chile, comparing the results with drug utilization, and determining if unnecessary expenditures have been paid out.


Work-related quality of life of Ugandan healthcare workers.
To describe perceived work-related quality of life of Ugandan healthcare workers. A secondary aim was to seek participant input on ways to improve work environments. Poor patient outcomes, decreased employee motivation and decisions to leave the organization have been linked to poor work conditions. Interventions to correct healthcare worker shortage in developing countries require information about work quality of life. Descriptive cross-sectional study conducted in health and educational settings in Uganda in July 2011. Participants completed the Biographical Information Scale demographic questionnaire and the validated 24-item Work-Related Quality of Life scale. Sample included 146 healthcare workers employed in various settings. Participants reported poorer quality of work life on the work conditions, control at work and home-work interface subscales. Participants perceived stress at work to be low and experienced higher job career satisfaction. There was a significant relationship between work-related quality of life, gender and hours worked. Participants' suggestions to improve work life ranged from simple no-cost suggestions to more complex system level interventions. Work-related quality of life was low in this convenience sample. Perceived stress at work was lower than expected, but may have been due to nurses' expectations of a normal work assignment. Predominantly women, the participants had significant caregiving responsibilities. Nurses must acquire a seat at the table where crucial decisions about nursing and its future are made. By advancing leadership skills, nurses can effectively advocate for organizational changes that address broad factors related to increasing job satisfaction, and retaining and attracting nurses. Nurses can influence work quality of life individually and collectively by identifying workplace concerns, demanding safe work environments, fostering teamwork and enhancing professional growth.


Generation of a MDCK cell line with constitutive expression of the Enteropathogenic E. coli effector protein Map as an in vitro model of pathogenesis.
Enteropathogenic E. coli (EPEC) cause diarrhea and are the major cause of mortality in developing countries. EPEC use a type III secretion system to deliver effector proteins into the host epithelial cells. To understand the functions of these effectors, majority of studies on EPEC pathogenesis have relied on infections of animals or cell lines with wild type strains of EPEC or mutant strains deficient in one or more effectors. While these studies have provided valuable data, it can be difficult to assess functions of an individual effector in the presence of other EPEC effectors. Recent studies have reported the use of transient transfections with plasmids encoding various EPEC effectors into different cell lines. However, variable transfection efficiencies and expression levels of the effector proteins coupled with their expression for relatively short periods of time pose a problem if the long term effects of these effectors need to be examined. We have generated a MDCK cell line with constitutive expression of the EPEC effector Map (Mitochondrial associated protein) for efficient stable expression of EGFP-tagged Map. We observed that the constitutive expression of Map increased the permeability of charged and non-charged molecules. We also generated polyclonal antibodies against Map and checked for their specificity in MDCK-Map expressing cells. Map has been reported to contribute to the onset of diarrhea but the underlying mechanism is yet to be identified. The MDCK-Map cell line and the anti-Map antibodies generated by us can be used for in vitro studies to examine the role of Map in EPEC pathogenesis.


Reviewing the reliability, effectiveness and applications of Licox in traumatic brain injury.
To review the pathophysiology, accuracy, effectiveness and use of Licox for brain tissue oxygen monitoring in traumatic brain injury (TBI). The Licox monitoring system allows continuous monitoring of partial pressure of brain tissue oxygen (PbO(2)), brain tissue temperature and intracranial pressure (ICP). The application and effectiveness of the use of Licox in TBI is not clearly explored within the literature. A date limit of 1995-2009, English language, all animal and human studies and the following terms were searched: Licox, brain tissue oxygenation, cerebral oxygenation and TBI. MEDLINE database was the primary data source. All paediatric papers were excluded from the search. Studies not related to pathophysiology and management of TBI and brain tissue oximetry in adults were excluded. Data relevant to the subject under consideration were extracted by three independent clinicians to form a narrative report. Studies were critically evaluated using the NHS Public Health Resource Unit's checklist for each study analysed. Licox offers new insights into cerebral pathology and physiology. The continuous bedside monitoring provides real-time data that can be used to improve patient management and prognosis in specialist units by trained and experienced staff. More research is required to understand the limitations of this technology and why it is not in widespread use. RELEVENCE TO CLINICAL PRACTICE: A clinical tool that could be utilized more often in the right setting to improve care to patients suffering from TBI by disseminating more information on this unique tool.


Prognostic factors in avalanche resuscitation: a systematic review.
Avalanche resuscitation will save lives if focussed on victims that have the potential to survive. The purpose of this systematic review was to examine 4 critical prognostic factors for burial victims in cardiac arrest. Time of burial, airway patency, core temperature and serum potassium level were analyzed as PICO (Patient/population, Intervention, Comparator, Outcome) questions within the 2010 Consensus on Science process of the International Liaison Committee on Resuscitation. The electronic databases of Medline via PubMed, EMBASE via OVID and the Cochrane Database of Systematic Reviews were searched using combinations of the search terms "avalanche", "air pocket", "hypothermia" and "serum potassium". Of 1910 publications that were identified 30 were found relevant. The predictive value for survival of a short time of burial or a patent airway after 35 min of burial is supported by 10 retrospective case-control studies, 4 case series and 2 experimental studies, while no studies are neutral or opposed. A core temperature of less than 32 degrees C with a patent airway is supported by 2 retrospective case-control studies and 3 case series, while 10 studies are neutral. Serum potassium level is supported by 6 retrospective case-control studies and 3 case reports, while 3 retrospective case-control studies and 1 animal model are neutral. After 35 min of burial, or where the core temperature is less than 32 degrees C, a patent airway is associated with survival to hospital discharge. A serum potassium of less than 7 mmol/L may be a valuable indicator for survival when other indicators are unclear. These findings should modify the current avalanche resuscitation scheme.


Pediatric deceased donor liver transplantation with in situ size reduction for recipient-graft size matching.
We present a case of pediatric deceased donor liver transplantation using a reduced whole liver graft in a 25-month-old boy weighing 12.7 kg. After he had undergone Kasai portoenterostomy for biliary atresia, his general condition deteriorated progressively. He was enrolled on the waiting list for liver transplantation with Pediatric End-stage Liver Disease score of 15. The donor was a 51-monthold boy with body weight of 20 kg. The donor-to-recipient body weight ratio was 158%. The liver graft appeared to be larger than the recipient's abdominal cavity. Thus, we planned to do in situ size reduction. Recipient surgery was performed following standard procedures. We performed graft outflow vein reconstruction using a modified piggyback technique like the double inferior vena cava method. Since the portal vein was hypoplastic, a side-to-side anastomosis technique was used. We also performed intraoperative portogram to embolize venous collaterals. After completing the graft implantation, we found that the liver graft was too large to be accommodated within the abdomen. After in situ resection of the left lateral section parenchyma, we successfully performed primary closure of the abdominal wound. This patient experienced episodes of acute rejection. He has been doing well for four years after the transplantation.


Rationale for large scale bone marrow hemopoietic stem cell manipulation.
Many years have passed since the first attempt in marrow grafting was performed (1939). During this period several techniques have been developed in marrow processing and manipulation to overcome bone marrow transplant complications: the ABO barrier in case of major incompatibility between donor and recipient, the graft-versus-host disease due to the presence of allogeneic mature T-lymphocytes in cellular suspension and the neoplastic cell residue in autografts. At the end, the final volume of autologous mononuclear cell suspension must be frozen and an optimized cryopreservation allows a cell viability and subsequently an adequate medullar repopulating capacity.


"That Should Be Left to Doctors, That's What They are There For!"-Exploring the Reflexivity and Trust of Young Adults When Seeking Health Information.
This paper explores the health information-seeking practices of healthy young adults and how they assess and rank sources of information through a qualitative study. The findings show that participants (a) are strongly committed to searching for information about health and lifestyle, especially via the Internet; (b) healthcare professionals were perceived as the most reliable source of health information and advice; (c) online health information, although frequently accessed and experienced as empowering, is seen as a potentially unreliable source. Findings evidence how becoming better informed about health-related topics plays a pivotal role in individuals' lives, most notably by using the Internet. Participants were able to reflect about what it means to know about health. The construction of trust regarding health information involved a heuristic process vis-à-vis source reliability and perceived credibility that places doctors as the most trustworthy medium of medical advice and health information. We conclude that participants' trust toward professionals suggests the preference and need for more personalized care; and it is a response to the ambiguity and uncertainty that permeates the health information landscape, particularly that which is web-based.


Molybdenum interlayers for nucleation enhancement in diamond CVD growth.
The use of a 50-nm thick Mo interlayer on silicon substrates for the nucleation enhancement of microcrystalline diamond (MCD) and nanocrystalline diamond (NCD) films synthesized by hot filament chemical vapour deposition was studied. The MCD and NCD films were deposited using methane concentrations of 1% and 2%, respectively. The presence of a Mo nucleation layer enabled the formation of more uniform NCD films with reduced surface roughness (rms roughness approximately 40 nm for a 750-nm thick layer) and with significantly less interfacial voids due to the superior nucleation densities and surface coverage in the early stages of NCD film formation. During the initial stages of MCD film growth, the nucleation density increased by one order of magnitude as compared to uncoated silicon. As a result, much thinner MCD films with smaller surface grain sizes and, thus, reduced surface roughness could be produced as well. The presence of a Mo nucleation layer not only leads to a structural optimization of NCD and MCD films but also allows fast nucleation and film growth kinetics at relatively low substrate temperatures (approximately 575 degrees C), relevant for the coating of substrate materials that do not withstand high substrate temperatures.


[Meyerbeer, spa curist, biography of J. -F. Struensee, physician and man of the modernist state].
In 1757, Struensee (1737-1772) graduated in medicine at Halle-Saale university, as his father a high dignitary in the lutherian church was, and supported by the presence of his grand-father the physician and scientist Samuel Carl. The family moved to Altona where he was nominated as physician in the city council. Then he largely dealt with medical and social items, for orphans and disabled, and attempted to prevent infectious deseases, small pox, typhus, scabies ans dysenteric syndroms. For sure when he practised his investigations on water samples with microscopy, Struensee acted as a pioneer to suspect microrganisms to be responsible for infectious diseases. Later on, he started his medical service dedicated to the Danish king Christian VII. This part of his life demonstrated the ambitious but highly capable man he was when running the whole government load for Denmark, in a liberal and advanced way. We link the drama of his death when he was condamned, to the symphony composed by Meyerbeer (1791-1864), known as an incidental music for Michael Beer's play Struensee, 1846.


Biased motion and molecular motor properties of bipedal spiders.
Molecular spiders are synthetic molecular motors featuring multiple legs that each can interact with a substrate through binding and cleavage. Experimental studies suggest the motion of the spider in a matrix is biased toward uncleaved substrates and that spider properties such as processivity can be altered by changing the binding strength of the legs to substrate [R. Pei, S. K. Taylor, D. Stefanovic, S. Rudchenko, T. E. Mitchell, and M. N. Stojanovic, J. Am. Chem. Soc. 128, 12693 (2006)]. We investigate the origin of biased motion and molecular motor properties of bipedal spiders using Monte Carlo simulations. Our simulations combine a realistic chemical kinetic model, hand-over-hand or inchworm modes of stepping, and the use of a one-dimensional track. We find that stronger binding to substrate, cleavage and spider detachment from the track are contributing mechanisms to population bias. We investigate the contributions of stepping mechanism to speed, randomness parameter, processivity, coupling, and efficiency, and comment on how these molecular motor properties can be altered by changing experimentally tunable kinetic parameters.


Association of the maternal 14-bp insertion polymorphism in the HLA-G gene in women with recurrent spontaneous abortions.
Human leukocyte antigen (HLA)-G has been postulated as an important immunotolerant molecule in maintaining fetal-maternal relationship. Recent reports indicated that the 14-bp deletion/insertion polymorphism in exon 8 of HLA-G gene influences HLA-G mRNA stability and isoform splicing patterns, thus modulating the levels of HLA-G expression. This might play an immunomodulatory role of HLA-G during implantation and pregnancy. In the present study, 109 unrelated fertile control women and 79 women who had experienced recurrent spontaneous abortion (RSA) were genotyped for the 14-bp insertion/deletion polymorphism. No significant difference was observed in the distribution of 14-bp insertion/deletion genotype between controls and the RSA group. However, a greater number of 14-bp insertion alleles exist in the RSA group than in the controls.


Willingness to pay to eliminate the risk of restenosis following percutaneous coronary intervention: a contingent valuation.
Percutaneous coronary intervention (PCI) remains limited by the risk of restenosis. Patients' perceptions of the health benefits and value of avoiding restenosis are incompletely known. We used a contingent valuation approach to assess the willingness to pay (WTP) for a hypothetical treatment that eliminates the risk of restenosis among 270 PCI patients. Patients were provided with a scenario describing a baseline 10% or 20% probability of restenosis in the year following the procedure, which could lead to repeat PCI or, more rarely, bypass surgery, without any increase in mortality. Six different "take it or leave it" bids ($500, $1000, $1500, $2000, $2500, and $3000) and both risk levels were randomly assigned. Multiple logistic regression was used to identify independent predictors of a positive response to the WTP question. Using nonparametric methods, the median WTP to eliminate the risk of restenosis was estimated at $2802. As expected, higher income was independently associated with a higher probability of a positive response to the WTP question (odds ratio, 2.81; 95% CI, 1.32 to 5.97). Bids also were independently associated with the probability of being willing to pay, and this association followed a quadratic effect. Below $1500, bid had little impact on patient answers. However, as prices increased, the probability of being willing to pay started to decrease sharply. The potential to eliminate the risk of restenosis, a benign complication, would have substantial value for patients undergoing PCI.


Lemierre Syndrome in a Patient With Splenectomy Secondary to Pyruvate Kinase Deficiency, Complicated by Heparin Resistance.
Lemierre syndrome was first documented in the literature in 1936, and is defined as septic thrombophlebitis of the internal jugular vein. It is typically a result of oropharyngeal infection causing local soft tissue inflammation, which spreads to vasculature, and promotes formation of septic thrombi within the lumen, persistent bacteremia, and septic emboli. We present the case of a 24-year-old incarcerated man, who presented with leukocytosis and a right-sided tender, swollen neck after undergoing left mandibular molar extraction for an infected tooth. Computed tomography revealed a persistent thrombus in the transverse and sigmoid sinuses bilaterally, extending downwards, into the upper jugular veins. He was started on empiric intravenous vancomycin, zosyn, and heparin, but subsequently demonstrated heparin resistance, and was thus anticoagulated with a lovenox bridge to warfarin. Throughout his hospital course, hemocultures demonstrated no growth, so antibiotic treatment was deescalated to oral metronidazole and ceftriaxone. On discharge, the patient was transitioned to oral amoxicillin and metronidazole for an additional 4 weeks with continuation of anticoagulation with warfarin for a total of 3 to 6 months. This case report details a unique presentation of Lemierre syndrome with bilateral transverse sinus, sigmoid sinus, and internal jugular vein thrombosis that was presumably secondary to an odontogenic infectious focus.


Salt controls endothelial and vascular phenotype.
High salt (NaCl) intake promotes the development of vascular diseases independent of a rise in blood pressure, whereas reduction of salt consumption has beneficial effects for the arterial system. This article summarizes our current understanding of the molecular mechanisms of high salt-induced alterations of the endothelial phenotype, the impact of the individual endothelial genotype, and the overall vascular phenotype. We focus on the endothelial Na(+) channel (EnNaC)-controlled nanomechanical properties of the endothelium, since high Na(+) leads to an EnNaC-induced Na(+)-influx and subsequent stiffening of endothelial cells. The mechanical stiffness of the endothelial cell (i.e., the endothelial phenotype) plays a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. This endothelium-born process is followed by the development of arterial stiffness (i.e., the vascular phenotype), predicting the development of vascular end-organ damage such as myocardial infarction, stroke, and renal impairment. In this context, we outline the potential clinical implication of direct (amiloride) and indirect (spironolactone) EnNaC inhibition on vascular function. However, interindividual differences exist in the response to high salt intake which involves different endothelial genotypes. Thus, selected genes and genetic variants contributing to the development of salt-induced endothelial dysfunction and hypertension are discussed. In this review, we focus on the role of salt in endothelial and vascular (dys)function and the link between salt-induced changes of the endothelial and vascular phenotype and its clinical implications.


Dietary patterns and risk of cardiovascular diseases: a review of the evidence.
CVD are the main cause of death especially in high-income countries. Previously, research focused on single nutrients including saturated and MUFA, sodium and dietary fibre, or specific foods such as fish, fruit and vegetables, and olive oil, in the aetiology of CVD. In recent years, however, the effects of complete dietary patterns on the prevention of CVD have gained interest, to account for diet heterogeneity and food-nutrient interactions. Several dietary patterns have been investigated, such as the Paleolithic diet, the vegetarian and vegan diets, the Diet Approaches to Stop Hypertension (DASH), the Nordic and Mediterranean diets, with many contradictions remaining. The aim of this review is to give an overview of the effects of these dietary patterns on CVD risk, to discuss their overall nutrient adequacy and briefly discuss their environmental impact.


Barley yellow dwarf virus Infection Leads to Higher Chemical Defense Signals and Lower Electrophysiological Reactions in Susceptible Compared to Tolerant Barley Genotypes.
Barley yellow dwarf virus (BYDV) is a phloem limited virus that is persistently transmitted by aphids. Due to huge yield losses in agriculture, the virus is of high economic relevance. Since the control of the virus itself is not possible, tolerant barley genotypes are considered as the most effective approach to avoid yield losses. Although several genes and quantitative trait loci are known and used in barley breeding for virus tolerance, little is known about molecular and physiological backgrounds of this trait. Therefore, we compared the anatomy and early defense responses of a virus susceptible to those of a virus-tolerant cultivar. One of the very early defense responses is the transmission of electrophysiological reactions. Electrophysiological reactions to BYDV infection might differ between susceptible and tolerant cultivars, since BYDV causes disintegration of sieve elements in susceptible cultivars. The structure of vascular bundles, xylem vessels and sieve elements was examined using microscopy. All three were significantly decreased in size in infected susceptible plants where the virus causes disintegration of sieve elements. This could be associated with an uncontrolled ion exchange between the sieve-element lumen and apoplast. Further, a reduced electrophysiological isolation would negatively affect the propagation of electrophysiological reactions. To test the influence of BYDV infection on electrophysiological reactions, electropotential waves (EPWs) induced by leaf-tip burning were recorded using aphids as bioelectrodes. EPWs in infected susceptible plants disappeared already after 10 cm in contrast to those in healthy susceptible or infected tolerant or healthy tolerant plants. Another early plant defense reaction is an increase in reactive oxygen species (ROS). Using a fluorescent dye, we found a significant increase in ROS content in infected susceptible plants but not in infected tolerant plants. Similar results were found for the phytohormones abscisic acid and three jasmonates. Salicylic acid levels were generally higher after BYDV infection compared to uninfected plants. Heat stimulation caused an increase in jasmonates. By shedding light on the plant defense mechanisms against BYDV, this study, provides further knowledge for breeding virus tolerant plants.


Conclusion: What We Learned and Next Steps.
In the previous articles, my colleagues have presented analyses of the survey data that have implications for professional preparation, practice and ongoing professional development. I will conclude this volume highlighting six areas that require further investigation, theoretical development and practical integration.


Cytomegalovirus disease in children with acute lymphoblastic leukemia.
Viral infections are an underrecognized problem in children on standard chemotherapy for acute lymphoblastic leukemia (ALL). In countries with high baseline seroprevalence of cytomegalovirus (CMV) such as India, it may be an important pathogen leading to fever, end-organ damage, and cytopenia. Data regarding the incidence and manifestations of CMV disease in pediatric ALL patients are scanty. The authors prospectively assessed all children on chemotherapy for ALL with prolonged febrile neutropenia (FN) for CMV disease over a 3-year period. Children with end-organ damage, including pneumonia, retinitis, and colitis, were also evaluated. Quantitative and qualitative polymerase chain reaction (PCR) from blood, body fluids, or tissue was done along with ophthalmologic evaluation. CMV disease was detected in 10% of the children with prolonged FN. In addition, other children were identified due to end-organ damage, lung and eye being the common organs of involvement. Time of CMV reactivation was essentially during nonintense phase of chemotherapy. Lymphopenia was present in most children, and prolonged lymphopenia was associated with relapse of CMV infection after therapy. The authors conclude that CMV is an important pathogen in children on standard chemotherapy for ALL. It has a good outcome with early detection and directed therapy. Parenteral ganciclovir is needed for a period of 14-21 days to prevent recurrence.


Circulating cell-free fetal nucleic acid analysis may be a novel marker of fetomaternal hemorrhage after elective first-trimester termination of pregnancy.
Analysis of cell-free fetal DNA (fDNA) and RNA in maternal plasma could be useful in the diagnosis and management of complications of pregnancy. In this review, we discuss our studies to investigate the potential of fetal nucleic acid measurement in maternal plasma as a marker of fetomaternal hemorrhage (FMH) after elective first-trimester termination of pregnancy (TOP). Using quantitative real-time PCR amplification of the DYS1 sequence, elevation of plasma fDNA levels after TOP was observed, especially in the late first trimester. This corresponds with the functional development of the placental vascular structure and fetal hematopoiesis. This Y sequence-based PCR amplification assay, however, limits the analysis to pregnant women carrying male fetuses. Therefore, we also developed a real-time quantitative reverse-transcriptase PCR assay of the gamma-globin transcript as a marker of fetal erythroid cells. Although plasma gamma-globin mRNA levels were decreased after TOP in many patients, an elevation was observed in some patients at greater than 9 weeks' gestation, which is consistent with the increase in plasma fDNA levels. Our data suggest that fetal hematopoietic cells contribute to the pool of fetal nucleic acids in the maternal circulation. Measurement of cell-free fetal nucleic acid levels in maternal plasma may have clinical application as a novel marker of FMH after 9 weeks of gestation.


Synthesis and characterization of cadmium phosphide quantum dots emitting in the visible red to near-infrared.
The synthesis of high-quality cadmium phosphide quantum dots with emission wavelength maxima in the range from 1200 to approximately 760 nm are reported. The results demonstrate that the nucleation and growth linked with the optical properties can be controlled by the temperature, the growth time, and the addition of ligands such as oleylamine and trioctylphosphine. Photoelectrochemical investigations revealed that the cadmium phosphide QD-derivatized electrodes show an optical response and that photocurrents of several nanoamperes per square centimeter can be obtained upon illumination.


[Studies on the appropriate administration of cisplatin based on pharmacokinetics and toxicity].
Ninety-six patients with non-small cell lung cancer were treated with cisplatin (80-150 mg/m2). The pharmacokinetics of cisplatin were studied in 27 of these patients. Cisplatin was administered intravenously for 30-120 min. Plasma concentrations of total platinum and ultrafilterable (non-protein-bound) platinum were monitored by flameless atomic absorption spectrophotometry. Maximum total platinum levels in plasma were attained at the end of infusion, and thereafter decayed in a biphasic fashion, with an initial phase half-life (t1/2 alpha) of 10.2 to 14.6 min and a secondary phase half-life (t1/2 beta) of 41.7 to 81.3 h. The half-life was prolonged as the dosage was increased. Non-protein-bound platinum was rapidly cleared to below the measurable level within 4 hours at 80 mg/m2 and 120 mg/m2 of cisplatin, but declined in a biphasic manner, with t1/2 alpha of 31.2 min and t1/2 beta of 20.1 h at 150 mg/m2 of cisplatin. Toxicities were increased according to dosage, and decreased with a 50 mg/m2 X 3 days regime. Nephrotoxicity and ototoxicity were the dose-limiting factors in the single-dose escalation scheme used. In conclusion, the optimal dosage of cisplatin appeared to be 120 mg/m2 considering its toxicity.


Frequent inactivation of CDKN2A and rare mutation of TP53 in PCNSL.
Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B-cell lymphomas and one T-cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG:Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl-2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.


Scalable Preparation of the Masked Acyl Cyanide TBS-MAC.
This paper describes the three-step synthesis of TBS-MAC, a masked acyl cyanide (MAC) and a versatile one-carbon oxidation state three synthon. We have developed a scalable and detailed synthesis that involves: (1) acetylation of malononitrile to form the sodium enolate, (2) protonation of the enolate to form acetylmalononitrile, and (3) epoxidation of the enol, rearrangement to an unstable alcohol, and TBS-protection to form the title compound. Both the sodium enolate and acetylmalononitrile are bench-stable precursors to the intermediate hydroxymalononitrile, which can be converted to other MAC reagents beyond TBS by varying the protecting group (Ac, MOM, EE, etc.).


Characterization of binding and utilization of hemoglobin by Prevotella nigrescens.
The ability of Prevotella nigrescens to utilize and bind to hemoglobin was investigated. Growth studies showed that P. nigrescens was able to utilize hemoglobin efficiently as an iron source. Binding of P. nigrescens to hemoglobin was demonstrated by dot blot assay. Heat and trypsin treatments of the bacteria led to a decrease in activity. Globin gave nearly complete inhibition of activity. Additionally, lactoferrin partially inhibited activity. In contrast, transferrin, cytochrome C and catalase exerted little or no inhibitory effect. Although the sugars tested did not affect activity, several of the amino acids tested, including arginine, cysteine, histidine and lysine, inhibited activity. In a solid phase assay, 41-, 56- and 59-kDa proteins of P. nigrescens reacted with hemoglobin. These results suggest that P. nigrescens utilizes hemoglobin for growth and 41-, 56- and 59-kDa proteins may be involved in hemoglobin binding.


Rat alpha- and beta-parvalbumins: comparison of their pentacarboxylate and site-interconversion variants.
Introduction of a fifth carboxylate into the ligand array of the CD site (via the combined S55D and E59D mutations) or the EF site (G98D) of rat alpha-parvalbumin substantially increases divalent ion affinity. This behavior, in conflict with that seen in model peptide systems, agrees with existing data for rat beta-parvalbumin [Henzl et al. (1996) Biochemistry 35, 5856-5869]. The complete analysis of the S55D/E59D double variant necessitated characterization of alpha E59D. Whereas the D59E mutation has minimal influence on beta CD site affinity, E59D has a major impact on the alpha CD site, lowering the apparent association constant by a factor of 14. The thermodynamic consequences of exchanging the rat alpha CD and EF site ligand arrays, which differ at the +z and -x coordination positions, were also examined. When the alpha CD array is imported into the EF site, it acquires a low-affinity phenotype, in agreement with previous findings for beta [Henzl et al. (1998) Biochemistry 37, 9101-9111]. However, when the EF ligand array is introduced into the alpha CD binding loop, it retains a high-affinity signature. This result, contrary to that observed in beta, suggests that the influence of the parvalbumin CD site environment supersedes the intrinsic behavior of the ligand array, a conclusion further supported by the disparate impact of the beta D59E and alpha E59D mutations.


Spirometric forced expiratory volumes measured in the standing versus the sitting posture.
To date, only one study has empirically examined the effects of sitting versus standing posture on the spirometric forced expiratory volumes. Because of design limitations, the small excess of sitting over standing values found in that study may have been due to a positive testing order effect. Using a crossover design, the present study of 90 middle-aged male subjects alternated the sitting-standing and standing-sitting testing sequence between subjects to avoid confounding by testing order effects. The major findings were that forced expiratory volumes in one and in six seconds and forced vital capacity were significantly larger (p less than 0.001) in the standing than in the sitting posture, with mean standing minus sitting differences ranging from +0.06 to +0.08 L for the 3 indexes. The larger expired volumes measured in the standing position in this study were probably due to the subjects taking slightly larger inspirations in this posture than in the sitting position.


Ecological niche models for sand fly species and predicted distribution of Lutzomyia longipalpis (Diptera: Psychodidae) and visceral leishmaniasis in Bahia state, Brazil.
Visceral leishmaniasis is a public health problem in Brazil. This disease is endemic in most of Bahia state, with increasing reports of cases in new areas. Ecological niche models (ENM) can be used as a tool for predicting potential distribution for disease, vectors, and to identify risk factors associated with their distribution. In this study, ecological niche models (ENMs) were developed for visceral leishmaniasis (VL) cases and 12 sand fly species captured in Bahia state. Sand fly data was collected monthly by CDC light traps from July 2009 to December 2012. MODIS satellite imagery was used to calculate NDVI, NDMI, and NDWI vegetation indices, MODIS day and night land surface temperature (LST), enhanced vegetation index (EVI), and 19 Bioclim variables were used to develop the ENM using the maximum entropy approach (Maxent). Mean diurnal range was the variable that most contributed to all the models for sand flies, followed by precipitation in wettest month. For Lutzomyia longipalpis (L. longipalpis), annual precipitation, precipitation in wettest quarter, precipitation in wettest month, and NDVI were the most contributing variables. For the VL model, the variables that contributed most were precipitation in wettest month, annual precipitation, LST day, and temperature seasonality. L. longipalpis was the species with the widest potential distribution in the state. The identification of risk areas and factors associated with this distribution is fundamental to prioritize resource allocation and to improve the efficacy of the state's program for surveillance and control of VL.


Female-biased population divergence in the venom of the Hentz striped scorpion (Centruroides hentzi).
Sex-biased genes are expressed at higher levels in one sex and contribute to phenotypic differences between males and females, as well as overall phenotypic variation within and among populations. Venom has evolved primarily for predation and defense, making venom expression a highly variable phenotype as a result of local adaptation. Several scorpion species have shown both intraspecific and intersexual venom variation, and males have been observed using venom in courtship and mating, suggesting the existence of venom-specific, sex-biased genes that may contribute to population divergence. We used reversed-phase high-performance liquid chromatography (RP-HPLC), Agilent protein bioanalyzer chips, nano-liquid chromatography mass spectrometry (nLC/MS/MS), and median lethal dose (LD50) assays in fruit flies (Drosophila melanogaster) and banded crickets (Gryllodes sigillatus) to investigate proteomic and functional venom variation within and among three Florida populations of the Hentz striped scorpion (Centruroides hentzi). We found significant venom variation among populations, with females, not males, being responsible for this divergence. We also found significant variation in venom expression within populations, with males contributing more to within population variation than females. Our results provide evidence that male and female scorpions experience different natural and sexual selective pressures that have led to the expression of sex-biased venom genes and that these genes may be consequential in population divergence.


Giving subjects the eye and showing them the finger: socio-biological cues and saccade generation in the anti-saccade task.
Pointing with the eyes or the finger occurs frequently in social interaction to indicate direction of attention and one's intentions. Research with a voluntary saccade task (where saccade direction is instructed by the colour of a fixation point) suggested that gaze cues automatically activate the oculomotor system, but non-biological cues, like arrows, do not. However, other work has failed to support the claim that gaze cues are special. In the current research we introduced biological and non-biological cues into the anti-saccade task, using a range of stimulus onset asynchronies (SOAs). The anti-saccade task recruits both top-down and bottom-up attentional mechanisms, as occurs in naturalistic saccadic behaviour. In experiment 1 gaze, but not arrows, facilitated saccadic reaction times (SRTs) in the opposite direction to the cues over all SOAs, whereas in experiment 2 directional word cues had no effect on saccades. In experiment 3 finger pointing cues caused reduced SRTs in the opposite direction to the cues at short SOAs. These findings suggest that biological cues automatically recruit the oculomotor system whereas non-biological cues do not. Furthermore, the anti-saccade task set appears to facilitate saccadic responses in the opposite direction to the cues.


Failure of initial 24-hour esophageal pH monitoring to predict refractoriness and intractability in reflux esophagitis.
Prolonged esophageal pH monitoring is considered to be the most sensitive and specific test for the diagnosis of gastroesophageal reflux disease (GERD). However, the role of pH monitoring in predicting the clinical and endoscopic response of reflux esophagitis is not well defined. In this study, 106 patients with moderate to severe symptoms of GERD and esophagitis (grades 0-IV) by endoscopy were initially studied by ambulatory esophageal pH monitoring, and their clinical response to standard H2 antagonist therapy was monitored at 8 wk. Refractory patients were defined as those who failed to heal and/or had intractable reflux symptoms after 8 wk of H2 antagonist therapy, and who required continuous therapy with higher doses of H2 antagonists, addition of prokinetic agents, or omeprazole. There was a positive correlation (r = 0.89) between endoscopic severity of esophagitis upon entry into the study and refractoriness to standard medical therapy. However, there were no differences in the various pH parameters analyzed between the 58 patients who responded and the 48 patients who were refractory to medical therapy, regardless of the endoscopic grading of their esophagitis. We conclude that 24-h ambulatory esophageal pH monitoring does not predict refractoriness of reflux esophagitis to standard therapy. The decision for more aggressive methods of treatment probably requires assessment of symptomatic and endoscopic response after 8 week standard H2 antagonist therapy.


Giant enhancement in vertical conductivity of stacked CVD graphene sheets by self-assembled molecular layers.
Layer-by-layer-stacked chemical vapour deposition (CVD) graphene films find applications as transparent and conductive electrodes in solar cells, organic light-emitting diodes and touch panels. Common to lamellar-type systems with anisotropic electron delocalization, the plane-to-plane (vertical) conductivity in such systems is several orders lower than its in-plane conductivity. The poor electronic coupling between the planes is due to the presence of transfer process organic residues and trapped air pocket in wrinkles. Here we show the plane-to-plane tunnelling conductivity of stacked CVD graphene layers can be improved significantly by inserting 1-pyrenebutyric acid N-hydroxysuccinimide ester between the graphene layers. The six orders of magnitude increase in plane-to-plane conductivity is due to hole doping, orbital hybridization, planarization and the exclusion of polymer residues. Our results highlight the importance of interfacial modification for enhancing the performance of LBL-stacked CVD graphene films, which should be applicable to other types of stacked two-dimensional films.


POWERDRESS-mediated histone deacetylation is essential for thermomorphogenesis in Arabidopsis thaliana.
Ambient temperature affects plant growth and even minor changes can substantially impact crop yields. The underlying mechanisms of temperature perception and response are just beginning to emerge. Chromatin remodeling, via the eviction of the histone variant H2A.Z containing nucleosomes, is a critical component of thermal response in plants. However, the role of histone modifications remains unknown. Here, through a forward genetic screen, we identify POWERDRESS (PWR), a SANT-domain containing protein known to interact with HISTONE DEACETYLASE 9 (HDA9), as a novel factor required for thermomorphogenesis in Arabidopsis thaliana. We show that mutations in PWR impede thermomorphogenesis, exemplified by attenuated warm temperature-induced hypocotyl/petiole elongation and early flowering. We show that inhibitors of histone deacetylases diminish temperature-induced hypocotyl elongation, which demonstrates a requirement for histone deacetylation in thermomorphogenesis. We also show that elevated temperature is associated with deacetylation of H3K9 at the +1 nucleosomes of PHYTOCHROME INTERACTING FACTOR4 (PIF4) and YUCCA8 (YUC8), and that PWR is required for this response. There is global misregulation of genes in pwr mutants at elevated temperatures. Meta-analysis revealed that genes that are misregulated in pwr mutants display a significant overlap with genes that are H2A.Z-enriched in their gene bodies, and with genes that are differentially expressed in mutants of the components of the SWR1 complex that deposits H2A.Z. Our findings thus uncover a role for PWR in facilitating thermomorphogenesis and suggest a potential link between histone deacetylation and H2A.Z nucleosome dynamics in plants.


The inter-examiner variation in rating dental formation from radiographs.
Six examiners evaluated dental formation on 191 radiographs, using an eight-stage system. Discrepancies between these examiners are generally of the order of +/- one stage, in about 20 to 25% of the cases. The authors thus suggest the use of reference radiographs, for the double purpose of ensuring a homogeneous rating by two examiners or more, as well as the assessment of eventual differences between populations.


Pharmacologic Treatments for Sleep Disorders in Children: A Systematic Review.
Sleep problems are common in children, especially those with neurodevelopmental disorders, and can lead to consequences in behavior, functioning, and quality of life. We systematically reviewed the efficacy and harms of pharmacologic treatments for sleep disorders in children and adolescents. We searched MEDLINE, Cochrane library databases, and PsycINFO through June 2018. We included 22 placebo-controlled randomized controlled trials (1-13 weeks' duration), involving 1758 children (mean age 8.2 years). Single randomized controlled trials of zolpidem and eszopiclone in children with attention-deficit/hyperactivity disorder (ADHD) showed no improvement in sleep or ADHD ratings. Clinical Global Impression Improvement/Severity scores significantly improved with zolpidem ( P = .03 and P = .006, respectively). A single, small randomized controlled trial of diphenhydramine reported small improvements in sleep outcomes (8-10 minutes' better sleep latency and duration) after 1 week. In 19 randomized controlled trials, melatonin significantly improved sleep latency (median 28 minutes; range 11-51 minutes), sleep duration (median 33 minutes; range 14-68 minutes), and wake time after sleep onset (range 12-43 minutes), but not number of awakenings per night (range 0-2.7). Function and behavior improvement varied. Improvement in sleep was greatest in children with autism or other neurodevelopmental disorders, and smaller in adolescents and children with chronic delayed sleep onset. Adverse events were infrequent with melatonin, but more frequent than placebo in children taking eszopiclone or zolpidem. These findings show that melatonin was useful in improving some sleep outcomes in the short term, particularly those with comorbid ASD and neurodevelopmental disorders. Other drugs and outcomes are inadequately studied.


Purging of acute myeloid leukemic cells by ether lipids and hyperthermia.
Ether lipids (EL) and hyperthermia have been shown to possess a relatively selective cytotoxicity to leukemic cells. In this study, the combined effects of EL (ET-18-OCH3, ET-16-NHCOCH3, or BM 41.440) and hyperthermia on the growth of hematopoietic progenitors, myeloid leukemic cell lines, and leukemic cells obtained from patients with acute myeloid leukemia (AML) were examined to determine if this combination resulted in a greater selective killing of leukemic cells than that achieved by either EL or heat alone. When the cells were treated simultaneously with EL (50 micrograms/mL) and hyperthermia (42 degrees C) for one hour, the killing of leukemic cell line cells was enhanced considerably. Among the three EL, however, the combination of ET-18-OCH3 and heat seemed to be the most cytotoxic to leukemic cell line cells with no effect on the growth of hematopoietic progenitors. An increase in the duration of treatment with ET-18-OCH3 to four hours with heat added during the last hour resulted in a further reduction of leukemic cell line cells while sparing 50% of hematopoietic progenitors after cryopreservation. The combined treatment with ET-18-OCH3 and heat also inhibited the growth of leukemic progenitors obtained from AML patients by 97% to 100%. These data indicate that the combined treatment with EL and hyperthermia might offer an efficient means to eliminate myeloid leukemic cells in vitro.


Agreement in assessing glaucomatous discs in a clinical teaching setting with stereoscopic disc photographs, planimetry, and laser scanning tomography.
Agreement between three observers--two recently trained fellows and their supervisor--was measured using estimations of cup/disc ratio from stereoscopic optic nerve head photographs and planimetric measurements of cup/disc ratio. Agreement between the clinicians' planimetric measurements of cup/disc ratio and laser scanning tomographic measurements of cup/disc ratio also was assessed. From 16 stereoscopic optic nerve head photographs of 16 subjects, the three observers performed clinical estimations of horizontal and vertical cup/disc ratios and planimetric measurements of cup/disc ratios. Interobserver agreement was measured using intraclass correlation coefficients (ICCs). Agreement between the planimetric cup/disc ratios and laser scanning tomographic cup/disc ratios obtained with the Heidelberg Retina Tomograph (HRT; Heidelberg Engineering, Heidelberg, Germany) also was measured using ICCs. The difference between the planimetric and HRT cup/disc ratios was calculated. The agreement between observers for clinical estimations from stereoscopic optic nerve head photographs (ICC = 0.74 horizontally and 0.83 vertically) was substantial. Agreement between the observers' planimetric measurements of cup/disc ratio was substantial (ICC = 0.79). Agreement between HRT cup/disc ratio and each observer's planimetric cup/disc ratio was moderate (ICC = 0.57-0.65), with large confidence intervals. The cup/disc ratio measured with HRT was an average of 0.07 to 0.11 larger than the planimetric cup/disc ratio. Substantial agreement between observers can be achieved when estimating cup/disc ratio with stereoscopic optic nerve head photographs and with planimetric measurements of cup/disc ratios, provided there is a standard protocol and sufficient training period. Good agreement is critical in a teaching institution to ensure accurate follow-up care of patients with glaucoma, especially if patients are examined by different clinicians. Laser scanning tomography is a more repeatable and objective method, which may provide further standardization of optic nerve head assessments. Future studies will determine the reference plane that optimizes agreement between the HRT findings and each clinician's estimations.


The effect of agitation on the morphology and penicillin production of Penicillium chrysogenum.
Penicillium chrysogenum strain P1 was grown on complex media in 10 and 100 L agitated fermenters at various aeration rates and stirrer speeds. Samples were removed at intervals for measurements of the culture morphology. At high stirrer speeds (1000 and 1200 rpm) in 10-L fermentations the rate of decrease in the mean effective hyphal length was faster and the rate of penicillin production was lower than fermentations done at 800 rpm. At similar power inputs per unit volume in 100-L fermentations, the change in mean effective hyphal length was less and higher penicillin production rates were observed. This work comparing the results at two scales has shown that neither of the concepts of impeller tip speed or the dissipation rate of turbulence have general validity as a measure of hyphal damage. Our results are reasonaby well correlated by groups similar to circulation rate (ND(i) (3)/V) with lower circulation rates being beneficial. An adaptation of the van Suijdam and Metz relationship, expressed as P/D(i) (3)t(c), was most successful. Our data are insufficient to demonstrate the generality of the relationship but do support the concept of a dispersion zone around the impellers in which mycelia may be damaged. The greater the frequency of circulation of mycelia through the zone the greater the damage and the lower the rate of penicillin synthesis by the culture.


Carotid artery atheroma: comparison of preoperative B-mode ultrasound appearance with carotid endarterectomy specimen pathology.
This paper describes a prospective study comparing the preoperative Duplex ultrasound appearance of carotid bifurcation atheroma with the pathological characteristics found in the endarterectomy specimens of the same vessels. Initial studies of carotid atheroma using Duplex scanning classified plaques into heterogeneous and homogeneous and found a strong correlation between heterogeneous lesions and the presence of intraplaque haemorrhage or ulceration in the endarterectomy specimen. The B-mode classification of plaque appearance described in this paper is an expansion of the above classification. The study group comprised 220 patients who underwent 244 procedures. The indication for carotid endarterectomy was symptomatic disease in the great majority of cases. We found a high incidence of unstable plaque pathology in the operative specimens, and a predominance of the more echolucent ultrasound plaque appearances (types 1 and 2). There is a statistically significant relationship (p less than 0.001) between ultrasound appearance types 1 and 2 and the presence of either intraplaque haemorrhage or ulceration in the endarterectomy specimen.


Association of left ventricular structural and functional abnormalities with aortic and brachial blood pressure variability in hypertensive patients: the SAFAR study.
Both brachial blood pressure (BP) level and its variability (BPV) significantly associate with left ventricular (LV) structure and function. Recent studies indicate that aortic BP is superior to brachial BP in the association with LV abnormalities. However, it remains unknown whether aortic BPV better associate with LV structural and functional abnormalities. We therefore aimed to investigate and compare aortic versus brachial BPV, in terms of the identification of LV abnormalities. Two hundred and three participants who underwent echocardiography were included in this study. Twenty-four-hour aortic and brachial ambulatory BP was measured simultaneously by a validated BP monitor (Mobil-O-Graph, Stolberg, Germany) and BPV was calculated with validated formulae. LV mass and LV diastolic dysfunction (LVDD) were evaluated by echocardiography. The prevalence of LV hypertrophy (LVH) and LVDD increased significantly with BPV indices (P⩽0.04) in trend tests. After adjustment to potential confounders, only aortic average real variability (ARV), but not brachial ARV or weighted s.d. (wSD, neither aortic nor brachial) significantly associated with LV mass index (P=0.02). Similar results were observed in logistic regression. After adjustment, only aortic ARV significantly associated with LVH (odds ratio (OR) and 95% confidence interval (CI): 2.28 (1.08, 4.82)). As for LVDD, neither the brachial nor the aortic 24-hour wSD, but the aortic and brachial ARV, associated with LVDD significantly, with OR=2.28 (95% CI: (1.03, 5.02)) and OR=2.36 (95% CI: (1.10, 5.05)), respectively. In summary, aortic BPV, especially aortic ARV, seems to be superior to brachial BPV in the association of LV structural and functional abnormalities.


Pharyngo-cutaneous fistula following anterior cervical fusion.
A 26-year-old man who underwent anterior cervical fusion for a compressed fracture of the C5 vertebra developed postoperatively partial extrusion of the bone graft, followed by progressive dysphagia and retropharyngeal emphysema. Although no definite perforation of the oesophagus or pharynx was detected at reoperation, an extensive pharyngocutaneous fistula formed subsequently through the operative wound. Open drainage in association with broad spectrum antibiotics, continuous nasopharyngeal suctioning, stopping of oral intake and gastrostomy feeding resulted in closure of the fistula. However, the fistula recurred twice soon after resumption of the oral feeding. The diagnostic difficulties in determining when the healing of a pharyngo-cutaneous fistula is complete are underlined. In addition, the importance of continued treatment for 4-6 weeks after first radiological evidence of closure of the fistula is emphasized.


Focal application of low-dose-rate brachytherapy for prostate cancer: a pilot study.
To evaluate the feasibility and to report the early outcomes of focal treatment of prostate cancer using low-dose-rate brachytherapy (LDR-PB). Seventeen patients were screened with multi-parametric magnetic resonance imaging (mpMRI), 14 of whom proceeded to receive trans-perineal template mapping biopsy (TTMB). Focal LDR-PB was performed on five eligible patients using dual air kerma strength treatment plans based on planning target volumes derived from cancer locations and determined by TTMB. Patient follow-up includes prostate specific antigen (PSA) measurements, urinary and sexual function questionnaires, repeated imaging and TTMB at specific intervals post-treatment. Feasibility of focal LDR-PB was shown and short-term outcomes are promising. While the detection rate of tumors, a majority of which were low grade GS 3 + 3, was found to be low on mpMRI (sensitivity of 37.5%), our results suggest the potential of mpMRI in detecting the presence of higher grade (GS ≥ 3 + 4), and bilateral disease indicating its usefulness as a screening tool for focal LDR-PB. Low-dose-rate brachytherapy is a favorable ablation option for focal treatment of prostate cancer, requiring minimal modification to the standard (whole gland) LDR-PB treatment, and appears to have a more favorable side effect profile. Further investigation, in the form of a larger study, is needed to assess the methods used and the long-term outcomes of focal LDR-PB.


Hematopoietic Stem Cell Transplantation in an Infant with Immunodeficiency, Centromeric Instability, and Facial Anomaly Syndrome.
Immunodeficiency, centromeric instability, and facial anomaly (ICF) syndrome is a rare autosomal recessive genetic condition with severe immunodeficiency, which leads to lethal infections if not recognized and treated in early childhood. Up-to-date treatment regimens consist of prophylactic and supportive treatment of the recurrent infections. Here, we report the case of a 1-year-old boy of Moroccan consanguineous parents, who was diagnosed at 4 months of age with ICF syndrome with a homozygous missense mutation in the DNMT3B gene. He was initially admitted to the hospital with recurrent pulmonary infections from the opportunistic pathogen Pneumocystis jirovecii (PJ). Further immunological workup revealed agammaglobulinemia in the presence of B cells. After successful recovery from the PJ pneumonia, he underwent hematopoietic stem cell transplantation (HSCT) from the HLA-matched healthy sister using a chemotherapeutic conditioning regimen consisting of treosulfan, fludarabine, and thiotepa. Other than acute chemotherapy-associated side effects, no serious adverse events occurred. Six months after HSCT immune-reconstitution, he had a stable chimerism with 2.9% autologous portion in the peripheral blood and a normal differential blood cell count, including all immunoglobulin subtypes. This is one of the first cases of successful HSCT in ICF syndrome. Early diagnosis and subsequent HSCT can prevent severe opportunistic infections and cure the immunodeficiency. Centromeric instability and facial anomaly remain unaffected. Although the long-term patient outcome and the neurological development remain to be seen, this curative therapy for immunodeficiency improves life expectancy and quality of life. This case is meant to raise physicians awareness for ICF syndrome and highlight the consideration for HSCT in ICF syndrome early on.


Professional ethics of psychologists and physicians: morality, confidentiality, and sexuality in Israel.
Clinical psychologists' and nonpsychiatric physicians' attitudes and behaviors in sexual and confidentiality boundary violations were examined. The 171 participants' responses were analyzed by profession, sex, and status (student, resident, professional) on semantic differential, boundary violation vignettes, and a version of Pope, Tabachnick, and Keith-Spiegel's (1987) ethical scale. Psychologists rated sexual boundary violation as more unethical than did physicians (p less than .001). Rationale (p less than .01) and timing (p less than .0001) influenced ratings. Psychologists reported fewer sexualized behaviors than physicians (p less than .05). Professional experience (p less than .01) and sex (p less than .05) were associated with confidence-violating behavior. Overall, 78% of the sample reported attitudes or behaviors associated with boundary violations. The behavior violations were correlated (r = .49). Actual violators rated vignette violators more leniently than did nonviolators (p less than .01).


Protease-activated receptor 2 exacerbates cisplatin-induced nephrotoxicity.
Acute kidney injury (AKI) is associated with hypercoagulability. Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade activate protease-activated receptor 2 (PAR2). Previously, we have shown that PAR2-mediated inflammation aggravates kidney injury in models of diabetic kidney disease and adenine-induced renal fibrosis. However, the role of PAR2 in AKI remains unclear. To clarify the role of PAR2, we administered cisplatin, one of the most common causal factors of AKI, to wild-type and PAR2-deficient mice. The expression levels of tissue factor and PAR2 were significantly increased in the kidneys of mice that were administered cisplatin. A lack of PAR2 corrected the levels of plasma blood urea nitrogen and creatinine as well as ameliorated the acute tubular injury score in the kidney. A lack of PAR2 corrected the infiltration of neutrophils and the gene expression levels of proinflammatory cytokines/chemokines in these mouse kidneys. Similarly, apoptotic markers, such as cleaved caspase-3-positive area and Bax/Bcl2 ratio, were attenuated via PAR2 deletion. Thus, elevated PAR2 exacerbates cisplatin nephrotoxicity, and targeting PAR2 is a novel therapeutic option that aids in the treatment of patients with cisplatin-induced AKI.


Evaluation of virtual microscopy in medical histology teaching.
Histology stands as a major discipline in the life science curricula, and the practice of teaching it is based on theoretical didactic strategies along with practical training. Traditionally, students achieve practical competence in this subject by learning optical microscopy. Today, students can use newer information and communication technologies in the study of digital microscopic images. A virtual microscopy program was recently introduced at Ghent University. Since little empirical evidence is available concerning the impact of virtual microscopy (VM) versus optical microscopy (OM) on the acquisition of histology knowledge, this study was set up in the Faculty of Medicine and Health Sciences. A pretest-post test and cross-over design was adopted. In the first phase, the experiment yielded two groups in a total population of 199 students, Group 1 performing the practical sessions with OM versus Group 2 performing the same sessions with VM. In the second phase, the research subjects switched conditions. The prior knowledge level of all research subjects was assessed with a pretest. Knowledge acquisition was measured with a post test after each phase (T1 and T2). Analysis of covariance was carried out to study the differential gain in knowledge at T1 and T2, considering the possible differences in prior knowledge at the start of the study. The results pointed to non-significant differences at T1 and at T2. This supports the assumption that the acquisition of the histology knowledge is independent of the microscopy representation mode (VM versus OM) of the learning material. The conclusion that VM is equivalent to OM offers new directions in view of ongoing innovations in medical education technology.


Cost Effective Staffing for an EHR Implementation.
This case study explores costs of electronic health record (EHR) implementation with the nursing super-user role in a metropolitan, not-for-profit health care system. Tapping the local pool of unemployed newly graduated nurses as half the required super-user workforce leveraged the technology skills of novice registered nurses (RNs) as trainers of experienced nurses in five hospitals. The novel workforce migrated from hospital to hospital, thereby reducing the number of experienced nurses reassigned to super-user duties in each hospital. This strategy reduced the amount of contract labor required to backfill nurse super-users' clinical shifts. Employment of the recently graduated nurses as RN residents upon completion of the EHR implementation enabled the organization to augment its clinical workforce with expert users of its EHR. The proposed innovative model increases super-users, minimizes disruption of core staffing, and dramatically reduces expense.


Renal Function, Weaning, and Survival in Patients With Ventilator-Dependent Respiratory Failure.
Acute kidney injury in acute critical illness has been associated with poor weaning and survival outcomes. The relation between renal dysfunction as defined by creatinine clearance (CrCl) and weaning from prolonged mechanical ventilation (PMV) is not known. The objective of this study was to determine the relation of measured CrCl to weaning and survival in patients on PMV. We retrospectively studied 167 patients on PMV admitted to a long-term acute care facility for weaning over a 3-year period. Data obtained included age, gender, admission blood urea nitrogen (BUN), serum creatinine, CrCl, random urine creatinine (RUCr), and 24-hour urinary creatinine (24UCr). Renal dysfunction was defined as normal (CrCl > 90 mL/min), mild (CrCl 60-90 mL/min), moderate (CrCl 30-59 mL/min), and severe (CrCl < 30 mL/min). Primary outcome measured was liberation from PMV, defined as being off ventilator for >7 days. Survival, defined as being alive at discharge, time to wean, and time to discharge alive were secondary outcomes. The association between the studied parameters and outcomes was determined by unpaired t test. The predictive value of studied parameters for weaning and survival was determined by multivariate logistic regression analysis. P < .05 was statistically significant. Mean age was 68.5 (14) years; 49% were males; 64% were liberated and 65.8% survived. Blood urea nitrogen, RUCr, 24Ucr, and CrCl had a significant association with successful weaning. These parameters (except BUN) also had a significant association with survival. A better outcome occurred with CrCl > 90 mL/min. Measured CrCl has a significant relation to successful weaning and survival in patients on PMV and may be useful in prognosticating their outcome.


Minimally invasive navigated knee surgery: a European perspective.
European surgeons and North American surgeons have different approaches to minimally invasive total knee arthroplasty (TKA). Computer-assisted navigation emphasizes these differences. In this article, the author rethinks what surgeons are trying to achieve and notes that quality control is demanded by patients and surgeons. Although minimally invasive TKA is an accepted procedure, reflection on the facts suggests that the use of minimally invasive surgery and TKA navigation are intertwined and cannot be separated.


Sinonasal desmoplastic small round cell tumor: a case report.
A case of sinonasal desmoplastic small round cell tumor in a 21-year-old woman is presented. The tumor possessed the diagnostic histologic, immunohistochemical, and genetic characteristics of desmoplastic small round cell tumor. Histologically, the tumor was composed of nests of tumor cells surrounded by a desmoplastic stroma. Immunohistochemical staining was positive for keratin, vimentin, desmin, and, focally, neuron-specific enolase. The desmin immunopositivity was of a classic dot-like perinuclear pattern. RT-PCR analysis showed the fusion transcript resulting from the t(11;22)(p13;q12) reciprocal translocation. This case of sinonasal desmoplastic small round cell tumor, the third reported case not associated with a serosal surface, further obscures the nature and histogenesis of this entity.


MOST PROBABLE NUMBER-POLYMERASE CHAIN REACTION-BASED QUANTIFICATION OF ENTEROTOXIGENIC ESCHERICHIA COLI FROM RAW MEATS IN SOUTHERN THAILAND.
The detection of enterotoxigenic Escherichia coli (ETEC) in food, especially raw meat, has rarely been documented in Thailand, although the presence of this bacterial pathogen is considered of important public health concern. The quantity of ETEC in 150 meat samples collected from fresh food markets in southern Thailand were determined using a most probable number (MPN)-PCR-based quantification approach. ETEC contamination of raw chicken, pork and beef samples was 42%, 25% and 12%, respectively (a significant difference between chicken and beef, p < 0.05). The maximum MPN/g value for enterotoxin gene est-positive ETEC from pork and elt-positive ETEC from chicken were > 1,100 MPN/g, but the range of MPN/g values was greater for ETEC from chicken than from pork or beef. ETEC from raw chicken meat contained significantly more elt- than est-positives (p < 0.05). Thus, a significant proportion of raw meat, in particular chicken, sold in fresh food markets in southern Thailand harbors ETEC and poses a potential threat to consumer health.


Impact of arteriovenous fistula blood flow on serum il-6, cardiovascular events and death: An ambispective cohort analysis of 64 Chinese hemodialysis patients.
Flows (Qa) of arteriovenous fistula (AVF) impact the dialysis adequacy in hemodialysis (HD) patients. However, data for different access flow levels on outcomes related to long-term dialysis patients, especially in Chinese patients, are limited. Herein, we performed an ambispective, mono-centric cohort study investigating the association between the AVF flows and inflammation, cardiovascular events and deaths in Chinese hemodialysis patients bearing a radio-cephalic fistula (AVF) from 2009 to 2015. Twenty-three patients (35.9%) developed at least one episode of cardiovascular disease (CVD) in two years after AVF creation. AVF Qa, IL-6 and hsCRP were significantly higher in patients with CVD than in patients without CVD. Multi-factorial binary logistic regression analysis found that the independent and strongest risk factor for CVD in HD patients was serum IL-6, which showed a positive association with AVF Qa levels in patients. Therefore, the linkage between AVF Qa tertiles and adverse clinical outcomes (cardiovascular events and mortality) was examined over a median follow-up of five years. IL-6 was significantly increased in the high AVF Qa (>1027.13 ml/min) group. Patients with median AVF Qa showed the lowest morbidity and mortality of CVD according to the AVF Qa tertiles, whereas higher Qa was associated with a higher risk of CVD, and lower AVF Qa (600 ml/min ≤AVF Qa <821.12 ml/min) had a higher risk of non-CVD death. Therefore, keeping the AVF Qa at an optimal level (821.12 to 1027.13 ml/min) would benefit HD patients, improve long-term clinical outcomes and lower AVF-induced inflammation.


Synthesis of unsymmetrical tweezer receptor libraries and identification of receptors for lys-D-ala-D-ala in aqueous solution.
Libraries of "unsymmetrical" tweezer receptors, featuring a guanidinium head group as a carboxylate binding site and two independently synthesized peptidic arms, have been prepared and screened to identify receptors for the N-Ac-Lys-D-Ala-D-Ala tripeptide sequence. The binding properties of one such receptor structure, with dye-labeled N-Ac-Lys-D-Ala-D-Ala, were investigated. These studies demonstrated that when attached to the solid-phase, the receptor binds dye-labeled N-Ac-Lys-D-Ala-D-Ala, in buffered aqueous media, with mM binding affinity.


A semi high-throughput method for screening small bispecific antibodies with high cytotoxicity.
Small bispecific antibodies that induce T-cell-mediated cytotoxicity have the potential to damage late-stage tumor masses to a clinically relevant degree, but their cytotoxicity is critically dependent on their structural and functional properties. Here, we constructed an optimized procedure for identifying highly cytotoxic antibodies from a variety of the T-cell-recruiting antibodies engineered from a series of antibodies against cancer antigens of epidermal growth factor receptor family and T-cell receptors. By developing and applying a set of rapid operations for expression vector construction and protein preparation, we screened the cytotoxicity of 104 small antibodies with diabody format and identified some with 103-times higher cytotoxicity than that of previously reported active diabody. The results demonstrate that cytotoxicity is enhanced by synergistic effects between the target, epitope, binding affinity, and the order of heavy-chain and light-chain variable domains. We demonstrate the importance of screening to determine the critical rules for highly cytotoxic antibodies.


Overexpression of IGF-1 During Early Development Expands the Number of Mammary Stem Cells and Primes them for Transformation.
Insulin-like growth factor I (IGF-1) has been implicated in breast cancer due to its mitogenic and anti-apoptotic effects. Despite substantial research on the role of IGF-1 in tumor progression, the relationship of IGF-1 to tissue stem cells, particularly in mammary tissue, and the resulting tumor susceptibility has not been elucidated. Previous studies with the BK5.IGF-1 transgenic (Tg) mouse model reveals that IGF-1 does not act as a classical, post-carcinogen tumor promoter in the mammary gland. Pre-pubertal Tg mammary glands display increased numbers and enlarged sizes of terminal end buds, a niche for mammary stem cells (MaSCs). Here we show that MaSCs from both wild-type (WT) and Tg mice expressed IGF-1R and that overexpression of Tg IGF-1 increased numbers of MaSCs by undergoing symmetric division, resulting in an expansion of the MaSC and luminal progenitor (LP) compartments in pre-pubertal female mice. This expansion was maintained post-pubertally and validated by mammosphere assays in vitro and transplantation assays in vivo. The addition of recombinant IGF-1 promoted, and IGF-1R downstream inhibitors decreased mammosphere formation. Single-cell transcriptomic profiles generated from 2 related platforms reveal that IGF-1 stimulated quiescent MaSCs to enter the cell cycle and increased their expression of genes involved in proliferation, plasticity, tumorigenesis, invasion, and metastasis. This study identifies a novel, pro-tumorigenic mechanism, where IGF-1 increases the number of transformation-susceptible carcinogen targets during the early stages of mammary tissue development, and "primes" their gene expression profiles for transformation.


Traffic of human α-mannosidase in plant cells suggests the presence of a new endoplasmic reticulum-to-vacuole pathway without involving the Golgi complex.
The transport of secretory proteins from the endoplasmic reticulum to the vacuole requires sorting signals as well as specific transport mechanisms. This work is focused on the transport in transgenic tobacco (Nicotiana tabacum) plants of a human α-mannosidase, MAN2B1, which is a lysosomal enzyme involved in the turnover of N-linked glycoproteins and can be used in enzyme replacement therapy. Although ubiquitously expressed, α-mannosidases are targeted to lysosomes or vacuoles through different mechanisms according to the organisms in which these proteins are produced. In tobacco cells, MAN2B1 reaches the vacuole even in the absence of mannose-6-phosphate receptors, which are responsible for its transport in animal cells. We report that MAN2B1 is targeted to the vacuole without passing through the Golgi complex. In addition, a vacuolar targeting signal that is recognized in plant cells is located in the MAN2B1 amino-terminal region. Indeed, when this amino-terminal domain is removed, the protein is retained in the endoplasmic reticulum. Moreover, when this domain is added to a plant-secreted protein, the resulting fusion protein is partially redirected to the vacuole. These results strongly suggest the existence in plants of a new type of vacuolar traffic that can be used by leaf cells to transport vacuolar proteins.


Cancellous bone strains indicate efficacy of stem augmentation in constrained condylar knees.
Modular augmented stems of a constrained condylar knee implant are intended to improve tibial fixation under increased varus/valgus loads, but conflicting studies have not yet indicated the factors determining stem usage and performance. To address this, we combined a paired-tibiae, cadaveric experiment of unstemmed and stemmed tibial components with specimen-specific computational models. We hypothesized that the stem would improve implant stability by decreasing implant motion and compressive strains in the proximal cancellous bone due to load transfer by the stem. The models also would indicate the important factors governing stem performance. Large variations of the displacements arose because of loading and biologic variability indicating the inconclusive effects of a stem. Despite these variations, the models showed that a stem augment consistently decreased the strains (30%-50%) in the bone beneath the tray. In tibiae of sufficient stiffness, the supporting cancellous bone did not approach yield, suggesting that a stem augment may not always be necessary. On the other hand, tibial specimens with reduced bone quality and lower stiffness benefited from a stem augment that transferred load to the distal cortical bone. Therefore, patient selection and proper sizing of the implant were identified as important factors in the analyses.