Characterization of the bacterial community in a biotrickling filter treating high loads of H(2)S by molecular biology tools.
The diversity and spatial distribution of bacteria in a lab-scale biotrickling filter treating high loads of hydrogen sulfide (H(2)S) were investigated. Diversity and community structure were studied by terminal-restriction fragment length polymorphism (T-RFLP). A 16S rRNA gene clone library was established. Near Full-length 16S rRNA gene sequences were obtained, and clones were clustered into 24 operational taxonomic units (OTUs). Nearly 74% and 26% of the clones were affiliated with the phyla Proteobacteria and Bacteroidetes, respectively. Beta-, epsilon- and gamma-proteobacteria accounted for 15, 9 and 48%, respectively. Around 45% of the sequences retrieved were affiliated to bacteria of the sulfur cycle including Thiothrix spp., Thiobacillus spp. and Sulfurimonas denitrificans. Sequences related to Thiothrix lacustris accounted for a 38%. Rarefaction curve demonstrated that clone library constructed can be sufficient to describe the vast majority of the bacterial diversity of this reactor operating under strict conditions (2,000 ppm(v) of H(2)S). A spatial distribution of bacteria was found along the length of the reactor by means of the T-RFLP technique. Although aerobic species were predominant along the reactor, facultative anaerobes had a major relative abundance in the inlet part of the reactor, where the sulfide to oxygen ratio is higher.


Naturally occurring and melengestrol acetate-associated reproductive tract lesions in zoo canids.
As husbandry practices have improved, safe and effective contraception for captive wildlife management has become a necessity. Melengestrol acetate (MGA), a synthetic progestin, is highly effective and has been used in many zoo species. Long-term use of MGA has been associated with uterine lesions in zoo felids, but effects in zoo canids have not been evaluated. This retrospective study documented spontaneously occurring lesions and investigated the impact of MGA on the reproductive health of zoo canids. Reproductive tracts from adult females were submitted by US zoos to the Association of Zoos & Aquariums' Wildlife Contraception Center Health Surveillance Program. Reproductive tracts were sampled and processed for histopathologic examination following standard protocols. Microscopic evaluations were performed without prior knowledge of MGA treatment status. Prevalence of uterine lesions was evaluated and compared between MGA-treated animals (n = 20) and control (untreated) animals (n = 61). Common lesions within the study population as a whole included endometrial hyperplasia (predominantly cystic) (53%), hydrometra (33%), and adenomyosis (25%). Treatment with MGA was a risk factor for endometrial hyperplasia, hydrometra, fibrosis, and adenomyosis. Uterine mineralization occurred exclusively in MGA-treated animals. Results indicate that MGA contraception can lead to lesions that may permanently impair the fertility of females. Therefore, if long-term contraception of zoo canids is necessary, the use of alternate methods of reproductive control such as gonadotropin-releasing hormone (GnRH) analogs or GnRH vaccines that reduce gonadal hormone exposure should be pursued.


Cerebral white matter integrity and cognitive aging: contributions from diffusion tensor imaging.
The integrity of cerebral white matter is critical for efficient cognitive functioning, but little is known regarding the role of white matter integrity in age-related differences in cognition. Diffusion tensor imaging (DTI) measures the directional displacement of molecular water and as a result can characterize the properties of white matter that combine to restrict diffusivity in a spatially coherent manner. This review considers DTI studies of aging and their implications for understanding adult age differences in cognitive performance. Decline in white matter integrity contributes to a disconnection among distributed neural systems, with a consistent effect on perceptual speed and executive functioning. The relation between white matter integrity and cognition varies across brain regions, with some evidence suggesting that age-related effects exhibit an anterior-posterior gradient. With continued improvements in spatial resolution and integration with functional brain imaging, DTI holds considerable promise, both for theories of cognitive aging and for translational application.


A Case with Gaucher-Like Cells.
Gaucher-like cells (GLC) are sometimes indistinguishable from real Gaucher cells. GLC can be detected in various diseases. We present a 4.5 year old boy with massive cervical lympadenopathy and an intraabdominal mass mimicking lymphoma. Many GLC were seen in the fine needle aspiration material of an enlarged lymph node. Ziehl-Neelsen stain of the aspirate revealed many acid-fast bacteria in the GLC. Fine needle aspiration might provide valuable information in the evaluation of enlarged lymph nodes.


Use of a Digital Modified Checklist for Autism in Toddlers - Revised with Follow-up to Improve Quality of Screening for Autism.
To assess changes in quality of care for children at risk for autism spectrum disorders (ASD) due to process improvement and implementation of a digital screening form. The process of screening for ASD was studied in an academic primary care pediatrics clinic before and after implementation of a digital version of the Modified Checklist for Autism in Toddlers - Revised with Follow-up with automated risk assessment. Quality metrics included accuracy of documentation of screening results and appropriate action for positive screens (secondary screening or referral). Participating physicians completed pre- and postintervention surveys to measure changes in attitudes toward feasibility and value of screening for ASD. Evidence of change was evaluated with statistical process control charts and χ2 tests. Accurate documentation in the electronic health record of screening results increased from 54% to 92% (38% increase, 95% CI 14%-64%) and appropriate action for children screening positive increased from 25% to 85% (60% increase, 95% CI 35%-85%). A total of 90% of participating physicians agreed that the transition to a digital screening form improved their clinical assessment of autism risk. Implementation of a tablet-based digital version of the Modified Checklist for Autism in Toddlers - Revised with Follow-up led to improved quality of care for children at risk for ASD and increased acceptability of screening for ASD. Continued efforts towards improving the process of screening for ASD could facilitate rapid, early diagnosis of ASD and advance the accuracy of studies of the impact of screening.


Ethanol-Mediated Stress Promotes Autophagic Survival and Aggressiveness of Colon Cancer Cells via Activation of Nrf2/HO-1 Pathway.
Epidemiological studies suggest that chronic alcohol consumption is a lifestyle risk factor strongly associated with colorectal cancer development and progression. The aim of the present study was to examine the effect of ethanol (EtOH) on survival and progression of three different colon cancer cell lines (HCT116, HT29, and Caco-2). Our data showed that EtOH induces oxidative and endoplasmic reticulum (ER) stress, as demonstrated by reactive oxygen species (ROS) and ER stress markers Grp78, ATF6, PERK and, CHOP increase. Moreover, EtOH triggers an autophagic response which is accompanied by the upregulation of beclin, LC3-II, ATG7, and p62 proteins. The addition of the antioxidant N-acetylcysteine significantly prevents autophagy, suggesting that autophagy is triggered by oxidative stress as a prosurvival response. EtOH treatment also upregulates the antioxidant enzymes SOD, catalase, and heme oxygenase (HO-1) and promotes the nuclear translocation of both Nrf2 and HO-1. Interestingly, EtOH also upregulates the levels of matrix metalloproteases (MMP2 and MMP9) and VEGF. Nrf2 silencing or preventing HO-1 nuclear translocation by the protease inhibitor E64d abrogates the EtOH-induced increase in the antioxidant enzyme levels as well as the migration markers. Taken together, our results suggest that EtOH mediates both the activation of Nrf2 and HO-1 to sustain colon cancer cell survival, thus leading to the acquisition of a more aggressive phenotype.


Silage review: Unique challenges of silages made in hot and cold regions.
Silage making can be conveniently divided into field, ensiling, storage, and feed-out phases. In all of these stages, controllable and uncontrollable components can affect silage quality. For instance, silages produced in hot or cold regions are strongly influenced by uncontrollable climate-related factors. In hot regions, crops for silage are influenced by (1) high temperatures negatively affecting corn yield (whole-crop and grain) and nutritive value, (2) butyric and alcoholic fermentations in warm-season grasses (Panicum, Brachiaria, and Pennisetum genera) and sugarcane, respectively, and (3) accelerated aerobic deterioration of silages. Ensiling expertise and economic factors that limit mechanization also impair silage production and utilization in hot environments. In cold regions, a short and cool growing season often limits the use of crops sensitive to cool temperature, such as corn. The fermentation triggered by epiphytic and inoculated microorganisms can also be functionally impaired at lower temperature. Although the use of silage inoculants has increased in Northern Europe, acid-based additives are still a good option in difficult weather conditions to ensure good fermentation quality, nutritive value, and high intake potential of silages. Acid-based additives have enhanced the quality of round bale silage, which has become a common method of forage preservation in Northern Europe. Although all abiotic factors can affect silage quality, the ambient temperature is a factor that influences all stages of silage making from production in the field to utilization at the feed bunk. This review identifies challenges and obstacles to producing silages under hot and cold conditions and discusses strategies for addressing these challenges.


Reinstrumentation for rapid curve progression after implant removal following posterior instrumented fusion in adolescent idiopathic scoliosis: a case report.
Spinal implants are occasionally removed due to infection or soft tissue irritation secondary to prominence. Several studies have reported loss of scoliotic curve correction after implant removal. However, further review of the literature reveals no similar cases of rapid curve progression following implant removal in patients with adolescent idiopathic scoliosis (AIS) necessitating repeat posterior instrumented fusion. To describe a 15-year-old female AIS patient treated by posterior instrumented fusion, who developed unusual rapid coronal and sagittal curve progression after implant removal. Case report. Retrospective case report. A 15-year-old female with Lenke type 1A AIS underwent a successful posterior spinal fusion with instrumentation. She initially had no complications after surgery, but three years after instrumentation, her implants were removed due to pain secondary to implant prominence. Fifteen months after removal, the main thoracic curve increased, compared with radiographs taken before removal, from 29° to 57°. This development required the patient to undergo additional surgery, which involved multiple osteotomies and posterior reinstrumentation. We must acknowledge that a remarkable amount of progression can occur rapidly following implant removal in scoliotic patients. Taking this into consideration,we need to carefully explain to patients that removal of their implants entails a risk of progressive deformity and that they need to follow-up with their physician after implant removal.


The important (but neglected) developmental value of roles: Findings from youth programs.
Developmental theory historically viewed demanding roles (at home, job) as important developmental contexts. However, adolescents' participation in these roles has fallen. This qualitative research examined role experiences in United States youth development programs. A central question among others was, "How can youth experience internal motivation fulfilling externally imposed role obligations?" We interviewed 73 youth with substantive work roles (e.g., Leader, Reporter, and Teacher) in 13 arts, science-technology, and leadership programs. Youth (51% female) were 14- to 18-years-old and ethnically diverse. We used grounded-theory methods suited to understanding youth's active learning processes in context. Findings illuminated youth's experiences in 4 important transactions or "steps." Youth: (a) accepted roles based on personal goals, (b) encountered difficult challenges similar to adult roles (e.g., conflicting viewpoints, role strain), (c) drew on resources to overcome challenges and fulfill role demands, and (d) learned through these experiences. Across these steps, findings suggested 3 powerful development processes. First, youth experienced multiple sources of internal motivation (e.g., agency within roles, personal and social investment, and "good pressure"), which fostered high engagement in role performance and learning. Second, experiences grappling with and fulfilling difficult role demands helped youth build important competencies for action (e.g., strategic thinking, perseverance). Third, youth's experience of accountability to others served as a powerful driver of responsibility development: Because youth were invested, they took ownership of obligations to others and learned responsive modes of thinking and acting, which they transferred to family, school, and elsewhere. We propose that teens would benefit from more opportunities for role experiences like these. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Clinical and socioeconomic factors associated with unrecognized peripheral artery disease.
Peripheral artery disease (PAD) is a highly prevalent condition that frequently goes undetected and untreated. Socioeconomic factors associated with unrecognized PAD are not known. The ankle-brachial index (ABI) was calculated in 1656 study participants undergoing non-emergent coronary angiography with PAD defined as an ABI <0.9. Subjects were followed for mortality and cardiovascular outcomes. Compared to those without PAD, those with unrecognized PAD at enrollment were older, had higher rates of cardiovascular comorbidities, and had higher major adverse cardiovascular events (MACE) (p<0.03 for all). Among those enrolling without a reported history of PAD, there was a higher prevalence of PAD with decreasing income (p=0.004), education level (p<0.001), social isolation (p=0.027) and depression (p=0.034); 50% of these individuals reported symptoms suggestive of claudication. In conclusion, the prevalence of unrecognized PAD is high amongst a cohort of high-risk individuals referred for coronary angiography. A profile of lower socioeconomic status is associated with unrecognized PAD. These subjects will report symptoms suggestive of claudication and impaired walking ability when directly queried.


Generation of Cerenkov radiation at 850 nm in higher-order-mode fiber.
We demonstrate generation of Cerenkov radiation at 850 nm in a higher-order-mode (HOM) fiber. The LP02 mode in this solid, silica-based fiber has anomalous dispersion from 690 nm to 810 nm. Cerenkov radiation with 3 nJ pulse energy is generated in this module, exhibiting 60% energy conversion efficiency from the input. The HOM fiber provides a valuable fiber platform for nonlinear wavelength conversion with pulse energies in-between index-guided silica-core photonic crystal fibers and air-core photonic bandgap fibers.


Separation of dynamic and nondynamic correlation.
The account of electron correlation and its efficient separation into dynamic and nondynamic parts plays a key role in the development of computational methods. In this paper we suggest a physically-sound matrix formulation to split electron correlation into dynamic and nondynamic parts using the two-particle cumulant matrix and a measure of the deviation from idempotency of the first-order density matrix. These matrices are applied to a two-electron model, giving rise to a simplified electron correlation index that (i) depends only on natural orbitals and their occupancies, (ii) can be straightforwardly decomposed into orbital contributions and (iii) splits into dynamic and nondynamic correlation parts that (iv) admit a local version. These expressions are shown to account for dynamic and nondynamic correlation in a variety of systems containing different electron correlation regimes, thus providing the first separation of dynamic and nondynamic correlation using solely natural orbital occupancies.


Prediction of the severity of acute myocardial infarction.
In 698 patients with suspected and definite acute myocardial infarction we tried to predict the severity of the infarction from clinical history and simple bedside evaluation soon after arrival in hospital. The severity of the infarction was judged from serum enzyme activity, 2-year survival, incidence and severity of congestive heart failure and incidence of severe ventricular arrhythmias during initial hospitalization. Entry characteristics which were positively associated with the severity of the infarction were intensity of pain, sign of congestive heart failure, high heart rate, ECG signs of acute myocardial infarction and presence of Q waves. Elderly patients and those with a history of hypertension also had a more severe clinical course.


Multi-Polygenic Score Approach to Identifying Individual Vulnerabilities Associated With the Risk of Exposure to Bullying.
Exposure to bullying is a prevalent experience with adverse consequences throughout the life span. Individual vulnerabilities and traits, such as preexisting mental health problems, may be associated with increased likelihood of experiencing bullying. Identifying such individual vulnerabilities and traits is essential for a better understanding of the etiology of exposure to bullying and for tailoring effective prevention. To identify individual vulnerabilities and traits associated with exposure to bullying in childhood and adolescence. For this study, data were drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort study. The initial ALSPAC sample consisted of 14 062 children born to women residing in Avon, United Kingdom, with an expected date of delivery between April 1, 1991, and December 31, 1992. Collection of the ALSPAC data began in September 6, 1990, and the last follow-up assessment of exposure to bullying was conducted when participants were 13 years of age. Data analysis was conducted from November 1, 2017, to January 1, 2019. The polygenic score approach was used to derive genetic proxies that indexed vulnerabilities and traits. A total of 35 polygenic scores were computed for a range of mental health vulnerabilities (eg, depression) and traits related to cognition (eg, intelligence), personality (eg, neuroticism), and physical measures (eg, body mass index), as well as negative controls (eg, osteoporosis). Single and multi-polygenic score regression models were fitted to test the association between indexed traits and exposure to bullying. Children completed the Bullying and Friendship Interview Schedule at the ages of 8, 10, and 13 years. A mean score of exposure to bullying across ages was used as the main outcome. A total of 5028 genotyped individuals (2481 boys and 2547 girls) with data on exposure to bullying were included. Among the 35 initially included polygenic scores, 11 were independently associated with exposure to bullying; no significant association was detected for the 24 remaining scores. In multivariable analyses, 5 polygenic scores were associated with exposure to bullying; the largest associations were present for genetic risk relating to mental health vulnerabilities, including diagnosis of depression (standardized b = 0.065; 95% CI, 0.035-0.095) and attention-deficit/hyperactivity disorder (standardized b = 0.063; 95% CI, 0.035-0.091), followed by risk taking (standardized b = 0.041; 95% CI, 0.013-0.069), body mass index (standardized b = 0.036; 95% CI, 0.008-0.064), and intelligence (standardized b = -0.031; 95% CI, -0.059 to 0.003). Using the multi-polygenic score approach, the findings implicate preexisting mental health vulnerabilities as risk factors for exposure to bullying. A mechanistic understanding of how these vulnerabilities link to exposure of bullying is important to inform prevention strategies.


Role of motility in adherence to and invasion of a fish cell line by Vibrio anguillarum.
To understand further the role of the flagellum of Vibrio anguillarum in virulence, invasive and adhesive properties of isogenic motility mutants were analyzed by using a chinook salmon embryo cell line. Adhesion was unaffected but invasion of the cell line was significantly decreased in nonmotile or partially motile mutants, and the chemotactic mutant was hyperinvasive. These results suggest that active motility aids invasion by V. anguillarum, both in vivo and in vitro.


Picocyanobacteria containing a novel pigment gene cluster dominate the brackish water Baltic Sea.
Photoautotrophic picocyanobacteria harvest light via phycobilisomes (PBS) consisting of the pigments phycocyanin (PC) and phycoerythrin (PE), encoded by genes in conserved gene clusters. The presence and arrangement of these gene clusters give picocyanobacteria characteristic light absorption properties and allow the colonization of specific ecological niches. To date, a full understanding of the evolution and distribution of the PBS gene cluster in picocyanobacteria has been hampered by the scarcity of genome sequences from fresh- and brackish water-adapted strains. To remediate this, we analysed genomes assembled from metagenomic samples collected along a natural salinity gradient, and over the course of a growth season, in the Baltic Sea. We found that while PBS gene clusters in picocyanobacteria sampled in marine habitats were highly similar to known references, brackish-adapted genotypes harboured a novel type not seen in previously sequenced genomes. Phylogenetic analyses showed that the novel gene cluster belonged to a clade of uncultivated picocyanobacteria that dominate the brackish Baltic Sea throughout the summer season, but are uncommon in other examined aquatic ecosystems. Further, our data suggest that the PE genes were lost in the ancestor of PC-containing coastal picocyanobacteria and that multiple horizontal gene transfer events have re-introduced PE genes into brackish-adapted strains, including the novel clade discovered here.


Developing RPC-Net: Leveraging High-Density Electromyography and Machine Learning for Improved Hand Position Estimation.
The purpose of this study was to develop and evaluate the performance of RPC-Net (Recursive Prosthetic Control Network), a novel method using simple neural network architectures to translate electromyographic activity into hand position with high accuracy and computational efficiency. RPC-Net uses a regression-based approach to convert forearm electromyographic signals into hand kinematics. We tested the adaptability of the algorithm to different conditions and compared its performance with that of solutions from the academic literature. RPC-Net demonstrated a high degree of accuracy in predicting hand position from electromyographic activity, outperforming other solutions with the same computational cost. Including previous position data consistently improved results across subjects and conditions. RPC-Net showed robustness against a reduction in the number of electromyography electrodes used and shorter input signals, indicating potential for further reduction in computational cost. The results demonstrate that RPC-Net is capable of accurately translating forearm electromyographic activity into hand position, offering a practical and adaptable tool that may be accessible in clinical settings. The development of RPC-Net represents a significant advancement. In clinical settings, its application could enable prosthetic devices to be controlled in a way that feels more natural, improving the quality of life for individuals with limb loss.


The clinical effectiveness and cost-effectiveness of ablative therapies in the management of liver metastases: systematic review and economic evaluation.
Many deaths from cancer are caused by metastatic burden. Prognosis and survival rates vary, but survival beyond 5 years of patients with untreated metastatic disease in the liver is rare. Treatment for liver metastases has largely been surgical resection, but this is feasible in only approximately 20-30% of people. Non-surgical alternatives to treat some liver metastases can include various forms of ablative therapies and other targeted treatments. To evaluate the clinical effectiveness and cost-effectiveness of the different ablative and minimally invasive therapies for treating liver metastases. Electronic databases including MEDLINE, EMBASE and The Cochrane Library were searched from 1990 to September 2011. Experts were consulted and bibliographies checked. Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost-effectiveness of ablative therapies and minimally invasive therapies used for people with liver metastases. Studies were any prospective study with sample size greater than 100 participants. A probabilistic model was developed for the economic evaluation of the technologies where data permitted. The evidence assessing the clinical effectiveness and cost-effectiveness of ablative and other minimally invasive therapies was limited. Nine studies of ablative therapies were included in the review; each had methodological shortcomings and few had a comparator group. One randomised controlled trial (RCT) of microwave ablation versus surgical resection was identified and showed no improvement in outcomes compared with resection. In two prospective case series studies that investigated the use of laser ablation, mean survival ranged from 41 to 58 months. One cohort study compared radiofrequency ablation with surgical resection and five case series studies also investigated the use of radiofrequency ablation. Across these studies the median survival ranged from 44 to 52 months. Seven studies of minimally invasive therapies were included in the review. Two RCTs compared chemoembolisation with chemotherapy only. Overall survival was not compared between groups and methodological shortcomings mean that conclusions are difficult to make. Two case series studies of laser ablation following chemoembolisation were also included; however, these provide little evidence of the use of these technologies in combination. Three RCTs of radioembolisation were included. Significant improvements in tumour response and time to disease progression were demonstrated; however, benefits in terms of survival were equivocal. An exploratory survival model was developed using data from the review of clinical effectiveness. The model includes separate analyses of microwave ablation compared with surgery and radiofrequency ablation compared with surgery and one of radioembolisation in conjunction with hepatic artery chemotherapy compared with hepatic artery chemotherapy alone. Microwave ablation was associated with an incremental cost-effectiveness ratio (ICER) of £3664 per quality-adjusted life-year (QALY) gained, with microwave ablation being associated with reduced cost but also with poorer outcome than surgery. Radiofrequency ablation compared with surgical resection for solitary metastases < 3 cm was associated with an ICER of -£266,767 per QALY gained, indicating that radiofrequency ablation dominates surgical resection. Radiofrequency ablation compared with surgical resection for solitary metastases ≥ 3 cm resulted in poorer outcomes at lower costs and a resultant ICER of £2538 per QALY gained. Radioembolisation plus hepatic artery chemotherapy compared with hepatic artery chemotherapy was associated with an ICER of £37,303 per QALY gained. There is currently limited high-quality research evidence upon which to base any firm decisions regarding ablative therapies for liver metastases. Further trials should compare ablative therapies with surgery, in particular. A RCT would provide the most appropriate design for undertaking any further evaluation and should include a full economic evaluation, but the group to be randomised needs careful selection. Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.


A randomized open-label study of gabapentin and lamotrigine in adults with learning disability and resistant epilepsy.
The aim of this study was to evaluate the efficacy and safety of gabapentin in patients with learning disabilities and resistant epilepsy, comparing the effects of gabapentin with lamotrigine on efficacy, behaviour and mood. An open-label, randomized, parallel group, multicentre add-on study comparing gabapentin with lamotrigine in 109 patients with drug-resistant localization-related epilepsy and learning disabilities was conducted: 39 patients were randomized to gabapentin and 44 to lamotrigine. The study population had a range of learning disabilities and severe partial epilepsy. The percentage of patients achieving a greater than or equal to 50% reduction in seizure frequency on gabapentin was 50%, (mean reduction in seizures was 51%). Compared to 48.6% of lamotrigine patients, no statistically significant treatment differences could be identified. The safety profile of both drugs was consistent with that seen in previous clinical trials. Carer-rated visual analogue scales detected significant improvements (P< 0.05) for the gabapentin-treated patients in seizure severity, attention, general health and sleeping pattern, while for lamotrigine seizure severity improved significantly. For learning disabled patients with resistant epilepsy, gabapentin and lamotrigine provide safe and effective treatment, with positive benefits on behaviour.


Breath-holding spells in childhood.
Childhood breath-holding spells are a common and frightening phenomenon occurring in healthy, otherwise normal children. They have been well recognized for several hundred years. There appear to be two clinical forms: the cyanotic type and the pallid type, referring to the color change exhibited by the child during the episode. Prior research concerning the underlying pathophysiologic mechanisms involved in breath-holding spells has implicated an autonomic nervous system dysregulation. Cerebral anoxia is the ultimate factor responsible for the loss of consciousness observed in the severe forms of breath-holding spells. The clinical and epidemiologic aspects of breath-holding spells are herein summarized. The pertinent respiratory and neural physiologic interactions involved are delineated, as well as practical treatment approaches.


Sebaceous carcinoma: evidence-based clinical practice guidelines.
Sebaceous carcinoma usually occurs in adults older than 60 years, on the eyelid, head and neck, and trunk. In this Review, we present clinical care recommendations for sebaceous carcinoma, which were developed as a result of an expert panel evaluation of the findings of a systematic review. Key conclusions were drawn and recommendations made for diagnosis, first-line treatment, radiotherapy, and post-treatment care. For diagnosis, we concluded that deep biopsy is often required; furthermore, differential diagnoses that mimic the condition can be excluded with special histological stains. For treatment, the recommended first-line therapy is surgical removal, followed by margin assessment of the peripheral and deep tissue edges; conjunctival mapping biopsies can facilitate surgical planning. Radiotherapy can be considered for cases with nerve or lymph node involvement, and as the primary treatment in patients who are ineligible for surgery. Post-treatment clinical examination should occur every 6 months for at least 3 years. No specific systemic therapies for advanced disease can be recommended, but targeted therapies and immunotherapies are being developed.


S100A8/A9: a Janus-faced molecule in cancer therapy and tumorgenesis.
Correlations exist between the abundance of S100 proteins and disease pathologies. Indeed, this is evidenced by the heterodimeric S100 protein complex S100A8/A9 which has been shown to be involved in inflammatory and neoplastic disorders. However, S100A8/A9 appears as a Janus-faced molecule in this context. On the one hand, it is a powerful apoptotic agent produced by immune cells, making it a very fascinating tool in the battle against cancer. It spears the risk to induce auto-immune response and may serve as a lead compound for cancer-selective therapeutics. In contrast, S100A8/A9 expression in cancer cells has also been associated with tumor development, cancer invasion or metastasis. Clearly, there is a dichotomy and future investigations into the role of S100A8/A9 in cancer biology need to consider both sides of the same coin.


Hadronization in heavy-ion collisions: recombination and fragmentation of partons.
We argue that the emission of hadrons with transverse momentum up to about 5 GeV/c in central relativistic heavy ion collisions is dominated by recombination, rather than fragmentation of partons. This mechanism provides a natural explanation for the observed constant baryon-to-meson ratio of about one and the apparent lack of a nuclear suppression of the baryon yield in this momentum range. Fragmentation becomes dominant at higher transverse momentum, but the transition point is delayed by the energy loss of fast partons in dense matter.


Considering culture in evacuation planning and consequence management.
Because culture profoundly affects human behavior, it is important that emergency management decision makers from both government and the private sector who will be involved in the management of evacuation operations build cultural considerations into their planning, preparations, education, and training from the very beginning. Preparation in this regard ensures that when the crisis hits, the response efforts undertaken will at a minimum not disregard culture or make situations worse because of a lack of cultural understanding and optimally will use the consideration of culture to frame the most effective response possible to ultimately save lives and relieve suffering. Whether it is recognizing that in some cultures the decision to comply with evacuation advice and orders will be made by a matriarch or patriarch of the family, or that the ability of an entire extended family unit to remain together in the evacuation process will be the key to compliance, culture may be the pivotal factor in a successful outcome. It is these (and many more) small cultural considerations and an overall understanding of the effect that culture has on behavior that can enhance the overall effectiveness of a culturally aware organization involved in the management of evacuation operations and emergency response. Hopefully, this initial work begins a deeper discussion and evaluation of cultural aspects both concerning the populations and cultures impacted by events, but just as importantly, the cultures and cultural understanding of the responding organizations.


Calcium supplementation and risk of dementia in women with cerebrovascular disease.
To determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up. This was a longitudinal population-based study. The sample was derived from the Prospective Population Study of Women and H70 Birth Cohort Study in Gothenburg, Sweden, and included 700 dementia-free women aged 70-92 years. At baseline in 2000-2001, and at follow-up in 2005-2006, the women underwent comprehensive neuropsychiatric and somatic examinations. A CT scan was performed in 447 participants at baseline. Information on the use and dosage of calcium supplements was collected. Dementia was diagnosed according to DSM-III-R criteria. Women treated with calcium supplements (n = 98) were at a higher risk of developing dementia (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.01-4.37, p = 0.046) and the subtype stroke-related dementia (vascular dementia and mixed dementia) (OR 4.40, 95% CI 1.54-12.61, p = 0.006) than women not given supplementation (n = 602). In stratified analyses, calcium supplementation was associated with the development of dementia in groups with a history of stroke (OR 6.77, 95% CI 1.36-33.75, p = 0.020) or presence of white matter lesions (OR 2.99, 95% CI 1.28-6.96, p = 0.011), but not in groups without these conditions. Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease. Because our sample was relatively small and the study was observational, these findings need to be confirmed.


Patient satisfaction with HIV service provision in NPMS hospitals: the development of a standard satisfaction questionnaire. NPMS Steering Group.
A self-completion satisfaction questionnaire evaluating the standard of care of HIV outpatient services was developed as part of the National Prospective Monitoring System on the Use, Cost and Outcome of HIV Service Provision in English Hospitals (NPMS). The questionnaire was designed in conjunction with service users and health care professionals, and piloted in three London and three non-London HIV clinics. In addition to testing alternative methods of administering the questionnaire, the pilot provided satisfaction scores on a variety of aspects of service provision for participating clinics. The questionnaire was completed by 548 respondents and was most effectively collected using a sealed box in the clinic waiting area. Mean satisfaction scores for the attitude and skills of staff members was 4.7 (95% CI 4.6-4.7) but satisfaction scores were significantly lower for the clinic environment with a mean of 4.1 (95% CI 4.1-4.2). Satisfaction scores did not differ significantly by gender, age, sexual orientation, ethnic group, employment status or severity of symptoms. London respondents were more satisfied with the clinic environment and seeing preferred members of staff than their non-London counterparts, however there were no other differences between clinics. The questionnaire functioned well in practice and provided meaningful and useful information for individual clinics as well as at aggregate level.


Detailed Vascular Anatomy and Flap Harvest Technique of the Serratus Anterior/Rib Composite Flap.
The hemodynamics of blood flowing from the anterior serratus to the ribs has yet to be analyzed in detail in serratus anterior/rib composite flaps. The authors focused on new blood circulation, whereby the slip arteries branched from the serratus anterior branch, off the thoracodorsal artery and the intercostal arteries, directly through the interconnecting vessels (axial route). The authors analyzed in detail the hemodynamics of serratus anterior/rib composite flaps and developed a new method for flap elevation. The axial route was identified and analyzed by performing macroscopic autopsies of formalin perfusion-fixed cadavers involving three-dimensional computed tomographic angiography and vascular corrosion casting. Flap elevation was performed with new blood circulation, which included the axial route, and blood flow was evaluated using indocyanine green fluorescence angiography. The interconnecting vessels penetrated the intercostal muscles at a mean distance of 4.5 cm from the anterior margin of the attachment sites of the serratus anterior muscle to the ribs and at a mean distance of 7.4 cm from the costochondral junction. The interconnecting vessels had a mean diameter of 0.5 mm. Vascular corrosion casting helped identify multiple capillaries that were distributed from the intercostal arteries to the periosteum of the ribs. In addition, intraoperative indocyanine green fluorescence angiography confirmed blood flow from the slip arteries to the intercostal arteries. Good blood flow in harvested graft tissue can be achieved by including the axial route with the periosteal blood circulation at the rib attachment sites of the serratus anterior in a serratus anterior/rib composite flap.


Concordance analysis of microarray studies identifies representative gene expression changes in Parkinson's disease: a comparison of 33 human and animal studies.
As the popularity of transcriptomic analysis has grown, the reported lack of concordance between different studies of the same condition has become a growing concern, raising questions as to the representativeness of different study types, such as non-human disease models or studies of surrogate tissues, to gene expression in the human condition. In a comparison of 33 microarray studies of Parkinson's disease, correlation and clustering analyses were used to determine the factors influencing concordance between studies, including agreement between different tissue types, different microarray platforms, and between neurotoxic and genetic disease models and human Parkinson's disease. Concordance over all studies is low, with correlation of only 0.05 between differential gene expression signatures on average, but increases within human patients and studies of the same tissue type, rising to 0.38 for studies of human substantia nigra. Agreement of animal models, however, is dependent on model type. Studies of brain tissue from Parkinson's disease patients (specifically the substantia nigra) form a distinct group, showing patterns of differential gene expression noticeably different from that in non-brain tissues and animal models of Parkinson's disease; while comparison with other brain diseases (Alzheimer's disease and brain cancer) suggests that the mixed study types display a general signal of neurodegenerative disease. A meta-analysis of these 33 microarray studies demonstrates the greater ability of studies in humans and highly-affected tissues to identify genes previously known to be associated with Parkinson's disease. The observed clustering and concordance results suggest the existence of a 'characteristic' signal of Parkinson's disease found in significantly affected human tissues in humans. These results help to account for the consistency (or lack thereof) so far observed in microarray studies of Parkinson's disease, and act as a guide to the selection of transcriptomic studies most representative of the underlying gene expression changes in the human disease.


Fish oil omega-3 fatty acids partially prevent lipid-induced insulin resistance in human skeletal muscle without limiting acylcarnitine accumulation.
Acylcarnitine accumulation in skeletal muscle and plasma has been observed in numerous models of mitochondrial lipid overload and insulin resistance. Fish oil n3PUFA (omega-3 polyunsaturated fatty acids) are thought to protect against lipid-induced insulin resistance. The present study tested the hypothesis that the addition of n3PUFA to an intravenous lipid emulsion would limit muscle acylcarnitine accumulation and reduce the inhibitory effect of lipid overload on insulin action. On three occasions, six healthy young men underwent a 6-h euglycaemic-hyperinsulinaemic clamp accompanied by intravenous infusion of saline (Control), 10% Intralipid® [n6PUFA (omega-6 polyunsaturated fatty acids)] or 10% Intralipid®+10% Omegaven® (2:1; n3PUFA). The decline in insulin-stimulated whole-body glucose infusion rate, muscle PDCa (pyruvate dehydrogenase complex activation) and glycogen storage associated with n6PUFA compared with Control was prevented with n3PUFA. Muscle acetyl-CoA accumulation was greater following n6PUFA compared with Control and n3PUFA, suggesting that mitochondrial lipid overload was responsible for the lower insulin action observed. Despite these favourable metabolic effects of n3PUFA, accumulation of total muscle acylcarnitine was not attenuated when compared with n6PUFA. These findings demonstrate that n3PUFA exert beneficial effects on insulin-stimulated skeletal muscle glucose storage and oxidation independently of total acylcarnitine accumulation, which does not always reflect mitochondrial lipid overload.


Positron emission tomography (PET): expanding the horizons of oncology drug development.
Positron emission tomography (PET) allows three-dimensional quantitative determination of the distribution of radioactivity permitting measurement of physiological, biochemical, and pharmacological functions at the molecular level. Until recently, no method existed to directly and noninvasively assess transport and metabolism of neoplastic agents as a function of time in various organs as well as in the tumor. Standard preclinical evaluation of potential anticancer agents entails radiolabeling the agent, usually with tritium or 14C, sacrifice experiments, and high-performance liquid chromatography (HPLC) analysis to determine the biodistribution and metabolism in animals. Radiolabeling agents with positron-emitting radionuclides allows the same information to be obtained as well as in vivo pharmacokinetic (PK) data by animal tissue and plasma sampling in combination with PET scanning. In phase I/II human studies, classic PK measurements can be coupled with imaging measurements to define an optimal dosing schedule and help formulate the design of phase III studies that are essential for drug licensure [1]. Many of the novel agents currently in development are cytostatic rather than cytotoxic and therefore, the traditional standard endpoints in phase I and II studies may no longer be relevant. The use of a specialized imaging modality that allows PK and pharmacodynamic (PD) evaluation of a drug of interest has been proposed to permit rapid and sensitive assessment of the biological effects of novel anticancer agents. The progress to date and the challenges of incorporating PET technology into oncology drug development from the preclinical to clinical setting are reviewed in this article.


Global overview of health systems oversight and financing for kidney care.
Reliable governance and health financing are critical to the abilities of health systems in different countries to sustainably meet the health needs of their peoples, including those with kidney disease. A comprehensive understanding of existing systems and infrastructure is therefore necessary to globally identify gaps in kidney care and prioritize areas for improvement. This multinational, cross-sectional survey, conducted by the ISN as part of the Global Kidney Health Atlas, examined the oversight, financing, and perceived quality of infrastructure for kidney care across the world. Overall, 125 countries, comprising 93% of the world's population, responded to the entire survey, with 122 countries responding to questions pertaining to this domain. National oversight of kidney care was most common in high-income countries while individual hospital oversight was most common in low-income countries. Parts of Africa and the Middle East appeared to have no organized oversight system. The proportion of countries in which health care system coverage for people with kidney disease was publicly funded and free varied for AKI (56%), nondialysis chronic kidney disease (40%), dialysis (63%), and kidney transplantation (57%), but was much less common in lower income countries, particularly Africa and Southeast Asia, which relied more heavily on private funding with out-of-pocket expenses for patients. Early detection and management of kidney disease were least likely to be covered by funding models. The perceived quality of health infrastructure supporting AKI and chronic kidney disease care was rated poor to extremely poor in none of the high-income countries but was rated poor to extremely poor in over 40% of low-income countries, particularly Africa. This study demonstrated significant gaps in oversight, funding, and infrastructure supporting health services caring for patients with kidney disease, especially in low- and middle-income countries.


Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer.
Malignant progression results from a dynamic cross-talk between stromal and cancer cells. Recent evidence suggests that this cross-talk is mediated to a significant extent by exosomes, nanovesicles secreted by most cell types and which allow the transfer of proteins, lipids, and nucleic acids between cells. Adipocytes are a major component of several tumor microenvironments, including that of invasive melanoma, where cells have migrated to the adipocyte-rich hypodermic layer of the skin. We show that adipocytes secrete exosomes in abundance, which are then taken up by tumor cells, leading to increased migration and invasion. Using mass spectrometry, we analyzed the proteome of adipocyte exosomes. Interestingly, these vesicles carry proteins implicated in fatty acid oxidation (FAO), a feature highly specific to adipocyte exosomes. We further show that, in the presence of adipocyte exosomes, FAO is increased in melanoma cells. Inhibition of this metabolic pathway completely abrogates the exosome-mediated increase in migration. Moreover, in obese mice and humans, both the number of exosomes secreted by adipocytes as well as their effect on FAO-dependent cell migration are amplified. These observations might in part explain why obese melanoma patients have a poorer prognosis than their nonobese counterparts. Cancer Res; 76(14); 4051-7. ©2016 AACR.


Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism.
The effects of the antiandrogen drugs cyproterone acetate (CPA) and spironolactone on hair growth and androgen levels were compared in a randomized study of 48 hirsute women. Twenty six subjects completed 6 months of therapy with 100 mg/day CPA and 19 subjects completed 6 months of 100 mg/day spironolactone. All except 10 subjects received concomitant estrogen therapy. Measured objectively, total hair diameter fell by 17.1% with spironolactone (P less than 0.001), and by 16.8% with CPA (P less than 0.001). The diameter of the hair medulla fell by 17.8% with spironolactone (P less than 0.01), and by 31.7% with CPA (P less than 0.001). There was no difference between the drugs in their effect on hair diameter. Plasma testosterone levels also fell significantly with both drugs. As a subjective assessment of treatment efficacy, the frequency with which subjects performed cosmetic measures was recorded. This fell by 38% with spironolactone and by 44.7% with CPA (P less than 0.001 both drugs), and again there was no difference between the drugs. Side effects caused cessation of treatment in one subject taking CPA and two subjects taking spironolactone, and milder side effects were noted in two further subjects from each treatment group. We conclude that spironolactone and CPA, in the dosages used in this study, are effective and well tolerated agents for the treatment of hirsutism, and that neither drug demonstrates a particular advantage over the other.


Promoter hypermethylation leads to decreased APC mRNA expression in familial polyposis and sporadic colorectal tumours, but does not substitute for truncating mutations.
Germline mutations in the tumour suppressor APC cause familial adenomatous polyposis (FAP), and somatic mutations are common in sporadic colorectal cancers (CRCs). Hypermethylation of APC promoter 1A has been reported in a substantial proportion of sporadic CRCs and may cause transcriptional silencing. Methylation has been proposed as an alternative to mutation or loss of heterozygosity as a mechanism of gene inactivation. However, the significance of APC methylation has remained unclear, because it has not previously been related to the presence of mono- or bi-allelic mutations at APC. We examined 103 FAP adenomas, 11 attenuated FAP adenomas, 31 sporadic CRCs and 30 CRC cell lines, all with known germline and/or somatic APC mutations. Overall, APC promoter 1A methylation was detected in 27-45% of colorectal tumours and cell lines, but generally not in histologically normal colorectum. In contrast to previous reports, methylation was detected in similar proportions of FAP/AFAP and sporadic CRCs. Importantly, methylation was independent of the presence, number and positions of APC mutations and was not associated with the CpG island methylator phenotype. Methylation resulted in a decrease or loss of 1A isoform mRNA and reduced total APC transcript levels, although expression was retained from promoter 1B. However, neither APC protein levels, nor transcription of a panel of Wnt target genes was associated with methylation status. Our data suggest that APC promoter 1A hypermethylation may influence APC expression levels in a subtle fashion, but methylation does not result in complete gene inactivation or act as a 'second hit'.


Laser Ablation of Abnormal Neurological Tissue Using Robotic Neuroblate System (LAANTERN): Procedural Safety and Hospitalization.
Stereotactic laser ablation (SLA) has demonstrated potential utility for a spectrum of difficult to treat neurosurgical pathologies in multiple small and/or retrospective single-institutional series. Here, we present the safety profile of SLA of intracranial lesions from the Laser Ablation of Abnormal Neurological Tissue using Robotic NeuroBlate System (LAANTERN; Monteris Medical) multi-institutional, international prospective observational registry. To determine the procedural safety of SLA for intracranial lesions. Prospective procedural safety and hospitalization data from the first 100 treated LAANTERN patients was collected and analyzed. Mean age and baseline Karnofsky Performance Status (KPS) were 51(± 17) yr and 83(± 15), respectively. In total, 81.2% of patients had undergone prior surgical or radiation treatment. Most patients had a single lesion (79%) ablated through 1 burr hole (1.2 ± 0.7 per patient), immediately following a lesion biopsy. In total, >90% of the lesion was ablated in 72% of treated lesions. Average total procedural time was 188.2 ± 69.6 min, and average blood loss was 17.7 ± 55.6 ccs. The average length of intensive care unit (ICU) and hospital stays before discharge were 38.1 ± 62.7 h and 61.1 ± 87.2 h, respectively. There were 5 adverse events (AEs) attributable to SLA (5/100; 5%). After the procedure, 84.8% of patients were discharged home. There was 1 mortality within 30 d of the procedure (1/100; 1%), which was not attributable to SLA. SLA is a safe, minimally invasive procedure with favorable postprocedural ICU and hospital utilization profiles.


Resting beta hypersynchrony in secondary dystonia and its suppression during pallidal deep brain stimulation in DYT3+ Lubag dystonia.
1) To characterize patterns of globus pallidus interna neural synchrony in patients with secondary dystonia; 2) to determine whether neural hypersynchrony in the globus pallidus externa (GPe) and interna (GPi) is attenuated during high frequency deep brain stimulation (HF DBS) in a patient with DYT3+ dystonia and in a patient with secondary dystonia due to childhood encephalitis. We recorded local field potentials from the DBS lead in the GPi of four patients (seven hemispheres) with secondary dystonia and from one patient (two hemispheres) with primary DYT3+ dystonia. In two patients, we also recorded pallidal local field potentials during the administration of 10 sec epochs of HF DBS. Power spectral densities during rest demonstrated visible peaks in the beta band in seven out of nine cases. In DYT3+ dystonia, power in the alpha and beta bands, but not theta band, was attenuated during HF DBS in the GPe and in GPi, and attenuation was most prominent in the high beta band. This patient demonstrated an early and maintained improvement in dystonia. There was no beta peak and the power spectrum was not attenuated during HF DBS in a patient with secondary dystonia due to childhood encephalitis. These results suggest that beta hypersynchrony, demonstrated now in both primary and secondary dystonia, may play a pathophysiological role in pathological hyperkinesis. Further investigation is needed in a larger cohort of well-characterized primary and secondary dystonia patients.


Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group.
The main difference between the two cooperative studies on therapy of childhood acute myelogenous leukemia AML-BFM-78 and AML-BFM-83 was the addition of an 8-day ADE (cytosine arabinoside, daunorubicin, etoposide) induction treatment in the second study. Due to this intensification, the relapse rate, but not the rate of induction failures, was reduced. The probability of a 6-year event-free survival increased from 38%, SD 4%, in study AML-BFM-78 to 49%, SD 4%, in study AML-BFM-83, P = .08. The improvement of the 6-year event-free interval (EFI) was significant in the second study (61%, SD 4%, versus 47%, SD 5%, P less than .05); it was restricted to the FAB types M1 through M4 (EFI: 67%, SD 5%, versus 45%, SD 5%, P less than .01). The difference in EFI seen in FAB M5 was not statistically significant (EFI: 40%, SD 10%, versus 63%, SD 11%, NS). According to the results of the second study, two different risk groups (low and high) could be identified by combinations of predominantly pretherapeutic parameters. The low risk group, comprising 37% of the patients who achieved complete remission, included the FAB types with granulocytic differentiation and specific additional features: FAB M1 with Auer rods, FAB M2 with white blood cell count of less than 20,000/microL, FAB M3 all patients, and FAB M4 with eosinophilia. The 6-year Kaplan-Meier estimation of EFI is 91%, SD 4%, compared with 42%, SD 6% in the high risk group. In future studies based on the AML-BFM-83 treatment, bone marrow transplantation in first remission should be mandatory only for children of the high risk group.


Monosodium urate monohydrate crystals inhibit osteoblast viability and function: implications for development of bone erosion in gout.
Bone erosion is a common manifestation of chronic tophaceous gout. To investigate the effects of monosodium urate monohydrate (MSU) crystals on osteoblast viability and function. The MTT assay and flow cytometry were used to assess osteoblast cell viability in the MC3T3-E1 and ST2 osteoblast-like cell lines, and primary rat and primary human osteoblasts cultured with MSU crystals. Quantitative real-time PCR and von Kossa stained mineralised bone formation assays were used to assess the effects of MSU crystals on osteoblast differentiation using MC3T3-E1 cells. The numbers of osteoblasts and bone lining cells were quantified in bone samples from patients with gout. MSU crystals rapidly reduced viability in all cell types in a dose-dependent manner. The inhibitory effect on cell viability was independent of crystal phagocytosis and was not influenced by differing crystal length or addition of serum. Long-term culture of MC3T3-E1 cells with MSU crystals showed a reduction in mineralisation and decreased mRNA expression of genes related to osteoblast differentiation such as Runx2, Sp7 (osterix), Ibsp (bone sialoprotein), and Bglap (osteocalcin). Fewer osteoblast and lining cells were present on bone directly adjacent to gouty tophus than bone unaffected by tophus in patients with gout. MSU crystals have profound inhibitory effects on osteoblast viability and differentiation. These data suggest that bone erosion in gout occurs at the tophus-bone interface through alteration of physiological bone turnover, with both excessive osteoclast formation, and reduced osteoblast differentiation from mesenchymal stem cells.


A module-based analytical strategy to identify novel disease-associated genes shows an inhibitory role for interleukin 7 Receptor in allergic inflammation.
The identification of novel genes by high-throughput studies of complex diseases is complicated by the large number of potential genes. However, since disease-associated genes tend to interact, one solution is to arrange them in modules based on co-expression data and known gene interactions. The hypothesis of this study was that such a module could be a) found and validated in allergic disease and b) used to find and validate one ore more novel disease-associated genes. To test these hypotheses integrated analysis of a large number of gene expression microarray experiments from different forms of allergy was performed. This led to the identification of an experimentally validated reference gene that was used to construct a module of co-expressed and interacting genes. This module was validated in an independent material, by replicating the expression changes in allergen-challenged CD4+ cells. Moreover, the changes were reversed following treatment with corticosteroids. The module contained several novel disease-associated genes, of which the one with the highest number of interactions with known disease genes, IL7R, was selected for further validation. The expression levels of IL7R in allergen challenged CD4+ cells decreased following challenge but increased after treatment. This suggested an inhibitory role, which was confirmed by functional studies. We propose that a module-based analytical strategy is generally applicable to find novel genes in complex diseases.


Stem cell secretome as a new booster for regenerative medicine.
Stem cells are an undifferentiated cell population that has the ability to develop into many different cell types and also has the ability to repair damaged tissues in some cases. For a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. This paracrine modulatory effect derives from secretome which comprises a diverse host of growth factors, cytokines, chemokines, angiogenic factors, and exosomes which are extracellular vesicles that are produced in the endosomal compartment of most eukaryotic cells and are from about 30 to several hundred nanometers in diameter. The role of these factors is being increasingly recognized as key to the regulation of many physiological processes including leading endogenous and progenitor cells to sites of injury as well as mediating apoptosis, proliferation, migration, and angiogenesis. In reality, the immunomodulatory and paracrine role of these factors may mainly account for the therapeutic effects of stem cells and a number of in vitro and in vivo researches have proved limited stem cell engraftment at the site of injury. As a cell-free way for regenerative medicine therapies, stem cell secretome has shown great potential in a variety of clinical applications including prevention of cardiac disfunction, neurodegenerative disease, type 1 diabetes, hair loss, tumors, and joint osteoarthritis.


In-vitro experimental evaluation of skin-to-surface recovery of four bacterial species by antibacterial and non-antibacterial medical examination gloves.
The number of bacteria recovered from a stainless steel coupon after touching a pigskin substrate with an examination glove coated on its outside with polyhexanide (PHMB), as compared to the number of bacteria recovered in the same manner with non-coated control gloves was evaluated. Suspensions containing 1 × 109 colony-forming units of 4 clinically relevant bacterial species (Enterococcus faecium ATCC #51559; Escherichia coli ATCC #25922; Klebsiella pneumoniae ATCC #4352; and Staphylococcus aureus ATCC #33591) were used to contaminate Gamma-irradiated pigskin substrates. Bacterial recoveries from the pigskin substrate, stainless steel coupons, and each glove swatch were performed. A difference in the bacterial recovery from the stainless steel coupons after touching with coated and uncoated control gloves was measured. For E. faecium, the coated glove showed a reduction of 4.63 log10 cfu recovery, when compared to control gloves. For E. coli, the coated glove showed 5.48 log10 cfu, for K. pneumoniae 5.03 log10 cfu, and for S. aureus 5.72 log10 cfu recovery, when compared to the non-coated control glove. An in-vitro experiment designed to mimic cross-contamination of clinically relevant bacteria in a simulated healthcare setting following glove contact with a contaminated biological surface and cross-transfer to a stainless steel surface has demonstrated that an examination glove coated on its outside surface with PHMB was able to reduce bacterial recovery from a contaminated surface by > 4 log10 cfu, compared to a control non-coated examination glove. These elaborated results may encourage further clinical investigation on the clinical impact of an antibacterial examination glove.


Quality of life in newly diagnosed children with specific learning disabilities (SpLD) and differences from typically developing children: a study of child and parent reports.
Research on quality of life (QoL) of school children with specific learning disabilities (SpLD) and their parents is scarce. The present study explores QoL deficits in newly diagnosed children with SpLD and their parents, in comparison to a similar age group of typically developing children. Possible associations between parental and child QoL were statistically explored in both groups of children. 70 newly diagnosed children with SpLD [International Classification of Diseases-10 (ICD-10) criteria] (38 boys, 32 girls, mean age 10.1 years) and a control group of 69 typically developing children of the same age (40 boys, 29 girls, mean age 10.6 years) were recruited. Children were of normal intelligence quotient, attending mainstream schools. Their parents were also recruited so a child's scores could be associated with corresponding parental scores (mother or father). Children's QoL was assessed by the German questionnaire for measuring quality of life in children and adolescents (KINDL(R) ) questionnaire and parental QoL by World Health Organization Quality of Life brief questionnaire (WHOQOL-BREF) of the World Health Organization. Children with SpLD in comparison to typically developing children reported according to the KINDL(R) measurement poorer emotional well-being, lower self-esteem and satisfaction in their relationships with family and friends. Surprisingly, school functioning was not reported by these children as an area of concern. Parents of children with SpLD indicated experiencing lower satisfaction in the WHOQOL-BREF domains of social relationships and environment. Correlational and regression analysis with parental-child QoL scores provided evidence that in the SpLD group, parental scores on WHOQOL-BREF social relationships and psychological health domains could be predictors of the child's emotional well-being, satisfaction with family, friends and school functioning. Stepwise regression analysis verified the effect of parents' WHOQOL-BREF social relationships domain on several dimensions of children's KINDL(R) QoL. The results may suggest certain significant effects of the SpLD condition on newly diagnosed children's QoL. Emotional and social deficits seem to be experienced by this cohort of children and their parents. Investigation into the possible interrelationships between parental and child QoL seems to indicate that parental social wellbeing may to a certain extend influence some dimensions of the child's QoL. The findings are useful for policy making and specialized interventions for children with SpLD and their families.


Recombinant human glycosylated granulocyte colony-stimulating factor (rhG-CSF)-combined regimen for allogeneic bone marrow transplantation in refractory acute myeloid leukemia.
Recombinant human glycosylated G-CSF (rhG-CSF) may stimulate proliferation of myeloid leukemia cells and thereby increase their susceptibility to anti-cancer agents. By in vitro colony assay, the rhG-CSF-responsive NFS-60 leukemic cell clones are more effectively killed by Ara C in the presence of rhG-CSF than in the absence of rhG-CSF, while the killing of the rhG-CSF-unresponsive HL-60 cell clones is unaffected by rhG-CSF. Leukemia cell colony forming units (L-CFU) derived from most AML patients demonstrate similar results to those of the NFS-60 cell clone when treated in vitro. Encouraged by these in vitro results, we used rhG-CSF as a component of a conditioning regimen for 15 relapsed AML patients who were receiving allogeneic BMT. The patients were conditioned with total body irradiation (TBI) and high-dose Ara C. rhG-CSF was infused continuously at a dose of 5 micrograms/kg/day from 24 h before the beginning of TBI to the end of Ara C therapy. Proliferation of the leukemia cells in vivo in response to rhG-CSF was confirmed in 7 of 14 patients tested and the combined use of rhG-CSF had no additional adverse effects. After BMT, four patients died of non-leukemic causes and three patients had leukemic relapse: the other eight patients have remained disease-free for 200-1600 (median 417) days. The actuarial probabilities of relapse and disease-free survival (DFS) at 4.4 years after BMT were 43.2% and 41.7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Better Care and Better Value for Canadians: A Review of RCT Studies of Nurse Interventions.
This review is focused on the effectiveness of nursing interventions for patient outcomes and healthcare costs. It was guided by ecological and economic evaluation frameworks. Restricting the first-tier search of over 4,000 articles to randomized controlled trials (RCTs) yielded 203 studies and 9 additional trials that used identical methods of cost evaluation. Of 212 RCTs, 37 met the eligibility criteria. Of the 37 articles, 29 came from the literature search and 8 came from the first author's research unit, which used identical methods of economic evaluation. Of the first 29 studies, 26 found that nurse interventions were more or equally effective and less or equally costly compared to usual care, as was true of 7 of the 9 RCTs with comprehensive economic evaluations. It is effective and efficient to deploy specialty-trained nurses to lead teams of professionals, including physicians, assembled to address complex patient needs. A nurse-led model of proactive and supplemental care for the chronically ill, versus the on-demand, physician-led model now in place, would be more or equally effective and less or equally costly.


Voices in the wilderness: Co-location meeting the needs of children in protective care.
To explore how access to a family medicine clinic co-locating with the Children's Aid Society (CAS) of Hamilton in Ontario helped meet the unique needs of children in care. Qualitative research using semistructured face-to-face and telephone interviews. The CAS of Hamilton. Nineteen foster parents. Stakeholders were invited to participate with flyers posted in the clinic, notices that were mailed to foster parents, personal invitations that were distributed during clinic visits, and an internal memo that was distributed to the CAS staff. Informed consent and assent where appropriate was obtained before an interview was started. Interviews were audiorecorded when and where feasible, transcribed, and subsequently underwent inductive, thematic analysis. Common themes evolved by consensus. Foster parents valued the family medicine clinic co-locating with the CAS. The co-location helped children in care to know that there were others in similar circumstances. Foster parents learned from and shared parenting skills with one another, which resulted in developing confidence in the care they provided. The clinic became a neutral place for children in care, foster parents, and birth parents. The clinic team gathered the children's complete health records and was responsible for sharing this information when appropriate. Access to a family medicine clinic designed specifically for children in care that co-located with the CAS enhanced not only the planning, management, and evaluation of care, but also provided a consistency that was not found in other parts of the children's lives; this helped generate trusting relationships over time. The co-location provided a strong spoke in the circle of care.


Dysbalance of angiogenic and angiostatic mediators in patients with mixed connective tissue disease.
Vascular disease is common in mixed connective tissue disease (MCTD). The aim of the present study was to investigate, whether dysbalance of angiogenic and angiostatic factors occurs in MCTD. In all, 38 patients with MCTD, and 40 patients with systemic sclerosis (SSc) for comparison, were included. Four centres contributed to this cross-sectional analysis. A total of 66 healthy volunteers were used as controls. The serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin were determined by ELISA. For comparisons between controls and patients with MCTD and detection of associations of serum levels with dichotomous clinical parameters in patients with MCTD the Mann-Whitney test was used. Serum levels of the angiogenic factor VEGF were significantly elevated in patients with MCTD and SSc. Significantly increased levels of the angiostatic factor endostatin were also detected in MCTD, but not in SSc. No differences were observed for bFGF. Levels of VEGF were higher in patients with MCTD with pulmonary arterial hypertension (PAH), acrosclerosis and myositis. In multivariate linear regression analysis, an additive model of PAH, myositis and lymphadenopathy accounted for 79% of the variability of the VEGF levels (r=0.889). Molecular factors modulating angiogenic responses are dysregulated in patients with MCTD and SSc with increases of VEGF in MCTD and SSc and selective upregulation of endostatin in MCTD. Furthermore, high serum levels of VEGF might characterise patients with MCTD with a more severe course of the disease with increased prevalence of PAH and myositis.


BRCT repeats as phosphopeptide-binding modules involved in protein targeting.
We used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. Using a library of partially degenerate phosphopeptides, we identified tandem BRCT (BRCA1 carboxyl-terminal) domains in PTIP (Pax transactivation domain-interacting protein) and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (ataxia telangiectasia-mutated) and ATR (ataxia telangiectasia- and RAD3-related) in response to gamma-irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1- and phospho-H2AX (gamma-H2AX)-containing nuclear foci, a marker of DNA damage. These findings provide a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation Met1775 --> Arg, which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer.


Proximity and Economic Activity: An Analysis of Vendor-University Transactions.
This paper using transaction based data to provide new insights into the link between the geographic proximity of businesses and associated economic activity. It contributes to the literature by developing both two new measures of distance and a set of stylized facts on the distances between observed transactions between vendors and customers for a research intensive sector - universities. We show that spending on research inputs is more likely to be expended at businesses physically closer to universities than those farther away. That relationship is stronger for High Tech and R&D performing businesses than businesses in general, which is consistent with theories emphasizing the role of tacit knowledge. We find that firms behave in a way that is consistent with the notion that propinquity is good for business: if a firm supplies a project at a university in a given year, it is more likely to open an establishment near that university in subsequent years than other firms. We also investigate the link between transactional distance and economic activity and show that when a vendor has been a supplier to a project at least one time, that vendor is subsequently more likely to be a vendor on the same or related project.


β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer's disease-related sites.
Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.


Expert consensus paper on the use of Vedolizumab for the management of patients with moderate-to-severe Inflammatory Bowel Disease.
Crohn's Disease (CD) and Ulcerative Colitis (UC) are chronic, relapsing conditions resulting from uncontrolled inflammation of the intestinal mucosa. Both conditions are associated with significant disability and patients with CD face higher mortality rates compared to the general population. The increasing understanding of the immunological basis of the disease led to the introduction of biologic therapies targeting key pathways of the natural and adaptive immune response such as Tumor Necrosis Factor α (TNF-α) inhibitors and, more recently, integrin-receptor antagonists. Treatment with TNF-α inhibitors improved clinical and patient-reported outcomes for many patients who did not benefit from conventional therapy. However, a sizeable share of patients still face suboptimal outcomes due to primary or secondary therapy failure. With the introduction of VDZ, a biologic treatment targeting novel IBD-relevant biologic pathways, it is crucial to understand how to integrate such innovations into current clinical practice. To this end, a panel of 14 Italian experts in the management of IBD met for a roundtable discussion. Recommendations concerning the management of moderate-to-severe IBD based on experts' opinions and literature review are discussed in the present report.


Pumping ability of the hypertrophying left ventricle of the spontaneously hypertensive rat.
Cardiac pumping ability was assessed during the natural development of left ventricular hypertrophy by elevating venous pressure by infusing Tyrode's solution intravenously to produce peak cardiac output. This experiment was performed on spontaneously hypertensive rats (SHR) of three age groups (11, 24, and 83 weeks). From 11 to 24 weeks, peak cardiac output of SHR increased in direct proportion to the abnormally increased ventricular mass; Thus peak cardiac output per gram of left ventricle (LV) remained stable. Similar results were obtained for two strains of normotensive rats at each of the same three age groups. Thus, in the normotensive animal peak cardiac output per gram of LV remained stable over a wide range of ages and varying left ventricular weights. However, with progressive elevation of arterial pressure in aging SHR (83 weeks), we observed severe ventricular hypertrophy (100% increases in left ventricular to body weight ratio). In this oldest SHR group, unlike age-matched normotensive rats, there was a marked reduction in the pumping ability per gram of LV. Thus, during the natural development of left ventricular hypertrophy SHR demonstrated both a stable stage of hypertrophy in which the increased left ventricular mass maintained its pumping ability, and a later stage of deterioration in which there was a loss of the normal relationship between ventricular mass and pumping ability.


Characterization of a Potyvirus Infecting Sunflower in Argentina.
A virus causing chlorotic mottling symptoms on sunflower was found in various locations in Argentina. Symptoms were small chlorotic spots, yellow blotches on leaves, and plant stunting. Virus transmission efficiency by mechanical inoculation was 73 to 100%, and by Myzus persicae was 31 to 49%. The host range included members of the Amaranthaceae, Asteraceae, Chenopodiaceae, and Solanaceae families. Electron microscopy of leaf dips from infected plants revealed flexuous particles 17 nm wide and 770 nm long. Cytoplasmic laminar aggregates and pinwheel inclusions were observed in ultrathin sections. Purified virus preparations analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis resolved a capsid protein of 33 kDa. A monoclonal antibody to aphid-transmitted potyviruses reacted with the capsid protein of this virus. In dot blot immunoassays, a polyclonal antiserum (early bleeding) reacted with infected sunflowers and weakly with Bidens mottle potyvirus, but not with either maize dwarf mosaic potyvirus or potato virus Y. The evidence suggests that a potyvirus is infecting sunflower, and a partial characterization of the causal agent is reported.


Insights into ligand stimulation effects on gastro-intestinal stromal tumors signalling.
Mutations in KIT or PDGFRA are responsible for >85% of gastrointestinal stromal tumors. The introduction of imatinib in the GIST therapy scheme revolutionized the patient outcome. Unfortunately, the therapy allows the disease stabilization instead of curation. Furthermore the resistance to the inhibitor arises in most cases within two first years of therapy. A thorough investigation of the signalling pathways activated by the major PDGFRA and KIT mutants encountered in the GIST landscape allowed to identify striking differences between the two receptor tyrosine kinases. PDGFRA mutants were not responsive to their ligand, PDGFAA, and displayed a high constitutive kinase activity. In contrast, all KIT mutants retained, in addition to their constitutive activation, the ability to be stimulated by their ligand. Kit mutants displayed a lower intrinsic kinase activity relative to PDGFRA mutants, while the KIT Exon 11 deletion mutant exhibited the highest intrinsic kinase activity among KIT mutants. At the transcriptomic level, the MAPK pathway was established as the most prominent activated pathway, which is commonly up-regulated by all PDGFRA and KIT mutants. Inhibition of this pathway, using the MEK inhibitor PD0325901, reduced the proliferation of GIST primary cells at nanomolar concentrations. Altogether, our data demonstrate the high value of MEK inhibitors for combination therapy in GIST treatment and more importantly the interest of evaluating the SCF expression profile in GIST patients presenting KIT mutations.


Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival.
Tumor hypoxia is known to be associated with resistance to chemotherapy, radiotherapy, and poorer survival. Recently, it is shown that hypoxia induces the expression of hypoxia-inducible factor-1alpha and 2alpha (HIF-1alpha and HIF-2alpha), which then up-regulates the expression of downstream genes such as carbonic anhydrase IX (CA IX) and vascular endothelial growth factor (VEGF). We examined the expression of HIF-1alpha, HIF-2alpha, CA IX, and VEGF by immunohistochemistry in nasopharyngeal carcinoma (NPC) biopsies from 90 consecutive patients recruited between 1994 and 1997 in a randomized controlled trial of chemoradiation in locally advanced NPC and investigated their relationship with survival. HIF-1alpha was expressed in 52 of 90 (58%), HIF-2alpha in 6 of 89 (7%), CA IX in 51 of 90 (57%), and VEGF in 54 of 90 (60%) of tumors. Tumor HIF-1alpha expression correlated significantly with that of CA IX (P = 0.008) and VEGF (P = 0.003). High tumor HIF-1alpha expression was associated with a trend for poor overall survival (P = 0.06). Tumors with a positive hypoxic profile (defined as high expression of both HIF-1alpha and CA9) were associated with worse progression-free survival (P = 0.04). Tumors with both hypoxic and angiogenic profile (defined as high VEGF expression) were associated with a worse progression-free survival (P = 0.0095). Overexpression of HIF-1alpha, CA IX, and VEGF is common in NPC, which is probably related to hypoxia up-regulated expression involving a HIF-dependent pathway, and is associated with poor prognosis. Targeting the hypoxia pathway may be useful in the treatment of NPC.


The receptor for advanced glycation end products (RAGE) contributes to the progression of emphysema in mice.
Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE) and its variants in chronic obstructive pulmonary disease (COPD). In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/-) exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema.


Microvessel Density as a Surrogate Prognostic Marker in Patients with Multiple Myeloma: A Meta-Analysis.
Bone marrow (BM) angiogenesis is considered a hallmark of multiple myeloma (MM) development and progression, and can be quantified with the use of microvessel density (MVD). The purpose of this study is to provide a review and a meta-analysis of the current literature regarding the prognostic value of MVD in the overall survival (OS) of MM patients. MEDLINE was screened for studies evaluating the OS of MM patients with regard to their MVD count in BM trephine. The pooled hazard ratio (HR) and its associated 95% confidence interval (CI) among MM patients with a high and low MVD count was the primary end point. Secondary outcomes included odds ratios (OR) for 12-, 36-, and 60-month survival. Ten eligible trials were identified for the analysis of the primary end point and 9 for the secondary end points. Pooled HR for OS was 1.85 (95% CI: 1.25-2.73, p = 0.002). The pooled OR of survival were 1.59 (95% CI: 1.02-2.46, p = 0.04) at 12 months, 2.90 (95% CI: 1.68-5.03, p = 0.0001) at 36 months, and 3.42 (95% CI: 2.41-4.85, p < 0.00001) at 60 months, in favor of the low MVD group. This meta-analysis provides persuasive evidence that MVD has significant impact on the clinical outcome of MM patients.


Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes.
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell-centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.


Supporting southern-led research: implications for North-South research partnerships.
Global health research partnerships are commonly led by Northern investigators who come from resource-rich research environments, while Southern partners participate with a paucity of research skills and resources. This power asymmetry within North-South research partnerships may further exacerbate the unequal distribution of benefits from the research process. This study is designed to present the benefits and challenges of engaging in the research process from the perspective of The AIDS Support Organization (TASO), an HIV/AIDS care and treatment organization that has been involved in global health research partnerships. It uses a validated research tool entitled "Is Research Working for You?" to facilitate qualitative interviews surrounding the experienced benefits and challenges in engaging in the research partnerships as described by TASO staff. Three key themes emerged from the content and thematic analysis: 1) the reported benefits of research (e.g., evidence-based management, advocacy, etc.), 2) the challenges the research committee members face in becoming more involved in the research process (e.g., lack of data analysis skill, lack of inclusion in the research process, etc.), and 3) the institutional ambition at TASO to develop a Southern-led research agenda. This is one of the few studies to document the development of a Southern-led research agenda in addition to the challenges of engaging in the research process. Mechanisms for moderating power dynamics within North-South partnerships can provide opportunities for improved research capacity and quality.


Comparative analysis of plant genomes allows the definition of the "Phytolongins": a novel non-SNARE longin domain protein family.
Subcellular trafficking is a hallmark of eukaryotic cells. Because of their pivotal role in the process, a great deal of attention has been paid to the SNARE proteins. Most R-SNAREs, or "longins", however, also possess a highly conserved, N-terminal fold. This "longin domain" is known to play multiple roles in regulating SNARE activity and targeting via interaction with other trafficking proteins. However, the diversity and complement of longins in eukaryotes is poorly understood. Our comparative genome survey identified a novel family of longin-related proteins, dubbed the "Phytolongins" because they are specific to land plants. Phytolongins share with longins the N-terminal longin domain and the C-terminal transmembrane domain; however, in the central region, the SNARE motif is replaced by a novel region. Phylogenetic analysis pinpoints the Phytolongins as a derivative of the plant specific VAMP72 longin sub-family and allows elucidation of Phytolongin evolution. "Longins" have been defined as R-SNAREs composed of both a longin domain and a SNARE motif. However, expressed gene isoforms and splice variants of longins are examples of non-SNARE motif containing longins. The discovery of Phytolongins, a family of non-SNARE longin domain proteins, together with recent evidence on the conservation of the longin-like fold in proteins involved in both vesicle fusion (e.g. the Trs20 tether) and vesicle formation (e.g. sigma and mu adaptin) highlight the importance of the longin-like domain in protein trafficking and suggest that it was one of the primordial building blocks of the eukaryotic membrane-trafficking machinery.


The fate of new fosfamides in phase III studies in advanced soft tissue sarcoma.
For decades, doxorubicin alone or in combination with ifosfamide has been used in advanced soft tissue sarcoma (STS). In 2014, a comparison of doxorubicin alone versus the combination with ifosfamide (in the randomised phase III EORTC 62012) showed no difference in overall survival (OS), but a difference in response and progression-free survival (PFS) were observed in favour of the combination but at the expense of increased toxicity. Newer fosfamides, with slightly different modes of action, and potentially less toxicity, namely evofosfamide and palifosfamide have recently been tested in randomised phase III clinical trials in STS. The TH CR-406/SARC021 (June 2017) and the PICASSO III (September 2016) studies compared doxorubicin, as the standard arm, to doxorubicin in combination with evofosfamide and palifosfamide, respectively. In both studies, the combination arm produced increased response rates but at the expense of higher toxicity. However, there was no difference in OS or PFS in favour of the combination. Importantly, the median OS of patients receiving standard of care, doxorubicin, in both studies appeared improved from 12.8 months (95.5% CI 10.5-14·III) in the EORTC 62012 to 16.9 months (95% CI 14.8 to 22.9) in PICASSO III and 19.0 months (95% CI 16.2-22.4) in TH CR-406/SARC021. The results of these three randomised phase III studies highlight several critical issues related to the design and conduct of such trials in STS. We discuss these issues aiming to contribute to the ongoing debate about the optimal approach to perform clinical research in STS.


A methodology for image quality evaluation of advanced CT systems.
This work involved the development of a phantom-based method to quantify the performance of tube current modulation and iterative reconstruction in modern computed tomography (CT) systems. The quantification included resolution, HU accuracy, noise, and noise texture accounting for the impact of contrast, prescribed dose, reconstruction algorithm, and body size. A 42-cm-long, 22.5-kg polyethylene phantom was designed to model four body sizes. Each size was represented by a uniform section, for the measurement of the noise-power spectrum (NPS), and a feature section containing various rods, for the measurement of HU and the task-based modulation transfer function (TTF). The phantom was scanned on a clinical CT system (GE, 750HD) using a range of tube current modulation settings (NI levels) and reconstruction methods (FBP and ASIR30). An image quality analysis program was developed to process the phantom data to calculate the targeted image quality metrics as a function of contrast, prescribed dose, and body size. The phantom fabrication closely followed the design specifications. In terms of tube current modulation, the tube current and resulting image noise varied as a function of phantom size as expected based on the manufacturer specification: From the 16- to 37-cm section, the HU contrast for each rod was inversely related to phantom size, and noise was relatively constant (<5% change). With iterative reconstruction, the TTF exhibited a contrast dependency with better performance for higher contrast objects. At low noise levels, TTFs of iterative reconstruction were better than those of FBP, but at higher noise, that superiority was not maintained at all contrast levels. Relative to FBP, the NPS of iterative reconstruction exhibited an ~30% decrease in magnitude and a 0.1 mm(-1) shift in the peak frequency. Phantom and image quality analysis software were created for assessing CT image quality over a range of contrasts, doses, and body sizes. The testing platform enabled robust NPS, TTF, HU, and pixel noise measurements as a function of body size capable of characterizing the performance of reconstruction algorithms and tube current modulation techniques.


Welcome to the splice age: antisense oligonucleotide-mediated exon skipping gains wider applicability.
Exon skipping uses antisense oligonucleotides (ASOs) to alter transcript splicing for the purpose of rescuing or modulating protein expression. In this issue of the JCI, Lee and colleagues developed and evaluated an ASO-dependent method for treating certain molecularly defined diseases associated with alterations in lamin A/C (LMNA) splicing. Exon skipping by ASOs is gaining traction as a therapeutic strategy, and the use of ASOs is now being applied to bypass mutations and generate modified but functional proteins for an array of genetic disorders.


Characterizations of realized metal-insulator-silicon-insulator-metal waveguides and nanochannel fabrication via insulator removal.
We investigate experimentally metal-insulator-silicon-insulator-metal (MISIM) waveguides that are fabricated by using fully standard CMOS technology. They are hybrid plasmonic waveguides, and they have a feature that their insulator is replaceable with functional material. We explain a fabrication process for them and discuss fabrication results based on 8-inch silicon-on-insulator wafers. We measured the propagation characteristics of the MISIM waveguides that were actually fabricated to be connected to Si photonic waveguides through symmetric and asymmetric couplers. When incident light from an optical source has transverse electric (TE) polarization and its wavelength is 1318 or 1554 nm, their propagation losses are between 0.2 and 0.3 dB/μm. Excess losses due to the symmetric couplers are around 0.5 dB, which are smaller than those due to the asymmetric couplers. Additional measurement results indicate that the MISIM waveguide supports a TE-polarized hybrid plasmonic mode. Finally, we explain a process of removing the insulator without affecting the remaining MISIM structure to fabricate ~30-nm-wide nanochannels which may be filled with functional material.