Differential impairment of remembering the past and imagining novel events after thalamic lesions.
Vividly remembering the past and imagining the future (mental time travel) seem to rely on common neural substrates and mental time travel impairments in patients with brain lesions seem to encompass both temporal domains. However, because future thinking-or more generally imagining novel events-involves the recombination of stored elements into a new event, it requires additional resources that are not shared by episodic memory. We aimed to demonstrate this asymmetry in an event generation task administered to two patients with lesions in the medial dorsal thalamus. Because of the dense connection with pFC, this nucleus of the thalamus is implicated in executive aspects of memory (strategic retrieval), which are presumably more important for future thinking than for episodic memory. Compared with groups of healthy matched control participants, both patients could only produce novel events with extensive help of the experimenter (prompting) in the absence of episodic memory problems. Impairments were most pronounced for imagining personal fictitious and impersonal events. More precisely, the patients' descriptions of novel events lacked content and spatio-temporal relations. The observed impairment is unlikely to trace back to disturbances in self-projection, scene construction, or time concept and could be explained by a recombination deficit. Thus, although memory and the imagination of novel events are tightly linked, they also partly rely on different processes.


Prescription medication nonadherence associated with food insecurity: a population-based cross-sectional study.
Food insecurity, defined as inadequate access to food owing to financial constraints, has been associated with poor disease management. Because cost-related nonadherence to prescription drugs is a possible explanation for such association, we examined the link between food insecurity and cost-related medication nonadherence in Canada. Drawing on data for adult respondents (age ≥ 18 yr) who participated in the Canadian Community Health Survey 2016 Rapid Response module on prescription medication use, we assessed the association between household food insecurity and cost-related nonadherence to prescription drugs in the previous 12 months. We further examined the self-perceived health consequences of cost-related nonadherence among nonadherents. We applied Poisson models with bootstrap weights adjusting for sociodemographic characteristics. Of the 11 172 respondents in our sample, 930 (8.3%) reported cost-related nonadherence. Food insecurity affected 10.5% (95% confidence interval [CI] 9.1% to 11.8%) of adherents and 47.9% (95% CI 38.1% to 57.7%) of nonadherents. After adjustment for confounders, moderate and severe food insecurity were associated with 3.83 (95% CI 2.44 to 6.03) and 5.05 (95% CI 3.27 to 7.81) times higher prevalence of cost-related nonadherence, respectively, relative to food security. Despite being associated with lower probability of cost-related nonadherence, having drug insurance did not change the relation between food insecurity and cost-related nonadherence (p > 0.1 for all interactions). Severe food insecurity was correlated with higher prevalence of health deterioration and greater use of health care services as perceived consequences of cost-related nonadherence (p < 0.01 for both). Food-insecure adults in Canada have a higher likelihood of cost-related nonadherence to prescription medications than their food-secure counterparts, which may constitute a burden on their health and lead to greater use of health care services.


Update on vitamin B12 deficiency.
Vitamin B(12) (cobalamin) deficiency is a common cause of megaloblastic anemia, a variety of neuropsychiatric symptoms, and elevated serum homocysteine levels, especially in older persons. There are a number of risk factors for vitamin B(12) deficiency, including prolonged use of metformin and proton pump inhibitors. No major medical organizations, including the U.S. Preventive Services Task Force, have published guidelines on screening asymptomatic or low-risk adults for vitamin B(12) deficiency, but high-risk patients, such as those with malabsorptive disorders, may warrant screening. The initial laboratory assessment of a patient with suspected vitamin B(12) deficiency should include a complete blood count and a serum vitamin B(12) level. Measurements of serum vitamin B(12) may not reliably detect deficiency, and measurement of serum homocysteine and/or methylmalonic acid should be used to confirm deficiency in asymptomatic high-risk patients with low normal levels of vitamin B(12). Oral administration of high-dose vitamin B(12) (1 to 2 mg daily) is as effective as intramuscular administration in correcting the deficiency, regardless of etiology. Because crystalline formulations are better absorbed than naturally occurring vitamin B(12), patients older than 50 years and strict vegetarians should consume foods fortified with vitamin B(12) and vitamin B(12) supplements, rather than attempting to get vitamin B(12) strictly from dietary sources. Administration of vitamin B(12) to patients with elevated serum homocysteine levels has not been shown to reduce cardiovascular outcomes in high-risk patients or alter the cognitive decline of patients with mild to moderate Alzheimer disease.


Ancient noncoding elements conserved in the human genome.
Cartilaginous fishes represent the living group of jawed vertebrates that diverged from the common ancestor of human and teleost fish lineages about 530 million years ago. We generated approximately 1.4x genome sequence coverage for a cartilaginous fish, the elephant shark (Callorhinchus milii), and compared this genome with the human genome to identify conserved noncoding elements (CNEs). The elephant shark sequence revealed twice as many CNEs as were identified by whole-genome comparisons between teleost fishes and human. The ancient vertebrate-specific CNEs in the elephant shark and human genomes are likely to play key regulatory roles in vertebrate gene expression.


Whole-column radioactivity detection: simultaneous separation and enhanced detectability.
The development of a whole-column radiation detector for measurement and separation of low amounts of beta emitting analytes is described. The design of this detector is unique with all of the chromatography media located within the detector volume. This whole-column design provides the advantage of increased radiation signal without loss of chromatographic efficiency, which translates to increased detectability. This increase was compared theoretically with flow-through radiation detection, and the theory was tested experimentally. Using two analytes, carbon-11-labeled m-hydroxyephedrine and alpha-methylepinephrine, only 3 and 8 Bq (80 and 220 pCi), respectively, were needed to obtain a 10% coefficient of variation using whole-column detection. For [11C]-m-hydroxyephedrine, 100 times more radioactivity was required to achieve the same coefficient of variation using flow-through detection. A limit of detection (LD) for the analytes of 2 Bq (54 pCi) was obtained for whole-column detection, an improvement of 50 in LD compared with flow-through detection. Signal improvement increased linearly with the chromatographic resolution. The whole-column detection method is robust and applicable to many chromatographic separations.


Developing New Treatments for Heart Failure: Focus on the Heart.
Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting.


PERTINENT DRY NEEDLING CONSIDERATIONS FOR MINIMIZING ADVERSE EFFECTS - PART TWO.
Dry needling (DN) is an evidence based treatment technique that is accepted and used by physical therapists in the United States. This clinical commentary is the second in a two-part series outlining some of the pertinent anatomy and other issues that are needed for optimal utilization of this treatment modality. Part one was an overview of the thorax with a summary of reported adverse effects (AEs) and the underlying anatomy that could be used to minimize patient risk. As is the case with any intervention, the technique of dry needling has some inherent patient risk. The incidence of AEs with this procedure is typically low, ranging from zero to approximately 10 percent. Knowledge of the underlying anatomy can be a key factor associated with decreasing the likelihood of an AE. The second part of this clinical commentary goes beyond the thorax, to explore the anatomy associated with dry needling the abdomen, pelvis, and back. In the abdomen, pelvis and back, dry needling can penetrate the peritoneal cavity or adjacent organs, resulting in AEs. A physiological reaction that is an AE secondary to a needle insertion, pain or fear, is an autonomic vasovagal response. Additionally, suggestions for dealing with the fearful patient, the obese patient, universal precautions, and other clinical considerations, are discussed. The purpose of parts one and part two of this clinical commentary is to minimize the risk of a dry needling AE. Dry needling is an effective adjunctive treatment procedure that is within the recognized scope of practice of the physical therapist. An evidence-based implementation of the procedure must be based on a thorough understanding of the underlying anatomy and the potential risks, with risks communicated to patients via informed consent. Level 5.


The impact of and responses to flooding in Thulamela Municipality, Limpopo Province, South Africa.
The frequency of climate-related disasters such as floods is growing due to environmental and human factors. This paper examines the impact of flooding and communities' perceptions towards responses to flooding in the cases of Maniini and Tshilungwi Villages in the Thulamela Municipality in the Limpopo Province of South Africa. A questionnaire survey was conducted with 60 household respondents in the two selected villages and then analysed. Key-informant interviews with community leaders and municipality officials established the key impact of and responses to the flooding. Secondary data on flooding provided useful historical trends in the region. Field observations assisted in corroborating information provided in interviews. The findings indicate that communities are vulnerable to flood disasters, and these disasters had a significant impact on infrastructure and the livelihood of the selected communities. An increase in household income and levels of education as well as access to grants decreased households' vulnerability in cases of flooding. The responses to flooding by the municipality were viewed negatively by the community who did not support permanent relocation. Hence, the article points out the need to strengthen coping mechanisms by local governments and communities themselves in order to cope with the impact of flooding.


Consensus statements on vaccination in patients with haemophilia-Results from the Italian haemophilia and vaccinations (HEVA) project.
Vaccination against communicable diseases is crucial for disease prevention, but this practice poses challenges to healthcare professionals in patients with haemophilia. Poor knowledge of the vaccination requirements for these patients and safety concerns often result in vaccination delay or avoidance. In order to address this issue, a panel of 11 Italian haemophilia and immunization experts conducted a Delphi consensus process to identify the main concerns regarding the safe use of vaccines in patients with haemophilia. The consensus was based on a literature search of the available evidence, which was used by the experts to design 27 consensus statements. A group of clinicians then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). The main issues identified by the expert panel included vaccination schedule for haemophilic patients; protocol and optimal route of vaccine administration; vaccination of haemophilic patients with antibodies inhibiting coagulation factor VIII (inhibitors); and vaccination and risk of inhibitor development. This manuscript discusses these controversial areas in detail supported by the available literature evidence and provides evidence- and consensus-based recommendations. Overall, participants agreed on most statements, except those addressing the potential role of vaccination in inhibitor formation. Participants agreed that patients with haemophilia should receive vaccinations according to the institutional schedule for individuals without bleeding disorders; however, vaccination of patients with haemophilia requires comprehensive planning, taking into account disease severity, type and route of vaccination, and bleeding risk. Data also suggest vaccination timing does not need to take into consideration when the patient received factor VIII replacement.


Enhanced Diffusion of Molecular Catalysts is Due to Convection.
Intriguing reports of enhanced diffusion in enzymes and molecular catalysts have spurred significant interest in experimental and theoretical investigations, and the mechanism of this phenomenon is the topic of lively debate. Here we use time-resolved diffusion NMR methods to measure the diffusion coefficients (D) of small molecule species involved in chemical reactions with high temporal resolution. We show the enhanced diffusion of small molecules cannot be explained by reaction velocity, and that apparent measurements of enhanced diffusion by small molecules appear to be caused by bulk fluid flow processes such as convection.


Cerebral Granulomatous Inflammation Secondary to Hydrophilic Polymer Embolization Following Thrombectomy.
BACKGROUND Given the recent completion of multiple trials demonstrating the benefit of endovascular mechanical thrombectomy for select patients with proximal large artery occlusive ischemic strokes, there has been a large increase in the performance of these procedures. In the context of increased thrombectomy performance, there have also been increased reports of rare occurrences of granulomatous inflammatory response to the hydrophilic polymer which coat many of these interventional devices. CASE REPORT A 59-year-old female presented with a complete occlusion of her right proximal middle cerebral artery (MCA) and imaging showed a large area of penumbra. Cerebral angiogram and mechanical thrombectomy were successfully performed with reversal of clinical symptoms. Eight months following her stroke, she developed progressive recurrence of left-sided neurological deficits. After extensive workup culminating in tissue sampling, she was found to have developed granulomatous inflammation surrounding microscopic embolization of hydrophilic polymer, which is used to coat many interventional devices such as wires and catheters. The patient responded both clinically and radiographically to anti-inflammatory steroid therapy. CONCLUSIONS Recognizing the significant potential morbidity of a large vessel ischemic stroke and the expanded use of endovascular interventions aimed at staving off this disability, there are emerging and at times indolent complications from the use of hydrophilic polymer coated wires and catheters. This rare and potentially under-recognized complication should be considered in the differential for any patient with new neurological findings following cerebral intervention, especially given the consideration that this appears to a treatable complication.


Glioblastomas require integrin αvβ3/PAK4 signaling to escape senescence.
Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvβ3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvβ3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvβ3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvβ3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.


Mapping Interactome Networks of DNAJC11, a Novel Mitochondrial Protein Causing Neuromuscular Pathology in Mice.
We previously identified DNAJC11, a mitochondrial outer membrane protein of unknown function, as a novel genetic cause in modeled neuromuscular disease. To understand the physiological role of DNAJC11, we employed a proteomic approach for the identification of the DNAJC11 interactome, through the expression of DNAJC11-FLAG in HEK293FT cells and transgenic mice. Our analysis confirmed known DNAJC11-interacting proteins including members of the MICOS complex that organize mitochondrial cristae formation. Moreover, we identified in both biological systems novel mitochondrial interactions including VDACs that exchange metabolites across the outer mitochondrial membrane. In HEK293FT cells, DNAJC11 preferentially interacted with ribosomal subunits and chaperone proteins including Hsp70 members, possibly correlating DNAJC11 with cotranslational folding and import of mitochondrial proteins in metabolically active cells. Instead, the DNAJC11 interactome in the mouse cerebrum was enriched for synaptic proteins, supporting the importance of DNAJC11 in synapse and neuronal integrity. Moreover, we demonstrated that the DUF3395 domain is critically involved in DNAJC11 protein-protein interactions, while the J-domain determines its mitochondrial localization. Collectively, these results provide a functional characterization for DNAJC11 domains, while the identified interactome networks reveal an emerging role of DNAJC11 in mitochondrial biogenesis and response to microenvironment changes and requirements.


Treatment of subperiodic Brugia malayi infection with a single dose of ivermectin.
A clinical trial on the efficacy of a single oral dose of ivermectin at 20, 50, 100, and 200 micrograms/kg was carried out in 40 subjects with subperiodic Brugia malayi microfilaremia. There was no significant difference in the clearance of microfilaremia in the four treatment groups, and the lowest geometric mean microfilarial count (GMC) achieved in the 40 subjects was 8.8/ml or 8.3% of the initial count (106.1/ml), at two weeks post-treatment. The GMC started to increase at one month post-treatment and by six months was 22.2% of the initial GMC. Only 27.5%, 23.1%, 15.0%, and 18.9% of subjects were amicrofilaremic at two, four, 12, and 24 weeks post-treatment, respectively. Mild fever in 35% of the subjects was the primary side reaction and was more common in those with microfilarial counts > or = 500/ml (85.7%) than in those with counts < 500/ml (32%). The clearance of B. malayi microfilaremia by ivermectin was less rapid than that reported for Wuchereria bancrofti. The smaller number of side reactions encountered in the present study compared with those reported for bancroftian filariasis is probably related to the lower microfilarial density in the present subjects. Since ivermectin at a single oral dose of 20-200 micrograms/kg can reduce the GMC to less than 10% at two weeks and maintain it below 25% of the initial level even at six months post-treatment, it is recommended that the drug be seriously evaluated for use in the control of brugian filariasis.


Development of natural protein microarrays for diagnosing cancer based on an antibody response to tumor antigens.
The detection of autoantibodies to tumor antigens has potential utility for the early diagnosis of cancers. In previous studies, we have identified tumor antigens based on Western blot analysis of tumor cell lysates that were incubated with subject sera to identify proteins that elicit specific reactivity in sera from patients with the corresponding tumor type. More recently, we have explored the use of microarrays spotted with tumor proteins as an alternative to Western blots. Microarrays provide a high throughput, high sensitivity alternative to the use of Western blots for tumor antigen profiling. In this study, we have assessed the reproducibility of natural protein microarrays and their ability to distinguish between lung cancer sera and controls. Protein lysates from the A549 human lung adenocarcinoma cell line were separated into 1840 fractions that were spotted in duplicate, along with various controls, on nitrocellulose coated slides. Sera from 18 newly diagnosed patients with lung cancer and from 15 healthy controls were each hybridized to an individual microarray. The reactivity of arrayed proteins with Ig was determined by incubation with biotinylated goat-anti-human-Ig followed by phycoerythrin-conjugated streptavidin. The intensity measures of duplicate spots (within-slide) and duplicate slides (between-slides) were highly reproducible, exhibiting correlation values >0.9. A total of 63 of the 1840 arrayed fractions demonstrated increased reactivity in cancer patients relative to controls as measured by a rank-based statistic (p < 0.008). Microarrays of tumor-derived proteins provide the means for uncovering a repertoire of tumor antigens that have induced an antibody response in patients with specific cancers.


Effect of honey solution and water acquisition on survival of starved solenopsis mealybug, Phenacoccus solenopsis.
The current study examined the effects of honey solution and water access on feeding behavior and survival of starving solenopsis mealybugs, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae). The electrical penetration graph technique and an artificial membrane system were used to check whether P. solenopsis could imbibe free water or other liquid, such as the honey solution used here, in its natural environment. The recorded electrical penetration graph waveforms revealed that P. solenopsis could continuously imbibe water-honey solution for several hours, which indicated that honey solution and water acquisition could possibly occur when P. solenopsis had access to such liquids in its natural environment. Waveforms of water-honey solution feeding alternated between two distinct feeding phases in a regular pattern, which was assumed to reflect inherent habits of feeding attempts. The effects of honey solution and water acquisition on survival of P. solenopsis was also examined. Comparison between P. solenopsis in different treatments (starved, water feeding, honey solution feeding, and cotton plant feeding) suggested that 1) P. solenopsis could accept but did not favor feeding on water or the honey solution, and 2) this feeding could prolong its survival, but had no effect on body size.


Effects of physical therapy delivery via home video telerehabilitation on functional and health-related quality of life outcomes.
This study examined functional outcomes, health-related quality of life (HRQoL), and satisfaction in a group of Veterans who received physical therapy via an in-home video telerehabilitation program, the Rural Veterans TeleRehabilitation Initiative (RVTRI). A retrospective, pre-post study design was used. Measures obtained from 26 Veterans who received physical therapy in the RVTRI program between February 22, 2010, and April 1, 2011, were analyzed. Outcomes were the Functional Independence Measure (FIM); Quick Disabilities of the Arm, Shoulder, and Hand measure; Montreal Cognitive Assessment (MoCA); and the 2-minute walk test (2MWT). HRQoL was assessed using the Veterans RAND 12-Item Health Survey (VR-12), and program satisfaction was evaluated using a telehealth satisfaction scale. Average length of participation was 99.2 +/- 43.3 d and Veterans, on average, received 15.2 +/- 6.0 therapeutic sessions. Significant improvement was shown in the participants' FIM (p < 0.001, r = 0.63), MoCA (p = 0.01, r = 0.44), 2MWT (p = 0.006, r = 0.73), and VR-12 (p = 0.02, r = 0.42). All Veterans reported satisfaction with their telerehabilitation experiences. Those enrolled in the RVTRI program avoided an average of 2,774.7 +/- 3,197.4 travel miles, 46.3 +/- 53.3 hr of driving time, and $1,151.50 +/- $1,326.90 in travel reimbursement. RVTRI provided an effective real-time, home-based, physical therapy.


Second cancers after childhood cancer--GPs beware!
One of the long-term effects in childhood cancer survivors (CCS) is the development of second cancers. In a cohort of CCS, this study describes how second cancers were presented, the way they were diagnosed, and the knowledge CCS had about their increased risk to develop a second cancer. Selected participants were all adult five-year CCS (n = 1275) who were treated at the University Medical Center Groningen since 1965. Of these, 84 (6.6%) had developed a second cancer, of which 27 had died. The 57 survivors were asked to participate in a telephone interview. Of the 57 CCS, 35 (61%) participated. Together they had developed 45 second cancers. Most participants (97%) were seen at the long-term follow-up clinic. Of all second cancers, 89% caused symptoms. Of all second cancers, the majority (56%) were first presented at the general practitioner's (GP's) office and 20% at follow-up testing. Of these CCS, only 28% were aware of their increased risk of developing a second cancer. It is important to inform CCS continuously regarding their increased risk, as a relatively small percentage are aware of this. Since most of these patients first reported their symptoms to the GP, all GPs should be aware of this increased risk, in particular because this concerns cancer at a younger age than normally expected. A survivor care plan might be an effective way of communication with both CCS and GPs.


Stainless and shape memory alloy coronary stents: a computational study on the interaction with the vascular wall.
Balloon-expandable and self-expandable stents are the two types of coronary stents available. Basically, they differ in the modality of expansion. The present study analyses the stress state induced on the vascular wall, by the expansion of balloon- and self-expandable stents, using the finite element method. Indeed, modified mechanical stress state is in part responsible in the restenosis process. The balloon-expandable stents herein investigated are assumed to be made of stainless steel, while the self-expandable stents are made of a shape memory alloy. The effects of the severity of the coronary stenosis, the atherosclerotic plaque stiffness and the stent design are investigated. Comparing the self-expandable stent with the balloon-expandable one, the former induces fewer stresses and lower damage to the vessel, but, on the other hand, its lower stiffness induces a lower capability to restore vasal lumen and to contrast arterial elastic recoil.


Loss of p53 gene mutation after irradiation is associated with increased aggressiveness in recurring head and neck cancer.
The p53 gene plays a pivotal role in the control of a checkpoint during G1 and in the apoptotic program. It has been postulated that alterations of p53 may influence radio-sensitivity and prognosis in several malignancies. We studied the p53 gene status of 35 consecutive head and neck cancer patients who failed primary radiotherapy (RT) in preirradiated and postirradiated tumor samples using DNA single-strand conformational polymorphism analysis. Sixteen of 35 (46%) preirradiated samples presented with band shifts suggestive of point mutations in one or two exons. Eleven of these tumors (69%) showed the same shift even in the postirradiated samples. Exons 5 and 8 were prevalently affected in this group. Five tumors (31%) lost the mutation following RT. The missed mutations clustered in exon 7. All mutations were confirmed by sequencing. Actuarial analysis demonstrated increased survival in patients with tumors bearing a p53 gene mutation in both preirradiated and postirradiated samples (P = 0.05 and P = 0.01, respectively). We also found that loss of p53 gene mutation in postirradiated cancers is associated with a significantly shorter disease-free interval (P < 0.02) and a worse prognosis (P < 0.05). A possible explanation in such cases is clonal selection by RT of more aggressive and radioresistant cell subpopulations, which are wild-type for the p53 gene. Taken together, our data suggest that not only p53 gene status but also the pattern of mutations could modulate the response of tumor cell to RT in vivo.


Antibacterial activity of a new, stable, aqueous extract of allicin against methicillin-resistant Staphylococcus aureus.
The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals and the community has led to a demand for new agents that could be used to decrease the spread of these bacteria. Topical agents such as mupirocin have been used to reduce nasal carriage and spread and to treat skin infections; however, resistance to mupirocin in MRSAs is increasing. Allicin is the main antibacterial agent isolated from garlic, but natural extracts can be unstable. In this study, a new, stable, aqueous extract of allicin (extracted from garlic) is tested on 30 clinical isolates of MRSA that show a range of susceptibilities to mupirocin. Strains were tested using agar diffusion tests, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Diffusion tests showed that allicin liquids produced zone diameters >33 mm when the proposed therapeutic concentration of 500 microg/mL (0.0005% w/v) was used. The selection of this concentration was based on evidence from the MIC, MBC and agar diffusion tests in this study. Of the strains tested, 88% had MICs for allicin liquids of 16 microg/mL, and all strains were inhibited at 32 microg/mL. Furthermore, 88% of clinical isolates had MBCs of 128 microg/mL, and all were killed at 256 microg/mL. Of these strains, 82% showed intermediate or full resistance to mupirocin; however, this study showed that a concentration of 500 microg/mL in an aqueous cream base was required to produce an activity equivalent to 256 microg/mL allicin liquid.


Monitoring progress in population health: trends in premature death rates.
Trends in population health outcomes can be monitored to evaluate the performance of population health systems at the national, state, and local levels. The objective of this study was to compare and contrast 4 measures for assessing progress in population health improvement by using age-adjusted premature death rates as a summary measure of the overall health outcomes in the United States and in all 50 states. To evaluate the performance of statewide population health systems during the past 20 years, we used 4 measures of age-adjusted premature (<75 years of age) death rates: current rates (2009), baseline trends (1990s), follow-up trends (2000s), and changes in trends from baseline to the follow-up periods (ie, "bending the curve"). Current premature death rates varied by approximately twofold, with the lowest rate in Minnesota (268 deaths per 100,000) and the highest rate in Mississippi (482 deaths per 100,000). Rates improved the most in New York during the baseline period (-3.05% per year) and in New Jersey during the follow-up period (-2.87% per year), whereas Oklahoma ranked last in trends during both periods (-0.30%/y, baseline; +0.18%/y, follow-up). Trends improved the most in Connecticut, bending the curve downward by -1.03%; trends worsened the most in New Mexico, bending the curve upward by 1.21%. Current premature death rates, recent trends, and changes in trends vary by state in the United States. Policy makers can use these measures to evaluate the long-term population health impact of broad health care, behavioral, social, and economic investments in population health.


The influence of impaired processing speed on cognition in first-episode antipsychotic-naïve schizophrenic patients.
Impaired cognition is a prominent feature of schizophrenia. To what extent the heterogeneous cognitive impairments can be accounted for by considering only a single underlying impairment or a small number of core impairments remains elusive. This study examined whether cognitive impairments in antipsychotic-naïve, first-episode schizophrenia patients may be determined by a relative slower speed of information processing. Forty-eight antipsychotic-naïve patients with first-episode schizophrenia and 48 matched healthy controls were administered a comprehensive battery of neuropsychological tests to assess domains of cognitive impairments in schizophrenia. Composite scores were calculated, grouping tests into cognitive domains. There were significant differences between patients and healthy controls on global cognition and all cognitive domains, including verbal intelligence, processing speed, sustained attention, working memory, reasoning and problem solving, verbal learning and memory, visual learning and memory, and reaction time. All these significant differences, except for verbal intelligence and global cognition, disappeared when processing speed was included as a covariate. At the first stage of illness, antipsychotic-naïve patients with schizophrenia display moderate/severe impairments in all the cognitive domains assessed. The results support the contention of a global cognitive dysfunction in schizophrenia that to some extent may be determined by impaired processing speed.


Understanding PTEN regulation: PIP2, polarity and protein stability.
The PTEN tumour suppressor is a lipid and protein phosphatase that inhibits phosphoinositide 3-kinase (PI3K)-dependent signalling by dephosphorylating phosphatidylinositol 3,4,5-trisphosphate (PtdInsP(3)). Here, we discuss the concept of PTEN as an 'interfacial enzyme', which exists in a high activity state when bound transiently at membrane surfaces containing its substrate and other acidic lipids, such as PtdIns(4,5)P(2) and phosphatidylserine (PtdSer). This mechanism ensures that PTEN functions in a spatially restricted manner, and may explain its involvement in forming the gradients of PtdInsP(3), which are necessary for generating and/or sustaining cell polarity during motility, in developing neurons and in epithelial tissues. Coordinating PTEN activity with alternative mechanisms of PtdInsP(3) metabolism, by the tightly regulated SHIP 5-phoshatases, synthesizing the independent second messenger PtdIns(3,4)P(2), may also be important for cellular polarization in some cell types. Superimposed on this interfacial mechanism are additional post-translational regulatory processes, which generally act to reduce PTEN activity. Oxidation of the active site cysteine residue by reactive oxygen species and phosphorylation of serine/threonine residues at sites in the C-terminus of the protein inhibit PTEN. These phosphorylation sites also appear to play a role in regulating both stability and localization of PTEN, as does ubiquitination of PTEN. Because genetic studies in mice show that the level of expression of PTEN in an organism profoundly influences tumour susceptibility, factors that regulate PTEN, localization, activity and turnover should be important in understanding its biological functions as a tumour suppressor.


Chromosomal location and inheritance of stem rust resistance transferred from Hordeum bulbosum into cultivated barley (H. vulgare).
Stem rust, caused by Puccinia graminis f. sp. tritici, is an important disease on barley (Hordeum vulgare). Host resistance has effectively controlled stem rust, primarily through use of gene Rpg1. However, virulence to Rpg1 is present in North America, and a new race (TTKSK, or Ug99) from eastern Africa threatens barley production. A search for novel resistance was previously conducted, and an interspecific barley breeding line (212Y1) with introgressed chromatin from H. bulbosum was identified as carrying resistance to races MCCF and QCCJ. This study evaluated the inheritance of resistance in 212Y1 using populations from crosses to Morex (Rpg1 donor) and Q21861 (rpg4 donor) and the pathogen races MCCF (avirulent on Rpg1 and rpg4) and QCCJ (virulent on Rpg1 and avirulent on rpg4), and determined the chromosomal position of the introgression using genomic in situ hybridization (GISH) and chromosome-specific polymerase chain reaction (PCR)-based markers. Progeny from the 212Y1/Q21861 F(2) population segregated for resistant and susceptible plants, indicating different gene loci. Genetic analyses of Morex/212Y1 F(3) families fit a 7 homozygous resistant (HR):8 segregating:1 homozygous susceptible (HS) family segregation ratio to race MCCF, indicating that two genes controlled resistance. Plants in segregating families were in 3R:1S (Rpg1), 13R:3S (Rpg1+212Y1), and 1R:3S (212Y1) ratios. Genetic analyses of the same F(3) families fit a 1HR:2 segregating:1HS family segregation ratio to race QCCJ, indicating monogenic inheritance. Plants in segregating families were in a 1R: 3S ratio, indicating recessive inheritance in 212Y1. The introgression from H. bulbosum into H. vulgare was positioned on chromosome 6HS based on GISH and the PCR-based markers. No known stem rust resistance gene has previously been mapped to that region. Thus, it is proposed to name this novel gene from H. bulbosum as rpg6.


Comparison of Endoscopic Dysplasia Detection Techniques in Patients With Ulcerative Colitis: A Systematic Review and Network Meta-analysis.
We assessed the comparative efficacy of different dysplasia detection techniques in patients with ulcerative colitis (UC) through a network meta-analysis and rated the quality of evidence using GRADE approach. Through a systematic literature review of multiple databases through June 30, 2017, we identified parallel-group randomized controlled trials (RCTs) in adults with long-standing UC undergoing surveillance colonoscopy with standard definition-white light endoscopy (SD-WLE), high-definition WLE (HD-WLE), narrow band imaging (NBI), or dye-based chromoendoscopy. The primary outcome was the total number of dysplastic lesions. Pairwise and network meta-analysis was performed; ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. Based on 8 parallel-group RCTs (924 patients), low-quality evidence supports chromoendoscopy over SD-WLE (odds ratio [OR], 2.37; 95% credible interval [CrI], 0.81-6.94) for any dysplasia detection, whereas very low-quality evidence supports using HD-WLE or NBI over SD-WLE (HD-WLE [vs SD-WLE]: OR, 1.21; 95% CrI, 0.30-4.85; NBI: OR, 1.68; 95% CrI, 0.54-5.22). Very low-quality evidence from indirect comparative analysis supports the use of chromoendoscopy over HD-WLE (OR, 1.96; 95% CrI, 0.72-5.34) or NBI (OR, 1.41; 95% CrI, 0.70-2.84) for any dysplasia detection. The number of patients with advanced neoplasia was very small, precluding meaningful analysis. Although we did not find any single technique to be superior, chromoendoscopy is probably more effective than SD-WLE for detecting any dysplasia, and there is low confidence in estimates supporting its use over HD-WLE or NBI. There is very low-quality evidence to inform the comparative efficacy of these interventions in detecting advanced neoplasia or preventing future colorectal cancer. Pragmatic, parallel-group RCTs with longitudinal follow-up are warranted to inform optimal dysplasia surveillance techniques. 10.1093/ibd/izy188_video1izy188.video15789702674001.


Treatment of eosinophilic esophagitis with specific food elimination diet directed by a combination of skin prick and patch tests.
Eosinophilic esophagitis (EE) is a recently described disorder identified in patients with symptoms suggestive of gastroesophageal reflux disease (GERD) but unresponsive to conventional reflux therapies. Therapies have included corticosteroids, elemental diet, and diet restriction. We report our experience with skin prick and atopy patch testing and food elimination diets in patients diagnosed as having EE. To identify food antigens that cause EE and the characteristics of patients who respond to food elimination vs those who are unresponsive. Patients diagnosed as having EE had restricted diets based on skin prick and atopy patch testing results. Additional biopsies were performed after 4 to 8 weeks of restricted diet. Demographics, atopic tendencies, and food antigens were identified retrospectively in our food allergy database. A total of 146 patients diagnosed as having EE were evaluated with skin prick and atopy patch testing. Thirty-nine patients had unequivocal demonstration of food causing EE, with normalization of biopsy results on elimination and reoccurrence on reintroduction. An additional 73 patients, for a total 112 (77%) of 146 patients, had resolution of their EE as demonstrated by biopsy results. Fifteen (10%) of 146 patients were nonresponders manifested by no significant reduction in esophageal eosinophils despite restricted diet based on skin prick and atopy patch testing. Egg, milk, and soy were identified most frequently with skin prick testing, whereas corn, soy, and wheat were identified most frequently with atopy patch testing. In more than 75% of patients with EE, both symptoms and esophageal inflammation can be significantly improved with dietary elimination of foods. Skin prick and atopy patch testing can help identify foods in most patients.


Effect of the immunosuppressants on hepatocyte cells proliferation and apoptosis during liver regeneration after hepatectomy - molecular studies.
The regeneration and remodeling of the transplanted liver is the result of hepatocyte proliferation and apoptosis (programmed cell death). The purpose of this study was to verify the influence of immunosuppressants on the expression levels of genes: IL-6 (regulator of hepatocyte proliferation), pro-apoptotic (Bak and Bax) and anti-apoptotic (Bcl-Xl and Bcl-2). 36 newborn suckling rats (age 5-7 days, weight 6-10 g) were divided into four groups: hepatectomy, hepatectomy plus methylprednisolone, hepatectomy plus CsA and hepatectomy plus Tac. The same experiments were performed in 24 weaning rats (age 21-23 days, weight 30-50 g). The animals were killed one day after the hepatectomy and the remnant livers were analyzed. The livers of all animals exhibited histological changes of liver regeneration. The immunosuppressants did not promote any alteration on IL-6 gene expression levels. Methylprednisolone and CsA increased the expression levels of Bak gene in newborn rats. However, methylprednisolone and Tac promoted increased expression levels of Bcl-2 in all groups. We hypothesize that these effects explain the efficacy of these drugs on the treatment of acute and chronic liver rejection as the expression of Bcl-2 in cholangiocytes is decreased as a consequence of bile duct lesions


Heat, work and subtle fluids: a commentary on Joule (1850) 'On the mechanical equivalent of heat'.
James Joule played the major role in establishing the conservation of energy, or the first law of thermodynamics, as a universal, all-pervasive principle of physics. He was an experimentalist par excellence and his place in the development of thermodynamics is unarguable. This article discusses Joule's life and scientific work culminating in the 1850 paper, where he presented his detailed measurements of the mechanical equivalent of heat using his famous paddle-wheel apparatus. Joule's long series of experiments in the 1840s leading to his realisation that the conservation of energy was probably of universal validity is discussed in context with the work of other pioneers, notably Sadi Carnot, who effectively formulated the principle of the second law of thermodynamics a quarter of a century before the first law was accepted. The story of Joule's work is a story of an uphill struggle against a critical scientific establishment unwilling to accept the mounting evidence until it was impossible to ignore. His difficulties in attracting funding and publishing in reputable journals despite the quality of his work will resonate with many young scientists and engineers of the present day. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.


The role of novel Rydberg-valence behaviour in the non-adiabatic dynamics of tertiary aliphatic amines.
Time-resolved photoelectron imaging was used to study non-adiabatic relaxation dynamics in N,N-dimethylisopropylamine, N,N-dimethylpropylamine and N-methylpyrrolidine following excitation at 200 nm. This series of tertiary aliphatic amines are all of similar chemical makeup, but exhibit differences in their structure - being branched, straight-chain and cyclic, respectively. Our experimental investigation, supported by extensive theoretical calculations, provides considerable new insight into the nature of the internal conversion processes that mediate dynamical evolution between electronic states of predominantly Rydberg character in this important class of model photochemical systems. In particular, the angle-resolved data afforded by the imaging approach (something not previously reported for tertiary aliphatic amines) offers novel and highly-detailed mechanistic information about the overall relaxation pathway. Strikingly, both the experimental and theoretical findings suggest that a critical factor driving the non-adiabatic dynamics is the evolution of valence character along an N-C stretching coordinate within a member of the 3p manifold. This is in stark contrast to primary and secondary amines, as well as many other small hetero-atom containing organic species, where evolution of valence character within the 3s state is now a well-established phenomenon implicated in mediating ultrafast non-adiabatic photochemistry.


Metabolomics analysis reveals both plant variety and choice of hormone treatment modulate vinca alkaloid production in Catharanthus roseus.
The medicinal plant Catharanthus roseus produces numerous secondary metabolites of interest for the treatment of many diseases - most notably for the terpene indole alkaloid (TIA) vinblastine, which is used in the treatment of leukemia and Hodgkin's lymphoma. Historically, methyl jasmonate (MeJA) has been used to induce TIA production, but in the past, this has only been investigated in whole seedlings, cell culture, or hairy root culture. This study examines the effects of the phytohormones MeJA and ethylene on the induction of TIA biosynthesis and accumulation in the shoots and roots of 8-day-old seedlings of two varieties of C. roseus. Using LCMS and RT-qPCR, we demonstrate the importance of variety selection, as we observe markedly different induction patterns of important TIA precursor compounds. Additionally, both phytohormone choice and concentration have significant effects on TIA biosynthesis. Finally, our study suggests that several early-induction pathway steps as well as pathway-specific genes are likely to be transcriptionally regulated. Our findings highlight the need for a complete set of'omics resources in commonly used C. roseus varieties and the need for caution when extrapolating results from one cultivar to another.


Anhedonia revisited: is there a role for dopamine-targeting drugs for depression?
It is 16 years since we reviewed anhedonia in depression. Since then, there have been important developments in the study of anhedonia, mainly using the new techniques that neuroimaging made available, which provide very interesting new insights. It is becoming increasingly apparent that anhedonia, with psychomotor retardation, defines a dimension in depressive disorder that seems to be distinct from a dimension encompassing mood plus somatic symptoms. These dimensions can coexist, but may also be present separately. The first appears associated with disturbances (under-functioning) in dopamine function; the other appears to be related to a similar under-functioning in the serotonin system. Furthermore, anhedonia itself increasingly appears to be a composite symptom, consisting of at least two dimensions (i.e. a motivational/appetitive and a consummatory one). Depression appears to be characteristically linked more to the first one, in contrast to what was originally thought. We discuss the significance of the above in the evolving treatment of depression and the potential use of dopamine-targeting drugs.


Opposing roles of Elk-1 and its brain-specific isoform, short Elk-1, in nerve growth factor-induced PC12 differentiation.
The ternary complex factor Elk-1, a major nuclear target of extracellular signal-regulated kinases, is a strong transactivator of serum-responsive element (SRE) driven gene expression. We report here that mature brain neurons and nerve growth factor (NGF)-differentiated PC12 cells also express a second, smaller isoform of Elk-1, short Elk-1 (sElk-1). sElk-1 arises from an internal translation start site in the Elk-1 sequence, which generates a protein lacking the first 54 amino acids of the DNA-binding domain. This deletion severely compromises the ability of sElk-1 to form complexes with serum response factor on the SRE in vitro and to activate SRE reporter genes in the presence of activated Ras. Instead, sElk, but not a mutant that cannot be phosphorylated, inhibits transactivation driven by Elk-1. More pertinent to the neuronal-specific expression of sElk-1, we show it plays an opposite role to Elk-1 in potentiating NGF-driven PC12 neuronal differentiation. Overexpression of sElk-1 but not Elk-1 increases neurite extension, an effect critically linked to its phosphorylation. Interestingly, in the presence of sElk-1, Elk-1 loses its strictly nuclear localization to resemble the nuclear/cytoplasm pattern observed in the mature brain. This is blocked by mutating a normally cryptic nuclear export signal in Elk-1. These data provide new insights into molecular events underlying neuronal differentiation of PC12 cells mediated by the NGF-ERK signaling cascade.


A multidisciplinary approach to the treatment of intestinal failure.
Intestinal failure is most commonly treated by the administration of total parenteral nutrition (TPN). In some patients, however, surgical therapy may increase the ability to use the intestine for nutrition and thereby decrease the complications of TPN therapy. A multidisciplinary comprehensive intestinal failure program was initiated at the University of Nebraska Medical Center in October 2000. Here we describe the surgical approaches to patients with short bowel syndrome and the subsequent impact on the need for TPN and on survival. Fifty patients (children=30, adults=20) underwent surgical procedures to restore intestinal continuity (n=5), repair enterocutaneous fistulas (n=5), resect dysmotile or strictured/obstructed bowel segments or mesenteric desmoid tumors (n=7), stricturoplasty (n=2), Bianchi tapering and lengthening (n=20), serial transverse enteroplasty (n=8), and other operations (n=8). Of these 50 patients, three patients did not require TPN after surgical intervention and seven had remnant small bowel anatomy that precluded TPN weaning (e.g., end duodenostomy) and were listed for transplantation or continued on full TPN support. Of the 40 remaining patients, most received the majority of calories from TPN at the time of referral, i.e., mean calories from TPN=90%. Subsequent to the surgical and medical therapy, 26 (65%) have been completely weaned off TPN. In addition, 10 had substantial decreases in their TPN requirements (i.e., from 85% of calories from TPN at onset decreased to a median 35% of required calories at most recent follow-up). Four patients remained on the same amount of TPN support. Four of the seven patients listed for transplantation underwent successful transplantation. Despite the complications of short bowel syndrome, 86% (n=43) of the patients are alive and well at a mean follow-up of 2 years. Patient deaths occurred primarily in those listed or eligible for transplantation and were related to advanced liver disease (n=3), gastrointestinal hemorrhage (n=1), or line sepsis (n=1). Two other patients died, one from influenza A infection and one from unknown cause at home, months after complete discontinuation of TPN. In this series of patients with short bowel syndrome, surgical intervention led to weaning or discontinuation of TPN support in 85% of patients. An organized multidisciplinary approach to the patient with short bowel syndrome is recommended.


Cell-free fetal DNA and spontaneous preterm birth.
Inflammation is known to play a key role in preterm and term parturition. Cell-free fetal DNA (cff-DNA) is present in the maternal circulation and increases with gestational age and some pregnancy complications (e.g. preterm birth, preeclampsia). Microbial DNA and adult cell-free DNA can be pro-inflammatory through DNA-sensing mechanisms such as Toll-like receptor 9 and the Stimulator of Interferon Genes (STING) pathway. However, the pro-inflammatory properties of cff-DNA, and the possible effects of this on pregnancy and parturition are unknown. Clinical studies have quantified cff-DNA levels in the maternal circulation in women who deliver preterm and women who deliver at term and show an association between preterm labor and higher cff-DNA levels in the 2nd, 3rd trimester and at onset of preterm birth symptoms. Together with potential pro-inflammatory properties of cff-DNA, this rise suggests a potential mechanistic role in the pathogenesis of spontaneous preterm birth. In this review, we discuss the evidence linking cff-DNA to adverse pregnancy outcomes, including preterm birth, obtained from preclinical and clinical studies.


Is base excision repair a tumor suppressor mechanism?
The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase beta and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.


A pilot study of myoelectrically controlled FES of upper extremity.
Functional electrical stimulation (FES) of upper limbs can be used for the recovery of some hand functions on patients with CNS lesions. This study deals with the control of FES by means of myoelectrical activity detected from voluntarily activated paretic muscles. The specific aim of this paper is to evaluate the accuracy of myoelectrical control in terms of produced force and movement. For this purpose, a specific device called myoelectrical controlled functional electrical stimulator (MeCFES) has been developed and applied to six tetraplegic patients with a spinal cord lesion and one stroke hemiplegic patient. Residual myoelectric signals from the paretic wrist extensor (m. extensor carpi radialis, ECR) have been used to control stimulation of either the wrist extension (i.e., the same muscle) or thumb flexion. A tracking test based on a visual feedback of the produced force or movement compared to a reference target trajectory was used to quantify control accuracy. A comparison was made between the tracking performances of each subject with and without the MeCFES and the learning process for two of the subjects were observed during consecutive sessions. Results showed that the wrist extension was improved in three out of five C5 SCI patients and the thumb flexion was largely increased in one incomplete C3 SCI patient. The hemiplegic patient showed limited thumb control with the MeCFES but indicated the possibility of a carry over effect. It was found that a low residual natural force resulted in a less accurate movement but also with a large increase (up to ten times) of the muscle output. On the contrary, persons with a medium residual force obtained a smaller amplification of muscle force with a higher tracking accuracy.


The influence of plastic pollution and ocean change on detrital decomposition.
Plastic pollution and ocean change have mostly been assessed separately, missing potential interactions that either enhance or reduce future impacts on ecosystem processes. Here, we used manipulative experiments with outdoor mesocosms to test hypotheses about the interactive effects of plastic pollution, ocean warming and acidification on macrophyte detrital decomposition. These experiments focused on detritus from kelp, Ecklonia radiata, and eelgrass, Zostera muelleri, and included crossed treatments of (i) no, low and high plastic pollution, (ii) current/future ocean temperatures, and (iii) ambient/future ocean partial pressure of carbon dioxide (pCO2). High levels of plastic pollution significantly reduced the decomposition rate of kelp and eelgrass by approximately 27% and 36% in comparison to controls respectively. Plastic pollution also significantly slowed the nitrogen liberation from seagrass and kelp detritus. Higher seawater temperatures significantly increased the decomposition rate of kelp and eelgrass by 12% and 5% over current conditions, respectively. Higher seawater temperatures were also found to reduce the nitrogen liberation in eelgrass. In contrast, ocean acidification did not significantly influence the rate of macrophyte decomposition or nutrient liberation. Overall, our results show how detrital processes might respond to increasing plastic pollution and ocean temperatures, which has implications for detrital-driven secondary productivity, nutrient dynamics and carbon cycling.


Pediatric cancers in the new millennium: dramatic progress, new challenges.
Over the past 50 years, great strides have been made in diagnosis, treatment, and survival of childhood cancer. In the 1960s the probability of survival for a child with cancer was less than 25%, whereas today it may exceed 80%. This dramatic change has occurred through significant and steady progress in our understanding of tumor biology, creation of specialized multidisciplinary care teams, incremental improvements in therapy, establishment of specialized centers with research infrastructure to conduct pivotal clinical studies, and the evolution of a cooperative group mechanism for clinical research. Most children with cancer in the United States, Europe, and Japan receive appropriate diagnosis and treatment, although access is limited in developing countries. The price of success, however, is the growing population of survivors who require medical and psychosocial follow-up and treatment for the late effects of therapy. Here we review the progress made in pediatric oncology over the past 3 decades and consider the new challenges that face us today.


Perceptions and preferences of medical students regarding teaching methods in a Medical College, Mangalore India.
In the complex setting of a medical school it becomes essential to utilize an approach to teaching and learning that is best suited to the needs of the students. In developing countries like India, where there is an exponential increase of institutions catering to medical students, it becomes a challenge to teach to large number of students per class. Hence, research is needed to identify the needs of students in relation to their day to day learning activities. To understand the preferences and perception of medical students about the current methods of teaching, aids used for teaching and also identify barriers in learning as perceived by the students. A Cross-sectional study was carried out at Kasturba Medical College, Mangalore during May 2012. Study participants included 2(nd) and 3(rd) year medical students. A semi-structured questionnaire was used to collect the information in relation to preferences and perceptions regarding teaching methods utilized for theory and clinical teaching. SPSS version 11.5 was used for analysis of data. The association between variables of interest was tested using Chi-square test. A total of 286 students (56.6 % females and 43.4% males) participated with a dropout rate of 10.6%. The study revealed that 71.3% of the students had an attendance above 75%. The most preferred teaching method was Problem Based Learning (PBL) (71.4%) as students felt that it enhanced lateral thinking while Didactic Lectures was the least preferred (32.8%). The most preferred modality of teaching aid was found to be Black board preferred by 46.9% students. In learning rare signs and cases, students preferred video lectures (41%) and mannequins (75.9%) in learning clinical skills. The main barrier in theory learning identified was inappropriate teaching methods (15%) and being new to clinical posting (38.5%) in case of learning clinical skills. The findings of the study suggest that a combination of traditional methods with other methods such as PBL, video lectures and mannequins could be an effective way of teaching theory and clinical skills.


A Gating Mechanism of the Serotonin 5-HT3 Receptor.
Our recently solved high-resolution structure of the serotonin 5-HT3 receptor (5-HT3R) delivered the first detailed structural insights for a mammalian pentameric ligand-gated ion channel. Based on this structure, we here performed a total of 2.8-μs all-atom molecular dynamics simulations to unravel at atomic detail how neurotransmitter binding on the extracellular domain induces sequential conformational transitions in the receptor, opening an ion channel and translating a chemical signal into electrical impulses across the membrane. We found that serotonin binding first induces distinct conformational fluctuations at the side chain of W156 in the highly conserved ligand-binding cage, followed by tilting-twisting movements of the extracellular domain which couple to the transmembrane TM2 helices, opening the hydrophobic gate at L260 and forming a continuous transmembrane water pathway. The structural transitions in the receptor's transmembrane part finally couple to the intracellular MA helix bundle, opening lateral ports for ion passage.


Reflective dialogue in clinical supervision: A pilot study involving collaborative review of supervision videos.
To pilot an intervention involving reflective dialogue based on video recordings of clinical supervision. Fourteen participants (seven psychotherapists and their supervisors) completed a reflective practice protocol after viewing a video of their most recent supervision session, then shared their reflections in a second session. Thematic analysis of individual reflections and feedback resulted in the following dominant themes: (1) Increased discussion of supervisee anxiety and the tensions between autonomy and dependence; (2) intentions to alter supervisory roles and practice; (3) identification of and reflection on parallel process (defined as the dynamic transmission of relationship patterns between therapy and supervision); and (4) a range of perceived impacts including improvements in supervisory alliance. The results suggest that reflective dialogue based on supervision videos can play a useful role in psychotherapy supervision, including with relatively inexperienced supervisees. Suggestions are provided for the encouragement of ongoing reflective dialogue in routine supervision practice.


Photodegradation of chlorpyrifos in water by UV/H2O2 treatment: toxicity evaluation.
Chlorpyrifos (CP) is an organophosphorus pesticide widely used in agriculture. Due to its toxicity, it has been necessary to develop a treatment to eliminate the environmental wastes generated by this substance. The combination of UV radiation and hydrogen peroxide seemed an interesting option to reduce the concentration of CP in water, as it has proved to be a simple and effective method to degrade other similar pesticides. The purpose of this work is to study the effect of different initial concentrations of H2O2 on the degradation of commercial CP in water using UV/H2O2. Conversions of 93% were achieved in 20 min with 450 mg L(-1) of H2O2 initial concentration (0.16 mg of CP degraded per mg of H2O2 consumed). The total organic carbon analysis showed interesting mineralization values, reaching a 70% conversion after 4 h of reaction. In addition, this degradation procedure leads to a clear reduction of the toxicity of the reaction mixture over Vibrio fischeri.


Molecular and biophysical mechanisms regulating hypertrophic differentiation in chondrocytes and mesenchymal stem cells.
Chondrocyte hypertrophy is one of the key physiological processes involved in the longitudinal growth of long bones, yet the regulation of hypertrophy is also becoming increasingly relevant for clinical application of mesenchymal stem cells (MSCs) and screening for drugs to treat hypertrophic osteoarthritis. The extraordinary cell volume increase during hypertrophy is accompanied by an up-regulation of collagen X, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF), all which are targets of the runt-related transcription factor 2 (Runx2). Many pathways, including parathyroid hormone-related protein (PTHrP)/Indian Hedgehog, Wingless/Int (Wnt)/β-catenin, and transforming growth factor beta (TGF-β)/Sma and Mad Related Family (Smad) pathways, can regulate hypertrophy, but factors as diverse as hypoxia, co-culture, epigenetics and biomaterial composition can also potently affect Runx2 expression. Control of hypertrophic differentiation can be exploited both for cartilage repair, where a stable phenotype is desired, but also in bone regeneration, where hypertrophic cartilage could act as a template for endochondral bone formation. We hope this review will motivate the design of novel engineered microenvironments for skeletal regeneration applications.


Effect of ultrasound radiation force on the choroid.
While visualization of the retina and choroid has made great progress, functional imaging techniques have been lacking. Our aim was to utilize acoustic radiation force impulse (ARFI) response to probe functional properties of these tissues. A single element 18-MHz ultrasound transducer was focused upon the retina of the rabbit eye. The procedure was performed with the eye proptosed and with the eye seated normally in the orbit. The transducer was excited to emit ARFI over a 10-ms period with a 25% duty cycle. Phase resolved pulse/echo data were acquired before, during, and following ARFI. In the proptosed eye, ARFI exposure produced tissue displacements ranging from 0 to 10 μm, and an immediate increase in choroidal echo amplitude to over 6 dB, decaying to baseline after about 1 second. In the normally seated eye, ultrasound phase shifts consistent with flow were observed in the choroid, but enhanced backscatter following ARFI rarely occurred. ARFI-induced displacements of about 10 μm were observed at the choroidal margins. Larger displacements occurred within the choroid and in orbital tissues. We hypothesize that elevated intraocular pressure occurring during proptosis induced choroidal ischemia and that acoustic radiation force produced a transient local decompression and reperfusion. With the eye normally seated, choroidal flow was observed and little alteration in backscatter resulted from exposure. Clinical application of this technique may provide new insights into diseases characterized by altered choroidal hemodynamics, including maculopathies, diabetic retinopathy, and glaucoma.


Comparative feeding strategies and kinematics in phocid seals: suction without specialized skull morphology.
Feeding kinematic studies inform our understanding of behavioral diversity and provide a framework for studying the flexibility and constraints of different prey acquisition strategies. However, little is known about the feeding behaviors used by many marine mammals. We characterized the feeding behaviors and associated kinematics of captive bearded (Erignathus barbatus), harbor (Phoca vitulina), ringed (Pusa hispida) and spotted (Phoca largha) seals through controlled feeding trials. All species primarily used a suction feeding strategy but were also observed using a biting strategy, specifically pierce feeding. Suction feeding was distinct from pierce feeding and was characterized by significantly faster feeding times, smaller gapes and gape angles, smaller gular depressions and fewer jaw motions. Most species showed higher variability in suction feeding performance than in pierce feeding, indicating that suction feeding is a behaviorally flexible strategy. Bearded seals were the only species for which there was strong correspondence between skull and dental morphology and feeding strategy, providing further support for their classification as suction feeding specialists. Harbor, ringed and spotted seals have been classified as pierce feeders based on skull and dental morphologies. Our behavioral and kinematic analyses show that suction feeding is also an important feeding strategy for these species, indicating that skull morphology alone does not capture the true diversity of feeding behaviors used by pinnipeds. The ability of all four species to use more than one feeding strategy is likely advantageous for foraging in spatially and temporally dynamic marine ecosystems that favor opportunistic predators.


Tissue energetics as measured by nuclear magnetic resonance spectroscopy during hemorrhagic shock.
The defect in energy production in an organism during shock states may be related to the impairment of mitochondrial respiration early in shock. The aim of this study was to investigate the timing and degree of cellular energetic changes during hemorrhagic shock in real time. Instrumented, splenectomized swine were randomized to undergo hemorrhagic shock, induced by a 35% blood volume bleed, for 90 min with (n = 10) or without (n = 9) subsequent resuscitation. Resuscitated animals received shed blood in two increments followed by two normal saline boluses (20 mL/kg/bolus). Throughout experimentation, tissue phosphoenergetics of liver and skeletal muscle were monitored using 31P nuclear magnetic resonance (NMR) spectroscopy via NMR coils on the liver and hindlimb. Near-infrared spectroscopy probes were used to measure liver, stomach, and skeletal muscle oxyhemoglobin saturation (StO2). Hemorrhagic shock induced an increase in phosphomonoesters in skeletal muscle (baseline: 7.09%, 90 min: 9.94% (P < 0.05); expressed as percent total phosphorus). This increase resolved in animals receiving resuscitation (n = 10) but remained elevated in those in unresuscitated shock (n = 9). Inorganic phosphate levels increased and betaATP levels decreased significantly in the liver of animals in shock as compared with baseline. StO2 in skeletal muscle, stomach, and liver correlated with whole organism oxygen delivery (r2 = 0.356, 0.368, and 0.432, respectively). We conclude that hemorrhagic shock induces early elevation of phosphomonoesters in skeletal muscle, which correlates with the severity of shock. This implies an early transition to anaerobic glycolysis during hemorrhagic shock, which may be indicative of early mitochondrial dysfunction.


Methodologic Considerations for Collecting Patient-reported Outcomes from Unselected Surgical Patients.
The impact of surgery on health is only appreciated long after hospital discharge. Furthermore, patients' perceptions of postoperative health are not routinely ascertained. The authors instituted the Systematic Assessment and Targeted Improvement of Services Following Yearlong Surgical Outcomes Surveys (SATISFY-SOS) registry to evaluate patients' postoperative health based on patient-reported outcomes (PROs). This article describes the methods of establishing the SATISFY-SOS registry from an unselected surgical population, combining perioperative PROs with information from electronic medical records. Patients enrolled during their preoperative visit were surveyed at enrollment, 30 days, and 1-yr postoperatively. Information on PROs, including quality of life, return to work, pain, functional status, medical complications, and cognition, was obtained from online, mail, or telephone surveys. Using structured query language, 44,081 patients were identified in the electronic medical records as having visited the Center for Preoperative Assessment and Planning for preoperative assessment between July 16, 2012, and June 15, 2014, and 20,719 patients (47%) consented to participate in SATISFY-SOS. Baseline characteristics and health status were similar between enrolled and not enrolled patients. The response rate for the 30-day survey was 62% (8% e-mail, 73% mail, and 19% telephone) and for the 1-yr survey was 71% (13% e-mail, 78% mail, and 8% telephone). SATISFY-SOS demonstrates the feasibility of establishing a PRO registry reflective of a busy preoperative assessment center population, without disrupting clinical workflow. Our experience suggests that patient engagement, including informed consent and multiple survey modalities, enhances PROs collection from a large cohort of unselected surgical patients. Initiatives like SATISFY-SOS could promote quality improvement, enable efficient perioperative research, and facilitate outcomes that matter to surgical patients.


Good maintenance of exercise-induced bone gain with decreased training of female tennis and squash players: a prospective 5-year follow-up study of young and old starters and controls.
This prospective 5-year follow-up study of 64 adult female racquet sports players and 27 controls assessed the changes in the playing-to-nonplaying arm bone mineral content (BMC) differences to answer three questions: (1) Are training-induced bone gains lost with decreased training? (2) Is the bone response to decreased training different if the playing career has been started before or at puberty rather than after it? (3) Are the possible bone changes related to the changes in training? The players were divided into two groups according to the starting age of their tennis or squash playing. The mean starting age was 10.5 years (SD, 2.2) among the players who had started training before or at menarche (young starters; n = 36) while 26.4 years (SD, 8.0) among those players who had begun training a minimum of 1 year after menarche (old starters; n = 28). At baseline of the 5-year follow-up, the mean age of the young starters was 21.6 years (SD, 7.6) and that of old starters was 39.4 years (SD, 10.5). During the follow-up, the young starters had reduced the average training frequency from 4.7 times a week (2.7) to 1.4 times a week (1.3) and the old starters from 4.0 times a week (1.4) to 2.0 times a week (1.4), respectively. The 5-year follow-up revealed that despite reduced training the exercise-induced bone gain was well maintained in both groups of players regardless of their clearly different starting age of activity and different amount of exercise-induced bone gain. The gain was still 1.3-2.2 times greater in favor of the young starters (at the follow-up, the dominant-to-nondominant arm BMC difference was 22% [8.4] in the humeral shaft of the young starters versus 10% [3.8] in the old starters, and 3.5% [2.4] in controls). In the players, changes in training were only weakly related to changes in the side-to-side BMC difference (r(s) = 0.05-0.34, all NS), and this was true even among the players who had stopped training completely a minimum 1 year before the follow-up. In conclusion, if controlled interventions will confirm our findings that an exercise-induced bone gain can be well maintained with decreased activity and that the maintenance of the bone gain is independent of the starting age of activity, exercise can be recommended for preventing osteoporosis and related fractures.


Missed opportunities for prevention in general internal medicine.
According to the Canadian Society of Internal Medicine, the Canadian general internist is in the ideal position to promote patient health through disease prevention. To explore the general internist's contribution to disease prevention, the authors quantified the extent to which opportunities for prevention were addressed by the general internal medicine (GIM) service in an acute care teaching hospital in Calgary. The authors interviewed 100 adult patients before discharge from the hospital's GIM service between May 14, 1997, and Dec. 2, 1997. The number of potential opportunities for preventive intervention were identified for each patient from 10 possible interventions recommended by the Canadian Task Force on the Periodic Health Examination (now the Canadian Task Force on Preventive Health Care): breast cancer screening, Papanicolaou smear for cervical cancer, counselling on menopausal hormone replacement therapy, digital rectal examination for prostate cancer, smoking cessation counselling, cholesterol measurement, therapy or monitoring for hypertension, influenza vaccination, pneumococcal vaccination and colorectal cancer screening. The authors determined which interventions the patient had undergone before the current admission to hospital and, using patient recall and postdischarge medical chart review, which opportunities for intervention were addressed by the GIM service during the current admission. An opportunity for preventive intervention was considered as addressed by the GIM service if it was performed during the current admission or if the general internist informed the patient or the patient's family physician of the need for such intervention in the near future. Among the 10 preventive interventions considered, a mean of 3.8 potential opportunities for prevention were identified for each patient. Of these, 46.5% had been addressed before the current admission, and 8.7% were addressed by the GIM service during the admission. Therefore, at the time of discharge, a mean of 55.2% of opportunities had been addressed. Among the opportunities not previously addressed, the GIM service most frequently addressed digital rectal examination for prostate cancer and cholesterol measurement. General internists are discharging patients without sufficiently addressing opportunities for disease prevention. Preventive care protocols may be needed to limit the frequency of missed opportunities for prevention in patients admitted to tertiary care GIM services.


A Mini-Atlas of Gene Expression for the Domestic Goat (Capra hircus).
Goats (Capra hircus) are an economically important livestock species providing meat and milk across the globe. They are of particular importance in tropical agri-systems contributing to sustainable agriculture, alleviation of poverty, social cohesion, and utilisation of marginal grazing. There are excellent genetic and genomic resources available for goats, including a highly contiguous reference genome (ARS1). However, gene expression information is limited in comparison to other ruminants. To support functional annotation of the genome and comparative transcriptomics, we created a mini-atlas of gene expression for the domestic goat. RNA-Seq analysis of 17 transcriptionally rich tissues and 3 cell-types detected the majority (90%) of predicted protein-coding transcripts and assigned informative gene names to more than 1000 previously unannotated protein-coding genes in the current reference genome for goat (ARS1). Using network-based cluster analysis, we grouped genes according to their expression patterns and assigned those groups of coexpressed genes to specific cell populations or pathways. We describe clusters of genes expressed in the gastro-intestinal tract and provide the expression profiles across tissues of a subset of genes associated with functional traits. Comparative analysis of the goat atlas with the larger sheep gene expression atlas dataset revealed transcriptional similarities between macrophage associated signatures in the sheep and goats sampled in this study. The goat transcriptomic resource complements the large gene expression dataset we have generated for sheep and contributes to the available genomic resources for interpretation of the relationship between genotype and phenotype in small ruminants.


Dissecting the electrostatic interactions and pH-dependent activity of a family 11 glycosidase.
Previous studies of the low molecular mass family 11 xylanase from Bacillus circulans show that the ionization state of the nucleophile (Glu78, pK(a) 4.6) and the acid/base catalyst (Glu172, pK(a) 6.7) gives rise to its pH-dependent activity profile. Inspection of the crystal structure of BCX reveals that Glu78 and Glu172 are in very similar environments and are surrounded by several chemically equivalent and highly conserved active site residues. Hence, there are no obvious reasons why their apparent pK(a) values are different. To address this question, a mutagenic approach was implemented to determine what features establish the pK(a) values (measured directly by (13)C NMR and indirectly by pH-dependent activity profiles) of these two catalytic carboxylic acids. Analysis of several BCX variants indicates that the ionized form of Glu78 is preferentially stabilized over that of Glu172 in part by stronger hydrogen bonds contributed by two well-ordered residues, namely, Tyr69 and Gln127. In addition, theoretical pK(a) calculations show that Glu78 has a lower pK(a) value than Glu172 due to a smaller desolvation energy and more favorable background interactions with permanent partial charges and ionizable groups within the protein. The pK(a) value of Glu172 is in turn elevated due to electrostatic repulsion from the negatively charged glutamate at position 78. The results also indicate that all of the conserved active site residues act concertedly in establishing the pK(a) values of Glu78 and Glu172, with no particular residue being singly more important than any of the others. In general, residues that contribute positive charges and hydrogen bonds serve to lower the pK(a) values of Glu78 and Glu172. The degree to which a hydrogen bond lowers a pK(a) value is largely dependent on the length of the hydrogen bond (shorter bonds lower pK(a) values more) and the chemical nature of the donor (COOH > OH > CONH(2)). In contrast, neighboring carboxyl groups can either lower or raise the pK(a) values of the catalytic glutamic acids depending upon the electrostatic linkage of the ionization constants of the residues involved in the interaction. While the pH optimum of BCX can be shifted from -1.1 to +0.6 pH units by mutating neighboring residues within the active site, activity is usually compromised due to the loss of important ground and/or transition state interactions. These results suggest that the pH optima of an enzyme might be best engineered by making strategic amino acid substitutions, at positions outside of the "core" active site, that electrostatically influence catalytic residues without perturbing their immediate structural environment.


Childhood asthma and indoor allergens in Native Americans in New York.
The objective of this study was to assess the correlation between childhood asthma and potential risk factors, especially exposure to indoor allergens, in a Native American population. A case-control study of St. Regis Mohawk tribe children ages 2-14 years, 25 diagnosed with asthma and 25 controls was conducted. Exposure was assessed based on a personal interview and measurement of mite and cat allergens (Der p 1, Fel d 1) in indoor dust. A non-significant increased risk of childhood asthma was associated with self-reported family history of asthma, childhood environmental tobacco smoke exposure, and air pollution. There was a significant protective effect of breastfeeding against current asthma in children less than 14 years (5.2 fold lower risk). About 80% of dust mite and 15% of cat allergen samples were above the threshold values for sensitization of 2 and 1 mug/g, respectively. The association between current asthma and exposure to dust mite and cat allergens was positive but not statistically significant. This research identified several potential indoor and outdoor risk factors for asthma in Mohawks homes, of which avoidance may reduce or delay the development of asthma in susceptible individuals.


Towards an ethical policy for the prevention of fetal sex selection in Canada.
The troubling practice of fetal sex selection has historically been considered an Asian phenomenon. However, recent evidence shows that a similar situation is emerging in North America, albeit on a smaller scale. The Society of Obstetricians and Gynaecologists of Canada has firmly stated its opposition to sex selection for non-medical reasons, as well as to the use of any technology used solely for the purpose of determining fetal sex. However, because fetal sex may be disclosed to the parents at the time of ultrasound examination if they request this information, guidance for health care professionals to assist in discouraging fetal sex selection would be useful. Because no declaration of motives or reasons is required when a woman seeks a termination of pregnancy, we suggest that health care professionals need not disclose the sex of a fetus until it has reached a gestational age at which abortion for non-medical purposes would not be possible. This proposal would facilitate consistency between clinical practice and the values of Canadian citizens, the SOGC, the Canadian Medical Association, and other professional organizations, while still respecting current laws pertaining to disclosure of patient information and patients' rights to autonomous decision-making.


Rats clearing a vaginal infection by Candida albicans acquire specific, antibody-mediated resistance to vaginal reinfection.
Oophorectomized, estrogen-treated rats were susceptible to experimental vaginal infection by Candida albicans. After spontaneous clearing of the primary infection, the animals were highly resistant to a second vaginal challenge with the fungus. The vaginal fluid of Candida-resistant rats contained antibodies directed against mannan constituents and secretory aspartyl proteinase(s) of C. albicans and was capable of transferring a degree of anti-Candida protection to naive, nonimmunized rats. This passive protection was mediated by the immunoglobulin fraction of the vaginal fluid and was substantially abolished by preabsorption of the vaginal fluid with C. albicans, but not with Saccharomyces cerevisiae, cells. Vaginal anti-mannan antibodies were also produced by active immunization with heat-killed cells of C. albicans or with a mannan extract when administered via the vaginal route. The protection conferred was comparable to that resulting from clearing of the primary infection. In summary, the data suggest that acquired anticandidal protection in this vaginitis model is mediated at least in part by antibodies, among which those directed against the mannan antigen(s) might play a dominant role.


Serum carnosinase activities in patients with alcoholic chronic skeletal muscle myopathy.
1. Serum carnosinase activity was assayed in a group of alcoholic patients with and without histologically proven atrophy of type II skeletal muscle fibres, and in control subjects. No significant activity was detected in muscle biopsy samples or washed erythrocytes. 2. Serum carnosinase activity was significantly lower in chronic alcoholic patients compared with a group of age-matched controls. Alcoholics with abnormal muscle biopsies had significantly lower enzyme activities than either those patients with normal muscle biopsies or the controls. Serum enzyme activities in patients with normal muscle biopsies were not significantly different from controls. 3. Serum carnosinase activity was inversely correlated with the degree of muscle atrophy as measured by the type II fibre atrophy factor. There was a positive correlation between the enzyme activity and skeletal muscle mass as reflected by the creatinine-height index. Furthermore, the enzyme activity significantly increased, with resolution or improvement in the myopathy, in patients who abstained from alcohol. 4. Kinetic studies showed that the reduced carnosinase activity was due mainly to a decrease in the apparent Vmax. The apparent Km was significantly higher in the myopathic compared with non-myopathic alcoholics. Mixing serum from controls and patients with myopathy gave the expected values, indicating the absence of a serum enzyme inhibitory factor. Acute alcohol loading had no effect on the serum carnosinase activity. 5. The decrease in serum carnosinase activity in alcoholics was not related to the severity of their liver disease. Assays of serum carnosinase in chronic alcoholics, can thus be used as a marker of their associated myopathy.


Sexual Size Dimorphism and Body Condition in the Australasian Gannet.
Sexual size dimorphism is widespread throughout seabird taxa and several drivers leading to its evolution have been hypothesised. While the Australasian Gannet (Morus serrator) has previously been considered nominally monomorphic, recent studies have documented sexual segregation in diet and foraging areas, traits often associated with size dimorphism. The present study investigated the sex differences in body mass and structural size of this species at two colonies (Pope's Eye, PE; Point Danger, PD) in northern Bass Strait, south-eastern Australia. Females were found to be 3.1% and 7.3% heavier (2.74 ± 0.03, n = 92; 2.67 ± 0.03 kg, n = 43) than males (2.66 ± 0.03, n = 92; 2.48 ± 0.03 kg, n = 43) at PE and PD, respectively. Females were also larger in wing ulna length (0.8% both colonies) but smaller in bill depth (PE: 2.2%; PD: 1.7%) than males. Despite this dimorphism, a discriminant function provided only mild accuracy in determining sex. A similar degree of dimorphism was also found within breeding pairs, however assortative mating was not apparent at either colony (R2 < 0.04). Using hydrogen isotope dilution, a body condition index was developed from morphometrics to estimate total body fat (TBF) stores, where TBF(%) = 24.43+1.94*(body mass/wing ulna length) - 0.58*tarsus length (r2 = 0.84, n = 15). This index was used to estimate body composition in all sampled individuals. There was no significant difference in TBF(%) between the sexes for any stage of breeding or in any year of the study at either colony suggesting that, despite a greater body mass, females were not in a better condition than males. While the driving mechanism for sexual dimorphism in this species is currently unknown, studies of other Sulids indicate segregation in foraging behaviour, habitat and diet may be a contributing factor.


Genome-scale identification of nucleosome positions in S. cerevisiae.
The positioning of nucleosomes along chromatin has been implicated in the regulation of gene expression in eukaryotic cells, because packaging DNA into nucleosomes affects sequence accessibility. We developed a tiled microarray approach to identify at high resolution the translational positions of 2278 nucleosomes over 482 kilobases of Saccharomyces cerevisiae DNA, including almost all of chromosome III and 223 additional regulatory regions. The majority of the nucleosomes identified were well-positioned. We found a stereotyped chromatin organization at Pol II promoters consisting of a nucleosome-free region approximately 200 base pairs upstream of the start codon flanked on both sides by positioned nucleosomes. The nucleosome-free sequences were evolutionarily conserved and were enriched in poly-deoxyadenosine or poly-deoxythymidine sequences. Most occupied transcription factor binding motifs were devoid of nucleosomes, strongly suggesting that nucleosome positioning is a global determinant of transcription factor access.


Analysis of small nucleolar RNAs in sputum for lung cancer diagnosis.
Molecular analysis of sputum presents a noninvasive approach for diagnosis of lung cancer. We have shown that dysregulation of small nucleolar RNAs (snoRNAs) plays a vital role in lung tumorigenesis. We have also identified six snoRNAs whose changes are associated with lung cancer. Here we investigated if analysis of the snoRNAs in sputum could provide a potential tool for diagnosis of lung cancer. Using qRT-PCR, we determined expressions of the six snoRNAs in sputum of a training set of 59 lung cancer patients and 61 cancer-free smokers to develop a biomarker panel, which was validated in a testing set of 67 lung cancer patients and 69 cancer-free smokers for the diagnostic performance. The snoRNAs were robustly measurable in sputum. In the training set, a panel of two snoRNA biomarkers (snoRD66 and snoRD78) was developed, producing 74.58% sensitivity and 83.61% specificity for identifying lung cancer. The snoRNA biomarkers had a significantly higher sensitivity (74.58%) compared with sputum cytology (45.76%) (P < 0.05). The changes of the snoRNAs were not associated with stage and histology of lung cancer (All P >0.05). The performance of the biomarker panel was confirmed in the testing cohort. We report for the first time that sputum snoRNA biomarkers might be useful to improve diagnosis of lung cancer.


The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.
Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRLhigh AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR-Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML.


Cognitive impairment in heart failure: A protective role for angiotensin-(1-7).
Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record