Assessing the cost of helping: the roles of body condition and oxidative balance in the Seychelles warbler (Acrocephalus sechellensis).
In cooperatively breeding species, helping close relatives may provide important fitness benefits. However, helping can be energetically expensive and may result in increased generation of reactive oxygen species. Consequently, an oxidant/antioxidant imbalance can lead to higher oxidative stress susceptibility. Given the potential costs of helping, it may be that only individuals with a sufficiently good body condition and/or stable oxidative balance can afford to help. Knowledge about relationships between social status and oxidative balance in cooperatively breeding systems is still limited. Studying these relationships is important for understanding the costs of helping and physiological pressures of reproduction. Here we evaluate the relationship between helping behaviour, body condition and oxidative balance in a wild population of the cooperatively breeding Seychelles warbler (Acrocephalus sechellensis). In this species, some subordinate individuals help dominant birds with the rearing of young, while others refrain from any assistance. We assessed body condition and oxidative parameters of birds of different social status caught during different breeding stages. We found that, prior to breeding, female subordinates that did not subsequently help (non-helpers) had significantly lower body condition and higher ROMs (reactive oxygen metabolites) than helpers and dominants. During the later stages of breeding, body condition was low in dominants and helpers, but high in non-helpers. Differences in oxidative balance between individuals of different social status were found only during nest care: Dominant males occupied with guarding behaviours tended to have relatively high oxidative stress susceptibility. Furthermore, dominant and helper females showed elevated antioxidant capacity (measured as OXY) in the weeks just prior to egg-laying, possibly representing a change in their reproductive physiology. The results imply that an individuals' oxidative balance may be influenced by factors related to reproduction, which can differ with sex and--within cooperative breeding systems--social status.


Glutamate receptors: desensitizing dimers.
Recent structural studies show, not only how the desensitization of a ligand-gated ion channel with bound agonist can be rationalized in terms of subunit-subunit instability, but also how a previously unknown mode of interaction may provide clues into how the receptor is tetramerically assembled in vivo.


Recovery from hybrid breakdown in a marine invertebrate is faster, stronger and more repeatable under environmental stress.
Understanding how environmental stress alters the consequences of hybridization is important, because the rate of hybridization and the likelihood of hybrid speciation both appear elevated in harsh, disturbed or marginal habitats. We assessed fitness, morphometrics and molecular genetic composition over 14 generations of hybridization between two highly divergent populations of the marine copepod Tigriopus californicus. Replicated, experimental hybrid populations in both control and high-salinity conditions showed a decline in fitness, followed by a recovery. Recovery was faster in the salinity stress treatment, returning to parental levels up to two generations earlier than in the control. This recovery was stable in the high-salinity treatment, whereas in the control treatment, fitness dropped back below parental levels at the final time point. Recovery in the high-salinity treatment was also stronger in terms of competitive fitness and heat-shock tolerance. Finally, consequences of hybridization were more repeatable under salinity stress, where among-replicate variance for survivorship and molecular genetic composition was lower than in the control treatment. In a system with low effective population sizes (estimates ranged from 17 to 63), where genetic drift might be expected to be the predominate force, strong selection under harsh environmental conditions apparently promoted faster, stronger and more repeatable recovery from depressed hybrid fitness.


Longitudinal employment outcomes of an early intervention vocational rehabilitation service for people admitted to rehabilitation with a traumatic spinal cord injury.
Longitudinal cohort design. First, to explore the longitudinal outcomes for people who received early intervention vocational rehabilitation (EIVR); second, to examine the nature and extent of relationships between contextual factors and employment outcomes over time. Both inpatient and community-based clients of a Spinal Community Integration Service (SCIS). People of workforce age undergoing inpatient rehabilitation for traumatic spinal cord injury were invited to participate in EIVR as part of SCIS. Data were collected at the following three time points: discharge and at 1 year and 2+ years post discharge. Measures included the spinal cord independence measure, hospital anxiety and depression scale, impact on participation and autonomy scale, numerical pain-rating scale and personal wellbeing index. A range of chi square, correlation and regression tests were undertaken to look for relationships between employment outcomes and demographic, emotional and physical characteristics. Ninety-seven participants were recruited and 60 were available at the final time point where 33% (95% confidence interval (CI): 24-42%) had achieved an employment outcome. Greater social participation was strongly correlated with wellbeing (ρ=0.692), and reduced anxiety (ρ=-0.522), depression (ρ=-0.643) and pain (ρ=-0.427) at the final time point. In a generalised linear mixed effect model, education status, relationship status and subjective wellbeing increased significantly the odds of being employed at the final time point. Tertiary education prior to injury was associated with eight times increased odds of being in employment at the final time point; being in a relationship at the time of injury was associated with increased odds of being in employment of more than 3.5; subjective wellbeing, while being the least powerful predictor was still associated with increased odds (1.8 times) of being employed at the final time point. EIVR shows promise in delivering similar return-to-work rates as those traditionally reported, but sooner. The dynamics around relationships, subjective wellbeing, social participation and employment outcomes require further exploration.


Evaluation of an extended diagnostic PCR assay for detection and verification of the common causes of bacterial meningitis in CSF and other biological samples.
A seminested polymerase chain reaction (PCR)-based diagnostic assay was evaluated for detection and verification of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Steptococcus agalactiae and Listeria monocytogenes in cerebrospinal fluid (CSF) and other biological samples. A general bacterial amplicon from the 16S rRNA gene was amplified in a first step, and species-specific regions in a second. The detection level was 4 fg DNA/reaction, corresponding to about one bacterial genome per reaction tube. Sample preparations (Dynabeads DNA DIRECT kit) were assayed from 140 bacterial strains suspended in saline. In CSF the detection level for bacteria was 10(3)CFU ml-1for N. meningitidis, H. influenzae and S. pneumoniae, 10(4)CFU ml-1for Escherichia coli and 10(5)CFU ml-1for S. agalactiae and L. monocytogenes. The detection levels for these bacteria were the same in the other tested biological samples, like blood with or without culture media. Clinical CSF samples were evaluated from 71 patients with proven bacterial meningitis, as were 61 CSF samples from individuals without bacterial meningitis. The diagnostic sensitivity of the assay in detecting bacteria in general was 0.97, and for the specific species in the clinical CSF samples 0.87-0.94. The specificity was 1.0 for detecting bacteria in general. Some cross-reactions were noted within the streptococcus group. The PCR results were verified by banding patterns of Hae III digested PCR products.


Evaluation of the MIDTAL microarray chip for monitoring toxic microalgae in the Orkney Islands, U.K.
Harmful or nuisance algal blooms can cause economic damage to fisheries and tourism. Additionally, toxins produced by harmful algae and ingested via contaminated shellfish can be potentially fatal to humans. The seas around the Orkney Islands, UK currently hold a number of toxic algal species which cause shellfishery closures in most years. Extensive and costly monitoring programs are carried out to detect harmful microalgae before they reach action levels. However, the ability to distinguish between toxic and non-toxic strains of some algae is not possible using these methods. The microarrays for the detection of toxic algae (MIDTAL) microarray contains rRNA probes for toxic algal species/strains which have been adapted and optimized for microarray use. In order to investigate the use of the chip for monitoring in the Orkney Islands, samples were collected between 2009 and 2011 from Brings Deep, Scapa Flow, Orkney Islands, UK; RNA was extracted and hybridized with generation 2 and 3.1 of the chip. The data were then compared to cell counts performed under light microscopy and in the case of Alexandrium tamarense to qPCR data targeting the saxitoxin gene and the LSU-rRNA gene. A good agreement between cell numbers and microarray signal was found for A. tamarense, Pseudo-nitzschia sp., Dinophysis sp. (r<0.5, for all) in addition to this there the chip successfully detected a large bloom of Karenia mikimotoi (r<0.70) in August and September 2011. Overall, there was good improvement in probe signal between generation 2 and generation 3.1 of the chip with much less variability and more consistent results and better correlation between the probes. The chip performed well for A. tamarense group I signal to cell numbers in calibrations (r>0.9). However, in field samples, this correlation was slightly lower suggesting interactions between all species in the sample may affect signal. Overall, the chip showed it could identify the presence of target species in field samples although some work is needed to improve the quantitative nature of the chip before it would be suitable for monitoring in the Orkney Islands.


Model Selection Using BICePs: A Bayesian Approach for Force Field Validation and Parameterization.
The Bayesian Inference of Conformational Populations (BICePs) algorithm reconciles theoretical predictions of conformational state populations with sparse and/or noisy experimental measurements. Among its key advantages is its ability to perform objective model selection through a quantity we call the BICePs score, which reflects the integrated posterior evidence in favor of a given model, computed through free energy estimation methods. Here, we explore how the BICePs score can be used for force field validation and parametrization. Using a 2D lattice protein as a toy model, we demonstrate that BICePs is able to select the correct value of an interaction energy parameter given ensemble-averaged experimental distance measurements. We show that if conformational states are sufficiently fine-grained, the results are robust to experimental noise and measurement sparsity. Using these insights, we apply BICePs to perform force field evaluations for all-atom simulations of designed β-hairpin peptides against experimental NMR chemical shift measurements. These tests suggest that BICePs scores can be used for model selection in the context of all-atom simulations. We expect this approach to be particularly useful for the computational foldamer design as a tool for improving general-purpose force fields given sparse experimental measurements.


Primary amyloidosis involving mesenteric lymph nodes: diagnosis by fine-needle aspiration cytology.
Mesenteric lymph node amyloid deposits are rare and may be seen in isolated or secondary amyloidosis. The diagnosis of mesenteric amyloidosis has conventionally relied on histopathological examination following an exploratory laparotomy or a biopsy. A 72-year-old male previously diagnosed with Waldenström's macroglobulinemia and multiple other malignancies was admitted for abdominal pain. An abdominal computed tomography (CT) scan revealed diffuse retroperitoneal and mesenteric lymphadenopathy associated with bowel wall thickening. A CT-guided fine-needle aspiration (FNA) cytology and core biopsies of mesenteric lymph nodes were performed. The FNA smears revealed irregular, waxy, basophilic clumps on a Diff-Quik stain and cyanophilic clumps of amorphous material on a Papanicolaou stain. The lymph node aspirates showed positivity for the Congo red stain, confirming it as amyloid. In situ hybridization studies revealed a predominance of λ light chains, and a diagnosis of primary amyloidosis involving mesenteric lymph nodes was made. Supplemental needle core biopsies showed positivity for Congo red and Crystal violet stains and exhibited the classic apple-green birefringence under polarized light. The involvement of lymph nodes in amyloidosis is not uncommon; however, the involvement of mesenteric lymph nodes in a setting of macroglobulinemia and its diagnosis by FNA cytology is novel to this case.


Dynamics and energetics: a consensus analysis of the impact of calcium on EF-CaM protein complex.
We have studied the relationship between dynamical correlations and energetic contributions in an attempt to model the transmission of information inside protein-protein complexes. The complex formed between the edema factor (EF) of Bacillus anthracis and calmodulin (CaM) was taken as an example, as the formation and stability of the complex depend on the calcium complexation level. The effect of calcium through EF-CaM residue network has been investigated with various approaches: 1), the elastic network model; 2), the local feature analysis; 3), the generalized correlations; and 4), the energetic dependency maps (EDMs), on 15-ns molecular dynamics simulations of the complex loaded with 0, 2, or 4 Ca2+ ions. The elastic network model correctly describes the basic architecture of the complex but is poorly sensitive to the level of calcium compared to the other methods. The local feature analysis allows us to characterize the local dynamics of the complex and the propagation of the calcium signal through CaM. The analyses of global dynamics and energetics--through generalized correlations and EDMs--provide a comprehensive picture of EF-CaM architecture and can be unified by using the concept of residue network connectedness. A medium connectedness, defined as the ability of each residue to communicate with all remaining parts of the complex, is observed for the 2Ca2+ level, which was experimentally identified as the most stable form of EF-CaM. The hierarchy of relative stabilities given by the EDMs sheds a new light on the EF-CaM interaction mechanism described experimentally and supports an organization of the complex architecture centered around nucleation points.


The Ph1 locus suppresses Cdk2-type activity during premeiosis and meiosis in wheat.
Despite possessing multiple sets of related (homoeologous) chromosomes, hexaploid wheat (Triticum aestivum) restricts pairing to just true homologs at meiosis. Deletion of a single major locus, Pairing homoeologous1 (Ph1), allows pairing of homoeologs. How can the same chromosomes be processed as homologs instead of being treated as nonhomologs? Ph1 was recently defined to a cluster of defective cyclin-dependent kinase (Cdk)-like genes showing some similarity to mammalian Cdk2. We reasoned that the cluster might suppress Cdk2-type activity and therefore affect replication and histone H1 phosphorylation. Our study does indeed reveal such effects, suggesting that Cdk2-type phosphorylation has a major role in determining chromosome specificity during meiosis.


Improving retention in HIV care among adolescents and adults in low- and middle-income countries: A systematic review of the literature.
Adolescents living with HIV are an underserved population, with poor retention in HIV health care services and high mortality, who are in need of targeted effective interventions. We conducted a literature review to identify strategies that could be adapted to meet the needs of adolescents living with HIV. We searched PubMed, Web of Science, Popline, USAID's AIDSFree Resource Library, and the USAID Development Experience Clearinghouse for relevant studies published within a recent five-year period. Studies were included if they described interventions to improve the retention in care of HIV-positive patients who are initiating or already receiving antiretroviral therapy in low- and middle-income countries. To assess the quality of the studies, we used the NIH NHLBI Study Quality Assessment Tools. Of 13,429 potentially relevant citations, 23 were eligible for inclusion. Most studies took place in sub-Saharan Africa. Only one study evaluated a retention intervention for youth (15-24 years); it found no difference in loss to follow-up between a youth-friendly clinic and a family-oriented clinic. A study of community-based service delivery which was effective for adults found no effect for youths. We found no relevant studies conducted exclusively with adolescent participants (10-19 years). Most studies were conducted with adults only or with populations that included adults and adolescents but did not report separate results for adolescents. Interventions that involved community-based services showed the most robust evidence for improving retention in care. Several studies found statistically significant associations between decentralization, down-referral of stable patients, task-shifting of services, and differentiated care, and retention in care among adults; however, most evidence comes from retrospective, observational studies and none of these approaches were evaluated among adolescents or youth. Interventions that target retention in care among adolescents living with HIV are rare in the published literature. We found only two studies conducted with youth and no studies with adolescents. Given the urgent need to increase the retention of adolescents in HIV care, interventions that are effective in increasing adult retention in care should be considered for adaptation and evaluation among adolescents and interventions specifically targeting the needs of adolescents must be developed and tested.


Variation and genetic control of gene expression in primary immunocytes across inbred mouse strains.
To determine the breadth and underpinning of changes in immunocyte gene expression due to genetic variation in mice, we performed, as part of the Immunological Genome Project, gene expression profiling for CD4(+) T cells and neutrophils purified from 39 inbred strains of the Mouse Phenome Database. Considering both cell types, a large number of transcripts showed significant variation across the inbred strains, with 22% of the transcriptome varying by 2-fold or more. These included 119 loci with apparent complete loss of function, where the corresponding transcript was not expressed in some of the strains, representing a useful resource of "natural knockouts." We identified 1222 cis-expression quantitative trait loci (cis-eQTL) that control some of this variation. Most (60%) cis-eQTLs were shared between T cells and neutrophils, but a significant portion uniquely impacted one of the cell types, suggesting cell type-specific regulatory mechanisms. Using a conditional regression algorithm, we predicted regulatory interactions between transcription factors and potential targets, and we demonstrated that these predictions overlap with regulatory interactions inferred from transcriptional changes during immunocyte differentiation. Finally, comparison of these and parallel data from CD4(+) T cells of healthy humans demonstrated intriguing similarities in variability of a gene's expression: the most variable genes tended to be the same in both species, and there was an overlap in genes subject to strong cis-acting genetic variants. We speculate that this "conservation of variation" reflects a differential constraint on intraspecies variation in expression levels of different genes, either through lower pressure for some genes, or by favoring variability for others.


HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells.
Human embryonic stem cells (hESCs) have been reported to exert cytoprotective activity in the area of tissue injury. However, hypoxia/oxidative stress prevailing in the area of injury could activate p53, leading to death and differentiation of hESCs. Here we report that when exposed to hypoxia/oxidative stress, a small fraction of hESCs, namely the SSEA3+/ABCG2+ fraction undergoes a transient state of reprogramming to a low p53 and high hypoxia inducible factor (HIF)-2α state of transcriptional activity. This state can be sustained for a period of 2 weeks and is associated with enhanced transcriptional activity of Oct-4 and Nanog, concomitant with high teratomagenic potential. Conditioned medium obtained from the post-hypoxia SSEA3+/ABCG2+ hESCs showed cytoprotection both in vitro and in vivo. We termed this phenotype as the "enhanced stemness" state. We then demonstrated that the underlying molecular mechanism of this transient phenotype of enhanced stemness involved high Bcl-2, fibroblast growth factor (FGF)-2, and MDM2 expression and an altered state of the p53/MDM2 oscillation system. Specific silencing of HIF-2α and p53 resisted the reprogramming of SSEA3+/ABCG2+ to the enhanced stemness phenotype. Thus, our studies have uncovered a unique transient reprogramming activity in hESCs, the enhanced stemness reprogramming where a highly cytoprotective and undifferentiated state is achieved by transiently suppressing p53 activity. We suggest that this transient reprogramming is a form of stem cell altruism that benefits the surrounding tissues during the process of tissue regeneration.


Study protocol for the Anesthesiology Control Tower-Feedback Alerts to Supplement Treatments (ACTFAST-3) trial: a pilot randomized controlled trial in intraoperative telemedicine.
Background: Each year, over 300 million people undergo surgical procedures worldwide. Despite efforts to improve outcomes, postoperative morbidity and mortality are common. Many patients experience complications as a result of either medical error or failure to adhere to established clinical practice guidelines. This protocol describes a clinical trial comparing a telemedicine-based decision support system, the Anesthesiology Control Tower (ACT), with enhanced standard intraoperative care. Methods: This study is a pragmatic, comparative effectiveness trial that will randomize approximately 12,000 adult surgical patients on an operating room (OR) level to a control or to an intervention group. All OR clinicians will have access to decision support software within the OR as a part of enhanced standard intraoperative care. The ACT will monitor patients in both groups and will provide additional support to the clinicians assigned to intervention ORs. Primary outcomes include blood glucose management and temperature management. Secondary outcomes will include surrogate, clinical, and economic outcomes, such as incidence of intraoperative hypotension, postoperative respiratory compromise, acute kidney injury, delirium, and volatile anesthetic utilization. Ethics and dissemination: The ACTFAST-3 study has been approved by the Human Resource Protection Office (HRPO) at Washington University in St. Louis and is registered at clinicaltrials.gov ( NCT02830126). Recruitment for this protocol began in April 2017 and will end in December 2018. Dissemination of the findings of this study will occur via presentations at academic conferences, journal publications, and educational materials.


Current antimicrobial use in farm animals in the Republic of Ireland.
Antimicrobial resistance has been recognised as one of the most difficult challenges facing human and animal health in recent decades. The surveillance of antimicrobial use in animal health plays a major role in dealing with the growing issue of resistance. This paper reviews current data available on antimicrobial use in farmed animals in the Republic of Ireland, including each of the major livestock production sectors; pigs, poultry, dairy, beef and sheep. A systematic literature search was conducted to identify relevant published literature, and ongoing research was identified through the network of authors and searches of each of the research databases of the main agriculture funding bodies in Ireland. The varying quantities and quality of data available across each livestock sector underlines the need for harmonisation of data collection methods. This review highlights the progress that has been made regarding data collection in the intensive production sectors such as pigs and poultry, however, it is clear there are significant knowledge gaps in less intensive industries such as dairy, beef and sheep. To comply with European regulations an antimicrobial data collection system is due to be developed for all food-producing animals in the future, however in the short-term surveillance studies have allowed us to build a picture of current use within the Republic of Ireland. Further studies will allow us to fill current knowledge gaps and build a more comprehensive overview of antimicrobial use in farm animals in Ireland.


The effect of botulinum-A toxin on patients with severe urge urinary incontinence.
We determined the effect of 150 units of botulinum-A toxin (Botox, Allergan, Irvine, California) on subjects with severe urge urinary incontinence (UUI). This was an open label uncontrolled clinical trial. Subjects were recruited from the female urology and urogynecology clinics at Duke University. Inclusion criteria included evidence of UUI on 3-day bladder diary, a 24-hour pad weight of 100 gm or greater, absent or minimal stress leakage, absent detrusor dysfunction, and a history of failed anticholinergic and physical therapies. Exclusion criteria included evidence of a urinary tract infection, or other correctable or neurological etiology for UUI. The detrusor of each subject was injected with 150 units of botulinum-A toxin. Evaluations were performed at 2 weeks, 6 weeks, 3 months and 6 months after injection. Outcome measures included daily incontinence episodes, Urogenital Distress Inventory and the Incontinence Impact Questionnaire, 24-hour pad weights, daily pad usage and urinalysis at all visits. Urodynamic studies were performed at the 6-week and 3-month visits. Three subjects had uncomplicated urinary tract infections during followup. No other adverse effects occurred. Statistically and clinically significant decreases greater than 50% were seen in virtually all outcome measures at all visits up to 3 months. Most subjects showed signs of recurrent UUI by 6 months. All subjects reported remarkable subjective improvement in incontinence. No significant changes in maximal cystometric capacity, maximal detrusor pressure, peak flow or post-void residual volumes were seen. Botulinum-A toxin can significantly decrease urge urinary incontinence and improve quality of life for 3 months after injection. Additional studies are needed to determine ideal doses, dosing intervals, safety and cost-effectiveness of this therapy.


FSTL3 is increased in renal dysfunction.
Follistatin-like 3 (FSTL3) is a novel cytokine that regulates insulin sensitivity and counteracts activin/myostatin signalling. In the present study, regulation of FSTL3 in renal dysfunction was investigated in both human chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Furthermore, mFSTL3 expression was analysed in insulin-sensitive tissues in a mouse model of CKD. Circulating FSTL3 was quantified by enzyme-linked immunosorbent assay in 581 patients with CKD covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5. Furthermore, FSTL3 was measured in 61 patients before and within 30 h after elective unilateral nephrectomy, an established model of AKD. Moreover, mFSTL3 mRNA expression was investigated in an animal CKD model, that is, eNOS-/-db/db mice, and compared with littermate controls. Median circulating FSTL3 levels significantly and continuously increased with deteriorating renal function (eGFR category G1: 6.1; G2: 8.2; G3: 12.7; G4: 18.5; G5: 32.1 µg/L; P < 0.001). In both human CKD and AKD, renal dysfunction remained the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. FSTL3 was independently associated with an adverse cardiometabolic profile. In CKD mice, hepatic mFSTL3 mRNA expression was increased more than 6-fold as compared with controls. Circulating FSTL3 is significantly and independently associated with renal function in both patients with CKD and AKD. Hepatic mFSTL3 mRNA upregulation might contribute to increased FSTL3 levels in CKD. Our results are in agreement with the hypothesis that FSTL3 is eliminated by the kidneys and might counteract adverse activin/myostatin signalling observed in renal dysfunction.


Indirect phosphorylation-dependent modulation of postsynaptic nicotinic acetylcholine responses by 5-hydroxytryptamine.
Ionotropic nicotinic acetylcholine (ACh) receptors have been shown to be modulated by protein kinase-mediated phosphorylation in vitro. Here we demonstrate that 5-hydroxytryptamine (5-HT) can downregulate postsynaptic nicotinic ACh responses, elicited in an identified arthropod motoneuron in situ, by a mechanism dependent on protein kinase activity. Serotonergic modulation can be mimicked by perfusion with membrane-permeable analogues of either adenine (cAMP) or guanine (cGMP) cyclic nucleotides, and is prolonged in the presence of phosphodiesterase inhibitors. Furthermore, suppression of the ACh response by 5-HT is blocked by specific competitive inhibitors of protein kinase A and G, as well as the broad specificity protein kinase inhibitor staurosporine. The protein phosphatase inhibitor cantharidin similarly blocks recovery of the ACh response from suppression mediated by 5-HT. Thus, it appears that the nicotinic ACh response is modulated by a cAMP-mediated phosphorylation-dependent intracellular signalling pathway that is distinct from the direct block of mammalian nicotinic ACh receptors by 5-HT previously reported in vitro.


RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.
The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.


Long-term effect of periodontal surgery on oral health and metabolic control of diabetics.
The objective of this study was to evaluate impact of periodontal surgery on periodontal health and on glycaemia control of type 1 and type 2 (T1DM; T2DM) diabetics with severe periodontitis, during 12 months follow-up, in comparison with non-diabetic controls. A total of 23 T1DM and 10 T2DM patients with respective number of matched non-diabetics were examined prior to, and 3, 6 and 12 months after periodontal surgery. Glycosylated haemoglobin (HbA1c) reflected control of DM. Periodontal parameters were oral debris (DI-S), probing pocket depth (PPD), clinical attachment loss (CAL) and bleeding on probing (BOP). Periodontal status in all diabetics improved after 3 months and remained so during follow-up: mean (SD) DI-S > 1 (T1DM 1.1(0.5)/0.9(0.7); T2DM 1.2(0.4)/0.8(0.4)), PPD >5 mm (T1DM 35.1(32.2)/5.1(7.8); T2DM 46.3(24.2)/13.0(10.9)), CAL ≥6 mm (T1DM 44.4(37.0)/24.52(27.2)); mean % BOP >50 % (T1DM 57.1(25.1)/22.8(20.8)), T2DM 59.4(20.8)/18.9(15.7)), p < 0.05. Mean HbA1c values decreased in T2DM patients after 3 months and remained stable during follow-up. No improvement of glycaemia control was observed in T1DM patients. Positive correlation between mean HbA1c and CAL changes was observed (r = 0.842, p < 0.05). Mean changes of periodontal parameters did not differ between diabetics and controls. Periodontal surgery improved significantly periodontal status of all patients and metabolic control of T2DM patients. Research findings concerning long-term effect of periodontal surgery among patients with diabetes mellitus are scarce. We found that surgical periodontal treatment positively affects periodontal health of all diabetics and improves metabolic control of type 2 DM. There is a positive correlation between clinical attachment loss and glycosylated haemoglobin levels.


Comparison of Shiga toxin-encoding bacteriophages in highly pathogenic strains of Shiga toxin-producing Escherichia coli O157:H7 in the UK.
Over the last 35 years in the UK, the burden of Shiga toxin-producing Escherichia coli (STEC) O157:H7 infection has, during different periods of time, been associated with five different sub-lineages (1983-1995, Ia, I/IIa and I/IIb; 1996-2014, Ic; and 2015-2018, IIb). The acquisition of a stx2a-encoding bacteriophage by these five sub-lineages appears to have coincided with their respective emergences. The Oxford Nanopore Technologies (ONT) system was used to sequence, characterize and compare the stx-encoding prophages harboured by each sub-lineage to investigate the integration of this key virulence factor. The stx2a-encoding prophages from each of the lineages causing clinical disease in the UK were all different, including the two UK sub-lineages (Ia and I/IIa) circulating concurrently and causing severe disease in the early 1980s. Comparisons between the stx2a-encoding prophage in sub-lineages I/IIb and IIb revealed similarity to the prophage commonly found to encode stx2c, and the same site of bacteriophage integration (sbcB) as stx2c-encoding prophage. These data suggest independent acquisition of previously unobserved stx2a-encoding phage is more likely to have contributed to the emergence of STEC O157:H7 sub-lineages in the UK than intra-UK lineage to lineage phage transmission. In contrast, the stx2c-encoding prophage showed a high level of similarity across lineages and time, consistent with the model of stx2c being present in the common ancestor to extant STEC O157:H7 and maintained by vertical inheritance in the majority of the population. Studying the nature of the stx-encoding bacteriophage contributes to our understanding of the emergence of highly pathogenic strains of STEC O157:H7.


Hematologist/oncologist disease-specific expertise and survival: lessons from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
The impact of physicians' disease-specific expertise on patient outcome is unknown. Although previous studies suggest a survival advantage for cancer patients cared for at high-volume centers, these observations may simply reflect referral bias or better access to advanced technologies, clinical trials, and multidisciplinary support at large centers. We evaluated time to first treatment (TTFT) and overall survival (OS) of patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) at a single academic center based on whether they were cared for by a hematologist/oncologist who subspecializes in CLL (CLL hematologist) or a hematologist/oncologist with expertise in other areas (non-CLL hematologist). Among 1309 newly diagnosed patients with CLL cared for between 1999 and 2009, 773(59%) were cared for by CLL hematologists and 536 were cared for by non-CLL hematologists. Among early-stage patients (Rai 0-I), median TTFT (9.2 vs 6.1 years; P < .001) and OS (10.5 years vs 8.8 years; P < .001) were longer for patients cared for by CLL hematologists. For all patients, OS was superior for patients cared for by CLL hematologists (10.5 years vs 8.4 years; P = .001). Physician's disease-specific expertise remained an independent predictor of OS after adjusting for age, sex, stage, and lymphocyte count at diagnosis. Patients seen by a CLL hematologist were also more likely to participate in clinical trials (48% vs 16%; P < .001). Physician disease-specific expertise appears to influence outcome in patients with CLL. To the greatest extent possible, patients should be cared for by a hematologist/oncologist expert in the care of their specific malignancy. When not possible, practice guidelines developed by disease-specific experts should be followed.


Harnessing the exosome-induced immune response for cancer immunotherapy.
In recent years exosomes have emerged as potent stimulators of immune responses and as agents for cancer therapy. Exosomes can carry a broad variety of immunostimulatory molecules depending on the cell of origin and in vitro culture conditions. Dendritic cell-derived exosomes (dexosomes) have been shown to carry NK cell activating ligands and can be loaded with antigen to activate invariant NKT cells and to induce antigen-specific T and B cell responses. Dexosomes have been investigated as therapeutic agents against cancer in two phase I clinical trials, with a phase II clinical trial currently ongoing. Dexosomes were well tolerated but therapeutic success and immune activation were limited. Several reports suggest that multiple factors need to be considered in order to improve exosomal immunogenicity for cancer immunotherapy. These include antigen-loading strategies, exosome composition and exosomal trafficking in vivo. Hence, a better understanding of how to engineer and deliver exosomes to specific cells is crucial to generate strong immune responses and to improve the immunotherapeutic potential of exosomes.


Oral administration of methylphenidate blocks the effect of cocaine on uptake at the Drosophila dopamine transporter.
Although our understanding of the actions of cocaine in the brain has improved, an effective drug treatment for cocaine addiction has yet to be found. Methylphenidate binds the dopamine transporter and increases extracellular dopamine levels in mammalian central nervous systems similar to cocaine, but it is thought to elicit fewer addictive and reinforcing effects owing to slower pharmacokinetics for different routes of administration between the drugs. This study utilizes the fruit fly model system to quantify the effects of oral methylphenidate on dopamine uptake during direct cocaine exposure to the fly CNS. The effect of methylphenidate on the dopamine transporter has been explored by measuring the uptake of exogenously applied dopamine. The data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter and the inhibition is concentration dependent. The peak height increased to 150% of control when cocaine was used to block the dopamine transporter for untreated flies but only to 110% for methylphenidate-treated flies. Thus, the dopamine transporter is mostly inhibited for the methylphenidate-fed flies before the addition of cocaine. The same is true for the rate of the clearance of dopamine measured by amperometry. For untreated flies the rate of clearance changes 40% when the dopamine transporter is inhibited with cocaine, and for treated flies the rate changes only 10%. The results were correlated to the in vivo concentration of methylphenidate determined by CE-MS. Our data suggest that oral consumption of methylphenidate inhibits the Drosophila dopamine transporter for cocaine uptake, and the inhibition is concentration dependent.


Do the socioeconomic impacts of antiretroviral therapy vary by gender? A longitudinal study of Kenyan agricultural worker employment outcomes.
As access to antiretroviral therapy (ART) has grown in Africa, attention has turned to evaluating the socio-economic impacts of ART. One key issue is the extent to which improvements in health resulting from ART allows individuals to return to work and earn income. Improvements in health from ART may also be associated with reduced impaired presenteeism, which is the loss of productivity when an ill or disabled individual attends work but accomplishes less at his or her usual tasks or shifts to other, possibly less valuable, tasks. Longitudinal data for this analysis come from company payroll records for 97 HIV-infected tea estate workers (the index group, 56 women, 41 men) and a comparison group of all workers assigned to the same work teams (n = 2485, 1691 men, 794 women) for a 37-month period covering two years before and one year after initiating ART. We used nearest neighbour matching methods to estimate the impacts of HIV/AIDS and ART on three monthly employment outcomes for tea estate workers in Kenya--days plucking tea, days assigned to non-plucking assignments, and kilograms harvested when plucking. The female index group worked 30% fewer days plucking tea monthly than the matched female comparison group during the final 9 months pre-ART. They also worked 87% more days on non-plucking assignments. While the monthly gap between the two groups narrowed after beginning ART, the female index group worked 30% fewer days plucking tea and about 100% more days on non-plucking tasks than the comparison group after one year on ART. The male index group was able to maintain a similar pattern of work as their comparison group except during the initial five months on therapy. Significant impaired presenteeism continued to exist among the female index group after one year on ART. Future research needs to explore further the socio-economic implications of HIV-infected female workers on ART being less productive than the general female workforce over sustained periods of time.


Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1.
Signal transduction through mitogen-activated protein kinases (MAPKs) is implicated in growth and proliferation control through translation regulation and involves posttranslational modification of translation initiation factors. For example, convergent MAPK signals to Mnk1 lead to phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which has been linked to malignant transformation. However, understanding the compound effects of mitogenic signaling on the translation apparatus and on protein synthesis control remains elusive. This is particularly true for the central scaffold of the translation initiation apparatus and ribosome adaptor eIF4G. To unravel the effects of signal transduction to eIF4G on translation, we used specific activation of protein kinase C (PKC)-Ras-Erk signaling with phorbol esters. Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKCα at Ser1186. We show that PKCα activation elicits a cascade of orchestrated phosphorylation events that may modulate eIF4G1 structure and control interaction with the eIF4E kinase, Mnk1.


A binary main-belt comet.
Asteroids are primitive Solar System bodies that evolve both collisionally and through disruptions arising from rapid rotation. These processes can lead to the formation of binary asteroids and to the release of dust, both directly and, in some cases, through uncovering frozen volatiles. In a subset of the asteroids called main-belt comets, the sublimation of excavated volatiles causes transient comet-like activity. Torques exerted by sublimation measurably influence the spin rates of active comets and might lead to the splitting of bilobate comet nuclei. The kilometre-sized main-belt asteroid 288P (300163) showed activity for several months around its perihelion 2011 (ref. 11), suspected to be sustained by the sublimation of water ice and supported by rapid rotation, while at least one component rotates slowly with a period of 16 hours (ref. 14). The object 288P is part of a young family of at least 11 asteroids that formed from a precursor about 10 kilometres in diameter during a shattering collision 7.5 million years ago. Here we report that 288P is a binary main-belt comet. It is different from the known asteroid binaries in its combination of wide separation, near-equal component size, high eccentricity and comet-like activity. The observations also provide strong support for sublimation as the driver of activity in 288P and show that sublimation torques may play an important part in binary orbit evolution.


Radiologist-Patient Communication: Current Practices and Barriers to Communication in Breast Imaging.
The aim of this study was to assess variability in radiologist-patient communication practices and barriers to communication among members of the Society of Breast Imaging (SBI). A 36-item questionnaire developed by the SBI Patient Care and Delivery Task Force was distributed electronically to SBI members to evaluate patient communication, education, and screening practices. Data from 14 items investigating patient communication (eg, practices, comfort, barriers to communication) were analyzed and compared with demographic variables using χ2 or independent t tests as appropriate. Ninety-three percent of radiologists reported that they directly communicate abnormal results of diagnostic mammographic examinations that require biopsy and malignant or high-risk biopsy results that require surgery. Radiologists (66%) and technologists (57%) often provide normal or negative diagnostic mammographic results. Most respondents were completely comfortable discussing the need for additional imaging, recommending biopsy, and discussing biopsy results directly with patients, and 71% rated their communication skills as excellent. Radiologists who spend less time in breast imaging reported only average communication skills. The most frequent barriers to communication were that practices were not set up for direct communication (loss of revenue) and discomfort with angry patients. Although variation in breast imaging communication practices exists among radiologists and practice types, the majority of radiologists directly communicate the most distressing results to patients, such as those regarding abnormal diagnostic mammographic findings requiring biopsies and abnormal biopsy results leading to cancer diagnoses and surgery. The majority of radiologists are completely comfortable with these conversations, but all feel that enhancing communication with patients will lead to greater patient satisfaction.


GAP45 phosphorylation controls assembly of the Toxoplasma myosin XIV complex.
Toxoplasma gondii motility is powered by the myosin XIV motor complex, which consists of the myosin XIV heavy chain (MyoA), the myosin light chain (MLC1), GAP45, and GAP50, the membrane anchor of the complex. MyoA, MLC1, and GAP45 are initially assembled into a soluble complex, which then associates with GAP50, an integral membrane protein of the parasite inner membrane complex. While all proteins in the myosin XIV motor complex are essential for parasite survival, the specific role of GAP45 remains unclear. We demonstrate here that final assembly of the motor complex is controlled by phosphorylation of GAP45. This protein is phosphorylated on multiple residues, and by using mass spectroscopy, we have identified two of these, Ser(163) and Ser(167). The importance of these phosphorylation events was determined by mutation of Ser(163) and Ser(167) to Glu and Ala residues to mimic phosphorylated and nonphosphorylated residues, respectively. Mutation of Ser(163) and Ser(167) to either Ala or Glu residues does not affect targeting of GAP45 to the inner membrane complex or its association with MyoA and MLC1. Mutation of Ser(163) and Ser(167) to Ala residues also does not affect assembly of the mutant GAP45 protein into the myosin motor complex. Mutation of Ser(163) and Ser(167) to Glu residues, however, prevents association of the MyoA-MLC1-GAP45 complex with GAP50. These observations indicate that phosphorylation of Ser(163) and Ser(167) in GAP45 controls the final step in assembly of the myosin XIV motor complex.


Functional versus fractional oxygen saturation readings: bias and agreement using simulated solutions and adult blood.
The purpose of this study was to examine the bias and agreement between functional oxygen saturation (SO2) and fractional oxyhemoglobin (HbO2) using simulated quality control (QC) solutions and adult blood. Using a hemoximeter, 5 analysts performed at least 5 tests each on QC solutions with 3 different hemoglobin (Hb) levels and on adult blood samples of various oxygen saturation levels representing venous or arterial samples. Bias and the limits of agreement were determined using the technique of Bland and Altman. Using QC solutions with low, normal, and high Hb levels, the bias for SO2 against HbO2 was 20.82 +/- 0.50 (n = 66), 19.14 +/- 0.56 (n = 81), and 19.59 +/- 0.43 (n = 79), respectively, with SO2 reading consistently higher. The correlation between SO2 and HbO2 was -0.49, -0.69, and -0.68, respectively. Using adult blood, the bias for SO2 against HbO2 was 1.29 +/- 0.48 for venous samples (n = 62) and 1.9 +/- 0.19 for fully oxygenated samples (n = 36), and the correlation between SO2 and HbO2 was 1.0 and 0.68, respectively. These findings suggest that the consistency between the measurements of SO2 and HbO2 may be dependent on hemoglobin levels and oxygenation status. Thus, caution is warranted when assuming that the measurements of SO2 and HbO2 are interchangeable.


Structure and reactivities of rhenium and technetium bis-arene sandwich complexes [M(η6-arene)2].
Sandwich complexes are important building blocks in medicinal inorganic chemistry for group 6 and 8 elements but are almost unknown for the manganese triad. We present the syntheses and full characterization of the mixed-arene 99Tc sandwich complexes [99Tc(η6-hmbz)(η6-C6H5-NH3)](PF6)2 and [99Tc(η6-hmbz)(η6-C6H5-Br)](PF6). Both comprise functionalities for conjugation to targeting molecules or for being included as substructures in pharmaceutically active lead compounds. Since η6-benzene ligands are too stably bound to be replaced with incoming ligands, we prepared naphthalene complexes [Re(η6-C6H6)(η6-napht)]+ and [Re(η6-napht)2]+. Their reactivities towards substitution are increased and one or both naphthalene ligands can be replaced with mono- or multi-dentate ligands. Combining the features of 99Tc and Re may lead to a molecule-based theranostic approach.


Update on Screening for Urological Malignancies.
Urological malignancies are a major source of morbidity and mortality in men over 40. Screening for those malignancies has a potential benefit of reducing both. However, even after more than two decades of screening for prostate cancer, the implications of most resulting information are still a matter of debate. Controversy extends over several aspects of prostate cancer screening programs, including age of onset, defining populations at risk, most appropriate intervals, as well as the optimal methods to be used for screening. The medical community is still divided regarding the effectiveness of prostate cancer-related death prevention and its benefits-to-harms ratio, reflecting an inconsistency regarding screening recommendations. Similarly, benefits of screening for urothelial and kidney tumors are yet lacking high-level evidence, although recent evidence supports screening of populations at risk. Clearly, the current era of evolving molecular and genetic biomarkers harbors the potential to change screening practice. In this paper, we review current guidelines as well as giving an update on new developments which might influence screening strategies in common urological malignancies.


Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4.
Small RNA viruses have evolved many mechanisms to increase the capacity of their short genomes. Here we describe the identification and characterization of a novel open reading frame (ORF4) encoded by the murine norovirus (MNV) subgenomic RNA, in an alternative reading frame overlapping the VP1 coding region. ORF4 is translated during virus infection and the resultant protein localizes predominantly to the mitochondria. Using reverse genetics we demonstrated that expression of ORF4 is not required for virus replication in tissue culture but its loss results in a fitness cost since viruses lacking the ability to express ORF4 restore expression upon repeated passage in tissue culture. Functional analysis indicated that the protein produced from ORF4 antagonizes the innate immune response to infection by delaying the upregulation of a number of cellular genes activated by the innate pathway, including IFN-Beta. Apoptosis in the RAW264.7 macrophage cell line was also increased during virus infection in the absence of ORF4 expression. In vivo analysis of the WT and mutant virus lacking the ability to express ORF4 demonstrated an important role for ORF4 expression in infection and virulence. STAT1-/- mice infected with a virus lacking the ability to express ORF4 showed a delay in the onset of clinical signs when compared to mice infected with WT virus. Quantitative PCR and histopathological analysis of samples from these infected mice demonstrated that infection with a virus not expressing ORF4 results in a delayed infection in this system. In light of these findings we propose the name virulence factor 1, VF1 for this protein. The identification of VF1 represents the first characterization of an alternative open reading frame protein for the calicivirus family. The immune regulatory function of the MNV VF1 protein provide important perspectives for future research into norovirus biology and pathogenesis.


Metabolic and Transcriptional Reprogramming in Developing Soybean (Glycine max) Embryos.
Soybean (Glycine max) seeds are an important source of seed storage compounds, including protein, oil, and sugar used for food, feed, chemical, and biofuel production. We assessed detailed temporal transcriptional and metabolic changes in developing soybean embryos to gain a systems biology view of developmental and metabolic changes and to identify potential targets for metabolic engineering. Two major developmental and metabolic transitions were captured enabling identification of potential metabolic engineering targets specific to seed filling and to desiccation. The first transition involved a switch between different types of metabolism in dividing and elongating cells. The second transition involved the onset of maturation and desiccation tolerance during seed filling and a switch from photoheterotrophic to heterotrophic metabolism. Clustering analyses of metabolite and transcript data revealed clusters of functionally related metabolites and transcripts active in these different developmental and metabolic programs. The gene clusters provide a resource to generate predictions about the associations and interactions of unknown regulators with their targets based on "guilt-by-association" relationships. The inferred regulators also represent potential targets for future metabolic engineering of relevant pathways and steps in central carbon and nitrogen metabolism in soybean embryos and drought and desiccation tolerance in plants.


Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP(+).
Assessment of the network of toxicity pathways by Omics technologies and bioinformatic data processing paves the road toward a new toxicology for the twenty-first century. Especially, the upstream network of responses, taking place in toxicant-treated cells before a point of no return is reached, is still little explored. We studied the effects of the model neurotoxicant 1-methyl-4-phenylpyridinium (MPP(+)) by a combined metabolomics (mass spectrometry) and transcriptomics (microarrays and deep sequencing) approach to provide unbiased data on earliest cellular adaptations to stress. Neural precursor cells (LUHMES) were differentiated to homogeneous cultures of fully postmitotic human dopaminergic neurons, and then exposed to the mitochondrial respiratory chain inhibitor MPP(+) (5 μM). At 18-24 h after treatment, intracellular ATP and mitochondrial integrity were still close to control levels, but pronounced transcriptome and metabolome changes were seen. Data on altered glucose flux, depletion of phosphocreatine and oxidative stress (e.g., methionine sulfoxide formation) confirmed the validity of the approach. New findings were related to nuclear paraspeckle depletion, as well as an early activation of branches of the transsulfuration pathway to increase glutathione. Bioinformatic analysis of our data identified the transcription factor ATF-4 as an upstream regulator of early responses. Findings on this signaling pathway and on adaptive increases of glutathione production were confirmed biochemically. Metabolic and transcriptional profiling contributed complementary information on multiple primary and secondary changes that contribute to the cellular response to MPP(+). Thus, combined 'Omics' analysis is a new unbiased approach to unravel earliest metabolic changes, whose balance decides on the final cell fate.


A robustness study of parametric and non-parametric tests in model-based multifactor dimensionality reduction for epistasis detection.
Applying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects. Our simulation study focuses on pure epistasis models with varying degrees of genetic influence on a quantitative trait. Conditional on a multilocus genotype, we consider quantitative trait distributions that are normal, chi-square or Student's t with constant or non-constant phenotypic variances. All data are analyzed with MB-MDR using the built-in Student's t-test for association, as well as a novel MB-MDR implementation based on Welch's t-test. Traits are either left untransformed or are transformed into new traits via logarithmic, standardization or rank-based transformations, prior to MB-MDR modeling. Our simulation results show that MB-MDR controls type I error and false positive rates irrespective of the association test considered. Empirically-based MB-MDR power estimates for MB-MDR with Welch's t-tests are generally lower than those for MB-MDR with Student's t-tests. Trait transformations involving ranks tend to lead to increased power compared to the other considered data transformations. When performing MB-MDR screening for gene-gene interactions with quantitative traits, we recommend to first rank-transform traits to normality and then to apply MB-MDR modeling with Student's t-tests as internal tests for association.


Multiplex polymerase chain reaction as a mastitis screening test for Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis in bulk milk samples.
Effective diagnostic tools for screening herds for mastitis pathogens are important in development and monitoring of mastitis control programmes. A multiplex polymerase chain reaction (PCR) assay for simultaneous detection of Staphylococcus aureus, Streptococcus agalactiae, Streptococcus dysgalactiae and Streptococcus uberis was used in preliminary studies to assess its applicability as an alternative method for monitoring mastitis caused by these organisms at the herd level. PCR was used to detect the presence of these organisms in bulk milk samples. Correlations with bulk milk somatic cell counts (BMCC), total bacteria counts and thermoduric bacteria counts were evaluated. A total of 176 bulk milk samples were collected from 42 herds on five consecutive occasions at approx. 10-d intervals. Str. uberis was the most common organism in these bulk milk samples. There was no relationship between presence of either Staph. aureus, Str. dysgalactiae or Str. uberis and BMCC, total bacteria counts or thermoduric bacteria counts. However, presence of Str. agalactiae was associated with high BMCC and total bacteria counts. The results of this study show that regular analysis of bulk milk using this multiplex PCR assay may be a useful tool for monitoring herd status with respect to Str. agalactiae, but is of less value for monitoring occurrence of Staph. aureus, Str. dysgalactiae and Str. uberis. Further investigations are needed to clarify the relationship between positive PCR results and the prevalence of infected cows in the herd.


Drinking water arsenic in Utah: A cohort mortality study.
The association of drinking water arsenic and mortality outcome was investigated in a cohort of residents from Millard County, Utah. Median drinking water arsenic concentrations for selected study towns ranged from 14 to 166 ppb and were from public and private samples collected and analyzed under the auspices of the State of Utah Department of Environmental Quality, Division of Drinking Water. Cohort members were assembled using historical documents of the Church of Jesus Christ of Latter-day Saints. Standard mortality ratios (SMRs) were calculated. Using residence history and median drinking water arsenic concentration, a matrix for cumulative arsenic exposure was created. Without regard to specific exposure levels, statistically significant findings include increased mortality from hypertensive heart disease [SMR = 2.20; 95% confidence interval (CI), 1.36-3.36], nephritis and nephrosis (SMR = 1.72; CI, 1.13-2.50), and prostate cancer (SMR = 1.45; CI, 1.07-1. 91) among cohort males. Among cohort females, statistically significant increased mortality was found for hypertensive heart disease (SMR = 1.73; CI, 1.11-2.58) and for the category of all other heart disease, which includes pulmonary heart disease, pericarditis, and other diseases of the pericardium (SMR = 1.43; CI, 1.11-1.80). SMR analysis by low, medium, and high arsenic exposure groups hinted at a dose relationship for prostate cancer. Although the SMRs by exposure category were elevated for hypertensive heart disease for both males and females, the increases were not sequential from low to high groups. Because the relationship between health effects and exposure to drinking water arsenic is not well established in U.S. populations, further evaluation of effects in low-exposure populations is warranted.


Building compassion literacy: Enabling care in primary health care nursing.
This paper introduces the concept of compassion literacy and discusses its place in nursing within the general practice setting. Compassion literacy is a valuable competency for sustaining the delivery of high quality care. Being compassion literate enables practice nurses to provide compassionate care to their patients and to recognise factors that may constrain this. A compassion literate practice nurse may be more protected from compassion fatigue and its negative consequences. Understanding how to enable self-compassion and how to support the delivery of compassionate care within the primary care team can enhance the care experienced by the patient while improving the positive engagement and satisfaction of the health professionals. The capacity to deliver compassionate care can be depleted by the day-to-day demands of the clinical setting. Compassion literacy enables the replenishing of compassion, but the development of compassion literacy can be curtailed by personal and workplace barriers. This paper articulates why compassion literacy should be an integral aspect of practice nursing and considers strategies for enabling compassion literacy to develop and thrive within the workplace environment. Compassion literacy is also a valuable opportunity for practice nurses to demonstrate their key role within the multidisciplinary team of general practice, directly enhancing the quality of the care delivered.


Network dynamics underlying OFF responses in the auditory cortex.
Across sensory systems, complex spatio-temporal patterns of neural activity arise following the onset (ON) and offset (OFF) of stimuli. While ON responses have been widely studied, the mechanisms generating OFF responses in cortical areas have so far not been fully elucidated. We examine here the hypothesis that OFF responses are single-cell signatures of recurrent interactions at the network level. To test this hypothesis, we performed population analyses of two-photon calcium recordings in the auditory cortex of awake mice listening to auditory stimuli, and compared them to linear single-cell and network models. While the single-cell model explained some prominent features of the data, it could not capture the structure across stimuli and trials. In contrast, the network model accounted for the low-dimensional organization of population responses and their global structure across stimuli, where distinct stimuli activated mostly orthogonal dimensions in the neural state-space.


Genetics of reproductive performance in seasonal calving beef cows and its association with performance traits.
Due primarily to a lack of phenotypic data, little research has been undertaken on the genetics of reproductive performance in beef cattle. The objective of this study was to quantify, using data from the Irish national cattle herd, the contribution of additive genetics to phenotypic differences in reproductive performance in beef cattle and to investigate whether routinely available early predictors of genetic merit for reproductive performance exist. Up to 218,718 parity records from 156,506 animals were used to estimate variance components for a range of reproductive traits using repeatability animal linear mixed models. Covariances with performance traits were estimated using bivariate sire linear mixed models. The reproductive traits were age at first calving, calving in the first 42 d of the calving seasons (defined separately in heifers and cows), calving interval between consecutive calving events, and survival to the next lactation. Performance traits included calving dystocia, linear type traits describing the skeletal, muscular, and functional characteristics of an animal, live weight and price, carcass traits, and producer subjectively scored traits of weanling quality and docility. Heritability for age at first calving was 0.31 while the heritability of the remaining reproductive traits ranged from 0.01 to 0.06; repeatability estimates varied from 0.02 to 0.06. Increased muscularity, measured either by trained assessors or producers on live animals, or by mechanical grading machines on slaughtered animals (i.e., carcass conformation), was genetically correlated with reduced reproductive performance for some of the reproductive variables assessed. This is one of the largest studies undertaken on the genetics of reproduction in beef herds and clearly shows that genetic selection for improved reproductive performance in beef herds is feasible. However, breeding goals that select for muscularity and live weight or growth rate should be cognizant of indirect response to selection that may cause any deterioration in reproductive performance.


A novel subclass of thalidomide analogue with anti-solid tumor activity in which caspase-dependent apoptosis is associated with altered expression of bcl-2 family proteins.
Thalidomide is clinically useful in a number of cancers. Antitumor activity may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-alpha and T-cell costimulatory and antiangiogenic activities. However, it may also involve direct antitumor effects. A series of second generation thalidomide analogues have been separated into two distinct groups of compounds, each with enhanced therapeutic potential, i.e., SelCIDs, which are phosphodiesterase (PDE) type IV inhibitors, and IMiDs, which have unknown mechanism(s) of action. We report here our efforts to determine direct antitumor effects of thalidomide and compounds from both groups. We found that one of the SelCID analogues (SelCID-3) was consistently effective at reducing tumor cell viability in a variety of solid tumor lines but had no effect on non-neoplastic cells. The antitumor activity was independent of known PDE4 inhibitory activity and did not involve cAMP elevation. Growth arrest was preceded by the early induction of G(2)-M cell cycle arrest, which led to caspase 3 mediated apoptosis. This was associated with increased expression of pro-apoptotic proteins and decreased expression of antiapoptotic bcl-2. Furthermore, extensive apoptosis in vivo was detected during SelCID-3-mediated inhibition of tumor growth in a murine xenotransplantation cancer model. Our results suggest that SelCID-3 represents a novel antitumor agent distinct from thalidomide and from previously characterized analogues with therapeutic potential against a range of solid tumors. This effect appears to be mediated via alterations in the expression of bcl-2 family proteins.


Chromosome-length polymorphism in fungi.
The examination of fungal chromosomes by pulsed-field gel electrophoresis has revealed that length polymorphism is widespread in both sexual and asexual species. This review summarizes characteristics of fungal chromosome-length polymorphism and possible mitotic and meiotic mechanisms of chromosome length change. Most fungal chromosome-length polymorphisms are currently uncharacterized with respect to content and origin. However, it is clear that long tandem repeats, such as tracts of rRNA genes, are frequently variable in length and that other chromosomal rearrangements are suppressed during normal mitotic growth. Dispensable chromosomes and dispensable chromosome regions, which have been well documented for some fungi, also contribute to the variability of the fungal karyotype. For sexual species, meiotic recombination increases the overall karyotypic variability in a population while suppressing genetic translocations. The range of karyotypes observed in fungi indicates that many karyotypic changes may be genetically neutral, at least under some conditions. In addition, new linkage combinations of genes may also be advantageous in allowing adaptation of fungi to new environments.


Transcriptome analysis of periodontitis-associated fibroblasts by CAGE sequencing identified DLX5 and RUNX2 long variant as novel regulators involved in periodontitis.
Periodontitis is affecting over half of the adult population, and represents a major public health problem. Previously, we isolated a subset of gingival fibroblasts (GFs) from periodontitis patients, designated as periodontitis-associated fibroblasts (PAFs), which were highly capable of collagen degradation. To elucidate their molecular profiles, GFs isolated form healthy and periodontitis-affected gingival tissues were analyzed by CAGE-seq and integrated with the FANTOM5 atlas. GFs from healthy gingival tissues displayed distinctive patterns of CAGE profiles as compared to fibroblasts from other organ sites and characterized by specific expression of developmentally important transcription factors such as BARX1, PAX9, LHX8, and DLX5. In addition, a novel long non-coding RNA associated with LHX8 was described. Furthermore, we identified DLX5 regulating expression of the long variant of RUNX2 transcript, which was specifically active in GFs but not in their periodontitis-affected counterparts. Knockdown of these factors in GFs resulted in altered expression of extracellular matrix (ECM) components. These results indicate activation of DLX5 and RUNX2 via its distal promoter represents a unique feature of GFs, and is important for ECM regulation. Down-regulation of these transcription factors in PAFs could be associated with their property to degrade collagen, which may impact on the process of periodontitis.


mtDNA phylogeography and postglacial patterns of subdivision in the meadow grasshopper Chorthippus parallelus.
A 300 bp portion of the mitochondrial cytochrome oxidase subunit I (COI) gene was used to investigate the intraspecific genetic structure of the European meadow grasshopper Chorthippus parallelus. Levels of genetic subdivision between geographical regions in Europe were assessed using the KST statistic and revealed patterns indicative of the postglacial history of this organism. Northern European populations are shown to share a very recent common ancestor with, and hence originate from, a Balkan expansion. Genetic distances between these areas and both southern Italy and central Spain are shown to be approximately equal, even though only the Spanish form is recognized as a distinct subspecies. Distance estimates indicate that the common ancestor of the two subspecies lived more than one glacial cycle ago, and the refugial populations have probably been diverging in isolation for five or six glacial cycles (approximately equal to 550,000 years). Comparisons are made to the analysis of a similar data set using an anonymous nuclear DNA marker (Cooper et al., 1995). Although the structure revealed is generally very similar, differences in the location of transition zones between different genetic forms of C. parallelus may reflect the different historical assortment of these molecules.


[Acute hepatotoxicity from intravenous amiodarone in a patient on hemodialysis].
Amiodarone is a class III antiarrhythmic drug used to treat several tachyarrhythmias. Although toxicity by long-term oral therapy is known, it is rare to observe the acute toxicity correlated to intravenous use. We report an unusual case of acute hepatotoxicity after the initiation of intravenous amiodarone for atrial fibrillation in a patient on regular hemodialysis. Liver enzymes progressively decreased and normalized upon discontinuing the drug. As a result, closely monitoring of liver enzyme is suggested when intravenous amiodarone is prescribed.


Leptin-deficient obesity prolongs survival in a murine model of myelodysplastic syndrome.
Obesity enhances the risk of developing myelodysplastic syndromes. However, the effect of obesity on survival is unclear. Obese people present with monocytosis due to inflammatory signals emanating from obese adipose tissue. We hypothesized that obesity-induced myelopoiesis would promote the transition of myelodysplastic syndrome to acute myeloid leukemia and accelerate mortality in obesity. Obese Ob/Ob mice or their lean littermate controls received a bone marrow transplant from NUP98-HOXD13 transgenic mice, a model of myelodysplastic syndrome. The metabolic parameters of the mice were examined throughout the course of the study, as were blood leukocytes. Myeloid cells were analyzed in the bone, spleen, liver and adipose tissue by flow cytometry halfway through the disease progression and at the endpoint. Survival curves were also calculated. Contrary to our hypothesis, transplantation of NUP98-HOXD13 bone marrow into obese recipient mice significantly increased survival time compared with lean recipient controls. While monocyte skewing was exacerbated in obese mice receiving NUP98-HOXD13 bone marrow, transformation to acute myeloid leukemia was not enhanced. Increased survival of obese mice was associated with a preservation of fat mass as well as increased myeloid cell deposition within the adipose tissue, and a concomitant reduction in detrimental myeloid cell accumulation within other organs. The study herein revealed that obesity increases survival in animals with myelodysplastic syndrome. This may be due to the greater fat mass of Ob/Ob mice, which acts as a sink for myeloid cells, preventing their accumulation in other key organs, such as the liver.


Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells.
The expression of a luciferase reporter gene under the control of the human glucose 6-phosphatase gene promoter was stimulated by both dexamethasone and dibutyryl cAMP in H4IIE hepatoma cells. A cis-active element located between nucleotides -161 and -152 in the glucose 6-phosphatase gene promoter was identified and found to be necessary for both basal reporter-gene expression and induction of expression by both dibutyryl cAMP and dexamethasone. Nucleotides -161 to -152 were functionally replaced by the consensus sequence for a cAMP response element. An antibody against the cAMP response element-binding protein caused a supershift in gel-electrophoretic-mobility-shift assays using an oligonucleotide probe representing the glucose 6-phosphatase gene promoter from nucleotides -161 to -152. These results strongly indicate that in H4IIE cells the glucose 6-phosphatase gene-promoter sequence from -161 to -152 is a cAMP response element which is important for the regulation of transcription of the glucose 6-phosphatase gene by both cAMP and glucocorticoids.


Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 1 diabetic patients.
To study the effect of vitamin E supplementation on platelet hyperaggregability in type 1 diabetic patients. Written informed consent according to the Institutional Review Board on Human Experimentation guidelines was obtained from diabetic patients (n = 29) and their age-matched normal siblings (n = 21) to participate in this study. Diabetic patients were supplemented with DL-alpha-tocopherol (vitamin E) capsule (orally, 100 IU/day) or placebo for 3 months in a double-blind clinical trial. Alternate diabetic patients were assigned to vitamin E or placebo during regular visits to the clinic. Fasting blood was collected from each diabetic patient before the start and after the vitamin E or placebo supplementation. Platelet aggregability was assessed by competitive enzyme-linked immunosorbent assay of the blood TxB2 (a stable thromboxane metabolite). Plasma vitamin E and MDA (malondialdehyde, a product of lipid peroxidation) was assessed by high-performance liquid chromatography. Data were analyzed statistically on 12 diabetic patients on vitamin E and 12 on placebo supplementation. Diabetic patients (n = 29) had 62% higher (P < 0.05) levels of TxB2 and 15% higher levels (P < 0.05) of MDA in comparison to normal subjects (n = 21). Plasma TxB2 levels had a significant correlation with MDA levels (r = 0.45, P < 0.02) but not with the HbA1 (r = -0.08), glucose (r = -0.13), duration of diabetes (r = -0.04), or age (r = 0.12) of diabetic patients. Vitamin E supplementation lowered MDA levels by 30% (P < 0.04), TxB2 levels by 51% (P < 0.03), and triglyceride levels by 22% (P < 0.04) in diabetic patients. There were no differences in these parameters before versus after placebo supplementation. The elevated blood level of TxB2 (hyperaggregability of platelets) is significantly related to the level of lipid peroxidation products (oxidative stress) in type 1 diabetic patients. Supplementation of modest doses of vitamin E (100 IU/day) significantly lowers blood TxB2 and lipid peroxidation products levels in type 1 diabetic patients.


[The relevance of urban environments and physical activity in older adults for Latin-America].
Aging in Latin-America has been characterised by its rapid pace which, in turn, has been accompanied by growing urbanisation and globalisation. These processes have been linked to the prevalence of physical inactivity thereby contributing to the appearance of chronic diseases, these being the primary cause of mortality in the region. The influence of public urban environment intervention policy on physical activity has been emphasised recently. This evidence comes mainly from studies conducted in the USA and Australia. However, this topic has scarcely been studied in Latin-America which has particular characteristics regarding aging and urban development. Cities, such as Curitiba and Bogota, have undergone significant urban changes which may be linked to physical activity and the quality of life, especially in older adults. Considering the particularities of urban development in Latin-America, it is thus concluded that multidisciplinary studies should be carried out thereby leading to better understanding of the links between urban environments and physical activity in older adults.


Molecular Hydrogen, a Neglected Key Driver of Soil Biogeochemical Processes.
The atmosphere of the early Earth is hypothesized to have been rich in reducing gases such as hydrogen (H2). H2 has been proposed as the first electron donor leading to ATP synthesis due to its ubiquity throughout the biosphere as well as its ability to easily diffuse through microbial cells and its low activation energy requirement. Even today, hydrogenase enzymes enabling the production and oxidation of H2 are found in thousands of genomes spanning the three domains of life across aquatic, terrestrial, and even host-associated ecosystems. Even though H2 has already been proposed as a universal growth and maintenance energy source, its potential contribution as a driver of biogeochemical cycles has received little attention. Here, we bridge this knowledge gap by providing an overview of the classification, distribution, and physiological role of hydrogenases. Distribution of these enzymes in various microbial functional groups and recent experimental evidence are finally integrated to support the hypothesis that H2-oxidizing microbes are keystone species driving C cycling along O2 concentration gradients found in H2-rich soil ecosystems. In conclusion, we suggest focusing on the metabolic flexibility of H2-oxidizing microbes by combining community-level and individual-level approaches aiming to decipher the impact of H2 on C cycling and the C-cycling potential of H2-oxidizing microbes, via both culture-dependent and culture-independent methods, to give us more insight into the role of H2 as a driver of biogeochemical processes.


Solution structure of the lyase domain of human DNA polymerase lambda.
DNA polymerase lambda (pol lambda) is a recently discovered nuclear enzyme belonging to the pol X family of DNA polymerases that exhibits a 32% sequence identity with the nuclear DNA repair protein, pol beta. Structural modeling suggests that pol lambda contains the palm, fingers, thumb, and 8 kDa lyase domains present in pol beta, as well as an additional N-terminal BRCT domain and a serine-proline-rich linker that are presumably involved in protein-protein interactions. The 8 kDa domain of pol beta is important for DNA binding and contains the dRP lyase activity, which is the rate-limiting step in the single-nucleotide base excision repair (BER) pathway of damaged DNA. Recently, it was shown that the 8 kDa domain of pol lambda also contains the dRP lyase activity. To gain further insight into the catalytic mechanism of dRP removal by pol lambda, we have determined the solution structure of the 8 kDa lyase domain of human DNA pol lambda via multidimensional NMR methods and the ARIA program. The resulting structures exhibited a high degree of similarity with the 8 kDa lyase domain of pol beta. Specifically, the side chains of residues W274, R275, Y279, K307, R308, and K312 are in similar positions to the functionally important side chains of residues H34, K35, Y39, K60, K68, and K72 in the 8 kDa lyase domain of pol beta. This suggests that, on the basis of the proposed roles of these residues in pol beta, the corresponding pol lambda side chains may be involved in DNA binding and dRP lyase activity. The structural alignment of W274 (pol lambda) with H34 (pol beta) indicates that the former is probably involved in a similar base stacking interaction with template DNA at the position of the gap, in contrast with several previous proposals which aligned D272 with H34. In a few cases for which there is a nonconservative substitution in the sequence alignment, a structural comparison shows a positionally and, hence, probably a functionally equivalent residue, e.g., K60 in pol beta and K307 in pol lambda. Additionally, on the basis of the structural alignment obtained, several previously proposed mechanistic hypotheses can be evaluated.


Physical activity and quality of life in long-term hospitalized patients with severe mental illness: a cross-sectional study.
Increasing physical activity in patients with severe mental illness is believed to have positive effects on physical health, psychiatric symptoms and as well quality of life. Till now, little is known about the relationship between physical activity and quality of life in long-term hospitalized patients with severe mental illness and knowledge of the determinants of behavioural change is lacking. The purpose of this study was to elucidate the relationship between objectively measured physical activity and quality of life, and explore modifiable psychological determinants of change in physical activity in long-term hospitalized patients with severe mental illness. In 184 inpatients, physical activity was measured using an accelerometer (ActiGraph GTX+). Quality of life was assessed by EuroQol-5D and WHOQol-Bref. Attitude and perceived self-efficacy towards physical activity were collected using the Physical Activity Enjoyment Scale and the Multidimensional Self Efficacy Questionnaire, respectively. Patient and disease characteristics were derived retrospectively from electronic patient records. Associations and potential predictors were analysed using hierarchical regression. Physical activity was positively related with and a predictor of all quality of life outcomes except on the environmental domain, independent of patient and disease characteristics. However, non-linear relationships showed that most improvement in quality of life lies in the change from sedentary to light activity. Attitude and self-efficacy were not related to physical activity. Physical activity is positively associated with quality of life, especially for patients in the lower spectrum of physical activity. An association between attitude and self-efficacy and physical activity was absent. Therefore, results suggest the need of alternative, more integrated and (peer-)supported interventions to structurally improve physical activity in this inpatient population. Slight changes from sedentary behaviour to physical activity may be enough to improve quality of life.


Regional-scale assembly rules and biodiversity of coral reefs.
Tropical reef fishes and corals exhibit highly predictable patterns of taxonomic composition across the Indian and Pacific Oceans. Despite steep longitudinal and latitudinal gradients in total species richness, the composition of these key taxa is constrained within a remarkably narrow range of values. Regional-scale variation in reef biodiversity is best explained by large-scale patterns in the availability of shallow-water habitat. Once habitat area is accounted for, there is surprisingly little residual effect of latitude or longitude. Low-diversity regions are most vulnerable to human impacts such as global warming, underscoring the urgent need for integrated management at multinational scales.


Echocardiography of coarctation of the aorta, aortic arch hypoplasia, and arch interruption: strategies for evaluation of the aortic arch.
Aim Echocardiography is the modality of choice for the diagnosis and serial follow-up of aortic arch pathology. In this article, we review the types of obstruction of the aortic arch, various classification schemes of coarctation of the aorta and interrupted aortic arch, methodology for optimal echocardiographic imaging of the aortic arch, and key echocardiographic measurements for accurate diagnosis of obstruction and hypoplasia of the aortic arch. Finally, we will discuss the limitations of echocardiography in optimal imaging of the aortic arch and the use of other non-invasive imaging modalities such as CT or MRI to provide additional information in these cases. Coarctation of the aorta is the more common lesion of the two, with an estimated incidence of four in every 10,000 live births in the United States of America. Interrupted aortic arch is rarer, with an incidence of 19 per one million live births. 1 There is a spectrum of pathology of obstruction of the aortic arch, ranging from coarctation of the aorta with and without hypoplasia of the arch to interrupted aortic arch. Both these lesions are frequently encountered in congenital cardiology practice, and will be discussed in the remainder of this article. Obstruction of the aortic arch in the setting of hypoplastic left heart structures or atresia of the aortic valve is beyond the scope of this review and will not be discussed further.


Algorithm for Management of the Refractive Aerosinusitis Patient.
For some career military aviators, their ability to continue on flight status is limited by the pressure and pain of aerosinusitis, which is present only while in the flying environment. Failure to treat their disease process can mean the end of their flying careers and the loss of valuable assets trained with taxpayer dollars. Because some medications commonly used in treatment of sinus diseases are not allowed in aviation, this presents a unique problem for their medical management. Surgical treatment must be aimed at treating to symptom relief and not solely disease mitigation. One alternative is operating "beyond the scope of disease" present during a one-atmosphere clinic visit. A case series of nine career aviators with aerosinusitis treated at one academic military Otolaryngology department in a tertiary care facility. Results from a treatment algorithm that balances symptomatology and staged surgical intervention are reviewed. The primary endpoint was return to flight duty. For patients treated according to this algorithm, the mean time to return to flight duty was 3.8 mo, requiring an average of 1.2 surgeries. To date, 100% of career aviators have returned to flight duty using this method. Refractory aerosinusitis represents a potentially career-ending medical condition for the aviator and lost training costs to the taxpayers. Using the treatment algorithm presented, 100% of aviators were able to return to flight duty; a savings of millions of dollars for taxpayers. Future work will focus on modifications to the surgical techniques to reduce the extent of surgery while maintaining satisfactory results. Additional study should be undertaken to assess generalizability of these results in the broader aviation community.


Homarus gammarus (Crustacea: Decapoda) larvae under an ocean acidification scenario: responses across different levels of biological organization.
The present study evaluated the effects of exposure to different target pCO2 levels: control (C: 370μatm, pH=8.15) and ocean acidification (OA: 710μatm, pH=7.85) on development and biochemical responses related with oxidative stress and energy metabolism during the crustacean Homarus gammarus (L.) larval development, integrating different levels of biological organization. After hatching in the laboratory, larvae from the same female brood were exposed to the described conditions from hatching until reaching Stage III (last larval stage - 11days). H. gammarus larvae demonstrated some susceptibility when addressing the predicted pCO2 levels for 2100. Further analysis at the biochemical and physiological level highlighted the occurrence of oxidative stress in the OA scenario (Superoxide Dismutase reduction and higher DNA damage) that was followed by developmental effects, increased inter-moult period from SII to SIII and reduced growth. The extended exposure to these conditions may affect organisms' key life-cycle functions such as physiological resistance, growth, sexual maturation, or reproduction with implications in their future fitness and population dynamics.


Histological changes associated with the use of intravenous cyclosporin in the treatment of severe ulcerative colitis may mimic dysplasia.
During six years experience of intravenous cyclosporin (i.v. Cy) for severe ulcerative colitis we have noted that changes of villous architecture and epithelial regeneration occur even when the disease fails to enter clinical remission and colectomy is required. To describe the histological changes in patients who received i.v. Cy and steroids compared with those treated with i.v. steroids alone. Two groups of histological sections were reviewed. The first group was of 23 colectomy specimens from patients who had been treated with i.v. Cy and steroids. For 11 patients pre-Cy histological sections were available. The second group was of 10 colectomy specimens from patients who had received i.v. steroids alone. Biopsies were scored for their histological disease activity (HDAI), villous architecture and epithelial regeneration. The HDAI assesses the degree of acute and chronic inflammation. The post-Cy group had higher median scores for villous architecture and epithelial regeneration compared to the pre-Cy and poststeroid groups. For the patients where both pre- and post-Cy histological sections were available 63% increased their villous score post-Cy and 82% increased their epithelial regeneration score post-Cy. Although villous transformation and epithelial regeneration may be seen in UC they are more frequent and more severe in those patients who received i.v. Cy and i.v. steroids, compared to controls who received i.v. steroids alone. These histological changes may mimic dysplasia. Increased awareness of this potential mimic of dysplasia is crucial for patient management.


Acute monocytic leukemia (French-American-British classification M5) does not have a worse prognosis than other subtypes of acute myeloid leukemia: a report from the Eastern Cooperative Oncology Group.
Acute monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to compare the outcome of patients with M5 to that of other subtypes of AML, and to identify differences in M5a and M5b. We reviewed all patients with AML M5 entered in three clinical trials for newly diagnosed AML conducted by the Eastern Cooperative Oncology Group between 1989 and 1998. Eighty-one patients, 21 with M5a and 60 with M5b, were identified. The complete remission rate was 62% for all patients with M5; 52% for patients with M5a and 65% for patients with M5b (P =.3), and 60% for the 1122 patients with non-M5 AML entered on the same clinical trials (P =.8 for M5 v non-M5). The 3-year disease-free survival was 26% for all M5 patients; 18% for M5a and 28% for M5b (P =.31), and 33% for non-M5 patients (P =.13 for M5 v non-M5). The 3-year overall survival was 31% for all M5 patients; 33% for M5a and 30% for M5b (P =.65), and 30% for non-M5 (P =.74 for M5 v non-M5). The karyotypes of patients with AML M5 were heterogeneous. CD11b was the only leukemic cell antigen expressed differently in M5a (53%) compared to M5b (77%) to a significant degree (P =.02). AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.


Push-pull effects of three plant secondary metabolites on oviposition of the potato tuber moth, Phthorimaea operculella.
The push-pull effects of three plant secondary metabolites, azadirachtin, eucalyptol, and heptanal, on the oviposition choices of potato tubers by the potato tuber moth, Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae) were tested in the laboratory. Azadirachtin at concentrations from 1.5 to 12 mg/L had a significant repellent effect on oviposition. Eucalyptol at concentrations from 3 to 12 mg/L promoted oviposition. Heptanal promoted oviposition at low concentrations from 0.1875 to 3.0 mg/L but repelled it at higher concentrations from 12 to 24 mg/L. The combination of azadirachtin (12 mg/L) with eucalyptol (3.0 mg/L) resulted in a significant pushpull effect of 56.3% on oviposition. The average maximum push-pull effects occurred with the combinations of azadirachtin with heptanal (12 and 0.375 mg/L, respectively; 38.7% push-pull effect), heptanal with eucalyptol (12 and 6 mg/L, respectively; 31.4% push-pull effect), and heptanal (high concentration) with heptanal (low concentration) (12.0 and 0.375 mg/L, respectively; 25% push-pull effect).