Impacts of increased ocean temperatures on a low-latitude coral reef fish - Processes related to oxygen uptake and delivery.

Increasing temperatures are expected to significantly affect the physiological performance of ectotherms, particularly in tropical locations. The shape of an organism's thermal reaction norm can provide important information on its capacity to persist under climate change scenarios; however, difficulty lies in choosing a measurable trait that best depicts physiological performance. This study investigated the effects of elevated temperatures on processes related to oxygen uptake and delivery, including oxygen consumption, haematology, and tissue health for a low-latitude population of coral reef damselfish. Acanthochromis polyacanthus were collected from the Torres Strait (10°31-46'S, 142°20-35'E) and maintained at current average ocean temperatures (+0 °C; seasonally cycling), + 1.5 °C and + 3 °C higher than present day temperatures for 10 months. Aerobic performance indicated a limit to metabolic function at + 3 °C (33 °C), following an increase in aerobic capacity at + 1.5 °C (31.5 °C). Neither haematological parameters nor gill morphology showed the same improvement in performance at + 1.5 °C. Gill histopathology provided the first indicator of a decline in organism health, which corresponded with mortality observations from previous research. Findings from this study suggest thermal specialisation in this low-latitude population as well as variation in thermal sensitivity, depending on the physiological trait.

Evaluation of a new commercial method for von Willebrand factor multimeric analysis.

INTRODUCTION: Evaluation of von Willebrand factor (VWF) multimeric distribution is useful for subclassification of von Willebrand disease (VWD). Multimer analysis has historically been a manual, labor-intensive laboratory-developed test. The first commercial method for multimeric analysis was recently developed that utilizes a single instrument for gel electrophoresis, staining, and densitometry. The current study was undertaken to evaluate the performance characteristics of the new commercial method. METHODS: Studies performed with the commercial method included evaluation of accuracy (method comparison), reference intervals (establishment of normal migration patterns in normal donor specimens), precision (multimer pattern reproducibility), and analytical sensitivity. RESULTS: In the method comparison studies, concordant interpretations were obtained in 19 of 24 comparisons, including normal and abnormal specimens. The 5 specimens with discordant interpretations all involved slight differences and none were considered clinically significant. Thirty-eight normal donor specimens demonstrated normal multimer patterns. Multimer pattern reproducibility was demonstrated in normal and abnormal controls tested on each gel. In the sensitivity studies, adequate visualization of multimers was determined to require VWF protein concentrations of approximately 5%-10% of normal. CONCLUSION: The commercial multimer method is a streamlined test that demonstrates comparable performance characteristics to our current laboratory-developed method and that provides the advantage of both electrophoresis gels and densitometry scans to aid interpretation.

Identifying transmission routes of Streptococcus pneumoniae and sources of acquisitions in high transmission communities.

Identifying the transmission sources and reservoirs of Streptococcus pneumoniae (SP) is a long-standing question for pneumococcal epidemiology, transmission dynamics, and vaccine policy. Here we use serotype to identify SP transmission and examine acquisitions (in the same household, local community, and county, or of unidentified origin) in a longitudinal cohort of children and adults from the Navajo Nation and the White Mountain Apache American Indian Tribes. We found that adults acquire SP relatively more in the household than other age groups, and children 2-8 years old typically acquire in their own or surrounding communities. Age-specific transmission probability matrices show that transmissions within household were mostly seen from older to younger siblings. Outside the household, children most often transmit to other children in the same age group, showing age-assortative mixing behavior. We find toddlers and older children to be most involved in SP transmission and acquisition, indicating their role as key drivers of SP epidemiology. Although infants have high carriage prevalence, they do not play a central role in transmission of SP compared with toddlers and older children. Our results are relevant to inform alternative pneumococcal conjugate vaccine dosing strategies and analytic efforts to inform optimization of vaccine programs, as well as assessing the transmission dynamics of pathogens transmitted by close contact in general.

Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin/+ mice.

Colon carcinogenesis is a multiple-step process involving the accumulation of a series of genetic and epigenetic alterations. The most commonly initiating event of intestinal carcinogenesis is mutation of the adenomatous polyposis coli (APC) gene, which leads to activation of the Wnt/ß-catenin pathway. Olfactomedin 4 (OLFM4) has emerged as an intestinal stem-cell marker, but its biological function in the intestine remains to be determined. Here we show that Olfm4 deletion induced colon adenocarcinoma in the distal colon of ApcMin/+ mice. Mechanistically, we found that OLFM4 is a target gene of the Wnt/ß-catenin pathway and can downregulate ß-catenin signaling by competing with Wnt ligands for binding to Frizzled receptors, as well as by inhibition of the Akt-GSK-3ß (Akt-glycogen synthase kinase-3ß) pathway. We have shown that both Wnt and nuclear factor-κB (NF-κB) signaling were boosted in tumor tissues of Apc Olfm4 double-mutant mice. These data establish OLFM4 as a critical negative regulator of the Wnt/ß-catenin and NF-κB pathways that inhibits colon-cancer development initiated by APC mutation. In addition, Olfm4 deletion significantly enhanced intestinal-crypt proliferation and inflammation induced by azoxymethane/dextran sodium sulfate. Thus, OLFM4 has an important role in the regulation of intestinal inflammation and tumorigenesis, and could be a potential therapeutic target for intestinal malignant tumors. Unlike the human colonic epithelium, the mouse colonic epithelium does not express OLFM4, but nevertheless, systemic OLFM4 deletion promotes colon tumorigenesis and that loss from mucosal neutrophils may have a role to play.

Experimental methods in aquatic respirometry: the importance of mixing devices and accounting for background respiration.

In light of an increasing trend in fish biology towards using static respirometry techniques without the inclusion of a mixing mechanism and without accurately accounting for the influence of microbial (background) respiration, this paper quantifies the effect of these approaches on the oxygen consumption rates (MO2 ) measured from juvenile barramundi Lates calcarifer (mean ± s.e. mass = 20·31 ± 0·81 g) and adult spiny chromis damselfish Acanthochromis polyacanthus (22·03 ± 2·53 g). Background respiration changed consistently and in a sigmoidal manner over time in the treatment with a mixing device (inline recirculation pump), whereas attempts to measure background respiration in the non-mixed treatment yielded highly variable estimates of MO2 that were probably artefacts due to the lack of water movement over the oxygen sensor during measurement periods. This had clear consequences when accounting for background respiration in the calculations of fish MO2 . Exclusion of a mixing device caused a significantly lower estimate of MO2 in both species and reduced the capacity to detect differences between individuals as well as differences within an individual over time. There was evidence to suggest that the magnitude of these effects was dependent on the spontaneous activity levels of the fish, as the difference between mixed and non-mixed treatments was more pronounced for L. calcarifer (sedentary) than for A. polyacanthus (more spontaneously active). It is clear that respirometry set-ups for sedentary species must contain a mixing device to prevent oxygen stratification inside the respirometer. While more active species may provide a higher level of water mixing during respirometry measurements and theoretically reduce the need for a mixing device, the level of mixing cannot be quantified and may change with diurnal cycles in activity. To ensure consistency across studies without relying on fish activity levels, and to enable accurate assessments of background respiration, it is recommended that all respirometry systems should include an appropriate mixing device.

A high-performance liquid chromatography method for the serotonin release assay is equivalent to the radioactive method.

INTRODUCTION: The serotonin release assay (SRA) is considered the gold standard laboratory test for heparin-induced thrombocytopenia (HIT). The historic SRA method uses platelets loaded with radiolabeled serotonin to evaluate platelet activation by HIT immune complexes. However, a nonradioactive method is desirable. We report the performance characteristics of a high-performance liquid chromatography (HPLC) SRA method. METHODS: We validated the performance characteristics of an HPLC-SRA method, including correlation with a reference laboratory using the radioactive method. Serotonin released from reagent platelets was quantified by HPLC using fluorescent detection. Results were expressed as % release and classified as positive, negative, or indeterminate based on previously published cutoffs. RESULTS: Serum samples from 250 subjects with suspected HIT were tested in the HPLC-SRA and with the radioactive method. Concordant classifications were observed in 230 samples (92%). Sera from 41 healthy individuals tested negative. Between-run imprecision studies showed standard deviation of <6 (% release) for positive, weak positive, and negative serum pools. Stability studies demonstrated stability after two freeze-thaw cycles or up to a week of refrigeration. CONCLUSION: The HPLC-SRA has robust performance characteristics, equivalent to the historic radioactive method, but avoids the complexities of working with radioactivity.

A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non-valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2).

BACKGROUND: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. OBJECTIVES: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). METHODS: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose-confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. RESULTS: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. CONCLUSIONS: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered.

Percolation on fitness-dependent networks with heterogeneous resilience.

The ability to understand the impact of adversarial processes on networks is crucial to various disciplines. The objects of study in this article are fitness-driven networks. Fitness-dependent networks are fully described by a probability distribution of fitness and an attachment kernel. Every node in the network is endowed with a fitness value and the attachment kernel translates the fitness of two nodes into the probability that these two nodes share an edge. This concept is also known as mutual attractiveness. In the present article, fitness does not only serve as a measure of attractiveness, but also as a measure of a node's robustness against failure. The probability that a node fails increases with the number of failures in its direct neighborhood and decreases with higher fitness. Both static and dynamic network models are considered. Analytical results for the percolation threshold and the occupied fraction are derived. One of the results is that the distinction between the dynamic and the static model has a profound impact on the way failures spread over the network. Additionally, we find that the introduction of mutual attractiveness stabilizes the network compared to a pure random attachment.

Mutual selection in time-varying networks.

Time-varying networks play an important role in the investigation of the stochastic processes that occur on complex networks. The ability to formulate the development of the network topology on the same time scale as the evolution of the random process is important for a variety of applications, including the spreading of diseases. Past contributions have investigated random processes on time-varying networks with a purely random attachment mechanism. The possibility of extending these findings towards a time-varying network that is driven by mutual attractiveness is explored in this paper. Mutual attractiveness models are characterized by a linking function that describes the probability of the existence of an edge, which depends mutually on the attractiveness of the nodes on both ends of that edge. This class of attachment mechanisms has been considered before in the fitness-based complex networks literature but not on time-varying networks. Also, the impact of mutual selection is investigated alongside opinion formation and epidemic outbreaks. We find closed-form solutions for the quantities of interest using a factorizable linking function. The voter model exhibits an unanticipated behavior as the network never reaches consensus in the case of mutual selection but stays forever in its initial macroscopic configuration, which is a further piece of evidence that time-varying networks differ markedly from their static counterpart with respect to random processes that take place on them. We also find that epidemic outbreaks are accelerated by uncorrelated mutual selection compared to previously considered random attachment.

Network growth model with intrinsic vertex fitness.

We study a class of network growth models with attachment rules governed by intrinsic node fitness. Both the individual node degree distribution and the degree correlation properties of the network are obtained as functions of the network growth rules. We also find analytical solutions to the inverse, design, problems of matching the growth rules to the required (e.g., power-law) node degree distribution and more generally to the required degree correlation function. We find that the design problems do not always have solutions. Among the specific conditions on the existence of solutions to the design problems is the requirement that the node degree distribution has to be broader than a certain threshold and the fact that factorizability of the correlation functions requires singular distributions of the node fitnesses. More generally, the restrictions on the input distributions and correlations that ensure solvability of the design problems are expressed in terms of the analytical properties of their generating functions.

Performance of a clinical prediction score for thrombotic thrombocytopenic purpura in an independent cohort.

BACKGROUND AND OBJECTIVES: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare, clinically diagnosed disorder characterized by widespread intravascular platelet thrombosis. The pathophysiology involves acquired deficiency of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats), the enzyme responsible for cleavage of high molecular weight vonWillebrand factor multimers. Disease mortality is high, although prompt treatment with plasma exchange is generally effective. A readily available and highly reliable method of identifying ADAMTS13-deficient patients for appropriate plasma exchange is therefore of interest. MATERIALS AND METHODS: Our initial study involved the assessment of multiple clinical and laboratory variables in patients with clinically suspected TTP for whom ADAMTS13 assay was performed. Five variables were found to be of significant predictive power. This enabled the development of a point-based scoring system to efficiently determine the likelihood of TTP and response to plasma exchange in a given patient. This current study involved a separate validation cohort of patients with clinically suspected TTP who underwent ADAMTS13 testing within two large healthcare systems in Utah between 2009 and 2011. The previously derived score was applied to this cohort and its performance was analysed. Additionally, the original and validation cohorts were combined to revisit the predictive power of individual variables and the five-variable prediction score. RESULTS: A total of 84 (11 paediatric cases excluded) patients comprised the validation population. The percentage of TTP diagnoses in this group (10%) was identical to that in the initial cohort. Using an ADAMTS13 activity of <10% of normal, our original score correctly predicted or excluded severe ADAMTS13 deficiency in all patients in the second cohort when data for all variables was available. Individual variables retained predictive power and the performance of a three-variable parsimonious model, as well as the ultimate diagnoses for patients in the second cohort are described. CONCLUSION: This work confirms the predictive power of a simple point-based score to exclude TTP as evidenced by severe ADAMTS13 deficiency in appropriately selected patients. It may enable clinicians to rapidly begin plasma exchange or to pursue an alternative cause of thrombotic microangiopathy.

Antidotes and treatments for chemical warfare/terrorism agents: an evidence-based review.

This article reviews the evidence supporting the efficacy of antidotes used or recommended for the potential chemical warfare agents of most concern. Chemical warfare agents considered include cyanide, vesicants, pulmonary irritants such as chlorine and phosgene, and nerve agents. The strength of evidence for most antidotes is weak, highlighting the need for additional research in this area.

Growing trees in internet news groups and forums.

We present an empirical study of the networks created by users within internet news groups and forums and show that they organize themselves into scale-free trees. The structure of these trees depends on the topic under discussion; specialist topics have trees with a short shallow structure whereas more universal topics are discussed widely and have a deeper tree structure. For news groups we find that the distribution of the time intervals between when a message is posted and when it receives a response exhibits a composite power-law behavior. From our statistics we can see if the news group or forum is free or is overseen by a moderator. The correlation function of activity, the number of messages posted in a given time, shows long-range correlations connected with the users' daily routines. The distribution of distances between each message and its root is exponential for most news groups and power law for the forums. For both formats we find that the relation between the supremacy (the total number of nodes that are under the node i, including node i) and the degree is linear s(k) approximately k, in contrast to the analytical relation for the Barabási-Albert network.

Expression of hGC-1 is correlated with differentiation of gastric carcinoma.

AIMS: The human G-CSF-stimulated clone-1 (hGC-1) gene encodes a 510-amino acid olfactomedin-related glycoprotein whose exact in vivo localization and function still remain elusive. The aim of this study was to demonstrate hGC-1 protein localization in the normal human gastrointestinal tract and to explore further a potential relationship between hGC-1 expression and gastric carcinoma. METHODS AND RESULTS: A specific hGC-1 polyclonal antibody raised against purified hGC-1 protein was developed and characterized. Using immunohistochemistry, it was demonstrated that hGC-1 is expressed in the oesophagus, stomach, small intestine and colon. The expression pattern of hGC-1 protein in 173 cases of gastric carcinoma was investigated and a striking correlation was demonstrated between hGC-1 expression and histological type and differentiation of gastric carcinoma. Enhanced hGC-1 expression was more frequently seen in intestinal-type adenocarcinoma, whereas loss of expression tended to occur in the diffuse type. hGC-1 was highly expressed in well or moderately differentiated cancers and was remarkably reduced or lost in poorly differentiated or undifferentiated tumours. CONCLUSIONS: These investigations have defined for the first time the expression pattern of hGC-1 in the normal human gastrointestinal tract and provide a novel and sensitive marker for the differentiation of gastric carcinoma.