The effect of sepsis and its inflammatory response on mechanical clot characteristics: a prospective observational study

Purpose: Sepsis and its progression are known to have a major influence on the coagulation system. Current coagulation tests are of limited use when assessing coagulation in sepsis patients. This study aims to assess the potential for a new functional biomarker of clot microstructure, fractal dimension, to identify changes in the mechanical properties of clot microstructure across the sepsis spectrum (sepsis, severe sepsis and septic shock). Methods: A total of 100 patients that presented acutely to a large teaching hospital were included in this prospective observational study (50 sepsis, 20 severe sepsis and 30 septic shock) against a matched control of 44 healthy volunteers. Fractal analysis was performed, as well as standard markers of coagulation, and six plasma markers of inflammation. Results: Fractal dimension was significantly higher in the sepsis and severe sepsis groups than the healthy control (1.78 ± 0.07 and 1.80 ± 0.05 respectively vs 1.74 ± 0.03) (p < 0.001), indicating a significant increase in mechanical clot strength and elasticity consistent with a hypercoagulable state. Conversely, fractal dimension was significantly lower in septic shock (1.66 ± 0.10, p < 0.001), indicating a significant reduction in mechanical clot strength and functionality consistent with a hypocoagulable state. This corresponded with a significant increase in the inflammatory response. Conclusions: This study confirms that clot microstructure is significantly altered through the various stages of sepsis. Of particular importance was the marked change in clot development between severe sepsis and septic shock, which has not been previously reported

Do female association preferences predict the likelihood of reproduction?

Sexual selection acting on male traits through female mate choice is commonly inferred from female association preferences in dichotomous mate choice experiments. However, there are surprisingly few empirical demonstrations that such association preferences predict the likelihood of females reproducing with a particular male. This information is essential to confirm association preferences as good predictors of mate choice. We used green swordtails (&lt;i&gt;Xiphophorus helleri&lt;/i&gt;) to test whether association preferences predict the likelihood of a female reproducing with a male. Females were tested for a preference for long- or short-sworded males in a standard dichotomous choice experiment and then allowed free access to either their preferred or non-preferred male. If females subsequently failed to produce fry, they were provided a second unfamiliar male with similar sword length to the first male. Females were more likely to reproduce with preferred than non-preferred males, but for those that reproduced, neither the status (preferred/non-preferred) nor the sword length (long/short) of the male had an effect on brood size or relative investment in growth by the female. There was no overall preference based on sword length in this study, but male sword length did affect likelihood of reproduction, with females more likely to reproduce with long- than short-sworded males (independent of preference for such males in earlier choice tests). These results suggest that female association preferences are good indicators of female mate choice but that ornament characteristics of the male are also important

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing

Cisplatin anti-tumour potentiation by tirapazamine results from a hypoxia-dependent cellular sensitization to cisplatin

Tirapazamine (TPZ) is a new anticancer drug that is activated specifically at the low oxygen level typically found in solid tumours. It exhibits preferential cytotoxicity towards hypoxic cells and has been shown in preclinical studies with transplanted tumours and in phase II and III clinical trials to potentiate the anti-tumour efficacy of cisplatin without increasing its systemic toxicity. At present, the mechanism for this potentiation is unknown. Here we show that there is a schedule-dependent enhancement of cisplatin cytotoxicity by TPZ for cells in vitro that is similar to that seen with transplanted murine tumours. This cisplatin potentiation depends on the TPZ exposure being at oxygen concentrations below 1%, which are typical of many cells in tumours but not in normal tissues. Also, the interaction between TPZ and cisplatin does not occur in cells mutant in ERCC4, a protein essential for repair of DNA interstrand cross-links. Incubation of the cells with TPZ under hypoxia prior to cisplatin treatment increases cisplatin-induced DNA interstrand cross-links with kinetics suggesting that TPZ inhibits or delays repair of the DNA cross-links. In conclusion, we show that the tumour-specific potentiation of cisplatin cytotoxicity is likely the result of an interaction between TPZ and cisplatin at the cellular level that requires the low oxygen levels typical of those in solid tumours. The mechanism of the interaction appears to be through a potentiation of cisplatin-induced DNA interstrand cross-links, possibly as a result of a diminished or delayed repair of these lesion

Aqueous tear assessment in dogs: Impact of cephalic conformation, inter‐test correlations, and test‐retest repeatability

Objective - To characterize diagnostic findings, test‐retest repeatability, and correlations among lacrimal tests in dogs of diverse cephalic conformations. Animal studied - Fifty healthy dogs (25 brachycephalic, 25 nonbrachycephalic). Procedures - A series of diagnostics were performed in each dog, allowing for a 10‐minute interval between tests and repeating each test 24 hours later under similar conditions: corneal tactile sensation (CTS), strip meniscometry test (SMT), phenol red thread test (PRTT), endodontic absorbent paper point tear test (EAPPTT), Schirmer tear test‐1 without (STT‐1) or with nasolacrimal stimulation (NL‐STT1), and Schirmer tear test‐2 (STT‐2). Results - Mean ± SD test values were lower in brachycephalic vs. nonbrachycephalic dogs (except for SMT; 7.4 ± 2.0 mm/5 seconds vs 7.3 ± 2.4 mm/5 seconds), with statistically significant differences noted for CTS (1.8 ± 0.5 cm vs 3.4 ± 0.8 cm), PRTT (37.2 ± 4.0 mm/15 seconds vs 41.1 ± 5.5 mm/15 seconds), STT‐1 (20.1 ± 3.4 mm/min vs 23.3 ± 5.7 mm/min), STT‐2 (13.0 ± 3.4 mm/min vs 16.9 ± 3.9 mm/min), and NL‐STT1 (23.2 ± 3.6 mm/min vs 27.1 ± 5.4 mm/min), and nonsignificant differences for EAPPTT (16.6 ± 2.7 mm/15 seconds vs 17.5 ± 2.9 mm/15 seconds). Nasolacrimal stimulation increased STT‐1 values by 18% on average. Correlations among tests were generally weak to moderate (r \u3c .70) except for a strong correlation between STT‐1 and NL‐STT1 (r = .83, P \u3c .001). Test reliability was good although test‐retest repeatability was generally poor to moderate, as depicted by low intraclass correlation coefficients (ICC ≤ 0.75) and wide 95% limits of agreement, except for CTS (ICC = 0.91). Conclusions - Corneal sensitivity and aqueous tear secretion are lower in brachycephalic dogs. A comprehensive assessment of the ocular surface requires the combination of several diagnostic tests. The nasolacrimal reflex may provide a useful diagnostic and therapeutic tool in dogs

Characterisation of Innate Fungal Recognition in the Lung

The innate recognition of fungi by leukocytes is mediated by pattern recognition receptors (PRR), such as Dectin-1, and is thought to occur at the cell surface triggering intracellular signalling cascades which lead to the induction of protective host responses. In the lung, this recognition is aided by surfactant which also serves to maintain the balance between inflammation and pulmonary function, although the underlying mechanisms are unknown. Here we have explored pulmonary innate recognition of a variety of fungal particles, including zymosan, Candida albicans and Aspergillus fumigatus, and demonstrate that opsonisation with surfactant components can limit inflammation by reducing host-cell fungal interactions. However, we found that this opsonisation does not contribute directly to innate fungal recognition and that this process is mediated through non-opsonic PRRs, including Dectin-1. Moreover, we found that pulmonary inflammatory responses to resting Aspergillus conidia were initiated by these PRRs in acidified phagolysosomes, following the uptake of fungal particles by leukocytes. Our data therefore provides crucial new insights into the mechanisms by which surfactant can maintain pulmonary function in the face of microbial challenge, and defines the phagolysosome as a novel intracellular compartment involved in the innate sensing of extracellular pathogens in the lung

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures

The "Ram Effect": A "Non-Classical" Mechanism for Inducing LH Surges in Sheep

During spring sheep do not normally ovulate but exposure to a ram can induce ovulation. In some ewes an LH surge is induced immediately after exposure to a ram thus raising questions about the control of this precocious LH surge. Our first aim was to determine the plasma concentrations of oestradiol (E2) E2 in anoestrous ewes before and after the "ram effect" in ewes that had a "precocious" LH surge (starting within 6 hours), a "normal" surge (between 6 and 28h) and "late» surge (not detected by 56h). In another experiment we tested if a small increase in circulating E2 could induce an LH surge in anoestrus ewes. The concentration of E2 significantly was not different at the time of ram introduction among ewes with the three types of LH surge. "Precocious" LH surges were not preceded by a large increase in E2 unlike "normal" surges and small elevations of circulating E2 alone were unable to induce LH surges. These results show that the "precocious" LH surge was not the result of E2 positive feedback. Our second aim was to test if noradrenaline (NA) is involved in the LH response to the "ram effect". Using double labelling for Fos and tyrosine hydroxylase (TH) we showed that exposure of anoestrous ewes to a ram induced a higher density of cells positive for both in the A1 nucleus and the Locus Coeruleus complex compared to unstimulated controls. Finally, the administration by retrodialysis into the preoptic area, of NA increased the proportion of ewes with an LH response to ram odor whereas treatment with the α1 antagonist Prazosin decreased the LH pulse frequency and amplitude induced by a sexually active ram. Collectively these results suggest that in anoestrous ewes NA is involved in ram-induced LH secretion as observed in other induced ovulators