Rates for repair of pBR 322 DNA radicals by thiols as measured by the gas explosion technique: evidence that counter-ion condensation and co-ion depletion are significant at physiological ionic strength.

Rates of rapair of pBR 322 plasmid DNA radicals by thiols of varying net charge (Z) at pH 7 and physiological ionic strength were measured using the oxygen explosion technique. The extent of conversion of supercoiled to relaxed circular plasmid was measured by HPLC as a function of the time of oxygen exposure before or after irradiation, the time-courses being fitted by a pseudo-first-order kinetic expression with k1 = k2[RSH]. Values of k2 (M-1 S-1) were: 2.1 x 10(5) (GSH, Z = -1), 1.4 x 10(6) (2-mercaptoethanol, Z = 0), 1.2 x 10(7) (cysteamine, Z = +1), 6.6 x 10(7) (WR-1065 or N-(2-mercaptoethyl)-1,3-diamino?? propane, Z = +2). The approximately 6-fold increase in rate with each unit increase in Z is attributed to concentration of cationic thiols near DNA as a consequence of counter-ion condensation and reduced levels of anionic thiols near DNA owing to co-ion depletion. The results are quantitatively consistent with chemical repair as a significant mechanism for radioprotection of cells by neutral and cationic thiols under aerobic conditions, but indicate that repair by GSH will compete effectively with oxygen only at low oxygen tension.

Physiological effects of platyhelminth FMRFamide-related peptides (FaRPs) on the motility of the monogenean Diclidophora merlangi

The actions of known platyhelminth FaRPs on the contractility of whole-worm preparations of the monogenean, Diclidophora merlangi have been examined in vitro for the first time. All of the peptides tested had excitatory effects on the motor activity of the worm. The order of potency for the peptides tested was: YIRFamide > GYIRFamide = RYIRFamide > GNFFRFamide = FLRFamide. However, although YIRFamide was more potent than GYIRFamide, the latter was the most efficacious on each of the motility parameters (tension, contraction amplitude and contraction frequency) examined at concentrations greater than or equal to 0.1 mu M. Serotonin, which stimulates contractility in the worm was used as a positive control. The excitatory activity of turbellarian and cestode neuropeptides on a monogenean indicates at least some structural similarities in the neuropeptide receptors of these classes of flatworm.

Physiological effects of platyhelminth RFamide peptides on muscle-strip preparations of Fasciola hepatica (Trematoda: Digenea)

The effects of each of the known platyhelminth neuropeptides were determined on muscle-strip preparations from the liver fluke, Fasciola hepatica. The activity of synthetic replicates of the C-terminal nonapeptide of neuropeptide F (NPF9, Moniezia expansa), and the FMRFamide-related peptides (FaRPs), GNFFRFamide, RYIRFamide, GYIRFamide and YIRFamide, were examined. Muscle-strip activity was recorded from 1 mm segments of muscle prepared from 28 to 32-day-old worms, using a photo-optic transducer system. None of the peptides (less than or equal to 10 mu M) altered baseline tension significantly; however, each of the peptides increased the amplitude and frequency of muscle contraction. The threshold for activity of each of the peptides examined was, respectively, 1 nM (RYIRFamide), 0.3 mu M (GYIRFamide and YIRFamide), and 10 mu M (GNFFRFamide and NPF9). All of the effects were reversible and repeatable, following wash-out. Muscle-strip integrity was tested following experimentation, using arecoline (10 mu M) and high-K+ bathing medium (90 mM K+).

Constitutive and Treatment-Induced CXCL8-Signalling Selectively Modulates the Efficacy of Anti-Metabolite Therapeutics in Metastatic Prostate Cancer

Background: The current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent.

Methods: The response of metastatic CaP cells to 5-Fluorouracil (5-FU), Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to determine effects of drugs or CXCL8 administration on target gene/protein expression.

Results: Administration of 5-FU but not pemetrexed potentiated CXCL8 secretion and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P,0.001), and increased 5-FU-induced apoptosis in PC3 cells (P,0.01). In contrast, while administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent experiments confirmed that administration of recombinant human CXCL8 increased TS expression, a response mediated in part by the CXCR2 receptor. Moreover, siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the sensitivity of PC3 cells to 5-FU.

Conclusions: CXCL8 signaling provides a selective resistance of metastatic prostate cancer cells to specific anti-metabolites by promoting a target-associated resistance, in addition to underpinning an evasion of treatment-induced apoptosis. © 2012 Wilson et al.

Methodology for Validating Artifact Removal Techniques for Physiological Signals

Artifact removal from physiological signals is an essential component of the biosignal processing pipeline. The need for powerful and robust methods for this process has become particularly acute as healthcare technology deployment undergoes transition from the current hospital-centric setting toward a wearable and ubiquitous monitoring environment. Currently, determining the relative efficacy and performance of the multiple artifact removal techniques available on real world data can be problematic, due to incomplete information on the uncorrupted desired signal. The majority of techniques are presently evaluated using simulated data, and therefore, the quality of the conclusions is contingent on the fidelity of the model used. Consequently, in the biomedical signal processing community, there is considerable focus on the generation and validation of appropriate signal models for use in artifact suppression. Most approaches rely on mathematical models which capture suitable approximations to the signal dynamics or underlying physiology and, therefore, introduce some uncertainty to subsequent predictions of algorithm performance. This paper describes a more empirical approach to the modeling of the desired signal that we demonstrate for functional brain monitoring tasks which allows for the procurement of a ground truth signal which is highly correlated to a true desired signal that has been contaminated with artifacts. The availability of this ground truth, together with the corrupted signal, can then aid in determining the efficacy of selected artifact removal techniques. A number of commonly implemented artifact removal techniques were evaluated using the described methodology to validate the proposed novel test platform. © 2012 IEEE.

Double blind cross-over placebo controlled study of omeprazole in the treatment of patients with reflux symptoms and physiological levels of acid reflux--the "sensitive oesophagus"

At least 10-15% of patients with reflux symptoms have a normal endoscopy and physiological levels of acid reflux on pH monitoring. Such patients with 50% or more of symptoms associated with acid reflux episodes have "a positive symptom index" (SI), and it has been proposed that this defines the "sensitive oesophagus".

Physiological correlates of memory recall in infancy:vagal tone, cortisol, and imitation in preterm and full-term infants at 6 months

We examined the role of physiological regulation (heart rate, vagal tone, and salivary cortisol) in short-term memory in preterm and full-term 6-month-old infants. Using a deferred imitation task to evaluate social learning and memory recall, an experimenter modeled three novel behaviors (removing, shaking, and replacing a glove) on a puppet. Infants were tested immediately after being shown the behaviors as well as following a 10-min delay. We found that greater suppression of vagal tone was related to better memory recall in full-term infants tested immediately after the demonstration as well as in preterm infants tested later after a 10-min delay. We also found that preterm infants showed greater coordination of physiology (i.e., tighter coupling of vagal tone, heart rate, and cortisol) at rest and during retrieval than full-term infants. These findings provide new evidence of the important links between changes in autonomic activity and memory recall in infancy. They also raise the intriguing possibility that social learning, imitation behavior, and the formation of new memories are modulated by autonomic activity that is coordinated differently in preterm and full-term infants.

Pain in the preterm neonate:behavioural and physiological indices

The impact of invasive procedures on preterm neonates has received little systematic attention. We examined facial activity, body movements, and physiological measures in 56 preterm and full-term newborns in response to heel lancing, along with comparison preparatory and recovery intervals. The measures were recorded in special care and full-term nurseries during routine blood sampling. Data analyses indicated that in all measurement categories reactions of greatest magnitude were to the lancing procedure. Neonates with gestational ages as short as 25-27 weeks displayed physiological responsivity to the heel lance, but only in the heart rate measure did this vary with gestational age. Bodily activity was diminished in preterm neonates in general, relative to full-term newborns. Facial activity increased with the gestational age of the infant. Specificity of the response to the heel lance was greatest on the facial activity measure. Identification of pain requires attention to gestational age in the preterm neonate.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomised placebo controlled trial

OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy.

BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI.

METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio.

RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P = 0.1).

CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

A direct physiological trade-off between personal and social immunity

1. Recent work shows that organisms possess two strategies of immune response: personal immunity, which defends an individual, and social immunity, which protects other individuals, such as kin. However, it is unclear how individuals divide their limited resources between protecting themselves and protecting others.
2. Here, with experiments on female burying beetles, we challenged the personal immune system and measured subsequent investment in social immunity (antibacterial activity of the anal exudates).
3. Our results show that increased investment in one aspect of personal immunity (wound repair) causes a temporary decrease in one aspect of the social immune response.
4. Our experiments further show that by balancing investment in personal and social immunity in this way during one breeding attempt, females are able to defend their subsequent lifetime reproductive success.
5. We discuss the nature of the physiological trade-off between personal and social immunity in species that differ in the degree of eusociality and coloniality, and suggest that it may also vary within species in relation to age and partner contributions to social immunity.

Behavioural and physiological responses of heifer calves to acute stressors: long-term consistency and relationship with adult reactivity to milking

The present study investigated the long-term consistency of individual differences in dairy cattles’ responses in tests of behavioural and hypothalamo–pituitary–adrenocortical (HPA) axis reactivity, as well as the relationship between responsiveness in behavioural tests and the reaction to first milking. Two cohorts of heifer calves, Cohorts 1 (N = 25) and 2 (N = 16), respectively, were examined longitudinally from the rearing period until adulthood. Cohort 1 heifers were subjected to open field (OF), novel object (NO), restraint, and response to a human tests at 7 months of age, and were again observed in an OF test during first pregnancy between 22 and 24 months of age. Subsequently, inhibition of milk ejection and stepping and kicking behaviours were recorded in Cohort 1 heifers during their first machine milking. Cohort 2 heifers were individually subjected to OF and NO tests as well as two HPA axis reactivity tests (determining ACTH and/or cortisol response profiles after administration of exogenous CRH and ACTH, respectively) at 6 months of age and during first lactation at approximately 29 months of age. Principal component analysis (PCA) was used to condense correlated response measures (to behavioural tests and to milking) within ages into independent dimensions underlying heifers’ reactivity. Heifers demonstrated consistent individual differences in locomotion and vocalisation during an OF test from rearing to first pregnancy (Cohort 1) or first lactation (Cohort 2). Individual differences in struggling in a restraint test at 7 months of age reliably predicted those in OF locomotion during first pregnancy in Cohort 1 heifers. Cohort 2 animals with high cortisol responses to OF and NO tests and high avoidance of the novel object at 6 months of age also exhibited enhanced cortisol responses to OF and NO tests at 29 months of age. Measures of HPA axis reactivity, locomotion, vocalisation and adrenocortical and behavioural responses to novelty were largely uncorrelated, supporting the idea that stress responsiveness in dairy cows is mediated by multiple independent underlying traits. Inhibition of milk ejection and stepping and kicking behaviours during first machine milking were not related to earlier struggling during restraint, locomotor responses to OF and NO tests, or the behavioural interaction with a novel object. Heifers with high rates of OF and NO vocalisation and short latencies to first contact with the human at 7 months of age exhibited better milk ejection during first machine milking. This suggests that low underlying sociality might be implicated in the inhibition of milk ejection at the beginning of lactation in heifers.