Division of labour in honey bees: age‐ and task‐related changes in the expression of octopamine receptor genes

The honey bee (Apis mellifera L.) has developed into an important ethological model organism for social behaviour and behavioural plasticity. Bees perform a complex age‐dependent division of labour with the most pronounced behavioural differences occurring between in‐hive bees and foragers. Whereas nurse bees, for example, stay inside the hive and provide the larvae with food, foragers leave the hive to collect pollen and nectar for the entire colony. The biogenic amine octopamine appears to play a major role in division of labour but the molecular mechanisms involved are unknown. We here investigated the role of two characterized octopamine receptors in honey bee division of labour. AmOctαR1 codes for a Ca²⁺‐linked octopamine receptor. AmOctβR3/4 codes for a cyclic adenosine monophosphate‐coupled octopamine receptor. Messenger RNA expression of AmOctαR1 in different brain neuropils correlates with social task, whereas expression of AmOctβR3/4 changes with age rather than with social role per se. Our results for the first time link the regulatory role of octopamine in division of labour to specific receptors and brain regions. They are an important step forward in our understanding of complex behavioural organization in social groups.     

Cost‐utility analysis of bevacizumab versus ranibizumab in neovascular age‐related macular degeneration using a Markov model

Objective To evaluate the cost‐effectiveness of intravitreal bevacizumab to ranibizumab in patients with neovascular age‐related macular degeneration (AMD). Methods A cost‐utility analysis using a Markov model was performed to evaluate incremental cost‐effectiveness ratio [ICER, $US per quality‐adjusted life year (QALY) gained] between bevacizumab and ranibizumab from a US payer perspective. Transition probabilities for ranibizumab and bevacizumab were extrapolated from published studies and local institutional data. Utility values, likewise, were obtained from another published study. Mortality rates were determined from the Centers for Disease Control 2003 Life Tables. Resource utilization and total direct costs were estimated using the Centers for Medicare and Medicaid Services and the Veterans Affairs Decision Support System. A hypothetical cohort of 1000 patients was simulated through the model for 20 years. Sensitivity analyses were performed using univariate and probabilistic sensitivity analysis (PSA) on all costs, transition probabilities and utility values. An acceptability curve was generated to illustrate the cost‐effectiveness probability of bevacizumab to ranibizumab with increasing willingness‐to‐pay (WTP). Results The cost‐effectiveness ratios (CER) for bevacizumab and ranibizumab were $1405 per QALY and $12 177 per QALY, respectively. The ICER for bevacizumab was dominant compared to ranibizumab. The base‐case CER was sensitive to drug costs of the study medications with a breakeven point of $44 for ranibizumab and $2666 for bevacizumab. PSA revealed a 95% probability of bevacizumab being more cost‐effective than ranibizumab at a WTP of $50 000 per QALY gained. Conclusion Based on a WTP defined at $50 000 per QALY gained, bevacizumab was cost‐effective versus ranibizumab 95% of the time because of lower acquisition costs and increased efficacy.     

Phosphorylation of spinal N‐methyl‐d‐aspartate receptor NR1 subunits by extracellular signal‐regulated kinase in dorsal horn neurons and microglia contributes to diabetes‐induced painful neuropathy

The N‐methyl‐d ‐aspartate receptor (NMDAR) contributes to central sensitization in the spinal cord, a phenomenon which comprises various pathophysiological mechanisms responsible for neuropathic pain‐like signs in animal models. NMDAR function is modulated by post‐translational modifications including phosphorylation, and this is proposed to underlie its involvement in the production of pain hypersensitivity. As in diabetic patients, streptozotocin‐induced diabetic rats exhibit or not somatic mechanical hyperalgesia; these rats were named DH and DNH respectively. At three weeks of diabetes, we present evidence that somatic mechanical hyperalgesia was correlated with an enhanced phosphorylation of the NMDAR NR1 subunit (pNR1) in the rat spinal cord. This increase was not found in normal and DNH rats, suggesting that this regulation was specific to hyperalgesia. Double immunofluorescence studies revealed that the numbers of pNR1‐immunoreactive neurons and microglial cells were significantly increased in all laminae (I—II and III—VI) of the dorsal horn from DH animals. Western‐blots analysis showed no change in NR1 protein levels, whatever the behavioural and glycemic status of the animals. Chronic intrathecal treatment (5μg/rat/day for 7 days) by U0126 and MK801, which blocked MEK (an upstream kinase of extracellular signal‐regulated protein kinase: ERK) and the NMDAR respectively, simultaneously suppressed somatic mechanical hyperalgesia developed by diabetic rats and decreased pNR1. These results indicate for the first time that increased expression of pNR1 is regulated by ERK and the NMDAR via a feedforward mechanism in spinal neurons and microglia and represents one mechanism involved in central sensitization and somatic mechanical hyperalgesia after diabetes.     

Depletion of capsaicin sensitive afferents prevents lamina‐dependent increases in spinal N‐methyl‐d‐aspartate receptor subunit 1 expression and phosphorylation associated with thermal hyperalgesia in neuropathic rats

Phosphorylation of the N‐methyl‐d ‐aspartate (NMDA) receptor NR1 subunit (pNR1) in the spinal cord is associated with increased neuronal responsiveness, which underlies the process of central sensitization. Because of the importance of NR1 in central sensitization, the first goal of this study was to examine both time‐ and lamina‐dependent changes in spinal NR1 and pNR1 expression in a chronic constriction injury (CCI) model of neuropathic pain. Increased excitability of capsaicin sensitive primary afferents (CSPAs), which express TRPV1 receptors, also contributes to central sensitization. Thus, we next examined whether the depletion of CSPAs with resiniferatoxin (RTX) modified the change of spinal NR1 and pNR1 expression induced by CCI. Experimental rats were euthanized at 1, 3, 7, 14, and 28 days post‐CCI surgery and spinal cords processed for NR1 or pNR1 immunostaining. The number of NR1 or pNR1‐immunoreactive neurons was significantly increased in all lamina (I–VI) of the ipsilateral L4/L5 dorsal horn from 1 or 7 days post‐CCI, respectively. Pretreatment with RTX (0.3mg/kg, s.c. in the scruff of the neck or intraplantar) 2 days prior to CCI completely prevented induction of thermal hyperalgesia, but not mechanical allodynia in neuropathic rats. Interestingly, RTX treatment significantly attenuated the CCI‐induced upregulation of NR1 and pNR1 in spinal laminae I–II and V–VI, but not laminae III–IV as compared with that of vehicle‐treated CCI rats. These findings demonstrate that the increased expression of NR1 and pNR1 in spinal laminae I–II and V–VI is dependent on activation of CSPAs, which ultimately contribute to the development of thermal hyperalgesia in neuropathic rats.     

Temporal age‐related changes in spectral,fractal and complexity characteristics of heart rate variability

Cross‐sectional studies have suggested that heart rate (HR) variability, analysed using traditional time and frequency domain methods, is related to ageing, but no longitudinal studies have estimated the age dependence of HR fluctuation. This study evaluated temporal age‐related changes in 12‐h measures of HR variability among 109 patients with coronary artery disease (CAD), who underwent repeat Holter recordings at 32‐month intervals. Time and frequency domain measures, along with fractal and complexity measures of HR variability, were determined at the baseline and after 32 months. Changes in HR dynamics were compared with various laboratory variables, exercise data and angiographic progression of CAD. Traditional time and frequency domain measures of HR variability did not change significantly during the follow‐up, but the power‐law scaling slope decreased from ?1·29 ± 0·20 to ?1·36 ± 0·23 (P<0·01) and the short‐term fractal exponent (α₁) of HR dynamics from 1·29 ± 0·14–1·22 ± 0·18 (P<0·001). The approximate entropy value also decreased from 1·00 ± 0·19 to 0·95 ± 0·18 (P<0·05). The changes in HR behaviour were not related to demographic data, laboratory values or angiographic progression of CAD. Only a weak correlation was observed between the change in the power‐law slope and the baseline glucose value (P<0·05). This longitudinal study shows that the fractal characteristics of HR dynamics and the complexity properties of R‐R intervals undergo rapid changes along with ageing, and that fractal and complexity analysis techniques are more sensitive than traditional analysis methods in documenting temporal age‐related changes in HR behaviour.     

Performance of age‐adjusted D‐dimer cut‐off to rule out pulmonary embolism

Summary: Background: Age‐adjusted D‐dimer cut‐off has recently been proposed to increase D‐dimer usefulness in older patients suspected of pulmonary embolism (PE). Objective: We externally validated this age‐adjusted D‐dimer cut‐off using different D‐dimer assays in a multicenter sample of emergency department patients. Methods: Secondary analysis of three prospectively collected databases (two European, one American) of patients suspected of having PE. D‐dimer performance for ruling out PE was assessed by calculating negative likelihood ratio (nLR) for D‐dimer with age‐adjusted D‐dimer cut‐off (< age × 10 in patients over 50 years) and with conventional cut‐off (< 500 μg dL^?1). Test efficiency was assessed by the number needed to test (NNT) to rule out PE in one patient. Results: Among 4537 patients included, overall PE prevalence was 10.1%. In the overall population, nLR was 0.06 (95% confidence interval, 0.03–0.09) with conventional cut‐off and 0.08 (0.05–0.12) with age‐adjusted cut‐off. Using age‐adjusted cut‐off, nLR was 0.08, 0.09 and 0.06 for Vidas^®, Liatest^® and MDA^® assays, respectively. Use of age‐adjusted cut‐off produced a favorable effect on NNT in the elderly; the greatest decrease was observed in patients > 75 years: NTT halved from 8.1 to 3.6. The proportion of patients over 75 years with normal D‐dimer was doubled (27.9% vs. 12.3%). Conclusions: Our study shows that age‐adjusted D‐dimer had low nLR, allowing its use as a rule‐out PE strategy in non‐high pretest clinical probability patients, as well as using Vidas^®, Liatest^® or MDA^® assays. This age‐adjusted cut‐off increased clinical usefulness of D‐dimer in older patients. A large prospective study is required to confirm these results.     

Systemic administration of adenosine ameliorates pentylenetetrazol-induced chemical kindling and secondary behavioural and biochemical changes in mice

Adenosine is one of the inhibitory neuromodulators in the brain and is considered to be responsible for seizure arrest and postictal refractoriness. Adenosine, adenosine receptor agonists, and adenosine uptake blockers are known to reduce the severity and duration of amygdala-kindled seizures. The present study was carried out to elucidate the anticonvulsant and neuromodulatory effect of systemic adenosine on the pentylenetetrazol (PTZ)-induced chemical kindling in mice. Kindling was induced by chronic administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.) on every other day for a total period of 9 days. Adenosine was administered daily, 30 min before PTZ or vehicle. The kindling score was recorded immediately following PTZ administration according to a prevalidated scoring scale. Various behavioral and biochemical estimations were performed on day 10 (i.e. 24 h after the last dose of PTZ). Chronic PTZ treatment progressively increased the seizure score with the maximum score reached on day 9. Behavioral analysis found hyperlocomotor activity, anxiogenic response, hyperalgesia and amnesia in kindled mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation (malondialdehyde levels), nitrite (NO(2-) levels), adenosine deaminase (ADA) and total RNA levels and decreased catalase, reduced glutathione (GSH) levels in brain homogenates, and a depletion of adrenal ascorbic acid. Daily treatment with adenosine (25 and 50 mg/kg, i.p.) for 9 days led to a significant decrease in PTZ-induced kindling score and also reversed various behavioral and biochemical alterations produced by PTZ. The results of the present study suggested that systemic adenosine administration reversed the behavioral and biochemical alterations induced by chronic PTZ.     

Evaluation of the age‐dependent dosing recommendations for the administration of daily tinzaparin in children with thrombosis

Essentials

• The once‐daily dosing of tinzaparin provides an advantage over other low molecular weight heparins.
• The recommended age‐dependent doses of tinzaparin in children have not previously been validated.
• Once‐daily administration of tinzaparin is a safe and effective treatment of childhood thrombosis.
• Recommended doses are appropriate but monitoring may be required due to inter‐individual variation.