Pulmonary vasoconstrictor action of KCNQ potassium channel blockers

KCNQ channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ channel blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim

Network 'small-world-ness': a quantitative method for determining canonical network equivalence

Background: Many technological, biological, social, and information networks fall into the broad class of 'small-world' networks: they have tightly interconnected clusters of nodes, and a shortest mean path length that is similar to a matched random graph (same number of nodes and edges). This semi-quantitative definition leads to a categorical distinction ('small/not-small') rather than a quantitative, continuous grading of networks, and can lead to uncertainty about a network's small-world status. Moreover, systems described by small-world networks are often studied using an equivalent canonical network model-the Watts-Strogatz (WS) model. However, the process of establishing an equivalent WS model is imprecise and there is a pressing need to discover ways in which this equivalence may be quantified. Methodology/Principal Findings: We defined a precise measure of 'small-world-ness' S based on the trade off between high local clustering and short path length. A network is now deemed a 'small-world' if S. 1-an assertion which may be tested statistically. We then examined the behavior of S on a large data-set of real-world systems. We found that all these systems were linked by a linear relationship between their S values and the network size n. Moreover, we show a method for assigning a unique Watts-Strogatz (WS) model to any real-world network, and show analytically that the WS models associated with our sample of networks also show linearity between S and n. Linearity between S and n is not, however, inevitable, and neither is S maximal for an arbitrary network of given size. Linearity may, however, be explained by a common limiting growth process. Conclusions/Significance: We have shown how the notion of a small-world network may be quantified. Several key properties of the metric are described and the use of WS canonical models is placed on a more secure footing

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

Are mice good models for human neuromuscular disease? Comparing muscle excursions in walking between mice and humans

The mouse is one of the most widely used animal models to study neuromuscular diseases and test new therapeutic strategies. However, findings from successful pre-clinical studies using mouse models frequently fail to translate to humans due to various factors. Differences in muscle function between the two species could be crucial but often have been overlooked. The purpose of this study was to evaluate and compare muscle excursions in walking between mice and humans

No Benefit from Chronic Lithium Dosing in a Sibling-Matched, Gender Balanced, Investigator-Blinded Trial Using a Standard Mouse Model of Familial ALS

Background: In any animal model of human disease a positive control therapy that demonstrates efficacy in both the animal model and the human disease can validate the application of that animal model to the discovery of new therapeutics. Such a therapy has recently been reported by Fornai et al. using chronic lithium carbonate treatment and showing therapeutic efficacy in both the high-copy SOD1G93A mouse model of familial amyotrophic lateral sclerosis (ALS), and in human ALS patients. Methodology/Principal Findings: Seeking to verify this positive control therapy, we tested chronic lithium dosing in a sibling-matched, gender balanced, investigator-blinded trial using the high-copy (average 23 copies) SOD1G93A mouse (n = 27–28/group). Lithium-treated mice received single daily 36.9 mg/kg i.p. injections from 50 days of age through death. This dose delivered 1 mEq/kg (6.94 mg/kg/day lithium ions). Neurological disease severity score and body weight were determined daily during the dosing period. Age at onset of definitive disease and survival duration were recorded. Summary measures from individual body weight changes and neurological score progression, age at disease onset, and age at death were compared using Kaplan-Meier and Cox proportional hazards analysis. Our study did not show lithium efficacy by any measure. Conclusions/Significance: Rigorous survival study design that includes sibling matching, gender balancing, investigato

Pulmonary histoplasmosis presenting as chronic productive cough, fever, and massive unilateral consolidation in a 15-year-old immune-competent boy: a case report

Severe histoplasmosis is known to be among the AIDS-defining opportunistic infections affecting patients with very low CD4 cell counts in histoplasmosis-endemic areas. Histoplasma capsulatum var. duboisii is common in West and Central Africa, where it occurs in both HIV/AIDS and non-HIV patients. Few cases of life-threatening histoplasmosis in immune-competent individuals have been reported worldwide. We describe a case of pulmonary histoplasmosis diagnosed on the basis of autopsy and histological investigations. A 15-year old East African immune-competent boy with a history of smear-positive tuberculosis and a two-year history of rock cutting presented to our hospital with chronic productive cough, fever, and massive unilateral consolidation. At the time of presentation to our hospital, this patient was empirically treated for recurrent tuberculosis without success, and he died on the seventh day after admission. The autopsy revealed a huge granulomatous lesion with caseation, but no acid-fast bacilli were detected on several Ziehl-Neelsen stains. However, periodic acid-Schiff staining was positive, and the histological examination revealed features suggestive of Histoplasma yeast cells. Severe pulmonary histoplasmosis should be considered in evaluating immune-competent patients with risk factors for the disease who present with pulmonary symptoms mimicking tuberculosis

Well-being outcomes of marine protected areas

Marine protected areas are advocated as a key strategy for simultaneously protecting marine biodiversity and supporting coastal livelihoods, but their implementation can be challenging for numerous reasons, including perceived negative effects on human well-being. We synthesized research from 118 peer-reviewed articles that analyse outcomes related to marine protected areas on people, and found that half of documented well-being outcomes were positive and about one-third were negative. No-take, well-enforced and old marine protected areas had positive human well-being outcomes, which aligns with most findings from ecological studies. Marine protected areas with single zones had more positive effects on human well-being than areas with multiple zones. Most studies focused on economic and governance aspects of well-being, leaving social, health and cultural domains understudied. Well-being outcomes arose from direct effects of marine protected area governance processes or management actions and from indirect effects mediated by changes in the ecosystem. Our findings illustrate that both human well-being and biodiversity conservation can be improved through marine protected areas, yet negative impacts commonly co-occur with benefits

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

Carbon sequestration via wood burial

To mitigate global climate change, a portfolio of strategies will be needed to keep the atmospheric CO2 concentration below a dangerous level. Here a carbon sequestration strategy is proposed in which certain dead or live trees are harvested via collection or selective cutting, then buried in trenches or stowed away in above-ground shelters. The largely anaerobic condition under a sufficiently thick layer of soil will prevent the decomposition of the buried wood. Because a large flux of CO2 is constantly being assimilated into the world's forests via photosynthesis, cutting off its return pathway to the atmosphere forms an effective carbon sink

Experiencing neutropenia: Quality of life interviews with adult cancer patients

BACKGROUND: Neutropenia is a common toxicity in chemotherapy but detailed information about how neutropenia is associated with changes in patients' quality of life is not readily available. This prospective study interviewed patients with grade 4 neutropenia to provide qualitative information on patients' experience of developing and coping with grade 4 neutropenia during a cycle of chemotherapy. METHODS: A sample of 34 patients who developed grade 4 neutropenia during the first cycle of chemotherapy completed a total of 100 structured clinical interviews. Interviews were transcribed, and 2 raters inductively developed 5 broad categories comprising 80 specific complaint domains nominated by patients. Thirty-five patient-nominated problems were mentioned in 5% or more of the interviews. RESULTS: Fatigue was the most common physical symptom. Interference in daily routine, negative self-evaluation, negative emotion, and social isolation were other common complaints associated with neutropenia. CONCLUSION: Neutropenia is associated with a number of negative experiences among cancer patients undergoing chemotherapy, and these negative experiences have an adverse effect on the patient's quality of life. Oncology nurses can play a key role in helping patients manage adverse effects to maintain their quality of life