AMPK Signalling and Defective Energy Metabolism in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is caused by selective loss of upper and lower motor neurons by complex mechanisms that are incompletely understood. Motor neurons are large, highly polarised and excitable cells with unusually high energetic demands to maintain resting membrane potential and propagate action potentials. This leads to higher ATP consumption and mitochondrial metabolism in motor neurons relative to other cells. Here, we review increasing evidence that defective energy metabolism and homeostasis contributes to selective vulnerability and degeneration of motor neurons in ALS. Firstly, we provide a brief overview of major energetic pathways in the CNS, including glycolysis, oxidative phosphorylation and the AMP-activated protein kinase (AMPK) signalling pathway, while highlighting critical metabolic interactions between neurons and astrocytes. Next, we review evidence from ALS patients and transgenic mutant SOD1 mice for weight loss, hypermetabolism, hyperlipidemia and mitochondrial dysfunction in disease onset and progression. Genetic and therapeutic modifiers of energy metabolism in mutant SOD1 mice will also be summarised. We also present evidence that additional ALS-linked proteins, TDP-43 and FUS, lead to energy disruption and mitochondrial defects in motor neurons. Lastly, we review emerging evidence including our own that dysregulation of the AMPK signalling cascade in motor neurons is an early and common event in ALS pathogenesis. We suggest that an imbalance in energy metabolism should be considered an important factor in both progression and potential treatment of ALS.     

Regional and seasonal variation in airborne grass pollen levels between cities of Australia and New Zealand

Although grass pollen is widely regarded as the major outdoor aeroallergen source in Australia and New Zealand (NZ), no assemblage of airborne pollen data for the region has been previously compiled. Grass pollen count data collected at 14 urban sites in Australia and NZ over periods ranging from 1 to 17 years were acquired, assembled and compared, revealing considerable spatiotemporal variability. Although direct comparison between these data is problematic due to methodological differences between monitoring sites, the following patterns are apparent. Grass pollen seasons tended to have more than one peak from tropics to latitudes of 37°S and single peaks at sites south of this latitude. A longer grass pollen season was therefore found at sites below 37°S, driven by later seasonal end dates for grass growth and flowering. Daily pollen counts increased with latitude; subtropical regions had seasons of both high intensity and long duration. At higher latitude sites, the single springtime grass pollen peak is potentially due to a cooler growing season and a predominance of pollen from C₃ grasses. The multiple peaks at lower latitude sites may be due to a warmer season and the predominance of pollen from C₄ grasses. Prevalence and duration of seasonal allergies may reflect the differing pollen seasons across Australia and NZ. It must be emphasized that these findings are tentative due to limitations in the available data, reinforcing the need to implement standardized pollen-monitoring methods across Australasia. Furthermore, spatiotemporal differences in grass pollen counts indicate that local, current, standardized pollen monitoring would assist with the management of pollen allergen exposure for patients at risk of allergic rhinitis and asthma.     

Variation of physico-chemical parameters along a river transect through the Okavango Delta,Botswana

The Okavango Delta depends on water quantity and quality to sustain its ecosystem services. Whereas many studies have been carried out on its hydrology, few have been done on water quality in the delta. Water pH, electrical conductivity (EC), dissolved oxygen (DO), turbidity, total suspended solids (TSS) and dissolved organic carbon (DOC) were monitored at 10 sites along the Okavango–Boro–Thamalakane–Lake Ngami system almost fortnightly from June 2008 to June 2010. Water quality in the delta was generally good, despite high evapotranspiration rates which would normally produce very saline waters. Electrical conductivity and water temperature increased with distance from Mohembo to Lake Ngami, the former most likely due to evapoconcentration. In contrast, pH, DO, turbidity and TSS decreased with distance from Mohembo to Boro at the lower end of the seasonal floodplain, before increasing again to Lake Ngami. Dissolved oxygen and TSS most likely declined due to biological uptake and particle sedimentation, respectively. Strong and significant relationships were observed between TSS and turbidity and between DOC and EC, indicating that turbidity and EC could be useful proxies for routine estimations of TSS and DOC, respectively, in the delta.     

Macroinvertebrates as bioindicators of water quality in the Mkondoa River,Tanzania, in an agricultural area

The suitability of using macroinvertebrates as bioindicators of stream water quality was tested in the Mkondoa River in an agricultural area at Kilosa, using the rapid bioassessment protocol. The family biotic index (FBI) showed marked variation in water quality along the stream from values ranging from 4.1 to 5.0 in the upstream reaches, indicating good water quality, 5.3 to 5.5 in the mid-reaches and 6.0 to 6.5 in the lower reaches. The water quality index (WQI) indicated that water quality was fair (77 ± 0.98) in the upstream reach of the Mkondoa, marginal (55 ± 0.86) in the midstream reach and poor (33 ± 0.45) in the downstream reach. There were significant relationships between biological oxygen demand and dissolved oxygen and the occurrence of specific taxa, mainly Chironomus and Caenis. Significant changes in macroinvertebrate abundance were mostly related to changes in water quality. As in other parts of the world, macroinvertebrate communities proved to be good biological indicators of water quality and they should be used as bioindicators in long-term monitoring of this river.     

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine

Rationale

The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays.

Methods

Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms.

Results

Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT_2A, 5-HT_2C, and 5-HT_2B, an inverse agonist at 5-HT₇, a partial agonist at D_2, D₅ and 5-HT₆, an agonist at 5-HT_1A and D₄ receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT_2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy.

Conclusions

The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.     

Integrating new practices: a qualitative study of how hospital innovations become routine

Background

Hospital quality improvement efforts absorb substantial time and resources, but many innovations fail to integrate into organizational routines, undermining the potential to sustain the new practices. Despite a well-developed literature on the initial implementation of new practices, we have limited knowledge about the mechanisms by which integration occurs.

Methods

We conducted a qualitative study using a purposive sample of hospitals that participated in the State Action on Avoidable Rehospitalizations (STAAR) initiative, a collaborative to reduce hospital readmissions that encouraged members to adopt new practices. We selected hospitals where risk-standardized readmission rates (RSRR) had improved (n?=?7) or deteriorated (n?=?3) over the course of the first 2 years of the STAAR initiative (2010–2011 to 2011–2012) and interviewed a range of staff at each site (90 total). We recruited hospitals until reaching theoretical saturation. The constant comparative method was used to conduct coding and identification of key themes.

Results

When innovations were successfully integrated, participants consistently reported that a small number of key staff held the innovation in place for as long as a year while more permanent integrating mechanisms began to work. Depending on characteristics of the innovation, one of three categories of integrating mechanisms eventually took over the role of holding new practices in place. Innovations that proved intrinsically rewarding to the staff, by making their jobs easier or more gratifying, became integrated through shifts in attitudes and norms over time. Innovations for which the staff did not perceive benefits to themselves were integrated through revised performance standards if the innovation involved complex tasks and through automation if the innovation involved simple tasks.

Conclusions

Hospitals have an opportunity to promote the integration of new practices by planning for the extended effort required to hold a new practice in place while integration mechanisms take hold. By understanding how integrating mechanisms correspond to innovation characteristics, hospitals may be able to foster integrating mechanisms most likely to work for particular innovations.

     

Microbial and biochemical basis of a Fusarium wilt-suppressive soil

Crops lack genetic resistance to most necrotrophic pathogens. To compensate for this disadvantage, plants recruit antagonistic members of the soil microbiome to defend their roots against pathogens and other pests. The best examples of this microbially based defense of roots are observed in disease-suppressive soils in which suppressiveness is induced by continuously growing crops that are susceptible to a pathogen, but the molecular basis of most is poorly understood. Here we report the microbial characterization of a Korean soil with specific suppressiveness to Fusarium wilt of strawberry. In this soil, an attack on strawberry roots by Fusarium oxysporum results in a response by microbial defenders, of which members of the Actinobacteria appear to have a key role. We also identify Streptomyces genes responsible for the ribosomal synthesis of a novel heat-stable antifungal thiopeptide antibiotic inhibitory to F. oxysporum and the antibiotic''s mode of action against fungal cell wall biosynthesis. Both classical- and community-oriented approaches were required to dissect this suppressive soil from the field to the molecular level, and the results highlight the role of natural antibiotics as weapons in the microbial warfare in the rhizosphere that is integral to plant health, vigor and development.     

Impact of Contextual Factors on the Effect of Interventions to Improve Health Worker Performance in Sub-Saharan Africa: Review of Randomised Clinical Trials

Background

Africa bears 24% of the global burden of disease but has only 3% of the world’s health workers. Substantial variation in health worker performance adds to the negative impact of this significant shortfall. We therefore sought to identify interventions implemented in sub-Saharan African aiming to improve health worker performance and the contextual factors likely to influence local effectiveness.

Methods and Findings

A systematic search for randomised controlled trials of interventions to improve health worker performance undertaken in sub-Saharan Africa identified 41 eligible trials. Data were extracted to define the interventions’ components, calculate the absolute improvement in performance achieved, and document the likelihood of bias. Within-study variability in effect was extracted where reported. Statements about contextual factors likely to have modified effect were subjected to thematic analysis. Interventions to improve health worker performance can be very effective. Two of the three trials assessing mortality impact showed significant reductions in death rates (age<5 case fatality 5% versus 10%, p<0.01; maternal in-hospital mortality 6.8/1000 versus 10.3/1000; p<0.05). Eight of twelve trials focusing on prescribing had a statistically significant positive effect, achieving an absolute improvement varying from 9% to 48%. However, reported range of improvement between centres within trials varied substantially, in many cases exceeding the mean effect. Nine contextual themes were identified as modifiers of intervention effect across studies; most frequently cited were supply-line failures, inadequate supervision or management, and failure to follow-up training interventions with ongoing support, in addition to staff turnover.

Conclusions

Interventions to improve performance of existing staff and service quality have the potential to improve patient care in underserved settings. But in order to implement interventions effectively, policy makers need to understand and address the contextual factors which can contribute to differences in local effect. Researchers therefore must recognise the importance of reporting how context may modify effect size.     

Decreased DNA repair in familial Alzheimer's disease

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.