IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons.

Signalling endosomes are essential for trafficking of activated ligand-receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, we describe a new modulator of signalling endosome trafficking, the insulin-like growth factor 1 receptor (IGF1R). We show that IGF1R inhibition increases the velocity of signalling endosomes in motor neuron axons, both in vitro and in vivo. This effect is specific, since IGF1R inhibition does not alter the axonal transport of mitochondria or lysosomes. Our results suggest that this change in trafficking is linked to the dynein adaptor bicaudal D1 (BICD1), as IGF1R inhibition results in an increase in the de novo synthesis of BICD1 in the axon of motor neurons. Finally, we found that IGF1R inhibition can improve the deficits in signalling endosome transport observed in a mouse model of amyotrophic lateral sclerosis (ALS). Taken together, these findings suggest that IGF1R inhibition may be a new therapeutic target for ALS.

The utility of hERG channel inhibition data in the derivation of occupational exposure limits.

Inhibition of the human ether-à-go-go (hERG) channel may lead to QT prolongation and fatal arrhythmia. While pharmaceutical drug candidates that exhibit potent hERG channel inhibition often fail early in development, many drugs with both cardiac and non-cardiac indications proceed to market. In this study, the relationship between in vitro hERG channel inhibition and published occupational exposure limit (OEL) was evaluated. A total of 23 cardiac drugs and 44 drugs with non-cardiac indications with published hERG channel IC50 and published OELs were identified. There was an apparent relationship between hERG IC50 potency and the OEL for cardiac and non-cardiac drugs. Twenty cardiac and non-cardiac drugs were identified that had a potent hERG IC50 (≤25 µM) and a contrastingly large OEL value (≥100 µg/m3). OELs or hazard banding corresponding to ≤100 µg/m3 should be sufficiently protective of effects following occupational exposure to the majority of APIs with hERG IC50 values ≤ 100 µM. It is important to consider hERG IC50 values and possible cardiac effects when deriving OEL values for drugs, regardless of indication. These considerations may be particularly important early in the drug development process for establishing exposure control bands for drugs that do not yet have full clinical safety data.

Regulation of Axonal Transport by Protein Kinases.

The intracellular transport of organelles, proteins, lipids, and RNA along the axon is essential for neuronal function and survival. This process, called axonal transport, is mediated by two classes of ATP-dependent motors, kinesins, and cytoplasmic dynein, which carry their cargoes along microtubule tracks. Protein kinases regulate axonal transport through direct phosphorylation of motors, adapter proteins, and cargoes, and indirectly through modification of the microtubule network. The misregulation of axonal transport by protein kinases has been implicated in the pathogenesis of several nervous system disorders. Here, we review the role of protein kinases acting directly on axonal transport and discuss how their deregulation affects neuronal function, paving the way for the exploitation of these enzymes as novel drug targets.

Defending the scientific integrity of conservation-policy processes.

Government agencies faced with politically controversial decisions often discount or ignore scientific information, whether from agency staff or nongovernmental scientists. Recent developments in scientific integrity (the ability to perform, use, communicate, and publish science free from censorship or political interference) in Canada, Australia, and the United States demonstrate a similar trajectory. A perceived increase in scientific-integrity abuses provokes concerted pressure by the scientific community, leading to efforts to improve scientific-integrity protections under a new administration. However, protections are often inconsistently applied and are at risk of reversal under administrations publicly hostile to evidence-based policy. We compared recent challenges to scientific integrity to determine what aspects of scientific input into conservation policy are most at risk of political distortion and what can be done to strengthen safeguards against such abuses. To ensure the integrity of outbound communications from government scientists to the public, we suggest governments strengthen scientific integrity policies, include scientists' right to speak freely in collective-bargaining agreements, guarantee public access to scientific information, and strengthen agency culture supporting scientific integrity. To ensure the transparency and integrity with which information from nongovernmental scientists (e.g., submitted comments or formal policy reviews) informs the policy process, we suggest governments broaden the scope of independent reviews, ensure greater diversity of expert input and transparency regarding conflicts of interest, require a substantive response to input from agencies, and engage proactively with scientific societies. For their part, scientists and scientific societies have a responsibility to engage with the public to affirm that science is a crucial resource for developing evidence-based policy and regulations in the public interest.

Increasing cefazolin use for surgical prophylaxis in penicillin-allergy-labeled patients.

Objective: Penicillin (PCN) allergy labels affect antimicrobial selection for surgical prophylaxis. We aimed to increase the percentage of cefazolin usage in patients with PCN allergy labels undergoing orthopedic surgery from 50% to 80%. Design: Quality improvement initiative. Setting: Children's Mercy Kansas City (CMKC), a freestanding children's hospital. Patients: Children scheduled for an orthopedic surgery (excluding spinal surgery) at CMKC who had a PCN allergy label and received a perioperative antibiotic. Methods: No standardized process existed to identify and clarify PCN-allergic-labeled patients preoperatively. We developed a process for patient identification combined with a pharmacist phone interview for PCN allergy clarification. In plan-do-study-act (PDSA) part 1, we implemented a computer-generated patient list. In PDSA part 2, we combined automated identification with a phone interview. In PDSA part 3, we enhanced the patient list, making it timely and concise. In PDSA part 4, we included a PCN allergy clarification electronic survey to caregivers via the electronic medical record. Results: Cefazolin use in PCN-allergic surgical patients increased from 50% to 74% following interventions. Patients who had their PCN allergy label clarified were 4 times more likely to receive cefazolin compared to those whose allergy labels were not clarified (OR, 4.21; 95% CI, 1.68-11.61; P = 0.003). Moreover, 90% of patients received cefazolin when their PCN allergy was clarified and cefazolin was recommended. When a PCN allergy label was not clarified, only 59% of patients received cefazolin. Conclusions: Appropriate clarification and documentation of PCN allergy labels increases the use of cefazolin for surgical prophylaxis.

BPA interferes with StAR-mediated mitochondrial cholesterol transport to induce germline dysfunctions.

Bisphenol A is an endocrine disruptor associated with hormone synthesis and reproduction alterations. However, the initiating events underpinning these dysfunctions are still unclear. Here, we address the hypothesis that BPA interferes with the highly evolutionary conserved process of mitochondrial cholesterol transport, a crucial step in steroid hormone biosynthesis, by using the model organism C. elegans. We observed that embryonic lethality and germline apoptosis, hallmarks of BPA's reproductive toxicity in C. elegans, are fully rescued by low exogenous cholesterol supplementation. We also observed that increasing BPA concentrations proportionally reduced mitochondrial cholesterol levels. Mutants for strl-1 (ortholog of StAR), but not C41G7.9 (ortholog of TSPO), show reproductive defects similar to BPA's while BPA exposure in a strl-1 background did not worsen these effects. Finally, cholesterol supplementation rescued these defects for all strl-1 genotype/BPA combinations assessed. Together, these results uncover a novel mechanism underlying BPA's germline toxicity through the alteration of cholesterol transport.

Inhibiting p38 MAPK alpha rescues axonal retrograde transport defects in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the degeneration of upper and lower motor neurons. Defects in axonal transport have been observed pre-symptomatically in the SOD1G93A mouse model of ALS, and have been proposed to play a role in motor neuron degeneration as well as in other pathologies of the nervous system, such as Alzheimer's disease and hereditary neuropathies. In this study, we screen a library of small-molecule kinase inhibitors towards the identification of pharmacological enhancers of the axonal retrograde transport of signalling endosomes, which might be used to normalise the rate of this process in diseased neurons. Inhibitors of p38 mitogen-activated protein kinases (p38 MAPK) were identified in this screen and were found to correct deficits in axonal retrograde transport of signalling endosomes in cultured primary SOD1G93A motor neurons. In vitro knockdown experiments revealed that the alpha isoform of p38 MAPK (p38 MAPKα) was the sole isoform responsible for SOD1G93A-induced transport deficits. Furthermore, we found that acute treatment with p38 MAPKα inhibitors restored the physiological rate of axonal retrograde transport in vivo in early symptomatic SOD1G93A mice. Our findings demonstrate the pathogenic effect of p38 MAPKα on axonal retrograde transport and identify a potential therapeutic strategy for ALS.

In vivo imaging of axonal transport in murine motor and sensory neurons.

BACKGROUND: Axonal transport is essential for neuronal function and survival. Defects in axonal transport have been identified as an early pathological feature in several disorders of the nervous system. The visualisation and quantitative analysis of axonal transport in vivo in rodent models of neurological disease is therefore crucial to improve our understanding of disease pathogenesis and for the identification of novel therapeutics. NEW METHOD: Here, we describe a method for the in vivo imaging of axonal transport of signalling endosomes in the sciatic nerve of live, anaesthetised mice. RESULTS: This method allows the multiparametric, quantitative analysis of in vivo axonal transport in motor and sensory neurons of adult mice in control conditions and during disease progression. COMPARISON WITH EXISTING METHODS: Previous in vivo imaging of the axonal transport of signalling endosomes has been limited to studies in nerve explant preparations or non-invasive approaches using magnetic resonance imaging; techniques that are hampered by major drawbacks such as tissue damage and low temporal and spatial resolution. This new method allows live imaging of the axonal transport of single endosomes in the sciatic nerve in situ and a more sensitive analysis of axonal transport kinetics than previous approaches. CONCLUSIONS: The method described in this paper allows an in-depth analysis of the characteristics of axonal transport in both motor and sensory neurons in vivo. It enables the detailed study of alterations in axonal transport in rodent models of neurological diseases and can be used to identify novel pharmacological modifiers of axonal transport.

Protecting endangered species: do the main legislative tools work?

It is critical to assess the effectiveness of the tools used to protect endangered species. The main tools enabled under the U.S. Endangered Species Act (ESA) to promote species recovery are funding, recovery plan development and critical habitat designation. Earlier studies sometimes found that statistically significant effects of these tools could be detected, but they have not answered the question of whether the effects were large enough to be biologically meaningful. Here, we ask: how much does the recovery status of ESA-listed species improve with the application of these tools? We used species' staus reports to Congress from 1988 to 2006 to quantify two measures of recovery for 1179 species. We related these to the amount of federal funding, years with a recovery plan, years with critical habitat designation, the amount of peer-reviewed scientific information, and time listed. We found that change in recovery status of listed species was, at best, only very weakly related to any of these tools. Recovery was positively related to the number of years listed, years with a recovery plan, and funding, however, these tools combined explain <13% of the variation in recovery status among species. Earlier studies that reported significant effects of these tools did not focus on effect sizes; however, they are in fact similarly small. One must conclude either that these tools are not very effective in promoting species' recovery, or (as we suspect) that species recovery data are so poor that it is impossible to tell whether the tools are effective or not. It is critically important to assess the effectiveness of tools used to promote species recovery; it is therefore also critically important to obtain population status data that are adequate to that task.

Modifying the PACIC to assess provision of chronic illness care: an exploratory study with primary health care nurses.

INTRODUCTION: In line with Wagner's Chronic Care Model, the Patient Assessment of Chronic Illness Care (PACIC) has been developed to evaluate chronic illness care delivery from the patient's perspective. Modification of the instrument to assess the same aspects of care delivery from the health practitioner's perspective would enable individual practitioners to evaluate their own provision of self-management support, and would also enable a more direct comparison between care provided and care received within the chronic illness context. AIM: To explore the potential of a modified PACIC instrument to assess individual health practitioners' delivery of care to chronic illness patients with a sample of primary health care nurses. METHODS: Seventy-seven primary care nurses completed the modified PACIC, reworded to ask about care provision rather than receipt of care. An additional seven cultural sensitivity items were included, as were questions about the suitability of the types of chronic illness care and who should be providing the care. RESULTS: The modified PACIC items appear to be appropriate for use with health practitioners. Agreement that the types of care described in the PACIC should be provided was almost unanimous, and the predominant view was that self-management support should be provided by both nurses and doctors. Mean scale scores were higher than those generally reported from studies using the PACIC. DISCUSSION: The results of this first evaluation of a modified PACIC suggest that the original items plus the cultural sensitivity items can be used to assess self-management support by individual health practitioners.

Providing and receiving self-management support for chronic illness: patients' and health practitioners' assessments.

INTRODUCTION: Providing care for people with chronic illness is a major issue for health practitioners around the world, especially as populations age. Encouraging self-management is beneficial in terms of relieving the burden on the health system and promoting better health and adherence to medication and advice amongst this group. AIM: To measure the level of self-management support being provided to and received by people living with chronic illness in a District Health Board (DHB) region. METHODS: Self-report questionnaires (PACIC) were completed by 341 people living with chronic illness to measure the self-management support they receive from general practitioners and nurses. A modified version of the PACIC was used with 12 GPs and 77 primary health nurses in the same region to assess the provision of self-management support. RESULTS: Patients' assessments suggest that they are receiving intermittent self-management support for their chronic illness. A comparison of ratings of different health practitioners revealed that nurses were reported to be providing support more consistently than GPs. The health practitioners rated themselves as providing self-management support more often than the patients reported receiving it. Many clinicians also suggested that not all forms of support are appropriate for everyone, suggesting the need to tailor support to the individual. DISCUSSION: Chronic illness support needs to be considered within the context ofthe individual and to be embedded in an ongoing relationship between the person and the provider. Findings highlightthe benefits of a multidisciplinaryteam approach to self-management support and education in chronic illness care.