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Contains fulltext : 290819.pdf (Publisher’s version ) (Open Access) At the 2015 World Health Assembly, UN member states adopted a resolution that committed to the development of national action plans (NAPs) for antimicrobial resistance (AMR). The political determination to commit to NAPs and the availability of robust governance structures to assure sustainable translation of the identified NAP objectives from policy to practice remain major barriers to progress. Inter-country variability in economic and political resilience and resource constraints could be fundamental barriers to progressing AMR NAPs. Although there have been regional and global analyses of NAPs from a One Health and policy perspective, a global assessment of the NAP objectives targeting antimicrobial use in human populations is needed. In this Health Policy, we report a systematic evidence synthesis of existing NAPs that are aimed at tackling AMR in human populations. We find marked gaps and variability in maturity of NAP development and operationalisation across the domains of: (1) policy and strategic planning; (2) medicines management and prescribing systems; (3) technology for optimised antimicrobial prescribing; (4) context, culture, and behaviours; (5) operational delivery and monitoring; and (6) patient and public engagement and involvement. The gaps identified in these domains highlight opportunities to facilitate sustainable delivery and operationalisation of NAPs. The findings from this analysis can be used at country, regional, and global levels to identify AMR-related priorities that are relevant to infrastructure needs and contexts.

Little is known about the impairments and pathological changes in the visual system in mild brain trauma, especially repetitive mild traumatic brain injury (mTBI). The goal of this study was to examine and compare the effects of repeated head impacts on the neurodegeneration, axonal integrity, and glial activity in the optic tract (OT), as well as on neuronal preservation, glial responses, and synaptic organization in the lateral geniculate nucleus (LGN) and superior colliculus (SC), in wild-type mice and transgenic animals with overexpression of human TDP-43 mutant protein (TDP-43G348C) at 6 months after repeated closed head traumas. Animals were also assessed in the Barnes maze (BM) task. Neurodegeneration, axonal injury, and gliosis were detected in the OT of the injured animals of both genotypes. In the traumatized mice, myelination of surviving axons was mostly preserved, and the expression of neurofilament light chain was unaffected. Repetitive mTBI did not induce changes in the LGN and the SC, nor did it affect the performance of the BM task in the traumatized wild-type and TDP-43 transgenic mice. Differences in neuropathological and behavioral assessments between the injured wild-type and TDP-43G348C mice were not revealed. Results of the current study suggest that repetitive mTBI was associated with chronic damage and inflammation in the OT in wild-type and TDP-43G348C mice, which were not accompanied with behavioral problems and were not affected by the TDP-43 genotype, while the LGN and the SC remained preserved in the used experimental conditions.

We examined damage and repair processes in the rat cerebellum within the first week following moderate traumatic brain injury (TBI) induced by lateral fluid percussion injury (LFPI) over the left parietal cortex. Rats were killed 1, 3, or 7 days after the injury or sham procedure. Fluoro-Jade B staining revealed 2 phases of neurodegenerative changes in the cell bodies and fibers: first, more focal, 1 day after the LFPI, and second, widespread, starting on post-injury day 3. Purkinje cell loss was detected in posterior lobule IX 1 day following LFPI. Apoptosis was observed in the cerebellar cortex, on days 1 and 7 following LFPI, and was not caspase- or apoptosis-inducing factor (AIF)-mediated. AIF immunostaining indicated axonal damage in the cerebellar white matter tracts 3- and 7-days post-injury. Significant astrocytosis and microgliosis were noticed on day 7 following LFPI at the sites of neuronal damage and loss. Immunohistochemical labeling with the presynaptic markers synaptophysin and growth-associated protein-43 revealed synaptic perturbations already on day 1 that were more pronounced at later time points following LFPI. These results provide new insights into pathophysiological alterations in the cerebellum and their mechanisms following cerebral TBI.

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.

We surveyed European medical schools regarding teaching of prudent antibiotic prescribing in the undergraduate curriculum. We performed a cross-sectional survey in 13 European countries (Belgium, Croatia, Denmark, France, Germany, Italy, Netherlands, Norway, Serbia, Slovenia, Spain, Switzerland, United Kingdom) in 2013. Proportional sampling was used, resulting in the selection of two to four medical schools per country. A standardized questionnaire based on literature review and validated by a panel of experts was sent to lecturers in infectious diseases, medical microbiology and clinical pharmacology. In-depth interviews were conducted with four lecturers. Thirty-five of 37 medical schools were included in the study. Prudent antibiotic use principles were taught in all but one medical school, but only four of 13 countries had a national programme. Interactive teaching formats were used less frequently than passive formats. The teaching was mandatory for 53% of the courses and started before clinical training in 71%. We observed wide variations in exposure of students to important principles of prudent antibiotic use among countries and within the same country. Some major principles were poorly covered (e.g. reassessment and duration of antibiotic therapy, communication skills). Whereas 77% of the respondents fully agreed that the teaching of these principles should be prioritized, lack of time, mainly due to rigid curriculum policies, was the main reported barrier to implementation. Given the study design, these are probably optimistic results. Teaching of prudent antibiotic prescribing principles should be improved. National and European programmes for development of specific learning outcomes or competencies are urgently needed. Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved

Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ(42)/Aβ(43) over Aβ(40), and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer’s disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the ‘human chemical exposome’ contains products able to favor the production of Aβ(42)/Aβ(43) over and shorter Aβs. To detect such products, we screened a library of 3500 + compounds in a cell-based assay for enhanced Aβ(42)/Aβ(43) production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3–10-fold increase in the production of extracellular Aβ(42) in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of Aβs cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ(42)/Aβ(43). Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ(42)/Aβ(43) in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ(42)/Aβ(43) peptides, suggesting the possible existence of environmental “Alzheimerogens” which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.

Screening tools for detecting potentially inappropriate medications (PIMs) represent an important way to assess drug prescribing in the elderly. Recently, we introduced a new comprehensive tool to detect both PIMs and clinically important drug-drug interactions (DDI). The aim of the study was to assess the applicability of the new tool. The new tool was used to detect PIMs and DDI and to assess their relation to morbidity and hospital admissions. It was also compared to the widely used Beers criteria. The study population included 454 consecutive patients aged ≥65 years who were acutely admitted to the Department of Internal Medicine of the University Hospital of Osijek. The Naranjo protocol was used to analyze the causal relationship between a drug and an adverse event. According to the new protocol, 44 % patients were taking PIMs, while 33 % patients were taking drugs with potentially serious DDIs. In 11 % of the overall number of patients, the cause of admission was adverse drug reaction (ADR), and among contributing drugs, 44 % were potentially inappropriate according to our protocol. Gastrointestinal bleeding was the most common diagnosis causing ADR-associated admission, and in 72 % cases, either PIM or a potentially serious DDI was involved. The new Croatian tool detected a high number of patients taking PIMs and/or having potentially important drug-drug interactions. The tool also detected almost half of the drugs contributing to ADR-associated admission. We expect the tool to be useful in prescription evaluation for the elderly inpatient and outpatient population.

Recombinant human erythropoietin (rhEpo) is a multi-functional drug with antioxidant potential. However, the underlying molecular mechanisms of its action are still unclear. The purpose of this study was to investigate the effects of rhEpo on the brain infarct volume as well as on the levels of the neuronal damage, oxidative stress parameters and active caspase- 3, nuclear factor erythroid 2-related factor 2 (Nrf2) and haemeoxygenase-1 (HO-1) expressions in the hippocampi of rats exposed to the right middle cerebral artery occlusion (MCAO) for 1 hr. Ischaemic animals received either vehicle or rhEpo (5000 IU/kg, i.p.) immediately or 3 hr after the induction of ischaemia. Sham- operated, vehicle-treated animals served as the control group.Rats were killed 24 hr after the onset of the ischaemic or sham experimental procedure. MCAO caused ipsilateral brain infarction within the striatum and cortex. In the CA1 region of the hippocampi, we did not find significant neuronal loss, but a statistically significant rise in the active caspase-3 and Nrf2 protein expressions was registered. We detected also significant increases in the hippocampal levels of oxidative stress parameters (thiobarbituric acid-reactive substances, superoxide dismutase, glutathione peroxidase). Post-ischaemic administration of rhEpo significantly reduced the brain infarct volume, decreased levels of all tested oxidative stress parameters and increased the Nrf2 expression level. These findings suggest that decrease in oxidative stress parameters in the hippocampus could be an early indicator of post-ischaemic neuroprotective effect of rhEpo in rats exposed to focal cerebral ischaemia and that this effect could be attributable to additional post-ischaemic activation of Nrf2 endogenous antioxidant system.

The prescribing of medicines is a fundamental component of care for the elderly ; however, there is increasing concern with polypharmacy and its impact on morbidity, mortality and costs. As a result, long-term prescription- medicine use and the prevalence of polypharmacy in the elderly in the Republic of Srpska were analyzed. The findings were subsequently used to suggest potential future measures. A retrospective study of all elderly patients during 2005-2010 stratified by age group (three groups), sex and long- term medicine use was performed. Polypharmacy (five or more medicines) increased from 1.4% of the elderly taking medicines long-term to 3.6% by 2010, with 53.6% of elderly taking two or more medicines long- term. The most prevalent diseases were cardiovascular diseases and diabetes. Most prescriptions were in accordance with recent guidelines ; however, there was a concern with appreciable prescribing of digoxin and aminophylline. Whilst polypharmacy rates are low in the Republic, the increasing rate is a concern. Further studies are planned.

Purpose The purpose of this study was to determine the prevalence of inappropriate prescribing to the elderly and to identify possible gender-related differences in prescribing certain potentially inappropriate medications (PIMs) to outpatients by using large administrative prescription database. Methods Medications prescribed for elderly outpatients (≥ 65 years) in Primorsko-Goranska County, Croatia, who received five or more different drugs simultaneously in 2010, were analyzed. The prevalence of potentially inappropriate drugs prescribed to the elderly was assessed using the new comprehensive protocol developed by authors Mimica Matanović and Vlahović-Palčevski. Results A total of 62.4 % of patients received at least one medication with unfavorable benefit/risk ratio in the elderly. Female patients were given inappropriate medications in a significantly higher percentage than men (69.3 % vs. 50.5 %; p65 years and receiving five or more drugs was potentially inappropriate. Elderly women were prescribed PIMs more often than men. Drugs of concern in female patients were benzodiazepines, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs). In male patients, there was a significantly higher proportion of possible interactions with warfarin, theophylline, and medications affecting the cardiovascular system, such as ACE inhibitors and amiodarone.

Elderly patients are at increased risk of drug-related morbidity and mortality. Avoiding the use of potentially inappropriate medications (PIMs) is one of the strategies that has been widely adopted to reduce the harmful consequences of drug use. There are several PIM screening tools available. In this review, we provide an overview of existing screening tools to detect PIMs in the elderly, emphasizing the advantages and disadvantages of each. Combining previously published and adopted tools (adjusted Beers list, French consensus panel, McLeod’s list, and Lindblad’s list of clinically important drug–disease interactions), we develop a new comprehensive tool that also includes the adjusted Hanlon’s and Malone’s lists of potentially serious drug–drug interactions in the elderly. In addition to listed PIMs and clinically important drug–drug interactions, alternative therapeutic solutions are suggested. The new protocol differentiates: drugs with an unfavorable benefit/risk ratio (to be avoided regardless of the underlying disease/condition), drugs with a questionable efficacy, and drugs to be avoided with certain diseases/conditions, and provides a list of potentially serious drug–drug interactions. A tool consisting of PIMs and potential drug–drug interactions within the same protocol provides more comprehensive quality assessment of drug-prescribing behavior to the elderly, which in turn may lead to better prescribing practices.