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Background: CDKL5 Deficiency Disorder (CDD) is a rare developmental and epileptic encephalopathy characterized by dominant X-linked inheritance and early infantile onset. To date, more than 300 pathogenic variants of the CDKL5 gene have been reported with different phenotypes. As a rare genetic disease, data on CDD are still limited, making the diagnostic and therapeutic process very challenging. The objective of our study was to provide a comprehensive overview of CDD, including those aspects of the disease for which there is unfortunately still limited knowledge., Materials and Methods: The presence of a CDKL5 variant, cognitive impairment/delayed psychomotor development, and onset of epilepsy within the first year of life were screened for the diagnosis. Comprehensive clinical assessment, laboratory and radiological investigations were performed., Results: Fifteen (n=15) patients were enrolled in the study. In most cases, concordance was found between our data and those already present in the literature. In contrast, some other features, including the development of macrocephaly and the presence of congenital gastrointestinal malformations and spinal cord abnormalities, differ from previous findings., Conclusions: Our study provides an overview on CDD, including those features for which we still have limited knowledge and, albeit on a limited sample, several insights on this rare condition., (Copyright © 2024. Published by Elsevier B.V.)

The objective of this study was to determine the efficiency of the microbial rhizosphere ( Canavalia ensiformis ) in the phytoremediation of sulfentrazone using quantification methods (CO2 evolution, microbial biomass carbon, and metabolic quotient) and identification of bacteria (PCR-DGGE technique). The experiment was conducted in a completely randomized design, in a 2x4 factorial scheme, with four replications. The treatments were composed of rhizospheric soil (cultivated with C. ensiformis ) and non-rhizosphere soil (uncultivated soil); and four levels of contamination by sulfentrazone (0, 200, 400, and 800 g ha -1 a.i.). The microbiota associated with the rhizosphere of C. ensiformis efficiently reduced sulfentrazone residues in the soil, with better performance at the dose of 200 g ha -1 a.i. Using the PCR-DGGE technique allowed the distinction of two profiles of bacteria in the rhizospheric activity of C. ensiformis . The second bacterial profile formed was more efficient in decontaminating soil contaminated with sulfentrazone residue. The microbiota associated with the rhizosphere of C. ensiformis has an efficient profile in decontaminating soils with residues equivalent to 200 g ha -1 a.i. the herbicide sulfentrazone.

Methicillin-resistant Staphylococcus aureus (MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level of resistance to β-lactam antibiotics in MRSA is attributed to the expression of penicillin-binding protein 2a (PBP2a), which catalyzes cell wall cross-linking. According to numerous research reports, the activity of the PBP2a protein is known to be regulated by an allosteric site distinct from the active site where cell wall cross-linking occurs. Here, we conducted a screening of 113 compounds containing a 1,3,4-oxadiazole core to design new covalent inhibitors targeting the allosteric site of PBP2a and establish their structural-activity relationship. The stereochemically selective synthesis of sulfonyl oxadiazole compounds identified in the initial screening resulted in a maximum eightfold enhancement in cell inhibition activity. The sulfonyl oxadiazole-based compounds formulated as PEG-based ointments, with low toxicity test results on human cells (CC 50 : >78μM), demonstrated potent antimicrobial effects not only in a mouse skin wound infection model but also against oxacillin-resistant clinical isolate MRSA (IC 50 ≈ 1μM), as evidenced by the results. Furthermore, additional studies utilizing LC-MS/MS and in-silico approaches clearly support the allosteric site covalent binding mechanism through the nucleophilic aromatic substitution (S N Ar) reaction, as well as its association with the closure of the major active site of PBP2a.

Introduction: Spinal cord stimulation is a widespread treatment of chronic neuropathic pain from different conditions. Several novel and improving technologies have been recently developed to increase the effect of neuromodulation in patients refractory to pharmacological therapy., Research Question: To explore spinal cord stimulation's mechanisms of action, indications, and management., Material and Methods: The paper initially explores the mechanism of action of this procedure based on the generation of an electric field between electrodes placed on the posterior dural surface of the spinal cord probably interfering with the transmission of pain stimuli to the brain. Subsequently, the most consolidated criteria for selecting patients for surgery, which constitute a major issue of debate, were defined. Thereafter, the fundamental patterns of stimulation were summarized by exploring the advantages and side effects. Lastly, the most common side effects and the related management were discussed., Results: Proper selection of the patient is of paramount importance to achieve the best results from this specific neuromodulation treatment. Regarding the different types of stimulation patterns, no definite evidence-based guidelines exist on the most appropriate approach in relation to the specific type of neuropathic pain. Both burst stimulation and high-frequency stimulation are innovative techniques that reduce the risk of paresthesias compared with conventional stimulation., Discussion and Conclusion: Novel protocols of stimulation (burst stimulation and high frequency stimulation) may improve the trade-off between therapeutic benefits and potential side effects. Likewise, decreasing the rates of hardware-related complications will be also useful to increase the application of neuromodulation in clinical settings., Competing Interests: The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript., (© 2024 The Authors.)

Background and Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated., Methods: Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis., Results: At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration., Interpretation: Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile., (© 2023 Peripheral Nerve Society.)

Klebsiella pneumoniae carbapenemase-2 (KPC-2) presents a clinical threat as this β-lactamase confers resistance to carbapenems. Recent variants of KPC-2 in clinical isolates contribute to concerning resistance phenotypes. Klebsiella pneumoniae expressing KPC-2 D179Y acquired resistance to the ceftazidime/avibactam combination affecting both the β-lactam and the β-lactamase inhibitor yet has lowered minimum inhibitory concentrations for all other β-lactams tested. Furthermore, Klebsiella pneumoniae expressing the KPC-2 D179N variant also manifested resistance to ceftazidime/avibactam yet retained its ability to confer resistance to carbapenems although significantly reduced. This structural study focuses on the inhibition of KPC-2 D179N by avibactam and relebactam and expands our previous analysis that examined ceftazidime resistance conferred by D179N and D179Y variants. Crystal structures of KPC-2 D179N soaked with avibactam and co-crystallized with relebactam were determined. The complex with avibactam reveals avibactam making several hydrogen bonds, including with the deacylation water held in place by Ω loop. These results could explain why the KPC-2 D179Y variant, which has a disordered Ω loop, has a decreased affinity for avibactam. The relebactam KPC-2 D179N complex revealed a new orientation of the diazabicyclooctane (DBO) intermediate with the scaffold piperidine ring rotated ~150° from the standard DBO orientation. The density shows relebactam to be desulfated and present as an imine-hydrolysis intermediate not previously observed. The tetrahedral imine moiety of relebactam interacts with the deacylation water. The rotated relebactam orientation and deacylation water interaction could potentially contribute to KPC-mediated DBO fragmentation. These results elucidate important differences that could aid in the design of novel β-lactamase inhibitors., Competing Interests: The authors declare no conflict of interest.

Significance: The prevalence of metabolic syndrome (MetS) and associated obesity has increased in recent years, affecting millions worldwide. One of the most common complications of obesity is damage to the peripheral nerve system, referred to as neuropathy. The lack of disease-modifying therapy for this complication is largely due to a poor understanding of the complex neurobiology underlying neuropathy. Recent preclinical studies suggest that in addition to glucotoxic events, other mechanisms, including lipid signaling, microbiome, or inflammation, may be viable targets to prevent nerve damage and neuropathic pain in obesity. Recent Advances: Clinical and preclinical studies using diet-induced obesity rodent models have identified novel interventions that improve neuropathy. Notably, mechanistic studies suggest that lipid, calcium signaling, and inflammation are converging pathways. Critical Issues: In this review, we focus on interventions and their mechanisms that are shown to ameliorate neuropathy in MetS obese models, including: (i) inhibition of a sensory neuron population, (ii), modification of dietary components, (iii) activation of nuclear and mitochondrial lipid pathways, (iv) exercise, and (v) modulation of gut microbiome composition and their metabolites. Future Directions: These past years, novel research increased our knowledge about neuropathy in obesity and discovered the involvement of nonglucose signaling. More studies are necessary to uncover the interplay between complex metabolic pathways in the peripheral nerve system of obese individuals. Further mechanistic studies in preclinical models and humans are crucial to create single- or multitarget interventions for this complex disease implying complex metabolic phenotyping. Antioxid. Redox Signal. 37, 597-612.

Background and Purpose: Intradural disc herniation (IDH) can manifest with radicular or medullary syndrome. In about 15% of cases, IDH may be responsible, through a dural laceration, for a CSF leak, determining spontaneous intracranial hypotension (SIH) and CNS superficial siderosis (CNSss). This paper attempts to present an overview on IDH as the cause for both CSF leak, and subsequent SIH, and CNSss, and to describe a peculiar clinical and neuroradiological scenario related to this condition., Methods: A search on the PUBMED database was performed. Although the investigation did not rigorously follow the criteria for a systematic review (we consider only articles about thoracic IDH), nonetheless, the best quality evidence was pursued. Furthermore, an illustrative case was presented., Results: A 69-year-old woman was referred to our hospital for slowly progressive gait disturbances and hearing impairment. Brain imaging revealed diffuse bilateral supratentorial and infratentorial superficial siderosis, mostly of the cerebellum, the eighth cranial nerves, and the brainstem. Spinal imaging disclosed a posterior disc herniation determining a dural tear at D6-D7. Lumbar puncture revealed low opening pressure and hemorrhagic CSF with siderophages. A posterior transdural herniectomy and dural sealing determined a stabilization of hearing and a significant improvement in both gait and balance., Conclusions: The diagnostic workup of CNSss with suspected CNS leak demands whole neuraxis imaging, especially in cases presenting SIH or myelopathic symptoms. This may avoid delays in detection of IDH and spinal dural leaks. The different forms of treatment available depend on the type and severity of the clinical picture., (© 2022. The Author(s).)

Implant infection impairs osseointegration of orthopaedic implants by inducing inflammation. Acinetobacter spp. are increasingly prevalent multi-drug resistant bacteria that can cause osteomyelitis. Acinetobacter spp. can also cause inflammation and thereby inhibit osseointegration in mice. The purpose of the present study was to investigate the role of quorum sensing in this context. Therefore, wild-type bacteria were compared with an isogenic abaI mutant defective in quorum sensing in a murine osseointegration model. The abaI quorum- sensing mutant affected significantly less osseointegration and interleukin (IL) 1β levels, without detectably altering other pro-inflammatory cytokines. Wild-type bacteria had fewer effects on IL1 receptor (IL1R)-/- mice. These results indicated that quorum sensing in Acinetobacter spp. contributed to IL1β induction and the resultant inhibition of osseointegration in mice. Moreover, targeting the Gram-negative acyl-homoserine lactone quorum sensing may be particularly effective for patients with Acinetobacter spp. infections.

Obesity is an epidemic, and it is characterized by a state of low-grade systemic inflammation. A key component of inflammation is the activation of inflammasomes, multiprotein complexes that form in response to danger signals and that lead to activation of caspase-1. Previous studies have found that a Westernized diet induces activation of inflammasomes and production of inflammatory cytokines. Gut microbiota metabolites, including the short-chain fatty acid butyrate, have received increased attention as underlying some obesogenic features, but the mechanisms of action by which butyrate influences inflammation in obesity remain unclear. We engineered a caspase-1 reporter mouse model to measure spatiotemporal dynamics of inflammation in obese mice. Concurrent with increased capsase-1 activation in vivo, we detected stronger biosensor signal in white adipose and heart tissues of obese mice ex vivo and observed that a short-term butyrate treatment affected some, but not all, of the inflammatory responses induced by Western diet. Through characterization of inflammatory responses and computational analyses, we identified tissue- and sex-specific caspase-1 activation patterns and inflammatory phenotypes in obese mice, offering new mechanistic insights underlying the dynamics of inflammation., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) present a global clinical threat, as these β-lactamases confer resistance to carbapenems and oxyimino-cephalosporins. Recent clinically identified KPC variants with substitutions at Ambler position D179, located in the Ω loop, are resistant to the β-lactam/β-lactamase inhibitor combination ceftazidime-avibactam, but susceptible to meropenem-vaborbactam. To gain insights into ceftazidime-avibactam resistance conferred by D179N/Y variants of KPC-2, crystal structures of these variants were determined. The D179N KPC-2 structure revealed that the change of the carboxyl to an amide moiety at position 179 disrupted the salt bridge with R164 present in wild-type KPC-2. Additional interactions were disrupted in the Ω loop, causing a decrease in the melting temperature. Shifts originating from N179 were also transmitted toward the active site, including ∼1-Å shifts of the deacylation water and interacting residue N170. The structure of the D179Y KPC-2 β-lactamase revealed more drastic changes, as this variant exhibited disorder of the Ω loop, with other flanking regions also being disordered. We postulate that the KPC-2 variants can accommodate ceftazidime because the Ω loop is displaced in D179Y or can be more readily displaced in D179N KPC-2. To understand why the β-lactamase inhibitor vaborbactam is less affected by the D179 variants than avibactam, we determined the crystal structure of D179N KPC-2 in complex with vaborbactam, which revealed wild-type KPC-2-like vaborbactam-active site interactions. Overall, the structural results regarding KPC-2 D179 variants revealed various degrees of destabilization of the Ω loop that contribute to ceftazidime-avibactam resistance, possible substrate-assisted catalysis of ceftazidime, and meropenem and meropenem-vaborbactam susceptibility.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P < 0.05) reduced in liver and DRG from streptozotocin (STZ)-induced type 1 diabetic rats, Zucker diabetic fatty (ZDF) rats, mice on a high-fat/ high-sugar diet and db/db type 2 diabetic mice. Hyperglycemia suppressed IGF-1 gene expression in cultured DRG neurons and this was reversed by exogenous IGF-1 or the aldose reductase inhibitor sorbinil. Transcription factors, such as NFAT1 and CEBPβ, were also less enriched at the IGF-1 promoter in DRG from diabetic rats vs control rats. CEBPβ overexpression promoted neurite outgrowth and mitochondrial respiration, both of which were blunted by knocking down or blocking IGF-1. Suppression of endogenous IGF-1 in diabetes may contribute to neuropathy and its upregulation at the transcriptional level by CEBPβ can be a promising therapeutic approach., (© 2022. The Author(s).)

Objective: The vagus nerve provides a direct line of communication between the gut and the brain for proper regulation of energy balance and glucose homeostasis. Short-chain fatty acids (SCFAs) produced via gut microbiota fermentation of dietary fiber have been proposed to regulate host metabolism and feeding behavior via the vagus nerve, but the molecular mechanisms have not yet been elucidated. We sought to identify the G-protein-coupled receptors within vagal neurons that mediate the physiological and therapeutic benefits of SCFAs., Methods: SCFA, particularly propionate, signaling occurs via free fatty acid receptor 3 (FFAR3), that we found expressed in vagal sensory neurons innervating throughout the gut. The lack of cell-specific animal models has impeded our understanding of gut/brain communication; therefore, we generated a mouse model for cre-recombinase-driven deletion of Ffar3. We comprehensively characterized the feeding behavior of control and vagal-FFAR3 knockout (KO) mice in response to various conditions including fasting/refeeding, western diet (WD) feeding, and propionate supplementation. We also utilized ex vivo organotypic vagal cultures to investigate the signaling pathways downstream of propionate FFAR3 activation., Results: Vagal-FFAR3KO led to increased meal size in males and females, and increased food intake during fasting/refeeding and WD challenges. In addition, the anorectic effect of propionate supplementation was lost in vagal-FFAR3KO mice. Sequencing approaches combining ex vivo and in vivo experiments revealed that the cross-talk of FFAR3 signaling with cholecystokinin (CCK) and leptin receptor pathways leads to alterations in food intake., Conclusion: Altogether, our data demonstrate that FFAR3 expressed in vagal neurons regulates feeding behavior and mediates propionate-induced decrease in food intake., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients., Methods: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected., Results: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%., Conclusions: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed., (© 2021. Fondazione Società Italiana di Neurologia.)

The increased survival of cancer patients has raised growing public health concern on associated long-term consequences of antineoplastic treatment. Chemotherapy-induced peripheral neuropathy (CIPN) is a primarily sensory polyneuropathy, which may be accompanied by pain, autonomic disturbances, and motor deficit. About 70% of treated cancer patients might develop CIPN during or after the completion of chemotherapy, and in most of them such complication persists after six months from the treatment. The definition of the potential risk of development and resolution of CIPN according to a clinical and biochemical profile would be certainly fundamental to tailor chemotherapy regimen and dosage on individual susceptibility. In recent years, patient-reported and clinician-related tools along with quality of life instruments have been featured as primary outcomes in clinical setting and randomized trials. New studies on metabolomics markers are further pursuing accurate and easily accessible indicators of peripheral nerve damage. The aim of this review is to outline the strengths and pitfalls of current knowledge on CIPN, and to provide a framework for future potential developments of standardized protocols involving clinical and biochemical markers for CIPN assessment and monitoring., (Copyright © 2021. Published by Elsevier Masson SAS.)

Competing Interests: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Chemotherapy-induced peripheral neuropathy (CIPN) has long been recognized as a clinically significant issue in patients treated with antineoplastic drugs. This common long-term toxic side-effect which negatively impacts the outcome of the disease can lead to disability and have detrimental effects on patients' quality of life. Since axonal injury is a prominent feature of CIPN, responsible for several sensory symptoms, including pain, sensory loss and hypersensitivity to mechanical and/or cold stimuli in the hands and feet, neurophysiological assessments remain the gold standard for clinical diagnosis of CIPN. Given the large impact of CIPN on cancer patients, there is increasing emphasis on biomarkers of adverse outcomes in safety assessment and translational research, to prevent permanent neuroaxonal damage. Since the results on reliable blood molecular markers for axonal degeneration are still controversial, here we provide a brief overview of blood molecular biomarkers used for assessing and/or predicting CIPN in preclinical and clinical settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The management of initial planting density can be a strategy to increase barium phytoextraction from soil, reducing the time required for soil decontamination. To delimit the ideal planting density for barium (Ba) phytoremediation using Typha domingensis, we conducted a 300-day experiment in an area accidentally contaminated with barite. Four initial planting densities were tested: 4, 8, 12, and 16 plantsm -2 (D4, D8, D12, and D16 treatments, respectively). Plant development was evaluated periodically, and the phytoextraction efficiency was determined at the end of the trial. The initial planting density affected Ba phytoremediation by T. domingensis monoculture. Phytoextraction potential was better represented by the mass-based translocation factor (mTF) than the concentration-based translocation factor. D16 promoted the highest final number of plants and biomass production, but the mass of Ba in the aerial part did not differ among D8, D12, and D16. D4 resulted in more Ba accumulated belowground than aboveground (6.3 times higher), whereas D12 and D16 achieved the greatest mTFs. Higher absorption of Ba from soil can be achieved using less T. domingensis individuals at the beginning of the treatment (D4 and D8) but with high accumulation in belowground tissues. We conclude that the D8 density is considered the most appropriate if considering the phytoextraction potential and field management facilitated using fewer plants., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Barite (BaSO 4 ) is a component of drilling fluids used in the oil and gas industry and may cause barium (Ba) contamination if it is spilled onto flooded soils. Under anoxic soil conditions and low redox potential, sulfate can be reduced to a more soluble form (sulfide), and Ba can be made available. To design a solution for such environmental issues, a field study was conducted in a Ba-contaminated flooded area in Brazil, in which we induced Ba phytoextraction from the management of the planting density of two intercropped macrophytes. Typha domingensis and Eleocharis acutangula were grown in four initial planting densities: "Ld" (low density: 4 and 32 plants m -2 ); "Md" (medium density: 8 and 64 plants m -2 ); "Hd" (high density: 12 and 128 plants m -2 ); "Vhd" (very high density: 16 and 256 plants m -2 ). Vhd produced the largest number of plants after 300 days. However, the treatments did not differ in terms of the amount of biomass. The increments in the initial planting density did not increase the Ba concentration in the aerial part. The greatest Ba phytoextraction (aerial part + root) was achieved by Ld treatment, which removed approximately 3 kg of Ba ha -1 . Md and Vhd treatments had the highest Ba translocation factors. Because more plants per area did not result in greater Ba phytoextraction, a lower planting density was recommended for the intercropping of T. domingensis and E. acutangula to promote the phytoextraction of barium, due to possible lower implementation costs in contaminated flooded environments., Competing Interests: Declaration of Competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: This study aims to evaluate the base-peak difference in levodopa response for detecting patients with motor fluctuations in Parkinson's disease (PD)., Methods: Two independent PD samples were evaluated at baseline and 2 h after the administration of the usual morning dose of levodopa using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III). The presence of motor fluctuations was defined by the UPDRS-IV. We quantified the magnitude of motor variation as absolute (Δ) and percentage (Δ%) change in UPDRS-III scores. Optimal cut-offs for each index distinguishing patients with or without fluctuations were calculated on the exploratory population. The accuracy of the identified cut-offs was then verified in a testing population., Results: In the exploratory population (N = 26), the optimal cut-off for detecting fluctuations was a Δ of 6 points and a Δ% of 18.4%. When we applied the identified thresholds to the testing population (N = 139), we found a sensitivity of 93.8% (95% CI: 89.7 to 97.8) and a specificity of 91.2% (95% CI: 86.5 to 95.9) for Δ, 83.3% (95% CI: 77.1 to 89.5) and 86.8% (95% CI: 81.2 to 92.4) for Δ%, respectively., Conclusions: The assessment of levodopa usual morning dose response through the base-peak evaluation represents an accurate method for detecting parkinsonian patients with motor fluctuations, and for defining the Minimal Important Difference (MID) in levodopa response suggesting the presence of motor fluctuations in PD patients demanding further therapeutic interventions.

Background and Purpose: Although Labrune syndrome is a well-known disorder characterized by a typical neuroradiological triad, namely leukoencephalopathy, intracranial calcifications and cysts, there are no reports of systemic involvement in this disorder. This paper attempts to describe a peculiar clinical manifestation related to a novel mutation in the SNORD118 gene., Methods: Clinical examination, brain and total-body imaging, and neurophysiological and ophthalmological investigations were performed. Amplification of the SNORD118 gene and Sanger sequencing were integrated to investigate potential causative mutations., Results: A 69-year-old woman, with a long history of episodes of vertigo and gait imbalance, was referred to our hospital for progressive cognitive and motor deterioration. Computed tomography and magnetic resonance imaging disclosed diffuse bilateral leukoencephalopathy in periventricular and deep white matter, widespread calcifications and numerous cysts in the brain, liver, pancreas and kidneys. The genetic analysis revealed two biallelic variants in the SNORD118 gene, one of which is novel (n.60G>C)., Conclusions: This is the first report of adult-onset Labrune syndrome with an unusual systemic involvement presenting a novel mutation in the SNORD118 gene., (© 2020 European Academy of Neurology.)

Introduction: Metabolomics is an emerging approach providing new insights into the metabolic changes and underlying mechanisms involved in the pathogenesis of neurological disorders., Areas Covered: Here, the authors present an overview of the current knowledge of metabolic profiling (metabolomics) to provide critical insight on the role of biochemical markers and metabolic alterations in neurological diseases., Expert Opinion: Elucidation of characteristic metabolic alterations in neurological disorders is crucial for a better understanding of their pathogenesis, and for identifying potential biomarkers and drug targets. Nevertheless, discrepancies in diagnostic criteria, sample handling protocols, and analytical methods still affect the generalizability of current study results.

Neuropathic pain caused by peripheral nerve injuries significantly affects sensory perception and quality of life. Accumulating evidence strongly link cholesterol with development and progression of Obesity and Diabetes associated-neuropathies. However, the exact mechanisms of how cholesterol/lipid metabolism in peripheral nervous system (PNS) contributes to the pathogenesis of neuropathy remains poorly understood. Dysregulation of LXR pathways have been identified in many neuropathic models. The cholesterol sensor, LXR α/β, expressed in sensory neurons are necessary for proper peripheral nerve function. Deletion of LXR α/β from sensory neurons lead to pain-like behaviors. In this study, we identified that LXR α/β expressed in sensory neurons regulates neuronal Neuregulin 1 (Nrg1), protein involved in cell-cell communication. Using in vivo cell-specific approaches, we observed that loss of LXR from sensory neurons altered genes in non-neuronal cells located in the sciatic nerve (potentially representing Schwann cells (SC)). Our data suggest that neuronal LXRs may regulate non-neuronal cell function via a Nrg1-dependent mechanism. The decrease in Nrg1 expression in DRG neurons of WD-fed mice may suggest an altered Nrg1-dependent neuron-SC communication in Obesity. The communication between neurons and non-neuronal cells such as SC could be a new biological pathway to study and understand the molecular and cellular mechanism underlying Obesity-associated neuropathy and PNS dysfunction.

In 2017, the WHO identified Acinetobacter baumannii as the top priority for the development of new antibiotics. Despite the need for new antibiotics, there remains a lack of well validated preclinical tools for A. baumannii. Here, we characterize and validate a mouse model for A. baumannii translational research. Antibiotic sensitivity for meropenem, amikacin, and polymyxin b was determined by the broth microdilution MIC assay. LD100 inoculums, in both blood and lung infection models, were determined in male and female C3HeB/FeJ mice that were challenged with various A. baumannii clinical isolates. Blood (blood infection model) or blood and lung tissue (lung infection model) were collected from infected mice at 2 and 18 hours and the bacterial burden was determined by quantitative culture. Blood chemistry was analyzed using the iStat system. Cytokines (IL-1ß, TNF, IL-6, and IL-10) were measured in the blood and lung homogenate by ELISA assay. Lung sections (H&E stains) were scored by a pathologist. In the blood infection model, the cytokines and physiological data indicate that mice become moribund due to sepsis (low blood pH, falling bicarbonate, and a rising base deficit), whereas mice become moribund due to respiratory failure (low blood pH, rising bicarbonate, and a falling base deficit) in the oral aspiration pneumonia model. We also characterized the timing of changes in various clinical and biomarker endpoints, which can serve as a basis for future interventional studies. Susceptibility was generally similar across gender and infection route. However, we did observe that female mice were approximately 2-fold more sensitive to LAC-4 ColR in the blood infection model. We also observed that female mice were more than 10-fold more resistant to VA-AB41 in the oral aspiration pneumonia model. These results establish parameters to follow in order to assess efficacy of novel preventative and therapeutic approaches for these infections., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: In the last 12 months, author BL has owned equity in Exbaq. In the last 12 months, author BS has consulted for Shionogi, Alexion, Synthetic Biologics, Paratek, TheoremDx, and Acurx, and has owned equity in Motif, BioAIM, Synthetic Biologics, Mycomed, and Exbaq.In the last 12 months, author RB has consulted for Merck, Allergan, Wockhardt, Shionogi, and Entasis. In the last 12 months, TN has owned equity in Exbaq and BioAim. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: In a precedent paper, we validated part IV of the Unified Parkinson's Disease Rating Scale (UPDRS) for detecting motor fluctuations in Parkinson's Disease (PD) patients using a 12-h Waking-Day Motor Assessment (WDMA) as gold standard, showing a high sensitivity (> 80%) and a lower specificity (< 45%). The aim of this study was to validate the Movement Disorder Society-UPDRS (MDS-UPDRS) part IV, especially items 4.3 and 4.5, using the same methodology., Methods: PD patients attending the Movement Disorders Clinic at the University Hospital in Catania were consecutively enrolled in the study. A diurnal WDMA was performed to detect motor fluctuations. At each time interval, the motor impairment was evaluated using the motor section of the MDS-UPDRS. Presence or absence of motor fluctuations and the type of motor fluctuation were assessed by four blinded expert raters in movement disorders, by evaluating the graphical representations of the WDMA. We evaluated sensitivity and specificity together with 95% Confidence Interval (CI) of items 4.3 and 4.5, using WDMA as gold standard., Results: We estimated for item 4.3 of the MDS-UPDRS a sensitivity of 74.3% (95% CI 56.7-87.5) and a specificity of 70.6% (95% CI 44-89.7), while for item 4.5, a sensitivity of 67.9% (95% CI 47.6-84.1) and a specificity of 66.7% (95% CI 44.7-84.4)., Conclusions: The present showed a higher specificity level for MDS-UPDRS with respect to the UPDRS, while a slightly lower sensitivity mainly for predictable OFF.

Macrophytes are widely used in water treatment and have potential for remediation of flooded soils. Many techniques have been proposed to increase the phytoextraction of metals by macrophytes, however, the knowledge of periods of maximum absorption and translocation is essential and is a gap in the management of phytoremediation. To evaluate the absorption and translocation of Ba over time by Eleocharis acutangula, a greenhouse experiment was conducted and the dry matter production of plants, Ba content in the roots and aerial parts, mass of Ba accumulated in plants, translocation factors and removal coefficients of Ba, and Ba content in two layers of the soil (0.0-0.1 m and 0.1-0.2 m) were determined. The highest translocation rates were observed after 105 days of cultivation, when the plants reached a state of hyperaccumulation. The maximum accumulation of barium occurred in the aerial parts of the plants at 105 days and in the roots at both 120 and 180 days. The barium content was reduced up to 120 days, as a result of an increase in available barium content in the soil layer of 0.0-0.1 m up to 105 days and in the layer 0.10-0.20 m up to 120 days, favoring the intense accumulation of Ba during this period. After 120 days of cultivation, the accumulation in the roots maintained a high coefficient of removal of Ba from the soil to the plant. After 180 days the available barium in the soil was depleted due to this high rate of removal by the roots., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual β-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC 50 s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain β-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual β-lactam treatment regimen. IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual β-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual β-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of β-lactam drugs., (Copyright © 2019 Pandey et al.)

In anoxic environmental conditions and with a drastic reduction of the redox potential, the barium sulphate used in petroleum drilling fluids becomes a hazard to the ecosystem. A field study was conducted in Brazil in an area with a history of accidental Barium (Ba) contamination to evaluate the role of frequent plant cutting on phytoremediation. The plant species Typha domingensis and Eleocharis acutangula, cultivated in a combined plantation, were subjected to four different cut frequencies: every 90 days (four cuts), 120 days (three cuts), 180 days (two cuts), or 360 days (one cut). The total amount of Ba extracted from the soil by the plants was evaluated for each treatment and at different soil depths Overall, total Ba in the soil decreased the most dramatically for cut frequencies of 120 (37.83%) and 180 (47.73%) days at 0-0.2 m below the surface, and with cut frequencies of 120 (51.98%) and 360 (31.79%) at 0.2-0.4 m depth. Further, total Ba in the plant biomass was greatest in the 120 and 360-days frequency groups. Thus, cuts at intervals of 120 days or more are associated with high levels of Ba in the plant tissue and a decrease of soil Ba., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To characterise the dissemination patterns of uropathogenic Escherichia coli (UPEC) in a community, we conducted a study utilising molecular and fundamental descriptive epidemiology. The subjects, consisted of women having community-acquired acute urinary tract infection (UTI), were enrolled in the study from 2011 to 2012. UPEC isolates were subjected to antibacterial-susceptibility testing, O serogrouping, phylotyping, multilocus-sequence typing with phylogenetic-tree analysis and pulsed-field-gel electrophoresis (PFGE). From the 209 unique positive urinary samples 166 UPEC were isolated, of which 129 were fully susceptible to the tested antibiotics. Of the 53 sequence types (STs), the four most prevalent STs (ST95, ST131, ST73 and ST357) accounted for 60% of all UPEC strains. Antimicrobial resistance was less frequently observed for ST95 and ST73 than for the others. A majority of rare STs and a few common STs constituted the diversity pattern within the population structure, which was composed of the two phylogenetically distinct clades. Eleven genetically closely related groups were determined by PFGE, which accounted for 42 of the 166 UPEC isolates, without overt geo-temporal clustering. Our results indicate that a few major lineages of UPEC, selected by unidentified factors, are disseminated in this community and contribute to a large fraction of acute UTIs.

Aquatic macrophytes are potentially useful for phytoremediation on flooded areas. A field study in Brazil was conducted to evaluate Eleocharis acutangula (E), Cyperus papyrus (C) and Typha domingensis (T) in monocropping and intercropping, aiming to phytoremediate barium-polluted flooded soils. The treatments were: monocroppings (E, C and T); double intercroppings (EC, ET and CT); and triple intercropping (ECT). The 180-d field trial was performed in a flooded area with high barium content, with a randomized complete block design and three replicates. Plant stand size, biomass yield, and Ba concentration aboveground/Ba concentration in roots (translocation factor - TF) as well as Ba mass aboveground/Ba mass in roots (mass translocation factor - mTF) were determined. Most of the treatments did not differ on dry biomass, except for EC, which showed the lowest yield. Consistently with its biology, E. acutangula in monocropping showed the largest plant stand. Otherwise, intercroppings with T. domingensis achieved the highest amounts of barium absorbed from the soil and transferred most of the barium content from belowground to aboveground (mTF > 1.0), especially ET, which showed the highest mTF among the intercroppings (2.03). Remarkably, TF values did not reflect such phytoextraction ability for CT and ECT. Thus, mTF was more appropriate than TF to assess phytoextraction capacity. Furthermore, it was demonstrated that intercropping can increase barium uptake from flooded soils. Particularly, the intercropping ET constituted the most cost-effective treatment, with the cyperaceous species providing high plant coverage while T. domingensis facilitated barium removal by translocating it to the aboveground biomass., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study evaluated remediation of the herbicide sulfentrazone in soils with three different mineralogies (kaolinite, hematite, and gibbsite) and three remediation sulfentrazone treatments (Canavalia ensiformis L., Crotalaria juncea L., and natural attenuation). This study was conducted in a factorial scheme, in triplicate with randomized block design. Sulfentrazone was applied at 0 and 400 g ha -1 . We analyzed sulfentrazone residue in the soils by high-performance liquid chromatography and confirmed the results with bioassays of Pennisetum glaucum. Herbicide movement was greater in the kaolinitic soil without plant species. The retention of herbicide in the kaolinitic soil occurred in larger quantities in the 0-12 cm layer, with higher levels found in the treatments with plants. In the hematitic soil with C. juncea, all applied herbicides were concentrated in the 0-12 cm layer. In the other hematitic soil treatments, sulfentrazone was not detected by chemical analysis at any soil depth, although in many treatments, it was detected in the bioassay. Phytoremediation was more efficient with C. ensiformis grown in gibbsitic soil, reducing the sulfentrazone load by approximately 27%. Natural attenuation was more efficient than phytoremediation in oxidic soils due to soil pH and texture soils favored microbial degradation of the compound. Highlights The influence of soil mineralogy of herbicide sulfentrazone retention was evaluated. Canavalia ensiformis and Crotalaria juncea were evaluated as phytoremediation plants. Kaolinite soils presented great movement of sulfentrazone in the soil. Natural attenuation is more efficient in oxide soils than phytoremediation.

Purpose: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum β-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E., Methods: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical-therapy and targeted-therapy cohorts., Results: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. β-lactam/β-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy., Conclusions: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Obesity is associated with many complications, including type 2 diabetes and painful neuropathy. There is no cure or prevention for obesity-induced pain, and the neurobiology underlying the onset of the disease is still obscure. In this study, we observe that western diet (WD)-fed mice developed early allodynia with an increase of ER stress markers in the sensory neurons of the dorsal root ganglia (DRG). Using cell-specific approaches, we demonstrate that neuronal liver X receptor (LXR) activation delays ER stress and allodynia in WD-fed mice. Our findings suggest that lipid-binding nuclear receptors expressed in the sensory neurons of the DRG play a role in the onset of obesity-induced hypersensitivity. The LXR and lipid-sensor pathways represent a research avenue to identify targets to prevent debilitating complications affecting the peripheral nerve system in obesity., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The use of barite (BaSO4) in drilling fluids for oil and gas activities makes barium a potential contaminant in case of spills onto flooded soils, where low redox conditions may increase barium sulfate solubility. In order to select plants able to remove barium in such scenarios, the following species were evaluated on barium phytoextraction capacity: Brachiaria arrecta, Cyperus papyrus, Eleocharis acutangula, E. interstincta, Nephrolepsis cf. rivularis, Oryza sativa IRGA 424, O. sativa BRS Tropical, Paspalum conspersum, and Typha domingensis. Plants were grown in pots and exposed to six barium concentrations: 0, 2.5, 5.0, 10.0, 30.0, and 65.0 mg kg -1 . To simulate flooding conditions, each pot was kept with a thin water film over the soil surface (∼1.0 cm). Plants were evaluated for biomass yield and barium removal. The highest amount of barium was observed in T. domingensis biomass, followed by C. papyrus. However, the latter exported most of the barium to the aerial part of the plant, especially at higher BaCl 2 doses, while the former accumulated barium preferentially in the roots. Thus, barium removal with C. papyrus could be achieved by simply harvesting aerial biomass. The high amounts of barium in T. domingensis and C. papyrus resulted from the combination of high barium concentration in plant tissues with high biomass production. These results make T. domingensis and C. papyrus potential candidates for phytoremediation schemes to remove barium from flooded soils., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Antibiotic resistance in Gram-negative resistance has developed without a commensurate response in the successful development of antibiotic agents, though recent progress has been made., Aims: This review aims to provide a summary of the existing evidence on efficacy, spectrum of activity and the development of resistance of new agents that have been licensed or have completed advanced clinical trials and that possess activity against resistant Gram-negative organisms., Sources: A review of the published literature via MEDLINE database was performed. Relevant clinical trials were identified with the aid of the clinicaltrials.gov registry. Further data were ascertained from review of abstracts from recent international meetings and pharmaceutical companies., Content: Data on the mechanism of action, microbiological spectrum, clinical efficacy and development of resistance are reported for new agents that have activity against Gram-negative organisms. This includes the β-lactam/β-lactamase inhibitor combinations ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, meropenem/vaborbactam and aztreonam/avibactam; cefiderocol, a siderophore cephalosporin; plazomicin and eravacycline., Implications: The development of new agents with activity against multidrug-resistant Gram-negative pathogens has provided important therapeutic options for clinicians. Polymyxins appear to have been supplanted by new agents as first-line therapy for Klebsiella pneumoniae carbapenemase producers. Cefiderocol and ceftazidime/avibactam/aztreonam are promising options for metallo-β-lactamase producers, and cefiderocol and ceftolozane/tazobactam for multiply resistant Pseudomonas aeruginosa, but definitive data showing clinical efficacy is as yet lacking. Reports of the development of resistance early after the release and use of new agents is of concern. Orally administered options and agents active effective against Acinetobacter baumannii are under-represented in clinical development., (Copyright © 2017. Published by Elsevier Ltd.)

Objectives: To provide a quantitative estimation of motor fluctuations in PD through a 12-h Waking-day Motor Assessment (WDMA) and to develop new WDMA-based tools, the Motor Fluctuation Indices., Methods: Two independent samples of PD patients (exploratory population N = 51, testing population N = 109) were examined. Patients underwent a WDMA using the Unified Parkinson's Disease Rating Scale (UPDRS) and were classified as either having or not having motor fluctuations. To quantify motor fluctuations, the Worsening Index (WI), the Mean Fluctuation Index (MFI) and the Coefficient of Variation (CV) were computed. The optimal cut-off for each index distinguishing patients with or without fluctuations was calculated on the exploratory population. Cut-offs' accuracy was then verified in the testing population., Results: Optimal cut-off scores to differentiate stable patients from fluctuating ones were 8.3 for WI, 5 for MFI and 12.9 for CV. Sensitivity and a specificity were 91.2% (95%CI: 85.9 to 96.5) and 87.8% (95%CI: 81.7 to 93.9) for WI; 75% (95%CI: 66.9 to 83.1) and 90.2% (95%CI: 84.7 to 95.8) for MFI; 69.1% (95%CI: 60.4 to 77.8) and 95.1% (95%CI: 91.1 to 99.2) for CV. Patients with a larger magnitude of fluctuation had higher values for all three indices, whereas patients with multiple daily fluctuations presented only higher WI values., Conclusions: WDMA-derived Motor Fluctuation Indices may represent reliable tools for evaluating and quantifying the severity of motor fluctuations in PD patients. Even if WDMA is a time-consuming procedure, the detection of Motor Fluctuation Indices could be helpful in assessing therapeutic efficacy on motor fluctuations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The management of infections with New Delhi metallo-beta-lactamase-1 (NDM)-producing bacteria remains clinically challenging given the multidrug resistant (MDR) phenotype associated with these bacteria. Despite resistance in vitro , ceftazidime-avibactam previously demonstrated in vivo activity against NDM-positive Enterobacteriaceae Herein, we observed in vitro synergy with ceftazidime-avibactam and aztreonam against an MDR Klebsiella pneumoniae harboring NDM. In vivo , humanized doses of ceftazidime-avibactam monotherapy resulted in >2 log 10 CFU bacterial reduction; therefore, no in vivo synergy was observed., (Copyright © 2017 American Society for Microbiology.)

Ubiquitin-like protein Ubl4A is a small, multi-functional protein with no ubiquitination activity. We have previously demonstrated that Ubl4A directly interacts with actin-related protein 2/3 complex (Arp2/3) and promotes Arp2/3-dependent actin branching, thereby accelerating plasma membrane translocation of protein kinase Akt upon insulin stimulation. Here, we show that Ubl4A is critical for plasma membrane protrusion and cell migration. Ubl4A, F-actin and Arp2/3 are co-localized at the cell leading edges during wound closure. Knockout of Ubl4A significantly reduces actin-mediated membrane protrusion and delays wound healing by primary mouse embryonic fibroblasts. Consistently, the ability of fibroblasts to migrate out of corneal tissue ex vivo is also impaired in Ubl4A-deficient mice. Furthermore, cell motility, but not phagocytosis, is significantly decreased in Ubl4A-deficient macrophages compared with wild-type controls. These results imply an important role for Ubl4A in cell migration-associated pathophysiological processes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Donor-derived infections with multidrug-resistant gram-negative bacteria are associated with poor outcomes, in part because of limited treatment options. Here, we describe a case of donor-derived, disseminated infection with colistin-resistant, carbapenemase-producing Klebsiella pneumoniae in a liver transplant recipient that was cured with addition of intravenous fosfomycin to a multidrug regimen, in conjunction with aggressive surgical source control. Intravenous fosfomycin represents a promising adjunctive agent for use in treatment of extensively drug-resistant infections in immunocompromised hosts., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patients infected or colonized with carbapenem-resistant Klebsiella pneumoniae (CRKp) are often chronically and acutely ill, which results in substantial mortality unrelated to infection. Therefore, estimating excess mortality due to CRKp infections is challenging. The Consortium on Resistance against Carbapenems in K. pneumoniae (CRACKLE) is a prospective multicenter study. Here, patients in CRACKLE were evaluated at the time of their first CRKp bloodstream infection (BSI), pneumonia or urinary tract infection (UTI). A control cohort of patients with CRKp urinary colonization without CRKp infection was constructed. Excess hospital mortality was defined as mortality in cases after subtracting mortality in controls. In addition, the adjusted hazard ratios (aHR) for time-to-hospital-mortality at 30 days associated with infection compared with colonization were calculated in Cox proportional hazard models. In the study period, 260 patients with CRKp infections were included in the BSI (90 patients), pneumonia (49 patients) and UTI (121 patients) groups, who were compared with 223 controls. All-cause hospital mortality in controls was 12%. Excess hospital mortality was 27% in both patients with BSI and those with pneumonia. Excess hospital mortality was not observed in patients with UTI. In multivariable analyses, BSI and pneumonia compared with controls were associated with aHR of 2.59 (95% CI 1.52-4.50, p <0.001) and 3.44 (95% CI 1.80-6.48, p <0.001), respectively. In conclusion, in patients with CRKp infection, pneumonia is associated with the highest excess hospital mortality. Patients with BSI have slightly lower excess hospital mortality rates, whereas excess hospital mortality was not observed in hospitalized patients with UTI., (Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Introduction: The UPDRS-IV represents the most common screening tool to assess motor fluctuations in patients with PD despite the lack of a clinimetric validation., Objectives: We evaluated sensitivity and specificity of UPDRS-IV using a 12-h waking-day motor assessment as the gold standard., Methods: We consecutively enrolled PD patients who underwent a 12-h waking-day motor assessment in the study. Patients were clinically evaluated every 2 h for 12 h using the UPDRS-III. Motor scores were reported as a line graph and six blinded raters classified patients as having or not having motor fluctuations. The UPDRS-IV was used in order to assess the presence of predictable and unpredictable motor fluctuations according to items 36-38., Results: Sixty two PD patients were enrolled in the study. According to the raters' evaluations, 39 (62.9%) were classified as having motor fluctuations, while according to the UPDRS-IV 47 (75.8%) presented a motor fluctuation giving a sensitivity of 87.2% (95%CI 72.6-95.7) and a specificity of 43.5% (95%CI 23.2-65.5)., Conclusion: Our study results confirm the high level of sensitivity with a lower level of specificity of UPDRS-IV to screen motor fluctuations in PD patients., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Class C β-lactamases poorly hydrolyze cephamycins (e.g., cefoxitin, cefotetan, and moxalactam). In the past 2 decades, a new family of plasmid-based AmpC β-lactamases conferring resistance to cefoxitin, the FOX family, has grown to include nine unique members descended from the Aeromonas caviae chromosomal AmpC. To understand the basis for the unique cephamycinase activity in the FOX family, we determined the first X-ray crystal structures of FOX-4, apo enzyme and the acyl-enzyme with its namesake compound, cefoxitin, using the Y150F deacylation-deficient variant. Notably, recombinant expression of N-terminally tagged FOX-4 also yielded an inactive adenylylated enzyme form not previously observed in β-lactamases. The posttranslational modification (PTM), which occurs on the active site Ser64, would not seem to provide a selective advantage, yet might present an opportunity for the design of novel antibacterial drugs. Substantial ligand-induced changes in the enzyme are seen in the acyl-enzyme complex, particularly the R2 loop and helix H10 (P289 to N297), with movement of F293 by 10.3 Å. Taken together, this study provides the first picture of this highly proficient class C cephamycinase, uncovers a novel PTM, and suggests a possible cephamycin resistance mechanism involving repositioning of the substrate due to the presence of S153P, N289P, and N346I substitutions in the ligand binding pocket., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Acinetobacter baumannii is an important cause of healthcare-associated infections, and is particularly problematic among patients who undergo organ transplantation. We describe a case of fulminant sepsis caused by carbapenem-resistant A. baumannii harboring the blaOXA-23 carbapenemase gene and belonging to international clone II. This isolate led to the death of a patient 6 days after simultaneous kidney-pancreas transplantation. Autopsy findings revealed acute mitral valve endocarditis, myocarditis, splenic and renal emboli, peritonitis, and pneumonia. This case highlights the severe nature of certain A. baumannii infections and the vulnerability of transplanted patients to the increasingly intractable "high-risk" clones of multidrug-resistant organisms., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an increasing global threat. Here, we describe the prevalence and impact of tigecycline use in a cohort of patients with CRKP bacteriuria nested within a multicentre, prospective study. In the 21-month study period, 260 unique patients were included. Tigecycline was given to 80 (31%) patients. The use of tigecycline during the index hospitalization was significantly associated with the subsequent development of tigecycline resistance in the same patient (OR, 6.13; 95% CI, 1.15-48.65; p 0.03). In conclusion, the use of tigecycline with CRKP bacteriuria is common, and is associated with the subsequent development of tigecycline resistance., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)