Intraspinal microstimulation and diaphragm activation after cervical spinal cord injury.

Intraspinal microstimulation (ISMS) using implanted electrodes can evoke locomotor movements after spinal cord injury (SCI) but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger midcervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5-21 days) C2 hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250-ms train stimulus (100 Hz, 100-200 µA) to the ventral C4 spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in ∼70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable "closed-loop-like" ISMS approaches to sustain ventilation after severe SCI.NEW & NOTEWORTHY We examined the feasibility of using intraspinal microstimulation (ISMS) of the cervical spinal cord to evoke diaphragm activity ipsilateral to acute and subacute hemisection of the upper cervical spinal cord of the rat. This proof-of-concept study demonstrated the efficacy of diaphragm activation, using an upper airway respiratory EMG signal to trigger ISMS at the level of the ipsilesional phrenic nucleus during acute and advanced postinjury intervals.

[Urinary catheters prevalence study in a university hospital]. / Enquête de prévalence sur le sondage vésical dans un centre hospitalo-universitaire.

INTRODUCTION: Urinary tract infection is the most common healthcare-association infection, especially because of urinary catheter. We evaluated our practices concerning catheter insertion and management in our institution. MATERIALS AND METHODS: We conducted a single-centre descriptive cross-sectional study during 1 week in September 2014 in all adult departments. We noted prevalence, indications, length, management of urinary catheter (UC) and symptomatic catheter-associated urinary tract infections (SCAUTI). RESULTS: Amongst 1046 patients audited, 125 (12%) had UC. The mean age was 72 years (64.8-79.2). UC prevalence was higher in surgical (88%) and medical (87%) intensive care, urology (50%), geriatrics (18%) and long-term care (18%) departments. The average catheterisation length was 7.8 days (3.8-11.8); it was shorter in surgery than in medicine departments (3.6 vs 9.7 days, P<0.001). Catheters were present for more than 4 days in 60% of the cases. Acute urinary retention was the most frequent indication (59%), significantly more in medical than surgical departments (75% vs 26%). Others indications were perioperative (17%), diuresis monitoring (12%), strict immobilization (4%) and unnecessary indications or staff comfort (4%). A SCAUTI was present in 10% of cases, mostly in medicine department (30% vs 8%). CONCLUSION: The prevalence of our institution is higher than the national prevalence (8.1%), but still below the European average (17.2%). Control of the risk of CAUTI requires compliance with UC appropriate indications, UC management, and prompt removal of unnecessary UC. LEVEL OF EVIDENCE: 4.

Partial depletion of the proinflammatory monocyte population is neuroprotective in the myenteric plexus but not in the basal ganglia in a MPTP mouse model of Parkinson's disease.

Parkinson's disease (PD) patients often suffer from gastrointestinal (GI) impairments that are associated with the alteration of dopaminergic (DAergic) neurons in the myenteric nervous system. Growing evidence suggests that inflammation originating from the gut may have a major impact in both the initiation and progression of PD. Here, we investigated the role of the innate immune response in neurodegeneration occurring in central nervous system (CNS) and enteric nervous system (ENS) in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that produces Parkinsonism in both humans and animal models. We found a strong immune response in the gut of mice treated with MPTP, as demonstrated by the prominent presence of macrophages derived from CD115(+) CD11b(+) Ly6C(Hi) monocytes, known as M1 monocytes, and increased production of IL-1ß and IL-6. Partial depletion of proinflammatory M1 monocytes through intravenous injections of clodronate-encapsulated liposome protects against MPTP-induced reduction of tyrosine hydroxylase (TH) expression in the ENS. In contrast, loss of striatal TH expression in the CNS after MPTP intoxication occurs regardless of partial monocyte depletion. Examination of brain tissue revealed that microglial activation, comprising the majority of the immune response in the CNS after MPTP injections is unaffected by M1 depletion. In vitro experiments revealed that MPTP and MPP(+) act directly on monocytes to elicit a proinflammatory response that is, in part, dependent on the MyD88/NF-κB signaling pathway resulting in nitrite and proinflammatory cytokine production. Taken together, our results demonstrate a critical role for proinflammatory M1 monocytes/macrophages in DAergic alterations occurring in the GI, but not in the brain, in the MPTP model of PD.

An event-based hydrologic simulation model for bioretention systems.

Bioretention systems are designed to treat stormwater and provide attenuated drainage between storms. Bioretention has shown great potential at reducing the volume and improving the quality of stormwater. This study introduces the bioretention hydrologic model (BHM), a one-dimensional model that simulates the hydrologic response of a bioretention system over the duration of a storm event. BHM is based on the RECARGA model, but has been adapted for improved accuracy and integration of pollutant transport models. BHM contains four completely-mixed layers and accounts for evapotranspiration, overflow, exfiltration to native soils and underdrain discharge. Model results were evaluated against field data collected over 10 storm events. Simulated flows were particularly sensitive to antecedent water content and drainage parameters of bioretention soils, which were calibrated through an optimisation algorithm. Temporal disparity was observed between simulated and measured flows, which was attributed to preferential flow paths formed within the soil matrix of the field system. Modelling results suggest that soil water storage is the most important short-term hydrologic process in bioretention, with exfiltration having the potential to be significant in native soils with sufficient permeability.

A LAMP point-of-care test to guide antimicrobial choice for treatment of Staphylococcus pseudintermedius pyoderma in dogs.

Staphylococcus pseudintermedius is the most common cause of pyoderma in dogs. We validated a point-of-care (PoC) test based on colorimetric loop-mediated isothermal amplification (LAMP) for rapid S. pseudintermedius identification and susceptibility testing for first line antimicrobials for systemic treatment of canine pyoderma, i.e., lincosamides, first generation cephalosporins and amoxicillin clavulanate. Newly designed LAMP primers targeting clinically relevant resistance genes were combined with a previously validated set of primers targeting spsL for species identification. After laboratory validation on 110 clinical isolates, we assessed the performance of the test on 101 clinical specimens using routine culture and susceptibility testing as a reference standard. The average hands-on and turnaround times for the PoC test were 30 and 90 min, respectively. The assay showed sensitivity and specificity near 100% for both species identification and susceptibility testing when performed on bacterial cultures or clinical specimens in the laboratory. However, the PoC test yielded less accurate results when performed on-site by clinical staff (92% sensitivity and 64% specificity for species identification, 67% sensitivity and 96% specificity for ß-lactam susceptibility, and 83% sensitivity and 71% specificity for lincosamide susceptibility). These results indicate that the PoC test should be adapted to a user-friendly technology to facilitate performance and interpretation of results by clinical staff. If properly developed, the test would allow veterinarians to gain rapid information on antimicrobial choice, limiting the risk of treatment failure and facilitating adherence to antimicrobial use guidelines in small animal veterinary dermatology.

Working memory and processing speed abilities are related to habituation and change detection in school-aged children: An ERP study.

High cognitive performance is related to efficient brain processing while accomplishing complex cognitive tasks. This efficiency is observed through a rapid engagement of the brain regions and the cognitive processes required for task accomplishment. However, it is unclear if this efficiency is also present in basic sensory processes such as habituation and change detection. We recorded EEG with 85 healthy children (51 males) aged between 4 and 13 years old, while they listened to an auditory oddball paradigm. Cognitive functioning was evaluated using the Weschler Intelligence Scales for Children Fifth Edition and the Weschler Preschool & Primary School for Intelligence Fourth Edition. Auditory evoked potentials (AEPs) analyses and repeated measure analysis of covariance as well as regression models were performed. The analysis revealed that P1 and N1 repetition effects were observed across levels of cognitive functioning. Further, working memory abilities were related to repetition suppression on the auditory P2 component amplitude, while faster processing speed was related to repetition enhancement on the N2 component amplitude. Also, Late Discriminative Negativity (LDN) amplitude, a neural correlate of change detection, increased with working memory abilities. Our results confirm that efficient repetition suppression (i.e. greater reduction in amplitudes with greater levels of cognitive functioning) and more sensitive change detection (greater amplitude changes of the LDN) are related to the level of cognitive functioning in healthy children. More specifically, working memory and processing speed abilities are the cognitive domains related to efficient sensory habituation and change detection.

Spondylodiscitis via enterospinal fistula after promontofixation.

Spondylodiscitis on enterospinal fistula after promontofixation. A case report and other spondylodiscitis etiologies.

Pollutant Pb burden in Mediterranean Centroscymnus coelolepis deep-sea sharks.

We report lead (Pb) analyses in juvenile (n = 37; mean length = 24.7 ±â€¯2.3 cm) and adult (n = 16; mean length = 52.3 ±â€¯9.3 cm) Centroscymnus coelolepis Mediterranean deep-sea sharks that are compared to Pb content in bathy-demersal, pelagic and shallow coastal sharks. Median Pb concentrations of C. coelolepis muscle (0.009-0.056 wet ppm) and liver (0.023-0.061 wet ppm) are among the lowest encountered in shark records. Stable Pb isotope imprints in adult C. coelolepis muscles highlight that most of Pb in C. coelolepis is from human origin. Lead isotopes reveal the persistence of gasoline Pb emitted in the 1970s in low-turnover adult shark's muscle while associated liver imprints are in equilibrium with recent pollutant Pb signatures suggesting an efficient pollutant Pb turnover metabolism. The comparison of Pb distribution between adult and juvenile cohorts suggests the role of dietary exposure and possible maternal offloading of Pb during gestation, likely associated to vitellogenesis in this aplacental viviparous deep-sea shark.

Early small bowel obstruction in laparoscopic Roux-en-Y gastric bypass.

Alimentary limb kinking after laparoscopic Roux-en-Y gastric bypass suggested by CT-scan and diagnosed at laparoscopic surgery. Surgical treatment principles.

Validation of the Seegene RV15 multiplex PCR for the detection of influenza A subtypes and influenza B lineages during national influenza surveillance in hospitalized adults.

Background. The Serious Outcomes Surveillance Network of the Canadian Immunization Research Network (CIRN SOS) has been performing active influenza surveillance since 2009 (ClinicalTrials.gov identifier: NCT01517191). Influenza A and B viruses are identified and characterized using real-time reverse-transcriptase polymerase chain reaction (RT-PCR), and multiplex testing has been performed on a subset of patients to identify other respiratory virus aetiologies. Since both methods can identify influenza A and B, a direct comparison was performed.Methods. Validated real-time RT-PCRs from the World Health Organization (WHO) to identify influenza A and B viruses, characterize influenza A viruses into the H1N1 or H3N2 subtypes and describe influenza B viruses belonging to the Yamagata or Victoria lineages. In a subset of patients, the Seeplex RV15 One-Step ACE Detection assay (RV15) kit was also used for the detection of other respiratory viruses.Results. In total, 1111 nasopharyngeal swabs were tested by RV15 and real-time RT-PCRs for influenza A and B identification and characterization. For influenza A, RV15 showed 98.0 % sensitivity, 100 % specificity and 99.7 % accuracy. The performance characteristics of RV15 were similar for influenza A subtypes H1N1 and H3N2. For influenza B, RV15 had 99.2 % sensitivity, 100 % specificity and 99.8 % accuracy, with similar assay performance being shown for both the Yamagata and Victoria lineages.Conclusions. Overall, the detection of circulating subtypes of influenza A and lineages of influenza B by RV15 was similar to detection by real-time RT-PCR. Multiplex testing with RV15 allows for a more comprehensive respiratory virus surveillance in hospitalized adults, without significantly compromising the reliability of influenza A or B virus detection.

Investigation into a new softening agent for use on formalin-fixed, paraffin wax-embedded tissue.

The use of tissue softening agents to improve microtomy of keratotic tissues is employed widely. Many of these softeners contain hazardous constituents such as phenol. In this study, the use of non-ionic surfactants or non-toxic ingredients are investigated with the aim of creating a new softening agent. The new agent should be more effective in facilitating the sectioning of hardened tissue while reducing toxicity and complications associated with sectioning hard tissue compared to a commercially available phenol-based formulation. Four formulations are compared against the commercial product for their capability to section routinely processed paraffin-embedded tissue under standard operating procedure parameters. The trial formulations were shown to be fast acting and enabled improved serial sectioning of hard keratotic tissue in nearly all the cases tested. There was no evidence of adverse staining using either tinctorial or immunohistochemical methods. The new formulations had advantages over the commercially available solutions, improving on the number and quality of sections attainable from the tissue blocks, as well as offering a composition less toxic than phenol-based products.

Pharmacokinetic and pharmacogenetic determinants of the activity and toxicity of irinotecan in metastatic colorectal cancer patients.

This study aims at establishing relationships between genetic and non-genetic factors of variation of the pharmacokinetics of irinotecan and its metabolites; and also at establishing relationships between the pharmacokinetic or metabolic parameters and the efficacy and toxicity of irinotecan. We included 49 patients treated for metastatic colorectal cancer with a combination of 5-fluorouracil and irinotecan; a polymorphism in the UGT1A1 gene (TA repeat in the TATA box) and one in the CES2 gene promoter (830C>G) were studied as potential markers for SN-38 glucuronidation and irinotecan activation, respectively; and the potential activity of CYP3A4 was estimated from cortisol biotransformation into 6beta-hydroxycortisol. No pharmacokinetic parameter was directly predictive of clinical outcome or toxicity. The AUCs of three important metabolites of irinotecan, SN-38, SN-38 glucuronide and APC, were tentatively correlated with patients' pretreatment biological parameters related to drug metabolism (plasma creatinine, bilirubin and liver enzymes, and blood leukocytes). SN-38 AUC was significantly correlated with blood leukocytes number and SN-38G AUC was significantly correlated with plasma creatinine, whereas APC AUC was significantly correlated with plasma liver enzymes. The relative extent of irinotecan activation was inversely correlated with SN-38 glucuronidation. The TATA box polymorphism of UGT1A1 was significantly associated with plasma bilirubin levels and behaved as a significant predictor for neutropoenia. The level of cortisol 6beta-hydroxylation predicted for the occurrence of diarrhoea. All these observations may improve the routine use of irinotecan in colorectal cancer patients. UGT1A1 genotyping plus cortisol 6beta-hydroxylation determination could help to determine the optimal dose of irinotecan.

Chronic activation of the D2 dopamine autoreceptor inhibits synaptogenesis in mesencephalic dopaminergic neurons in vitro.

Chronic blockade or activation of dopamine receptors is critical for the pharmacological treatment of diseases like schizophrenia, Parkinson's or attention deficit and hyperactivity disorder. However, the long-term impact of such treatments on dopamine neurons is unclear. Chronic blockade of the dopamine D2 receptor in vivo triggers an increase in the axonal arborization of dopamine neurons [European Journal of Neuroscience, 2002, 16, 787-794]. However, the specific involvement of presynaptic (autoreceptors) vs. postsynaptic D2 receptors as well as the molecular mechanisms involved have not been determined. Here, we examined the role of D2 autoreceptors in regulating the ability of mouse dopamine neurons to establish axon terminals. Chronic activation of this receptor with quinpirole, a specific agonist, decreased the number of axon terminals established by isolated dopamine neurons. This effect was accompanied by a decrease in dopamine release and was mediated through inhibition of protein kinase A. The decrease in axon terminal number induced by D2 receptor activation was also occluded when the mammalian Target of Rapamycin pathway of mRNA translation was blocked. Our results suggest that chronic activation of the D2 autoreceptor inhibits synaptogenesis by mesencephalic dopamine neurons through translational regulation of the synthesis of proteins required for synapse formation. This study provides a better understanding of the impact of long-term pharmacological interventions acting through the D2 receptor.

The influence of fluorouracil outcome parameters on tolerance and efficacy in patients with advanced colorectal cancer.

The purpose of this study was to determine simple genetic factors helpful to tailor 5-FU administration and determine strategy in first-line chemotherapy of advanced colorectal cancer. In 76 patients initially treated by 5-FU, thymidylate synthase, dihydropyrimidine dehydrogenase and methylene tetrahydrofolate reductase germinal polymorphisms, dihydrouracil/uracil plasma ratio and 5-FU plasma clearance were investigated and correlated for tolerance (10.5% grade 3 and 4 toxicity) and efficacy (32.9% objective response rate and 20 months median overall survival time). Toxicity was linked to performance status >2 (P=0.004), low UH2/U ratio, 2846 A>T, IVS 14+1G>A for DPD (P=0.031), and homozygoty C/C for MTHFR 1298 A>C (P=0.0018). The overall survival of the patients with a 3R/3R TS genotype associated with C/C for 677 C>T or A/A for 1298 A>C was statistically shorter (log-rank test P=0.0065). Genetic factors permit the tailoring of 5-FU treatment. They should occupy center stage in future clinical trials for specifically designing treatment for patients with a given biologic feature.

5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency.

UNLABELLED: 5-Fluorouracil (5-FU)-related early toxicity, due to a metabolic deficiency, is rare but is potentially severe and even lethal (0.1%). It is due to dihydropyrimidine dehydrogenase (DPYD) gene polymorphism or some epigenetic factors. The detection of metabolic change could prevent severe toxicity, but until now it has not been carried out in clinical practice. PURPOSE: To find the simplest and most accurate pretherapeutic test to predict DPD deficiency in patients treated with 5-FU by comparing different approaches. RESULTS: Two hundred and fifty two French Caucasian patients treated by 5-FU infusion were studied. A two-step strategy, combining firstly SNP detection and uracil plasma measurement, followed, in cases where metabolic deficiency was suspected, by dihydrouracil/uracil ratio determination to confirm deficiency and to determine the optimum 5-FU dosage, appeared the best approach, with 83% and 82% sensitivity and specificity, respectively. CONCLUSION: These data support the future use of this approach, suitable to clinical practice, as screening test to identify DPD deficiency before 5-FU-based therapy.

The Impact of Breakthrough Therapy Designation on Development Strategies and Timelines for Nononcology Drugs and Vaccines.

The US Food and Drug Administration (FDA) Safety and Innovation Act (FDASIA, 2012) introduced the Breakthrough Therapy Designation (BTD), a new tool to expedite development of medicines to treat serious or life-threatening diseases. The majority of BTDs have gone to oncology drugs, and a recent publication by Shea et al.1 reviewed the impact of BTD on oncology drug development. This article reviews the impact of BTD on development strategies and timelines for nononcology drugs.

Closing the drug lag for new drug submission and review in Japan: An industry perspective.

Previous publications have focused on drug lag in Japan and the government's initiatives to address the situation.(1) Japan is the third largest pharmaceutical market, and yet has experienced significant drug lag for many years. This article reviews the progress resulting from industry adaptation of new regulatory paradigms that include Japan in global drug development programs.

Activation and inhibition of rat neuronal nicotinic receptors by ABT-418.

1. ABT-418 appeared to function as a relatively broad spectrum activator of neuronal nicotinic receptors, expressed in Xenopus oocytes, with little cross reactivity to the mammalian muscle receptor subtype. However, the relative potencies of ABT-418 at the various subtypes differed from those acetylcholine (ACh). For example, ACh was most potent at alpha 3 beta 2 (EC50 approximately 30 microM) and least potent at alpha 2 beta 2 (EC50 approximately 500 microM). ABT-418 was most potent at alpha 4 beta 2 and alpha 2 beta 2 (EC50 approximately 6 microM and 11 microM, respectively) and least potent at alpha 3 beta 4 (EC50 approximately 188 microM). 2. In addition to activating neuronal receptors, ABT-418 exhibited complex properties, including the inhibition of ACh responses. 3. The current responses elicited by relatively high concentrations of ABT-418 on the alpha 4 beta 2 receptor subtype were protracted beyond the application interval. The coapplication of ABT-418 with either of the use-dependent inhibitors bis(1,2,2,6,6-tetramethyl-4-pipendimyl)sebacate (BTMPS) or tetramethyl-pipenidine (TMP) eliminated the late protracted phase of the currents with only small effects on the initial activation phase. When the reversible inhibitor TMP was washed from the bath, the previously inhibited late current reappeared, suggesting that the observed mixed agonist-antagonist effects of ABT-418 and (+/-)-epibatidine on alpha 4 beta 2 were due to a concentration-dependent noncompetitive inhibition, an effect similar to that obtained for (-)-nicotine. 4. The inhibition of alpha 4 beta 2 receptors by ABT-418 was voltage-dependent. When high concentrations of ABT-418 were applied under depolarizing conditions, additional late currents could be observed under conditions which suggested that a build up of ABT-418 in an unstirred layer over the surface of the oocyte was occurring. This may have been due to the dissociation of the drug from channel blocking sites on the receptors themselves, or alternatively, from the plasma membrane of the cells.