Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Coadministration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when th

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Reversible behavioral deficits in rats during a cycle of demyelination-remyelination of the fimbria.

Traumatic brain injury (TBI) selectively damages white matter. White matter damage does not produce deficits in many behavioral tests used to analyze experimental TBI. Rats were impaired on an active place avoidance task following inactivation of one hippocampal injection of tetrodotoxin. The need for both hippocampi suggests that acquisition of the active place avoidance task may require interhippocampal communication. The controlled cortical impact model of TBI demyelinates midline white matter and impairs rats on the active place avoidance task. One white matter region that is demyelinated is the fimbria that contains hippocampal commissural fibers. We therefore tested whether demyelination of the fimbria produces deficits in active place avoidance. Lysophosphatidylcholine (LPC) was injected stereotaxically to produce a cycle of demyelination-remyelination of the fimbria. At 4 days, myelin loss was observed in the fimbria of LPC-, but not saline-injected rats. Fourteen days after injection, myelin content increased in LPC-, but not saline-injected rats. Three days after injection, both saline- and LPC-injected rats had similar performance on an open field and passive place avoidance task in which the rat avoided a stationary shock zone on a stationary arena. The following day, on the active place avoidance task, LPC-injected rats had a significantly higher number of shock zone entrances suggesting learning was impaired. At 14 days after injection, saline- and LPC-injected rats had similar performance on open field and passive place avoidance. On active place avoidance, however, saline- and LPC-injected rats had a similar number of total entrances suggesting that the impairment seen at 4 days was no longer present at 14 days. These data suggest that active place avoidance is highly sensitive to white matter injury

Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis

ObjectiveThe antifibrinolytic agent tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding, but its effectiveness in patients with traumatic brain injury (TBI) is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hemorrhage (ICH) secondary to TBI, does TXA compared to placebo improve patients' outcomes?MethodsMEDLINE, EMBASE, CINAHL, and other databases were searched for randomized controlled trial (RCT) or quasi-RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurologic function, hematoma expansion, and adverse effects. We used "Grading quality of evidence and strength of recommendations" to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate.ResultsOf 1030 references identified through the search, 2 high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk of 0.64 (95% confidence interval [CI], 0.41-1.02); on unfavorable functional status, a relative risk of 0.77 (95% CI, 0.59-1.02); and on ICH progression, a relative risk of 0.76 (95% CI, 0.58-0.98). No serious adverse effects (such as thromboembolic events) associated with TXA group were reported in the included trials.ConclusionPooled results from the 2 RCTs demonstrated statistically significant reduction in ICH progression with TXA and a nonstatistically significant improvement of clinical outcomes in ED patients with TBI. Further evidence is required to support its routine use in patients with TBI

Measurements of rat behavior during open field, passive place avoidance and active place avoidance.

<p>Measurements of rat behavior during open field, passive place avoidance and active place avoidance.</p

Behavioral analyses at times of demyelination and remyelination.

<p><b>Panel A,</b> Total distance traveled during active place avoidance. Rats injected with LPC or saline traveled a similar distance at both 4 and 14 days (F_(3,19)  = 1.71). <b>Panel B,</b> Representative tracks of rats 4 or 14 days after saline or LPC injection on the final (6^th) trial of active place avoidance. Red lines indicate the shock zone boundaries and the red circles indicate the locations where shocks were delivered. <b>Panel C,</b> Summary of the number of shock zone entrances in each trial of active place avoidance. At 4 days, saline- and LPC-injected animals showed a significant effect of treatment (F_(1,10)  = 16.31, p<0.005) and trial (F_(5,50)  = 4.20, p<0.005) with no interaction of treatment and trial (F_(5,50)  = 0.47). At 14 days, saline and LPC-injected animals had an no significant effect of treatment (F_(1,10)  = 0.23), but there was a significant effect of trial (F_(5,55)  = 5.81, p<0.001). Saline-treated animals analyzed at 4 and 14 days showed no significant effect of days (F_(1,12)  = 1.78), but there was a significant effect of trial (F_(5,60)  = 3.35, p<0.0005). LPC-injected rats at 4 and 14 days, trended toward an effect of days (F_(1,9)  = 4.0, p = 0.08) but had a significant effect of trial (F_(5,45)  = 10.4 p<0.0001) and a significant interaction of treatment and trial (F_(5,45)  =  2.62, p<0.05). These data suggest that saline-injected animals acquired the active place avoidance task at both 4 and 14 days, whereas LPC-injected animals acquired the task only at 14 days. Saline- and LPC-injected animals differed in their acquisition the task at 4, but not 14 days.</p

MINO plus NAC prevented myelin loss.

<p><b>Panel A</b>, Schematic of the regions of interest (ROIs) from a coronal section located −3.36 mm from Bregma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012490#pone.0012490-Paxinos1" target="_blank">[40]</a>. The ROIs were: corpus callosum (A), dorsal hippocampal commissure (B), stratum radiatum (C), fimbria (D), internal capsule (E), fornix (F), mammilothalamic tract (G). <b>Panel B</b>, Representative images of corpus callosum and dorsal hippocampal commissure stained with luxol fast blue. B1, Sham-CCI-saline; B2 CCI-saline; B3, CCI-MINO plus NAC. The scale bar corresponds to 100µm.</p

MINO provided a modest improvement of active place avoidance following moderate CCI.

<p>The total number of entrances into the shock zone was assayed in the 6 trials of active place avoidance training.</p

Measurements of rat behavior during open field, passive place avoidance and active place avoidance.

<p>Rats received either sham- or moderate-CCI. Beginning one hour after surgery the rats received either saline, cyclosporine (CYCLO) simvastatin (SIM), progesterone (PROG), minocycline (MINO), n-acetyl cysteine (NAC) or MINO plus NAC. Seven days later all groups were tested on the hierarchy of three behavioral tasks. In the open field test, there was no effect of treatment on total distance traveled (F_7,40 = 0.40, p>0.8). In passive place avoidance, there was no effect of treatment on either average distance over 4 trials or shock zone entrances (total distance, F_7,40 = 0.67, p>0.6; entrances, F_7,40 = 0.48, p>0.8). In massed active place avoidance testing on the 6^th trial of the first day, there was no effect of treatment on speed (F_7,40 = 0.44, p>0.8) or linearity (F_7,40 = 0.25, p>0.9)). The number of shocks per entrance in CCI-saline treated rats was not changed by the drugs individually or in combination (F_7,40 = 0.39, p>0.6). In contrast, there was a significant treatment effect with MINO or MINO plus NAC significantly improved time to first entrance (F_4,35 = 26.7, p<0.0001; **p<0.001, *p<0.05; post-hoc test).</p