Exposure of Escherichia coli to antibiotic-efflux pump inhibitor combinations in a pharmacokinetic model: impact on bacterial clearance and drug resistance.

BACKGROUND: Efflux pump inhibitors (EPIs) offer an attractive therapeutic option when combined with existing classes. However, their optimal dosing strategies are unknown. METHODS: MICs of ciprofloxacin (CIP)+/-chlorpromazine, phenylalanine-arginine ß naphthylamide (PAßN) and a developmental molecule MBX-4191 were determined and the pharmacodynamics (PD) was studied in an in vitro model employing Escherichia coli MG1655 and its isogenic MarR mutant (I1147). Exposure ranging experiments were performed initially then fractionation. Changes in bacterial load and population profiles were assessed. Strains recovered after EPI simulations were studied by WGS. RESULTS: The CIPMICs for E. coli MG1655 and I1147 were 0.08 and 0.03 mg/L. Chlorpromazine at a concentration of 60 mg/L, PAßN concentrations of 30 mg/L and MBX-4191 concentrations of 0.5-1.0 mg/L reduced CIP MICs for I1147 and enhanced bacterial killing. Using CIP at an AUC of 1.2 mg·h/L, chlorpromazine AUC was best related to reduction in bacterial load at 24 h, however, when the time drug concentration was greater than 25 mg/L (T > 25 mg/L) chlorpromazine was also strongly related to the effect. For PaßN with CIP AUC, 0.6 mg·h/L PaßN AUC was best related to a reduction in bacterial load. MBX-4191T > 0.5-0.75 mg·h/L was best related to reduction in bacterial load. Changes in population profiles were not seen in experiments of ciprofloxacin + EPIs. WGS of recovered strains from simulations with all three EPIs showed mutations in gyrA, gyrB or marR. CONCLUSIONS: AUC was the pharmacodynamic driver for chlorpromazine and PAßN while T > threshold was the driver for MBX-4191 and important in the activity of chlorpromazine and PAßN. Changes in population profiles did not occur with combinations of ciprofloxacin + EPIs, however, mutations in gyrA, gyrB and marR were detected.

A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder.

Exercise is an efficacious treatment for major depressive disorder (MDD) and has independently been shown to have anti-inflammatory effects in non-depressed subjects. Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinically relevant. In the TReatment with Exercise Augmentation for Depression (TREAD) study, participants who were partial responders to a selective serotonin reuptake inhibitor were randomized to receive one of two doses of exercise: 16 kilocalories per kilogram of body weight per week (KKW), or 4 KKW for 12 weeks. Blood samples were collected before initiation and again at the end of the 12-week exercise intervention. Serum was analyzed using a multiplexed ELISA for interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period (P<0.0001). In addition, a significant positive correlation between change in IL-1ß and change in depression symptom scores was observed (P=0.04). There were no significant changes in mean level of any cytokine following the 12-week intervention, and no significant relationship between exercise dose and change in mean cytokine level. Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response. Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1ß to positive depression treatment outcomes.

A review of echocardiography in anaesthetic and peri-operative practice. Part 1: impact and utility.

Echocardiography is migrating rapidly across speciality boundaries and clinical demand is expanding. Echocardiography shows promise for evolving applications in the peri-operative assessment and therapeutic management of patients undergoing non-cardiac surgery, whether it be elective or emergency. Although evidence is limited with regard to significant impact on outcomes from anaesthesia and surgery, there is little doubt about the validity and power of two-dimensional real-time viewing of cardiac anatomy and function. Echocardiography can be used to assist in decision-making along the entire peri-operative pathway, and is increasingly delivered by the previously referring physicians. The discussion around more widespread incorporation of cardiac ultrasound into anaesthetic practice must take into account competency, training and governance. Failure to do so adequately may mean that the use of echocardiography is poorly applied and costly.

The genetically isolated populations of Finland and sardinia may not be a panacea for linkage disequilibrium mapping of common disease genes.

The choice of which population to study in the mapping of common disease genes may be critical. Isolated founder populations, such as that found in Finland, have already proved extremely useful for mapping the genes for specific rare monogenic disorders and are being used in attempts to map the genes underlying common, complex diseases. But simulation results suggest that, under the common disease-common variant hypothesis, most isolated populations will prove no more useful for linkage disequilibrium (LD) mapping of common disease genes than large outbred populations. There is very little empirical data to either support or refute this conclusion at present. Therefore, we evaluated LD between 21 common microsatellite polymorphisms on chromosome 18q21 in 2 genetic isolates (Finland and Sardinia) and compared the results with those observed in two mixed populations (United Kingdom and United States of America). Mean levels of LD were similar across all four populations. Our results provide empirical support for the expectation that genetic isolates like Finland and Sardinia will not prove significantly more valuable than general populations for LD mapping of common variants underlying complex disease.

Quantitative neurodegenerative pathology does not explain the degree of hippocampal atrophy on MRI in degenerative dementia.

OBJECTIVE: The purpose of this study was to investigate the neuropathological substrates underlying in vivo hippocampal atrophy on magnetic resonance imaging (MRI) in autopsy confirmed neurodegenerative dementia cases. METHODS: Thirty-one neuropathologically verified cases (23 with Lewy body dementia (LBD) and eight with Alzheimer's disease (AD)) were included who had undergone an MRI scan close to death (mean 1.5 years). Manual volumetric measurements were undertaken for the hippocampus, entorhinal cortex and amygdala on MRI, along with quantitative neuropathological analysis of plaque, tangle and Lewy body pathology in the same regions. The relationship between neuropathology and MRI volumes was assessed using correlations and linear regression. RESULTS: Hippocampal and amygdala volumes were significantly smaller in cases with AD than with LBD, but there was no difference in entorhinal cortex volume. Analysing all cases together, a significant positive correlation was observed between normalised hippocampal volume and percent area of Lewy bodies in the hippocampus (r=0.449, p=0.017) but not with tangles (r=0.059, p=0.766) or plaques (r=-0.361, p=0.119). There were no other significant correlations between regional MRI volume and measures of neuropathology. Regression analysis showed that overall diagnosis of AD rather than burden of individual pathological changes was the most significant predictor of hippocampal volume loss in autopsy confirmed cases. CONCLUSION: Our results suggest that (i) hippocampal and amygdala but not entorhinal cortex, volumes differ between AD and LBD and (ii) factors other than current markers of neurodegenerative pathological change are responsible for atrophy of medial temporal lobe structures in AD and LBD.

Health self-advocacy training for persons with intellectual disabilities.

BACKGROUND: People with intellectual disabilities (ID) have unequal access to health care. While systemic efforts are addressing health inequalities, there remains a need to demonstrate that persons with ID can increase their health self-advocacy skills. METHOD: A randomised control design with up to 6-month follow-up was used to evaluate the 3Rs (Rights, Respect and Responsibility) health self-advocacy training program for persons with ID (n = 31). Training involved teaching participants to recognise and redress health rights violations in the context of respect and responsibility. Training materials included PowerPoint slides and interactive video scenarios illustrating health rights, respect and responsibility problem and non-problems. Two-hour training sessions were conducted twice a week in a group format where participants played a game and answered questions. RESULTS: The health rights training group made significantly more correct responses on post training and follow-up tests than the control group. Training effects generalised to untrained scenarios and in situ health interviews. CONCLUSIONS: The results of this study suggest that persons with ID can learn complex skills related to health self-advocacy. More research is needed to improve in situ generalisation.

Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease.

Essential metals such as copper (Cu) and zinc (Zn) are important cofactors in diverse cellular processes, while metal imbalance may impact or be altered by disease state. Cu is essential for aerobic life with significant functions in oxidation-reduction catalysis. This redox reactivity requires precise intracellular handling and molecular-to-organismal levels of homeostatic control. As the central organ of Cu homeostasis in vertebrates, the liver has long been associated with Cu storage disorders including Wilson Disease (WD) (heritable human Cu toxicosis), Idiopathic Copper Toxicosis and Endemic Tyrolean Infantile Cirrhosis. Cu imbalance is also associated with chronic liver diseases that arise from hepatitis viral infection or other liver injury. The labile redox characteristic of Cu is often discussed as a primary mechanism of Cu toxicity. However, work emerging largely from the study of WD models suggests that Cu toxicity may have specific biochemical consequences that are not directly attributable to redox activity. This work reviews Cu toxicity with a focus on the liver and proposes that Cu accumulation specifically impacts Zn-dependent processes. The prospect that Cu toxicity has specific biochemical impacts that are not entirely attributable to redox may promote further inquiry into Cu toxicity in WD and other Cu-associated disorders.

Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis.

The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.

Evaluation of brain tissue or cerebrospinal fluid with broadly reactive polymerase chain reaction for Ehrlichia, Anaplasma, spotted fever group Rickettsia, Bartonella, and Borrelia species in canine neurological diseases (109 cases).

BACKGROUND: Vector-transmitted microorganisms in the genera Ehrlichia, Anaplasma, Rickettsia, Bartonella, and Borrelia are commonly suspected in dogs with meningoencephalomyelitis (MEM), but the prevalence of these pathogens in brain tissue and cerebrospinal fluid (CSF) of dogs with MEM is unknown. HYPOTHESIS/OBJECTIVES: To determine if DNA from these genera is present in brain tissue and CSF of dogs with MEM, including those with meningoencephalitis of unknown etiology (MUE) and histopathologically confirmed cases of granulomatous (GME) and necrotizing meningoencephalomyelitis (NME). ANIMALS: Hundred and nine dogs examined for neurological signs at 3 university referral hospitals. METHODS: Brain tissue and CSF were collected prospectively from dogs with neurological disease and evaluated by broadly reactive polymerase chain reaction (PCR) for Ehrlichia, Anaplasma, Spotted Fever Group Rickettsia, Bartonella, and Borrelia species. Medical records were evaluated retrospectively to identify MEM and control cases. RESULTS: Seventy-five cases of MUE, GME, or NME, including brain tissue from 31 and CSF from 44 cases, were evaluated. Brain tissue from 4 cases and inflammatory CSF from 30 cases with infectious, neoplastic, compressive, vascular, or malformative disease were evaluated as controls. Pathogen nucleic acids were detected in 1 of 109 cases evaluated. Specifically, Bartonella vinsonii subsp. berkhoffii DNA was amplified from 1/6 dogs with histopathologically confirmed GME. CONCLUSION AND CLINICAL IMPORTANCE: The results of this investigation suggest that microorganisms in the genera Ehrlichia, Anaplasma, Rickettsia, and Borrelia are unlikely to be directly associated with canine MEM in the geographic regions evaluated. The role of Bartonella in the pathogenesis of GME warrants further investigation.

Thermal neutron transmutation doping of GaN semiconductors.

High quality Ge doping of GaN is demonstrated using primarily thermal neutrons for the first time. In this study, GaN was doped with Ge to concentrations from 1016 Ge atoms/cm3 to 1018 Ge atoms/cm3. The doping concentrations were measured using gamma-ray spectroscopy and confirmed using SIMS analysis. The data from SIMS analysis also show consistent Ge doping concentration throughout the depth of the GaN wafers. After irradiation, the GaN was annealed in a nitrogen environment at 950 °C for 30 min. The neutron doping process turns out to produce spatially uniform doping throughout the whole volume of the GaN substrate.

An emerging framework for fully incorporating public involvement (PI) into patient-reported outcome measures (PROMs).

Patient-reported outcome measures (PROMs) are widely used in the United Kingdom (UK) and internationally to report and monitor patients' subjective assessments of their symptoms and functional status and also their quality of life. Whilst the importance of involving the public in PROM development to increase the quality of the developed PROM has been highlighted this practice is not widespread. There is a lack of guidance on how public involvement (PI) could be embedded in the development of PROMs, where the roles can be more complex than in other types of research. This paper provides a timely review and sets out an emerging framework for fully incorporating PI into PROM development.

The visualization of concanavalin A binding sites in Purkinje cell somata and dendrites of rat cerebellum.

The localization of concanavalin A (Con A) binding sites in Purkinje cell somata and dendrites has been studied using a peroxidase labeling technique. In the somata, the nuclear, Golgi, and endoplasmic reticulum (ER) membranes are rich in Con A binding sites. The hypolemmal cisternae, which are continuous with the ER from the soma and throughout the dendritic tree of Purkinje cells, are also rich in Con A binding sites. Other cisternae seen in these dendrites do not bind detectable amounts of Con A. The results suggest that a cisternal system, rich in carbohydrate, may be continuous from the nuclear envelope to distal dendritic segments of Purkinje cells. Such a system could play a role in the movement of materials from Purkinje somata to dendrites.

Biological consequences of el nino.

Observations of the 1982-1983 El Niño make it possible to relate the anomalous ocean conditions to specific biological responses. In October 1982 upwelling ecosystems in the eastern equatorial Pacific began a series of transitions from the normal highly productive condition to greatly reduced productivity. The highly productive condition had returned by July 1983. Nutrients, phytoplankton biomass, and primary productivity are clearly regulated by the physical changes of El Niño. Evidence from 1982 and 1983 also suggests effects on higher organisms such as fish, seabirds, and marine mammals, but several more years of observation are required to accurately determine the magnitude of the consequences on these higher trophic levels.

Mercury concentrations in recent and ninety-year-old benthopelagic fish.

Several species of bottom-dwelling fish from 2500 meters with similar feeding habits had mercury concentrations that differed by an order of magnitude. Within one species there was a correlation between size and concentration, with the larger individuals having mercury concentrations as high as 0.8 part per million (wet weight). The mercury content of the water in the deep-ocean habitat of these fish appears not to determine the mercury content of a particular fish; species-specific factors and size do appear to determine this concentration. The species-specific variation between the recent fish also existed between the same two species in specimens collected 90 years ago from a depth of 2000 meters, and a 90-year-old specimen fit closely the size-concentration regression curve for nine recent individuals of the same species.

Biological consequences of the 1975 el nino.

The weak El Niño event of 1975 had a clearly defined effect on the biological productivity of the southeastern tropical Pacific. During February and March 1975, warm (27 degrees C) water of low salinity (33.5 parts per thousand) and low nutrient content extended south across the equator east of the Galápagos Islands, replacing the nutrient-rich water normally supplied by equatorial upwelling. Equatorial primary production was less than 0.2 gram of carbon per square meter per day, one-fifth of the normal value. At the maximum development of the 1975 event, the coastal region of Peru continued to have strong nearshore upwelling with primary production values greater than 2.5 grams of carbon per square meter per day, although the zone of high production was confined to a 250-kilometer-wide band, one-half its normal width. The biological effects of the 1975 event were short-lived; in April and May 1975 the equatorial region had begun to reestablish its normal levels of primary production.

Physical and biological controls on carbon cycling in the equatorial pacific.

The equatorial Pacific is the largest oceanic source of carbon dioxide to the atmosphere and has been proposed to be a major site of organic carbon export to the deep sea. Study of the chemistry and biology of this area from 170 degrees to 95 degrees W suggests that variability of remote winds in the western Pacific and tropical instability waves are the major factors controlling chemical and biological variability. The reason is that most of the biological production is based on recycled nutrients; only a few of the nutrients transported to the surface by upwelling are taken up by photosynthesis. Biological cycling within the euphotic zone is efficient, and the export of carbon fixed by photosynthesis is small. The fluxes of carbon dioxide to the atmosphere and particulate organic carbon to the deep sea were about 0.3 gigatons per year, and the production of dissolved organic carbon was about three times as large. The data establish El Niño events as the main source of interannual variability.

High Nitrite Levels off Northern Peru: A Signal of Instability in the Marine Denitrification Rate.

During February and March 1985, nitrite levels along the northern (approximately 7 degrees to 10 degrees S) Peruvian coast were unusually high. These accumulations occurred in oxygen-deficient waters, suggesting intensified denitrification. In a shallow offshore nitrite maximum, concentrations were as high as 23 micromoles per liter (a record high). Causes for the unusual conditions may include a cold anomaly that followed the 1982-83 El Niño. The removal of combined nitrogen (approximately 3 to 10 trillion grams of nitrogen per year) within zones of new or enhanced denitrification observed between 7 degrees to 16 degrees S suggests a significant increase in oceanic denitrification.

Lattice Boltzmann model for thermal transpiration.

The conventional Navier-Stokes-Fourier equations with no-slip boundary conditions are unable to capture the phenomenon of gas thermal transpiration. While kinetic approaches such as the direct simulation Monte Carlo method and direct solution of the Boltzmann equation can predict thermal transpiration, these methods are often beyond the reach of current computer technology, especially for complex three-dimensional flows. We present a computationally efficient nonequilibrium thermal lattice Boltzmann model for simulating temperature-gradient-induced flows. The good agreement between our model and kinetic approaches demonstrates the capabilities of the proposed lattice Boltzmann method.

Degenerative myelopathy in two Boxer dogs.

Degenerative myelopathy (DM) is a common, slowly progressive, debilitating disease reported in several dog breeds, including the German Shepherd Dog and Pembroke Welsh Corgi. Boxer dogs present occasionally for a thoracolumbar myelopathy for which no cause is identified on MRI or cerebrospinal fluid analysis. Despite a lack of a histologic description of DM in the Boxer in the veterinary literature, such dogs are presumed to have DM. Here we report 2 histologically confirmed cases of DM in the Boxer breed in which histologic studies disclosed marked degenerative changes in the spinal cord that were most prominent in the thoracic and cranial lumbar segments. Lesions consisted of myelin vacuolation and degeneration, myelophagocytosis, reactive astrocytosis, and ellipsoid formation most prominent in the lateral and ventral funiculi. We present a detailed histologic description of DM in the Boxer dog and compare it to DM in other purebred dogs.