The resolution of inflammation: a mathematical model of neutrophil and macrophage interactions.
There is growing interest in inflammation due to its involvement in many diverse medical conditions, including Alzheimer's disease, cancer, arthritis and asthma. The traditional view that resolution of inflammation is a passive process is now being superceded by an alternative hypothesis whereby its resolution is an active, anti-inflammatory process that can be manipulated therapeutically. This shift in mindset has stimulated a resurgence of interest in the biological mechanisms by which inflammation resolves. The anti-inflammatory processes central to the resolution of inflammation revolve around macrophages and are closely related to pro-inflammatory processes mediated by neutrophils and their ability to damage healthy tissue. We develop a spatially averaged model of inflammation centring on its resolution, accounting for populations of neutrophils and macrophages and incorporating both pro- and anti-inflammatory processes. Our ordinary differential equation model exhibits two outcomes that we relate to healthy and unhealthy states. We use bifurcation analysis to investigate how variation in the system parameters affects its outcome. We find that therapeutic manipulation of the rate of macrophage phagocytosis can aid in resolving inflammation but success is critically dependent on the rate of neutrophil apoptosis. Indeed our model predicts that an effective treatment protocol would take a dual approach, targeting macrophage phagocytosis alongside neutrophil apoptosis.


Photosynthesis of overwintering evergreen plants.
In this review we focus on photosynthetic behavior of overwintering evergreens with an emphasis on both the acclimative responses of photosynthesis to cold and the winter behavior of photosynthesis in conifers. Photosynthetic acclimation is discussed in terms of the requirement for a balance between the energy absorbed through largely temperature-insensitive photochemical processes and the energy used for temperature-sensitive biochemical processes and growth. Cold acclimation transforms the xanthophyll-mediated nonphotochemical antenna quenching of absorbed light from a short-term dynamic response to a long-term sustained quenching for the whole winter period. This acclimative response helps protect the evergreen foliage from photooxidative damage during the winter when photosynthesis is restricted or prevented by low temperatures. Although the molecular mechanisms behind the sustained winter excitation quenching are largely unknown, it does involve major alterations in the organization and composition of the photosystem II antenna. In addition, photosystem I may play an important role in overwintering evergreens not only by quenching absorbed light photochemically via its support of cyclic electron transport at low temperatures, but also by nonphotochemical quenching of absorbed light irrespective of temperature. The possible role of photosystem II reaction centers in nonphotochemical quenching of absorbed energy in overwintering evergreens is also discussed. Processes like chlororespiration and cyclic electron transport may also be important for maintaining the functional integrity of the photosynthetic apparatus of overwintering evergreens both during periods of thawing in winter and during recovery from winter stress in spring. We suggest that the photosynthetic acclimation responses of overwintering evergreens represent specific evolutionary adaptations for plant species that invest in the long-term maintenance of leaf structure in cold climatic zones as exemplified by the boreal forests of the Northern Hemisphere.


Natural product diversity associated with the nematode symbionts Photorhabdus and Xenorhabdus.
Xenorhabdus and Photorhabdus species dedicate a large amount of resources to the production of specialized metabolites derived from non-ribosomal peptide synthetase (NRPS) or polyketide synthase (PKS). Both bacteria undergo symbiosis with nematodes, which is followed by an insect pathogenic phase. So far, the molecular basis of this tripartite relationship and the exact roles that individual metabolites and metabolic pathways play have not been well understood. To close this gap, we have significantly expanded the database for comparative genomics studies in these bacteria. Clustering the genes encoded in the individual genomes into hierarchical orthologous groups reveals a high-resolution picture of functional evolution in this clade. It identifies groups of genes-many of which are involved in secondary metabolite production-that may account for the niche specificity of these bacteria. Photorhabdus and Xenorhabdus appear very similar at the DNA sequence level, which indicates their close evolutionary relationship. Yet, high-resolution mass spectrometry analyses reveal a huge chemical diversity in the two taxa. Molecular network reconstruction identified a large number of previously unidentified metabolite classes, including the xefoampeptides and tilivalline. Here, we apply genomic and metabolomic methods in a complementary manner to identify and elucidate additional classes of natural products. We also highlight the ability to rapidly and simultaneously identify potentially interesting bioactive products from NRPSs and PKSs, thereby augmenting the contribution of molecular biology techniques to the acceleration of natural product discovery.


Assessing shoreline exposure and oyster habitat suitability maximizes potential success for sustainable shoreline protection using restored oyster reefs.
Oyster reefs provide valuable ecosystem services that contribute to coastal resilience. Unfortunately, many reefs have been degraded or removed completely, and there are increased efforts to restore oysters in many coastal areas. In particular, much attention has recently been given to the restoration of shellfish reefs along eroding shorelines to reduce erosion. Such fringing reef approaches, however, often lack empirical data to identify locations where reefs are most effective in reducing marsh erosion, or fully take into account habitat suitability. Using monitoring data from 5 separate fringing reef projects across coastal Louisiana, we quantify shoreline exposure (fetch + wind direction + wind speed) and reef impacts on shoreline retreat. Our results indicate that fringing oyster reefs have a higher impact on shoreline retreat at higher exposure shorelines. At higher exposures, fringing reefs reduced marsh edge erosion an average of 1.0 m y(-1). Using these data, we identify ranges of shoreline exposure values where oyster reefs are most effective at reducing marsh edge erosion and apply this knowledge to a case study within one Louisiana estuary. In Breton Sound estuary, we calculate shoreline exposure at 500 random points and then overlay a habitat suitability index for oysters. This method and the resulting visualization show areas most likely to support sustainable oyster populations as well as significantly reduce shoreline erosion. Our results demonstrate how site selection criteria, which include shoreline exposure and habitat suitability, are critical to ensuring greater positive impacts and longevity of oyster reef restoration projects.


Rapid and sensitive detection of Shiga toxin-producing Escherichia coli from nonenriched stool specimens by real-time PCR in comparison to enzyme immunoassay and culture.
Shiga toxin (Stx)-producing Escherichia coli (STEC) bacteria are a frequent cause of food-borne gastroenteritis, hemorrhagic colitis, and hemolytic uremic syndrome. Because antimicrobial agents are generally contraindicated in patients infected with STEC, a sensitive and specific diagnostic test with rapid turnaround is essential. Current culture methods may fail to detect non-O157 STEC. We evaluated a Stx gene real-time PCR assay using hybridization probes and the LightCycler instrument with 204 prospectively collected stool specimens, which were also tested for Stx by enzyme immunoassay (EIA) (ProSpecT STEC; Remel, Lenexa, KS) and by culturing on chromogenic agar (Chromagar O157; BD BBL, Sparks, MD). In addition, 85 archived stool specimens previously tested for Stx (by EIA) and/or E. coli O157:H7 (by culture) were tested by PCR. Sample preparation for PCR included mixing the stool in sterile water and extraction of nucleic acid using the MagNA Pure LC instrument (Roche Diagnostics). The PCR assay had 100% sensitivity and specificity compared to EIA and culture for specimens collected prospectively (4 of 204 specimens were positive) and compared to culture and/or EIA for archival specimens (42 of 85 specimens were positive). Both the EIA and PCR produced positive results from a specimen containing an O103 serotype STEC in the prospective specimens, and the PCR test detected three positive specimens that contained nonviable STEC in the archived specimens. The PCR assay demonstrated 100% sensitivity and specificity compared to EIA and/or culture and more rapid turnaround than either EIA or culture.


Normative data for subcortical regional volumes over the lifetime of the adult human brain.
Normative data for volumetric estimates of brain structures are necessary to adequately assess brain volume alterations in individuals with suspected neurological or psychiatric conditions. Although many studies have described age and sex effects in healthy individuals for brain morphometry assessed via magnetic resonance imaging, proper normative values allowing to quantify potential brain abnormalities are needed. We developed norms for volumetric estimates of subcortical brain regions based on cross-sectional magnetic resonance scans from 2790 healthy individuals aged 18 to 94years using 23 samples provided by 21 independent research groups. The segmentation was conducted using FreeSurfer, a widely used and freely available automated segmentation software. Models predicting subcortical regional volumes of each hemisphere were produced including age, sex, estimated total intracranial volume (eTIV), scanner manufacturer, magnetic field strength, and interactions as predictors. The mean explained variance by the models was 48%. For most regions, age, sex and eTIV predicted most of the explained variance while manufacturer, magnetic field strength and interactions predicted a limited amount. Estimates of the expected volumes of an individual based on its characteristics and the scanner characteristics can be obtained using derived formulas. For a new individual, significance test for volume abnormality, effect size and estimated percentage of the normative population with a smaller volume can be obtained. Normative values were validated in independent samples of healthy adults and in adults with Alzheimer's disease and schizophrenia.


Diabetes and cancer risk: A Mendelian randomization study.
Earlier cohort studies using conventional regression models have consistently shown an increased cancer risk among individuals with type 2 diabetes. However, reverse causality and residual confounding due to common risk factors could exist, and it remains unclear whether diabetes per se contributes to cancer development. Mendelian randomization analyses might clarify the true association between diabetes and cancer risk. We conducted a case-cohort study with 10,536 subcohort subjects and 3,541 newly diagnosed cancer cases derived from 32,949 eligible participants aged 40-69 years within the Japan Public Health Center-based Prospective Study. With 29 known type 2 diabetes susceptibility variants, we used an inverse variance-weighted method to estimate hazard ratios for the associations of diabetes with risks of total and site-specific cancers. The hazard ratios of cancer per doubling of the probability of diabetes were 1.03 (95% confidence interval [CI], 0.92-1.15) overall, 1.08 (95% CI: 0.73-1.59) for the pancreas, 0.80 (95% CI: 0.57-1.14) for the liver and 0.90 (95% CI: 0.74-1.10) for the colorectum. Additional analyses, using publicly available large-scale genome-wide association study data on colorectal cancer in Japan, resulted in a narrower CI (hazard ratio: 1.00; 95% CI: 0.93-1.07). In this prospective Mendelian randomization study with a large number of incident cancer cases, we found no strong evidence to support associations between diabetes and overall and site-specific cancer risks. Our findings suggest that there is little evidence to support the genetic role of type 2 diabetes in cancer development in the Japanese population.


[Diagnosis and treatment of extrauterine pregnancy in The Netherlands].
To inventory current policy in the diagnosis and treatment of ectopic pregnancy (EP) in the Netherlands. Questionnaire. Academic Medical Centre, Amsterdam, the Netherlands. A questionnaire was sent to all I30 departments of gynaecology in the Netherlands. The response rate was 94% (n = 122). Transvaginal ultrasonography was very widely used, whereas results of serum hCG measurements were only available within 24 h in 75% of the departments. Eighty-three per cent of the respondents screen for EP in high-risk patients. Laparoscopic surgery was used in 62% of the departments, open surgery in 9%, whereas in 28% the surgical technique depended upon the skills of the operating gynaecologist. If desire for pregnancy was present, 53% of the departments operated always conservatively, 2% always radically, whereas in 43% conservative surgery was performed only in case of a healthy ipsilateral tube. Methotrexate was used in 38% of the departments for persistent trophoblast, in 16% as primary treatment of interstitial pregnancies and in 13% as primary treatment for tubal pregnancy. Diagnostic strategies for EP in the Netherlands are homogeneous and in conformity with the state of the art in the literature. For treatment, laparoscopic techniques are widely used. In almost all departments, conservative surgery is the treatment of choice. Use of methotrexate is so far limited to treatment of persistent trophoblast after a failure of conservative surgery.


CABG in 2012: Evidence, practice and the evolution of guidelines.
In the management of coronary artery disease (CAD) it is important to ensure that all patients are receiving optimal medical therapy irrespective of whether any intervention, by stents or surgery, is planned. Furthermore it is important to establish if a proposed intervention is for symptomatic and/or prognostic reasons. The latter can only be justified if there is demonstration of a significant volume of ischaemia (>10% of myocardial mass). Taking together evidence from the most definitive randomized trial and its registry component (SYNTAX), almost 79% of patients with three vessel CAD and almost two thirds of patients with LMS disease have a survival benefit and marked reduction in the need for repeat revascularisation with CABG in comparison to stents, implying that CABG is still the treatment of choice for most of these patients. This conclusion which is apparently at odds with the results of most previous trials of stenting and surgery but entirely consistent with the findings of large propensity matched registries can be explained by the fact that SYNTAX enrolled 'real life' patients rather than the highly select patients usually enrolled in previous trials. SYNTAX also shows that for patients with less severe coronary artery disease there is no difference in survival between CABG and stents but a lower incidence of repeat revascularisation with CABG. At three years, SYNTAX shows no difference in stroke between CABG and stents for three-vessel disease but a higher incidence of stroke with CABG in patients with left main stem disease. In contrast the PRECOMBAT trial of stents and CABG in patients with left main stem disease showed no excess of mortality or stroke with CABG in comparison to stents in relatively low risk patients. Finally the importance of guidelines and multidisciplinary/heart teams in making recommendations for interventions is emphasised.


The Patient Voice: Stent Experiences After Ureteroscopy-Insights from In-Depth Interviews with Participants in the USDRN STENTS Nested Qualitative Cohort Study.
Purpose: Ureteral stents are commonly used after ureteroscopy and cause significant discomfort, yet qualitative perspectives on patients' stent experiences remain unknown. We describe psychological, functional, and interpersonal effects of post-ureteroscopy stents and whether additional patient-reported assessments may be needed. Materials and Methods: Using a qualitative descriptive study design, we conducted in-depth interviews with a nested cohort of participants in the STudy to Enhance uNderstanding of sTent-associated Symptoms (STENTS). Participants shared their symptoms with a post-ureteroscopy stent and described symptom bother and impact on daily activities. All interviews were audio-recorded, transcribed, and analyzed using applied thematic analysis. During analysis, participants' experiences with interference in daily activities were categorized into three groups based on their impact: minimal, moderate, and substantial. Results: All 39 participants experienced pain, although descriptions varied and differentiated between feelings of pain vs discomfort. Almost all experienced urinary symptoms. Only a few reported other physical symptoms, although several psychological aspects were identified. In the areas of sleep, mood, life enjoyment, work, exercise, activities of daily living, driving, childcare, and leisure/social activities, the stent had little impact on daily living among participants placed in the minimal group (n = 12) and far greater impact for participants in the substantial group (n = 8). For patients in the moderate group (n = 19), some daily activities were moderately or substantially affected, whereas other activities were minimally affected. Conclusions: Counseling to better prepare patients for the impact of stent-associated symptoms may help mitigate symptom burden. While existing instruments adequately cover most symptoms, additional assessments for other domains, particularly psychological factors, may be needed.


Implication of the tRNA initiation step for human immunodeficiency virus type 1 reverse transcriptase in the mechanism of 3'-azido-3'-deoxythymidine (AZT) resistance.
There is a lack of correlation between biochemical studies and the observed clinical resistance of AIDS patients on long-term AZT therapy. Mutant HIV-1 reverse transcriptase in the viral isolates from these patients shows a 100-fold decrease in sensitivity to AZT whereas little or no difference is observed in kinetic parameters in vitro using steady-state kinetic analysis. A pre-steady-state kinetic analysis was used to examine the binding and incorporation of 2'-deoxythymidine 5'-triphosphate (dTTP) and 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) by wild-type HIV-1 reverse transcriptase and a clinically important AZT-resistant mutant form of the enzyme (D67N, K70R, T215Y, K219Q) utilizing a physiologically relevant RNA 18-mer/RNA 36-mer primer-template substrate. It was determined that with this RNA/RNA substrate there is a 2.6-fold increase in the selection for incorporation of the natural nucleotide dTTP over the unnatural nucleoside analogue AZTTP by AZT-resistant reverse transcriptase as compared to its wild-type form. This observation indicates that the tRNALys initiation step plays an important role in the development of drug resistance. Furthermore, this result implies that the structural basis of AZT resistance in HIV-1 reverse transcriptase involves the conformation of the RNA-DNA junction (formed upon attachment of a deoxynucleotide to the RNA primer). Taken together, these observations suggest a new pharmacological basis for the development of more effective and novel AIDS drugs.


Protective Effects of Defatted Sticky Rice Bran Extracts on the Early Stages of Hepatocarcinogenesis in Rats.
Use of natural products is one strategy to lessen cancer incidence. Rice bran, especially from colored rice, contains high antioxidant activity. Cancer chemopreventive effects of hydrophilic purple rice bran extract (PRBE) and white rice bran extract (WRBE) on carcinogen-induced preneoplastic lesion formation in livers of rats were investigated. A 15-week administration of PRBE and WRBE did not induce hepatic glutathione S-transferase placental form (GST-P) positive foci formation as the biomarker of rat hepatocarcinogenesis. PRBE and WRBE at 500 mg/kg body weight significantly decreased number and size of GST-P positive foci in diethylnitrosamine (DEN)-initiated rats. The number of proliferating nuclear antigen positive hepatocytes were also reduced in preneoplastic lesions in both PRBE and WRBE fed DEN-treated rats. Notably, the inhibitory effect on GST-P positive foci formation induced by DEN during the initiation stage was found only in rats treated by PRBE for five weeks. Furthermore, PRBE attenuated the expression of proinflammatory cytokines involving genes including TNF-α, iNOS, and NF-κB. PBRE contained a higher number of anthocyanins and other phenolic compounds and vitamin E. PRBE might protect DEN-induced hepatocarcinogenesis in rats via attenuation of cellular inflammation and cell proliferation. Anthocyanins and other phenolic compounds, as well as vitamin E, might play a role in cancer chemopreventive activity in rice bran extract.


Accumulation and trapping of hepatitis A virus particles by electrohydrodynamic flow and dielectrophoresis.
Hepatitis A virus particles (d = 27 nm) were successfully accumulated and trapped in a microfluidic system by means of a combination of electrohydrodynamic flow and dielectrophoretic forces. Electric fields were generated in a field cage consisting of eight microelectrodes. In addition, high medium conductance (0.3 S/m) resulted in sufficient Joule heating and the corresponding spatial variation of temperature, density, and permittivity to induce electrohydrodynamic flow in the vicinity of the field cage. Flow vortices transport particles toward the center of the field cage, where dielectrophoretic forces cause permanent entrapment and particle aggregation. Spatial distribution of temperature, density, and permittivity as well as resulting flow patterns were modeled numerically and are in good agreement with experimental results. This accumulation scheme might be applicable to sample concentration enhancement in biosensor applications.


Vps13 is required for timely removal of nurse cell corpses.
Programmed cell death and consecutive removal of cellular remnants is essential for development. During late stages of Drosophila melanogaster oogenesis, the small somatic follicle cells that surround the large nurse cells promote non-apoptotic nurse cell death, subsequently engulf them, and contribute to the timely removal of nurse cell corpses. Here, we identify a role for Vps13 in the timely removal of nurse cell corpses downstream of developmental programmed cell death. Vps13 is an evolutionarily conserved peripheral membrane protein associated with membrane contact sites and lipid transfer. It is expressed in late nurse cells, and persistent nurse cell remnants are observed when Vps13 is depleted from nurse cells but not from follicle cells. Microscopic analysis revealed enrichment of Vps13 in close proximity to the plasma membrane and the endoplasmic reticulum in nurse cells undergoing degradation. Ultrastructural analysis uncovered the presence of an underlying Vps13-dependent membranous structure in close association with the plasma membrane. The newly identified structure and function suggests the presence of a Vps13-dependent process required for complete degradation of bulky remnants of dying cells.


All-optical tunable pulse frequency chirp via slow light.
We theoretically investigate slow light via stimulated Raman scattering, paying special attention to the picosecond regime where chromatic dispersion and cross-phase modulation must be considered. In addition to the control of the Raman pulse walk-off, we demonstrate that the cross-phase-modulation-induced frequency chirp can also be all-optically tuned via Raman slow light. We further demonstrate that this new implication is a consequence of the fact that the group velocity is significantly more affected than the phase velocity in slow-light media.


Functional long-range interactions of the IgH 3' enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells.
To better understand the mechanisms underlying the role of the immunoglobulin heavy-chain gene (IgH) 3' enhancers on bcl-2 transcriptional deregulation in t(14;18) lymphoma, we characterized the physical interactions of the IgH 3' enhancer region with the bcl-2 promoters. Using the chromosome conformation capture technique, we found that the IgH 3' enhancers physically interact with the bcl-2 promoter region over a 350 kb genomic region in t(14;18) lymphoma cells. No interactions of the bcl-2 promoter region with sequences distant to the IgH enhancers were observed. The physical interactions of the IgH enhancers with the bcl-2 5' region are functionally involved in the transcriptional control of bcl-2. The histone deacetylase inhibitor, trichostatin A, repressed bcl-2 transcription and decreased the IgH enhancer-bcl-2 promoter region interactions. We showed by chromatin immunoprecipitation assay and small interference RNA transfection studies that the POU2 family transcription factor Oct-2 and its cofactor Bob-1 have an important function in mediating the IgH enhancer-bcl-2 promoter region interactions. This study reveals a new aspect of the regulatory role of the IgH 3' enhancers on bcl-2 transcription in t(14;18) lymphomas.


Elevated liver function enzymes are related to the development of prediabetes and type 2 diabetes in younger adults: the Bogalusa Heart Study.
Elevations in alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT), surrogate markers of liver dysfunction and nonalcoholic fatty liver, are considered as part of metabolic syndrome and related type 2 diabetes. However, information is limited regarding the long-term predictability of ALT and GGT in the development of prediabetes and type 2 diabetes. In this retrospective cohort study, normoglycemic (n = 874), prediabetic (n = 101), and diabetic (n = 80) adults aged 26-50 years (average age 41.3 years) were followed over an average period of 16 years since their young adulthood (aged 18-38 years, average age 25.1 years), with measurements of cardiometabolic risk factor variables including ALT and GGT. The follow-up prevalence rate of adult diabetes status by quartiles of baseline ALT and GGT levels showed an adverse trend for both prediabetes (P < 0.05) and diabetes (P < 0.01). In a longitudinal multivariate logistic regression analysis that included anthropometric, hemodynamic, and metabolic variables, as well as alcohol consumption and smoking, individuals with elevated baseline ALT and GGT levels (per 1-SD increment) were 1.16 and 1.20 times, respectively, more likely to develop diabetes (P = 0.05 for ALT and P < 0.01 for GGT); no such associations were noted for prediabetes. Regarding the predictive value of ALT and GGT, the area under the receiver operating curve analysis yielded C values ranging from 0.70 to 0.82, with values significantly higher for diabetes compared with prediabetes. These findings in younger adults suggest potential clinical utility of including ALT and GGT as biomarkers in diabetes risk assessment formulations.


Mitochondrial oxidative stress mediates high-phosphate-induced secretory defects and apoptosis in insulin-secreting cells.
Inorganic phosphate (Pi) plays an important role in cell signaling and energy metabolism. In insulin-releasing cells, Pi transport into mitochondria is essential for the generation of ATP, a signaling factor in metabolism-secretion coupling. Elevated Pi concentrations, however, can have toxic effects in various cell types. The underlying molecular mechanisms are poorly understood. Here, we have investigated the effect of Pi on secretory function and apoptosis in INS-1E clonal β-cells and rat pancreatic islets. Elevated extracellular Pi (1~5 mM) increased the mitochondrial membrane potential (ΔΨm), superoxide generation, caspase activation, and cell death. Depolarization of the ΔΨm abolished Pi-induced superoxide generation. Butylmalonate, a nonselective blocker of mitochondrial phosphate transporters, prevented ΔΨm hyperpolarization, superoxide generation, and cytotoxicity caused by Pi. High Pi also promoted the opening of the mitochondrial permeability transition (PT) pore, leading to apoptosis, which was also prevented by butylmalonate. The mitochondrial antioxidants mitoTEMPO or MnTBAP prevented Pi-triggered PT pore opening and cytotoxicity. Elevated extracellular Pi diminished ATP synthesis, cytosolic Ca(2+) oscillations, and insulin content and secretion in INS-1E cells as well as in dispersed islet cells. These parameters were restored following preincubation with mitochondrial antioxidants. This treatment also prevented high-Pi-induced phosphorylation of ER stress proteins. We propose that elevated extracellular Pi causes mitochondrial oxidative stress linked to mitochondrial hyperpolarization. Such stress results in reduced insulin content and defective insulin secretion and cytotoxicity. Our data explain the decreased insulin content and secretion observed under hyperphosphatemic states.


Fusion Assessment by MRI in Comparison With CT in Anterior Lumbar Interbody Fusion: A Prospective Study.
Prospective cohort study. To evaluate the role of magnetic resonance imaging (MRI) in evaluation of fusion status following anterior lumbar interbody fusion (ALIF) and compare agreement and confidence in assessing fusion or its absence on MRI to the current standard computed tomography (CT). A prospective follow up of patients undergoing surgery by 2 spine surgeons between 2012 and 2015 at a single institution. Fusion was assessed at different time points in these patients by 2 independent musculoskeletal radiologists. Fusion was analyzed in coronal and sagittal planes using both imaging modalities, with confidence being attributed on a scale of 0 to 3. Assessors were blinded to patient data. Fourteen patients (25 levels) with mean follow-up of 10.2 months (range 2.4-20.3 years) and age of 41 years (range 20.7-61.5 years) were assessed. MRI within the interbody cage in coronal (κ = .58) and sagittal (κ = .50) planes had the highest interobserver agreement. CT anterior to the cage in coronal (κ = .48) and sagittal (κ = .44) planes, as well as within the cage in coronal (κ = .50) and sagittal planes (κ = .44) showed moderate agreement. Confidence anterior to the interbody cage using MRI scan was reduced when compared with remaining angles and imaging modalities. The study demonstrates that MRI may be a useful tool in the assessment of fusion following ALIF with results comparable to CT, and that it may have a useful role in select patients especially considering marked radiation exposure reduction.


[Elective caesarean section].
As a part of the ongoing debate surrounding the steady increase in the rate of caesarean sections in general, the issue of elective caesarean section - following a complication-free pregnancy and in the absence of clear medical evidence actively suggesting a caesarean section - has likewise been addressed in greater depth. The progressive decline in mortality attending a well-planned caesarean section along with the reduction in morbidity brought about by improvements in caesarean section techniques have served to direct the attention towards the less apparent maternal and fetal risks of vaginal delivery. At the same time, the growing importance attached to the patient's input has made a clear definition of the concept of 'indication' more difficult. However, the distinction between medical indications and the freedom of choice of the patient is, in the predominant number of cases, an artificial one - in the ideal scenario, obstetrician and patient arrive at a joint decision after carefully considering the advantages and disadvantages of all relevant alternatives. Hence the term 'caesarean section on demand' needs to be recognized as prejudicial and needs to be replaced with the more accurate 'elective caesarean section'. Not only is ethical dilemma avoided in the process, but medical insurance agencies are left with no reasonable grounds to refuse support to such a procedure.


Mothers improve their daughters' vegetable intake: a randomized controlled trial.
The increasing prevalence of childhood overweight makes children an important target for health promotion programmes. An intervention was designed for mothers to provide more vegetables to their daughters' diet. A randomized controlled trial compared a self-regulation condition with a control condition in 155 mothers aged 25-50 years. Dependent variable was children's (aged 6-11 years) vegetable consumption which was reported by their mothers at three points in time. After baseline (Time 1), the intervention group received theory-based instructional leaflets to promote self-regulatory skills for providing a healthy nutrition for children. Changes were assessed after two weeks (Time 2) and at three-month follow-up (Time 3). The self-regulation intervention in mothers led to an increase in vegetable intake among their daughters at Time 2 but not at Time 3. However, maintenance of vegetable consumption at Time 3 was mediated by the amount of vegetable intake at Time 2. Engaging mothers in self-regulatory health promotion programmes may be a feasible strategy to facilitate more vegetable intake among their daughters.


In vitro pharmacology of ACEA-1021 and ACEA-1031: systemically active quinoxalinediones with high affinity and selectivity for N-methyl-D-aspartate receptor glycine sites.
N-methyl-D-aspartate (NMDA) receptor antagonists show therapeutic potential as neuroprotectants, analgesics, and anticonvulsants. In this context, we used electrical recording techniques to study the in vitro pharmacology of two novel quinoxalinediones, i.e., ACEA-1021 and ACEA-1031 (5-nitro-6,7- dichloro- and 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione, respectively). Assays with NMDA receptors expressed by rat brain poly(A)+ RNA in Xenopus oocytes and with NMDA receptors in cultured rat cortical neurons indicated that ACEA-1021 and ACEA-1031 are potent competitive antagonists at NMDA receptor glycine sites. Apparent dissociation constants (Kb values) for ACEA-1021 and ACEA-1031 ranged between 6 and 8 nM for oocyte assays and between 5 and 7 nM for neuronal assays. Cloned NMDA receptors expressed in oocytes showed up to 50-fold variation in sensitivity, depending upon subunit composition. For example, using fixed agonist concentrations (10 microM glycine and 100 microM glutamate) IC50 values for ACEA-1021 with four binary combinations were as follows: NMDA receptor (NR)1A/2A, 29 nM; NR1A/2B, 300 nM; NR1A/2C, 120 nM; NR1A/2D, 1500 nM. Measurement of EC50 for glycine and calculation of Kb for the inhibitors indicated that differences in IC50 values are due to subunit-dependent variations in glycine affinity (EC50 ranged between approximately 0.1 and 1 microM) combined with variations in affinity of the antagonists themselves (Kb of approximately 2-13 nM). In addition to the strong antagonism of NMDA receptors, ACEA-1021 and ACEA-1031 were also moderately potent competitive inhibitors of non-NMDA receptors activated either by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or by kainate. Antagonist affinities were similar whether measured with receptors expressed by rat brain poly(A)+ RNA in oocytes (Kb of 1-2 microM) or with cultured neurons (Kb of 1.5-3.3 microM). Our results suggest that the in vivo neuro-protective actions of ACEA-1021 and ACEA-1031 are predominantly due to inhibition at NMDA receptor glycine sites, although additional inhibition at non-NMDA receptors may play an ancillary role.


Illness perception of dropout patients followed up at bipolar outpatient clinic, Turkey.
Dropout is a common problem in the treatment of psychiatric illnesses including bipolar disorders (BD). The aim of the present study is to investigate illness perceptions of dropout patients with BD. A cross sectional study was done on the participants who attended the Mood Disorder Outpatient Clinic at least 3 times from January 2003 through June 2008, and then failed to attend clinic till to the last one year, 2009, determined as dropout. Thirty-nine dropout patients and 39 attendent patients with BD were recruited for this study. A sociodemographic form and brief illness perception questionnaire were used to capture data. The main reasons of patients with BD for dropout were difficulties of transport (31%), to visit another doctor (26%), giving up drugs (13%) and low education level (59%) is significant for dropout patients. The dropout patients reported that their illness did not critically influence their lives, their treatment had failed to control their illnesses, they had no symptoms, and that their illness did not emotionally affect them. In conclusion, the nonattendance of patients with serious mental illness can result in non-compliance of therapeutic drug regimens, and a recurrence of the appearance symptoms. The perception of illness in dropout patients with BD may be important for understanding and preventing nonattendance.


The effect of age on human cone and rod ganzfeld electroretinograms.
The ganzfeld-evoked electroretinogram (ERG) is the most effective measure of the mass electrical response of cones and rods; however, all variables affecting the various components of the ERG have not been identified. The scotopic b-wave amplitude has been appreciated to be age-dependent, but little or no information exists in the literature regarding age dependency for other components. Linear regression analysis against age and multiple regression analysis against age and log intensity of the stimulus were performed on ERG responses from 24 prospectively normal subjects. Significant age dependency was found for scotopic rod-mediated b-wave amplitude, scotopic mixed rod-and cone-mediated bx-wave amplitude, and for photopic cone-mediated and b-wave amplitude. No significant age correlation was found for dark-adapted cone a-wave amplitude, scotopic cone-mediated x-wave amplitude, scotopic a-wave amplitude from mixed rod and cone responses to bright stimuli, or for implicit times for any scotopic or photopic responses. These findings indicate that for clinical patient evaluation, age-corrected normal ranges derived from linear or multiple regression coefficients should be used for rod- and cone-mediated b-wave response, whereas normal ranges derived from mean and standard deviation are more appropriate for scotopic a-wave amplitude, scotopic cone-mediated x-wave amplitude, and for all implicit times.


Quality assurance of clinical transfusion practice by implementation of the privilege of blood prescription and computerized prospective audit of blood requests.
Guidelines, algorithms and recommendations have been issued in the attempt to ensure appropriateness of transfusion practice, but the results are less than satisfactory, mainly due to the difficulty to turn paper procedures into actual practice. In our hospital we have tried to overcome this difficulty through the implementation of a quality assurance programme which includes giving the privilege of nonurgent blood prescription to a limited number of physicians and a computerized prospective audit of blood requests. The latter is performed through verification of the compliance of blood requests, which are designed to include a patient's laboratory and clinical data, with hospital guidelines for the proper use of blood. In the 12 months since implementation of the computerized prospective audit the transfusion service has evaluated 7884 requests. Of these, 63.4% (n = 4998) were for red blood cells, 21.1% (n = 1664) for platelets and 15.5% (n = 1222) for fresh frozen plasma. The prospective audit showed that 96.8% and 98.1% of requests for red units and platelets were appropriate, respectively. Conversely, approximately 27% of plasma requests did not comply with guidelines, mainly because the evidence of coagulopathy was missing. However, inappropriateness of plasma requests for elective general surgery decreased from 39% at the onset of the programme to 14% in the last trimester considered. Moreover, the evaluation by retrospective audit of the proportion of patients transfused with both red blood cells and plasma in the perioperative period out of those transfused with red blood cells only, as an indicator of unwanted reconstitution of whole blood, showed that this proportion decreased from 47.6% (320/672) in the 12 months before implementation of computerized audit to 37.8% (244/646) in the following 12 months (difference = -9.8%, 95% confidence interval of the difference from -4.5% to -15.1%; P < 0.005 by chi 2 test). Our initial experience, together with the present system, shows that (1) the restriction of nonurgent blood prescription to a group of clinicians more educated in transfusion medicine than average clinicians practicing in a large multispecialty hospital is feasible; (2) prospective audit is a useful tool for assuring the quality of blood requesting.


Metalloproteinase binding proteins: WO2009097397.
MMPs are a group of metalloendopeptidases whose major role is in extracellular matrix (ECM) catabolism under physiological and pathological conditions. ECM catabolism is often associated with different diseases, and accumulated studies support the causal relationship between MMPs and different diseases especially with cancer and arthritis. Therefore, MMPs have been considered as therapeutic target molecules. However, multiple failures of MMP inhibitor drugs in clinical trials from late 1990s to early 2000s resulted in the consideration that wide inhibitory spectrum inhibitors of metalloproteinases may not be desirable for treatment of diseases. On the other hand, developing low molecular mass selective inhibitor(s) targeting the active site is not a very easy task. One way to overcome this problem is to develop biologic inhibitors, namely antibodies. In this patent application, Dyax Corp. reported that a binding protein (such as an antibody) against metalloproteinases, especially membrane-type 1 MMP (MMP-14) can be used as a therapeutic drug against different diseases including cancer. They succeeded in generating a selective MMP-14 inhibitory antibody with a K(i) of 0.6 nM, which showed significant suppression of different tumour growth in mice. Further development of such an antibody as a drug may fulfil an unmet area of disease treatment targeting uncontrolled cell invasion and tissue destruction.


Differences in elements between intact and disrupted human ligamenta capitum femorum.
To compare the element compositions between intact (i.e., intact throughout its length) and disrupted (i.e., ligament no longer attached to the attachment) ligaments, the contents of elements in the human ligamenta capitum femorum (LCF) were analyzed by inductively coupled plasma-atomic emission spectrometry. Histological and immunohistological assessments were also performed in both groups. The subjects were 8 men and 32 women. Trace element analyses showed that the sulfur and iron contents were significantly greater in the intact group than in the disrupted group, while the phosphorus and magnesium contents were significantly smaller in the intact group than in the disrupted group. The calcium and zinc contents were smaller in the intact group than in the disrupted group, with no significant differences. Histologically, there were fibrocartilage cells and extracellular matrix metachromasia in ligaments of the intact group. In contrast, fibrocartilage cells disappeared, and fat cells appeared instead of collagen fibrils in ligaments of the disrupted group. The LCFs of the intact group were immunohistologically positive for all components examined including collagens, glycosaminoglycans, and proteoglycans. The increase in sulfur suggested the presence of high glycosaminoglycan levels associated with fibrocartilaginous metaplasia in the ligament by compressive force. The reduction in iron may show a decreased number of blood vessels in the synovium after ligament disruption. The increases in phosphorus, magnesium, and calcium are indicative of degenerative changes including calcification and ossification. We conclude that differences in the contents of elements between intact and disrupted LCFs indicate degenerative alterations to the ligament structure after disruption.


The status of chondrichthyan conservation in the Indo-Australasian region.
The status of chondrichthyan (sharks, batoids and chimaeras) conservation in the Indo-Australasian region is examined, and issues relevant to the conservation of this fauna at the subregional level [Australia, Indonesia (excluding West Papua), New Guinea (West Papua and Papua New Guinea), New Caledonia and New Zealand] are discussed. According to the 2009 IUCN Red List of Threatened Species, c. 21% of Indo-Australasian chondrichthyans are classified as threatened (critically endangered, endangered and vulnerable) and c. 40% are of conservation concern (threatened and near threatened). The proportion of threatened species is highest in New Guinea (c. 39%) and Indonesia (c. 35%) and least in New Zealand (c. 11%). In New Guinea, three quarters of the species are of conservation concern; in Indonesia, nearly two thirds are of conservation concern. Within the region, the proportion of threatened batoids (c. 29%) is higher than threatened sharks (c. 17%), while there are no threatened chimaeras. Conservation status is discussed at the order (for sharks), suborder (for batoids) and family level. Issues relating to the conservation status of chondrichthyans vary greatly between each subregion, but they mostly relate to targeted or incidental capture in fisheries. A handful of sharks and batoids are protected within Australian waters, while one species is protected in New Zealand. Both Australia and New Zealand have developed National Plans of Action for the Conservation and Management of Sharks (NPOA-Sharks), but these are lacking elsewhere. Development and implementation of NPOA-Sharks are a priority in order to drive the conservation of the regional fauna. Sustainable fisheries management (including by-catch), confronting the challenge of illegal, unreported and unregulated fishing, species protection where appropriate and marine protected areas (MPA) are all likely to prove vital in ensuring the long-term conservation of Indo-Australasian sharks, batoids and chimaeras.


Steady-state metabolism of ethanol in perfused rat livers treated with cyanamide: quantitative analysis of acetaldehyde effects on the metabolic flux rates.
Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol in mammals. The steady-state metabolic flux of ethanol has been poorly understood. We investigated flux rates of the individual steps of ethanol metabolism in perfused rat livers treated with ALDH inactivator cyanamide as an attempt to mimic human ALDH2 deficiency commonly seen in East Asians. The net rates of ethanol oxidation, acetaldehyde oxidation, and acetate activation were determined with a set of defined equations, based on the set influx rates of ethanol and the measured efflux rates of ethanol, acetaldehyde, and acetate. After intraperitoneal injections of 0.2 and 1.5 mg/kg cyanamide, hepatic activities of mitochondrial ALDH2 and cytoplasmic ALDH1A1 decreased to a similar degree, that is, 51 to 57% and 69 to 74%, compared with the corresponding controls, respectively, whereas cytoplasmic ADH1 activity remained unchanged. At infusing 2 mM ethanol, acetaldehyde oxidation rate well matched (99%) the net ethanol oxidation rate in control liver. Both the ethanol and acetaldehyde oxidation rates were significantly decreased after cyanamide treatments. At 10 mM ethanol, the efflux acetaldehyde was significantly higher than that infusing 2 mM ethanol in both control and cyanamide groups. Seventy-eight percent of the oxidized ethanol released as efflux acetate. At 2 mM ethanol, the apparent flux control coefficients of ADH1 were assessed to be 0.78, 0.54, and 0.39, respectively, in control, low, and high cyanamide-treated livers. Kinetic simulations revealed that inhibition by acetaldehyde may largely account for the observed reduction of ADH1 oxidation rates after cyanamide treatment. Our results provide the first flux evidence that ADH and ALDH are steps influencing steady-state metabolism of ethanol in rat livers with inactivated ALDHs.


Phenotype-specific bacterial communities in the cold-water coral Lophelia pertusa (Scleractinia) and their implications for the coral's nutrition, health, and distribution.
The pseudocolonial coral Lophelia pertusa (Scleractinia, Caryophylliidae) is a eurybathic, stenothermal cosmopolitan cold-water species. It occurs in two color varieties, white and red. L. pertusa builds vast cold-water coral reefs along the continental margins, which are among the most diverse deep-sea habitats. Microbiology of L. pertusa has been in scientific focus for only a few years, but the question of whether the coral holds a host-specific bacterial community has not been finally answered. Bacteria on coral samples from the Trondheimsfjord (Norway) were characterized by the culture-independent 16S rRNA gene-based techniques terminal restriction fragment length polymorphism and sequence analysis. L. pertusa revealed a high microbial richness. Clone sequences were dominated by members of the Alpha- and Gammaproteobacteria. Other abundant taxa were Bacteroidetes, Actinobacteria, Verrucomicrobia, Firmicutes, and Planctomycetes. The bacterial community of L. pertusa not only differed conspicuously from that of the environment but also varied with both the location and color variety of its host. Therefore, the microbial colonization cannot be termed "specific" sensu stricto. However, similarities to other coral-bacterium associations suggest the existence of "cold-water coral-specific" bacterial groups sensu lato. L. pertusa-associated bacteria appear to play a significant role in the nutrition of their host by degradation of sulfur compounds, cellulose, chitin, and end products of the coral's anaerobic metabolism. Some coral-associated microbes were regarded as opportunistic pathogens. Dominance of mixotrophic members of the Rhodobacteraceae in white L. pertusa could explain the wider dispersal of this phenotype by supplementary nutrition.


Effect of probiotics on lipid profiles and blood pressure in patients with type 2 diabetes: A meta-analysis of RCTs.
This meta-analysis aimed to systematically evaluate the effects of probiotics on blood lipid and blood pressure among patients with type 2 diabetes mellitus (T2DM) based on the randomized controlled studies. PubMed, Cochrane, Embase, Wanfang, China National Knowledge Infrastructure, and VIP database were searched by the index words to identify the qualified randomized control trial. The latest research was done in the January 2017. Mean difference (MD) along with 95% confidence interval (CI) was used to analyze the included outcomes. Ten trials were included at last with 297 patients in the treatment group and 294 patients in the control group. Probiotics significantly decreased the value of total cholesterol (SMD -0.57, 95% CI -0.92 to 0.21), triglyceride (SMD -0.66, 95% CI -0.93 to 0.39), low-density lipoprotein (SMD -0.40, 95% CI -0.79 to 0.01), systolic blood pressure (WMD -5.04, 95% CI -8.8 to 1.20), diastolic blood pressure (SMD -0.39, 95% CI -0.62 to 0.17), fasting blood glucose (FBG) (SMD 3.54, 95% CI 1.94-5.15) compared with the placebo treatment. Apart from this, probiotics could significantly improve the value of high-density lipoprotein (SMD 0.38, 95% CI 0.03-0.73). Probiotics may decrease the indexes of lipid profile, blood pressure, and FBG in patients with T2DM; application of probiotics might be a new method for lipid profiles and blood pressure management in T2DM.


Species tree phylogeny and biogeography of the Neotropical genus Pradosia (Sapotaceae, Chrysophylloideae).
Recent phylogenetic studies in Sapotaceae have demonstrated that many genera need to be redefined to better correspond to natural groups. The Neotropical genus Pradosia is believed to be monophyletic and includes 26 recognized species. Here we reconstruct the generic phylogeny by a species-tree approach using (∗)BEAST, 21 recognized species (36 accessions), sequence data from three nuclear markers (ITS, ETS, and RPB2), a relaxed lognormal clock model, and a fossil calibration. We explore the evolution of five selected morphological characters, reconstruct the evolution of habitat (white-sand vs. clayish soils) preference, as well as space and time by using a recently developed continuous diffusion model in biogeography. We find Pradosia to be monophyletic in its current circumscription and to have originated in the Amazon basin at ∼47.5Ma. Selected morphological characters are useful to readily distinguish three clades. Preferences to white-sand and/or clay are somewhat important for the majority of species, but speciation has not been powered by habitat shifts. Pradosia brevipes is a relative young species (∼1.3Ma) that has evolved a unique geoxylic life strategy within Pradosia and is restricted to savannahs. Molecular dating and phylogenetic pattern indicate that Pradosia reached the Brazilian Atlantic coast at least three times: at 34.4Ma (P. longipedicellata), at 11.7Ma (P. kuhlmannii), and at 3.9Ma (weakly supported node within the red-flowered clade).


Widespread changes in network activity allow non-invasive detection of mesial temporal lobe seizures.
Decades of experience with intracranial recordings in patients with epilepsy have demonstrated that seizures can occur in deep cortical regions such as the mesial temporal lobes without showing any obvious signs of seizure activity on scalp electroencephalogram. Predicated on the idea that these seizures are purely focal, currently, the only way to detect these 'scalp-negative seizures' is with intracranial recordings. However, intracranial recordings are only rarely performed in patients with epilepsy, and are almost never performed outside of the context of epilepsy. As such, little is known about scalp-negative seizures and their role in the natural history of epilepsy, their effect on cognitive function, and their association with other neurological diseases. Here, we developed a novel approach to non-invasively identify scalp-negative seizures arising from the mesial temporal lobe based on scalp electroencephalogram network connectivity measures. We identified 25 scalp-negative mesial temporal lobe seizures in 10 patients and obtained control records from an additional 13 patients, all of whom underwent recordings with foramen ovale electrodes and scalp electroencephalogram. Scalp data from these records were used to train a scalp-negative seizure detector, which consisted of a pair of logistic regression classifiers that used scalp electroencephalogram coherence properties as input features. On cross-validation performance, this detector correctly identified scalp-negative seizures in 40% of patients, and correctly identified the side of seizure onset for each seizure detected. In comparison, routine clinical interpretation of these scalp electroencephalograms failed to identify any of the scalp-negative seizures. Among the patients in whom the detector raised seizure alarms, 80% had scalp-negative mesial temporal lobe seizures. The detector had a false alarm rate of only 0.31 per day and a positive predictive value of 75%. Of the 13 control patients, false seizure alarms were raised in only one patient. The fact that our detector specifically recognizes focal mesial temporal lobe seizures based on scalp electroencephalogram coherence features, lends weight to the hypothesis that even focal seizures are a network phenomenon that involve widespread neural connectivity. Our scalp-negative seizure detector has clear clinical utility in patients with temporal lobe epilepsy, and its potential easily translates to other neurological disorders, such as Alzheimer's disease, in which occult mesial temporal lobe seizures are suspected to play a significant role. Importantly, our work establishes a novel approach of using computational approaches to non-invasively detect deep seizure activity, without the need for invasive intracranial recordings.


The dopaminergic reward system underpins gender differences in social preferences.
Women are known to have stronger prosocial preferences than men, but it remains an open question as to how these behavioural differences arise from differences in brain functioning. Here, we provide a neurobiological account for the hypothesized gender difference. In a pharmacological study and an independent neuroimaging study, we tested the hypothesis that the neural reward system encodes the value of sharing money with others more strongly in women than in men. In the pharmacological study, we reduced receptor type-specific actions of dopamine, a neurotransmitter related to reward processing, which resulted in more selfish decisions in women and more prosocial decisions in men. Converging findings from an independent neuroimaging study revealed gender-related activity in neural reward circuits during prosocial decisions. Thus, the neural reward system appears to be more sensitive to prosocial rewards in women than in men, providing a neurobiological account for why women often behave more prosocially than men.


Diet rich in alpha-lactalbumin improves memory in unmedicated recovered depressed patients and matched controls.
Depression is associated with reduced brain serotonin (5-hydroxytryptamine; 5-HT) function and with cognitive dysfunctions. A diet rich in alpha-lactalbumin protein has been found to increase the ratio tryptophan /large neutral amino acids (Trp/SigmaLNAA), and to improve cognitive functioning in individuals with high neuroticism scores. Since cognitive dysfunctions sometimes persist after remission of depression, the present study investigated the effects of alpha-lactalbumin-enriched diet on cognition in recovered depressed patients. Twenty-three recovered depressed patients and 20 healthy matched controls without a history of depression consumed meals rich in alpha-lactalbumin or casein protein in a double-blind crossover design. Mood, cognitive function and plasma amino acids were assessed at both sessions before and after dietary intake. Alpha-lactalbumin protein had no effect on mood, but improved abstract visual memory and impaired simple motor performance. These effects were independent of history of depression. Supplements of lactalbumin may be useful for nutrition research in relation to age- or disease-related memory decline. The present findings should be further examined in different (e.g. medicated) samples. The long-term effects of alpha-lactalbumin should also be investigated.


Plasma oxygen during cardiopulmonary bypass: a comparison of blood oxygen levels with oxygen present in plasma lipid.
1. Although not often appreciated, it is a fact that molecular oxygen is more soluble in lipids than in aqueous solution. We have recently developed a method to monitor oxygen within the lipid content of plasma. Monitoring plasma oxygen is one essential element during open heart surgery using a cardiopulmonary bypass pump and oxygenator. Currently oxygen is monitored electrochemically and is based upon monitoring the partial pressure of oxygen in a gas equilibrated with whole blood. 2. To determine the relative importance of lipid-associated oxygen in blood and assess the potential use of such a measurement we present comparisons of changes in oxygen associated with whole blood and lipid content of plasma before, during and after cardiac surgery. 3. In a limited number of patients studied (n = 28), aged between 34 and 86 years, oxygen in lipid increased with decreased extracorporeal blood temperature during cardiopulmonary bypass, increased in proportion to oxygen supplied and appeared to be a better monitor of oxygen than conventional electrochemical systems currently in use. Oxygen associated with whole blood and plasma lipid was markedly below normal on aortic declamping after cardiopulmonary bypass, suggesting an hypoxic episode at this point. Levels of oxygen in the lipid phase of plasma returned to normal presurgical values 6-8 h after surgery. 4. Calculation of the concentration of lipid-associated oxygen present in plasma suggests that plasma lipids contain up to 25% of that typically ascribed to haemoglobin. Thus, we suggest that monitoring lipid-associated oxygen may prove a better alternative to current methods of measuring oxygen status. Furthermore, we suggest that plasma lipid is a hitherto unsuspected pool of circulating oxygen which may play a significant role in tissue oxygen supply.


Crystal structure of a CAP-DNA complex: the DNA is bent by 90 degrees.
The 3 angstrom resolution crystal structure of the Escherichia coli catabolite gene activator protein (CAP) complexed with a 30-base pair DNA sequence shows that the DNA is bent by 90 degrees. This bend results almost entirely from two 40 degrees kinks that occur between TG/CA base pairs at positions 5 and 6 on each side of the dyad axis of the complex. DNA sequence discrimination by CAP derives both from sequence-dependent distortion of the DNA helix and from direct hydrogen-bonding interactions between three protein side chains and the exposed edges of three base pairs in the major groove of the DNA. The structure of this transcription factor--DNA complex provides insights into possible mechanisms of transcription activation.


Mortality following bone metastasis and skeletal-related events among women with breast cancer: a population-based analysis of U.S. Medicare beneficiaries, 1999-2006.
The aim of the study is to quantify the impact of bone metastasis and skeletal-related events (SREs) on mortality in older breast cancer patients. Using the linked Surveillance, Epidemiology and End Results-Medicare database, we identified women aged 65 years or older diagnosed with breast cancer between July 1, 1999 and December 31, 2005 and followed them to determine deaths occurring through December 31, 2006. We classified patients as having possible bone metastasis and SREs using discharge diagnoses from inpatient claims and diagnoses paired with procedure codes from outpatient claims. We used Cox regression to estimate mortality hazards ratios (HR) among women with bone metastasis with or without SRE, compared with women without bone metastasis. Among 98,260 women with breast cancer (median follow-up, 3.3 years), 7,189 (7.3%) had bone metastasis either at breast cancer diagnosis (1.5%) or during follow-up (5.8%). SREs occurred in 3,319 (46%) of women with bone metastasis. HRs for risk of death were 4.9 (95% CI 4.7-5.1) and 6.2 (95% CI 5.9-6.5), respectively, for women with bone metastasis but no SRE and for women with bone metastasis plus SRE, compared with women without bone metastasis. In analyses restricted to women with bone metastasis, the adjusted HR was 1.5 (95% CI 1.4-1.6) for women with bone metastasis plus SRE, compared with women with bone metastasis but without SRE. Having a bone metastasis, as indicated by Medicare claims, was associated strongly with mortality among women with breast cancer. This association was stronger for bone metastasis complicated by SRE than for bone metastasis without SRE.


Time Trends in the Incidence of Parkinson Disease.
Changes over time in the incidence of parkinsonism and Parkinson disease (PD) remain uncertain. To investigate secular trends (period effects) and birth cohort trends in the incidence of parkinsonism and PD over 30 years in a geographically defined American population. We used the medical records-linkage system of the Rochester Epidemiology Project to identify incidence cases of PD and other types of parkinsonism in Olmsted County, Minnesota, from 1976 to 2005. All cases were classified by a movement disorder specialist using defined criteria through the review of the complete medical records within the system. The analyses for this study were conducted between May 2015 and January 2016. Incidence rates of parkinsonism and PD over 30 years. We tested for secular trends (period effects) using negative binomial regression models and for birth cohort effects using age-period-cohort models. Of 906 patients with parkinsonism, 501 were men, and the median age at onset was 74 years (interquartile range, 66-81 years). Of the 464 patients with PD, 275 were men, and the median age at onset was 73 years (interquartile range, 64-80 years). The overall incidence rates increased significantly over 30 years in men for both parkinsonism (relative risk [RR], 1.17 per decade; 95% CI, 1.03-1.33) and PD (RR, 1.24 per decade; 95% CI, 1.08-1.43). These trends were driven primarily by the older age groups. In particular, for men 70 years or older, incidence rates increased for both parkinsonism (RR, 1.24 per decade; 95% CI, 1.07-1.44) and PD (RR, 1.35 per decade; 95% CI, 1.10-1.65). The secular trends were not significant for women overall or in age strata. We observed an increased risk for both men and women born in the 1920 cohort (1915-1924). However, this birth cohort effect was significant only for PD and only in men. Our study suggests that the incidence of parkinsonism and PD may have increased between 1976 and 2005, particularly in men 70 years and older. These trends may be associated with the dramatic changes in smoking behavior that took place in the second half of the 20th century or with other lifestyle or environmental changes. However, the trends could be spurious and need to be confirmed in other populations.


Nitric oxide dose-response study in the isolated perfused rat kidney after inhibition of endothelium-derived relaxing factor synthesis: the role of serum albumin.
The dose-response relationship of steady-state nitric oxide (NO) administration on renal vascular resistance in isolated rat kidneys (IPRK) perfused at constant pressure was investigated after inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMMA). To study the influence of biological thiols on renovascular NO effects, experiments were carried out with Krebs-Henseleit (KH) perfusate solutions alone, and in combination with bovine serum albumin (KH-ALB). Steady-state administration of NO by gassing the perfusate with 0 to 340 ppm NO led to graded decreases in renovascular tone. The minimal effective NO perfusate concentration in the absence of endogenous NO synthesis was about 6 to 8 nM, whereas a near-maximal effect was observed with approximately 200 nM. The presence of albumin reduced the speed of onset of renal vasodilation and the maximal effect at a given concentration of NO. After termination of NO administration, NO-induced vasodilation persisted in KH-ALB perfused kidneys for 30 min, whereas KH-perfused kidneys showed a rapid reconstriction. These findings suggest that the prolonged, potent renal vasodilation was caused by a reaction of bovine serum albumin (BSA) with oxides of nitrogen to form S-nitroso-BSA. Nitrosothiol levels in the KH-ALB perfusate were found to be proportional to the concentration of NO administered. The above-mentioned findings, confirmed in identical experiments with diethylamine NONOate, a novel NO-liberating substance, support the biological importance of S-nitrosothiols (RS-NO) in the action and metabolism of endothelium-derived relaxing factor (EDRF) in the IPRK.


Which way was I going? Contextual retrieval supports the disambiguation of well learned overlapping navigational routes.
Groundbreaking research in animals has demonstrated that the hippocampus contains neurons that distinguish between overlapping navigational trajectories. These hippocampal neurons respond selectively to the context of specific episodes despite interference from overlapping memory representations. The present study used functional magnetic resonance imaging in humans to examine the role of the hippocampus and related structures when participants need to retrieve contextual information to navigate well learned spatial sequences that share common elements. Participants were trained outside the scanner to navigate through 12 virtual mazes from a ground-level first-person perspective. Six of the 12 mazes shared overlapping components. Overlapping mazes began and ended at distinct locations, but converged in the middle to share some hallways with another maze. Non-overlapping mazes did not share any hallways with any other maze. Successful navigation through the overlapping hallways required the retrieval of contextual information relevant to the current navigational episode. Results revealed greater activation during the successful navigation of the overlapping mazes compared with the non-overlapping mazes in regions typically associated with spatial and episodic memory, including the hippocampus, parahippocampal cortex, and orbitofrontal cortex. When combined with previous research, the current findings suggest that an anatomically integrated system including the hippocampus, parahippocampal cortex, and orbitofrontal cortex is critical for the contextually dependent retrieval of well learned overlapping navigational routes.


Prevalence and genetic and environmental influences on anxiety disorders in 6-year-old twins.
Prevalence of childhood anxiety disorders at specific ages and genetic etiological influences on anxiety disorders in young children have been little studied. The present study reports prevalence estimates in a community sample of 6-year-old twins, and patterns of genetic and environmental influences on these early-onset anxiety disorders. Using a two-phase design 4,662 twin-pairs were sampled and 854 pairs were assessed in the second phase by maternal-informant diagnostic interview using DSM-IV criteria. The most common conditions were separation anxiety disorder (SAD) [2.8%, 95% confidence interval (CI) 2.1-3.8, for current disorder] and specific phobia (10.8%, 95% CI 8.4-13.6, for current disorder). Behavioral genetic modeling was feasible for these two conditions, applied to two phenotypes: symptom syndrome (regardless of impairment) and the narrower one of diagnostic status (symptom syndrome with associated impairment). The heritability estimate for SAD diagnostic status was high, 73%, with remaining variance attributed to non-shared environment. The heritability estimates for specific phobia were also high, 80% for the symptom syndrome and 60% for diagnostic status, with remaining variance attributed in both cases to non-shared environment. Compared with previous epidemiological surveys of children and adolescents in wide age-bands, the current estimates suggest that rates of anxiety disorders assessed in young childhood are generally at least as high and perhaps higher compared with those found in older children. The heritability estimates suggest that the genetic effects on these early-onset anxiety disorders are substantial and more significant than environmental effects, whether shared or non-shared.


DNA polymerase beta: analysis of the contributions of tyrosine-271 and asparagine-279 to substrate specificity and fidelity of DNA replication by pre-steady-state kinetics.
DNA polymerase beta (pol beta) from rat brain, overexpressed in Escherichia coli, was used as a model to study the factors responsible for substrate specificity [kpol, Kd(app) and kpol/Kd(app)] and fidelity during DNA synthesis. The roles of two active-site residues, Asn-279 and Tyr-271, were examined by construction of N279A, N279Q, Y271A, Y271F and Y271S mutants followed by structural analyses by NMR and CD and functional analyses by pre-steady-state kinetics. The results are summarized as follows. (i) None of the two-dimensional NMR spectra of the mutants was significantly perturbed relative to that for wild-type pol beta, suggesting that Tyr-271 and Asn-279 are not important for the global structure of the protein. (ii) CD analyses of guanidinium hydrochloride-induced denaturation showed that all mutants behaved similarly to the wild type in the free energy of denaturation, suggesting that Tyr-271 and Asn-279 are not critical for the conformational stability of pol beta. (iii) The Kd(app) for the correct dNTP was lower than that for the incorrect dNTP by a factor of 10-30 in the case of wild-type pol beta. Upon mutation to give N279A and N279Q, the Kd(app) for the correct dNTP increased by a factor of 15-25. As a consequence, the Kd(app) values for the correct and incorrect nucleotides were similar for N279A and N279Q, suggesting that the main function of the side chain of Asn-279 is in discrimination between the binding of correct and incorrect dNTPs. (iv) In the case of the Y271A mutant, the fidelity and the catalytic efficiency kpol/Kd(app) were little perturbed relative to the wild type. However, both the kpol and Kd(app) values for dNTP were 4-8 times lower in the case of the Y271A mutant than the corresponding values for wild-type pol beta. Since the chemical step may not be rate-limiting for wild-type pol beta, the effect on kpol could be quite significant if it is caused by a perturbation in the chemical step. (v) Pol beta displayed the greatest specificity towards the G:C base pair, which is incorporated during base excision repair of G:U and G:T mispairs. This specificity was slightly enhanced for the Y271F mutant.


Variations in terrigenous input into the deep equatorial atlantic during the past 24,000 years.
Estimates of terrigenous fluxes at three different water depths at two sites in the equatorial Atlantic by normalization against excess (230)Th flux indicate that the flux of terrigenous material to the seafloor was significantly higher during the last glacial period than it is today. Fluxes started to decrease during deglaciation and reached minimal values in the middle of the Holocene. From 15,000 to 5,000 years ago, there was a substantial increase in flux with increasing water depth below 2,800 meters; this increase may reflect resuspension and lateral transport of slope and rise sediment, possibly because of intensification of deepwater circulation during that period.


The Role of Suppressing Inflammation in the Treatment of Atherosclerotic Cardiovascular Disease.
To review the 3 anti-inflammatory drugs, canakinumab, colchicine, and methotrexate, that have been investigated in major clinical trials for treating patients with atherosclerotic cardiovascular disease (ASCVD). An Ovid MEDLINE literature search (1946 to February 2, 2020) was performed using search strategy [(C-reactive protein OR ASCVD OR cardiac disease OR cardiovascular disease) AND (canakinumab OR methotrexate OR Colchicine)]. Additional references were identified from the citations. English-language studies assessing the impact of these 3 drugs on inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) or the association with reducing ASCVD events were included. Canakinumab and colchicine significantly reduced ASCVD events in high-risk patients with median baseline hs-CRP levels of ~4.0 mg/L. Methotrexate was ineffective at reducing ASCVD events in high-risk patients, but their baseline hs-CRP concentrations were a median of <2 mg/L. In subgroup analyses of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), patients whose baseline hs-CRP was 2 to 4 mg/L had benefits from canakinumab therapy similar to those with baseline levels exceeding 4. Even with the best current drug therapies, patients with underlying inflammation can benefit from the addition of both colchicine and canakinumab to further lower CV events. Given its cost, colchicine is a more attractive option. Patients at high risk of recurrent cardiovascular disease events with an hs-CRP of 2 mg/L or greater can reduce the occurrence of ASCVD events with canakinumab or colchicine therapy. Colchicine is the preferable option, in particular for those with myocardial infarction, given its more reasonable cost.


Acrophialophora fusispora brain abscess in a child with acute lymphoblastic leukemia: review of cases and taxonomy.
A 12-year-old girl with acute lymphoblastic leukemia was referred to King Faisal Specialist Hospital and Research Center. The diagnosis without central nervous system (CNS) involvement was confirmed on admission, and chemotherapy was initiated according to the Children Cancer Group (CCG) 1882 protocol for high-risk-group leukemia. During neutropenia amphotericin B (AMB) (1 mg/kg of body weight/day) was initiated for presumed fungal infection when a computed tomography (CT) scan of the chest revealed multiple nodular densities. After 3 weeks of AMB therapy, a follow-up chest CT revealed progression of the pulmonary nodules. The patient subsequently suffered a seizure, and a CT scan of the brain was consistent with infarction or hemorrhage. Because of progression of pulmonary lesions while receiving AMB, antifungal therapy was changed to liposomal AMB (LAMB) (6 mg/kg/day). Despite 26 days of LAMB, the patient continued to have intermittent fever, and CT and magnetic resonance imaging of the brain demonstrated findings consistent with a brain abscess. Aspiration of brain abscess was performed and the Gomori methenamine silver stain was positive for hyphal elements. Culture of this material grew Acrophialophora fusispora. Lung biopsy showed necrotizing fungal pneumonia with negative culture. The dosage of LAMB was increased, and itraconazole (ITRA) was added; subsequently LAMB was discontinued and therapy was continued with ITRA alone. The patient demonstrated clinical and radiological improvement. In vitro, the isolate was susceptible to low concentrations of AMB and ITRA. A. fusispora is a thermotolerant, fast-growing fungus with neurotropic potential. We report the first case of human infection involving the CNS. Acrophialophora resembles Paecilomyces but differs in having colonies that become dark and in the development of phialides along the sides or at the tips of echinulate brown conidiophores. Conidia are borne in long chains and are smooth or ornamented with fine-to-coarse echinulations, sometimes in spiral bands. The taxonomy of the genus Acrophialophora is reviewed, and Acrophialophora nainiana and Acrophialophora levis are considered as synonyms of A. fusispora.


The Mycobacterium tuberculosis membrane protein Rv0180c: Evaluation of peptide sequences implicated in mycobacterial invasion of two human cell lines.
The identification and characterization of hypothetical membrane proteins from Mycobacterium tuberculosis have led to a better understanding of the mechanisms used by this pathogen to invade and survive inside host cells. This study assessed the presence, transcription, localization and possible biological activity of the conserved hypothetical protein Rv0180c from M. tuberculosis. Bioinformatics analyses indicated that Rv0180c contains a signal peptide, six possible transmembrane helices and a Plasmodium Export Element (PEXEL)-like motif. PCR analyses showed the presence of the Rv0180c gene in strains from the M. tuberculosis complex; but transcription was not detected in Mycobacterium microti. Sera against synthetic peptides of Rv0180c recognized two protein bands in M. tuberculosis H37Rv sonicate: a ∼48-kDa band close to the predicted molecular mass of Rv0180c (47.6 kDa), and a 63-kDa band probably caused by protein modifications. Moreover, the same sera located the protein on the surface of M. tuberculosis H37Rv bacilli by immunoelectron microscopy. Twenty-three synthetic peptides spanning the entire length of Rv0180c were tested for their ability to bind to U937 and A549 cells, finding nine high-activity binding peptides (HABPs) specific for both cell types, two HABPs specific for A549 cells (namely 31032 and 31044) and two HABPs specific for U937 cells (namely 31025 and 31041). HABPs inhibited invasion of M. tuberculosis H37Rv into A549 or U937 cells by significant percentages and facilitated internalization of latex beads in A549 cells. The Rv0180c HABPs herein reported could be preliminary candidates to be assessed as components of a multiepitope, chemically synthesized, subunit-based vaccine against tuberculosis.


Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: implication in osteoarthritis pathogenesis.
Objectives were to investigate whether interactions between human osteoarthritic chondrocytes and 4-hydroxynonenal (HNE)-modified type II collagen (Col II) affect cell phenotype and functions and to determine the protective role of carnosine (CAR) treatment in preventing these effects. Human Col II was treated with HNE at different molar ratios (MR) (1:20 to 1:200; Col II:HNE). Articular chondrocytes were seeded in HNE/Col II adduct-coated plates and incubated for 48 hours. Cell morphology was studied by phase-contrast and confocal microscopy. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and α1β1 integrin at protein and mRNA levels were quantified by Western blotting, flow cytometry and real-time reverse transcription-polymerase chain reaction. Cell death, caspases activity, prostaglandin E2 (PGE2), metalloproteinase-13 (MMP-13), mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) were assessed by commercial kits. Col II, cyclooxygenase-2 (COX-2), MAPK, NF-κB-p65 levels were analyzed by Western blotting. The formation of α1β1 integrin-focal adhesion kinase (FAK) complex was revealed by immunoprecipitation. Col II modification by HNE at MR approximately 1:20, strongly induced ICAM-1, α1β1 integrin and MMP-13 expression as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and NF-κB-p65 phosphorylation without impacting cell adhesion and viability or Col II expression. However, Col II modification with HNE at MR approximately 1:200, altered chondrocyte adhesion by evoking cell death and caspase-3 activity. It inhibited α1β1 integrin and Col II expression as well as ERK1/2 and NF-κB-p65 phosphorylation, but, in contrast, markedly elicited PGE2 release, COX-2 expression and p38 MAPK phosphorylation. Immunoprecipitation assay revealed the involvement of FAK in cell-matrix interactions through the formation of α1β1 integrin-FAK complex. Moreover, the modification of Col II by HNE at a 1:20 or approximately 1:200 MR affects parameters of the cell shape. All these effects were prevented by CAR, an HNE-trapping drug. Our novel findings indicate that HNE-binding to Col II results in multiple abnormalities of chondrocyte phenotype and function, suggesting its contribution in osteoarthritis development. CAR was shown to be an efficient HNE-snaring agent capable of counteracting these outcomes.


Neuropeptide Y and tuberoinfundibular dopamine activities are altered during lactation: role of prolactin.
During lactation the suckling stimulus increases the activity of two populations of neuropeptide Y (NPY) neurons in the hypothalamus, the caudal portion of the arcuate nucleus (ARH) and the dorsomedial hypothalamus (DMH), and suppresses the activity of TIDA neurons in the ARH. In the present study, an acute resuckling model was used to examine the role of suckling-induced hyperprolactinemia in modulating the activity of these systems. Lactating rats were deprived of their eight-pup litters on day 9 postpartum, and 48 h later, the animals served either as nonsuckled controls (0 pups) or were suckled for 24 h. In addition, some of the resuckled animals received two s.c. injections of bromocriptine (0.5 mg/rat x injection), a dopamine D2 agonist, to inhibit suckling-induced PRL secretion. In situ hybridization was performed for rat NPY messenger RNA (mRNA) and tyrosine hydroxylase (TH) mRNA to provide an index for NPY and TIDA neuronal activities, respectively. Resuckling for 24 h induced a significant increase in NPY mRNA levels in the caudal portion of the ARH and in the DMH. Bromocriptine treatment did not alter the increase in NPY mRNA levels in the ARH, whereas the treatment greatly attenuated the increase in NPY mRNA in the DMH. TH mRNA levels in the rostral ARH area returned to basal levels in the nonsuckled control animals, and 24 h of resuckling significantly suppressed TH mRNA expression in this area. Bromocriptine treatment caused a significant increase in TH mRNA levels compared with those in the eight-pup suckled group. Thus, the results from the present study demonstrate that the suckling stimulus activated the two populations of NPY neurons and suppressed TIDA activity. Suckling-induced hyperprolactinemia did not participate in the increase in ARH NPY activity, whereas it played a major stimulatory role in suckling-induced activation of NPY neurons in the DMH and an inhibitory role in suckling-induced suppression of TIDA activity. The increase in TIDA activity after bromocriptine treatment was unexpected and suggests that the role of PRL in the regulation of TIDA activity is significantly altered during lactation.


Bilateral adrenocortical adenomas causing adrenocorticotropic hormone-independent Cushing's syndrome: A case report and review of the literature.
Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome (CS) is mostly due to unilateral tumors, with bilateral tumors rarely reported. Its common causes include primary pigmented nodular adrenocortical disease, ACTH-independent macronodular adrenal hyperplasia, and bilateral adrenocortical adenomas (BAAs) or carcinomas. BAAs causing ACTH-independent CS are rare; up to now, fewer than 40 BAA cases have been reported. The accurate diagnosis and evaluation of BAAs are critical for determining optimal treatment options. Adrenal vein sampling (AVS) is a good way to diagnose ACTH-independent CS. A 31-year-old woman had a typical appearance of CS. The oral glucose tolerance test showed impaired glucose tolerance and obviously increased insulin and C-peptide levels. Her baseline serum cortisol and urine free cortisol were elevated and did not show either a circadian rhythm or suppression with dexamethasone administration. The peripheral 1-deamino-8-D-arginine-vasopressin (DDVAP) stimulation test showed a delay of the peak level, which was 1.05 times as high as the baseline level. Bilateral AVS results suggested the possibility of BAAs. Abdominal computed tomography showed bilateral adrenal adenomas with atrophic adrenal glands (right: 3.1 cm × 2.0 cm × 1.9 cm; left: 2.2 cm × 1.9 cm × 2.1 cm). Magnetic resonance imaging of the pituitary gland demonstrated normal findings. A left adenomectomy by retroperitoneoscopy was performed first, followed by resection of the right-side adrenal mass 3 mo later. Biopsy results of both adenomas showed cortical tumors. Evaluations of ACTH and cortisol showed a significant decrease after left adenomectomy but could still not be suppressed, and the circadian rhythm was absent. Following bilateral adenomectomy, this patient has been administered with prednisone until now, all of her symptoms were alleviated, and she had normal blood pressure without edema in either of her lower extremities. BAAs causing ACTH-independent CS are rare. AVS is of great significance for obtaining information on the functional state of BAAs before surgery.


Prognosis importance of low flow in aortic stenosis with preserved LVEF.
Previous studies using echocardiography suggested that a low flow (LF) defined as an indexed stroke volume (SVi) <35 mL/m(2) may be an important determinant of outcome in patients with severe aortic stenosis (AS). We sought to assess the prognostic importance of stroke volume derived from invasive data. The aim of this study was to determine the impact of LF, purposely derived from cardiac catheterisation data, on outcome of patients with severe AS and preserved LVEF. Between 2000 and 2010, 768 patients with preserved LVEF (>50%) and severe AS (valve area ≤1 cm(2)) without other valvular heart disease underwent cardiac catheterisation. The long-term overall mortality was assessed as the primary end-point. Mean age was 74±8 years, 58% were men, 46% had coronary artery disease and mean LVEF was 72±10%. Low SVi was found in 27% (n=210) of patients with AS. As compared with patients with normal SVi, those with low SVi were significantly older (p<0.0001) with higher rate of atrial fibrillation (p<0.0001). Additionally, they had lower LVEF (p=0.046), aortic valve area (p<0.0001), mean pressure gradient (p<0.0001), systemic arterial compliance (p<0.0001) and higher systemic vascular resistances (p<0.0001). Eight-year survival was significantly reduced in patients with low SVi as compared with those with normal SVi (51±5% vs 67±3%; p<0.0001). After adjustment for all other risk factors, reduced SVi was independently associated with long-term mortality (HR=1.45, 95% CI 1.1 to 2.1; p=0.048). In patients with severe AS and preserved LVEF, LF, as assessed using cardiac catheterisation is frequent, and is an independent predictor of mortality. Consequently, the measurement of SVi should be systematically included in the assessment of these patients.


The experimental induction of out-of-body experiences.
I report an illusion in which individuals experience that they are located outside their physical bodies and looking at their bodies from this perspective. This demonstrates that the experience of being localized within the physical body can be determined by the visual perspective in conjunction with correlated multisensory information from the body.


A pilot project using evidence-based clinical pathways and payment reform in China's rural hospitals shows early success.
Reforming China's public hospitals to curb widespread overtreatment and improve the quality and affordability of care has been the most challenging aspect of that nation's ambitious health reform, which began in 2009. This article describes a pilot project under way in several of China's provinces that combines payment reform with the implementation of evidence-based clinical pathways at a few hospitals serving rural areas. Results to date include reduced length-of-stay and prescription drug use and higher patient and provider satisfaction. These early results suggest that the pilot may be achieving its goals, which may have far-reaching and positive implications for China's ongoing reform.


Surgical Predictors of Clinical Outcomes After Revision Anterior Cruciate Ligament Reconstruction.
Revision anterior cruciate ligament (ACL) reconstruction has been documented to have worse outcomes compared with primary ACL reconstruction. Certain factors under the control of the surgeon at the time of revision surgery can both negatively and positively affect outcomes. Case-control study; Level of evidence, 3. Patients undergoing revision ACL reconstruction were identified and prospectively enrolled between 2006 and 2011. Data collected included baseline demographics, intraoperative surgical technique and joint disorders, and a series of validated patient-reported outcome instruments (International Knee Documentation Committee [IKDC] subjective form, Knee Injury and Osteoarthritis Outcome Score [KOOS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC], and Marx activity rating scale) completed before surgery. Patients were followed up for 2 years and asked to complete an identical set of outcome instruments. Regression analysis was used to control for age, sex, body mass index (BMI), activity level, baseline outcome scores, revision number, time since last ACL reconstruction, and a variety of previous and current surgical variables to assess the surgical risk factors for clinical outcomes 2 years after revision ACL reconstruction. A total of 1205 patients (697 male [58%]) met the inclusion criteria and were successfully enrolled. The median age was 26 years, and the median time since their last ACL reconstruction was 3.4 years. Two-year follow-up was obtained on 82% (989/1205). Both previous and current surgical factors were found to be significant contributors toward poorer clinical outcomes at 2 years. Having undergone previous arthrotomy (nonarthroscopic open approach) for ACL reconstruction compared with the 1-incision technique resulted in significantly poorer outcomes for the 2-year IKDC ( P = .037; odds ratio [OR], 2.43; 95% CI, 1.05-5.88) and KOOS pain, sports/recreation, and quality of life (QOL) subscales ( P ≤ .05; OR range, 2.38-4.35; 95% CI, 1.03-10.00). The use of a metal interference screw for current femoral fixation resulted in significantly better outcomes for the 2-year KOOS symptoms, pain, and QOL subscales ( P ≤ .05; OR range, 1.70-1.96; 95% CI, 1.00-3.33) as well as WOMAC stiffness subscale ( P = .041; OR, 1.75; 95% CI, 1.02-3.03). Not performing notchplasty at revision significantly improved 2-year outcomes for the IKDC ( P = .013; OR, 1.47; 95% CI, 1.08-1.99), KOOS activities of daily living (ADL) and QOL subscales ( P ≤ .04; OR range, 1.40-1.41; 95% CI, 1.03-1.93), and WOMAC stiffness and ADL subscales ( P ≤ .04; OR range, 1.41-1.49; 95% CI, 1.03-2.05). Factors before revision ACL reconstruction that increased the risk of poorer clinical outcomes at 2 years included lower baseline outcome scores, a lower Marx activity score at the time of revision, a higher BMI, female sex, and a shorter time since the patient's last ACL reconstruction. Prior femoral fixation, prior femoral tunnel aperture position, and knee flexion angle at the time of revision graft fixation were not found to affect 2-year outcomes in this revision cohort. There are certain surgical variables that the physician can control at the time of revision ACL reconstruction that can modify clinical outcomes at 2 years. Whenever possible, opting for an anteromedial portal or transtibial surgical exposure, choosing a metal interference screw for femoral fixation, and not performing notchplasty are associated with significantly better 2-year clinical outcomes.


CMOS-compatible optical switching concept based on strain-induced refractive-index tuning.
In this paper we present a planar lightwave switching mechanism based on large refractive index variations induced by electrically-driven strain control in a CMOS-compatible photonic platform. Feasibility of the proposed concept, having general validity, is numerically analyzed in a specific case-study given by a Mach-Zehnder Interferometer with Ge waveguides topped by a piezoelectric stressor. The stressor can be operated in order to dynamically tune the strain into the two interferometric arms. The strain modifies the Ge band structure and can induce refractive index variations up to 0.05. We demonstrate that this approach can enable ultra-compact devices featuring low loss propagation for light wavelengths below the waveguide band gap energy, high extinction ratios (>30 dB) and low intrinsic insertion losses (2 dB). The operation wavelength can be extended in the whole FIR spectrum by using SiGe(Sn) alloy waveguides.


Angiogenesis in bladder cancer--prognostic marker and target for future therapy.
Angiogenesis is the process by which tumours induce a blood supply, crucial for growth and metastasis. Evidence for its role in bladder carcinogenesis, its usefulness as a marker of patient prognosis, and potential anti-angiogenic therapies for future development are discussed in this chapter.


A palaeolimnological investigation into nutrient impact and recovery in an agricultural catchment.
Widespread deterioration in water quality as a result of anthropogenic activity has led to the development and implementation of measures aimed at the protection of water resources in the EU. To date, however, relatively little attention has been paid to the effectiveness of these measures. Evidence from an enrichment-sensitive lake permitted reconstructions of changes in ecological and chemical water quality over the last c. 150-200 years, a period that includes a mid to late 20th century intensification of agriculture that was widely experienced across the European Union and the subsequent implementation of measures aimed at protecting water resources against pollution from farming. The data show the development of a more nutrient-tolerant diatom community from early in the 20th century, while the main trophic changes occurred from the 1950s, with the site becoming eutrophic by the 1960s. Heightened enrichment is thought to be linked to enhanced levels of phosphorus (P) transfers from the surrounding grassland catchment owing to an intensification of agricultural activities locally. Most recently, since the late 1990s and particularly post-2007, evidence suggests a decrease in aquatic enrichment, despite continued increases in agricultural intensification. This decoupling is likely to mark a successful implementation in 2006 of measures aimed at decreasing diffuse nutrient transfers from catchments linked to agri-environmental policies in Europe. The research highlights the importance of enrichment-sensitive water bodies as sentinel sites in the monitoring of both external and internal nutrient loadings as agricultural activities and other pressures change within the context of implementing regulatory responses to earlier declines in water quality.