Free will in Bayesian and inverse Bayesian inference-driven endo-consciousness.
How can we link challenging issues related to consciousness and/or qualia with natural science? The introduction of endo-perspective, instead of exo-perspective, as proposed by Matsuno, Rössler, and Gunji, is considered one of the most promising candidate approaches. Here, we distinguish the endo-from the exo-perspective in terms of whether the external is or is not directly operated. In the endo-perspective, the external can be neither perceived nor recognized directly; rather, one can only indirectly summon something outside of the perspective, which can be illustrated by a causation-reversal pair. On one hand, causation logically proceeds from the cause to the effect. On the other hand, a reversal from the effect to the cause is non-logical and is equipped with a metaphorical structure. We argue that the differences in exo- and endo-perspectives result not from the difference between Western and Eastern cultures, but from differences between modernism and animism. Here, a causation-reversal pair described using a pair of upward (from premise to consequence) and downward (from consequence to premise) causation and a pair of Bayesian and inverse Bayesian inference (BIB inference). Accordingly, the notion of endo-consciousness is proposed as an agent equipped with BIB inference. We also argue that BIB inference can yield both highly efficient computations through Bayesian interference and robust computations through inverse Bayesian inference. By adapting a logical model of the free will theorem to the BIB inference, we show that endo-consciousness can explain free will as a regression of the controllability of voluntary action.


Concussion BASICS III: Serum biomarker changes following sport-related concussion.
To evaluate changes in serum biomarker concentrations (β-amyloid peptide 42 [Aβ42], total tau, ubiquitin carboxy-terminal hydrolyzing enzyme L1, S100 calcium binding protein B [S100B], glial fibrillary acidic protein [GFAP], microtubule associated protein 2 [MAP2], and 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase]) after sport-related concussion (SRC) in a sample of collegiate athletes. Associations with clinical outcomes were also investigated. Participants in this case-control study included 36 athletes (50% male, 61% white, aged 19.7 ± 1.0 years) with SRC. Twenty-nine also had baseline blood drawn, allowing for within-patient analyses of concentration changes. Between-group analyses incorporated 86 demographically matched controls (51% male, 63% white, aged 19.6 ± 1.1 years). Biomarker sensitivity/specificity for SRC vs controls and relative to standardized normative cutoffs was evaluated (receiver operating characteristics). We also analyzed associations between post-SRC clinical outcomes and both biomarker change from baseline and post-SRC concentrations. The majority of blood samples had concentrations of GFAP, MAP2, and CNPase below limits of quantification. Within-patient analyses indicated elevated S100B after SRC (p = 0.003, 67% of patients elevated), especially for blood samples collected <4 hours post-SRC (88% of patients). Significant between-group differences were limited to blood draws <4 hours post-SRC: Aβ42 (81% of SRC > control median, area under the curve [AUC] = 0.75 [95% confidence interval 0.59-0.91]), total tau (75% SRC > control, AUC = 0.74 [0.56-0.79]), and S100B (88% SRC > control; AUC [specific to white race] = 0.82 [0.72-0.93]). Using standardized normative cutoffs (z > 1.0), specificity ranged from 79.1% to 89.3% while sensitivity was <70%. Biomarkers were not associated with clinical outcomes. For SRC, diagnostic accuracy of serum biomarkers appears best if blood is collected within a few hours. Accurate blood marker identification of SRC appears somewhat dependent on the "healthy" comparison. Additional research must evaluate whether physiologic changes in the absence of clinical changes, or vice versa, are relevant for concurrent or future neurologic health. This study provides Class III evidence that certain serum biomarkers are elevated from baseline and higher than demographically matched controls after sport-related concussion.


Experiences from intrathecal baclofen treatment based on medical records and patient- and proxy-reported outcome: a multicentre study.
To investigate patient satisfaction with intrathecal baclofen treatment, complications from the treatment, and the impact of general expectations on treatment outcome in relation to satisfaction. A multicentre study with cross-sectional design. Data were collected through questionnaires and patient records. Patients were recruited from six outpatient intrathecal baclofen clinics in Sweden. Eighty-three patients who had been treated with intrathecal baclofen for 1-4 years were included. For patients unable to communicate, data were collected through a proxy. The Patient Global Impression of Change was used to measure patients' general satisfaction with change from intrathecal baclofen treatment. The Life Orientation Test - revised, was used to measure general expectations/optimism. General satisfaction with intrathecal baclofen treatment was high; 51/77 patients reported "much improved" or "very much improved." There was no relationship between the two main outcomes (general satisfaction and general expectations/optimism) (rs = 0.12, p = 0.382). The two groups; those who could and those who could not communicate, did differ regarding personal characteristics and should be evaluated as such. Most patients/proxies reported a high level of satisfaction with intrathecal baclofen treatment. The reported satisfaction with intrathecal baclofen treatment was not dependent on general expectations. Implications for Rehabilitation Patients with intrathecal baclofen treatment report low levels of health and quality of life at the same time as they are highly satisfied with their treatment. Intrathecal baclofen should be equally offered to both optimistic and less optimistic patients. Patients who are able to/not able to communicate, differs in characteristics and should be informed and followed up in different ways in daily clinical practice.


Long non-coding RNAs in cancer invasion and metastasis.
Recent large-scale transcriptome analyses have revealed that the human genome contains more than just protein-coding genes. Indeed, a large number of transcripts, including long non-coding RNAs (lncRNAs), lack protein-coding capacity, and increasing evidence suggests that lncRNAs could have a critical role in the regulation of diverse cellular processes, such as stem cell pluripotency, development, cell growth and apoptosis, and cancer invasion and/or metastasis. Furthermore, the aberrant expression of several lncRNAs is closely linked to cancer invasion and/or metastasis. Although the underlying molecular mechanisms by which lncRNAs regulate cancer invasion and/or metastasis are not clearly understood, recent studies have revealed that aberrant lncRNAs expression affects the progression of cancer. In this review, we highlight recent findings regarding the roles of lncRNAs in cancer invasion and/or metastasis.


Intravenous administration of the endothelin-1 antagonist BQ-123 does not ameliorate myocardial ischaemic injury following acute coronary artery occlusion in the dog.
It has been proposed that myocardial ischaemic injury is modulated in part by the release of endothelin-1 from the coronary endothelium either during ischaemia or following reperfusion. Release of sufficient amounts of endothelin-1 would result in coronary vasoconstriction and could potentiate ischaemic damage. An endothelin-1 antagonist, BQ-123, was given intravenously to evaluate the role of endothelin-1 in postischaemic injury and determine whether blockade of the ETA receptor would afford protection from ischaemia/reperfusion injury. Myocardial injury was induced in anaesthetised dogs using 90 min of left circumflex coronary artery occlusion followed by 4 h of reperfusion. Animals treated with a continuous intravenous infusion of BQ-123 (0.1 mg.kg-1.min-1), begun 10 min before ischaemia and continued throughout ischaemia and reperfusion, were compared to saline treated animals. After 4 h of reperfusion the myocardial infarct size measured by triphenyltetrazolium chloride staining was not different between the two groups. Infarct size in the control group was 25.7 (SEM 5.4)% of the area at risk while BQ-123 treatment resulted in an infarct size of 29.2(7.1)% of the area at risk (p = 0.70). Plasma endothelin-1 concentration measured at the coronary sinus was only significantly increased following 5 min of reperfusion. The intravenous administration of a specific ETA receptor antagonist does not protect against ischaemia/reperfusion injury. These results suggest that endothelin-1 receptor antagonists require access to the area at risk during occlusion to protect the myocardium from ischaemic injury.


7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway.
Hypercholesterolemia is one of the risk factors for poor outcome in breast cancer therapy. To elucidate the influence of the main circulating oxysterols, cholesterol oxidation products, on the cell-killing effect of doxorubicin, cells were exposed to oxysterols at a subtoxic concentration. When cells were exposed to oxysterols in fetal bovine serum-supplemented medium, 7-ketocholesterol (7-KC), but not 27-hydroxycholesterol (27-HC), decreased the cytotoxicity of doxorubicin in MCF-7 (high estrogen receptor (ER)α/ERβ ratio) cells and the decreased cytotoxicity was restored by the P-glycoprotein inhibitor verapamil. 7-KC stimulated the efflux function of P-glycoprotein and reduced intracellular doxorubicin accumulation in MCF-7 but not in ERα(-) MDA-MB-231 and the resistant MCF-7/ADR cells. In MCF-7 cells, 7-KC increased the mRNA and protein levels of P-glycoprotein. The 7-KC-suppressed doxorubicin accumulation was restored by the fluvestrant and ERα knockdown. In a yeast reporter assay, the ERα activation by 7-KC was more potent than 27-HC. 7-KC, but not 27-HC, stimulated the expression of an ER target, Trefoil factor 1 in MCF-7 cells. When charcoal-stripped fetal bovine serum was used, both 7-KC and 27-HC induced Trefoil factor 1 expression and reduced doxorubicin accumulation in MCF-7 cells. 7-KC-reduced doxorubicin accumulation could be reversed by inhibitors of phosphatidylinositol 3-kinase, Akt, and mammalian target of rapamycin (mTOR). These findings demonstrate that 7-KC decreases the cytotoxicity of doxorubicin through the up-regulation of P-glycoprotein in an ERα- and mTOR-dependent pathway. The 7-KC- and 27-HC-elicited estrogenic effects are crucial in the P-glycoprotein induction in breast cancer cells.


Impacts of COVID-19 on contraceptive and abortion services in low- and middle-income countries: a scoping review.
The COVID-19 pandemic has disproportionate effects on people living in low- and middle-income countries (LMICs), exacerbating weak health systems. We conducted a scoping review to identify, map, and synthesise studies in LMICs that measured the impact of COVID-19 on demand for, provision of, and access to contraceptive and abortion-related services, and reproductive outcomes of these impacts. Using a pre-established protocol, we searched bibliographic databases (December 2019-February 2021) and key grey literature sources (December 2019-April 2021). Of 71 studies included, the majority (61%) were not peer-reviewed, and 42% were based in Africa, 35% in Asia, 17% were multi-region, and 6% were in Latin America and the Caribbean. Most studies were based on data through June 2020. The magnitude of contraceptive service-related impacts varied widely across 55 studies (24 of which also included information on abortion). Nearly all studies assessing changes over time to contraceptive service provision noted declines of varying magnitude, but severe disruptions were relatively uncommon or of limited duration. Twenty-six studies addressed the impacts of COVID-19 on abortion and postabortion care (PAC). Overall, studies found increases in demand, reductions in provision and increases in barriers to accessing these services. The use of abortion services declined, but the use of PAC was more mixed with some studies finding increases compared to pre-COVID-19 levels. The impacts of COVID-19 varied substantially, including the country context, health service, and population studied. Continued monitoring is needed to assess impacts on these key health services, as the COVID-19 pandemic evolves.


Projected impacts of climate change on a continent-wide protected area network.
Despite widespread concern, the continuing effectiveness of networks of protected areas under projected 21st century climate change is uncertain. Shifts in species' distributions could mean these resources will cease to afford protection to those species for which they were originally established. Using modelled projected shifts in the distributions of sub-Saharan Africa's entire breeding avifauna, we show that species turnover across the continent's Important Bird Area (IBA) network is likely to vary regionally and will be substantial at many sites (> 50% at 42% of IBAs by 2085 for priority species). Persistence of suitable climate space across the network as a whole, however, is notably high, with 88-92% of priority species retaining suitable climate space in >or= 1 IBA(s) in which they are currently found. Only 7-8 priority species lose climatic representation from the network. Hence, despite the likelihood of significant community disruption, we demonstrate that rigorously defined networks of protected areas can play a key role in mitigating the worst impacts of climate change on biodiversity.


Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.
To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.


Mild myocardial stunning affects platelet aggregation and certain hemostatic factors in swine.
Myocardial stunning is characterized by transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. Platelet activation and hemostatic abnormalities have been described in patients with unstable angina and acute myocardial infarction, however, their role in the pathogenesis of myocardial stunning is unknown. The purpose of this study was to determine if platelet aggregation and certain hemostatic factors change during myocardial stunning following brief coronary arterial occlusion. Nine Yorkshire swine underwent left anterior descending coronary artery occlusion for 8 minutes followed by 90 minutes of reperfusion. Blood samples were obtained at baseline, at 4 and 8 minutes of occlusion, and at 60 and 90 minutes of reperfusion. Platelet aggregability and concentrations of antithrombin III, protein C, protein S, fibronectin, endothelin 1, and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1a) were measured in systemic circulation. The occlusion phase was associated with a decline of endothelin 1 (-13.6%), and TxB2 (-19.6%), and elevation of antithrombin III (+40.2%) and protein C (+22.9%). Mild myocardial stunning was associated with a significant increase in platelet aggregation (+33.7%), endothelin-1 (+24.7%), 6-keto-PGF1a (+41.5%), TxB2 (+11.9%), and protein C (+42.3%) during the reperfusion phase. There were no changes in plasma fibronectin and total protein S. Thus, mild myocardial stunning following brief coronary artery occlusion is associated with substantial dynamic changes in platelet aggregability and certain hemostatic factors. These results may be relevant to understanding the mechanisms determining myocardial stunning and coronary arterial patency following reperfusion.


Palmitoylethanolamide stimulates phagocytosis of Escherichia coli K1 by macrophages and increases the resistance of mice against infections.
Palmitoylethanolamide (PEA), an endogenous lipid and a congener of anandamide, possesses a wide range of effects related to metabolic and cellular homeostasis including anti-inflammatory and neuroprotective properties. In vitro, we studied the ability of macrophages to phagocytose Escherichia coli K1 after stimulation with increasing doses of PEA. In vivo, wild-type mice were treated with PEA intraperitoneally 12 hours and 30 minutes before infection. Meningoencephalitis or sepsis was induced by intracerebral or intraperitoneal infection with E. coli K1. Stimulation of macrophages with PEA for 30 minutes increased the phagocytosis of E. coli K1 without inducing the release of TNFα or CXCL1. Intracellular killing of E. coli K1 was higher in PEA-stimulated than in unstimulated peritoneal macrophages and microglial cells. Pre-treatment with PEA significantly increased survival of mice challenged intracerebrally or intraperitoneally with E. coli K1. This effect was associated with a decreased production of CXCL1, IL-1β and IL-6 in homogenates of spleen and cerebellum in mice treated with PEA. Our observations suggest that these protective effects of PEA in mice can increase the resistance to bacterial infections without the hazard of collateral damage by excessive stimulation of phagocytes.


General model for lipid-mediated two-dimensional array formation of membrane proteins: application to bacteriorhodopsin.
Based on experimental evidence for 2D array formation of bacteriorhodopsin, we propose a general model for lipid-mediated 2D array formation of membrane proteins in lipid bilayers. The model includes two different lipid species, "annular" lipids and "neutral" lipids, and one protein species. The central assumption of the model is that the annular lipids interact more strongly with the protein than with the neutral lipids. Monte Carlo simulations performed on this model show that 2D arrays of proteins only form when there are annular lipids present. In addition, no arrays form if all of the lipids present are annular lipids. The geometry of the observed arrays is for the most part hexagonal. However, for a certain range of low annular lipid/protein ratios, arrays form that have geometries other than hexagonal. Using the assumption that the hydrocarbon chains of the annular lipids are restricted in motion when close to a protein, we expand the model to include a ground state and an excited state of the annular lipids. The main result from the extended model is that within a certain temperature range, increasing the temperature will lead to larger and more regular protein arrays.


Cell cycle specificity of certain antimicrotubular drugs in Schizosaccharomyces pombe.
Of the seven antimicrotubular drugs tested, nocodazole, mebendazole and trifluralin at saturable concentrations failed to inhibit cell division in Schizosaccharomyces pombe, while carbendazim, thiabendazole and chloropropham each at 50 micrograms ml- and amiprophos methyl at 200 micrograms ml-1 completely arrested cell division. This inhibition was associated with striking morphological changes in which carbendazim- and thiabendazole-treated cells became elongated and pseudohyphal, whereas chloropropham- and amiprophos methyl-treated cells appeared small and rounded with occasional V-shaped pairs. Lomofungin staining revealed that nuclear division was also arrested by these drugs. Suspected blockage of defined cell cycle stages was confirmed by pulse-induction experiments which revealed that cells could be synchronized into division using exposure to a drug for one generation. Further experiments with synchronous cultures prepared by size selection showed that different drugs possessed different transition points; for example, carbendazim and thiabendazole were effective in blocking a late stage of the cell cycle just prior to division, whereas amiprophos methyl affected a very early stage. The results suggest that some of the drugs used exert cell cycle specificity in S. pombe either by impairing microtubule assembly mechanisms (as with carbendazim and thiabendazole) or by inhibiting synthesis of tubulin subunits (as with amiprophos methyl). These drugs could prove useful in studies of microtubule biogenesis during the cell cycle in yeast.


Effect on mother and child of eculizumab given before caesarean section in a patient with severe antiphospholipid syndrome: A case report.
Antiphospholipid syndrome (APS) in pregnancy may trigger the life-threatening catastrophic antiphospholipid syndrome (CAPS). Complement activation is implicated in the pathogenesis, and inhibition of complement factor C5 is suggested as an additional treatment option. We present a pregnant patient treated with the C5-inhibitor eculizumab due to high risk of developing devastating APS-related complications. The complement inhibitory effects of the treatment were examined both in the patient and the premature infant. Complement activity in the mother recovered considerably faster than anticipated; however, no new thrombosis or CAPS developed during the last week of pregnancy or postpartum. Blood sampling from the umbilical vein and artery, and from the infant after delivery showed low complement activity; however, only 0.3% of the eculizumab concentration detected in the mother, consistent with low placental passage of eculizumab. The data underscore the importance of close monitoring of complement inhibition and individualizing dosage regimens in pregnant patients receiving eculizumab. We document how traditional functional complement activity tests cannot assess the effect of eculizumab in premature infants due to the very low levels of complement factors detected in this infant born in gestational week 33. Only trace amounts of eculizumab passed the placenta. In conclusion, complement C5 inhibition might be a safe candidate treatment option for APS during pregnancy and delivery, and additionally, enables prolongation of pregnancy with important weeks.


NK cells control HIV-1 infection of macrophages through soluble factors and cellular contacts in the human decidua.
During the first trimester of pregnancy, HIV-1 in utero transmission is rare despite the permissivity of the placenta and the decidua (the uterine mucosa during pregnancy) to infection. In the decidua from the first trimester of pregnancy, macrophages (dMs) are the HIV-1 main target cells. Decidual natural killer (dNK) cells account for 70 % of decidual leukocytes. They display distinct phenotype and functions compared to peripheral NK cells. At the periphery, NK cells are involved in the control of HIV-1 infection. In this study, we investigate whether human decidual natural killer (dNK) cells control dM HIV-1 infection. Autologous cocultures of infected dMs with dNK cells reveal that dNK cells strongly inhibit dM HIV-1 infection. The addition of dNK cells to dMs at different times after infection suggests that the control occurs before the complete establishment of the infection. Double chamber cocultures show that cellular contacts are necessary for an optimal control of infection. Nevertheless, soluble factors secreted by dMs and dNK cells in double chamber cocultures partially inhibit dM HIV-1 infection, indicating that soluble factors have also a role in the control of infection. IFN-γ secretion is increased in infected and uninfected cocultures. We show that IFN-γ is involved in the control of dM HIV-1 infection by dNK cells. These results demonstrate that human dNK cells inhibit efficiently HIV-1 infection in dMs in vitro, and highlight the role of innate immune determinants in the control of HIV-1 transmission.


Cadaveric fascia lata versus intravaginal slingplasty for the pubovaginal sling: surgical outcome, overall success and patient satisfaction rates.
A wide variety of surgical procedures has been used to treat female stress urinary incontinence (SUI). The purpose of this study was to compare cadaveric fascia lata (CFL) sling with intravaginal slingplasty (IVS) in the surgical treatment of SUI. One hundred and thirty-nine women with SUI were randomly assigned to either CFL sling (n = 67) or IVS (n = 72). Concomitant urinary urge incontinence was present in 49 patients (73%) in the CFL sling and 44 patients (61%) in the IVS group. Daily mean pad usage was 4.1 +/- 3.5 in the CFL sling and 2.9 +/- 1.7 in the IVS group. The objective cure rate was evaluated by the pad test, and patient satisfaction rate was assessed by a subjective questionnaire. The surgical results of both procedures with a follow-up 12 months were documented. The overall success rate was 79% in the CFL sling and 70.8% in the IVS (p = 0.261). In contrast patient satisfaction rates were 82 and 87.5%, respectively (p = 0.210). Comparison of the CFL sling with IVS showed persistent urinary urge incontinence in 67 and 25% (p = 0.0001) and de novo urinary urge incontinence in 22 and 6.9%, respectively (p = 0.009). The groups did not differ significantly with respect to intraoperative and postoperative complications. There is no statistical difference in the overall success, satisfaction and complication rates in either group. In our series, both procedures were found to be effective, durable and significantly improved quality of life in patients with SUI but long-term results are awaited.


Assessment and training of brain-damaged drivers.
This paper describes a driving assessment and training program that is primarily for patients discharged from the hospital and who may be experiencing residual impairment from some form of brain damage. Assessment is carried out by an occupational therapist and consists of several off-road tests (vision, reaction timing, computerized preview tracking test, general medical/psychological appraisal), and an on-road test. More than 300 patients have been seen since the program's inception in 1977, and trends indicated by their assessment results are: twice as many male as female referrals; a low fail rate among nonbrain-involved patients; diagnosis as a poor predictor of outcome; no significant difference between fail rates of right and left stroke patients; significant difference in average tracking task performance between the Pass, Borderline, and Fail assessment groups. Off-road testing complements, rather than replaces, on-road testing. Thirty-eight of the 300 patients were given special training, and 15 of these were unable to reach an acceptable level. This reflects a difficulty in predicting the outcome of unlicensed patients with severe disabilities.


Cooked oatmeal consumption is associated with better diet quality, better nutrient intakes, and reduced risk for central adiposity and obesity in children 2-18 years: NHANES 2001-2010.
None of the studies of whole grains that have looked either at diet or weight/adiposity measures have focused exclusively on oatmeal. The objective of this study was to assess the association between oatmeal consumption and nutrient intake, diet quality, and weight/adiposity of children aged 2-18. A nationally representative sample of children aged 2-18 (N=14,690) participating in National Health and Nutrition Examination Survey 2001-2010 was used. Intake was determined from a single 24-h dietary recall. Diet quality was measured using the Healthy Eating Index-2010 (HEI-2010). Covariate-adjusted regression analyses, using appropriate sample weights, were used to determine differences between oatmeal consumers and non-consumers for demographics, nutrient intakes, diet quality, and weight/adiposity measures (p<0.01). Logistic regression was performed to calculate odds ratios for weight measures and obesity (p<0.05). Compared to non-consumers, oatmeal consumers were more likely to be younger and less likely to be smokers. Consumers had higher intakes of dietary fiber, vitamin A, thiamin, riboflavin, calcium, phosphorus, magnesium, iron, copper, and potassium, and significantly lower intakes of total, monounsaturated and saturated fatty acids, cholesterol, and sodium. Oatmeal consumers had higher dietary quality scores attributable to higher intakes of whole grains and lower intakes of refined grains and empty calories. Children consuming oatmeal were at lower risk for having central adiposity and being obese. Consumption of oatmeal by children was associated with better nutrient intake, diet quality, and reduced risk for central adiposity and obesity and should be encouraged as part of an overall healthful diet.


Asymmetric organocatalytic methods for the synthesis of tetrahydropyrans and their application in total synthesis.
Recent advancement in the area of asymmetric organocatalysis led to the development of new methodologies for the construction of valuable enantiopure molecules, including various heterocycles. As one of the latter class of compounds tetrahydropyrans (THPs) constitute a core structure of a wide array of bioactive natural products. A noticeable growth has been observed in the asymmetric synthesis of THPs using small organic molecules as catalysts. This Tutorial Review describes the organocatalytic methods available to furnish THPs as well as the application of these methodologies in the total synthesis of THP-based natural products.


Diversity and composition of herbaceous angiosperms along gradients of elevation and forest-use intensity.
Terrestrial herbs are important elements of tropical forests; however, there is a lack of research on their diversity patterns and how they respond to different intensities of forest-use. The aim of this study was to analyze the diversity of herbaceous angiosperms along gradients of elevation (50 m to 3500 m) and forest-use intensity on the eastern slopes of the Cofre de Perote, Veracruz, Mexico. We recorded the occurrence of all herbaceous angiosperm species within 120 plots of 20 m x 20 m each. The plots were located at eight study locations separated by ~500 m in elevation and within three different habitats that differ in forest-use intensity: old-growth, degraded, and secondary forest. We analyzed species richness and floristic composition of herb communities among different elevations and habitats. Of the 264 plant species recorded, 31 are endemic to Mexico. Both α- and γ-diversity display a hump-shaped relation to elevation peaking at 2500 m and 3000 m, respectively. The relative contribution of between-habitat β-diversity to γ-diversity also showed a unimodal hump whereas within-habitat β-diversity declined with elevation. Forest-use intensity did not affect α-diversity, but β-diversity was high between old-growth and secondary forests. Overall, γ-diversity peaked at 2500 m (72 species), driven mainly by high within- and among-habitat β-diversity. We infer that this belt is highly sensitive to anthropogenic disturbance and forest-use intensification. At 3100 m, high γ-diversity (50 species) was driven by high α- and within-habitat β-diversity. There, losing a specific forest area might be compensated if similar assemblages occur in nearby areas. The high β-diversity and endemism suggest that mixes of different habitats are needed to sustain high γ-richness of terrestrial herbs along this elevational gradient.


Hemichorea after hyperglycemia correction: A case report and a short review of hyperglycemia-related hemichorea at the euglycemic state.
Hyperglycemic hemichorea tends to affect elderly patients with type 2 diabetes, women, and the Asian population. The onset of involuntary movement typically occurs at the hyperglycemic state and subsides at the euglycemic state. In this report, we present an unusual case that developed delayed-onset hemichorea after hyperglycemia correction. A 70-year-old man was admitted to neurology ward with symptoms of subacute dizziness. Hyperglycemia and high level ketone body was incidentally noted. Hemichorea occurred in his left limbs 2 days after hyperglycemia correction. Patient remained conscious, and no other focal neurological deficits were noted while hemichorea occurred. Blood test revealed no contributory cause. Brain magnetic resonance imaging revealed no lesions in the putamen or subthalamus. A diagnosis of probable hyperglycemia-related hemichorea was made. Haloperidol (2 mg, 3 times per day) was prescribed. Hemichorea improved gradually before discharge and resolved 4 months later. Differential diagnosis of hemichorea should include delayed-onset hemichorea after hyperglycemia correction.


Serial prostate specific antigen screening for prostate cancer: a computer model evaluates competing strategies.
We compare prostate specific antigen (PSA) screening strategies in terms of expected years of life saved with screening, number of screens, number of false-positive screens and rates of over diagnosis, defined as detection by PSA screening of patients who would never have been diagnosed without screening. A computer model of disease progression, clinical diagnosis, PSA growth and PSA screening was used. Under baseline conditions, when screening is not considered, the model replicates clinical diagnosis and disease mortality rates recorded by the Surveillance, Epidemiology and End Results Program of the National Cancer Institute in the mid 1980s. Biannual screening with PSA greater than 4.0 ng./ml. was projected to reduce the number of screens and false-positive tests by almost 50% relative to annual screening while retaining 93% of years of life saved. With annual screening use of an age specific bound for PSA to consider a test positive instead of the standard 4.0 ng./ml. was projected to reduce false-positive screens by 27% and over diagnosis by a third while retaining almost 95% of years of life saved. Sensitivity analyses did not change the relative efficacy of biannual screening. Under the model assumptions biannual PSA screening is a cost-effective alternative to annual PSA screening for prostate cancer. With annual screening use of an age specific bound for PSA positivity appears to reduce false-positive results and over diagnosis rates sharply relative to a bound of 4 ng./ml. while retaining most of the survival benefits.


Transcriptional activation by the adenovirus larger E1a product is mediated by members of the cellular transcription factor ATF family which can directly associate with E1a.
We recently isolated three cDNA clones encoding closely related proteins (ATFa1, ATFa2, and ATFa3) that belong to the activating transcription factor-cyclic AMP-responsive element family of cellular transcription factors. Using cotransfection experiments, we showed that these proteins mediate the transcriptional activation induced by the adenovirus E1a 13S mRNA gene product and that the zinc-binding domains present in both E1a conserved region 3 and the most N-terminal portion of the ATFa proteins play crucial roles in this activity. Reciprocal coimmunoprecipitation experiments demonstrated direct interactions between these proteins. Neither the conserved region 3 domain of E1a nor the N-terminal metal-binding element of ATFa is essential for these interactions. The simultaneous alteration of both the N-terminal and the C-terminal domains of ATFa abolished E1a binding, while either mutation alone failed to impair these interactions.


Rapid onset pressor response to exercise in young women with a family history of hypertension.
What is the central question of this study? Alterations in blood pressure control at exercise onset are apparent in older adults with established cardiovascular disease. It is currently not known whether these alterations are evident in young adults with a family history of hypertension. What is the main finding and its importance? We demonstrate that young women with a family history of hypertension display a larger change in blood pressure within the first 10 s of isometric exercise. These data suggest altered blood pressure control in young women with a family history of hypertension. Hypertensive adults demonstrate atypical increases in blood pressure (BP) and muscle sympathetic nerve activity (MSNA) at the immediate onset of static muscle contraction. However, it is unknown whether these abnormal responses occur in young, otherwise healthy adults at risk for developing future disease, such as those with a family history of hypertension (+FH). We tested the hypothesis that +FH young women have exaggerated increases in BP and MSNA at the onset of static muscle contraction compared with those without a family history of hypertension (-FH). We retrospectively examined beat-by-beat BP and MSNA during the initial 30 s of isometric handgrip exercise (30% of maximal voluntary contraction) in 16 +FH (22 ± 2 years old, 22 ± 3 kg m-2 ) and 16 -FH (22 ± 3 years old, 22 ± 3 kg m-2 ) women. Resting mean arterial pressure (+FH 80 ± 11 mmHg versus -FH 84 ± 13 mmHg), MSNA burst frequency (+FH 7 ± 3 bursts min-1 versus -FH 9 ± 5 bursts min-1 ) and burst incidence [+FH 12 ± 4 bursts (100 heart beats)-1 versus -FH 12 ± 8 bursts (100 heart beats)-1 ] were similar between groups (all P > 0.05). Within the first 10 s of exercise, changes in mean arterial pressure (+FH Δ8 ± 6 mmHg versus -FH Δ3 ± 2 mmHg, P < 0.05) and heart rate (+FH Δ8 ± 5 beats min-1 versus -FH Δ4 ± 4 beats min-1 , P < 0.05) were greater in +FH women. Absolute MSNA burst frequency during the first 30 s of exercise was not different between groups (-FH 7 ± 5 bursts min-1 versus +FH 9 ± 3 bursts min-1 ). Cardiovascular and sympathetic responses during the cold pressor test were not different between groups. These data demonstrate that young women at risk for developing cardiovascular disease exhibit greater changes in BP at the onset of static muscle contraction.


Changes in health state utilities with changes in body mass in the Diabetes Prevention Program.
Health utilities are measures of health-related quality of life (HRQL) used in cost-effectiveness research. We evaluated whether changes in body weight were associated with changes in health utilities in the Diabetes Prevention Program (DPP) and whether associations differed by treatment assignment (lifestyle intervention, metformin, placebo) or baseline obesity severity. We constructed physical (PCS-36) and mental component summary (MCS-36) subscales and short-form-6D (SF-6D) health utility index for all DPP participants completing a baseline 36-item short form (SF-36) HRQL assessment (N = 3,064). We used linear regression to test associations between changes in body weight and changes in HRQL indicators, while adjusting for other demographic and behavioral variables. Overall differences in HRQL between treatment groups were highly statistically significant but clinically small after 1 year. In multivariable models, weight change was independently associated with change in SF-6D score (increase of 0.007 for every 5 kg weight loss; P < 0.001), but treatment effects independent of weight loss were not. We found no significant interaction between baseline obesity severity and changes in SF-6D with changes in body weight. However, increases in physical function (PCS-36) with weight loss were greater in persons with higher baseline obesity severity. In summary, improvements in HRQL are associated with weight loss but not with other effects of obesity treatments that are unrelated to weight loss. Although improvements in the SF-6D did not exceed commonly reported thresholds for a minimally important difference (0.04), these changes, if causal, could still have a significant impact on clinical cost-effectiveness estimates if sustained over multiple years.


Involvement of the Sonic hedgehog gene in chick feather formation.
To elucidate the molecular mechanisms of chick feather formation, we observed expression patterns of the Sonic hedgehog (Shh) gene, which is one of the vertebrate homologs of the Drosophila segment polarity gene, hedgehog, and encodes a signaling molecule functioning in limb pattern formation and motor neuron induction. We found that the Shh gene is also expressed in the apical region of the feather placodes and then in nine to eleven longitudinal stripes along feather filaments. The stripe was found to correspond to one of the outer marginal zones of each barb ridge, termed the zone of Shh expression. No significant expression signal was detected in the scale bud of developing legs. Thus, Shh is likely to function as an epithelial signaling molecule in epithelio-mesenchymal interaction during feather formation. Furthermore, since genes of bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-4 (FGF-4) are coexpressed with Shh during feather formation as observed in limb morphogenesis, interactions among FGF-4, Shh and BMP-2 may be involved in formation of feather filaments and barbs in a similar fashion as elucidated in limb pattern formation.


The evolution of social behavior in the prehistoric American southwest.
Long House Valley, located in the Black Mesa area of northeastern Arizona (USA), was inhabited by the Kayenta Anasazi from circa 1800 B.C. to circa A.D. 1300. These people were prehistoric precursors of the modern Pueblo cultures of the Colorado Plateau. A rich paleoenvironmental record, based on alluvial geomorphology, palynology, and dendroclimatology, permits the accurate quantitative reconstruction of annual fluctuations in potential agricultural production (kg maize/hectare). The archaeological record of Anasazi farming groups from A.D. 200 to 1300 provides information on a millennium of sociocultural stasis, variability, change, and adaptation. We report on a multi-agent computational model of this society that closely reproduces the main features of its actual history, including population ebb and flow, changing spatial settlement patterns, and eventual rapid decline. The agents in the model are monoagriculturalists, who decide both where to situate their fields and where to locate their settlements.


Isolation and genomic analysis of circulating tumor cells from castration resistant metastatic prostate cancer.
The number of circulating tumor cells (CTCs) in metastatic prostate cancer patients provides prognostic and predictive information. However, it is the molecular characterization of CTCs that offers insight into the biology of these tumor cells in the context of personalized treatment. We developed a novel approach to isolate CTCs away from hematopoietic cells with high purity, enabling genomic analysis of these cells. The isolation protocol involves immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). To evaluate the feasibility of isolation of CTCs by IE/FACS and downstream genomic profiling, we conducted a pilot study in patients with metastatic castration resistant prostate cancer (CRPC). Twenty (20) sequential CRPC patients were assayed using CellSearch™. Twelve (12) patients positive for CTCs were subjected to immunomagnetic enrichment and fluorescence activated cell sorting (IE/FACS) to isolate CTCs. Genomic DNA of CTCs was subjected to whole genome amplification (WGA) followed by gene copy number analysis via array comparative genomic hybridization (aCGH). CTCs from nine (9) patients successfully profiled were observed to have multiple copy number aberrations including those previously reported in primary prostate tumors such as gains in 8q and losses in 8p. High-level copy number gains at the androgen receptor (AR) locus were observed in 7 (78%) cases. Comparison of genomic profiles between CTCs and archival primary tumors from the same patients revealed common lineage. However, high-level copy number gains in the AR locus were observed in CTCs, but not in the matched archival primary tumors. We developed a new approach to isolate prostate CTCs without significant leukocyte admixture, and to subject them to genome-wide copy number analysis. Our assay may be utilized to explore genomic events involved in cancer progression, e.g. development of castration resistance and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner.


Evaluation of pelvic floor kinematics in continent and incontinent women during running: An exploratory study.
Impact activity like running is associated with an increase in intra-abdominal pressure which needs to be sufficiently countered by pelvic floor muscle (PFM) activity to secure continence. The aim of this study was to investigate and compare PFM kinematics in continent and incontinent women during running. Three-dimensional position and orientation was measured with the electromagnetic tracking device trakSTAR™. One sensor was attached to the vaginal probe and a second one was secured to the subjects' skin at the height of the second sacral vertebrae. Cranial-caudal and forward-backward displacement of the vaginal probe was measured during 10 sec running on a treadmill at the speeds 7, 11, and 15 km/h. Displacement data from 100 ms before to 300 ms after heel-strike were analyzed. Nineteen incontinent and twenty-seven continent women were included in this study. Before the foot touched the ground caudal translation and forward rotation of the vaginal probe was detected, whereas after heel-strike a cranial translation and backward rotation was measured. Cranial-caudal translation as well as backward-forward-rotation did not differ significantly between continent and incontinent subjects for the three speeds. Analysis of maximum displacements showed significantly increasing displacement with increasing speeds. Kinematic measurements during impact activity of running demonstrated caudal translation before and cranial translation after heel-strike. The hypothesis of caudal translation through impact activity was not confirmed. Patterns seem similar between continent and incontinent subjects. Associations between the direction of displacement and muscle action of PFMs remain assumptions.


Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec, in Children and Adolescents With Type 1 Diabetes: The onset 7 Trial.
To confirm efficacy and safety of fast-acting insulin aspart (faster aspart) versus insulin aspart (IAsp), both with basal insulin degludec, in a pediatric population with type 1 diabetes. After a 12-week run-in, this treat-to-target, 26-week, multicenter trial randomized participants (1 to <18 years) to double-blind mealtime faster aspart (n = 260), mealtime IAsp (n = 258), or open-label postmeal faster aspart (n = 259). The primary end point was change from baseline in glycated hemoglobin (HbA1c) after 26 weeks of treatment. All available information regardless of treatment discontinuation was used for the evaluation of treatment effect. At week 26, mealtime and postmeal faster aspart were noninferior to IAsp regarding change from baseline in HbA1c (P < 0.001 for noninferiority [0.4% margin]), with a statistically significant difference in favor of mealtime faster aspart (estimated treatment difference -0.17% [95% CI -0.30; -0.03], -1.82 mmol/mol [-3.28; -0.36]; P = 0.014). Change from baseline in 1-h postprandial glucose increment significantly favored mealtime faster aspart versus IAsp at breakfast, main evening meal, and over all meals (P < 0.01 for all). No statistically significant differences in the overall rate of severe or blood glucose-confirmed hypoglycemia were observed. Mean total daily insulin dose was 0.92 units/kg for mealtime faster aspart, 0.92 units/kg for postmeal faster aspart, and 0.88 units/kg for mealtime IAsp. In children and adolescents with type 1 diabetes, mealtime and postmeal faster aspart with insulin degludec provided effective glycemic control with no additional safety risks versus IAsp. Mealtime faster aspart provided superior HbA1c control compared with IAsp.


SARS-CoV-2 Consensus-Sequence and Matching Overlapping Peptides Design for COVID19 Immune Studies and Vaccine Development.
Synthetic antigens based on consensus sequences that represent circulating viral isolates are sensitive, time saving and cost-effective tools for in vitro immune monitoring and to guide immunogen design. When based on a representative sequence database, such consensus sequences can effectively be used to test immune responses in exposed and infected individuals at the population level. To accelerate immune studies in SARS-CoV-2 infection, we here describe a SARS-CoV-2 2020 consensus sequence (CoV-2-cons) which is based on more than 1700 viral genome entries in NCBI and encompasses all described SARS-CoV-2 open reading frames (ORF), including recently described frame-shifted and length variant ORF. Based on these sequences, we created curated overlapping peptide (OLP) lists containing between 1500 to 3000 peptides of 15 and 18 amino acids in length, overlapping by 10 or 11 residues, as ideal tools for the assessment of SARS-CoV-2-specific T cell immunity. In addition, CoV-2-cons sequence entropy values are presented along with variant sequences to provide increased coverage of the most variable sections of the viral genome. The identification of conserved protein fragments across the coronavirus family and the corresponding OLP facilitate the identification of T cells potentially cross-reactive with related viruses. This new CoV-2-cons sequence, together with the peptides sets, should provide the basis for SARS-CoV-2 antigen synthesis to facilitate comparability between ex-vivo immune analyses and help to accelerate research on SARS-CoV-2 immunity and vaccine development.


Marriage promotion and missing men: African American women in a demographic double bind.
Since 1996, state legislators, members of the U.S. Congress, and more recently President George W. Bush, have called for the protection of monogamous, heterosexual marriage and the promotion of marriage among poor women. The thrust of this policy making is directed at African American families, among which female headship doubled between 1965 and 1990. This doubling is temporally associated with enacting the legislation directed toward the War on Drugs, which resulted in a tripling of the African American prison population. In Syracuse, New York, the swelling African American population behind bars has resulted in a skewed sex ratio, in which women significantly outnumber men. The authors use national, state, and local epidemiological, environmental, and ethnographic data to argue that the proliferation of marriage-promotion policies is heterosexist and blames African American women for demographic realities over which they have little control.


Impacts of Salmonella enterica Serovar Typhimurium and Its speG Gene on the Transcriptomes of In Vitro M Cells and Caco-2 Cells.
Microfold or membranous (M) cells are specialized intestinal epithelial cells responsible for host immunity. The speG mutant of Salmonella Typhimurium (S. Typhimurium) is a nonreplicating strain within human cells to be a candidate vaccine vector for interacting with M cells. We conducted this study to identify the genes are differently expressed between in vitro M cells and Caco-2 cells, and to determine whether S. Typhimurium and speG affect the transcriptomes of both cell types. In vitro M cells and Caco-2 cells were infected with wild-type (WT) S. Typhimurium, its ΔspeG mutant, or none for 1 h for RNA microarrays; the transcriptomes among the 6 pools were pairwisely compared. Genetic loci encoding scaffold (e.g., HSCHR7_CTG4_4, HSCHR9_CTG9_35), long noncoding RNA, membrane-associated protein (PITPNB), neuron-related proteins (OR8D1, OR10G9, and NTNG2), and transporter proteins (MICU2 and SLC28A1) were significantly upregulated in uninfected M cells compared with uninfected Caco-2 cells; and their encoding proteins are promising M-cell markers. Significantly upregulated HSCHR7_CTG4_4 of uninfected in vitro M cells were speG-independently downregulated by S. Typhimurium infection that is a remarkable change representing an important but unreported characteristic of M cells. The immune responses of in vitro M cells and Caco-2 cells can differ and reply on speG or not, with speG-dependent regulation of KYL4, SCTR, IL6, TNF, and CELF4 in Caco-2 cells, JUN, KLF6, and KCTD11 in M cells, or speG-independent modulation of ZFP36 in both cells. This study facilitates understanding of the immune responses of in vitro M cells after administering the S. Typhimurium ΔspeG mutant as a future vaccine vector.


The effects of chronic hyperphenylalaninaemia on mouse brain protein synthesis can be prevented by other amino acids.
A prolonged elevation in the concentrations of circulating phenylalanine was maintained in newborn mice by daily injections of phenylalanine and a phenylalanine hydroxylase inhibitor, alpha-methylphenylalanine. The result of this chronic hyperphenylalaninaemia was an accumulation of vacant or inactive monoribosomes that persisted for 18 h of each day. An elongation assay in vitro with brain postmitochondrial supernatants demonstrated that, in addition, there was an equally prolonged decrease in the rates of polypeptide-chain elongation by the remaining brain polyribosomes. Analyses of the free amino acid composition in the brains of hyperphenylalaninaemic mice showed a loss of several amino acids from the brain, particularly the large, neutral amino acids, which are co- or counter-transported across plasma membranes with phenylalanine. When a mixture of these amino acids (leucine, isoleucine, valine, threonine, tryptophan, tyrosine, methionine) was injected into hyperphenylalaninaemic mice, there was an immediate cessation of monoribosome accumulation in the brain and there was no inhibition of the rates of polypeptide-chain elongation. Although the concentrations of the large, neutral amino acids in the brain were partially preserved by treatment of hyperphenylalaninaemic mice with the amino acid mixture, the elevated concentrations of phenylalanine remained unaltered. The amino acid mixture had no detectable effect on brain protein synthesis in the absence of the hyperphenylalaninaemic condition.


Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man.
It is clearly established that emotional events tend to be remembered particularly vividly. The neurobiological substrates of this phenomenon are poorly understood. Recently, the noradrenergic system has been implicated in that beta blockade has been shown to reduce significantly the delayed recall of emotional material with matched neutral material being unaffected. In the present study, 36 healthy young adults were randomly allocated to receive either yohimbine, which stimulates central noradrenergic activity, metoprolol which blocks noradrenergic activity, or matched placebo. The three groups were well matched. All capsules were taken orally, prior to viewing a narrated 11 slide show described a boy being involved in an accident. Yohimbine significantly elevated, and metoprolol reduced mean heart rate during the slide show relative to placebo, thus confirming the efficacy of the pharmacological manipulation. One week later, in a surprise' test, memory for the slide show was tested. As predicted, yohimbine-treated subjects recalled significantly more and metoprolol subjects fewer slides relative to placebo. This result was confirmed via analysis of multiple-choice recognition memory scores. We conclude that stimulation of the noradrenergic system results in the enhancement and blockade in a reduction of recall and recognition of emotional material in man.


The expression of heterologous MAM-7 in Lactobacillus rhamnosus reduces its intrinsic capacity to inhibit colonization of pathogen Vibrio parahaemolyticus in vitro.
Vibrio parahaemolyticus (V. parahaemolyticus) is a Gram-negative, halophilic bacterium recognized as one of the most important foodborne pathogen. When ingested, V. parahaemolyticus causes a self-limiting illness (Vibriosis), characterized mainly by watery diarrhoea. Treatment is usually oral rehydration and/or antibiotics in complicated cases. Since 1996, the pathogenic and pandemic V. parahaemolyticus O3:K6 serotype has spread worldwide, increasing the reported number of vibriosis cases. Thus, the design of new strategies for pathogen control and illness prevention is necessary. Lactobacillus sp. grouped Gram positive innocuous bacteria, part of normal intestinal microbiota and usually used as oral vaccines for several diarrheic diseases. Recombinants strains of Lactobacillus (RL) expressing pathogen antigens can be used as part of an anti-adhesion strategy where RL block the pathogen union sites in host cells. Thus, we aimed to express MAM-7 V. parahaemolyticus adhesion protein in Lactobacillus sp. to generate an RL that prevents pathogen colonization. We cloned the MAM-7 gene from V. parahaemolyticus RIMD 2210633 in Lactobacillus expression vectors. Recombinant strains (Lactobacillus rhamnosus pSEC-MAM7 and L. rhamnosus pCWA-MAM7) adhered to CaCo-2 cells and competed with the pathogen. However, the L. rhamnosus wild type strain showed the best capacity to inhibit pathogen colonization in vitro. In addition, LDH-assay showed that recombinant strains were cytotoxic compared with the wild type isogenic strain. MAM-7 expression in lactobacilli reduces the intrinsic inhibitory capacity of L. rhamnosus against V. parahaemolyticus.


Conservative therapy in microinvasive adenocarcinoma of the uterine cervix is justified: an analysis of 59 cases and a review of the literature.
This study aimed to evaluate the treatment and follow-up in a large series of women with early cervical adenocarcinoma (AC), stages IA1 and IA2, and to perform an extensive review of the literature in an effort to ascertain whether conservative therapy is justified. Records of 59 cases of microinvasive AC diagnosed between 1987 and 2006 in the Rotterdam district, the Netherlands, were retrieved. Clinical and pathological data were reviewed and analyzed. A mesh review of all relevant literature concerning stage IA1 and IA2 was performed. Of all patients, 33 had stage IA1 and 26 stage IA2 cervical AC. Also, 42 patients were treated conservatively (ie, conization or simple hysterectomy) and 17 patients were treated radically (ie, radical hysterectomy/trachelectomy with lymph node dissection). Recurrence occurred in 1 patient (1.7%) with stage IA1 disease (grade 1 adenocarcinoma, depth 1.4 mm, and width 3.8 mm, with lymph vascular space involvement [LVSI]) treated by vaginal hysterectomy. The mean follow-up was 79.9 months. From the literature, pooling all data from patients with stage IA1 and IA2 AC, the risk of recurrent disease was 1.5% after conservative therapy and 2.0% after radical therapy. Extensive treatment such as radical hysterectomy with pelvic lymph node dissection or trachelectomy does not prevent recurrent disease. Patients with microinvasive AC should be treated identically to patients with SCC. In stage IA1 and IA2 AC, we recommend conservative therapy (by conization). In cases with LVSI, an additional lymphadenectomy is advised. For patients with stage IA2 AC with LVSI, a trachelectomy/radical hysterectomy with lymph node dissection should be considered.


Alcohol Use and HIV Prevention Among Personnel in the Belize Defence Force.
To evaluate the effect of a peer-based risk reduction project on alcohol use and sexual behavior within Belize Defence Force personnel. We used a quasi-experimental, mixed quantitative and qualitative methods design to evaluate project outcomes. Two serial cross-sectional surveys were conducted [baseline (n = 126) and 6-month follow-up (n = 128)] using computer assisted self-interview. Semistructured interviews were collected from 12 peer counselors 3 months after the beginning of the project. The proportion of respondents screening positive for alcohol dependence decreased significantly from 80 % at preintervention to 66 % at postintervention (p = 0.045), and the percentage of respondents reporting that they normally drink alcohol before work decreased from 11 to 3 % (p = 0.013). Alcohol abuse and dependency scores correlated positively with the overall number of sexual partners in both male and female respondents. There was a slight decrease in the percentage of female respondents' reporting inconsistent condom use for vaginal sex (baseline 100 %, follow-up 83 %, p = 0.088), but there was no appreciable change reported in condom use among male respondents. Qualitative findings suggest that techniques to reduce the quantity of alcohol consumed were a salient focus of peer counselors, and administrative barriers can readily mitigate implementation of such interventions. In this evaluation of a risk reduction program with the BDF, we found evidence of a reduction in types of alcohol use from baseline to follow-up. Alcohol-related risk reductions carry implications for reducing sexual risk behavior in military personnel. Future research with stronger experimental design strategies may better elucidate how substance use reduction is linked with sexual risk reduction in military personnel.


Factors influencing students' receptivity to formative feedback emerging from different assessment cultures.
Feedback after assessment is essential to support the development of optimal performance, but often fails to reach its potential. Although different assessment cultures have been proposed, the impact of these cultures on students' receptivity to feedback is unclear. This study aimed to explore factors which aid or hinder receptivity to feedback. Using a constructivist grounded theory approach, the authors conducted six focus groups in three medical schools, in three separate countries, with different institutional approaches to assessment, ranging from a traditional summative assessment structure to a fully implemented programmatic assessment system. The authors analyzed data iteratively, then identified and clarified key themes. Helpful and counterproductive elements were identified within each school's assessment system. Four principal themes emerged. Receptivity to feedback was enhanced by assessment cultures which promoted students' agency, by the provision of authentic and relevant assessment, and by appropriate scaffolding to aid the interpretation of feedback. Provision of grades and comparative ranking provided a helpful external reference but appeared to hinder the promotion of excellence. This study has identified important factors emerging from different assessment cultures which, if addressed by programme designers, could enhance the learning potential of feedback following assessments. Students should be enabled to have greater control over assessment and feedback processes, which should be as authentic as possible. Effective long-term mentoring facilitates this process. The trend of curriculum change towards constructivism should now be mirrored in the assessment processes in order to enhance receptivity to feedback.


Electrically Conducting Hydrogel Graphene Nanocomposite Biofibers for Biomedical Applications.
Conductive biomaterials have recently gained much attention, specifically owing to their application for electrical stimulation of electrically excitable cells. Herein, flexible, electrically conducting, robust fibers composed of both an alginate biopolymer and graphene components have been produced using a wet-spinning process. These nanocomposite fibers showed better mechanical, electrical, and electrochemical properties than did single fibers that were made solely from alginate. Furthermore, with the aim of evaluating the response of biological entities to these novel nanocomposite biofibers, in vitro studies were carried out using C2C12 myoblast cell lines. The obtained results from in vitro studies indicated that the developed electrically conducting biofibers are biocompatible to living cells. The developed hybrid conductive biofibers are likely to find applications as 3D scaffolding materials for tissue engineering applications.


Familial hypercholesterolemia with multiple large tendinous xanthomas and advanced coronary artery atherosclerosis.
We herein report the case of a 53-year-old man with severe coronary ischemia who underwent successful coronary artery bypass surgery. Of note, he had hypercholesterolemia and presented with multiple large tendinous xanthomas and thickened Achilles tendons that had been present for more than two decades. Together with a family history of dyslipidemia, the patient was diagnosed as having familial hypercholesterolemia. Irrespective of an extensive search for possible mutations in the genes presumably involved in the patient's pathophysiology, including low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), autosomal recessive hypercholesterolemia (ARH) and apolipoprotein B (APOB), we were not able to identify the gene mutations responsible for the phenotype observed in the present case.


Zinc protoporphyrin IX binds heme crystals to inhibit the process of crystallization in Plasmodium falciparum.
The intraerythrocytic Plasmodium falciparum parasite converts most of host hemoglobin heme into a nontoxic heme crystal. Erythrocyte zinc protoporphyrin IX, normally present at 0.5 microM, which is a ratio of 1:40,000 hemes, can elevate 10-fold in some of the anemias associated with malaria disease protection. This work examines a binding mechanism for zinc protoporphyrin IX inhibition of heme crystallization similar to the antimalarial quinolines. Zinc protoporphyrin IX neither forms crystals alone nor extends on preformed heme crystals. Inhibition of both seed heme crystal formation and crystal extension occurs with an inhibitory concentration (IC)50 of 5 microM. Field emission in-lens scanning electron microscopy depicts the transition and inhibition of heme monomer aggregates to heme crystals with and without seeding of preformed hemozoin templates. In vitro zinc protoporphyrin IX, like the quinolines, binds to heme crystals in a saturable, specific, pH, and time-dependent manner. The ratio at saturation is approximately 1 zinc protoporphyrin IX per 250 hemes of the crystal. Unlike the quinolines, zinc protoporphyrin IX binds measurably in the absence of heme. Isolated ring and trophozoite stage parasites have an elevated zinc protoporphyrin IX to heme ratio 6 to 10 times that in the erythrocyte cytosol, which also corresponds to elevated ratios found in heme crystals purified from Plasmodium parasites. This work implicates protection from malaria by a mechanism where elevated zinc protoporphyrin IX in anemic erythrocytes binds to heme crystals to inhibit further crystallization. In endemic malaria areas, severe iron deficiency anemia should be treated with antimalarials along with iron replenishment.


Sites of institutional racism in public health policy making in New Zealand.
Although New Zealanders have historically prided ourselves on being a country where everyone has a 'fair go', the systemic and longstanding existence of health inequities between Māori and non-Māori suggests something isn't working. This paper informed by critical race theory, asks the reader to consider the counter narrative viewpoints of Māori health leaders; that suggest institutional racism has permeated public health policy making in New Zealand and is a contributor to health inequities alongside colonisation and uneven access to the determinants of health. Using a mixed methods approach and critical anti-racism scholarship this paper identifies five specific sites of institutional racism. These sites are: majoritarian decision making, the misuse of evidence, deficiencies in both cultural competencies and consultation processes and the impact of Crown filters. These findings suggest the failure of quality assurance systems, existing anti-racism initiatives and health sector leadership to detect and eliminate racism. The author calls for institutional racism to be urgently addressed within New Zealand and this paper serves as a reminder to policy makers operating within other colonial contexts to be vigilant for such racism.


Gene Augmentation Therapy for a Missense Substitution in the cGMP-Binding Domain of Ovine CNGA3 Gene Restores Vision in Day-Blind Sheep.
Applying CNGA3 gene augmentation therapy to cure a novel causative mutation underlying achromatopsia (ACHM) in sheep. Impaired vision that spontaneously appeared in newborn lambs was characterized by behavioral, electroretinographic (ERG), and histologic techniques. Deep-sequencing reads of an affected lamb and an unaffected lamb were compared within conserved genomic regions orthologous to human genes involved in similar visual impairment. Observed nonsynonymous amino acid substitutions were classified by their deleteriousness score. The putative causative mutation was assessed by producing compound CNGA3 heterozygotes and applying gene augmentation therapy using the orthologous human cDNA. Behavioral assessment revealed day blindness, and subsequent ERG examination showed attenuated photopic responses. Histologic and immunohistochemical examination of affected sheep eyes did not reveal degeneration, and cone photoreceptors expressing CNGA3 were present. Bioinformatics and sequencing analyses suggested a c.1618G>A, p.Gly540Ser substitution in the GMP-binding domain of CNGA3 as the causative mutation. This was confirmed by genetic concordance test and by genetic complementation experiment: All five compound CNGA3 heterozygotes, carrying both p.Arg236* and p.Gly540Ser mutations in CNGA3, were day-blind. Furthermore, subretinal delivery of the intact human CNGA3 gene using an adeno-associated viral vector (AAV) restored photopic vision in two affected p.Gly540Ser homozygous rams. The c.1618G>A, p.Gly540Ser substitution in CNGA3 was identified as the causative mutation for a novel form of ACHM in Awassi sheep. Gene augmentation therapy restored vision in the affected sheep. This novel mutation provides a large-animal model that is valid for most human CNGA3 ACHM patients; the majority of them carry missense rather than premature-termination mutations.


Mandating education of dental graduates to provide care to individuals with intellectual and developmental disabilities.
In 2004, The Commission on Dental Accreditation adopted new standards for dental and dental hygiene education programs to ensure the preparation of practitioners to provide oral health services for persons with special health care needs. The course of action leading to the adoption of the new standards, together with the continuing obstacles of limited government support for dental services and the availability of faculty members to provide the needed dental educational experiences is reviewed. Expanding Health Resources and Services Administration definition of medically underserved areas is presented as one approach to improving the delivery of dental services.


Involuntary inhibition of movement initiation alters oculomotor competition resolution.
Identifying a stimulus as the target for a goal-directed movement involves inhibiting competing responses. Separable inhibitory interconnections bias local competition to ensure only one stimulus is selected and to alter movement initiation. Behavioural evidence of these inhibitory processes comes from the effects of distracters on oculomotor landing positions and saccade latencies. Here, we investigate the relationship between these two sources of inhibition. Targets were presented with or without close and remote distracters. In separate experiments the possible position and identity of the target and distracters were manipulated. In all cases saccade landing position was found to be less affected by the presence of the close distracter when remote distracters were also present. The involuntary increase in the latency of saccade initiation caused by the presence of the remote distracters alters the state of competitive processes involved in selecting the saccade target thus changing its landing position.


Killer Cell Lectin-like Receptor G1 Inhibits NK Cell Function through Activation of Adenosine 5'-Monophosphate-Activated Protein Kinase.
NK cells are the first line of defense against infected and transformed cells. Defective NK cell activity was shown to increase susceptibility for viral infections and reduce tumor immune-surveillance. With age, the incidence of infectious diseases and malignancy rises dramatically, suggesting that impaired NK cell function might contribute to disease in these individuals. We found an increased frequency of NK cells with high expression of the inhibitory killer cell lectin-like receptor G1 (KLRG1) in individuals >70 y. The role of KLRG1 in ageing is not known, and the mechanism of KLRG1-induced inhibition of NK cell function is not fully understood. We report that NK cells with high KLRG1 expression spontaneously activate the metabolic sensor AMP-activated protein kinase (AMPK) and that activation of AMPK negatively regulates NK cell function. Pre-existing AMPK activity is further amplified by ligation of KLRG1 in these cells, which leads to internalization of the receptor and allows interaction with AMPK. We show that KLRG1 activates AMPK by preventing its inhibitory dephosphorylation by protein phosphatase-2C rather than inducing de novo kinase activation. Finally, inhibition of KLRG1 or AMPK prevented KLRG1-induced activation of AMPK and reductions in NK cell cytotoxicity, cytokine secretion, proliferation, and telomerase expression. This novel signaling pathway links metabolic sensing, effector function, and cell differentiation with inhibitory receptor signaling that may be exploited to enhance NK cell activity during ageing.


Geographic Distribution and rDNA-ITS Region Sequence Diversity of Waitea circinata var. circinata Isolated from Annual Bluegrass in the United States.
Waitea circinata var. circinata is the causal agent of brown ring patch, an emergent disease of turfgrass in the United States. Forty-two isolates from annual bluegrass were obtained from California, Connecticut, Idaho, Illinois, Massachusetts, New York, Ohio, Oregon, and Rhode Island. Almost all isolates produced white to orange sclerotia (bulbils), 2 to 5 mm in size, that turned dark brown after 21 days on ¼-strength potato dextrose agar. The ribosomal DNA internal transcribed spacer regions and 5.8S region (ITS) were analyzed by restriction fragment length polymorphism (RFLP) analysis using MspI and sequencing to attempt identification of the isolates. Some isolates were heterozygous at the MspI restriction site, results not found in previous reports using the RFLP technique for identification. Four additional nucleotide positions were found to be variable within ITS based on sequence analysis, including two indels and two additional heterozygous positions. A total of 17 ITS haplotypes were found, and there was no obvious relationship between ITS haplotype and the geographic distribution of the isolates. Results of this work indicate that W. circinata var. circinata is present in multiple states and provide an initial understanding of the diversity of the pathogen in the United States.


Heterosubtypic antiviral activity of hemagglutinin-specific antibodies induced by intranasal immunization with inactivated influenza viruses in mice.
Influenza A virus subtypes are classified on the basis of the antigenicity of their envelope glycoproteins, hemagglutinin (HA; H1-H17) and neuraminidase. Since HA-specific neutralizing antibodies are predominantly specific for a single HA subtype, the contribution of antibodies to the heterosubtypic immunity is not fully understood. In this study, mice were immunized intranasally or subcutaneously with viruses having the H1, H3, H5, H7, H9, or H13 HA subtype, and cross-reactivities of induced IgG and IgA antibodies to recombinant HAs of the H1-H16 subtypes were analyzed. We found that both subcutaneous and intranasal immunizations induced antibody responses to multiple HAs of different subtypes, whereas IgA was not detected remarkably in mice immunized subcutaneously. Using serum, nasal wash, and trachea-lung wash samples of H9 virus-immunized mice, neutralizing activities of cross-reactive antibodies were then evaluated by plaque-reduction assays. As expected, no heterosubtypic neutralizing activity was detected by a standard neutralization test in which viruses were mixed with antibodies prior to inoculation into cultured cells. Interestingly, however, a remarkable reduction of plaque formation and extracellular release of the H12 virus, which was bound by the H9-induced cross-reactive antibodies, was observed when infected cells were subsequently cultured with the samples containing HA-specific cross-reactive IgA. This heterosubtypic plaque reduction was interfered when the samples were pretreated with anti-mouse IgA polyclonal serum. These results suggest that the majority of HA-specific cross-reactive IgG and IgA antibodies produced by immunization do not block cellular entry of viruses, but cross-reactive IgA may have the potential to inhibit viral egress from infected cells and thus to play a role in heterosubtypic immunity against influenza A viruses.


The megabiota are disproportionately important for biosphere functioning.
A prominent signal of the Anthropocene is the extinction and population reduction of the megabiota-the largest animals and plants on the planet. However, we lack a predictive framework for the sensitivity of megabiota during times of rapid global change and how they impact the functioning of ecosystems and the biosphere. Here, we extend metabolic scaling theory and use global simulation models to demonstrate that (i) megabiota are more prone to extinction due to human land use, hunting, and climate change; (ii) loss of megabiota has a negative impact on ecosystem metabolism and functioning; and (iii) their reduction has and will continue to significantly decrease biosphere functioning. Global simulations show that continued loss of large animals alone could lead to a 44%, 18% and 92% reduction in terrestrial heterotrophic biomass, metabolism, and fertility respectively. Our findings suggest that policies that emphasize the promotion of large trees and animals will have disproportionate impact on biodiversity, ecosystem processes, and climate mitigation.


Gene Microarray Analyses of Daboia russelli russelli Daboiatoxin Treatment of THP-1 Human Macrophages Infected with Burkholderia pseudomallei.
Burkholderia pseudomallei is the causative agent of melioidosis and represents a potential bioterrorism threat. In this study, the transcriptomic responses of B. pseudomallei infection of a human macrophage cell model were investigated using whole-genome microarrays. Gene expression profiles were compared between infected THP-1 human monocytic leukemia cells with or without treatment with Daboia russelli russelli daboiatoxin (DRRDbTx) or ceftazidime (antibiotic control). Microarray analyses of infected and treated cells revealed differential upregulation of various inflammatory genes such as interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF-α), cyclooxygenase (COX-2), vascular endothelial growth factor (VEGF), chemokine C-X-C motif ligand 4 (CXCL4), transcription factor p65 (NF-kB); and several genes involved in immune and stress responses, cell cycle, and lipid metabolism. Moreover, following DRR-DbTx treatment of infected cells, there was enhanced expression of the tolllike receptor 2 (TLR-2) mediated signaling pathway involved in recognition and initiation of acute inflammatory responses. Importantly, we observed that highly inflammatory cytokine gene responses were similar in infected cells exposed to DRR-DbTx or ceftazidime after 24 h. Additionally, there were increased transcripts associated with cell death by caspase activation that can promote host tissue injury. In summary, the transcriptional responses during B. pseudomallei infection of macrophages highlight a broad range of innate immune mechanisms that are activated within 24 h post-infection. These data provide insights into the transcriptomic kinetics following DRR-DbTx treatment of human macrophages infected with B. pseudomallei.


Method of hologram multiplexing by use of a fiber bundle with rotary movement.
A simple method of rotating an optical fiber bundle is presented to apply the random-pattern referencing scheme to hologram multiplexing. In the theoretical study, a dependence of the diffraction efficiency on the number of spatial frequencies in the reference pattern is estimated with the Bragg diffraction theory. In the experiment, hologram multiplexing is performed in which 30 holograms are recorded in a LiNbO3 crystal and are read out by rotating a fiber bundle. The result shows that this simple approach enables us to perform the hologram multiplexing and also contributes to the building of a compact optical setup.


Listeria monocytogenes induces apoptosis of infected hepatocytes.
Infection with blood-borne Listeria monocytogenes results in their early uptake by the liver. Foci of hepatocytes become heavily infected and develop into microabscesses. Infection results in apoptosis of the hepatocytes. This is particularly evident in the edge of the microabscess, where hepatocytes are not yet destroyed by the neutrophil. It is also apparent when neutrophils are depleted from the circulation. Infection of hepatocytes in culture induces their death by apoptosis with the release of neutrophil chemoattractants. Cytokines do not reduce the multiplication of Listeria in cultured hepatocytes. This study calls attention to an early program of inflammation induced in infected cells that are unresponsive to cytokines.


One-Year Adherence to the Otago Exercise Program With or Without Motivational Interviewing in Community-Dwelling Older Adults.
This study investigated if behavioral factors, treatment with behavioral support, readiness to change, fall self-efficacy, and activity habits could predict long-term adherence to an exercise program. Included in this study were 114 community-dwelling older adults who had participated in one of two home-based exercise interventions. Behavioral factors associated with adherence to the exercise program over 52 weeks were analyzed. The behavioral factors, specifically activity habits at baseline, significantly predicted adherence to the exercise program, with an odds ratio = 3.39, 95% confidence interval [1.38, 8.32], for exercise and an odds ratio = 6.11, 95% confidence interval [2.34, 15.94], for walks. Being allocated to a specific treatment including motivational interviewing was also significantly predictive: odds ratio = 2.47, 95% confidence interval [1.11, 5.49] for exercise adherence. In conclusion, activity habits and exercise in combination with motivational interviewing had a significant association with adherence to the exercise program at a 1-year follow-up.


Epidemiology of tick-borne encephalitis (TBE) in Europe and its prevention by available vaccines.
Tick-borne Encephalitis (TBE), which is caused by a Flavivirus, is the most common tick-transmitted disease in Central and Eastern Europe and Russia. Today, TBE is endemic in 27 European countries, and has become an international public health problem. The epidemiology of TBE is changing owing to various factors, such as improvements in diagnosis and case reporting, increased recreational activities in areas populated by ticks, and changes in climatic conditions affecting tick habitats. Vaccination remains the most effective protective measure against TBE for people living in risk zones, occupationally exposed subjects and travelers to endemic areas. The vaccines currently in use are FSME-Immun(®), Encepur(®), EnceVir(®) and TBE vaccine Moscow(®). The numerous studies performed on the efficacy and safety of these vaccines have shown a high level of immunogenicity and an excellent safety profile. Several studies have also shown a high level of cross-protection among strains belonging to different subtypes. In the present paper we attempted to describe the continuously changing epidemiology of TBE in European States and to overview clinical development of available vaccines paying particular attention on cross-protection elicited by the vaccines.


The EXpert PANel Decision (EXPAND) method: a way to measure the impact of diverse quality improvement activities of clinical networks.
Objectives and importance of study: Evaluating impacts of quality improvement activities across diverse clinical focus areas is challenging. However, evaluation is necessary to determine if the activities had an impact on quality of care and resulted in system-wide change. Clinical networks of health providers aim to provide a platform for accelerating quality improvement activities and adopting evidence based practices. However, most networks do not collect primary data that would enable evaluation of impact. We adapted an established expert panel approach to measure the impacts of efforts in 19 clinical networks to improve care and promote health system change, to determine whether these efforts achieved their purpose. A retrospective cross-sectional study of 19 clinical networks using multiple methods of data collection including the EXpert PANel Decision (EXPAND) method. Network impacts were identified through interviews with network managers (n = 19) and co-chairs (n = 32), and document review. The EXPAND method brought together five independent experts who provided initial individual ratings of overall network impact. After attendance at an in-person moderated meeting where aggregate scores were discussed, the experts provided a final rating. Median scores of postmeeting ratings were the final measures of network impact. Among the 19 clinical networks, experts rated 47% (n = 9) as having a limited impact on improving quality of care, 37% (n = 7) as having a moderate impact and 16% (n = 3) as having a high impact. The experts rated 26% (n = 5) of clinical networks as having a limited impact on facilitating system-wide change, 37% (n = 7) as having a moderate impact and 37% (n = 7) as having a high impact. The EXPAND method enabled appraisal of diverse clinical networks in the absence of primary data that could directly evaluate network impacts. The EXPAND method can be applied to assess the impact of quality improvement initiatives across diverse clinical areas to inform healthcare planning, delivery and performance. Further research is needed to assess its reliability and validity.


Occurrence of ectomycorrhizal fungi on the forefront of retreating Lyman Glacier (Washington, USA) in relation to time since deglaciation.
Glacier forefronts provide a unique system for studying primary succession of plants and fungi. We constructed a chronosequence of ectomycorrhizal fungus occurrence on the forefront of Lyman Glacier in the North Cascades mountain range in Washington, USA. The plant communities established on non-vegetated substrate as patchily distributed plant individuals and developed towards complex vegetation with a variety of ectomycorrhizal hosts, including Salix commutata, S. phylicifolia, Abies lasiocarpa, Larix lyallii, Pinus contorta, Tsuga mertensiana and additional infrequent taxa. A most probable number assay of non-vegetated substrates over the chronosequence indicated that ectomycorrhizal propagules were few or absent in the non-vegetated areas adjacent to the glacier terminus but increased with time since deglaciation. Ectomycorrhizal fungus sporocarps occurred as soon as the first host plants of substantial size were present. However, none were observed with the most recently established hosts--small A. lasiocarpa seedlings. Only four species (Cortinarius decipiens, C. tenebricus, Inocybe lacera, and Laccaria cf. montana) occurred on substrate deglaciated for less than 40 years. Three of these species (C. tenebricus, I. lacera, and L. cf. montana) occurred along the chronosequence to the terminal moraine on substrate deglaciated for 70-100 years. An additional five species (one unidentified species each of Cortinarius and Lactarius, Cortinarius mutabilis, Lactarius uvidus var. montanus, and Suillus cavipes) occurred only on the oldest substrate. Our results support the current "early- and late-stage" model of ectomycorrhizal fungus succession in that additional species enter the community over time. However, we hypothesize that diversification of the mycorrhizal fungus community in this primary successional habitat resulted from an increasing diversity of host plants along with changing habitat attributes.


AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK-, ERK-, and PDK1-dependent activation of atypical PKC.
Activators of 5'-AMP-activated protein kinase (AMPK) 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR), metformin, and exercise activate atypical protein kinase C (aPKC) and ERK and stimulate glucose transport in muscle by uncertain mechanisms. Here, in cultured L6 myotubes: AICAR- and metformin-induced activation of AMPK was required for activation of aPKC and ERK; aPKC activation involved and required phosphoinositide-dependent kinase 1 (PDK1) phosphorylation of Thr410-PKC-zeta; aPKC Thr410 phosphorylation and activation also required MEK1-dependent ERK; and glucose transport effects of AICAR and metformin were inhibited by expression of dominant-negative AMPK, kinase-inactive PDK1, MEK1 inhibitors, kinase-inactive PKC-zeta, and RNA interference (RNAi)-mediated knockdown of PKC-zeta. In mice, muscle-specific aPKC (PKC-lambda) depletion by conditional gene targeting impaired AICAR-stimulated glucose disposal and stimulatory effects of both AICAR and metformin on 2-deoxyglucose/glucose uptake in muscle in vivo and AICAR stimulation of 2-[(3)H]deoxyglucose uptake in isolated extensor digitorum longus muscle; however, AMPK activation was unimpaired. In marked contrast to AICAR and metformin, treadmill exercise-induced stimulation of 2-deoxyglucose/glucose uptake was not inhibited in aPKC-knockout mice. Finally, in intact rodents, AICAR and metformin activated aPKC in muscle, but not in liver, despite activating AMPK in both tissues. The findings demonstrate that in muscle AICAR and metformin activate aPKC via sequential activation of AMPK, ERK, and PDK1 and the AMPK/ERK/PDK1/aPKC pathway is required for metformin- and AICAR-stimulated increases in glucose transport. On the other hand, although aPKC is activated by treadmill exercise, this activation is not required for exercise-induced increases in glucose transport, and therefore may be a redundant mechanism.


Molecular characterization of Staphylococcus aureus isolates from various healthcare institutions in Nairobi, Kenya: a cross sectional study.
Staphylococcus aureus (S. aureus) has established itself over the years as a major cause of morbidity and mortality both within the community and in healthcare settings. Methicillin resistant S. aureus (MRSA) in particular has been a major cause of nosocomial infections resulting in significant increase in healthcare costs. In Africa, the MRSA prevalence has been shown to vary across different countries. In order to better understand the epidemiology of MRSA in a setting, it is important to define its population structure using molecular tools as different clones have been found to predominate in certain geographical locations. We carried out PFGE, MLST, SCCmec and spa typing of selected S. aureus isolates from a private and public referral hospital in Nairobi, Kenya. A total of 93 S. aureus isolates were grouped into 19 PFGE clonal complexes (A-S) and 12 singletons. From these, 55 (32 MRSA and 23 MSSA) representative isolates from each PFGE clonal complex and all singletons were spa typed. There were 18 different MRSA spa types and 22 MSSA spa types. The predominant MRSA spa type was t037 comprising 40.6 % (13/32) of all MRSA. In contrast, the MSSA were quite heterogeneous, only 2 out of 23 MSSA shared the same spa type. Two new MRSA spa types (t13149 and t13150) and 3 new MSSA spa types (t13182, t13193 and t13194) were identified. The predominant clonal complex was CC 5 which included multi-locus sequence types 1, 8 and 241. In contrast to previous studies published from Kenya, there's marked genetic diversity amongst clinical MRSA isolates in Nairobi including the presence of well-known epidemic MRSA clones. Given that these clones are resident within our referral hospitals, adherence to strict infection control measures needs to be ensured to reduce morbidity and mortality associated with hospital acquired MRSA infections.


A Review on the Surgical Management of Subvalvular Aneurysm.
The present perspective is a synthesis of published investigations in the setting of subvalvular aortic aneurysms. We identified 75 investigations and reviewed the clinical presentation, diagnostic modalities used, surgical techniques employed, and their outcomes. Clinical presentation, radiographic findings, transthoracic and transesophageal echocardiography, electrocardiogram-gated computerized tomography, and magnetic resonance imaging provided the diagnostic information and were used to define the disease entity before surgery. In this article, we have attempted to address several issues concerning establishment of diagnosis, varied clinical presentation, and their management. We submit that an increased appreciation of this disease entity will contribute to improved surgical management.


Spatially modulated illumination microscopy allows axial distance resolution in the nanometer range.
For an improved understanding of the structural basis of cellular mechanisms, it is highly desirable to develop methods for a detailed topological analysis of biological nanostructures and their dynamics in the interior of three-dimensionally conserved cells. We present a method of far-field laser fluorescence microscopy to measure relative axial positions of pointlike fluorescent targets and the distance between each target in the range of a few nanometers. The physical principle behind this approach can be extended to the determination of three-dimensional (3D) positions and 3D distances between any number of objects that can be discriminated owing to their spectral signature, thus allowing topological measurements so far regarded to be beyond the capabilities of light microscopy.


Dopamine transporter loss in 6-OHDA Parkinson's model is unmet by parallel reduction in dopamine uptake.
The dopamine transporter (DAT) regulates synaptic dopamine (DA) in striatum and modulation of DAT can affect locomotor activity. Thus, in Parkinson's disease (PD), DAT loss could affect DA clearance and locomotor activity. The locomotor benefits of L-DOPA may be mediated by transport through monoamine transporters and conversion to DA. However, its impact upon DA reuptake is unknown and may modulate synaptic DA. Using the unilateral 6-OHDA rat PD model, we examined [(3)H]DA uptake dynamics in relation to striatal DAT and tyrosine hydroxylase (TH) protein loss compared with contralateral intact striatum. Despite >70% striatal DAT loss, DA uptake decreased only ∼25% and increased as DAT loss approached 99%. As other monoamine transporters can transport DA, we determined if norepinephrine (NE) and serotonin (5-HT) differentially modulated DA uptake in lesioned striatum. Unlabeled DA, NE, and 5-HT were used, at a concentration that differentially inhibited DA uptake in intact striatum, to compete against [(3)H]DA uptake. In 6-OHDA lesioned striatum, DA was less effective, whereas NE was more effective, at inhibiting [(3)H]DA uptake. Furthermore, norepinephrine transporter (NET) protein levels increased and desipramine was ∼two-fold more effective at inhibiting NE uptake. Serotonin inhibited [(3)H]DA uptake, but without significant difference between lesioned and contralateral striatum. L-DOPA inhibited [(3)H]DA uptake two-fold more in lesioned striatum and inhibited NE uptake ∼five-fold more than DA uptake in naïve striatum. Consequently, DA uptake may be mediated by NET when DAT loss is at PD levels. Increased inhibition of DA uptake by L-DOPA and its preferential inhibition of NE over DA uptake, indicates that NET-mediated DA uptake may be modulated by L-DOPA when DAT loss exceeds 70%. These results indicate a novel mechanism for DA uptake during PD progression and provide new insight into how L-DOPA affects DA uptake, revealing possible mechanisms of its therapeutic and side effect potential.