Escherichia coli cells are primed for survival before lethal antibiotic stress.
Non-genetic factors can cause significant fluctuations in gene expression levels. Regardless of growing in a stable environment, this fluctuation leads to cell-to-cell variability in an isogenic population. This phenotypic heterogeneity allows a tiny subset of bacterial cells in a population called persister cells to tolerate long-term lethal antibiotic effects by entering into a non-dividing, metabolically repressed state. We occasionally noticed a high variation in persister levels, and to explore this, we tested clonal populations starting from a single cell using a modified Luria-Delbrück fluctuation test. Although we kept the conditions same, the diversity in persistence level among clones was relatively consistent: varying from ~60- to 100- and ~40- to 70-fold for ampicillin and apramycin, respectively. Then, we divided and diluted each clone to observe whether the same clone had comparable persister levels for more than one generation. Replicates had similar persister levels even when clones were divided, diluted by 1:20, and allowed to grow for approximately five generations. This result explicitly shows a cellular memory passed on for generations and eventually lost when cells are diluted to 1:100 and regrown (>seven generations). Our result demonstrates (1) the existence of a small population prepared for stress ("primed cells") resulting in higher persister numbers; (2) the primed memory state is reproducible and transient, passed down for generations but eventually lost; and (3) a heterogeneous persister population is a result of a transiently primed reversible cell state and not due to a pre-existing genetic mutation. IMPORTANCE Antibiotics have been highly effective in treating lethal infectious diseases for almost a century. However, the increasing threat of antibiotic resistance is again causing these diseases to become life-threatening. The longer a bacteria can survive antibiotics, the more likely it is to develop resistance. Complicating matters is that non-genetic factors can allow bacterial cells with identical DNA to gain transient resistance (also known as persistence). Here, we show that a small fraction of the bacterial population called primed cells can pass down non-genetic information ("memory") to their offspring, enabling them to survive lethal antibiotics for a long time. However, this memory is eventually lost. These results demonstrate how bacteria can leverage differences among genetically identical cells formed through non-genetic factors to form primed cells with a selective advantage to survive antibiotics.


Antineutrophil cytoplasm antibody in crescentic glomerulonephritis.
Antineutrophil cytoplasm antibody (ANCA) has been reported in the sera of adults with Wegener's granulomatosis and microscopic polyarteritis, but this phenomenon has not so far been described in children. We report three children with crescentic glomerulonephritis in whom ANCA concentrations were raised at presentation. Two cases were idiopathic, and the other later developed features of Wegener's granulomatosis. In all three, plasma exchange and immunosuppression removed ANCA, but in only one case was there clinical improvement. This child later developed classical nasal lesions of Wegener's granulomatosis associated with a decline in renal function and a rise in ANCA. Plasma exchange and immunosuppression again produced a good clinical response and removed ANCA. This suggests that ANCA is either a marker of disease activity, or is involved in the pathogenesis of disease.


Some guidelines for family therapists working with the traumatically brain injured and their families.
A summary is presented of the major sequelae of traumatic brain injury and of the effects of these on the individual and the family. A series of guidelines is offered for use by family therapists when working with this population. The therapists must be directive, informed and informing. At times the therapist is an advocate, a model, a monitor and an agent of generalization.


A NOTCH4 association with multiple sclerosis is secondary to HLA-DR*1501.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with supposedly autoimmune features known to be associated with a specific HLA DR-DQ haplotype (DR15, DQ6, or HLDRB1*1501,DRB5*0101,DQA1*0102,DQB1*0602). We have previously reported that the associated haplotype extends to HLA-B and described an independent association with HLA-A alleles in MS. Owing to a complex situation with extensive linkage disequilibria, it is still unclear whether classical HLA genes are responsible or whether associations may be due to other genes in this region. Here, we analyzed an association in MS with the NOTCH4 and TNFalpha (tumor necrosis factor-alpha) genes, located between the HLA-DRB1 gene and the HLA-A gene. For NOTCH4, located 0.4 Mb telomeric to HLA-DRB1, an SNP at position -25 and a trinucleotide repeat were investigated in 181 MS patients, and 180 controls also typed P = 0.027 for HLA-DRB and HLA-A. A modest association was observed (OR = 3.44) with the C-25 allele. However, two-locus analysis revealed that this association was secondary to the classical association with HLA-DRB1. For TNF, located 0.7 Mb telomeric of NOTCH4, SNPs at positions -308 and -238 were studied in the same dataset. We found no association between these TNFalpha gene polymorphisms and MS in this dataset, although there was linkage disequilibrium (LD) between DRB1 and TNF and between HLA-A and TNF. We conclude that alleles of the NOTCH4 and TNFalpha genes are unlikely to be of importance for the susceptibility to MS, although specific alleles of these genes are often carried on the same haplotype as DR15, DQ6.


Characteristics of clients attending confidential versus anonymous testing clinics for human immunodeficiency virus.
To compare risk behavior between subjects attending anonymous and confidential clinics for human immunodeficiency virus testing, and to assess whether anonymous testing results in a higher accrual of persons at risk for HIV. An anonymous questionnaire that addressed sociodemographic and risk behavior aspects was administered to 140 subjects attending an anonymous clinic and 124 attending a confidential clinic in the Tel Aviv area. A logistic regression analysis was used to compare the effects of various behavioral factors on the probability of attending each clinic. Chronological age, age at first sexual intercourse, and the percent of married subjects were similar in both clinics. However, there was a significant difference in the sex ratio and in educational attainment (85.0% versus 55.6% were males, P < 0.001; and 58% vs. 34% had over 12 years of education, P < 0.001, in the anonymous and confidential clinics respectively). There was a striking difference between the two clinics with regard to sexual experience characteristics: of the subjects reaching the anonymous clinic 21.4% were homosexual and 10.0% bisexual versus a total of 2.6% in the confidential clinic. A logistic regression analysis, comparing the effects of various behavioral factors on the probability of attending each clinic, showed that gender (male), high education, homosexuality, number of partners and sexual encounter with sex workers were the strongest predictors for selecting anonymous HIV examination. Individuals at high risk for HIV, such as homosexuals and bisexuals, prefer to attend an anonymous clinic.


Long-term stability of Wechsler Intelligence Scale for Children-fifth edition scores in a clinical sample.
This study investigated the stability of Wechsler Intelligence Scale for Children-Fifth Edition (WISC-V) scores for 225 children and adolescents from an outpatient neuropsychological clinic across, on average, a 2.6 year test-retest interval. WISC-V mean scores were relatively constant but subtest stability score coefficients were all below 0.80 (M = 0.66) and only the Verbal Comprehension Index (VCI), Visual Spatial Index (VSI), and omnibus Full Scale IQ (FSIQ) stability coefficients exceeded 0.80. Neither intraindividual subtest difference scores nor intraindividual composite difference scores were stable across time (M = 0.26 and 0.36, respectively). Rare and unusual subtest and composite score differences as well as subtest and index scatter at initial testing were unlikely to be repeated at retest (kappa = 0.03 to 0.49). It was concluded that VCI, VSI, and FSIQ scores might be sufficiently stable to support normative comparisons but that none of the intraindividual (i.e. idiographic, ipsative, or person-relative) measures were stable enough for confident clinical decision making.


Re-Epithelialization Appraisal of Skin Wound in a Porcine Model Using a Salmon-Gelatin Based Biomaterial as Wound Dressing.
The design of new functional materials for skin tissue engineering is an area of constant research. In this work, a novel wound-dressing biomaterial with a porous structure, previously formulated using salmon-gelatin as main component (called salmon-gelatin biomaterial (SGB)), was tested in vivo using pigs as skin wound models. Four weeks after cutaneous excision and implantation in the animals, the healing process did not show apparent symptoms of inflammation or infection. Interestingly, the temporal evolution of wound size from 100% to around 10% would indicate a faster recovery when SGB was compared against a commercial control. Histological analysis established that wounds treated with SGB presented similar healing and epithelialization profiles with respect to the commercial control. Moreover, vascularized granulation tissue and epithelialization stages were clearly identified, indicating a proliferation phase. These results showed that SGB formulation allows cell viability to be maintained. The latter foresees the development of therapeutic alternatives for skin repair based on SGB fabricated using low cost production protocols.


Fine-structural studies of the gametes and embryo of Fucus vesiculosus L. (Phaeophyta). II. The cytoplasm of the egg and young zygote.
Following fertilization, there are rapid changes in the appearance of the Fucus egg. Large electron-translucent vesicles (V1) accumulate fibrillar material, and following pronuclear fusion, they are largely electron-opaque. These vesicles (V1) are formed originally in unfertilized eggs by smooth endoplasmic reticulum (SER) after release of the eggs from the oogonium. Golgi complex hypertrophy follows fertilization, and this increased activity continues throughout early embryogenesis. Wall formation begins after penetration of the egg by the sperm. Vesicles (V2) of unknown origin, which have homogeneously fibrillar contents, and Golgi vesicles (V3) merge with SER-derived vesicles (V1) after wall formation begins. Osmiophilic bodies are a prominent feature of the egg and embryo. They are penetrated by SER, and subsequently there is a loss of electron-opaque material. Alternatively, they discharge concentrically whorled material into the cytoplasm. The nuclear surface of the egg is convoluted in the period close to fertilization, and electron-opaque material is segregated in the cytoplasmic matrix lying within the nuclear invaginations.


Visualizing temporal brain-state changes for fMRI using t-distributed stochastic neighbor embedding.
Purpose: Currently, functional magnetic resonance imaging (fMRI) is the most commonly used technique for obtaining dynamic information about the brain. However, because of the complexity of the data, it is often difficult to directly visualize the temporal aspect of the fMRI data. Approach: We outline a t -distributed stochastic neighbor embedding (t-SNE)-based postprocessing technique that can be used for visualization of temporal information from a 4D fMRI data. Apart from visualization, we also show its utility in detection of major changes in the brain meta-states during the scan duration. Results: The t-SNE approach is able to detect brain-state changes from task to rest and vice versa for single- and multitask fMRI data. A temporal visualization can also be obtained for task and resting state fMRI data for assessing the temporal dynamics during the scan duration. Additionally, hemodynamic delay can be quantified by comparison of the detected brain-state changes with the experiment paradigm for task fMRI data. Conclusion: The t-SNE visualization can visualize help identify major brain-state changes from fMRI data. Such visualization can provide information about the degree of involvement and attentiveness of the subject during the scan and can be potentially utilized as a quality control for subject's performance during the scan.


Lymphocyte-C-reactive protein ratio can differentiate disease severity of COVID-19 patients and serve as an assistant screening tool for hospital and ICU admission.
In this study, we aimed to explore whether lymphocyte-C-reactive protein ratio (LCR) can differentiate disease severity of coronavirus disease 2019 (COVID-19) patients and its value as an assistant screening tool for admission to hospital and intensive care unit (ICU). A total of 184 adult COVID-19 patients from the COVID-19 Treatment Center in Heilongjiang Province at the First Affiliated Hospital of Harbin Medical University between January 2020 and March 2021 were included in this study. Patients were divided into asymptomatic infection group, mild group, moderate group, severe group, and critical group according to the Diagnosis and Treatment of New Coronavirus Pneumonia (ninth edition). Demographic and clinical data including gender, age, comorbidities, severity of COVID-19, white blood cell count (WBC), neutrophil proportion (NEUT%), lymphocyte count (LYMPH), lymphocyte percentage (LYM%), red blood cell distribution width (RDW), platelet (PLT), C-reactive protein (CRP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (SCr), albumin (ALB), total bilirubin (TB), direct bilirubin (DBIL), indirect bilirubin (IBIL), and D-dimer were obtained and collated from medical records at admission, from which sequential organ failure assessment (SOFA) score and LCR were calculated, and all the above indicators were compared among the groups. Multiple clinical parameters, including LYMPH, CRP, and LCR, showed significant differences among the groups. The related factors to classify COVID-19 patients into moderate, severe, and critical groups included age, number of comorbidities, WBC, LCR, and AST. Among these factors, the number of comorbidities showed the greatest effect, and only WBC and LCR were protective factors. The area under the receiver operating characteristic (ROC) curve of LCR to classify COVID-19 patients into moderate, severe, and critical groups was 0.176. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 1,780.7050 and 84.6% and 66.2%, respectively. The related factors to classify COVID-19 patients into severe and critical groups included the number of comorbidities, PLT, LCR, and SOFA score. Among these factors, SOFA score showed the greatest effect, and LCR was the only protective factor. The area under the ROC curve of LCR to classify COVID-19 patients into severe and critical groups was 0.106. The cutoff value of LCR and the sensitivity and specificity of the ROC curve were 571.2200 and 81.3% and 90.0%, respectively. In summary, LCR can differentiate disease severity of COVID-19 patients and serve as a simple and objective assistant screening tool for hospital and ICU admission.


Low voltage scanning electron microscopy of uncoated kidney stones.
Some organic kidney stone components are easily damaged by a 10-30 kV electron beam used in conventional scanning electron microscopy. To avoid beam damage and reduce charging, it is desirable to study kidney stones by low voltage (1-5 kV) scanning electron microscopy (LVSEM) even though image resolution will suffer and X-ray microanalysis will not be available. If one is proficient in crystal morphology one can analyze gold-coated kidney stones by LVSEM without much difficulty. Stone components examined include calcium oxalate monohydrate, calcium oxalate dihydrate, struvite, calcium apatite, brushite, whitlockite, cystine, uric acid, uric acid dihydrate and ammonium acid urate. For all these components with the exception of the very small whitlockite and ammonium acid urate crystals, uncoated kidney stones can be examined with a 1 kV electron beam.


Relation between antibiotic susceptibility and ultrastructure of Staphylococcus aureus biofilms on surgical suture.
Infectious biofilms are recalcitrant to antimicrobial therapy, but the mechanism(s) responsible for the greater resistance are unclear. Experiments were designed to clarify the association between antibiotic resistance and biofilm ultrastructure. Staphylococcus aureus was cultivated for 24 h on silk suture, where robust biofilms formed. Initial experiments compared the susceptibilities of planktonic (free-living) cells and mechanically dispersed biofilm cells to ampicillin, oxacillin, and vancomycin. Antibiotics in bactericidal concentrations were then incubated overnight with 24-h biofilms, and subsequent assays determined the viability of cells in mechanically dispersed biofilms, biofilm metabolic capacity and biomass, and biofilm ultrastructure (scanning electron microscopy). Planktonic and biofilm cells had similar intrinsic antibiotic susceptibility. Nonetheless, a stable population of bacteria remained viable after biofilms were incubated with inhibitory drug concentrations, although biofilm metabolic capacity often was not detected, and biomass generally was reduced. Electron microscopy revealed that control (no drug) biofilms consisted primarily of bacterial clusters amid fibrillar elements. Antibiotic-treated biofilms had some staphylococci with smooth cells walls similar to planktonic cells, but other cocci were encased in extracellular material. This material was more abundant in antibiotic-treated than in control biofilms. In the presence of high antibiotic concentrations, dense extracellular material may inhibit interaction of antibiotics with their bacterial targets.


The multidimensionality of female mandrill sociality-A dynamic multiplex network approach.
The structure and dynamics of primate social groups are shaped by the social relationships of its members. These relationships are based on different types of interactions and vary in relation to the identity of the interactants and over time. Social network analysis tools represent a powerful and comprehensive method to characterise social interactions and recent methodological advances now allow the study of the multidimensionality of sociality via multilayer networks that incorporate multiple types of interactions. Here, we use a multidimensional network approach to investigate the multidimensionality of sociality of females in a captive group of mandrills. We constructed two multiplex networks based on agonistic, proximity and grooming interactions of 6-7 mature females to analyse the multidimensionality of relationships within two independent observation periods; and three multiplex networks (one for each interaction type) to examine how relationships changed between periods. Within each period, different individuals were the most central in each layer and at the multiplex level, and different layers (i.e., interaction types) contributed non-redundant information to the multilayer structure. Across periods, relationships based on the same interaction type also contained non-redundant information. These results indicate that female mandrills engage in multidimensional and dynamic relationships, suggesting that in order to represent the full complexity of relationships, networks need to be constructed from more than a single type of interaction and across time. Our results provide evidence for the potential value of the multilayer network approach to characterise the multidimensionality of primate sociality.


Nitric oxide generation in Vicia faba phloem cells reveals them to be sensitive detectors as well as possible systemic transducers of stress signals.
Vascular tissue was recently shown to be capable of producing nitric oxide (NO), but the production sites and sources were not precisely determined. Here, NO synthesis was analysed in the phloem of Vicia faba in response to stress- and pathogen defence-related compounds. The chemical stimuli were added to shallow paradermal cortical cuts in the main veins of leaves attached to intact plants. NO production in the bare-lying phloem area was visualized by real-time confocal laser scanning microscopy using the NO-specific fluorochrome 4,5-diaminofluorescein diacetate (DAF-2 DA). Abundant NO generation in companion cells was induced by 500 microm salicylic acid (SA) and 10 microm hydrogen peroxide (H(2)O(2)), but the fungal elicitor chitooctaose was much less effective. Phloem NO production was found to be dependent on Ca(2+) and mitochondrial electron transport and pharmacological approaches found evidence for activity of a plant NO synthase but not a nitrate reductase. DAF fluorescence increased most strongly in companion cells and was occasionally observed in phloem parenchyma cells. Significantly, accumulation of NO in sieve elements could be demonstrated. These findings suggest that the phloem perceives and produces stress-related signals and that one mechanism of distal signalling involves the production and transport of NO in the phloem.


Blood group antigen A carriers exhibit an extended progression-free survival with no more immune-related adverse events.
Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N=168), antigen A carriers (blood type A and AB) exhibited an extended progression-free survival (PFS, hazard ratio [HR]=0.58, 95% confidence interval [CI]=0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N=202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR=0.61, 95% CI=0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P-value=0.003, HR=0.60, 95% CI=0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.


American Heart Association's Life's Simple 7: Lifestyle Recommendations, Polygenic Risk, and Lifetime Risk of Coronary Heart Disease.
Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association's Life's Simple 7 (LS7) guidelines in a population-based cohort study. Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (<20th percentile), intermediate, and high (>80th percentile). An overall LS7 score was calculated at baseline and categorized into "poor," "intermediate," and "ideal" cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories. The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score. Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.


Genetic correlations between body weight change and reproduction traits in Merino ewes depend on age.
Merino sheep in Australia experience periods of variable feed supply. Merino sheep can be bred to be more resilient to this variation by losing less BW when grazing poor quality pasture and gaining more BW when grazing good quality pasture. Therefore, selection on BW change might be economically attractive but correlations with other traits in the breeding objective need to be known. The genetic correlations (rg) between BW, BW change, and reproduction were estimated using records from approximately 7,350 fully pedigreed Merino ewes managed at Katanning in Western Australia. Number of lambs and total weight of lambs born and weaned were measured on approximately 5,300 2-yr-old ewes, approximately 4,900 3-yr-old ewes, and approximately 3,600 4-yr-old ewes. On a proportion of these ewes BW change was measured: approximately 1,950 2-yr-old ewes, approximately 1,500 3-yr-old ewes, and approximately 1,100 4-yr-old ewes. The BW measurements were for 3 periods. The first period was during mating period over 42 d on poor pasture. The second period was during pregnancy over 90 d for ewes that got pregnant on poor and medium quality pasture. The third period was during lactation over 130 d for ewes that weaned a lamb on good quality pasture. Genetic correlations between weight change and reproduction were estimated within age classes. Genetic correlations were tested to be significantly greater magnitude than 0 using likelihood ratio tests. Nearly all BW had significant positive genetic correlations with all reproduction traits. In 2-yr-old ewes, BW change during the mating period had a positive genetic correlation with number of lambs weaned (rg = 0.58); BW change during pregnancy had a positive genetic correlation with total weight of lambs born (rg = 0.33) and a negative genetic correlation with number of lambs weaned (rg = -0.49). All other genetic correlations were not significantly greater magnitude than 0 but estimates of genetic correlations for 3-yr-old ewes were generally consistent with these findings. The direction of the genetic correlations mostly coincided with the energy requirements of the ewes and the stage of maturity of the ewes. In conclusion, optimized selection strategies on BW changes to increase resilience will depend on the genetic correlations with reproduction and are dependent on age.


CuS2-passivated Au-core, Au3Cu-shell nanoparticles analyzed by atomistic-resolution Cs-corrected STEM.
Au-core, Au3Cu-alloyed shell nanoparticles passivated with CuS2 were fabricated by the polyol method, and characterized by Cs-corrected scanning transmission electron microscopy. The analysis of the high-resolution micrographs reveals that these nanoparticles have decahedral structure with shell periodicity, and that each of the particles is composed by Au core and Au3Cu alloyed shell surrounded by CuS2 surface layer. X-ray diffraction measurements and results from numerical simulations confirm these findings. From the atomic resolution micrographs, we identified edge dislocations at the twin boundaries of the particles, as well as evidence of the diffusion of Cu atoms into the Au region, and the reordering of the lattice on the surface, close to the vertices of the particle. These defects will impact the atomic and electronic structures, thereby changing the physical and chemical properties of the nanoparticles. On the other hand, we show for the first time the formation of an ordered superlattice of Au3Cu and a self-capping layer made using one of the alloy metals. This has significant consequences on the physical mechanism that form multicomponent nanoparticles.


Coffee extracts suppress tryptophan breakdown in mitogen-stimulated peripheral blood mononuclear cells.
Coffee consumption is considered to exert an influence on mood, the immune system, cardiovascular disease, and cancer development, but the mechanisms of action of coffee and its compounds are only partly known and understood. Immunomodulatory effects of filtered extracts of coffee and decaffeinated coffee as well as coffee compounds were investigated in human peripheral blood mononuclear cells (PBMCs) stimulated with mitogen phytohemagglutinin (PHA). The activation of PBMCs was monitored by the breakdown of tryptophan to kynurenine via enzyme indoleamine 2,3-dioxygenase (IDO) and the production of the immune activation marker neopterin by GTP-cyclohydrolase I (GCH1). Both of these biochemical pathways are induced during cellular immune activation in response to the Th1-type cytokine interferon-γ (IFN-γ). Filtered extracts of coffee and decaffeinated coffee both suppressed tryptophan breakdown and neopterin formation in mitogen-stimulated PBMCs efficiently and in a dose-dependent manner. Of 4 coffee compounds tested individually, only gallic acid and less strong also caffeic acid had a consistent suppressive influence but also affected cell viability, whereas pure caffeine and chlorogenic acid exerted no relevant effect in the PBMC assay. The parallel influence of extracts on tryptophan breakdown and neopterin production shows an anti-inflammatory and immunosuppressive property of coffee extracts and some of its compounds. When extrapolating the in vitro results to in vivo, IFN-γ-mediated breakdown of tryptophan could be counteracted by the consumption of coffee or decaffeinated coffee. This may increase tryptophan availability for the biosynthesis of the neurotransmitter 5-hydroxytryptamine (serotonin) and thereby improve mood and quality of life.


Partial synthesis of serum carotenoids and their metabolites.
Human serum and tissues contain in excess of 12 dietary carotenoids and several metabolites that originate from consumption of fruits and vegetables. Among these are hydroxycarotenoids: (3R,3'R,6'R)-lutein (1), (3R,3'R)-zeaxanthin (2), (3R,6'R)-α-cryptoxanthin (3), and (3R)-β-cryptoxanthin (4). In addition, several dehydration products of 1 have also been identified in human serum, these are: (3R,6'R)-3-hydroxy-3',4'-didehydro-β,γ-carotene (5), (3R,6'R)-3-hydroxy-2',3'-didehydro-β,ε-carotene (6), and (3R)-3-hydroxy-3',4'-didehydro-β,β-carotene (7). Several metabolites of 1 and/or 2, namely, (3R,3'S,6'R)-lutein (3'-epilutein, 8) and (3R,3'S;meso)-zeaxanthin (9) have also been characterized in human serum and ocular tissues. Semi-synthetic processes have been developed that separately transform commercially available 1 into 4 via 7 as well as 1 into 8. While 8 is converted into 2 by base-catalyzed isomerization, 7 is transformed into 2 and its (3R,3'S;meso)-stereoisomer (9) by regioselective hydroboration.


NMR Metabolomics Analysis of Parkinson's Disease.
Parkinson's disease (PD) is a neurodegenerative disease, which is characterized by progressive death of dopaminergic neurons in the substantia nigra pars compacta. Although mitochondrial dysfunction and oxidative stress are linked to PD pathogenesis, its etiology and pathology remain to be elucidated. Metabolomics investigates metabolite changes in biofluids, cell lysates, tissues and tumors in order to correlate these metabolomic changes to a disease state. Thus, the application of metabolomics to investigate PD provides a systematic approach to understand the pathology of PD, to identify disease biomarkers, and to complement genomics, transcriptomics and proteomics studies. This review will examine current research into PD mechanisms with a focus on mitochondrial dysfunction and oxidative stress. Neurotoxin-based PD animal models and the rationale for metabolomics studies in PD will also be discussed. The review will also explore the potential of NMR metabolomics to address important issues related to PD treatment and diagnosis.


[Adverse effects of hypolipemic drugs: how to treat in clinical practice].
Hypolipemic drugs improve coronary morbidity and mortality and appear to be safe; nevertheless appropriate monitoring is recommended. Adverse effects are reported that are frequently transitory. Severe adverse effects are infrequent, but clinicians must correctly screen them; symptoms and laboratory changes must be carefully interpreted. Often they call for special treatment and replacement of the hypolipemic drugs in use. This article emphasizes how to treat dyslipidemia if skeletal muscle and liver involvement are present. Briefly other adverse effects are also reported.


Falls among Koreans 45 years of age and older: incidence and risk factors.
The aim of the study was to determine the incidence of falls according to age and risk factors among Korean adults 45 years of age and older. Falling is a known critical incident that results in injuries and limits the daily activities of older adults. The 2006 Korean Longitudinal Study of Aging, a publicly available database, was used for this study, which was conducted in 2006 with a total of 10,254 respondents. The variables used in this study were selected from the demographic and health sections of the larger study. The overall incidence of any type of fall was 4.0%, and the incidence of injurious falls tended to increase with increasing age; however, people below 65 years of age had a greater proportion of injurious falls than any of the older adult groups. All types of falls were more likely to occur among older adults and those with arthritis, visual deficits, cognitive impairments and depression. In addition, older age, visual deficits, weak grip, cognitive impairment and depression were key risk factors for falls requiring treatment and those resulting in difficulties in activities of daily living. Falls resulting in hip fractures occurred more frequently among women, people with visual deficits and those with depression. Future assessments of the incidence and risk factors for falls and studies of fall interventions should begin with younger age groups, namely those 45 years of age and older.


High-capacity and high-power collective charging with spin chargers.
Quantum battery works as a micro- or nanodevice to store and redistribute energy at the quantum level. Here we propose a spin-charger protocol, in which the battery cells are charged by a finite number of spins through a general Heisenberg XY interaction. Under the isotropic interaction, the spin-charger protocol is endowed with a higher capacity in terms of the maximum stored energy than the conventional protocols, where the battery is charged by a continuous-variable system, e.g., a cavity mode. By tuning the charger size, a tradeoff between the maximum stored energy and the average charging power is found in comparison to the cavity-charger protocol in the Tavis-Cummings model. Quantum advantage of our protocol is manifested by the scaling behavior of the optimal average power with respect to the battery size, in comparing the collective charging scheme to its parallel counterpart. We also discuss the detrimental effect on the charging performance from the anisotropic interaction between the battery and the charger, the nonideal initial states for both of them, and the crosstalk among the charger spins. A strong charger-charger interaction can be used to decouple the battery and the charger. Our findings about the advantages of the spin-charger protocol over the conventional cavity-charger protocols, including the high capacity of energy storage and the superior power law in the collective charging, provide an insight to exploit an efficient quantum battery based on the spin-spin-environment model.


Investigating recent trends in the U.S. teen birth rate.
We investigate trends in the U.S. rate of teen childbearing between 1981 and 2010, focusing specifically on the sizable decline since 1991. We focus on establishing the role of state-level demographic changes, economic conditions, and targeted policies in driving recent aggregate trends. We offer three main observations. First, the recent decline cannot be explained by the changing racial and ethnic composition of teens. Second, the only targeted policies that have had a statistically discernible impact on aggregate teen birth rates are declining welfare benefits and expanded access to family planning services through Medicaid, but these policies can account for only 12.6 percent of the observed decline since 1991. Third, higher unemployment rates lead to lower teen birth rates and can account for 16 percent of the decline in teen birth rates since the Great Recession began.


Stereotactic body radiation therapy for non-small cell lung cancer: A review.
Stereotactic body radiation therapy (SBRT) is the treatment of choice for medically inoperable patients with early stage non-small cell lung cancer (NSCLC). A literature search primarily based on PubMed electronic databases was completed in July 2018. Inclusion and exclusion criteria were determined prior to the search, and only prospective clinical trials were included. Nineteen trials from 2005 to 2018 met the inclusion criteria, reporting the outcomes of 1434 patients with central and peripheral early stage NSCLC. Patient eligibility, prescription dose and delivery, and follow up duration varied widely. Three-years overall survival ranged from 43% to 95% with loco-regional control of up to 98% at 3 years. Up to 33% of patients failed distantly after SBRT at 3 years. SBRT was generally well tolerated with 10%-30% grade 3-4 toxicities and a few treatment-related deaths. No differences in outcomes were observed between conventionally fractionated radiation therapy and SBRT, central and peripheral lung tumors, or inoperable and operable patients. SBRT remains a reasonable treatment option for medically inoperable and select operable patients with early stage NSCLC. SBRT has shown excellent local and regional control with toxicity rates equivalent to surgery. Decreasing fractionation schedules have been consistently shown to be both safe and effective. Distant failure is common, and chemotherapy may be considered for select patients. However, the survival benefit of additional interventions, such as chemotherapy, for early stage NSCLC treated with SBRT remains unclear.


Biomonitoring DNA Adducts of Cooked Meat Carcinogens in Human Prostate by Nano Liquid Chromatography-High Resolution Tandem Mass Spectrometry: Identification of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine DNA Adduct.
Epidemiologic studies have reported an association between frequent consumption of well-done cooked meats and prostate cancer risk. However, unambiguous physiochemical markers of DNA damage from carcinogens derived from cooked meats, such as DNA adducts, have not been identified in human samples to support this paradigm. We have developed a highly sensitive nano-LC-Orbitrap MS n method to measure DNA adducts of several carcinogens originating from well-done cooked meats, tobacco smoke, and environmental pollution, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-9H-pyrido[2,3-b]indole (AαC), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), benzo[a]pyrene (B[a]P), and 4-aminobiphenyl (4-ABP). The limit of quantification (LOQ) of the major deoxyguanosine (dG) adducts of these carcinogens ranged between 1.3 and 2.2 adducts per 10 9 nucleotides per 2.5 μg of DNA assayed. The DNA adduct of PhIP, N-(deoxyguanosin-8-yl)-PhIP (dG-C8-PhIP) was identified in 11 out of 35 patients, at levels ranging from 2 to 120 adducts per 10 9 nucleotides. The dG-C8 adducts of AαC and MeIQx, and the B[a]P adduct, 10-(deoxyguanosin-N 2 -yl)-7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (dG-N 2 -B[a]PDE) were not detected in any specimen, whereas N-(deoxyguanosin-8-yl)-4-ABP (dG-C8-4-ABP) was identified in one subject (30 adducts per 10 9 nucleotides). PhIP-DNA adducts also were recovered quantitatively from formalin fixed paraffin embedded (FFPE) tissues, signifying FFPE tissues can serve as biospecimens for carcinogen DNA adduct biomarker research. Our biomarker data provide support to the epidemiological observations implicating PhIP, one of the most mass-abundant heterocyclic aromatic amines formed in well-done cooked meats, as a DNA-damaging agent that may contribute to the etiology of prostate cancer.


[Characteristics of protein metabolism changes in oncology patients with surgical and combined treatment].
Combined approach (surgery and chemotherapy) have been acknowledged as the optimal treatment scheme in oncology. The purpose of this case study was to detect and compare the changes in metabolism emerging in combined treatment method for the purpose of working out, later, a therapeutic correction scheme to correct such changes. Two groups of patients, 20 subjects in each, were examined to establish a basic higher degree of the protein-and-energetic insufficiency and a changed immune response, due to which metabolism in patients with combined treatment normalizes slower than in patient with surgical treatment. Special scheme, worked out for the purpose, are needed to correct the progressing lesions.


A rat model of chronic moderate alcohol consumption and risk of decompression sickness.
This study aimed to establish if chronic, moderate, pre-dive alcohol consumption had any affect upon susceptibility to decompression sickness (DCS) in rats. A treatment group of 15 rats were given water containing 12 mL ·L ⁻¹ of ethanol for four weeks. Controls (n = 15) were given water. Both groups were compressed with air to 1,000 kPa, followed by staged decompression. An additional 30 control rats from a similar previous experiment were added, raising the control-treatment ratio to 3:1. Rats in the treatment group consumed the equivalent of an 80 kg man drinking 2 L of 5 % alcohol by volume beer per day, which is three times the recommended daily limit for men. Overall, comparing the treatment group with the combined control groups neither weight (P = 0.23) nor alcohol consumption (P = 0.69) were associated with DCS. We observed that chronic, moderate alcohol consumption prior to compression was neither prophylactic nor deleterious for DCS in young, male rats.


Removal and recovery of toxic silver ion using deep-sea bacterial generated biogenic manganese oxides.
Products containing silver ion (Ag(+)) are widely used, leading to a large amount of Ag(+)-containing waste. The deep-sea manganese-oxidizing bacterium Marinobacter sp. MnI7-9 efficiently oxidizes Mn(2+) to generate biogenic Mn oxide (BMO). The potential of BMO for recovering metal ions by adsorption has been investigated for some ions but not for Ag(+). The main aim of this study was to develop effective methods for adsorbing and recovering Ag using BMO produced by Marinobacter sp. MnI7-9. In addition, the adsorption mechanism was determined using X-ray photoelectron spectroscopy analysis, specific surface area analysis, adsorption kinetics and thermodynamics. The results showed that BMO had a higher adsorption capacity for Ag(+) compared to the chemical synthesized MnO2 (CMO). The isothermal absorption curves of BMO and CMO both fit the Langmuir model well and the maximum adsorption capacities at 28°C were 8.097 mmol/g and 0.787 mmol/g, for BMO and CMO, respectively. The change in enthalpy (ΔH(θ)) for BMO was 59.69 kJ/mol indicating that it acts primarily by chemical adsorption. The change in free energy (ΔG(θ)) for BMO was negative, which suggests that the adsorption occurs spontaneously. Ag(+) adsorption by BMO was driven by entropy based on the positive ΔS(θ) values. The Ag(+) adsorption kinetics by BMO fit the pseudo-second order model and the apparent activation energy of Ea is 21.72 kJ/mol. X-ray photoelectron spectroscopy analysis showed that 15.29% Ag(+) adsorbed by BMO was transferred to Ag(0) and meant that redox reaction had happened during the adsorption. Desorption using nitric acid and Na2S completely recovered the Ag. The results show that BMO produced by strain MnI7-9 has potential for bioremediation and reutilization of Ag(+)-containing waste.


[Anorectal lesions in HIV-positive patients using highly active antiretroviral therapy].
Anorectal lesions are common in patients with human immunodeficiency virus (HIV). Highly active anti-retroviral therapy (HAART) has little influence on the progression of anal neoplasms. The prevalence of anorectal lesions in 88 HIV-positive patients attended at the infectious diseases service of the University Hospital of Brasília who were using HAART was studied. Sociodemographic data were collected using a pre-prepared questionnaire and then the patients underwent proctological examination. Around 71% of the patients said they practiced anal intercourse. 30.7% were using a protease inhibitor. The prevalence of anorectal lesions was 36.4%, and condyloma acuminata and anal fissure were the most frequent of these. Condyloma acuminata was the most prevalent anorectal lesion and was strongly associated with the use of lopinavir/ritonavir. Screening for anorectal lesions caused by human papillomavirus in HIV/AIDS patients who use protease inhibitors is suggested.


The national response for preventing healthcare-associated infections: infrastructure development.
In 2009, the US Department of Health and Human Services (HHS) launched the Action Plan to Prevent Healthcare-associated Infections (HAIs). The Action Plan adopted national targets for reduction of specific infections, making HHS accountable for change across the healthcare system over which federal agencies have limited control. This article examines the unique infrastructure developed through the Action Plan to support adoption of HAI prevention practices. Interviews of federal (n=32) and other stakeholders (n=38), reviews of agency documents and journal articles (n=260), and observations of interagency meetings (n=17) and multistakeholder conferences (n=17) over a 3-year evaluation period. We extract key progress and challenges in the development of national HAI prevention infrastructure--1 of the 4 system functions in our evaluation framework encompassing regulation, payment systems, safety culture, and dissemination and technical assistance. We then identify system properties--for example, coordination and alignment, accountability and incentives, etc.--that enabled or hindered progress within each key development. The Action Plan has developed a model of interagency coordination (including a dedicated "home" and culture of cooperation) at the federal level and infrastructure for stimulating change through the wider healthcare system (including transparency and financial incentives, support of state and regional HAI prevention capacity, changes in safety culture, and mechanisms for stakeholder engagement). Significant challenges to infrastructure development included many related to the same areas of progress. The Action Plan has built a foundation of infrastructure to expand prevention of HAIs and presents useful lessons for other large-scale improvement initiatives.


Community, facility and individual level impact of integrating mental health screening and treatment into the primary healthcare system in Sehore district, Madhya Pradesh, India.
Programme for Improving Mental Health Care (PRIME) designed a comprehensive mental healthcare plan (MHCP) for Sehore district, Madhya Pradesh, India. The objective of this paper is to describe the findings of the district-level impact evaluation of the MHCP. Repeat community-based CS were conducted to measure change in population-level contact coverage for depression and alcohol use disorders (AUD), repeat FDS were conducted to assess change in detection and initiation of treatment for depression and AUD, and the effect of treatment on patient outcomes was assessed using disorder-specific prospective cohort studies. PRIME MHCP did not have any impact on contact coverage/treatment seeking for depression (14.8% at the baseline and 10.5% at the follow-up) and AUD (7.7% at the baseline and 7.3% at the follow-up) and had a small impact on detection and initiation of treatment for depression and AUD (9.7% for depression and 17.8% for AUD compared with 0% for both at the baseline) in the health facilities. Patients with depression who received care as part of the MHCP had higher rates of response (52.2% in the treatment group vs 26.9% in the comparison/usual care group), early remission (70.2% in the treatment group vs 44.8% in the comparison/usual care group) and recovery (56.1% in the treatment group vs 28.5% in the comparison/usual care group), but there was no impact of treatment on their functioning. While dedicated human resources (eg, Case Managers) and dedicated space for mental health clinics (eg, Mann-Kaksha) strengthen the 'formal' healthcare platform, without substantial additional investments in staff, such as Community Health Workers/Accredited Social Health Activists to improve community level processes and provision of community-based continuing care to patients, we are unlikely to see major changes in coverage or clinical outcomes.


[Mesenteric cyst as a cause of acute abdomen. Report of 3 cases].
Mesenteric cyst is a tumor of multiple origins that surely are found more frequently than the literature report, at any rate, this tumor is uncommon. Because of absence of characteristic clinical findings, diagnosis cumbersome, until these cysts are of such a size that palpation becomes possible or when they cause compression to nearby viscera. Occasionally, diagnosis is made during surgery, even when it was emergency surgery. The present paper reports on three patients with mesenteric cyst found during surgery as emergency treatment. Histopathologic reports showed lymphangioma in two cases and leiomyosarcoma in one case, quite uncommon in this kind of lesion.


Combining Fluorination and Bioreducibility for Improved siRNA Polyplex Delivery.
Polycations are promising vectors for the delivery of siRNA therapeutics but they often suffer from toxicity and low in vivo delivery efficacy. This study tests the hypothesis that combining fluorination and bioreducibility of polycations will overcome problems with both the toxicity and delivery efficacy. To test the hypothesis, we synthesized bioreducible (RHB) and nonreducible (NHB) poly(amido amine)s. The RHB were additionally fluorinated using reaction with heptafluorobutyric anhydride to obtain F-RHB. We found that both RHB and F-RHB showed significantly reduced cytotoxicity compared with NHB, which allowed their safe use in a wider range of doses than NHB. All three synthesized polycations formed polyplexes with siRNA. F-RHB achieved the best siRNA silencing efficacy in multiple cell lines in vitro, which was at least in part because of fluorination-induced enhancement of cellular uptake and improved endosomal escape. Lastly, F-RHB showed greatly improved Luc silencing efficacy in tumors in vivo when compared with polyplexes based on RHB, NHB, as well as control poly(ethylenimine) (PEI). This study suggests that combining fluorination with bioreducibility of polycations is a promising strategy to the design of siRNA delivery vectors with improved toxicity and in vivo activity profiles.


The fitness effects of outcrossing in Calylophus serrulatus, a permanent translocation heterozygote.
Small and relatively isolated populations that occupy fragmented habitat are at risk of local extinction. However, fitness consequences of fragmentation related to mating distance, such as inbreeding depression following increased self- and near-neighbor mating, may not follow standard expectations in species with specialized genetic systems. We investigated the effect of mating distance on progeny fitness in Calylophus serrulatus, a primarily autogamous, permanent translocation heterozygote that is restricted to prairie fragments in the North American tallgrass prairie region. We pollinated flowers by hand in the field with pollen sampled at various distances from the maternal parent within and between three populations in southeastern Minnesota. We raised the progeny in a greenhouse and measured fitness-related characters. Because their genetic system prevents loss of heterozygosity throughout much of the genome, regardless of inbreeding, permanent translocation heterozygotes are not expected to exhibit inbreeding depression. Consistent with this expectation, in no case did progeny of self matings suffer significantly reduced mean fitness compared to progeny from crosses between plants. Crosses between plants in the two closely situated (2 km) populations yielded progeny with fitness intermediate to their parents, but crosses between each of those populations and the more distant (20 km) population yielded progeny with reduced fitness, suggesting outbreeding depression at this largest spatial scale. Similarly, fitness of self-pollinated progeny and progeny from "near" crosses (<2 m) within populations tended to be higher than "mid" (10-25 m) and "far" (>35 m) cross-progeny fitness. Under the current conditions of fragmentation, it seems likely that the distant matings that produce outbreeding depression are rare. It appears that mean fitness in this species is maintained in the context of severe fragmentation of its populations, largely because of its genetic system.


[Antioxidant systems of erythrocytes in rheumatism].
Patients with inactive and active rheumatic fever were examined for the intensity of lipid peroxidation of red blood cell membranes, lipid antioxidant system of tocopherol, non-lipid system of glutathione and related total activity of the pentosophosphate pathway of carbohydrate metabolism in red blood cells. It was established that activation of rheumatic process is accompanied by a increase in the content of diene conjugates in lipids of red blood cell membranes, a reduction of the tocopherol content in blood plasma, activation of glutathione reductase and glucose-6-phosphate dehydrogenase with the lowering of the total activity of the pentose cycle in red blood cells. The characteristics under study depended to a lesser degree on circulation insufficiency. The interrelationship between the shifts revealed is discussed, the mechanism by which they develop is suggested.


Role of angiotensin II in the remodeling induced by a chronic increase in flow in rat mesenteric resistance arteries.
Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N(G)-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II.


Interparental aggression and parent-adolescent salivary alpha amylase symmetry.
The present study examined salivary alpha amylase (sAA), a putative marker of adrenergic activity, in family members engaging in family conflict discussions. We examined symmetry among family members' sAA levels at baseline and in response to a conflict discussion. The relation between a history of interparental aggression on parent-adolescent sAA symmetry also was examined. Participants were 62 families with a mother, father, and biological child age 13-18 (n=29 girls). After engaging in a relaxation procedure, families participated in a 15-minute triadic family conflict discussion. Participants provided saliva samples at post-relaxation/pre-discussion, immediately post-discussion, and at 10 and 20 min post-discussion. Participants also reported on interparental physical aggression during the previous year. Across the sample we found evidence of symmetry between mothers' and adolescents' sAA levels at baseline and around the discussion. Interparental aggression was associated with lower sAA levels among fathers. Interparental aggression also affected patterns of parent-child sAA response symmetry such that families reporting interparental aggression exhibited greater father-adolescent sAA symmetry than did those with no reports of interparental aggression. Among families with no interparental aggression history, we found consistent mother-adolescent symmetry. These differences suggest different patterns of parent-adolescent physiological attunement among families with interparental aggression.


Crucial role for the VWF A1 domain in binding to type IV collagen.
Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis.


Nucleotide 'maps' of digests of deoxyribonucleic acid.
Various digests of (32)P-labelled DNA were examined by two-dimensional ionophoresis on cellulose acetate and DEAE-cellulose paper. The products from digestion with pancreatic deoxyribonuclease and Neurospora crassa endonuclease were qualitatively closely similar, but very complex, and were used to investigate the mapping behaviour of nucleotides in various ionophoretic systems. Ionophoresis on DEAE-cellulose paper in triethylamine carbonate, pH 9.7, followed by ionophoresis in the second dimension at pH1.9 gave high resolution of nucleotides in very complex mixtures and permitted the fractionation of larger quantities than is possible on cellulose acetate. High resolution of nucleotides in compact spots was obtained with two-dimensional ionophoresis on cellulose acetate and AE-cellulose paper, a system that is a useful supplement to those based on DEAE-cellulose paper.


Outcome of patients with residual germ cell or non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer.
To identify prognostic variables and outcomes in patients with primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) with postchemotherapy resection of persistent cancer. Forty-seven consecutive patients with residual cancer after resection of PMNSGCT were retrospectively reviewed. Univariate comparisons were performed. At diagnosis, 43 patients had elevated serum tumor markers (STMs), and 20 had extramediastinal disease. At resection, 21 patients had elevated STMs. After resection, 26 patients had germ cell tumors (GCT), 12 had malignant transformation of teratoma with elements of non-GCT, and nine had both GCT and non-GCT. Sixteen of 47 patients continuously have no evidence of disease (NED). This includes eight of 26 patients with GCT histology and two of 12 patients with non-GCT histology. Of 27 patients with mediastinal-only disease at presentation, 14 have continuously NED. Of 20 patients with extramediastinal disease at presentation, two have continuously NED. Seven of 21 patients with elevated STMs at time of resection have continuously NED. Sixteen patients received adjuvant chemotherapy, and seven have continuously NED. Overall, 16 of 47 patients have continuously NED, an additional four patients have NED with further therapy (currently NED), two patients are alive with disease, 23 patients died of disease, and two patients died postoperatively. The presence of elevated STMs at resection does not appear to alter outcome if residual disease is completely resected. In this poor-risk patient population, surgical resection of persistent cancer, even in the presence of elevated STMs, can still achieve long-term survival.


Pretreatment with statins improves early outcome in patients with first-ever ischaemic stroke: a pleiotropic effect of statins or a beneficial effect of hypercholesterolemia?
Data from different studies suggest a favourable association between pretreatment with statins or hypercholesterolemia and outcome after ischaemic stroke. We examined whether there were differences in in-hospital mortality according to the presence or absence of statin therapy in a large population of first-ever ischaemic stroke patients and assessed the influence of statins upon early death and spontaneous neurological recovery. In 2,082 consecutive patients with first-ever ischaemic stroke collected from a prospective hospital-based stroke registry during a period of 19 years (1986-2004), statin use or hypercholesterolemia before stroke was documented in 381 patients. On the other hand, favourable outcome defined as grades 0-2 in the modified Rankin scale was recorded in 382 patients. Early outcome was better in the presence of statin therapy or hypercholesterolemia (cholesterol levels were not measured) with significant differences between the groups with and without pretreatment with statins in in-hospital mortality (6% vs 13.3%, P = 0.001) and symptom-free (22% vs 17.5%, P = 0.025) and severe functional limitation (6.6% vs 11.5%, P = 0.002) at hospital discharge, as well as lower rates of infectious respiratory complications during hospitalization. In the logistic regression model, statin therapy was the only variable inversely associated with in-hospital death (odds ratio 0.57) and directly associated with favourable outcome (odds ratio 1.32). Use of statins or hypercholesterolemia before first-ever ischaemic stroke was associated with better early outcome with a reduced mortality during hospitalization and neurological disability at hospital discharge. However, statin therapy may increase the risk of intracerebral haemorrhage, particularly in the setting of thrombolysis.


Engineered 3D Microvascular Networks for the Study of Ultrasound-Microbubble-Mediated Drug Delivery.
Localized and targeted drug delivery can be achieved by the combined action of ultrasound and microbubbles on the tumor microenvironment, likely through sonoporation and other therapeutic mechanisms that are not well understood. Here, we present a perfusable in vitro model with a realistic 3D geometry to study the interactions between microbubbles and the vascular endothelium in the presence of ultrasound. Specifically, a three-dimensional, endothelial-cell-seeded in vitro microvascular model was perfused with cell culture medium and microbubbles while being sonicated by a single-element 1 MHz focused transducer. This setup mimics the in vivo scenario in which ultrasound induces a therapeutic effect in the tumor vasculature in the presence of flow. Fluorescence and bright-field microscopy were employed to assess the microbubble-vessel interactions and the extent of drug delivery and cell death both in real time during treatment as well as after treatment. Propidium iodide was used as the model drug while calcein AM was used to evaluate cell viability. There were two acoustic parameter sets chosen for this work: (1) acoustic pressure: 1.4 MPa, pulse length: 500 cycles, duty cycle: 5% and (2) acoustic pressure: 0.4 MPa, pulse length: 1000 cycles, duty cycle: 20%. Enhanced drug delivery and cell death were observed in both cases while the higher pressure setting had a more pronounced effect. By introducing physiological flow to the in vitro microvascular model and examining the PECAM-1 expression of the endothelial cells within it, we demonstrated that our model is a good mimic of the in vivo vasculature and is therefore a viable platform to provide mechanistic insights into ultrasound-mediated drug delivery.


The association between the longitudinal course of common mental disorders and subsequent physical activity status in young adults: A 30-year birth cohort study.
Low physical activity is a major public health concern. There has been extensive research examining the role of physical activity as a potentially modifiable risk factor for the onset of mental illness. However, fewer studies have reported how mental disorders affect future physical activity. Using data from a large birth cohort, the current study explored the association between the longitudinal course of common mental disorders (affective disorders, anxiety disorders, and substance use disorders, as well as any common mental disorder) and subsequent physical activity status among young adults living in Australia. Prospective data from the Mater-University of Queensland Study of Pregnancy, consisting of 1611 young adults, were analyzed. The longitudinal course of mental disorder diagnoses between ages 21 and 30 was derived from the Composite International Diagnostic Interview. Physical activity status at age 30 was estimated using International Physical Activity Questionnaire long form. Logistic regression was used to examine the association between the longitudinal course of common mental disorders between 21 and 30 years and subsequent physical activity status at age 30. After adjusting for confounding factors, there was no association between the longitudinal course of affective disorders, anxiety disorders, substance use disorders, or any common mental disorder at ages 21 and 30 and physical activity status at age 30. Our findings suggest that there is no longitudinal association between the common mental disorder diagnoses and physical activity status among young adults living in Australia.


ALK-positive lymphoma: a single disease with a broad spectrum of morphology.
The t(2;5)(p23;q35) translocation, associated with anaplastic large-cell lymphoma (ALCL), results in the expression of a chimeric NPM-ALK protein that can be detected by the ALK1 monoclonal antibody. This report describes the morphologic and phenotypic spectrum of 123 cases of lymphoma that all express ALK protein. The results provide strong evidence that the morphologic patterns of ALCL described in previous reports as representing possible subtypes of ALCL, eg, common type, lymphohistiocytic, or small cell patterns, are morphologic variants of the same disease entity. All of these morphologic patterns could be found within this series, and in some patients different subtypes coexisted in a single biopsy or were found in successive biopsies from a single patient. The link between these morphologic subtypes is further reinforced by the presence in all cases of a highly characteristic large cell, with an eccentric nucleus and an eosinophilic paranuclear region. We suggest that this cell can be considered as a major distinguishing feature of ALK-positive lymphomas. Another characteristic of these tumors was the perivascular pattern of neoplastic cell infiltration seen in a significant number of cases. In addition to ALK protein, all tumors expressed epithelial membrane antigen and lacked CD15, features that may be of value in differentiating ALCL from Hodgkin's disease. In the majority of cases (84%), malignant cells showed both a cytoplasmic and nuclear staining for ALK1 and thus presumably carried the 2;5 translocation, but staining was restricted to the cytoplasm in a few cases, suggesting that translocations other than t(2;5) may induce expression of ALK protein. We conclude from this study that ALK-positive neoplasms represent a distinct entity. Because their morphology is often neither anaplastic nor large cell, we suggest that they should henceforward be referred to as ALK lymphomas.


1,25-Dihydroxyvitamin D3 protects human leukemic cells from tumor necrosis factor-induced apoptosis via inactivation of cytosolic phospholipase A2.
The mechanism by which tumor necrosis factor (TNF) induces death of cancer cells appears to involve the activation of cytosolic phospholipase A2 (cPLA2). U937 human leukemic cells treated with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; 10(-8) M] become resistant to TNF, an effect that is independent of cell cycle status and expression of TNF receptors or BCL-2. In this study, TNF produced a dose- and time-dependent enhancement of [3H]arachidonic acid release in U937 cells. The amount of [3H]arachidonic acid release was positively associated with TNF-induced apoptosis. Both immunofluorescence microscopy and Western blotting of cell subcompartments demonstrated translocation of cPLA2 from the cytosol to the cell membrane in response to TNF. In addition, TNF up-regulated expression of cPLA2 mRNA. An antisense oligonucleotide to cPLA2 and the cPLA2 inhibitor 4-bromophenacyl bromide significantly inhibited TNF-induced cytotoxicity. Prior incubation of cells with 1,25(OH)2D3 significantly inhibited (a) TNF-induced [3H]arachidonic acid release and apoptosis, (b) TNF-induced translocation of cPLA2 to the membrane, and (c) the up-regulation of cPLA2 mRNA with TNF. Furthermore, the inhibitory effect of 1,25(OH)2D3 was not reversed by inhibitors of transcription or translation. The data suggest that activation of cPLA2 is involved in TNF-induced apoptosis of leukemic cells. 1,25(OH)2D3 directly inhibits cPLA2 translocation and mRNA up-regulation induced by TNF. Disruption of cPLA2 activation may represent a possible mechanism whereby leukemic cells can become resistant to TNF-mediated killing.


Porous photonic crystal external cavity laser biosensor.
We report the design, fabrication, and testing of a photonic crystal (PC) biosensor structure that incorporates a porous high refractive index TiO2 dielectric film that enables immobilization of capture proteins within an enhanced surface-area volume that spatially overlaps with the regions of resonant electromagnetic fields where biomolecular binding can produce the greatest shifts in photonic crystal resonant wavelength. Despite the nanoscale porosity of the sensor structure, the PC slab exhibits narrowband and high efficiency resonant reflection, enabling the structure to serve as a wavelength-tunable element of an external cavity laser. In the context of sensing small molecule interactions with much larger immobilized proteins, we demonstrate that the porous structure provides 3.7× larger biosensor signals than an equivalent nonporous structure, while the external cavity laser (ECL) detection method provides capability for sensing picometer-scale shifts in the PC resonant wavelength caused by small molecule binding. The porous ECL achieves a record high figure of merit for label-free optical biosensors.


Role of ER export signals in controlling surface potassium channel numbers.
Little is known about the identity of endoplasmic reticulum (ER) export signals and how they are used to regulate the number of proteins on the cell surface. Here, we describe two ER export signals that profoundly altered the steady-state distribution of potassium channels and were required for channel localization to the plasma membrane. When transferred to other potassium channels or a G protein-coupled receptor, these ER export signals increased the number of functional proteins on the cell surface. Thus, ER export of membrane proteins is not necessarily limited by folding or assembly, but may be under the control of specific export signals.


Some biological consequences of environmental change: a study using barnacles (Cirripedia: Balanomorpha) and gum trees (Angiospermae: Myrtaceae).
Uniformitarianism permits understanding of the past on the basis of the present, and modeling the future through consideration of the fossil record. The present paper addresses the impact environmental (climatic) change has had on acorn barnacles and eucalyptus trees. Acorn barnacles (Balanomorpha) are first recorded after the K/T mass-extinction event. In the Paleogene, rapid radiation resulted in their occupying most marine environments. That balanomorphs survived both the Paleocene-Eocene thermal maximum and the Pleistocene glaciation is testament to their ability to adapt to opportunities; they are known from the littoral (Chamaesipho) to depths of 3600 m (Tetrachaelasma) and within this from diverse substrates: rock, wood and miscellaneous flotsam, plus in symbiosis or commensalism with most larger marine organisms. Darwin's (1854) view of the late Tertiary as the age of barnacles is reflected in their diversity, distribution and biomass. Barnacles are contrasted with the Australian Myrtaceae: plants ranging from woody shrubs to tall trees. The most significant is Eucalyptus sensu lato, which typifies Australia's flora, and is characterized by aromatic leaves that produce eucalyptol. Eucalyptus has evolved strategies that result in its domination of Australian open woodlands: these include production of highly flammable eucalyptol oil (with a flashpoint of 49 °C) and an unprecedented ability to regenerate following forest fires. Gum trees and barnacles first appear in the Paleogene, their earliest records are Australasian, and they both demonstrate extraordinary resilience when environmental conditions are optimal.


The functional domain specificity of self-esteem and the differential prediction of aggression.
On the basis of an evolutionary theory of self-esteem (SE), it was hypothesized that the SE-aggression relationship differs across functionally distinct domains of SE and across contexts. In 2 experiments, participants had the opportunity to aggress against the evaluator of an essay they had written. In Study 1, self-perceived superiority was positively related to aggression, whereas social inclusion was inversely related to aggression. In Study 2, in which the context was altered to simulate a mating competition, only a measure of self-perceived mate value emerged as a (positive) predictor of aggression. Global SE failed to contribute to the prediction of aggression in either experiment. Statistically controlling for narcissism did not eliminate either set of findings. Implications for the conceptualization and measurement of SE and narcissism are discussed.


Structure-function relationship of different domains of the rat corticotropin-releasing factor receptor.
The significance of different domains of corticotropin-releasing factor receptor, type 1, (CRFR1) for ligand binding and cAMP accumulation was investigated with C-terminally truncated forms of rat CRFR1 (rCRFR1) tagged by a sequence of six histidine residues (His-tag) to facilitate protein purification and identification. These different forms of the receptor were N-glycosylated and transported properly to the membranes of transfected mammalian cells as indicated by Western blot analysis and immunocytochemical staining with two polyclonal antibodies developed against the N- and C-terminus of rCRFR1. The N-terminal fragment, rCRFR1(23-121), expressed in Escherichia coli bound oCRF specifically, but with low affinity. Several mutants lacking transmembrane domain (TM) 7 and the C-terminus exhibited similarly low affinities to oCRF after expression in transfected mammalian cells. None of these cells produced significant amounts of cAMP after exposure to oCRF. Only mutants containing the N-terminus, all loops and TMs bound oCRF and produced cAMP with high affinity (Kd = 62 nM) and efficacy (EC50 = 0.8 nM). The additional presence of the C-terminus provided similar characteristics (Kd = 5 nM, EC50 = 0.3 nM) as known for the native receptor. It is suggested on the basis of these data that the last extracellular loop is involved in ligand binding.


Uptake of sulfate but not phosphate by Mycobacterium tuberculosis is slower than that for Mycobacterium smegmatis.
Knowledge of the metabolic pathways used by Mycobacterium tuberculosis during infection is important for understanding its nutrient requirements and host adaptation. However, uptake, the first step in the utilization of nutrients, is poorly understood for many essential nutrients, such as inorganic anions. Here, we show that M. tuberculosis utilizes nitrate as the sole nitrogen source, albeit at lower efficiency than asparagine, glutamate, and arginine. The growth of the porin triple mutant M. smegmatis ML16 in media with limiting amounts of nitrate and sulfate as sole nitrogen and sulfur sources, respectively, was delayed compared to that of the wild-type strain. The uptake of sulfate was 40-fold slower than that of the wild-type strain, indicating that the efficient uptake of these anions is dependent on porins. The uptake by M. tuberculosis of sulfate and phosphate was approximately 40- and 10-fold slower than that of M. smegmatis, respectively, which is consistent with the slower growth of M. tuberculosis. However, the uptake of these anions by M. tuberculosis is orders of magnitude faster than diffusion through lipid membranes, indicating that unknown outer membrane proteins are required to facilitate this process.


[Control of the alternative pathway of electron transfer in mitochondria of the yeast Candida lipolytica].
The dependence of the activity of the alternative cyanide-resistant electron transfer pathway in mitochondria of the yeast Candida lipolytica on the functional state of the main phosphorylating respiratory chain was studied. Oxidation of NAD-linked substrates both in active or uncoupled and controlled states by cyanide-resistant mitochondria was shown to be performed solely by the main respiratory chain. Succinate or alpha-glycerophosphate in the active or uncoupled state of the respiratory chain are oxidized solely by the main respiratory chain, whose changes in the controlled state are accompanied by activation of the alternative pathway of electron transfer. Exogenous NADH is oxidized both in active and controlled states of the respiratory chain by the main respiratory chain and the alternative pathway simultaneously. The transition of the respiratory chain from active to controlled state is followed therewith by an additional activation of the alternative pathway. It was concluded that the alternative pathway contribution to the total oxygen consumption by mitochondria is controlled by the activity of the main respiratory chain. The alternative pathway accomplishes the transfer of reducing equivalents excessive for the main respiratory chain.


Internal urethrotomy combined with antegrade flexible cystoscopy for management of obliterative urethral stricture.
We studied the safety and efficacy of flexible cystoscopy-guided internal urethrotomy in the management of obliterative urethral strictures. Forty-three flexible cystoscopy-guided internal urethrotomies were performed between 1999 and 2005. The indication for the procedure was nearly blinded bulbar or membranous urethral strictures not longer than 1 cm that would not allow passage of guide wire. Candidates were those who refused or were unable to undergo urtheroplasty. By monitoring any impression of the urethrotome on the monitor through the flexible cystoscope, we were able to do under-vision urethrotomy. All of the patients were started clean intermittent catheterization afterwards which was tapered over the following 6 months. Follow-up continued for 24 months after the last internal urethrotomy. Seventeen patients were younger than 65 years with a history of failed posterior urethroplasty, and 26 were older than 65 with poor cardiopulmonary conditions who had bulbar urethral stricture following straddle or iatrogenic injuries. Urethral stricture stabilized in 16 patients (37.2%) with a single session of urethrotomy and in 17 (39.5%) with 2 urethrotomies. Overall, urethral stricture stabilized in 76.7% of patients with 1 or 2 internal urethrotomies within 24 months of follow-up. No severe complication was reported. Flexible cystoscopy-guided internal urethrotomy is a simple, safe, and under-vision procedure in obliterative urethral strictures shorter than 1 cm. It can be an ideal option for patients who do not accept posterior urethroplasty or are in a poor cardiopulmonary condition that precludes general anesthesia.


Optical analogue of the spin Hall effect in a photonic cavity.
We observe anisotropy in the polarization flux generated in a GaAs/AlAs photonic cavity by optical illumination, equivalent to spin currents in strongly coupled microcavities. Polarization rotation of the scattered photons around the Rayleigh ring is due to the TE-TM splitting of the cavity mode. Resolving the circular polarization components of the transmission reveals a separation of the polarization flux in momentum space. These observations constitute the optical analogue of the spin Hall effect.


Vessel-associated stem cells from skeletal muscle: From biology to future uses in cell therapy.
Over the last years, the existence of different stem cells with myogenic potential has been widely investigated. Besides the classical skeletal muscle progenitors represented by satellite cells, numerous multipotent and embryologically unrelated progenitors with a potential role in muscle differentiation and repair have been identified. In order to conceive a therapeutic approach for degenerative muscle disorders, it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo. Among all emerging populations, vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy. In vitro and in vivostudies have already tested the effectiveness and safety of vessel-associated stem cells in animal models. This leads to the concrete possibility in the future to start pilot human clinical trials, hopefully opening the way to a turning point in the treatment of genetic and acquired muscle disorders.


Detection of abnormal pretransplant clones in progenitor cells of patients who developed myelodysplasia after autologous transplantation.
Secondary myelodysplastic syndromes (MDS) have been reported after autologous transplantation. It is not known whether the MDS results from the pretransplant conventional-dose chemotherapy or from the high-dose chemotherapy (HDC) used for the transplant procedure. We performed a multicenter, retrospective analysis of morphologically normal pretransplant marrow or stem cell specimens from 12 patients who subsequently developed myelodysplasia after HDC. To determine if the abnormal clone was present before HDC, we used fluorescence in situ hybridization (FISH) to detect the cytogenetic markers observed at the onset of posttransplant MDS. Cryopreserved, pretransplant bone marrow, peripheral blood stem cell specimens, obtained at the time of harvest, or archival smears were used. Standard cytogenetic analysis had been performed pretransplant in four patients, showing a normal karyotype. In 9 of 12 cases, the same cytogenetic abnormality observed at the time of MDS diagnosis was detected by FISH in the pre-HDC specimens. Our findings support the hypothesis that, in many cases of posttransplant MDS, the stem cell damage results from prior conventional-dose chemotherapy and may be unrelated to HDC or the transplantation process itself.


Contrasting effects of growth hormone and insulin-like growth factor I on the biological activities of endotoxin in the rat.
We previously demonstrated that GH potentiates the biological activities of endotoxin in the rat. In the present study, we wanted to determine if the potentiating effects of GH on the biological activities of endotoxin could be reproduced by insulin-like growth factor I (IGF-I). Endotoxin (5 mg/kg BW) was injected in rats primed with or without GH or IGF-I for 3 days. As expected, endotoxin administration markedly increased circulating tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) and induced organ injury, hypoglycemia, and hyperlipidemia. In GH-primed rats, endotoxin induced a further increase of serum IFN gamma (but not TNF); and five out of six of those rats died within 15 h after giving endotoxin. However, little difference between endotoxin-treated rats with and without IGF-I priming could be seen. Furthermore, IGF-I infusion altered blood glucose, urea, and circulating ICF-I levels more than GH infusion. Therefore, IGF-I does not enhance the biological activities of endotoxin in the rat, suggesting that the enhancement of endotoxin effects by GH is via an IGF-I-independent pathway. Priming rats by GH (but not by IGF-I) induced a further increased response of serum IFN gamma but not TNF to subsequent endotoxin challenge, suggesting that IFN gamma rather than TNF is likely to be involved in this process.


Not all zirconia femoral heads degrade in vivo.
Degradation of yttria-stabilized zirconia femoral heads in vivo has been linked to increased roughening and even fracture of the femoral head. To determine whether magnesia-stabilized zirconia is better suited to resist degradation, we characterized the monoclinic phase concentration, surface topography, and microhardness of retrieved zirconia femoral heads. From previous work, we expected yttria-stabilized zirconia heads to undergo considerable tetragonal-to-monoclinic phase transformation in vivo, leading to considerably increased roughness and decreased microhardness, whereas magnesia-stabilized zirconia heads would not experience phase transformation and thus would not roughen or exhibit decreased microhardness. We studied seven yttria-stabilized zirconia and 12 magnesia-stabilized zirconia femoral heads. Yttria-stabilized zirconia heads explanted after 5 years exhibited a rough orange peel-like surface under light microscopy and were rougher than magnesia-stabilized zirconia heads (average roughness approximately 20 nm versus 7.5 nm, respectively), likely attributable to increased mono-clinic phase transformation (approximately 37% by weight) caused by low-temperature aging. The microhardness of yttria-stabilized zirconia heads decreased with age, but the relationship was not noteworthy. In contrast, magnesia-stabilized zirconia retrievals showed no change in monoclinic phase concentration, surface roughness, or microhardness with age. The properties of the yttria-stabilized zirconia evaluated in our study deteriorated in vivo, whereas magnesia-stabilized zirconia did not degrade and appears to be a superior biomaterial for bearing in total joint arthroplasty.


Racial/ethnic differences in cardiovascular risk factors among women veterans.
Heart disease is the leading cause of death for women in the United States, accounting for 24.5 % of all deaths among women. Earlier research has demonstrated racial/ethnic differences in prevalence of cardiovascular (CVD) risk factors. To empirically examine the prevalence of CVD risk factors among a national sample of women Veterans by race/ethnicity, providing the first portrait of women Veterans' cardiovascular care needs. Cross-sectional, national population-based telephone survey of 3,611 women Veterans. Women Veterans were queried about presence of diabetes, hypertension, obesity, tobacco use and physical activity. Four racial/ethnic categories were created: Hispanic, Non-Hispanic White (White), Non-Hispanic Black (Black), and Other. Logistic regressions were conducted for each risk factor to test for racial/ethnic differences, controlling for age (under 40 vs. 40 and over). Racial/ethnic differences in CVD risk factors persisted after adjusting for age. Black women Veterans were more likely to report a diagnosis of diabetes (OR: 2.58, 95 % CI: 1.07, 6.21) or hypertension (OR: 2.31, 95 % CI: 1.10, 4.83) and be obese (OR: 2.06, 95 % CI: 1.05, 3.91) than White women Veterans. Hispanic women Veterans were more likely than White women Veterans to report diabetes (OR: 4.20, 95 % CI: 1.15, 15.39) and daily smoking (OR: 3.38, 95 % CI: 1.01, 11.30), but less likely to report a hypertension diagnosis (OR 0.21, 95% CI: 0.07, 0.64) or to be obese (OR: 0.39, 95 % CI: 0.18, 0.81). Among women Veterans, CVD risks vary by race/ethnicity. Black women Veterans consistently face higher CVD risk compared to White women Veterans, while results are mixed for Hispanic women Veterans.


Synthesis of bioactive hemoglobin-based oxygen carrier nanoparticles via metal-phenolic complexation.
The transfusion of donor red blood cells (RBCs) is seriously hampered by important drawbacks that include limited availability and portability, the requirement of being stored in refrigerated conditions, a short shelf life or the need for RBC group typing and crossmatching. Thus, hemoglobin (Hb)-based oxygen (O2) carriers (HBOCs) which make use of the main component of RBCs and the responsible protein for O2 transport, hold a lot of promise in modern transfusion and emergency medicine. Despite the great progress achieved, it is still difficult to create HBOCs with a high Hb content to attain the high O2 demands of our body. Herein a metal-phenolic self-assembly approach that can be conducted in water and in one step to prepare nanoparticles (NPs) fully made of Hb (Hb-NPs) is presented. In particular, by combining Hb with polyethylene glycol, tannic acid (TA) and manganese ions, spherical Hb-NPs with a uniform size around 350-525 nm are obtained. The functionality of the Hb-NPs is preserved as shown by their ability to bind and release O2 over multiple rounds. The binding mechanism of TA and Hb is thoroughly investigated by UV-vis absorption and fluorescence spectroscopy. The binding site number, apparent binding constant at two different temperatures and the corresponding thermodynamic parameters are identified. The results demonstrate that the TA-Hb interaction takes place through a static mechanism in a spontaneous process as shown by the decrease in Gibbs free energy. The associated increase in entropy suggests that the TA-Hb binding is dominated by hydrophobic interactions.


Synthesis of new thiazolo[4,5-d]pyrimidines as Corticotropin releasing factor modulators.
Corticotropin-releasing factor (CRF) is a neurohormone that plays a crucial role in integrating the body's overall response to stress. It appears necessary and sufficient for the organism to mount functional, physiological and endocrine responses to stressors. CRF is released in response to various triggers such as chronic stress. The role of CRF and its involvement in these neurological disorders suggest that new drugs that can target the CRF function or bind to its receptors may represent a new development of neuropsychiatric medicines to treat various stress-related disorders including depression, anxiety and addictive disorders. Based on pharmacophore of the CRF1 receptor antagonists, a new series of thiazolo[4,5-d] pyrimidines were synthesized as Corticotropin-releasing factor (CRF) receptor modulators and the prepared compounds carry groups shown to produce optimum binding affinity to CRF receptors. Twenty two compounds were evaluated for their CRF1 receptor binding affinity in HEK 293 cell lines and two compounds 5o and 5s showed approximately 25% binding affinity to CRF1 receptors. Selected compounds (5c and 5f) were also evaluated for their effect on expression of genes associated with depression and anxiety disorders such as CRF1, CREB1, MAO-A, SERT, NPY, DatSLC6a3, and DBH and significant upregulation of CRF1 mRNA has been observed with compound 5c.


Clinical implications and management of bleeding events in patients with acute coronary syndromes.
In the past decades, there has been a significant development in the management of patients with acute coronary syndromes (ACS), largely driven by advances in antithrombotic and antiplatelet agents. Despite significant improvements in efficacy end points such as death, myocardial infarction and repeated revascularization, these therapies are still associated with a significant risk of bleeding. Such bleedings are independent predictors of long-term adverse clinical events. Data that are currently available on the magnitude and the predictors of bleeding complications in patients with ACS have been obtained from randomized clinical trials. However, patients perceived to be at higher risk of complications, including the elderly or those with renal insufficiency, are often excluded from these trials, but constitute a significant percentage of patients treated for ACS. For these reasons, new bleeding risk scores are under evaluation to facilitate management and subsequent treatment decisions in the real world. Better identification of higher risk patients, careful dosing and appropriate monitoring of antithrombotic therapies, and incorporation of various peri-procedural strategies in routine clinical practice may potentially reduce the risk of bleeding of patients with ACS and further improve their clinical outcomes.


Robotic-assisted single-position lateral for multilevel circumferential lumbar interbody fusion: how I do it.
Lateral lumbar interbody fusion supplemented with insertion of pedicle screws is a surgical procedure that has gained popularity in the last years, becoming an important tool in the armamentarium of spine surgeons. In recent years, there is a trend to complete both procedures in a single position, thus avoiding flipping the patient prone to insert the pedicle screws. We describe a step-by-step workflow of the robotic-assisted technique for multilevel lateral lumbar interbody fusion supplemented with posterior instrumentation. The surgical procedure is performed in a single lateral position. For access to L4-5 or L5-S1, an oblique abdominal incision is performed in the same position, and the desired disc space is approached through an oblique or anterior corridor in the retroperitoneal space. Robotic-assisted single-position lateral for multilevel circumferential lumbar interbody fusion is a safe and effective procedure in patients where lumbar stabilization is required. This technique provides patients with a faster recovery and low risk of complications.


Electrophoretic and centrifugation behaviour of mitochondrial ribonucleic acid from Walker 256 carcinosarcoma.
To investigate the possibility that mitochondrial transcription could be altered in tumours we started by characterizing the RNA obtained from mitochondria, isolated from Walker carcinosarcoma and purified by a procedure devised to compensate for the lower size and density of these organelles in 10-day tumours. The RNA was extracted by the 'hot phenol' technique and analysed by electrophoresis in 2.7 and 2.5% polyacrylamide gels at different running times, identifying the usual cytoplasmic contaminants 28 and 18S peaks plus the other five major peaks at 40, 20.5, 16.3, 15.4, and 4Se. The 28 and 18Se peaks were not eliminated by digitonin treatment of the mitochondria, indicating that they arise from cytoplasmic ribosomes tightly associated with the mitochondria. From its sensitivity to DNAase (deoxyribonuclease), resistance to RNAase (ribonuclease) and coincidence with external marker DNA, the 40Se peak was identified as containing mainly DNA. Sucrosegradient centrifugation for different periods showed a major component at 16.2S, the 28 and 18S cytoplasmic RNA species, peaks at 13.8, 6.4 and 4S and a small 19.5S peak. By polyacrylamide-gel electrophoresis of the purified RNA classes separated by one or two cycles of centrifugation, the following correlation were established: 20.5Se19.5S; 16.3Se16.2S; 15.4Se13.8S. The 6.4S RNA ran as a mixture of 4 and 4.7Se species. When the 20.5Se and 15.4Se RNA species were centrifuged, they behaved as 16.2S and 13.8S respectively, thus suggesting that the 16.2S (16.3Se) arises by cleavage from the 19.5S(20.5Se), the 13.8S (15.4Se) being the other RNA from mitochondrial ribosomes.