Persistent disparities in antiretroviral treatment (ART) coverage and virological suppression across Europe, 2004 to 2015.
Direct comparisons between countries in core HIV care parameters are often hampered by differences in data collection. Within the EuroSIDA study, we compared levels of antiretroviral treatment (ART) coverage and virological suppression (HIV RNA < 500 copies/mL) across Europe and explored temporal trends. In three cross-sectional analyses in 2004-05, 2009-10 and 2014-15, we assessed country-specific percentages of ART coverage and virological suppression among those on ART. Temporal changes were analysed using logistic regression. Overall, the percentage of people on ART increased from 2004-05 (67.8%) to 2014-15 (78.2%), as did the percentage among those on ART who were virologically suppressed (75.2% in 2004-05, 87.7% in 2014-15). However, the rate of improvement over time varied significantly between regions (p < 0.01). In 2014-15, six of 34 countries had both ART coverage and virological suppression of above 90% among those on ART. The pattern varied substantially across clinics within countries, with ART coverage ranging from 61.9% to 97.0% and virological suppression from 32.2% to 100%. Compared with Western Europe (as defined in this study), patients in other regions were less likely to be virologically suppressed in 2014-15, with the lowest odds of suppression (adjusted odds ratio = 0.16; 95% confidence interval (CI): 0.13-0.21) in Eastern Europe. Despite overall improvements over a decade, we found persistent disparities in country-specific estimates of ART coverage and virological suppression. Underlying reasons for this variation warrant further analysis to identify a best practice and benchmark HIV care across EuroSIDA.


Differences in Chemical Composition among Commercially Important Cultivars of Genus Camellia.
Leaves from plants of the genus Camellia are used to make beverages and food products; however, there is limited data that compares the chemical composition of the unprocessed leaves of cultivars traditionally used to make these products. Plucked, fresh leaves from 14 commercially important cultivars were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. On the basis of assessment of 61 compounds that are known to be affected by postharvest tea processing methods, significant variation among unprocessed cultivar leaves was observed for compounds in five chemical classes: amino acids, catechins, flavonoids and flavone glycosides, phenolic acids, and alkaloids. These chemical differences were of sufficient magnitude to render two distinct chemically defined clusters of Camellia cultivars that did not reflect the traditional grouping of these cultivars based by species variant, tea type, or production region. Advanced statistical techniques identified candidate biomarkers for each chemical class to guide the development of comprehensive targeted analyses for constituents of biosynthetic pathways in which marked expression plasticity was observed. Targeted analyses of this type have the potential to identify Camellia species/cultivars that will facilitate the formulation of new beverages and designer foods with improved organoleptic characteristic and enhanced prebiotic or nutraceutical activity.


Comparison of in vitro developmental competence of cloned caprine embryos using donor karyoplasts from adult bone marrow mesenchymal stem cells vs ear fibroblast cells.
The aim of this study was to produce cloned caprine embryos using either caprine bone marrow-derived mesenchymal stem cells (MSCs) or ear fibroblast cells (EFCs) as donor karyoplasts. Caprine MSCs were isolated from male Boer goats of an average age of 1.5 years. To determine the pluripotency of MSCs, the cells were induced to differentiate into osteocytes, chondrocytes and adipocytes. Subsequently, MSCs were characterized through cell surface antigen profiles using specific markers, prior to their use as donor karyoplasts for nuclear transfer. No significant difference (p > 0.05) in fusion rates was observed between MSCs (87.7%) and EFCs (91.3%) used as donor karyoplasts. The cleavage rate of cloned embryos derived with MSCs (87.0%) was similar (p > 0.05) to those cloned using EFCs (84.4%). However, the in vitro development of MSCs-derived cloned embryos (25.3%) to the blastocyst stage was significantly higher (p < 0.05) than those derived with EFCs (20.6%). In conclusion, MSCs could be reprogrammed by caprine oocytes, and production of cloned caprine embryos with MSCs improved their in vitro developmental competence, but not in their fusion and cleavage rate as compared to cloning using somatic cells such as EFCs.


Gentamicin and methicillin resistant Staphylococcus aureus in Dublin hospitals: molecular studies.
A large number of Staphylococcus aureus strains resistant to gentamicin, methicillin and other antibiotics, isolated in several Dublin hospitals during a 4-year period, were screened for plasmid DNA. Isolates assigned to four principal phage groups showed uniform plasmid profiles. A plasmid of mol. wt 21.0 x 10(6) encoding penicillin resistance was present in all isolates screened. A tetracycline resistance plasmid of mol. wt 24.0 x 10(6) was present in 40% of isolates of phage types 90 and 5/47/54/84/85 whereas a plasmid of mol. wt 3.0 x 10(6) was responsible for tetracycline resistance in isolates of phage types 77 and 85. Aminoglycoside, methicillin and erythromycin resistances were apparently not encoded on plasmids. Gentamicin resistance was transduced at low frequency between several strains of S. aureus and the resistance phenotype was due, in part at least, to the production of an inactivating enzyme.


Sickle erythrocyte adherence to vascular endothelium. Morphologic correlates and the requirement for divalent cations and collagen-binding plasma proteins.
Increased adherence of sickle erythrocytes to vascular endothelium has been suggested by Hebbel and his colleagues to play a role in vasocclusive events of sickle cell disease. To define the role of cell membrane changes and plasma factors in cell adherence, a micropipette technique previously developed by us to obtain a direct, quantitative measure of cell adherence was used to evaluate the adhesivity of different morphologic classes of sickle cells to endothelial cells in various suspending media. Irregularly shaped, deformable sickle cells were four- to fivefold more adherent than discoid sickle cells, whereas rigid irreversibly sickled cells were least adherent. Sickle erythrocytes adhered to endothelial cells when suspended in autologous citrated or heparinized plasma but were totally nonadherent when suspended in autologous EDTA plasma. Removal of the divalent cation chelator and addition of calcium to EDTA plasma restored its ability to promote adhesion, implying an absolute requirement for divalent cations in sickle cell adherence. Sickle cells also did not adhere to endothelial cells in protein-free media containing divalent cations, suggesting an additional requirement for plasma proteins. Removal of collagen-binding proteins from citrated sickle plasma resulted in a three- to fivefold reduction in its ability to promote cell adhesion, suggesting an important role for these plasma proteins in sickle cell adherence. The results of this study imply that sickle cell adherence to vascular endothelium is a complex process in which temporal changes in the numbers of cells identified to be most adhesive and the plasma concentration of protein(s) involved in the adhesive process determine the extent of in vivo sickle cell adherence.


Associations between dietary pesticide residue mixture exposure and mortality in a population-based prospective cohort of men and women.
There is a concern that pesticide residues, regularly detected in foods, might pose a health risk to the consumer, but epidemiological evidence is limited. We assessed the associations between dietary exposure to a mixture of pesticide residues and mortality. Food consumption was assessed in 68,844 participants from the Swedish Mammography Cohort and the Cohort of Swedish Men, 45-83 years at baseline (1997). Concentrations of pesticide residues detected in foods on the Swedish market (1996-1998), mainly fruits and vegetables, were obtained via monitoring programs. To assess mixture effects, we summed per food item the ratios of each single pesticide mean residue concentration divided by its acceptable daily intake to create for each participant a Dietary Pesticide Hazard Index (adjusted for energy intake and expressed per kilogram of body weight). Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 %CI). During 15 years of follow-up (1998-2014), a total of 16,527 deaths occurred, of which 6,238 were caused by cardiovascular disease (CVD) and 5,364 by cancer. Comparing extreme quintiles of Dietary Pesticide Hazard Index, the highest category was inversely associated with CVD mortality HR, 0.82 (95 % CI, 0.75-0.90) and with cancer mortality HR 0.82 (95 % CI 0.75-0.91). In analyses stratified by high/low Dietary Pesticide Hazard Index, similar inverse associations were observed by increasing fruit and vegetable consumption. We observed no indications that dietary exposure to pesticide residue mixtures was associated with increased mortality, nor any clear indications that the benefits of fruit and vegetable consumption on mortality was compromised. Yet, our results need to be interpreted with caution.


Herpes simplex virus type 1 origin-dependent DNA replication in insect cells using recombinant baculoviruses.
The minimal set of seven herpes simplex virus type 1 (HSV-1) genes required for viral origin-dependent DNA synthesis was previously identified using a transient replication assay in a mammalian cell line permissive for HSV-1 growth. We have constructed recombinant baculoviruses which efficiently express the products of each of these seven genes in infected Spodoptera frugiperda (Sf) insect cells. When Sf cells were transfected with a plasmid containing a functional HSV-1 origin of replication, and subsequently superinfected with a mixture of these seven viruses, the input plasmid was amplified. This amplification exhibited properties characteristic of genuine HSV-1 DNA replication: all seven HSV-1 replication gene products were required, replicated DNA was detected as concatemers, and mutated origins were impaired to similar extents in insect cells and cells permissive for HSV-1 replication. These results demonstrate that the HSV-1 proteins expressed in Sf cells are fully competent for viral DNA synthesis, and indicate that any host function essential in mammalian cells must also be present in the infected insect cells. This system also provides a convenient method by which mutated replication proteins can be screened for function and produced in amounts sufficient for biochemical studies. Using this approach we show that the ability of the UL9 protein to bind to the viral origins of replication is not sufficient for it to facilitate DNA synthesis.


Transcriptional Repression of IFN Regulatory Factor 7 by MYC Is Critical for Type I IFN Production in Human Plasmacytoid Dendritic Cells.
Type I IFNs are crucial mediators of human innate and adaptive immunity and are massively produced from plasmacytoid dendritic cells (pDCs). IFN regulatory factor (IRF)7 is a critical regulator of type I IFN production when pathogens are detected by TLR 7/9 in pDC. However, hyperactivation of pDC can cause life-threatening autoimmune diseases. To avoid the deleterious effects of aberrant pDC activation, tight regulation of IRF7 is required. Nonetheless, the detailed mechanisms of how IRF7 transcription is regulated in pDC are still elusive. MYC is a well-known highly pleiotropic transcription factor; however, the role of MYC in pDC function is not well defined yet. To identify the role of transcription factor MYC in human pDC, we employed a knockdown technique using human pDC cell line, GEN2.2. When we knocked down MYC in the pDC cell line, production of IFN-stimulated genes was dramatically increased and was further enhanced by the TLR9 agonist CpGB. Interestingly, MYC is shown to be recruited to the IRF7 promoter region through interaction with nuclear receptor corepressor 2/histone deacetylase 3 for its repression. In addition, activation of TLR9-mediated NF-κB and MAPK and nuclear translocation of IRF7 were greatly enhanced by MYC depletion. Pharmaceutical inhibition of MYC recovered IRF7 expression, further confirming the negative role of MYC in the antiviral response by pDC. Therefore, our results identify the novel immunomodulatory role of MYC in human pDC and may add to our understanding of aberrant pDC function in cancer and autoimmune disease.


Comparison of the levels of quality of inpatient care delivered by pediatrics residents and by private, community pediatricians at one hospital.
To compare the quality and cost of inpatient care provided by pediatrics residents with the quality and cost of that provided by private, practicing pediatricians. Valley Children's Hospital--a 175-bed, private, nonprofit, university-affiliated pediatric hospital located in Fresno, California--has both a resident service and a community physician service. From May 1994 to March 1995 a total of 154 pediatric patients (64 from the resident service, 90 from the community service) were selected for the study using incidental sampling. In order to be included in the study, patients had discharge diagnoses of uncomplicated gastroenteritis or asthma. The parent or guardian of each patient completed a satisfaction questionnaire at discharge and agreed to a home visit one month later, when the same questionnaire and another were completed. Patients' charts were studied for treatment procedures, and follow-up data for a year were compiled. Statistical analyses were conducted with analysis of variance for continuous measures and chi-squares for dichotomous variables. The findings indicated no difference between the two services in terms of the parents' and guardians' satisfaction with patient care, hospital charges, and degrees of adherence to follow-up care after discharge. The community physicians were more likely than were the residents to employ non-standard laboratory and management procedures with both the asthma and gastroenteritis patients. The asthma patients cared for by community physicians had significantly more frequent asthma attacks after discharge, with a higher frequency of patients being subsequently treated in the emergency room and readmitted to the hospital, than did the asthma patients cared for by the residents. Common perceptions that physicians-in-training (1) overuse medical services and (2) fail, due to their inexperience, to provide high-quality services were not supported in this study.


Computational modelling of linear motif-mediated protein interactions.
Chemical information can be used to inform biology through being employed to develop bioinformatic tools. One area where bioinformatic tools are valuable is the study of linear motif-mediated protein interactions. Linear motifs are short sequences found mostly in disordered regions of proteins that function in cellular signaling and regulation, by binding to protein interaction domains or by being the target of post-translational modifications. Linear motifs pose difficulty not only to experimental study, but also computational methods; they are difficult to identify due to their small size; and their binding specificity is affected by several factors acting in concert. We discuss the different ways linear motifs can be represented computationally, and how computational approaches can integrate the different specificity-determining factors. We illustrate these issues on our own work focusing on the use of three-dimensional structural information in predicting protein phosphorylation sites, and the integration of diverse types of data in predicting nuclear localization. Computational approaches will play an increasing role in the future, allowing new relationships and system-wide understanding to be unearthed from the large datasets becoming available through high-throughput studies.


Long-term clinical outcome in vestibular neuritis.
To review recent work on clinical and imaging aspects of vestibular neuritis (or acute vestibular syndrome), in particular with a view to identifying factors predicting long-term clinical outcome. Evidence for a role of inflammation in the vestibular nerve, and the presence of Gadolinium enhancement acutely in vestibular neuritis, is accruing. Visual dependence, anxiety and somatization traits predict the development of chronic dizziness after acute vestibular neuritis. Adaptation to asymmetric rotation is impaired in vestibular neuritis and this may indicate insufficient central compensation in chronic dizzy patients. Corticosteroids appear ineffective at improving long-term clinical outcome. Functional imaging changes during the central compensation period lead to structural brain changes; both processes correlate with clinical recovery. Vestibular neuritis appears to be the result of postviral neuroinflammation of the vestibular nerve. However, long-term prognosis is not dependent on the magnitude of the peripheral residual damage (as measured with caloric and video head-impulse test). Instead, a combination of visuovestibular psychophysical factors (visual dependence), psychological traits and dysfunctional vestibular perception are relevant. Several functional and structural neuroimaging changes develop after vestibular neuritis, which reflect and underlie the aforementioned psychophysiological and psychological features.


Neutrophil primary granule release and maximal superoxide generation depend on Rac2 in a common signalling pathway.
Neutrophils play an integral role in innate immunity by undergoing degranulation and respiratory burst in response to inflammatory stimuli. Rac2, a monomeric GTP-binding protein, has been shown to be involved in several neutrophil functions, including primary granule release and superoxide (O(2)(-.) generation. We hypothesized that Rac2 is a common signalling molecule required for primary granule translocation and maximal O(2)(-.) production. Using bone marrow neutrophils from Rac2 knockout (KO) mice and wild type C57Bl/6 mice, we found that primary granule elastase and myeloperoxi dase release were absent in Rac2 KO neutrophils upon chemoattractant stimulation. Rac2 KO neutrophils also failed to produce maximal levels of extracellular O(2(-.) generation in response to phorbol myristate acetate (PMA). Although PMA was ineffective at eliciting primary granule mediator release, it induced secondary granule exocytosis in both WT and Rac2 KO neutrophils. Thus, the signalling pathway leading to primary granule release utilized Rac2, which was also necessary for full activation of O(2)(-.) generation in stimulated neutrophils. These findings indicate that O(2)(-.) release and secondary granule secretion may use protein kinase C (PKC) - dependent pathways, whereas primary granule exocytosis appears to rely on PKC-independent signalling events. These findings shed light on possible signalling mechanisms involved in granule secretion from activated neutrophils responding to different stimuli.


[Immediate results of the surgical treatment of gynecologic neoplasm patients over 60].
Surgery was carried out in 1,229 cases (346 (28.1%) aged 60 and older) at the gynecological department of the Dispensary in 1976-1983. The operability rate in the aged and old-age bracket was 55.2%. Malignancies were registered in 239 benign tumors--in 107 cases. 16 patients died (4.6%), thromboembolism of the lung artery being the most frequent cause of postoperative mortality. A combination of neuroleptanalgetics, barbiturates and nitrous oxide is recommended for anesthesia.


Effect of long-term food restriction on pituitary sensitivity to cLHRH-I in broiler breeder females.
The effect of long-term food restriction on the sensitivity of the pituitary to exogenously administered chicken luteinizing hormone releasing hormone I (cLHRH-I) was investigated in three groups of broiler breeder females fed ad libitum, fed a restricted quantity of food or fed a restricted quantity of food to obtain an intermediate body weight between those of the first two groups. At 16 weeks of age, basal FSH release was higher in ad libitum fed birds, culminating in ovarian development and subsequent oestradiol production by the small follicles. At this age, LH secretion was independent of ovarian feedback factors. In all groups, cLHRH-I was most active in releasing LH in intact and ovariectomized animals and, to a lesser extent, in releasing FSH in ovariectomized birds. At 39 weeks of age, basal FSH concentrations were similar among intact animals of all groups, whereas LH concentrations differed among groups, with higher values in the restricted birds. This food effect was enhanced in ovariectomized birds. Furthermore, the high response to cLHRH-I in the ovariectomized, restricted birds compared with the ad libitum, ovariectomized group suggests an improved sensitivity of the hypothalamic-pituitary axis. In conclusion, birds fed ad libitum showed the highest responsiveness to ovarian factors and to cLHRH-I in releasing FSH in the period before sexual maturity. No effect of amount of feeding could be observed for LH. However, during the egg laying period, LH release by cLHRH-I was highly dependent on amount of feeding and on ovarian feedback regulation. This finding indicates that the amount of feeding can modify the sensitivity of the pituitary to cLHRH-I, and possibly to gonadal hormones, during the laying period.


Post-procedure surveillance in liver biopsy: how long is long enough?
To assess the incidence of complications following liver biopsy and the impact of pre-procedural pethidine on complications and analgesia administration. A retrospective audit of percutaneous liver biopsies undertaken at Dunedin Public Hospital (2001-2006). Patients' medical files were consulted for demographics, biopsy indication, complications, frequency, and timing of analgesia. 447 biopsies were analysed. Primary indications included: hepatitis C (38.8%), abnormal liver function tests (18.3%), methotrexate therapy (12.5%), and malignancy (10.3%). 303 (68%) biopsies resulted in no complications. Major complications were not experienced. Minor complications included: pain (32.2%), hypotension (1.3%), nausea/vomiting (0.9%), and alcohol withdrawal (0.2%). More females (47%) than males (31%) reported complications. Post-procedural analgesia was administered in 31% of biopsies; only 9% required analgesia more than 2 hours after biopsy. Patients who had pre-procedural pethidine experienced similar rates of complications as patients not receiving pre-procedural pethidine, but received less post-procedural opiate analgesia. No major complications occurred, whilst the rate of minor complications was comparable with previous studies. Pain was the most common complication, although use of analgesia after 2 hours of observation was low. Our findings suggest that post-procedural observation may safely be reduced to two hours but it is currently unknown if early mobilisation following discharge will lead to complications.


Stable Transformation of the Actinobacteria Frankia spp.
A stable and efficient plasmid transfer system was developed for nitrogen-fixing symbiotic actinobacteria of the genus Frankia, a key first step in developing a genetic system. Four derivatives of the broad-host-range cloning vector pBBR1MCS were successfully introduced into different Frankia strains by a filter mating with Escherichia coli strain BW29427. Initially, plasmid pHKT1 that expresses green fluorescent protein (GFP) was introduced into Frankia casuarinae strain CcI3 at a frequency of 4.0 × 10-3, resulting in transformants that were tetracycline resistant and exhibited GFP fluorescence. The presence of the plasmid was confirmed by molecular approaches, including visualization on agarose gel and PCR. Several other pBBR1MCS plasmids were also introduced into F. casuarinae strain CcI3 and other Frankia strains at frequencies ranging from 10-2 to 10-4, and the presence of the plasmids was confirmed by PCR. The plasmids were stably maintained for over 2 years and through passage in a plant host. As a proof of concept, a salt tolerance candidate gene from the highly salt-tolerant Frankia sp. strain CcI6 was cloned into pBBR1MCS-3. The resulting construct was introduced into the salt-sensitive F. casuarinae strain CcI3. Endpoint reverse transcriptase PCR (RT-PCR) showed that the gene was expressed in F. casuarinae strain CcI3. The expression provided an increased level of salt tolerance for the transformant. These results represent stable plasmid transfer and exogenous gene expression in Frankia spp., overcoming a major hurdle in the field. This step in the development of genetic tools in Frankia spp. will open up new avenues for research on actinorhizal symbiosis.IMPORTANCE The absence of genetic tools for Frankia research has been a major hindrance to the associated field of actinorhizal symbiosis and the use of the nitrogen-fixing actinobacteria. This study reports on the introduction of plasmids into Frankia spp. and their functional expression of green fluorescent protein and a cloned gene. As the first step in developing genetic tools, this technique opens up the field to a wide array of approaches in an organism with great importance to and potential in the environment.


The syndrome of delayed post-hypoxic leukoencephalopathy.
Delayed post-hypoxic leukoencephalopathy (DPHL) is a demyelinating syndrome characterized by acute onset of neuropsychiatric symptoms days to weeks following apparent recovery from coma after a period of prolonged cerebral hypo-oxygenation. It is diagnosed, after excluding other potential causes of delirium, with a clinical history of carbon monoxide poisoning, narcotic overdose, myocardial infarction, or another global cerebral hypoxic event. The diagnosis can be supported by neuroimaging evidence of diffuse hemispheric demyelination sparing cerebellar and brainstem tracts, or by an elevated cerebrospinal fluid myelin basic protein. Standard or hyperbaric oxygen following CO poisoning may reduce the likelihood of DPHL or other neurologic sequelae. Bed rest and avoidance of stressful procedures for the first 10 days following any prolonged hypoxic event may also lower the risk. Gradual recovery over a 3 to 12 month period is common, but impaired attention or executive function, parkinsonism, or corticospinal tract signs can persist. Stimulants, amantadine or levodopa may be considered for lasting cognitive or parkinsonian symptoms. Anticipation and recognition of DPHL should lead to earlier and more appropriate utilization of health care services.


Is the error-related negativity amplitude related to error detectability? Evidence from effects of different error types.
The present study tested error detection theories of the error-related negativity (ERN) by investigating the relation between ERN amplitude and error detectability. To this end, ERN amplitudes were compared with a behavioral measure of error detectability across two different error types in a four-choice flanker task. If an erroneous response was associated with the flankers, it was considered a flanker error, otherwise it was considered a nonflanker error. Two experiments revealed that, whereas detectability was better for nonflanker errors than for flanker errors, ERN amplitudes were larger for flanker errors than for nonflanker errors. Moreover, undetected errors led to strongly reduced ERN amplitudes relative to detected errors. These results suggest that, although error detection is necessary for an ERN to occur, the ERN amplitude is not related to error detectability but rather to error significance.


Host factors mediating HIV-1 replication.
Human immunodeficiency virus type 1(HIV-1) infection is the leading cause of death worldwide in adults attributable to infectious diseases. Although the majority of infections are in sub-Saharan Africa and Southeast Asia, HIV-1 is also a major health concern in most countries throughout the globe. While current antiretroviral treatments are generally effective, particularly in combination therapy, limitations exist due to drug resistance occurring among the drug classes. Traditionally, HIV-1 drugs have targeted viral proteins, which are mutable targets. As cellular genes mutate relatively infrequently, host proteins may prove to be more durable targets than viral proteins. HIV-1 replication is dependent upon cellular proteins that perform essential roles during the viral life cycle. Maraviroc is the first FDA-approved antiretroviral drug to target a cellular factor, HIV-1 coreceptor CCR5, and serves to intercept viral-host protein-protein interactions mediating entry. Recent large-scale siRNA and shRNA screens have revealed over 1000 candidate host factors that potentially support HIV-1 replication, and have implicated new pathways in the viral life cycle. These host proteins and cellular pathways may represent important targets for future therapeutic discoveries. This review discusses critical cellular factors that facilitate the successive steps in HIV-1 replication.


Comparative Toxicological Effects of Perfluorooctane Sulfonate and Its Alternative 6:2 Chlorinated Polyfluorinated Ether Sulfonate on Earthworms.
High levels of 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), which is a substitute for perfluorooctane sulfonate (PFOS), are detected in various environmental matrices, wildlife, and humans. Chlorinated polyfluorinated ether sulfonate has received increased attention due to its potential risk to ecosystems. However, its toxicity in the soil organisms remains unclear. In the present study, a comparative investigation was conducted on the toxicities of 6:2 Chlorinated polyfluorinated ether sulfonate (F-53B) and PFOS to the earthworm Eisenia. fetida. F-53B was significantly more acutely toxic to earthworms than PFOS, with median lethal concentrations of 1.43 and 1.83 mmol/kg dry soil (~816 and 984 mg/kg dry soil), respectively. Although both F-53B and PFOS, at 0.4 mmol/kg dry soil (=228 and 215 mg/kg dry soil) caused oxidative stress in earthworms, as evidenced by increased superoxide dismutase, peroxidase, and catalase activities as well as malondialdehyde level, the stress caused by F-53B was higher than that caused by PFOS. In transcriptomic and metabolomic studies, negative effects of PFOS and F-53B were observed on several metabolic processes in earthworms, including protein digestion and amino acid absorption, lipid metabolism, and the immune response. Compared with PFOS, F-53B exhibited a weaker disruption of lipid metabolism, comparable potency for toxicity to the immune response, and a stronger potency in extracellular matrix destruction along with apoptosis and ferroptosis induction. Hence, our data suggest that F-53B is more toxic than PFOS to earthworms. The findings provide some new insights into the potential toxicity of F-53B to soil organisms. Environ Toxicol Chem 2023;00:1-12. © 2023 SETAC.


Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes.
Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-omega but not IFN-alpha showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.


Measurement of lateral preferences and schizophrenia: results of the Edinburgh High-Risk Study and methodological issues.
The assessment and measurement of handedness has varied across studies, limiting the comparability of results. Data from the Edinburgh High Risk for Schizophrenia Study were analyzed to investigate the effect of different methods of assessment and scoring of hand preferences on the prevalence of handedness type and on between-group differences in handedness. Handedness was measured using both the Edinburgh Handedness Inventory and the Annett Handedness Scale in 143 subjects at high risk for schizophrenia, 31 control subjects, and 27 patients with a first episode of schizophrenia. Hand preferences were identified through demonstration of items and by verbal report. No group differences were found, although the prevalence of hand preferences changed substantially depending on the definition used. Significant correlations with socio-demographic factors were found in some instances, but these correlations depended on the definition of handedness. No sex differences were identified. The magnitude of group differences remained similar, although the prevalence of handedness types varied greatly with changes in definition of handedness. Care should be taken in correlation studies to avoid spurious relationships between handedness and other factors. To allow for comparability of results across studies, researchers should adopt a standard definition of handedness.


The mitotic cell cycle-associated nomogram predicts overall survival in lung adenocarcinoma.
This study aimed to develop a prognostic model for lung adenocarcinoma (LUAD) associated with mitotic cell cycle. The model will predict the probability of survival at different time points and serve as a reference tool to evaluate the effectiveness of LUAD treatment. A cohort of 442 patients with LUAD from the gene expression omnibus (GEO) database was randomly divided into a training group (n = 299) and a validation group (n = 99). The least absolute shrinkage and selection operator (LASSO)-COX algorithm was used to reduce the number of predictors based on the clinicopathological and RNA sequencing data to establish mutant characteristics that could predict patient survival. Additionally, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis (GSVA), and gene set enrichment analysis (GSEA) analyses were conducted on the mutant characteristics. The performance of the developed nomogram was evaluated using calibration curves and the C-index. The mutant characteristics had prognostic value for LUAD and acted as an independent prognostic factor. The mutant characteristics profile derived from the LASSO-COX algorithm demonstrated a significant association with overall survival in patients with LUAD. Functional annotation based on the mutant score, its involvement in the phase transition of the mitotic cell cycle, and its regulatory processes. The nomogram, which combined the mutant score with clinical factors associated with prognosis, showed robust accuracy in both the training and validation groups. This study presents the first individualized model that establishes a mutant score for predicting survival in LUAD. This model can be used as a predictive tool for determining 1-, 2-, 3-, and 5-year survival probabilities in patients with LUAD.


Decreased muscle sympathetic nerve activity does not explain increased vascular conductance during contralateral isometric exercise in humans.
At the onset of both electrically evoked (STIM) and voluntary (VOL) isometric calf exercise there is an increase in vascular conductance of the contralateral lower limb, suggesting withdrawal of muscle sympathetic nerve activity (MSNA). Seven subjects performed STIM or VOL ischaemic calf exercise at 30% maximum voluntary contraction in a seated position. Blood pressure, heart rate and peroneal MSNA in the resting contralateral lower limb were recorded. During both STIM and VOL exercise blood pressure increased (P < 0.05). Blood flow increased by 40 +/- 3 and 35 +/- 3% and conductance increased by 37 +/- 3 and 31 +/- 4% (P < 0.05) after 10 s of STIM and VOL, respectively, and thereafter declined. The time course and direction of these changes persisted with subjects in a semisupine position, confirming that the transient conductance changes were not an artefact of the dependent leg position. Thigh cuff inflation for 1 min without exercise caused a 47 +/- 7.5% (P < 0.05) reduction in MSNA, which recovered when the circulation was restored. However, when cuff inflation was followed by STIM or VOL exercise, MSNA did not fall further. These data suggest that the transient increase in vascular conductance at the onset of contralateral electrically evoked or voluntary lower limb exercise is unrelated to MSNA.


Metal nanoparticles triggered persistent negative photoconductivity in silk protein hydrogels.
Silk protein is a natural biopolymer with intriguing properties, which are attractive for next generation bio-integrated electronic and photonic devices. Here, we demonstrate the negative photoconductive response of Bombyx mori silk protein fibroin hydrogels, triggered by Au nanoparticles. The room temperature electrical conductivity of Au-silk hydrogels is found to be enhanced with the incorporation of Au nanoparticles over the control sample, due to the increased charge transporting networks within the hydrogel. Au-silk lateral photoconductor devices show a unique negative photoconductive response under an illumination of 325 nm, with excitation energy higher than the characteristic metal plasmon resonance band. The enhanced photoconductance yield in the hydrogels over the silk protein is attributed to the photo-oxidation of amino groups in the β-pleated sheets of the silk around the Au nanoparticles followed by the breaking of charge transport networks. The Au-silk nanocomposite does not show any photoresponse under visible illumination because of the localization of excited charges in Au nanoparticles. The negative photoconductive response of hybrid Au-silk under UV illumination may pave the way towards the utilization of silk for future bio-photonic devices using metal nanoparticle platforms.


Matrix stiffening and β1 integrin drive subtype-specific fibroblast accumulation in lung cancer.
The crucial role of tumor-associated fibroblasts (TAF) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here, the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from nonmalignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable with that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by β1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in β1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, because SCC-TAFs exhibited higher FAK (pY397), β1 expression, and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SCC-TAFs (>50%) compared with ADC-TAFs (10%-20%). In contrast, SCC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or β1 integrin-dependent mechano regulation may be effective against SCC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. This study reveals distinct mechanisms underlying the abnormal accumulation of tumor-supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.


Interaction between gut microbiota and ethnomedicine constituents.
Covering: 2000 to 2018 (October) Trillions of microbes, collectively termed as gut microbiota, reside in the gastrointestinal tract and are involved in the physiology of their hosts. In humans, disease incidence and medical therapy are found to be associated with gut microbiota composition. Since ethnomedicines are largely plant-derived and orally ingested, this review summarizes the interactions of gut microbiota with ethnomedicine constituents (overwhelmingly, natural phytochemicals) to highlight the knowledge accumulation in (1) the modulation of the gut microbiota profile by ingested natural compounds, and (2) the gut microbial conversion of natural products into the 'daughter molecules' with potent bioactivities. By understanding such complex interactions of gut microbiota with ethnomedicines and/or the phytochemicals thereof, a fascinating frontier of natural-product chemistry may be substantially activated to conceptualize future therapeutic strategies.


[Pseudohermaphroditism and bisexuality. Apropos of a sex change].
A case of change of sex at the age of twelve is reported in a patient with male pseudohermaphroditism who has been regularly followed-up for ten years after the change. This case exemplifies the maturation and identification problems which arise when the patient is assigned to the wrong sex as a result of organic abnormalities. The doubt concerning sexual identity which appears at the time of birth is instrumental in the child's psychic development and produces both intellectual dullness and libidinal fixation to preoedipal stages.


Transfusion Timing and Postoperative Myocardial Infarction and Death in Patients Undergoing Common Vascular Procedures.
Perioperative allogenic blood transfusions, specifically packed red bloods cells (pRBC), after vascular surgery procedures are modifiable risk factors that are associated with increased cardiovascular events and 30-day mortality. The aim of this study is to evaluate the effect of transfusion timing (intraoperative vs. postoperative) on the rate of postoperative myocardial infarction (POMI) and death. Six surgical and endovascular modules within the Vascular Quality Initiative (VQI) from 2013 to 2017 were reviewed at a single institution. Transfusion data on elective and urgent cases were abstracted and all patients who underwent inpatient procedures had routine postoperative troponin/ECG testing. The primary endpoint was POMI utilizing the American Heart Association's third universal definition for myocardial infarction. These criteria include the detection of a rise/and or fall of cTnT with at least one value above the 99th percentile and with at least one of the following 1) symptoms of acute myocardial ischemia, 2) new ischemic ECG changes, 3) development of pathological Q waves, 4) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with ischemic etiology. The secondary endpoint was 30-day all-cause mortality. Multivariable logistic regression analysis was utilized to evaluate the risk of transfusions on POMI and death. We identified 1,154 cases for analysis (299 abdominal aortic aneurysm [EVAR], 117 infrainguinal bypasses, 127 open abdominal aortic aneurysm [AAA], 41 suprainguinal bypasses, 168 thoracic endovascular aortic repair [TEVAR], and 402 peripheral vascular interventions). Overall, the POMI rate was 2% and mortality 1%. Rates of POMI differed by procedure type (P = 0.04), where infrainguinal bypass had the highest rate of POMI at 4%. Death rates did not vary by type of procedure (P = 0.89). Mean number of intraoperative pRBC and postoperative pRBC transfusion was higher for patients with POMI (intraop: 1.3 vs. 0.3, postop: 1.8 vs. 0.4, both P < 0.01) and death (intraop: 1.4 vs. 0.3, postop: 2.5 vs. 0.4, both P < 0.01). In addition, older age and coronary artery disease (CAD) were associated with POMI on univariate analysis. On multivariable analysis for POMI, CAD (odds ratio [OR] = 5.15, 95% confidence interval [CI] [2.00-13.24], P < 0.001), receiving both an intraoperative and postoperative transfusion (OR = 6.20, 95% CI [1.78-21.55], P < 0.01) as well as a postoperative transfusion only (OR = 5.70, 95% CI [1.81-17.94], P < 0.01) compared to no transfusion were associated with higher odds of POMI; however intraoperative transfusion only was not (OR = 3.42, 95% CI [0.88-13.31], P = 0.08). On multivariable analysis, increasing age of the patient was associated with higher odds of death (OR = 1.08, 95% CI [1.01-1.15], P = 0.02) and statin use was highly protective (OR = 0.27, 95% CI [0.10-0.74], P = 0.01), but any intraoperative or postoperative transfusion compared to no transfusion was not associated with death after adjustment. In our series with routine postoperative troponin screening in the inpatient setting, the use of an isolated postoperative transfusion as well as cases requiring both an intraoperative and postoperative transfusion was associated with POMI. However, isolated intraoperative transfusion was not associated with POMI, and we did not identify an association of transfusion with 30-day mortality. These data suggest that the perioperative setting of transfusions is important in its impact on postoperative outcomes and needs to be accounted for when evaluating transfusion outcomes and indications.


DNA origami based visualization system for studying site-specific recombination events.
Site-specific recombination involves reciprocal exchange between defined DNA sites. The reaction initiates from the formation of a recombinase-DNA synaptic complex, in which two recombination sites arrange in an appropriate configuration. However, there is incomplete information about how the topological state of the substrate influences the synapsis and outcome of the reaction. Here, we show that Cre-mediated recombination can be regulated by controlling the orientation and topology of the loxP substrate in a DNA frame nanoscaffold. High-speed atomic force microscopy analyses revealed that the loxP-containing substrate strands in the antiparallel orientation can be recombined only through formation of synaptic complexes. By tethering Holliday junction (HJ) intermediates to DNA frames in different connection patterns and using them as a starting substrate, we found that the topological state of the HJ intermediates dictates the outcome of the resolution. Our approach should provide a new platform for structural-functional studies of various DNA targeting enzymes, especially which require formation of synaptic complexes.


SWSSL: Sliding Window-Based Self-Supervised Learning for Anomaly Detection in High-Resolution Images.
Anomaly detection (AD) aims to determine if an instance has properties different from those seen in normal cases. The success of this technique depends on how well a neural network learns from normal instances. We observe that the learning difficulty scales exponentially with the input resolution, making it infeasible to apply AD to high-resolution images. Resizing them to a lower resolution is a compromising solution and does not align with clinical practice where the diagnosis could depend on image details. In this work, we propose to train the network and perform inference at the patch level, through the sliding window algorithm. This simple operation allows the network to receive high-resolution images but introduces additional training difficulties, including inconsistent image structure and higher variance. We address these concerns by setting the network's objective to learn augmentation-invariant features. We further study the augmentation function in the context of medical imaging. In particular, we observe that the resizing operation, a key augmentation in general computer vision literature, is detrimental to detection accuracy, and the inverting operation can be beneficial. We also propose a new module that encourages the network to learn from adjacent patches to boost detection performance. Extensive experiments are conducted on breast tomosynthesis and chest X-ray datasets and our method improves 8.03% and 5.66% AUC on image-level classification respectively over the current leading techniques. The experimental results demonstrate the effectiveness of our approach.


Compartmentation of ATP:citrate lyase in plants.
Extracts prepared from young leaves of Pea (Pisum sativum), tobacco (Nicotiana tabacum), rape (Brassica napus), and spinach (Spinacia oleracea) all contained ATP:citrate lyase (ACL) activity, which was most active in rape leaflets (130 nmol min(-1) g fresh weight). In rape and spinach, ACL activity was predominantly localized in the plastids (between about 78% and 90% of the total activity), whereas in pea and tobacco, distribution was mainly cytosolic (about 85% and 78%, respectively, of the total). These distributions were calculated from the relative distributions of plastid and cytosol marker enzymes. Cross-reactivity between plant and rat ACL antibody was carried out by immunoblot analysis and, in rape and spinach, showed that a 120-kD protein, presumably indicating homomeric ACL proteins, was present in both cytosolic and plastidic fractions. In pea, two cross-reacting proteins were detected, the major material being in the cytosol fraction. Therefore, ACL occurs both in the cytosol and plastids of higher plants, but the distribution of activity changes according to the species. The plastidic ACL is proposed to function for the supply of acetyl-coenzyme A for lipid biosynthesis de novo, whereas the cytosolic ACL may provide acetyl-coenzyme A for the mevalonate pathway or fatty acid elongation.


[Immunotherapy for Lung Cancer:Current Status and Future Prospects].
Immune checkpoint inhibitors( ICI) became available in the field of non-small cell lung cancer in 2015. Nine years have already passed since their use in clinical practice, and ICI are now being developed for clinical application not only in un-resectable advanced stage lung cancer but also in peri-operative treatment. In this report, we review the history of immunotherapy and summarize the current status of clinical development of ICI in advanced lung cancer and its use as peri-operative treatment. The biomarkers analysis and management of immune-related adverse events, which are important in the treatment of ICI, will also be discussed in this review.


A survey on critical care resources and practices in low- and middle-income countries.
Timely and appropriate care is the key to achieving good outcomes in acutely ill patients, but the effectiveness of critical care may be limited in resource-limited settings. This study sought to understand how to implement best practices in intensive care units (ICU) in low- and middle-income countries (LMIC) and to develop a point-of-care training and decision-support tool. An internationally representative group of clinicians performed a 22-item capacity-and-needs assessment survey in a convenience sample of 13 ICU in Eastern Europe (4), Asia (4), Latin America (3), and Africa (2), between April and July 2012. Two ICU were from low-income, 2 from low-middle-income, and 9 from upper-middle-income countries. Clinician respondents were asked about bed capacity, patient characteristics, human resources, available medications and equipment, access to education, and processes of care. Thirteen clinicians from each of 13 hospitals (1 per ICU) responded. Surveyed hospitals had median of 560 (interquartile range [IQR]: 232, 1,200) beds. ICU had a median of 9 (IQR: 7, 12) beds and treated 40 (IQR: 20, 67) patients per month. Many ICU had ≥ 1 staff member with some formal critical care training (n = 9, 69%) or who completed Fundamental Critical Care Support (n = 7, 54%) or Advanced Cardiac Life Support (n = 9, 69%) courses. Only 2 ICU (15%) used any kind of checklists for acute resuscitation. Ten (77%) ICU listed lack of trained staff as the most important barrier to improving the care and outcomes of critically ill patients. In a convenience sample of 13 ICU from LMIC, specialty-trained staff and standardized processes of care such as checklists are frequently lacking. ICU needs-assessment evaluations should be expanded in LMIC as a global priority, with the goal of creating and evaluating context-appropriate checklists for ICU best practices.


Intravenous heparin for the prevention of stroke progression in acute partial stable stroke.
In a double-blind, placebo-controlled trial, 225 patients with acute partial stable thrombotic stroke were randomly assigned to receive continuous intravenous heparin therapy or placebo for 7 days for the prevention of stroke progression or death. No statistically significant difference between the two groups was found in degree of neurologic change; incidence of stroke progression after 7 days; or functional activity level of survivors at 7 days, 3 months and at 1 year after treatment. Compared with controls, a statistically significant greater number of patients in the group receiving heparin died in the year after the stroke. These deaths occurred 3 to 12 months after the initial stroke and probably were not related to treatment. Results of this study do not support the use of intravenous heparin to treat patients who have had acute partial stroke.


[A rapid method for determining the fatty acid composition of lipid A].
Lipid A is the most conservative part of LPS. Its fatty acids composition can serve as an important taxonomic marker of bacteria. The isolation of LPS and studying their chemical composition are difficult and protracted procedure. We propose the rapid method of determining the prevailed fatty acids of lipid A without isolation of LPS from the cell. The essence of the method is in the release of cell from the lipids which are not components of LPS. These lipids, in contrast to the lipid A, are more easily extractable from the cell structures. The fatty acids, which prevailed in the lipid-free cells, are the structural components of lipid A.


[An aphasic man with high fever; difficulty with diagnostic procedure].
A 73-year-old man, with known motor aphasia presented with high fever, dyspnoea, and vomiting. Only after several days it appeared that these signs were due to a sepsis as a consequence of a phlegmon of the neck, caused by an aspired part of his set of false teeth. The delay before diagnosis was due to the fact that adequate medical history taking was difficult because of the aphasia and attempts at non-verbal communication were poorly understood. The localization of the corpus alienum was a second pitfall, because it could not be visualized during physical examination or on the initial chest X-ray. The increased risk of colonization of dentures with pathogenic micro-organisms in nursing home residents may have played a role in the severe course of this infection. This case illustrates the diagnostic problems that may exist in patients who are unable to communicate adequately.


Efficient Bayesian inference of fully stochastic epidemiological models with applications to COVID-19.
Epidemiological forecasts are beset by uncertainties about the underlying epidemiological processes, and the surveillance process through which data are acquired. We present a Bayesian inference methodology that quantifies these uncertainties, for epidemics that are modelled by (possibly) non-stationary, continuous-time, Markov population processes. The efficiency of the method derives from a functional central limit theorem approximation of the likelihood, valid for large populations. We demonstrate the methodology by analysing the early stages of the COVID-19 pandemic in the UK, based on age-structured data for the number of deaths. This includes maximum a posteriori estimates, Markov chain Monte Carlo sampling of the posterior, computation of the model evidence, and the determination of parameter sensitivities via the Fisher information matrix. Our methodology is implemented in PyRoss, an open-source platform for analysis of epidemiological compartment models.


Presacral schwannoma treated as irritable bowel syndrome.
Presacral tumours represent a heterogeneous group of predominantly benign and occasionally malignant neoplasms. These tumours, though rare, frequently present either incidentally or with vague symptoms. Schwannomas of the presacral region are one variant described as benign tumours of neurogenic origin. The case of a large presacral schwannoma in a 26-year-old man, who was treated for irritable bowel syndrome for 4 years, is presented. The patient presented with intermittent constipation, a feeling of incomplete evacuation of the bowel and vague abdominal discomfort relieved by defecation. The symptomatology worsened and constipation became frequent, and the patient experienced increased urinary frequency. Baseline investigations were normal and ultrasonography of the abdomen revealed a pelvic mass, which on CT scanning was revealed to be a large retrorectal mass. The tumour was resected and histology revealed it to be a schwannoma. This unique case is presented to emphasise that irritable bowel syndrome must be a diagnosis of exclusion, especially if atypical symptoms are present.


A rare case of imitation injury.
The impact of media on cognitions and behaviors of adolescents is well-known. High frequency of exposure to media may distort the reality testing among predisposed youth, hence the rise in risk taking behaviors among this population. We present a rare manifestation of risk taking behavior in an adolescent who injected mercury in his body after exposure to a Hollywood film. The results of investigations and possible explanation to understand risk taking behavior in the present case are discussed.


Differentiation among bio- and augmented- feedback in technologically assisted rehabilitation.
Introduction: In rehabilitation practice, the term 'feedback' is often improperly used, with augmented feedback and biofeedback frequently confused, especially when referring to the human-machine interaction during technologically assisted training. The absence of a clear differentiation between these categories represents an unmet need for rehabilitation, emphasized by the advent of new technologies making extensive use of video feedback, exergame, and virtual reality.Area covered: In this review we tried to present scientific knowledge about feedback, biofeedback, augmented feedback and neurofeedback, and related differences in rehabilitation settings, for a more proper use of this terminology. Despite the continuous expansion of the field, few researches clarify the differences among these terms. This scoping review was conducted through the searching of current literature up to May 2020, using following databases: PUBMED, EMBASE and Web of Science. After literature search a classification system, distinguishing feedback, augmented feedback, and biofeedback, was applied.Expert opinion: There is a need for clear definitions of feedback, biofeedback, augmented feedback, and neurofeedback in rehabilitation, especially in the technologically assisted one based on human-machine interaction. In fact, the fast development of new technologies requires to be based on solid concepts and on a common terminology shared among bioengineers and clinicians.


Expression of IFN-alpha and IFN-gamma receptors on normal human small resting T lymphocytes and large granular lymphocytes.
The expression of interferon (IFN) receptors was studied on freshly isolated human lymphocytes from normal donors. Highly enriched populations of small resting T lymphocytes and large granular lymphocytes (LGL) were found to constitutively express high-affinity receptors for IFN-alpha and IFN-gamma. Both types of lymphocytes also had lower-affinity IFN-alpha binding sites. T lymphocytes had a mean of 230 IFN-alpha and 520 IFN-gamma high-affinity receptors per cell, whereas LGL had 520 IFN-alpha and 760 IFN-gamma receptors. However, because LGL were larger than the T lymphocytes, the IFN receptor density was similar on the two types of lymphocytes. The affinity of binding was similar on the two types of normal lymphocytes and on the cultured lymphoblastoid cell line Daudi. The number of IFN receptors per cell and the affinities of the IFN-receptor interactions varied little among the normal donors. Both the freshly isolated normal lymphocytes and the cultured cell line Daudi had separate receptors for type I (alpha and beta) and type II (gamma) IFN. Taken together, our data indicate that two types of freshly isolated normal lymphocytes constitutively express IFN receptors that are similar to those present on the lymphoblastoid cell line Daudi derived from a patient with Burkitt's lymphoma.


Antimicrobially impregnated catheters: An overview of randomized controlled trials.
In order to acquire an overview of the effectiveness of antimicrobially impregnated catheters on the prevention of catheter related bloodstream infections (CRI), we conducted a systematic review concentrating on randomized controlled trials (RCTs). The analysis end point was CRI; therefore, studies focussing only on catheter colonization were excluded. We did not consider abstracts for analysis. We identified 24 RCTs investigating the effectiveness of antimicrobially impregnated catheters. In addition, we discovered five meta-analyses and four studies investigating cost effectiveness. For the majority of antimicrobially impregnated catheter types only a few studies were available, and not enough to draw conclusions. Therefore, despite a relatively large number of RCTs available, the routine use of antimicrobially impregnated catheters as a measure for CRI prevention remains controversial, with a need for more high quality studies.


Genetic variation influences glutamate concentrations in brains of patients with multiple sclerosis.
Glutamate is the main excitatory neurotransmitter in the mammalian brain. Appropriate transmission of nerve impulses through glutamatergic synapses is required throughout the brain and forms the basis of many processes including learning and memory. However, abnormally high levels of extracellular brain glutamate can lead to neuroaxonal cell death. We have previously reported elevated glutamate levels in the brains of patients suffering from multiple sclerosis. Here two complementary analyses to assess the extent of genomic control over glutamate levels were used. First, a genome-wide association analysis in 382 patients with multiple sclerosis using brain glutamate concentration as a quantitative trait was conducted. In a second approach, a protein interaction network was used to find associated genes within the same pathway. The top associated marker was rs794185 (P < 6.44 x 10(-7)), a non-coding single nucleotide polymorphism within the gene sulphatase modifying factor 1. Our pathway approach identified a module composed of 70 genes with high relevance to glutamate biology. Individuals carrying a higher number of associated alleles from genes in this module showed the highest levels of glutamate. These individuals also showed greater decreases in N-acetylaspartate and in brain volume over 1 year of follow-up. Patients were then stratified by the amount of annual brain volume loss and the same approach was performed in the 'high' (n = 250) and 'low' (n = 132) neurodegeneration groups. The association with rs794185 was highly significant in the group with high neurodegeneration. Further, results from the network-based pathway analysis remained largely unchanged even after stratification. Results from these analyses indicated that variance in the activity of neurochemical pathways implicated in neurodegeneration is explained, at least in part, by the inheritance of common genetic polymorphisms. Spectroscopy-based imaging provides a novel quantitative endophenotype for genetic association studies directed towards identifying new factors that contribute to the heterogeneity of clinical expression of multiple sclerosis.


Angiogenesis, lymphangiogenesis and atopic dermatitis.
Angiogenesis and morphological and functional alterations of microvessels are hallmark features of chronic inflammatory disorders, including certain skin diseases. Vascular endothelial growth factors (VEGFs) are key regulators of blood vessel growth. The VEGF family includes VEGF-A, -B, -C, -D and placental growth factor. VEGF-A and -B are the most important proangiogenic factors, while VEGF-C and -D primarily regulate lymphangiogenesis. Angiopoietins are promoters of neovascularization by interacting with Tie-1 and Tie-2 receptors present on endothelial cells. High levels of VEGF-A have been detected in skin tissue of atopic dermatitis (AD) patients and correlate with disease activity. The vascular changes in the skin of AD patients appear to be linked to the inflammatory process. Effector cells of skin inflammation (human mast cells, basophils, eosinophils, macrophages, lymphocytes, etc.) are major sources of a vast array of angiogenic and lymphangiogenic factors. The role of lymphangiogenesis in AD is largely unknown.


Granulocytic ehrlichiosis in the laboratory mouse.
C3H mice that were inoculated with ehrlichiae isolated from a patient with human granulocytic ehrlichiosis (HGE) developed anemia and leukopenia, but by day 24, they returned to normal values. Granulocytic morulae were present in peripheral blood and spleen smears on days 5 and 10, and there was a reduction in morulae on day 17. Ehrlichiae were present in HL-60 cell cultures of blood and spleen from all mice at all intervals. Pathogenicity, but not infectivity, waned with mouse passage but could be resurrected by SCID mouse passage. Various methods were tested for their relative sensitivity in detecting infection: blood smears, HL-60 cell cultures, polymerase chain reaction (PCR) amplification of a 16S recombinant DNA target, and a mouse infectivity assay. All assays detected the HGE agent in blood during early infection, but PCR and the mouse infectivity assay were most sensitive during late infection. Xenodiagnosis demonstrated that mice remain persistently infected through 55 days.


Gallstones in obesity and weight loss.
The prevalence of cholesterol gallstones is increased in obese persons. The risk is especially high in those with the highest body mass index (relative risk 5-6). Weight loss further increases the risk of gallstones: the prevalence of new gallstones reaches 10-12% after 8-16 weeks of low-calorie diet and more than 30% within 12-18 months after gastric by-pass surgery. About one-third of the stones are symptomatic. The increased prevalence of stones is mostly due to supersaturation of bile with cholesterol, because of an increased synthesis by the liver and secretion into bile. Saturation is further increased during weight loss. It returns toward normal after weight stabilization at a lower level, allowing spontaneous stone dissolution in some cases. Identified risk factors for gallstones during weight loss are a relative loss of weight greater than 24% of initial body weight, a rate of weight loss greater than 1.5 kg per week, a very low calorie diet with no fat, a long overnight fast period and a high serum triglyceride level. Ursodeoxycholic acid decreases cholesterol saturation of bile and gallstone incidence during weight loss. Other preventive measures include a control of weight loss rate, a reduction of the length of overnight fast, and maintenance of a small amount of fat in the diet.


Photoelectric emission from the alkali metal doped vacuum-ice interface.
The photoelectron photoemission spectra and thresholds for low coverages of Li and K adsorbed on water-ice have been measured, compared with photoionization spectra of the gas-phase atoms, and modeled by quantum chemical calculations. For both alkali metals the threshold for photoemission is dramatically decreased and the cross section increased on adsorption to the water-ice surface. Quantum chemical calculations suggest that the initial state is formed by the metal atoms adsorbed into the water-ice surface, forming a state with a delocalized electron distribution. This state is metastable and decays on the hundreds of seconds time scale at 92 K. The decay is markedly faster for Li than for K, probably due to diffusion into the ice film.


[Design of a population-based study of cardiovascular risk in Castile and Leon [Spain] through primary care teams].
We describe the design and the response indicators in a cross sectional study to estimate several factors associated with cardiovascular risk in the population of Castile and Leon. A sample of 4,950 individuals aged 15 years and above was obtained in two stages: in the first stage, 198 primary care physicians were selected and in the second stage a sample of 25 persons from each primary care physician's list was obtained. The response rate was 98% among primary care physicians and 80% among the population. Statistically significant differences were found in age distribution between the frame sample and the definitive sample. After applying design adjustments, only the group aged 35-64 years was significantly overdimensioned. Access to the general population in primary health care is a feasible and effective procedure. A high response rate contributes to the validity of the information.


The biological impact of blood pressure-associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle.
Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention.


Determinants of dental care visits among low-income African-American children.
The objective of the authors' analysis was to investigate the determinants of dental care visits among young, low-income African-American children. Trained researchers interviewed a representative sample of low-income black families (caregivers and children aged 0 through 5 years) in Detroit to assess their dental visit history, dental insurance status and oral health behaviors. Dental examinations were conducted using the International Caries Diagnosis Assessment System (ICDAS). Of the 1,021 families who completed an interview and examination, a subset of the 552 children aged 3 to 5 years (and their primary caregivers) was the focus of this analysis. Children with private dental insurance had four times higher odds of having visited a dentist compared with those who had no dental insurance, and the odds for children receiving Medicaid were about 1.5 times higher. A child's age and a caregiver's educational attainment were positive and significant determinants of child dental visits. Caregivers who visited a dentist for preventive reasons were five times more likely to have taken their children to visit the dentist. Visiting a dentist was associated with an increased mean number of filled or missing tooth surfaces, but it was not significantly associated with the mean number of untreated decayed teeth. Children's dental insurance status was a significant determinant of their having visited a dentist. Even after the authors accounted for insurance status and other risk indicators, they found that children of caregivers who reported visiting a dentist for preventive care had a higher number of dental care visits. Determinants of caregivers' preventive dental visits must be identified and encouraged to improve the percentage of low-income children who visit dentists.


[Nurse-patient relationship].
The reason for the publication of this article is the author's concern with the quality of nursing assistance in psychiatric hospitals and the differences found among nursing schools in the teaching of psychiatric nursing to undergraduate students. She tried synthetize the basic knowledge needed for understanding the therapeutic nurse-patient relationship.


Performance of conventional echocardiographic parameters and myocardial measurements in the sequential evaluation of left ventricular function.
Echocardiography is frequently used for sequential evaluation of left ventricular (LV) function, although the reproducibility of such conventional measurements as LV ejection fraction (EF) have been questioned. The utility of such newer measurements as tissue Doppler imaging and left atrial (LA) size in serial clinical testing are undefined. The magnitude and clinical relevance of changes in conventional and new measurements of LV function were investigated and compared in 346 consecutive patients undergoing sequential echocardiography. Change in LA area, LVEF, tissue E velocity (Em), and transmitral E to Em ratio (E/Em) were compared over 304 +/- 239 days. Changes within and between parameters (after mean correction to make measurements comparable) were assessed in groups designated as stable (n = 144) or unstable (n = 202) according to clinical progress. A single observer remeasured these parameters in stable patients individually and with paired studies side by side. Significant variability was seen in all measurements, with change in LVEF the only parameter differing between stable and unstable groups (6.4 +/- 8.9% vs 9.4 +/- 5.4%; p <0.001). Tissue Em and E/Em ratio were more variable than LA area or LVEF. In stable patients, LVEF changed the least and E/Em changed the most over time (p <0.05). With a single blinded observer, Em had improved reproducibility (1.5 +/- 1.9 vs 2.3 +/- 2.6 cm/s; p <0.001), as did visual EF. In conclusion, variability in all measurements was high irrespective of clinical status. Newer measurements were no better than LVEF in detecting changes in clinical status. Sequential LV assessment should be interpreted with caution, and more robust measurements are needed.


Distribution of acid protease activity in the squid nervous system.
Acid protease activity was measured in homogenized stellate ganglion, axoplasm extruded from the squid giant axon, homogenized fin nerves, and in lysed synaptosomes prepared from the optic lobe of the squid. At least two different acid protease classes were distinguished on the bases of their inhibitor profiles. Acid protease activity was present in each of the above tissues except extruded axoplasm. This result suggests that the acid protease activity found in our homogenized fin nerves might be located not within the axons but rather in glial cells or extracellular tissue. The absence of acid protease activity in extruded axoplasm indicates that acid proteases are unlikely to play a significant role in the catabolism of intracellular proteins along the length of the axon.


Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update.
To update the ASCO clinical practice guideline on adjuvant endocrine therapy on the basis of emerging data on the optimal duration of treatment, particularly adjuvant tamoxifen. ASCO convened the Update Committee and conducted a systematic review of randomized clinical trials from January 2009 to June 2013 and analyzed three historical trials. Guideline recommendations were based on the Update Committee's review of the evidence. Outcomes of interest included survival, disease recurrence, and adverse events. This guideline update reflects emerging data on duration of tamoxifen treatment. There have been five studies of tamoxifen treatment beyond 5 years of therapy. The two largest studies with longest reported follow-up show a breast cancer survival advantage with 10-year durations of tamoxifen use. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer. Previous ASCO guidelines recommended treatment of women who have hormone receptor-positive breast cancer and are premenopausal with 5 years of tamoxifen, and those who are postmenopausal a minimum of 5 years of adjuvant therapy with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor (in sequence). If women are pre- or perimenopausal and have received 5 years of adjuvant tamoxifen, they should be offered 10 years total duration of tamoxifen. If women are postmenopausal and have received 5 years of adjuvant tamoxifen, they should be offered the choice of continuing tamoxifen or switching to an aromatase inhibitor for 10 years total adjuvant endocrine therapy.


T lymphocyte phenotypic profile in lung segments affected by cavitary and non-cavitary tuberculosis.
Clinical manifestations of pulmonary tuberculosis (TB) may depend on a complex interaction between the host and the pathogen. Clinical outcomes of pulmonary tuberculosis are variable, ranging from asymptomatic lifelong infection to parenchymal lung destruction, resulting in cavitary lesions. To investigate the hypothesis that local cellular immune response may affect presentation and outcome in tuberculosis, we performed bronchoalveolar lavage (BAL) in lung segments affected by cavitary and non-cavitary tuberculosis. We then correlated the type of cellular response at the level of the involved lung segments with clinical evolution in terms of cavity formation. We found alveolar lymphocytosis in patients with both cavitary and non-cavitary pulmonary tuberculosis, with increased CD4+ lymphocytes in patients with non-cavitary pulmonary tuberculosis. A predominant Th1 immune response has been observed in non-cavitary patients, while cavitary involved segments exhibit the presence of Th2 lymphocyte subsets. These data, while confirming the importance of Th1-type CD4+ cells and IFN-gamma in effective cellular immunity in active pulmonary tuberculosis, also suggest that the presence of Th2 lymphocytes may contribute to tissue necrosis phenomena associated with cavitary evolution of pulmonary tuberculosis. Our observations indicate the importance of the type of local immune response at the site of disease in the development of different clinical characteristics and outcome in pulmonary tuberculosis.


The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders.
Recent advances in genetics and genomics have unveiled numerous cases of autism spectrum disorders (ASDs) associated with rare, causal genetic variations. These findings support a novel view of ASDs in which many independent, individually rare genetic variants, each associated with a very high relative risk, together explain a large proportion of ASDs. Although these rare variants impact diverse pathways, there is accumulating evidence that synaptic pathways, including those involving synaptic cell adhesion, are disrupted in some subjects with ASD. These findings provide insights into the pathogenesis of ASDs and enable the development of model systems with construct validity for specific causes of ASDs. In several neurodevelopmental disorders frequently associated with ASD, including fragile X syndrome, Rett syndrome and tuberous sclerosis, animal models have led to the development of new therapeutic approaches, giving rise to optimism with other causes of ASDs.


Genomic rearrangements of the GREM1-FMN1 locus cause oligosyndactyly, radio-ulnar synostosis, hearing loss, renal defects syndrome and Cenani--Lenz-like non-syndromic oligosyndactyly.
Limb development is a complex process requiring proper spatio-temporal expression of a network of limb specific morphogens. Grem1 and Fmn1 play an important role in mouse and chick limb development. The mouse limb deformity (ld) phenotype with digit reduction, syndactyly, radio-ulnar synostosis, variable renal defects and absent fibulae is caused by loss of Grem1 function. This could be due to either coding Grem1 homozygous mutations or homozygous deletions of the neighbouring Fmn1 gene, which also removes limb specific regulatory sequences of Grem1. Recent studies reinforce the hypothesis that a loss of Fmn1 protein could also contribute to the observed ld anomalies. In addition, an over-expression of Grem1 in developing chick limbs represses the programmed cell death in the interdigital mesenchyme, resulting in interdigital webbing and truncation of distal cartilage elements. For the first time, chromosomal imbalances in the GREM1 FMN1 region in individuals with limb defects are reported here. A 263 Kb homozygous deletion of FMN1 was associated with oligosyndactyly, radioulnar synostosis, hearing loss and renal defects, features identical to ld mice. A 1.7 Mb duplication encompassing both the GREM1 and FMN1 genes was detected in a patient with isolated Cenani-Lenz-like oligosyndactyly of the hands, resembling the transgenic chick wings in which Grem1 was over-expressed. The phenotypes of these two patients represent new entities/syndromes within the Cenani-Lenz clinical spectrum: (1) an autosomal recessive oligosyndactyly, radio-ulnar synostosis, hearing loss and renal defect syndrome; and (2) an autosomal dominant Cenani-Lenz-like non-syndromic oligosyndactyly.


A cytochrome P450 regulates a domestication trait in cultivated tomato.
Domestication of crop plants had effects on human lifestyle and agriculture. However, little is known about the underlying molecular mechanisms accompanying the changes in fruit appearance as a consequence of selection by early farmers. We report the fine mapping and cloning of a tomato (Solanum lycopersicum) fruit mass gene encoding the ortholog of KLUH, SlKLUH, a P450 enzyme of the CYP78A subfamily. The increase in fruit mass is predominantly the result of enlarged pericarp and septum tissues caused by increased cell number in the large fruited lines. SlKLUH also modulates plant architecture by regulating number and length of the side shoots, and ripening time, and these effects are particularly strong in plants that transgenically down-regulate SlKLUH expression carrying fruits of a dramatically reduced mass. Association mapping followed by segregation analyses revealed that a single nucleotide polymorphism in the promoter of the gene is highly associated with fruit mass. This single polymorphism may potentially underlie a regulatory mutation resulting in increased SlKLUH expression concomitant with increased fruit mass. Our findings suggest that the allele giving rise to large fruit arose in the early domesticates of tomato and becoming progressively more abundant upon further selections. We also detected association of fruit weight with CaKLUH in chile pepper (Capsicum annuum) suggesting that selection of the orthologous gene may have occurred independently in a separate domestication event. Altogether, our findings shed light on the molecular basis of fruit mass, a key domestication trait in tomato and other fruit and vegetable crops.


Profiling of promoter occupancy by PPARalpha in human hepatoma cells via ChIP-chip analysis.
The transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is an important regulator of hepatic lipid metabolism. While PPARalpha is known to activate transcription of numerous genes, no comprehensive picture of PPARalpha binding to endogenous genes has yet been reported. To fill this gap, we performed Chromatin immunoprecipitation (ChIP)-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARalpha agonist GW7647. We found that GW7647 increased PPARalpha binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARalpha, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARalpha binding to their promoter. A GW7647-induced PPARalpha-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARalpha and SREBP signaling. Our data furthermore demonstrate interaction between PPARalpha and STAT transcription factors in PPARalpha-mediated transcriptional repression, and suggest interaction between PPARalpha and TBP, and PPARalpha and C/EBPalpha in PPARalpha-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARalpha in human liver and highlight the importance of cross-talk with other transcription factors.


Down-regulation of poly(rC)-binding protein 1 correlates with the malignant transformation of hydatidiform moles.
To analyze the expression patterns of poly(rC)-binding protein 1 (PCBP1) in complete hydatidiform moles (HMs) and to determine the predictive value of PCBP1 during postmolar follow-up after uterine evacuation. The PCBP1 protein expression profile was investigated in 10 complete moles that remained benign, 10 complete moles that underwent malignant transformation, and 10 choriocarcinoma tissues using Western blot analysis. The PCBP1 protein expression patterns in complete HM samples gathered from 69 patients were also detected by immunohistochemical analysis. The association of PCBP1 protein expression with the progression in HMs was subsequently assessed. The expression of PCBP1 was significantly lower in malignant-transformed moles than benign moles. The PCBP1 expression level was negatively associated with malignant transformation and serum human chorionic gonadotropin levels. Logistic regression analysis indicated that complete moles with high PCBP1 expression levels had a significantly lower risk of progression to gestational trophoblastic tumors (odds ratio, 0.22; 95% confidence interval, 0.07-0.67). These observations suggest that PCBP1 may be important in the pathogenesis of gestational trophoblastic tumors. In addition to the β-fraction of human chorionic gonadotropin, decreased expression of PCBP1 protein may be a strong predictor of the malignant transformation of complete moles.


[Eosinophilic granuloma of the cervical spine with atypical neurological, cerebrospinal fluid and radiological manifestations].
A case of eosinophilic granuloma of the cervical spine in a ten year-old white boy is reported. The patient complained of posterior cervical pain at the level of C5-C6 and right hemiparesis that progressed to mixed tetraparesis (lower motor neuron in upper limbs and upper motor neuron in lower limbs). Examination of the cerebrospinal fluid (CSF) disclosed an inflammatory reaction; radiologic studies of the cervical spine showed an irregular aspect with demineralization at the base of spinous process of C6. The patient was treatet intermitently with corticosteriods (prednisone); there was an improvement of neurologic symptoms and the examination of the CSF was normal within a few days, each time he took the drug. Neurologic symptons and abnormalities of the CSF recurred after discontinuation of corticotherapy. Examination of a fragment of the spinous process and neighboring tissues of C6, taken by biopsy, disclosed eosinophilic granuloma. Radiotherapy was then indicated, plus corticosteroids. There was remission of all neurologic symptoms and signs. The unusual features of the case are discussed in relation to others reported in the literature.


Imbalanced base excision repair increases spontaneous mutation and alkylation sensitivity in Escherichia coli.
Inappropriate expression of 3-methyladenine (3MeA) DNA glycosylases has been shown to have harmful effects on microbial and mammalian cells. To understand the underlying reasons for this phenomenon, we have determined how DNA glycosylase activity and substrate specificity modulate glycosylase effects in Escherichia coli. We compared the effects of two 3MeA DNA glycosylases with very different substrate ranges, namely, the Saccharomyces cerevisiae Mag1 and the E. coli Tag glycosylases. Both glycosylases increased spontaneous mutation, decreased cell viability, and sensitized E. coli to killing by the alkylating agent methyl methanesulfonate. However, Tag had much less harmful effects than Mag1. The difference between the two enzymes' effects may be accounted for by the fact that Tag almost exclusively excises 3MeA lesions, whereas Mag1 excises a broad range of alkylated and other purines. We infer that the DNA lesions responsible for changes in spontaneous mutation, viability, and alkylation sensitivity are abasic sites and secondary lesions resulting from processing abasic sites via the base excision repair pathway.


Protecting the public's health in an era of bioterrorism: the Model State Emergency Health Powers Act.
During the fall of 2001, public health law scholars at the Center for Law and the Public's Health at Georgetown and Johns Hopkins Universities were asked by the Centers for Disease Control and Prevention (CDC) and a series of national partners to develop the Model State Emergency Health Powers Act (MSEHPA). The MSEHPA provides a series of modern powers for states to consider in responding to catastrophic public health emergencies, including bioterrorism events. Since December 2001, provisions based on the MSEHPA have been introduced in nearly 40 states and passed in 20. Underlying the development of the act is a long-standing debate between legal and ethical scholars and law- and policymakers as to the appropriate ways to balance individual and communal rights. The drafting challenge was to create a comprehensive model law that provides adequate powers to protect the public's health while also respecting individual and group rights. The MSEHPA empowers public health agents with broad authority and simultaneously limits the exercise of power in time, duration, and scope to accomplish communal goals of abating serious public health threats. Coercive public health powers, particularly isolation and quarantine, are exercised on a temporary basis, only so long as are reasonably necessary and only among persons who justifiably may pose a risk to others because of their contagious conditions. Individual rights to contest the coercive use of public health powers, even during an emergency, are secured.


Proteins of the extracellular matrix are sensitizers of photo-oxidative stress in human skin cells.
Sensitized production of reactive oxygen species after photo-excitation of endogenous chromophores is thought to contribute to skin photo-oxidative stress. Here we present experimental evidence in support of a potential role of extracellular matrix proteins as skin photosensitizers. Human and bovine type I collagen and elastin sensitized of hydrogen peroxide generation upon irradiation with solar simulated light or ultraviolet A. Induction of intracellular oxidative stress by extracellular matrix-protein sensitization was demonstrated by flow cytometric analysis of fibroblasts preloaded with the intracellular redox dye dihydrorhodamine 123 and exposed to pre-irradiated type I collagen. Pre-irradiated collagen and elastin induced pronounced inhibition of proliferation in cultured keratinocytes and fibroblasts, which was reversed by antioxidant or catalase treatment and reproduced by exposure to concentrations of H2O2 formed during extracellular matrix-protein irradiation. In fibroblasts, chromosomal DNA damage as a consequence of collagen-sensitized H2O2 formation was demonstrated using a single cell electrophoresis assay. The enzymatic cross-links pyridinoline and desmosine were examined as candidate sensitizer chromophores contained in collagen and elastin, respectively. Pyridinoline, but not desmosine, sensitized light-driven H2O2 production and inhibition of fibroblast proliferation. Our results support the hypothesis that extracellular matrix proteins play a functional role in skin photoaging and carcinogenesis by sensitization of photo-oxidative damage.


Consumer preferences for fresh tomato at the European scale: a common segmentation on taste and firmness.
Although tomato flavor has not been a major goal for breeders, nowadays it becomes important as it is a subject of consumer complaint. A better knowledge of tomato consumer preferences, at the European level, should provide the basis for improvement of fruit quality and for market segmentation. In the framework of a large European project, 806 consumers from 3 countries, The Netherlands, France, and Italy, were presented with a set of 16 varieties representing the diversity of fresh tomato offer in order to evaluate their preferences. In parallel, sensory profiles were constructed by expert panels in each country. Preference maps were then constructed in each country revealing the structure of consumer preferences and allowing identification of the most important characteristics. Then a global analysis revealed that preferences were quite homogeneous across countries. This study identified the overall flavor and firmness as the most important traits for improving tomato fruit quality. It showed that consumer preferences from different European countries, with different cultures and food practices, are segmented following similar patterns when projected onto a common referential plan. Moreover, the results clearly showed that diversification of taste and texture is required to satisfy all consumers' expectations as some consumers preferred firm tomatoes, while others preferred melting ones and were more or less demanding in terms of sweetness and flavor intensity. Detailed comparisons also showed the importance of the fruit appearance in consumer preference.


Comparison of Survival Outcomes Following Postsurgical Radioactive Iodine Versus External Beam Radiation in Stage IV Differentiated Thyroid Carcinoma.
There is a lack of well-powered data regarding outcomes in stage IV differentiated thyroid carcinoma (DTC) treated with postsurgical radiation. The objective of this study was to examine survival in patients with stage IV papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) who received radioactive iodine (RAI), external beam radiation therapy (EBRT), or neither following surgery. In this retrospective cohort study, data collected from the National Cancer Data Base (NCDB) yielded 11,832 patients with stage IV DTC who underwent primary surgical treatment between 2002 and 2012. Patients were stratified by histology and sub-stage. Fully parametric, multilevel survival-time models were used to evaluate survival outcomes in three adjuvant treatment groups: RAI, EBRT, or no adjuvant radiation. Hazard ratios (HR) and time ratios (TR) were calculated against patients who did not receive radiation. All models were adjusted for demographic and clinical factors. The mean age of all patients was 61.6 years (SD = 11.6), and 57.5% were female. Patients who received EBRT had significantly higher 5- and 10-year hazards of death in several PTC sub-stages (10-year HRPTC Stage IV-A = 2.12 [confidence interval (CI) 1.79-2.52]; HRPTC Stage IV-B = 2.03 [CI 1.33-3.10]). For stage IV-B PTC requiring EBRT, lifespan after diagnosis was shortened by a factor of 3 when compared to patients who did not receive radiation (TRPTC Stage IV-B = 0.32 [CI 0.16-0.62]). In contrast, RAI was significantly associated with improved 5- and 10-year survival in both PTC and FTC patients regardless of pathological sub-stage. Large reductions in mortality were observed in patients with FTC who were treated with RAI (HRFTC Stage IV-C = 0.19 [CI 0.06-0.65]). When patients with stage IV-C FTC were treated with RAI, life-span after diagnosis doubled (TRFTC Stage IV-C = 1.98 [CI 1.31-3.00]). Through the NCDB, this study sought to describe prognosis and survival for adjuvant radiation in stage IV DTC. RAI was associated with improved survival for stage IV DTC. Despite treatment benefits conferred by adjuvant EBRT, indications to treat with EBRT were associated with poorer survival outcomes in patients with advanced-stage DTC, particularly PTC.