Assessment of cardiac autonomic modulation during graded head-up tilt by symbolic analysis of heart rate variability.
Two symbolic indexes, the percentage of sequences characterized by three heart periods with no significant variations (0V%) and that with two significant unlike variations (2UV%), have been found to reflect changes in sympathetic and vagal modulations, respectively. We tested the hypothesis that symbolic indexes may track the gradual shift of the cardiac autonomic modulation during an incremental head-up tilt test. Symbolic analysis was carried out over heart period variability series (250 cardiac beats) derived from ECG recordings during a graded head-up tilt test (0, 15, 30, 45, 60, 75, and 90 degrees ) in 17 healthy subjects. The percentage of subjects showing a significant linear correlation (Spearman rank-order correlation) with tilt angles was utilized to evaluate the performance of symbolic analysis. Spectral analysis was carried out for comparison over the same series. 0V% progressively increased with tilt angles, whereas 2UV% gradually decreased. The decline of 2UV% was greater than the increase of 0V% at low tilt angles. Linear correlation with tilt angles was exhibited in a greater percentage of subjects for 0V% and 2UV% than for any spectral index. Our findings suggest that symbolic analysis performed better than spectral analysis and, thus, is a suitable methodology for assessment of the subtle changes of cardiac autonomic modulation induced by a graded head-up tilt test. Moreover, symbolic analysis indicates that the changes of cardiac sympathetic and vagal modulations observed during this protocol were reciprocal but characterized by different absolute magnitudes.


Binding of a glucagon photoaffinity label to rat liver plasma membranes and its effect on adenylate cyclase activity before and after photolysis.
The concentration-dependent stimulation of adenylate cyclase by the photoaffinity reagent 2-[(2-nitro-4-azidophenyl)sulfenyl]-Trp25-glucagon (glucagon-NAPS) and also its binding characteristics were compared with those of the native hormone. The derivative was found to be slightly more potent in stimulating adenylate cyclase than glucagon, in the presence of guanosine 5'-triphosphate (GTP). 125I-Labeled glucagon-NAPS or 125I-labeled glucagon bound rapidly to receptors and was competitively displaced by unlabeled glucagon or glucagon-NAPS. Glucagon-NAPS displaced bound radiolabeled hormone at a lower concentration than did glucagon in the absence of GTP. Scatchard analysis of the binding data obtained from displacement of bound radiolabeled ligand with unlabeled peptide demonstrated a heterogeneous population of saturable glucagon binding sites. Glucagon-NAPS displayed a higher affinity (0.7 nM) for the high-capacity sites (80-90% of total binding sites) than glucagon (4.0 nM) in the absence of GTP. In the presence of the nucleotide, both ligands had approximately the same affinity (0.5-0.6 nM). Hill plot analysis of the binding data suggested noncooperative interactions. Photoaffinity labeling of plasma membranes with glucagon-NAPS resulted in an irreversible activation of adenylate cyclase with a reduced response to further stimulation by glucagon, glucagon-NAPS, and NaF.


Customized SmartPeg for measurement of resonance frequency of mini dental implants.
One-piece narrow diameter implants (NDIs) have been recommended as "Single-tooth replacements in the anterior zones, single posterior, multiple-unit fixed dental prosthesis (FDP), edentulous jaws to be rehabilitated with FDP, and edentulous jaws rehabilitation with overdentures in situations with reduced mesiodistal space or reduced ridge width." (ITI consensus 2013). Since NDIs can be immediately loaded, it is important to be able to carry out stability testing. We developed and validated a customized SmartPeg for this type of implant to measure the Implant Stability Quotient (ISQ). The ISQ of mini dental implants (MDIs) was measured and compared with the stability of standard and in a rabbit model. The aim of the study is to test the feasibility of a customized SmartPeg for resonance frequency measurement of single-piece mini dental implants and to compare primary stability of a standard and the mini dental implant (3M™ESPE™ MDI) in a rabbit model after 6 weeks of healing. Eight New Zealand white rabbits were used for the study. The protocol was approved by the McGill University Animal Ethics Review Board. Sixteen 3M™ESPE™ MDI and equal number of standard implants (Ankylos® Friadent, Dentsply) were inserted into the tibia/femur of the rabbits and compared. Each rabbit randomly received two 3M™ESPE™ MDI and two Ankylos® implants in each leg. ISQ values were measured with the help of an Osstell ISQ device using custom-made SmartPegs for the MDIs and implant-specific SmartPegs™ (Osstell) for the Ankylos®. Measurements were obtained both immediately following implant placement surgery and after a 6-week healing period. Each reading was taken thrice and their average compared using Wilcoxon matched pairs signed-rank tests. The median ISQ and interquartile range (IQR) values were 53.3 (8.3) at insertion and 60.5 (5.5) at 6 weeks for the 3M™ESPE™MDI and, respectively, 58.5 (4.75) and 65.5 (9.3) for the Ankylos® implant. These values also indicate that both types of implants achieved primary and secondary stability, and this is supported by histological data. ISQ values of both 3M™ESPE™ MDI and Ankylos® increased significantly from the time of insertion to 6 weeks post-insertion (p < 0.05). The new custom-made SmartPeg is suitable for measuring the Implant Stability Quotient of 3M™ESPE™MDIs. The primary stability of 3M™ESPE™MDIs is similar to the primary stability attained by standard implants in the rabbit tibia.


The neurotranscriptome of the Aedes aegypti mosquito.
A complete genome sequence and the advent of genome editing open up non-traditional model organisms to mechanistic genetic studies. The mosquito Aedes aegypti is an important vector of infectious diseases such as dengue, chikungunya, and yellow fever and has a large and complex genome, which has slowed annotation efforts. We used comprehensive transcriptomic analysis of adult gene expression to improve the genome annotation and to provide a detailed tissue-specific catalogue of neural gene expression at different adult behavioral states. We carried out deep RNA sequencing across all major peripheral male and female sensory tissues, the brain and (female) ovary. Furthermore, we examined gene expression across three important phases of the female reproductive cycle, a remarkable example of behavioral switching in which a female mosquito alternates between obtaining blood-meals from humans and laying eggs. Using genome-guided alignments and de novo transcriptome assembly, our re-annotation includes 572 new putative protein-coding genes and updates to 13.5 and 50.3 % of existing transcripts within coding sequences and untranslated regions, respectively. Using this updated annotation, we detail gene expression in each tissue, identifying large numbers of transcripts regulated by blood-feeding and sexually dimorphic transcripts that may provide clues to the biology of male- and female-specific behaviors, such as mating and blood-feeding, which are areas of intensive study for those interested in vector control. This neurotranscriptome forms a strong foundation for the study of genes in the mosquito nervous system and investigation of sensory-driven behaviors and their regulation. Furthermore, understanding the molecular genetic basis of mosquito chemosensory behavior has important implications for vector control.


Presence of autism, hyperserotonemia, and severe expressive language impairment in Williams-Beuren syndrome.
Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized. Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined. The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production. Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.


Nrf2 as a therapeutic target for rheumatic diseases.
Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular protective processes. Rheumatic diseases are chronic conditions characterized by inflammation, pain, tissue damage and limitations in function. Main examples are rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis and osteoporosis. Their high prevalence constitutes a major health problem with an important social and economic impact. A wide range of evidence indicates that Nrf2 may control different mechanisms involved in the physiopathology of rheumatic conditions. Therefore, the appropriate expression and balance of Nrf2 is necessary for regulation of oxidative stress, inflammation, immune responses, and cartilage and bone metabolism. Numerous studies have demonstrated that Nrf2 deficiency aggravates the disease in experimental models while Nrf2 activation results in immunoregulatory and anti-inflammatory effects. These reports reinforce the increasing interest in the pharmacologic regulation of Nrf2 and its potential applications. Nevertheless, a majority of Nrf2 inducers are electrophilic molecules which may present off-target effects. In recent years, novel strategies have been sought to modulate the Nrf2 pathway which has emerged as a therapeutic target in rheumatic conditions.


The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions.
A paramount role of telomeres is to prevent chromosome fusions. The fission yeast Taz1 protein regulates diverse telomere functions but is not essential for growth under stress-free conditions. Strikingly, however, taz1(-) cells exhibit lethal telomere fusions when subjected to nitrogen starvation, a treatment that induces an uncommitted G1 state. These fusions are formed by Ku-dependent nonhomologous end joining. Fusions also occur during normal growth in taz1(-) cells that lack rad22(+), a gene involved in homologous recombination. Our data suggest a model whereby taz1(-) telomeres are exposed to the prevailing mode of DNA repair, which is dictated by the cell cycle. Thus, Taz1 caps chromosome ends and provides the telomerespecific interaction that prevents Ku from treating telomeres as double-strand breaks.


Bullous scleroderma.
Bullae arose in two patients with scleroderma and in one patient with a similar condition, eosinophilic fasciitis. Biopsy specimens from two of the patients demonstrated prominent dermal lymphatic dilation. We hypothesize that these lesions occurred after the development of lymphatic obstruction secondary to dermal sclerosis.


Ultradeep (>300 kilometers) ultramafic xenoliths: petrological evidence from the transition zone.
The seismologically delineated transition zone, at depths between 400 and 670 kilometers, is a fundamental discontinuity in the earth that separates the upper mantle from the lower mantle. Xenoliths from within or close to the transition zone are dominated by pyropic garnet and associated pyroxene or mineralogically heterogeneous garnet lherzolite. These xenoliths show evidence for the high-pressure (90 to 120 kilobars) transformation of pyroxene to a solid solution of pyroxene in garnet (majorite) and silicon in octahedral coordination; low-pressure (less than 80 kilobars) exsolution of clinopyroxene or orthopyroxene from the original majorite is preserved. Although mineral modes and rock proportions below the transition zone and the relative amount of eclogite present cannot be accurately assessed from the xenoliths, it is likely that both majorite and beta-spinel help produce the observed seismic gradient of the transition zone.


Interactions between orientation and contrast modulations suggest limited cross-cue linkage.
Recent studies of texture segmentation and second-order vision have proposed very similar models for the detection of orientation modulation and contrast modulation (OM and CM). From the similarity of the models it is tempting to assume that the two cues might be processed by a single generalised texture mechanism; however, recent results (Kingdom et al, 2003 Visual Neuroscience 2 65-76) have suggested that these cues are detected independently, or at least in a mechanism that is able to maintain an apparent independence between the cues. We tested new combinations of OM and CM and found that CM at 0.4 cycle deg(-1) facilitates the detection of OM at 0.2 cycle deg(-1) when the peaks of contrast align with the extremes of orientation. There is also some evidence of weak facilitation of CM by OM under the same conditions. Further, this facilitation can be predicted by filter--rectify--filter channels optimised for the detection of each cue, adding weight to the argument that texture cues are processed in a single generalised mechanism that nonetheless achieves cue independence or near-independence in many circumstances. We also found that the amount of suprathreshold masking produced by an orientation cue depends on the overall percept formed by that cue.


Single-mode optical waveguides fabricated from fluorinated polyimides.
Buried channel optical waveguides were fabricated from fluorinated polyimides. They operated in single mode and showed an optical loss of less than 0.3 and 0.7 dB/cm for TE and TM polarizations, respectively, at a wavelength of 1.3 mum. Moreover, these waveguides had high heat and moisture resistance; the optical loss did not significantly change after heating at 380 degrees C for 1 h or after exposure to 85% relative humidity at 85 degrees C for over 200 h.


Interconversion of the salicylic acid signal and its glucoside in tobacco.
Salicylic acid (SA) has been proposed to play a role in the induction of pathogenesis-related (PR) proteins and systemic acquired resistance (SAR) in tobacco. Since SA is rapidly converted to salicylic acid beta-glucoside (SAG) in tobacco, we have attempted to assess the role of SAG in pathogenesis by application of chemically synthesized SAG to tobacco leaves. SAG was as active as SA in induction of PR-1 gene expression. This induction was preceded by a transient release of SA, which occurred in the extracellular spaces. The existence of a mechanism that releases SA from SAG suggests a possible role for SAG in SAR.


A mathematical programming method for formulating a fuzzy regression model based on distance criterion.
Fuzzy regression models are useful to investigate the relationship between explanatory and response variables with fuzzy observations. Different from previous studies, this correspondence proposes a mathematical programming method to construct a fuzzy regression model based on a distance criterion. The objective of the mathematical programming is to minimize the sum of distances between the estimated and observed responses on the X axis, such that the fuzzy regression model constructed has the minimal total estimation error in distance. Only several alpha-cuts of fuzzy observations are needed as inputs to the mathematical programming model; therefore, the applications are not restricted to triangular fuzzy numbers. Three examples, adopted in the previous studies, and a larger example, modified from the crisp case, are used to illustrate the performance of the proposed approach. The results indicate that the proposed model has better performance than those in the previous studies based on either distance criterion or Kim and Bishu's criterion. In addition, the efficiency and effectiveness for solving the larger example by the proposed model are also satisfactory.


Sox3 expression identifies neural progenitors in persistent neonatal and adult mouse forebrain germinative zones.
Neural precursors persist throughout life in the rodent forebrain subventricular zone (SVZ) and hippocampal dentate gyrus. The regulation of persistent neural stem cells is poorly understood, in part because of the lack of neural progenitor markers. The Sox B1 subfamily of HMG-box transcription factors (Sox1-3) is expressed by precursors in the embryonic nervous system, where these factors maintain neural progenitors in an undifferentiated state while suppressing neuronal differentiation. Sox2 expression persists in germinative zones of the adult rodent brain, but Sox3 expression in the postnatal brain remains largely unexplored. Here we examine Sox3 expression in the neonatal and adult mouse brain to gain insight into its potential involvement in regulating persistent neural stem cells and neurogenesis. We also investigate Sox3 expression during expansion and neural differentiation of postnatal mouse SVZ neural stem cell and human embryonic stem cell (hESC) cultures. We find that Sox3 is expressed transiently by proliferating and differentiating neural progenitors in the SVZ-olfactory bulb pathway and dentate gyrus. Sox3 immunoreactivity also persists in specific postmitotic neuronal populations. In vitro, high Sox3 protein expression levels in undifferentiated, SVZ-derived neurospheres decline markedly with differentiation. Sox3 immunoreactivity in hESCs appears upon differentiation to neural progenitors and then decreases as cells differentiate further into neurons. These findings suggest that Sox3 labels specific stages of hESC-derived and murine neonatal and adult neural progenitors and are consistent with a role for Sox3 in neural stem cell maintenance. Persistent Sox3 expression in some mature neuronal populations suggests additional undefined roles for Sox3 in neuronal function.


Medicare Payment Policy Creates Incentives For Long-Term Care Hospitals To Time Discharges For Maximum Reimbursement.
Long-term care hospitals are postacute care facilities for patients requiring extended hospital-level care. These facilities are reimbursed by Medicare under a prospective payment system with a short-stay outlier policy, which results in substantially lower payments for patients discharged before a diagnosis-related group-specific short-stay threshold. Using Medicare data, we examined the impact of the short-stay policy on lengths-of-stay and Medicare reimbursement among patients in long-term care hospitals who require prolonged mechanical ventilation. After accounting for case-mix and facility-level differences, we found that discharges for reasons other than death in the period 2005-10 were most likely to occur on the day of or immediately after the short-stay threshold; this held true regardless of facility ownership. In contrast, live discharges in 2002—the year before the prospective payment system started phasing out cost-based payment—were evenly distributed around the day that later became the short-stay threshold. Our findings confirm that the short-stay outlier payment policy created a strong financial incentive for long-term care hospitals to time patient discharges to maximize Medicare reimbursement. The results suggest that the new very-short-stay policy implemented in December 2012 could have a similar effect.


Global children's surgery: Economic and policy priorities.
An estimated two-thirds of the world's children and adolescents, most of whom live in low- and middle- income countries lack access to safe, quality, and timely surgical care. While much efforts have been made in the last decade to advocate for children' surgery, several economic and policy gaps remain, hampering progress and investments. These gaps range from lack of adequate data on costs and cost-effectiveness, high rate of out-of-pocket payments and limited health insurance coverage, to non-inclusion of children's surgical care in public child health policies and surgical plans. Given the magnitude of the limitations, actions and initiatives need to be prioritised to facilitate coordinated investments. Urgent investments are required to generate reliable and convincing data on costs of children's surgical care, as well as costs of equipment and supplies. To support actions and initiatives, children's surgery should be included in any existing and planned child public health initiatives and surgical plans. Integration of injury prevention and early identification of surgical conditions into school health initiatives would also strengthen care. The overall return on investment in children's surgical care are enormous with implications for child survival, family, and society stability as well as country workforce and economy. Investments should be well coordinated at country, regional and global levels to avoid waste of resources and duplication of efforts, while encouraging convergence of efforts.


Virulence Genes of S. aureus from Dairy Cow Mastitis and Contagiousness Risk.
Staphylococcus aureus (S. aureus) is a major agent of dairy cow intramammary infections: the different prevalences of mastitis reported might be related to a combination of S. aureus virulence factors beyond host factors. The present study considered 169 isolates from different Italian dairy herds that were classified into four groups based on the prevalence of S. aureus infection at the first testing: low prevalence (LP), medium-low (MLP), medium-high (MHP) and high (HP). We aimed to correlate the presence of virulence genes with the prevalence of intramammary infections in order to develop new strategies for the control of S. aureus mastitis. Microarray data were statistically evaluated using binary logistic regression and correspondence analysis to screen the risk factors and the relationship between prevalence group and gene. The analysis showed: (1) 24 genes at significant risk of being detected in all the herds with infection prevalence >5%, including genes belonging to microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), immune evasion and serine proteases; and (2) a significant correlation coefficient between the genes interacting with the host immune response and HP isolates against LP ones. These results support the hypothesis that virulence factors, in addition to cow management, could be related to strain contagiousness, offering new insights into vaccine development.


Individual and combined effects of two types of phenological shifts on predator-prey interactions.
Timing of phenological events varies among years with natural variation in environmental conditions and is also shifting in response to climate change. These phenological shifts likely have many effects on species interactions. Most research on the ecological consequences of phenological shifts has focused on variation in simple metrics such as phenological firsts. However, for a population, a phenological event exhibits a temporal distribution with many attributes that can vary (e.g., mean, variance, skewness), each of which likely has distinct effects on interactions. In this study, we manipulated two attributes of the phenological distribution of a prey species to determine their individual and combined effects on predator-prey interactions. Specifically, we studied how shifts in the mean and variation around the mean (i.e., synchrony) of hatching by tadpoles (Hyla cinerea) affected interactions with predatory dragonfly naiads (Tramea carolina). At the end of larval development, we quantified survival and growth of predator and prey. We found that both types of shifts altered demographic rates of the prey; that the effects of synchrony shifts, though rarely studied, were at least as strong as those due to mean shifts; and that the combined effects of shifts in synchrony and mean were additive rather than synergistic. By dissecting the roles of two types of shifts, this study represents a significant step toward a comprehensive understanding of the complex effects of phenological shifts on species interactions. Embracing this complexity is critical for predicting how climate change will alter community dynamics.


Continuous professional development for GPs: experience from Denmark.
Continuous professional development (CPD) for Danish general practitioners (GPs) is voluntary and based on funded accredited activities. There is an ongoing discussion on how to improve this current system by introducing mandatory elements. To inform this debate, we set out to identify GPs' current use of CPD and to explore the motives behind their choices. A mixed-methods study with a combined qualitative and quantitative approach was used. In 2012, two focus group interviews were conducted, followed up the same year by an online questionnaire sent to 1079 randomly chosen Danish GPs. Focus groups: CPD activities are chosen based on personal needs analysis, and in order to be professionally updated, to meet engaged colleagues and to prevent burnout. GPs also attend CPD to assess their own pre-existing level of competence. CPD activities need to be experienced as being both meaningful and relevant in order to have an impact. Questionnaire: The response rate was 686/1079 (63%). GPs spend on average 10.5 days per year on accredited, voluntary CPD activities. Workplace-related CPD activities and practice-based small group learning played a significant role. The main motivation for choice of CPD activities included academic interest, experience of patient-related problems in their own surgeries and medical topics where the GPs felt insufficiently confident. Danish GPs are frequent users of voluntary accredited CPD. Their CPD choices are motivated by topics strengthening their professional capacity and preventing burnout. There would seem to be no need for a mandatory system.


Childhood exposure to fine particulate matter and black carbon and the development of new wheeze between ages 5 and 7 in an urban prospective cohort.
While exposures to urban fine particulate matter (PM(2.5)) and soot-black carbon (soot-BC) have been associated with asthma exacerbations, there is limited evidence on whether these pollutants are associated with the new development of asthma or allergy among young inner city children. We hypothesized that childhood exposure to PM(2.5) and the soot-BC component would be associated with the report of new wheeze and development of seroatopy in an inner city birth cohort. As part of the research being conducted by the Columbia Center of Children's Environmental Health (CCCEH) birth cohort study in New York City, two-week integrated residential monitoring of PM(2.5), soot-BC (based on a multi-wavelength integrating sphere method), and modified absorption coefficient (Abs*; based on the smoke stain reflectometer) was conducted between October 2005 and May 2011 for 408 children at ages 5-6 years old. Residential monitoring was repeated 6 months later (n=262) to capture seasonal variability. New wheeze was identified through the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires during up to 3 years of follow-up and compared to a reference group that reported never wheeze, remitted wheeze, or persistent wheeze. Specific immunoglobulin (Ig) E against cockroach, mouse, cat, and dust mite and total IgE levels was measured in sera at ages 5 and 7 years. PM(2.5), soot-BC, and Abs* measured at the first visit were correlated moderately with those at the second visit (Pearson r>0.44). Using logistic regression models, a positive association between PM(2.5) and new wheeze was found with adjusted odds ratio [95% confidence intervals] of 1.51 [1.05-2.16] per interquartile range (IQR). Positive but non-significant association was found between the development of new wheeze and soot-BC and (OR 1.40 [0.96-2.05]), and Abs* (OR 1.57 [0.91-2.68]); Significantly positive associations were found between air pollutant measurements and new wheeze when restricting to those participants with repeat home indoor measurements 6 months apart. Associations between pollutants and IgE levels were not detected. Our findings suggest that childhood exposure to indoor air pollution, much of which penetrated readily from outdoor sources, may contribute to the development of wheeze symptoms among children ages 5 to 7 years.


Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: a review of the National Cancer Database.
For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival.


Three images of interdisciplinary team meetings.
Teams are an essential aspect of health care today, especially in rehabilitation or chronic illness where the course of care is frequently long, complex, and unpredictable. The coordinative function of teams and their interdisciplinary aspects are thought to improve patient care because team members bring their unique professional skills together to address patient problems. This coordination is enacted through the team meeting, which typically results in an integrated care plan. This professional image of team meetings is explicit and addresses the description and provision of care as objective and rational activities. In contrast, the constructed and ritualistic images of health care team meetings are implicit and concern the less objective and rational aspects of planning care. The constructed image pertains to the definitional activity of team members as they try to understand patient troubles and achieve consensus. This process involves the individual clinical reasoning of team members and the collective reasoning of the group. The ritualistic image is that aspect of team meetings in which the team affirms and reaffirms its collective identity. Drawing from field research of geropsychiatric team meetings, this article defines and explicates these images, focusing on the constructed and ritualistic aspects of team meetings and the influence of these images on group function.


Actual and undiagnosed HIV prevalence in a community sample of men who have sex with men in Auckland, New Zealand.
The prevalence of HIV infection and how this varies between subgroups is a fundamental indicator of epidemic control. While there has been a rise in the number of HIV diagnoses among men who have sex with men (MSM) in New Zealand over the last decade, the actual prevalence of HIV and the proportion undiagnosed is not known. We measured these outcomes in a community sample of MSM in Auckland, New Zealand. The study was embedded in an established behavioural surveillance programme. MSM attending a gay community fair day, gay bars and sex-on-site venues during 1 week in February 2011 who agreed to complete a questionnaire were invited to provide an anonymous oral fluid specimen for analysis of HIV antibodies. From the 1304 eligible respondents (acceptance rate 48.5%), 1049 provided a matched specimen (provision rate 80.4%). HIV prevalence was 6.5% (95% CI: 5.1-8.1). After adjusting for age, ethnicity and recruitment site, HIV positivity was significantly elevated among respondents who were aged 30-44 or 45 and over, were resident outside New Zealand, had 6-20 or more than 20 recent sexual partners, had engaged in unprotected anal intercourse with a casual partner, had had sex with a man met online, or had injected drugs in the 6 months prior to survey. One fifth (20.9%) of HIV infected men were undiagnosed; 1.3% of the total sample. Although HIV prevalence did not differ by ethnicity, HIV infected non-European respondents were more likely to be undiagnosed. Most of the small number of undiagnosed respondents had tested for HIV previously, and the majority believed themselves to be either "definitely" or "probably" uninfected. There was evidence of continuing risk practices among some of those with known HIV infection. This is the first estimate of actual and undiagnosed HIV infection among a community sample of gay men in New Zealand. While relatively low compared to other countries with mature epidemics, HIV prevalence was elevated in subgroups of MSM based on behaviour, and diagnosis rates varied by ethnicity. Prevention should focus on raising condom use and earlier diagnosis among those most at risk, and encouraging safe behaviour after diagnosis.


Purification of the Staphylococcus aureus bacteriophages VDX-10 on methacrylate monoliths.
Bacteriophages (phages) are known to be useful in many fields from medicine to agriculture, and for a broad range of applications, including phage therapy and phage display. For some applications, especially in medicine, high purity and viability of phages are required. Methacrylate monoliths (Convective Interaction Media [CIM] monolithic columns), designed for purification of bionanoparticles, were applied for the purification of Staphylococcus aureus phages VDX-10 from bacterial lysate. With a single step purification method, more than 99% of host cell DNA and more than 90% of proteins were removed, with 60% recovery of viable phages. Comparable results were obtained when the purification method was scaled-up from a CIM monolithic disk to a larger CIM monolithic column. Additionally, the dynamic binding capacity of a methacrylate monolith column for S. aureus phages VDX-10 was determined.


Continuous monitoring of intracranial pressure with a miniaturized fiberoptic device.
A No. 4 French fiberoptic catheter initially developed as an intravascular pressure sensor was incorporated into a system to be used as an intracranial pressure (ICP) monitor. Initially, a series of acute and chronic animal experiments carried out in the rabbit and pig, respectively, demonstrated the reliability and safety of the device. Subsequently, this new monitor was compared to a concurrently functioning ICP monitor in 15 adult and five pediatric patients. This clinical experience also confirmed the safety, accuracy, and reliability of the device. Since these initial studies, this monitor has been used to routinely measure ICP in a large number of adult and pediatric patients. The monitor has functioned well, and there have been no complications related to its use except for an occasional problem with breakage of the optic fiber as a result of patient movement or nursing maneuvers, which has been easily corrected by replacement of the probe. As nursing personnel and ancillary services have become familiar with this new monitor, breakage has not been a problem. This new device can be placed into the ventricular system, the brain parenchyma, or the subdural space, and appears to offer substantial advantages over other monitors presently in use.


Monte Carlo-based inverse model for calculating tissue optical properties. Part II: Application to breast cancer diagnosis.
The Monte Carlo-based inverse model of diffuse reflectance described in part I of this pair of companion papers was applied to the diffuse reflectance spectra of a set of 17 malignant and 24 normal-benign ex vivo human breast tissue samples. This model allows extraction of physically meaningful tissue parameters, which include the concentration of absorbers and the size and density of scatterers present in tissue. It was assumed that intrinsic absorption could be attributed to oxygenated and deoxygenated hemoglobin and beta-carotene, that scattering could be modeled by spheres of a uniform size distribution, and that the refractive indices of the spheres and the surrounding medium are known. The tissue diffuse reflectance spectra were evaluated over a wavelength range of 400-600 nm. The extracted parameters that showed the statistically most significant differences between malignant and nonmalignant breast tissues were hemoglobin saturation and the mean reduced scattering coefficient. Malignant tissues showed decreased hemoglobin saturation and an increased mean reduced scattering coefficient compared with nonmalignant tissues. A support vector machine classification algorithm was then used to classify a sample as malignant or nonmalignant based on these two extracted parameters and produced a cross-validated sensitivity and specificity of 82% and 92%, respectively.


Comparing the Outcomes of Adults With Enterobacteriaceae Bacteremia Receiving Short-Course Versus Prolonged-Course Antibiotic Therapy in a Multicenter, Propensity Score-Matched Cohort.
The recommended duration of antibiotic treatment for Enterobacteriaceae bloodstream infections is 7-14 days. We compared the outcomes of patients receiving short-course (6-10 days) vs prolonged-course (11-16 days) antibiotic therapy for Enterobacteriaceae bacteremia. A retrospective cohort study was conducted at 3 medical centers and included patients with monomicrobial Enterobacteriaceae bacteremia treated with in vitro active therapy in the range of 6-16 days between 2008 and 2014. 1:1 nearest neighbor propensity score matching without replacement was performed prior to regression analysis to estimate the risk of all-cause mortality within 30 days after the end of antibiotic treatment comparing patients in the 2 treatment groups. Secondary outcomes included recurrent bloodstream infections, Clostridium difficile infections (CDI), and the emergence of multidrug-resistant gram-negative (MDRGN) bacteria, all within 30 days after the end of antibiotic therapy. There were 385 well-balanced matched pairs. The median duration of therapy in the short-course group and prolonged-course group was 8 days (interquartile range [IQR], 7-9 days) and 15 days (IQR, 13-15 days), respectively. No difference in mortality between the treatment groups was observed (adjusted hazard ratio [aHR], 1.00; 95% confidence interval [CI], .62-1.63). The odds of recurrent bloodstream infections and CDI were also similar. There was a trend toward a protective effect of short-course antibiotic therapy on the emergence of MDRGN bacteria (odds ratio, 0.59; 95% CI, .32-1.09; P = .09). Short courses of antibiotic therapy yield similar clinical outcomes as prolonged courses of antibiotic therapy for Enterobacteriaceae bacteremia, and may protect against subsequent MDRGN bacteria.


Asymptomatic Clostridium perfringens Inhabitation in Intestine Can Cause Inflammation, Apoptosis, and Disorders in Brain.
Clostridium perfringens (CP) is a foodborne pathogen. The bacterium can also inhabit human gut without symptoms of foodborne illness. However, the clinical symptoms of long-term inhabitation have not been known yet. Therefore, the objective of this study was to elucidate the relationship between intestinal CP and other internal organs. Phosphate-buffered saline (PBS) and CP were orally injected into 5-week-old (YOUNG) and 12-month-old C57BL6/J (ADULT) mice. Gene expression levels related to inflammation (tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, and IL-6) and oxidative stress (superoxide dismutase [SOD]1, SOD2, SOD3, glutathione reductase [GSR], glutathione peroxidase [GPx]3, and catalase [CAT]) responses were evaluated in the brain, small intestine, and liver. In addition, apoptosis-related (BCL2-associated X [BAX]1 and high-mobility group box-1 [HMGB1]) and brain disorder-related genes (CCAAT-enhancer-binding protein [C/EBP]-β, C/EBPδ, C/EBP homologous protein [CHOP], and amyloid precursor protein [APP]) as brain damage markers were examined. The protein expressions in the brain were also measured. Gene expression levels of inflammation and oxidative stress responses were higher (p < 0.05) in brains of CP-YOUNG and CP-ADULT mice, compared with PBS-YOUNG and PBS-ADULT, and the gene expression levels were higher (p < 0.05) in brains of CP-ADULT mice than CP-YOUNG mice. Apoptosis-related (BAX1 and HMGB1) and brain disorder-related genes (C/EBPβ, C/EBPδ, CHOP, and APP) were higher (p < 0.05) in brains of CP-challenged mice, compared with PBS-challenged mice. Even oxidative stress response (GPx and SOD2), cell damage-related (HMGB1), and β-amyloid proteins were higher (p < 0.05) in brains of CP- than in PBS-challenged mice. C/EBP protein was higher (p < 0.05) in CP-YOUNG, compared with PBS-YOUNG mice. However, these clinical symptoms were not observed in small intestine and liver. These results indicate that although asymptomatic intestinal CP do not cause foodborne illness, their inhabitation may cause brain inflammation, oxidative stress, apoptosis, and cell damage, which may induce disorders, especially for the aged group.


[Identification of the public health nurse within the public health work force in the Regional Health Department-6 of Ribeirão Preto, SP, (Brazil)].
The general purpose of this study was the identification of the nurse within the public health work force in the Regional Health Department of Ribeirão Preto of the State Health Secretariat of S. Paulo. A questionnaire the options of which included: identification, level of training, progress in career, function, future professional expectations and membership of professional associations, was the chief data source. Of the group studies 35 were female, 40% of whom were between 20 and 39 years old, 51.5% were married and 77.2% had been in service for from zero to fifteen years. Regarding the other categories, distribution was as follows: 1 nurse per 13.5 assistants; 1 nurse per 9.1 doctors. Concerning professional training, 71.5% were qualified in Public Health Nursing and 8.6% specialized in Public Health. No career opportunities were available in the nursing profession and their salaries ranged from two to seven minimum salaries, only one receiving ten. All condemned the system of performance assessment. All nurses performed largely administrative services and the inspectors did so for some 65% of their time. Among nursing assistants this percentage rose to 73.3% for those in charge. The nurses were prepared to participate in primary care programmes and 84.3% intended to continue working until retirement.


Photocatalytic removal of 2-nitrophenol using silver and sulfur co-doped TiO₂under natural solar light.
To overcome the drawback of poor solar light utilization brought about by the narrow photoresponse range of TiO₂, a silver and sulfur co-doped TiO₂was synthesized. Using the prepared catalyst, solar photocatalytic degradation of 2-nitrophenol (2-NP) by a TiO₂-based catalyst was studied for the first time. Effects of the co-doping on the structural, optical and morphological properties of the synthesized nanoparticles were investigated by different characterization methods: X-ray diffraction, N2 adsorption-desorption measurements, scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, UV-visible diffuse reflectance spectroscopy and Fourier transform infrared spectroscopy. Solar experiments showed that the co-doping with silver and sulfur significantly increased the photocatalytic activity. In various initial concentrations of 2-NP more than 99% of the contaminant was decomposed by Ag-S/TiO₂in less than 150 minutes, while the degradation efficiency was much less in the presence of bare TiO₂. Kinetic studies suggested that solar photocatalytic degradation of 2-NP is consistent with the Langmuir-Hinshelwood model. The rate constant of the reaction and adsorption constant of the modified photocatalyst were found to be 2.4 and 4.1 times larger than that of bare TiO₂, respectively.


Prevalence of human papillomavirus genotypes and precancerous cervical lesions in a screening population in the Republic of Korea, 2014-2016.
Knowledge regarding the prevalence and distribution of human papillomavirus (HPV) genotyping in healthy women is important in establishing strategies for cervical cancer screening and HPV vaccination. A total of 18,170 women who visited a Korean Medical Institute for health check-ups were recruited retrospectively; they underwent HPV genotyping and conventional cervical cytology. An HPV DNA test was performed using the Anyplex™ II HPV 28 detection system (Seegene) or HPV Liquid Bead Microarray (Osang Healthcare). The distribution of HPV genotypes was assessed according to cervical cytology and age. HPV was detected in 3,037 (16.71%) of the 18,170 women enrolled, and 2,268 (12.48%) were positive for high-risk (HR) HPV. In total, HPV 53 (9.69% of all detected HPV viruses) was the most common type; HPV 58 (7.90%) and 52 (7.81%) were also common. HPV 54 (6.99%) was common in low-risk subjects. Overall and in the normal cytology group, the most common HPV genotype was HPV 53, whereas HPV 58 was more common in women who had atypical squamous cells of undetermined significance or low-grade squamous intraepithelial neoplasia cervical cytology. In addition, HPV 16 was the most common type in cases with high-grade squamous intraepithelial neoplasia (HSIL)/atypical squamous cells-cannot exclude HSIL. Among women with normal cytology, 76 of 231 (32.9%) women under 24 years of age were positive for HR HPV, whereas 84 of 852 (9.9%) women aged 55-59 years were positive. HPV 53 was the most prevalent genotype in healthy women. Distribution of HPV genotypes varied with cervical cytology and age. Our study provides important baseline data for the recently implemented national HPV vaccination program.


Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases.
This phase II randomized, placebo-controlled study was conducted to evaluate efficacy and safety of radium-223 in patients with castration-resistant prostate cancer (CRPC) and painful bone metastases. Twelve- and 18-month survival results were reported previously. Here we report 24-month overall survival (OS) and safety data from the period 12 to 24 months after the first injection of study medication. Patients with CRPC and bone pain were randomized 1:1 to receive 4 injections of radium-223 (50 kBq/kg [n = 33]) or placebo (n = 31) after external-beam radiotherapy; each injection was given every 4 weeks. Endpoints for this report were 24-month OS, long-term safety, and treatment-related adverse events (AEs) occurring in the 12- to 24-month period. After 24 months, 10 (30%) patients were alive in the radium-223 group compared with 4 patients (13%) in the placebo group. Patients who received at least 1 dose of study medication had a median OS of 65 weeks in the radium-223 group vs. 46 weeks in the placebo group (log-rank P = .056). The hazard ratio (HR) for OS, adjusted for baseline covariates, was 0.476 (95% confidence interval [CI], 0.258-0.877; Cox regression P = .017). The most frequent cause of death for both arms was disease progression. There were no reports of treatment-related AEs or long-term hematologic toxicity during the 12- to 24-month follow-up. Radium-223 had a highly favorable safety profile, with no evidence of second malignancies at 24-month follow-up. The significant improvement in OS observed in patients receiving radium-223 vs. placebo suggests that treatment of bone disease with radium-223 has survival benefits.


Evolving norms at the intersection of health and trade.
There has been growing tension at the intersection of health and economic policy making as global governance has increased across sectors. This tension has been particularly evident between tobacco control and trade policy, as the international norms that frame them -- particularly the Framework Convention on Tobacco Control and the World Trade Organization (WTO) -- have continued to institutionalize. Using five case studies of major tobacco-related trade disputes from the principal multilateral system of trade governance -- the WTO/General Agreement on Tariffs and Trade -- we trace the evolution of these interacting norms over nearly twenty-five years. Our analytic framework focuses on the actors that advance, defend, and challenge these norms. We find that an increasingly broad network, which includes governments, intergovernmental organizations, nongovernmental organizations, and members of the epistemic community, is playing a more active role in seeking to resolve these tensions. Moreover, key economic actors are beginning to incorporate health more actively into their messaging and activities. We also demonstrate that the most recent resonant messages reflect a more nuanced integration of the two norms. The tobacco control example has direct relevance to related policy areas, including environment, safety, access to medicines, diet, and alcohol.


Genome-wide high throughput analysis of DNA methylation in eukaryotes.
Cytosine methylation is the quintessential epigenetic mark. Two well-established methods, bisulfite sequencing and methyl-DNA immunoprecipitation (MeDIP) lend themselves to the genome-wide analysis of DNA methylation by high throughput sequencing. Here we provide an overview and brief review of these methods. We summarize our experience with MeDIP followed by high throughput Illumina/Solexa sequencing, exemplified by the analysis of the methylated fraction of the Neurospora crassa genome ("methylome"). We provide detailed methods for DNA isolation, processing and the generation of in vitro libraries for Illumina/Solexa sequencing. We discuss potential problems in the generation of sequencing libraries. Finally, we provide an overview of software that is appropriate for the analysis of high throughput sequencing data generated by Illumina/Solexa-type sequencing by synthesis, with a special emphasis on approaches and applications that can generate more accurate depictions of sequence reads that fall in repeated regions of a chosen reference genome.


Factors associated with disparities in emergency department use among Latino children with asthma.
Significant disparities in emergency department (ED) rates exist for Latinos; however, few studies have investigated the factors that may account for these disparities. To examine individual/family and health system factors among Latino and non-Latino white (NLW) children with asthma to explain disparities in ED rates. The study was carried out in Puerto Rico (PR) and Rhode Island (RI) with the same design: a cross-sectional, observational approach with repeated measurements of selected variables. The sample was composed of 804 children ages 7 to 15 years, with 405 from PR and 399 from RI. Latino children from both sites had significantly higher rates of ED use as compared with NLWs from RI. Regression analyses showed site, asthma control, parental reported severity of asthma and public insurance to be significantly associated with ED use. Latino ethnicity and public insurance were among the most important factors related to frequent ED use. Revisions of the policies driving public insurance to assure better access to specialists, preventive education, and evidence-based treatment are needed. The results also suggest the need for the development of interventions in the ED that are geared toward educating families on how best to use emergency services.


The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse.
Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.


The oral health of people with intellectual disability participating in the UK Special Olympics.
Research on the dental health of people with intellectual disability has consistently reported more untreated dental disease, more extractions and fewer fillings than in the general population. This paper describes the oral health of participants at the 2005 Glasgow Special Olympics (SO), relating this to the general population studied in the 1998 UK Adult Dental Health Survey (ADHS) and to participants' age and region of residence. Consenting SO participants were offered oral examinations which followed the standardized SO protocol plus an innovative soft tissue examination. Urgency of any treatment required was noted and reported to participants and carers. Three measures of good dental health--having 21 or more natural teeth, absence of fillings and having no obvious untreated decay--were compared across age groups, regions and with the general population. Logistic regression was used to control for age differences between regions. In total, 1021 oral examinations were completed. Older SO participants were more likely to have fewer than 21 teeth and to have fillings, untreated decay, gum inflammation and heavy plaque levels. In all, 28% of SO participants had 21 or more teeth, no fillings and no obvious decay. Those from the north, midlands and south regions of England had significantly more chance of good dental health so defined compared with participants from Scotland [ORs 1.67 (1.09, 2.67), 1.69 (1.12, 2.54), 1.99 (1.26, 3.16), respectively]. Compared with the general population surveyed in the 1998 ADHS study, SO participants were more likely to be free from fillings and obvious untreated decay, but fewer had 21 or more natural teeth among older age groups. Nine per cent were found to have soft tissue problems, and one in four of these required follow-up. Gum inflammation was common. Overall, 5% of participants were judged to require urgent treatment for dental or soft tissue problems and 40% to require non-urgent treatment. This rose to 9% and 66% respectively among those aged 35 years and over. The low prevalence of untreated decay and fillings among SO participants compared with the general population may be due to their being well supported by family and carers. The study identifies the vulnerability of the older participants to dental problems, and this may indicate greater difficulty maintaining surveillance as individuals age or informal carers become less able or available. Regional variations are similar to those found in the general population. The implications for the organization of care for this group are discussed.


Percutaneous transluminal revascularization for renal artery stenosis: Veterans Affairs Puget Sound Health Care System experience.
The safety and efficacy of percutaneous transluminal intervention for renal artery stenosis is improving. This study evaluates the immediate and long-term anatomic and functional outcomes of percutaneous transluminal angioplasty and stenting for atherosclerotic renal artery stenosis in a Veterans Affairs population. We performed a retrospective analysis of records from patients who underwent renal artery angioplasty with or without stenting at the Veterans Affairs Puget Sound Health Care System between January 1990 and June 1999. Indications for intervention included hypertension (78%) and rising serum creatinine (78%). Seventy-six patients (74 men, average age of 67 years, range 42-83 years) underwent 88 attempted interventions. Seventy-two percent of contralateral kidneys had significant disease (47% had a >60% stenosis; 16% were nonfunctioning or absent). Of the 88 planned interventions, 86 were successfully performed with placement of 46 stents (52%). Technical success (defined by <30% residual stenosis) was achieved in 78 vessels (89%). The procedure-related complication rate was 5%. Patient mortality by life table analysis was 49% at 5 years. Assisted primary patency rate at 5 years was 100%. Primary and secondary restenosis rates were 37% +/- 8% and 31% +/- 8% at 5 years, respectively. Sixty-eight percent of patients treated for hypertension demonstrated clinical benefit (improved or cured hypertension). This clinical benefit was maintained in 52% of the patients at 5 years, as measured by life table analysis. Serum creatinine was lowered or maintained in 88% of the patients, but this clinical benefit was only maintained in 25% of patients at 5 years. Transluminal intervention for clinically symptomatic atherosclerotic renal artery stenosis is technically successful and safe. There are excellent assisted-patency and low restenosis rates. There is immediate clinical benefit for most patients, as evidenced by improved control of hypertension and preservation of renal function. However, within 5 years the benefit is not maintained for either hypertension (50%) or renal function (20%). Therefore, although technically successful, functional outcomes after endoluminal intervention are not maintained in the long term.


Graph Theoretical Characteristics of EEG-Based Functional Brain Networks in Patients With Epilepsy: The Effect of Reference Choice and Volume Conduction.
It is well-established that both volume conduction and the choice of recording reference (montage) affect the correlation measures obtained from scalp EEG, both in the time and frequency domains. As a result, a number of correlation measures have been proposed aiming to reduce these effects. In our previous work, we have showed that scalp-EEG based functional brain networks in patients with epilepsy exhibit clear periodic patterns at different time scales and that these patterns are strongly correlated to seizure onset, particularly at shorter time scales (around 3 and 5 h), which has important clinical implications. In the present work, we use the same long-duration clinical scalp EEG data (multiple days) to investigate the extent to which the aforementioned results are affected by the choice of reference choice and correlation measure, by considering several widely used montages as well as correlation metrics that are differentially sensitive to the effects of volume conduction. Specifically, we compare two standard and commonly used linear correlation measures, cross-correlation in the time domain, and coherence in the frequency domain, with measures that account for zero-lag correlations: corrected cross-correlation, imaginary coherence, phase lag index, and weighted phase lag index. We show that the graphs constructed with corrected cross-correlation and WPLI are more stable across different choices of reference. Also, we demonstrate that all the examined correlation measures revealed similar periodic patterns in the obtained graph measures when the bipolar and common reference (Cz) montage were used. This includes circadian-related periodicities (e.g., a clear increase in connectivity during sleep periods as compared to awake periods), as well as periodicities at shorter time scales (around 3 and 5 h). On the other hand, these results were affected to a large degree when the average reference montage was used in combination with standard cross-correlation, coherence, imaginary coherence, and PLI, which is likely due to the low number of electrodes and inadequate electrode coverage of the scalp. Finally, we demonstrate that the correlation between seizure onset and the brain network periodicities is preserved when corrected cross-correlation and WPLI were used for all the examined montages. This suggests that, even in the standard clinical setting of EEG recording in epilepsy where only a limited number of scalp EEG measurements are available, graph-theoretic quantification of periodic patterns using appropriate montage, and correlation measures corrected for volume conduction provides useful insights into seizure onset.


Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo.
Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction. The binding of pVHL to HIFalpha requires that HIFalpha be hydroxylated on one of two prolyl residues. We introduced HIF1alpha and HIF2alpha variants that cannot be hydroxylated on these sites into the ubiquitously expressed ROSA26 locus along with a Lox-stop-Lox cassette that renders their expression Cre-dependent. Expression of the HIF2alpha variant in the skin and liver induced changes that were highly similar to those seen when pVHL is lost in these organs. Dual expression of the HIF1alpha and HIF2alpha variants in liver, however, more closely phenocopied the changes seen after pVHL inactivation than did the HIF2alpha variant alone. Moreover, gene expression profiling confirmed that the genes regulated by HIF1alpha and HIF2alpha in the liver are overlapping but non-identical. Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes.


A longitudinal analysis of the public perception of the opportunities and challenges of the Internet of Things.
The Internet of Things (or IoT), which enables the networked interconnection of everyday objects, is becoming increasingly popular in many aspects of our lives ranging from entertainment to health care. While the IoT brings a set of invaluable advantages and opportunities with it, there is also evidence of numerous challenges that are yet to be resolved. This is certainly the case with regard to ensuring the cyber security of the IoT, and there are various examples of devices being hacked. Despite this evidence, little is known about the public perceptions of the opportunities and challenges presented by the IoT. To advance research in this direction, we mined the social media platform Twitter to learn about public opinion about the IoT. Analysing a longitudinal dataset of more than 6.7 million tweets, we reveal insights into public perceptions of the IoT, identifying big data analytics as the most positive aspect, whereas security issues are the main public concern on the negative side. Our study serves to highlight the importance of keeping IoT devices secure, and remind manufacturers that it is a concern that remains unresolved, at least insofar as the public believes.


Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning.
In addition to gene expression differences in distinct cell types, there is substantial post-transcriptional regulation driven in part by RNA binding proteins (RBPs). Loss-of-function RBP mutations have been associated with neurodevelopmental disorders, such as Fragile-X syndrome and syndromic autism. Work performed in animal models to elucidate the influence of neurodevelopmental disorder-associated RBPs on distinct behaviors has showed a connection between normal post-transcriptional regulation and conditioned learning. We previously reported cognitive inflexibility in a mouse model null for the RBP CUG-BP, Elav-like factor 6 (CELF6), which we also found to be associated with human autism. Specifically, these mice failed to potentiate exploratory hole-poking behavior in response to familiarization to a rewarding stimuli. Characterization of Celf6 gene expression showed high levels in monoaminergic populations such as the dopaminergic midbrain populations. To better understand the underlying behavioral disruption mediating the resistance to change exploratory behavior in the holeboard task, we tested three hypotheses: Does Celf6 loss lead to global restricted patterns of behavior, failure of immediate response to reward or failure to alter behavior in response to reward (conditioning). We found the acute response to reward was intact, yet Celf6 mutant mice exhibited impaired conditioned learning to both reward and aversive stimuli. Thus, we found that the resistance to change by the Celf6 mutant in the holeboard was most parsimoniously explained as a failure of conditioning, as the mice had blunted responses even to potent rewarding stimuli such as cocaine. These findings further support the role of RBPs in conditioned learning.


Effect of short-term hyperglycemia on protein kinase C alpha activation in human erythrocytes.
Diabetes mellitus, characterized by chronic hyperglycemia, is known to have a deleterious effect on erythrocyte structure and hemodynamic characteristics, which eventually contribute to diabetes-associated vascular complications. Protein kinase C alpha (PKCα) is a major regulator of many metabolic processes and structural changes in erythrocytes, and may play a significant role in the development of hyperglycemia-mediated cellular abnormalities. We hypothesized that acute hyperglycemic stress may affect erythrocyte structure and metabolic properties through its effect on PKCα membrane content and activity. Erythrocytes, from healthy individuals acutely exposed to a glucose enriched media, showed a significant decrease in the membranous fraction of PKCα and its phosphorylation (p = 0.005 and p = 0.0004, respectively). These alterations correlated with decreased affinity of PKCα to its membrane substrates (4.1R and GLUT1) and reduced RBC deformability (p = 0.017). Pre-activation of erythrocytes with PKC activator, PMA, minimized the effect of glucose on the membrane PKCα fraction and RBC deformability (p > 0.05). Acute glycemia-induced inhibition of PKCα membranous translocation and activation is associated with reduced erythrocyte membrane deformability.


Health resource utilization of labor induction versus expectant management.
Although induction of labor of low-risk nulliparous women at 39 weeks reduces the risk of cesarean delivery compared with expectant management, concern regarding more frequent use of labor induction remains, given that this intervention historically has been thought to incur greater resource utilization. The objective of the study was to determine whether planned elective labor induction at 39 weeks among low-risk nulliparous women, compared with expectant management, was associated with differences in health care resource utilization from the time of randomization through 8 weeks postpartum. This is a planned secondary analysis of a multicenter randomized trial in which low-risk nulliparous women were assigned to induction of labor at 39 weeks or expectant management. We assessed resource utilization after randomization in 3 time periods: antepartum, delivery admission, and discharge through 8 weeks postpartum. Of 6096 women with data available, those in the induction of labor group (n = 3059) were significantly less likely in the antepartum period after randomization to have at least 1 ambulatory visit for routine prenatal care (32.4% vs 68.4%), unanticipated care (0.5% vs 2.6%), or urgent care (16.2% vs 44.3%), or at least 1 antepartum hospitalization (0.8% vs 2.2%, P < .001 for all). They also had fewer tests (eg, sonograms, blood tests) and treatments (eg, antibiotics, intravenous hydration) prior to delivery. During the delivery admission, women in the induction of labor group spent a longer time in labor and delivery (median, 0.83 vs 0.57 days), but both women (P = .002) and their neonates (P < .001) had shorter postpartum stays. Women and neonates in both groups had similar frequencies of postpartum urgent care and hospital readmissions (P > .05 for all). Women randomized to induction of labor had longer durations in labor and delivery but significantly fewer antepartum visits, tests, and treatments and shorter maternal and neonatal hospital durations after delivery. These results demonstrate that the health outcome advantages associated with induction of labor are gained without incurring uniformly greater health care resource use.


Is the lung a 'target organ' in diabetes mellitus?
Histopathologic evidence of lung involvement in subjects with diabetes mellitus has included thickened alveolar epithelial and pulmonary capillary basal laminae, the latter being suggestive of existing pulmonary microangiopathy. Abnormal pulmonary function has been detected in some diabetic patients; the most consistent abnormalities are reduced lung volumes in young (aged less than 25 years) insulin-dependent diabetic subjects, reduced pulmonary elastic recoil in both young and adult (aged greater than 25 years) diabetic subjects, and impaired diffusion due to a reduced pulmonary capillary blood volume in the adult group. Nonenzymatic glycosylation-induced alteration of lung connective tissue is the most likely pathogenetic mechanism underlying mechanical pulmonary dysfunction in diabetic subjects, while the most tenable explanation for impaired pulmonary microangiopathy. these patients is the presence of underlying pulmonary microangiopathy. The finding of abnormal lung function in some diabetic subjects suggests that the lung should be considered a "target organ" in diabetes mellitus; however, the clinical implications of these findings in terms of respiratory disease are at present unknown.


AI in Medical Imaging Informatics: Current Challenges and Future Directions.
This paper reviews state-of-the-art research solutions across the spectrum of medical imaging informatics, discusses clinical translation, and provides future directions for advancing clinical practice. More specifically, it summarizes advances in medical imaging acquisition technologies for different modalities, highlighting the necessity for efficient medical data management strategies in the context of AI in big healthcare data analytics. It then provides a synopsis of contemporary and emerging algorithmic methods for disease classification and organ/ tissue segmentation, focusing on AI and deep learning architectures that have already become the de facto approach. The clinical benefits of in-silico modelling advances linked with evolving 3D reconstruction and visualization applications are further documented. Concluding, integrative analytics approaches driven by associate research branches highlighted in this study promise to revolutionize imaging informatics as known today across the healthcare continuum for both radiology and digital pathology applications. The latter, is projected to enable informed, more accurate diagnosis, timely prognosis, and effective treatment planning, underpinning precision medicine.


Primary cutaneous aspergillosis caused by Aspergillus ustus following reduced-intensity stem cell transplantation.
A 19-year-old woman with myelodysplastic syndrome underwent reduced-intensity stem cell transplantation [RIST: (cladribine 0.11 mg/kg for 6 days, busulfan 4 mg/kg for 2 days, and rabbit antithymocyte globulin)] from her one HLA-mismatched mother. Prophylaxis against graft-versus-host disease (GVHD) was performed with cyclosporine A (CSA) alone. Severe acute GVHD in the skin, gut, and liver developed concurrently with stable engraftment, and methylprednisolone was administered (1-2 mg/kg per day, then pulse therapy with 1 g/day for 3 days) until day 40 of transplant, when a necrotic lesion of 10 mm in diameter appeared on the right cheek. The initial skin biopsy of the affected area showed a nonspecific inflammatory change. Routine X-ray and computed tomography examinations of the sinuses, chest, and abdomen disclosed no particular abnormalities. Despite intensive antibiotic therapy, the lesion rapidly extended to form an ulcer. A second biopsy specimen obtained from the lesion showed massive septa hyphae, suggesting mold infection. Although we immediately started amphotericin B, she died of multiorgan failure on day 68. Postmortem DNA sequence analysis of the specimen using the polymerase chain reaction identified Aspergillus ustus. Although this is an extremely rare complication after transplantation, this case highlights that we should pay more attention to primary cutaneous aspergillosis in severely immunosuppressed patients.


The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth.
Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth, we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metalloprotease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.


Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii.
Geldanamycin (GA), a benzoquinone ansamycin antibiotic has been shown in vitro to possess anti-plasmodial activity. Pharmacological activity of this drug is attributed to its ability to inhibit PfHSP90. The parasite growth arrest has been shown to be due to drug-induced blockage of the transition from ring to trophozoite stage. To further evaluate the consequences of this pharmacodynamic feature, the anti-malarial activity of GA analogs with enhanced drug properties in a Plasmodium-infected animal model have been evaluated for their capacity to induce clearance of the parasite. In the process, a hypothesis was subsequently tested regarding the susceptibility of the cured animals to malaria reflected in an attenuated parasite load that may be evoked by a protective immune response in the host. Six weeks old Swiss mice were infected with a lethal Plasmodium yoelii (17XL) strain. On appearance of clinical symptoms of malaria, these animals were treated with two different GA derivatives and the parasite load was monitored over 15-16 days. Drug-treated animals cured of the parasite were then re-challenged with a lethal dose of P. yoelii 17XL. Serum samples from GA cured mice that were re-challenged with P. yoelii 17XL were examined for the presence of antibodies against the parasite proteins using western blot analysis. Treatment of P. yoelii 17XL infected mice with GA derivatives showed slow recovery from clinical symptoms of the disease. Blood smears from drug treated mice indicated a dominance of ring stage parasites when compared to controls. Although, P. yoelii preferentially invades normocytes (mature rbcs), in drug-treated animals there was an increased invasion of reticulocytes. Cured animals exhibited robust protection against subsequent infection and serum samples from these animals showed antibodies against a vast majority of parasite proteins. Treatment with GA derivatives blocked the transition from ring to trophozoite stage presumably by the inhibition of HSP90 associated functions. Persistence of parasite in ring stage leads to robust humoral immune response as well as a shift in invasion specificity from normocytes to reticulocyte. It is likely that the treatment with the water-soluble GA derivative creates an attenuated state (less virulent with altered invasion specificity) that persists in the host system, allowing it to mount a robust immune response.


Photoinduced anisotropy in a family of amorphous azobenzene polyesters for optical storage.
We investigate parameters associated with optical data storage in a variety of amorphous side-chain azobenzene-containing polyesters denoted as E1aX. The polyesters possess a common cyano-substituted azobenzene chromophore as a side chain, but differ in their main-chain polyester composition. Seventeen different polymers from the E1aX family divided into four classes, depending on the type of the main-chain substituent (one-, two-, and three-ring aromatic or alicyclic) have been thoroughly investigated. Various parameters characterizing the photoinduced birefringence in these materials, such as the response time, thermal and light stability, and long-term stability under ambient light at room temperature have been measured. Each of these parameters is quantitatively represented and therefore it is possible to make a clear comparison between the properties of the polymers. The results indicate that the long-term stability at ambient temperature is closely related to the thermal stability of the photoinduced birefringence. A strong correlation has also been found between the response time and the stability of the induced anisotropy toward illumination with unpolarized white light. One of the classes of E1aX polymers characterized by two-ring aromatic substituent in the main chain is a good candidate for optical data storage media. A recording energy of approximately 2 J/cm2 is sufficient to induce high refractive-index modulations of deltan = 0.13 in these materials, which is retained even at elevated temperatures (>130 degrees C). Long-term stability of greater than one year for the induced anisotropy has also been achieved.


[SAMHD1 acts at stalled replication forks to prevent interferon induction].
DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.


Fluoride Varnishes against Dental Erosion Caused by Soft Drink Combined with Pediatric Liquid Medicine.
The present study evaluated the effect of NaF and CPP-ACP/NaF varnishes to reduce erosion produced by soft drink (SD) combined or not with pediatric liquid medicine. Enamel specimens were pre-treated with fluoride varnish, according to the following groups: NaF varnish (Duraphat®) or CPP-ACP/NaF varnish (MI varnishTM). Two types of erosive cycles were made: by soft drink erosion (SDE) or by pediatric liquid medicine plus soft drink erosion (PLM/SDE). Bovine enamel specimens were randomly assigned in six groups (n=10): G1=NaF + SDE; G2=CPP-ACP/NaF + SDE; G3=Distilled and deionized (DD) water + SDE; G4=NaF + PLM/SDE; G5=CPP-ACP/NaF + PLM/SDE and G6=DD water + PLM/SDE. Before treatments, the sample surface was divided in two areas (unexposed area-UA and exposed area-EA). The specimens were evaluated by 3D non-contact profilometry technique to determinate tooth structure loss (TSL) and surface roughness (Sa). Scanning electron microscopy (SEM) analysis was also performed. After SDE, G2 presented the lowest TSL values compared to G3 (p=0.008). G1 and G2 did not differ between them (p=0.203) and no groups differed among them despite Sa. Regarding TSL and Sa, G4 and G5 differed from G6 (p=0.0001), but not between them (p=1.00). Examining 3D and SEM images, the greatest differences between UA and EA were observed for G3 and G6. CPP-ACP/NaF varnish seems to be a promising treatment to reduce enamel loss from the erosion produced by a soft drink. Both varnishes also showed capacity to reduce TSL and Sa after erosion by soft drink combined to pediatric liquid medicine.


Evaluation of the quality of Permalloy gratings by diffracted magneto-optical spectroscopy.
Magneto-optical Kerr effect (MOKE) spectroscopy in the -1st diffraction order with p-polarized incidence is applied to study arrays of submicron Permalloy wires at polar magnetization. A theoretical approach combining two methods, the local modes method neglecting the edge effects of wires and the rigorous coupled wave analysis, is derived to evaluate the diffraction losses due to irregularities of the wire edges. A new parameter describing the quality of the edges is defined according to their contribution in the diffracted MOKE. The quality factor, evaluated for two different samples, is successfully compared with irregularities visible on atomic force microscopy pictures.


Men at risk; a qualitative study on HIV risk, gender identity and violence among men who have sex with men who report high risk behavior in Kampala, Uganda.
In Uganda, men who have sex with men (MSM) are at high risk for HIV. Between May 2008 and February 2009 in Kampala, Uganda, we used respondent driven sampling (RDS) to recruit 295 MSM≥18 years who reported having had sex with another man in the preceding three months. The parent study conducted HIV and STI testing and collected demographic and HIV-related behavioral data through audio computer-assisted self-administered interviews. We conducted a nested qualitative sub-study with 16 men purposively sampled from among the survey participants based on responses to behavioral variables indicating higher risk for HIV infection. Sub-study participants were interviewed face-to-face. Domains of inquiry included sexual orientation, gender identity, condom use, stigma, discrimination, violence and health seeking behavior. Emergent themes included a description of sexual orientation/gender identity categories. All groups of men described conflicting feelings related to their sexual orientation and contextual issues that do not accept same-sex identities or behaviors and non-normative gender presentation. The emerging domains for facilitating condom use included: lack of trust in partner and fear of HIV infection. We discuss themes in the context of social and policy issues surrounding homosexuality and HIV prevention in Uganda that directly affect men's lives, risk and health-promoting behaviors.


Stabilization of epigenetic states of CpG islands by local cooperation.
DNA methylation of CpG sites is an important epigenetic mark in mammals. Active promoters are often associated with unmethylated CpG sites, whereas methylated CpG sites correlate with silenced promoters. Methylation of CpG sites must be generally described as a dynamical process that is mediated by methylation enzymes, such as DNMT1 and DNMT3a/b. However, there are several models of how CpG sites can be protected from methylation and thereby remain unmethylated. In this paper we examine the combination of both: the positive feedbacks of DNA methylation and a short range counterpart which in turn protects-and thereby maintains-the unmethylated state. The emergent dynamics is provided by collaborative, re-enforcing feedbacks in favor of methylated CpG islands and cooperative protection of one CpG site by another in favor of unmethylated CpG sites. Our results suggest that this synthesis of mechanisms provides equally robust maintenance of both the unmethylated and methylated states of CpG islands.


Impact of urbanization on tuberculosis and leprosy prevalence in medieval Denmark.
The consequences of urbanization, such as increased exposure to pathogens, have long been considered detrimental to human health. During the first half of the Danish medieval period, towns were established and throughout the period population increased. The following study analyzes the relationship between urbanization and disease frequency - specifically leprosy and tuberculosis - in four skeletal samples from medieval Denmark using a paleoepidemiological approach. Skeletons from two urban sites (Ole Wormsgade and Ribe Grey Friary) and two rural sites (Øm Kloster and Sejet), all located in the Jutland region of Denmark, were selected for this analysis (n = 204). All skeletons included date to the middle part of the Danish medieval period (AD 1200-1400). Six skeletal leprosy indicators and six skeletal tuberculosis indicators were analyzed, and disease frequencies in the samples were estimated using a probabilistic approach based on lesion sensitivity and specificity. The effect of tuberculosis on survival in urban and rural samples was evaluated using Kaplan-Meier survival analyses. The frequency of leprosy at death varied between four and 19 percent among the four cemeteries with Ole Wormsgade having the highest frequency. The estimated frequency of tuberculosis at death varied between 39 and 69 percent. Here, Sejet cemetery had the highest frequency. There were significant differences in survival for those with and without tuberculosis-related lesions between sites, but there were no significant differences between urban and rural sites. The analyses presented in this paper suggest that disease prevalence in skeletal samples cannot be sufficiently explained by urbanization alone; rather, there are likely other biological and behavioral sources of heterogeneity that are contributing factors to past disease experience.


Evaluation of methods used to estimate inhaled dose of carbon monoxide.
We have compared estimation of alveolar carbon monoxide measured either as end-expired or mixed-expired carbon monoxide tension with two spectrophotometric estimations of venous blood carboxyhaemoglobin (COHb). Estimation of mixed-expired carbon monoxide proved more convenient for patients than the end-expired method, and this estimation of carbon monoxide exposure discriminated between non-smokers and smokers as well as measurements of COHb. The technique is bloodless, economical, and simple to perform. It should prove a valuable method for validating reported smoking habits of people attending smoking advisory centres and for epidemiological surveys of smoking.


Diagnostic and prognostic significance of the CFU-c assay in acute nonlymphoblastic leukemia.
A simplified system for classification of aggregate incidence and growth pattern in the CFU-c (colony-forming units in culture) assay, allowing simple and reproducible interpretation of test results, was developed and applied to 552 bone marrow samples from 202 patients with acute leukemia. Ninety-six consecutive patients with acute nonlymphoblastic leukemia were studied at diagnosis. The microcluster growth pattern ("acute myeloid leukemia-type") found in 57% of the patients was significantly associated with higher remission induction rates on both protocols (p = 0.004). No relationship between growth pattern at diagnosis and remission duration was observed. The acute myeloid leukemia-type growth pattern was found to be more frequent in leukemias exhibiting morphological evidence for partial myeloid or monocytic differentiation. The favorable prognostic significance of Auer rods previously described was recognized in two CFU-c growth pattern categories. Of patients exhibiting an acute myeloid leukemia-growth pattern and Auer rods, 89% obtained complete remissions compared to 38% in the Auer rod-negative group showing other growth pattern variants. The CFU-c assays performed during complete remission on 354 samples of 48 patients with acute nonlymphoblastic leukemia and, as a control, on 85 samples of 43 patients with acute lymphoblastic leukemia revealed marked spontaneous as well as chemotherapy-related fluctuations of aggregate incidence and growth pattern. These and similar observations obtained with other assay systems are probably of major pathophysiological significance but preclude clinical application of the CFU-c assay to the monitoring of remission status in patients with acute nonlymphoblastic leukemia.


Carcinoid Heart Disease: Early Outcomes after Surgical Valve Replacement in Nine Patients.
To describe the early outcomes of carcinoid patients undergoing surgical heart valve replacement. In a retrospective study, records of patients with symptomatic carcinoid heart disease referred for valve surgery between 2012 and 2016 were reviewed. The perioperative and early postoperative outcomes were analyzed. Nine patients, with a mean age of 61 years (range 55-70 years) underwent cardiac surgery for carcinoid syndrome. 3 patients had quadruple valve replacement, 5 had tricuspid and pulmonary valves changed, while one had tricuspid, pulmonary, and aortic valves replaced. Right-sided valves were replaced with biological valves in 8 patients and a mechanical valve in 1 patient. Left-sided valves were replaced with a mechanical valve in 2 patients and with a biological valve in 1 patient. Mean postoperative follow-up was 24 months (range 6-50 months, median 16 months). All patients had a good left ventricle except one, in whom it was mildly impaired. The right ventricle was severely dilated in 4 patients, moderately in 2, and mildly in 3. One patient died of heart failure 10 days postoperatively. Functional improvement was noted in all survivors, and they were in New York Heart Association class I at last follow up. Although carcinoid syndrome is a rare and progressive disease, valve replacement in symptomatic patients is a reasonable option with survival benefit, low early postoperative mortality, without valve-related complications, and with functional improvement. Cardiac assessment is required in all patients with carcinoid disease from the earliest time of medical treatment to improve patients' result.


Mutation of zebrafish Snapc4 is associated with loss of the intrahepatic biliary network.
Biliary epithelial cells line the intrahepatic biliary network, a complex three-dimensional network of conduits. The loss of differentiated biliary epithelial cells is the primary cause of many congenital liver diseases. We identified a zebrafish snapc4 (small nuclear RNA-activating complex polypeptide 4) mutant in which biliary epithelial cells initially differentiate but subsequently disappear. In these snapc4 mutant larvae, biliary epithelial cells undergo apoptosis, leading to degeneration of the intrahepatic biliary network. Consequently, in snapc4 mutant larvae, biliary transport of ingested fluorescent lipids to the gallbladder is blocked. Snapc4 is the largest subunit of a protein complex that regulates small nuclear RNA (snRNA) transcription. The snapc4(s445) mutation causes a truncation of the C-terminus, thereby deleting the domain responsible for a specific interaction with Snapc2, a vertebrate specific subunit of the SNAP complex. This mutation leads to a hypomorphic phenotype, as only a subset of snRNA transcripts are quantitatively altered in snapc4(s445) mutant larvae. snapc2 knockdown also disrupts the intrahepatic biliary network in a similar fashion as in snapc4(s445) mutant larvae. These data indicate that the physical interaction between Snapc2 and Snapc4 is important for the expression of a subset of snRNAs and biliary epithelial cell survival in zebrafish.


Clonally dominant cardiomyocytes direct heart morphogenesis.
As vertebrate embryos develop to adulthood, their organs undergo marked changes in size and tissue architecture. The heart acquires muscle mass and matures structurally to fulfil increasing circulatory needs, a process that is incompletely understood. Here we used multicolour clonal analysis to define the contributions of individual cardiomyocytes as the zebrafish heart undergoes morphogenesis from a primitive embryonic structure into its complex adult form. We find that the single-cardiomyocyte-thick wall of the juvenile ventricle forms by lateral expansion of several dozen cardiomyocytes into muscle patches of variable sizes and shapes. As juvenile zebrafish mature into adults, this structure becomes fully enveloped by a new lineage of cortical muscle. Adult cortical muscle originates from a small number of cardiomyocytes--an average of approximately eight per animal--that display clonal dominance reminiscent of stem cell populations. Cortical cardiomyocytes initially emerge from internal myofibres that in rare events breach the juvenile ventricular wall, and then expand over the surface. Our results illuminate the dynamic proliferative behaviours that generate adult cardiac structure, revealing clonal dominance as a key mechanism that shapes a vertebrate organ.