School absenteeism during menstruation amongst adolescent girls in Delhi, India.
Girls' health and education form the cornerstone of development and the gateway to full participation as women in political, economic, and cultural life of a country. Poor menstrual hygiene management has been shown to result in a sense of shame, anxiety, and embarrassment that contributes to absenteeism and poor performance at school. The objectives of this study were to determine the percentage of girls absent from school during menstruation, to evaluate the various factors associated with school absenteeism during menstruation, and to assess the practices regarding menstrual hygiene. A mixed method research of combined cross-sectional study and qualitative research was conducted in six government schools of Delhi by means of a questionnaire survey and focus group discussions. The sample size was 600 adolescent girls. Out of 600, 245 (40%) girls remained absent from school during their menstruation. School absenteeism was significantly associated with the type of absorbent used, lack of privacy at school, restrictions imposed on girls during menstruation, mother's education, and source of information on menstruation. Nearly 65% reported that it affected their daily activities at school and that they had to miss their class tests and classes as a result of pain, anxiety, shame, anxiety about leakage, and staining of their uniform. Since mothers are the primary source of information, they should be counseled to dispose of their taboos about discussing issues related to menstruation. They should be taught about the ill effects of adhering to taboos related to menstruation. The curriculum on general biology should have more detail on menstruation.


Supramolecular complexation for environmental control.
Supramolecular complexes offer a new and efficient way for the monitoring and removal of many substances emanating from technical processes, fertilization, plant and animal protection, or e.g. chemotherapy. Such pollutants range from toxic or radioactive metal ions and anions to chemical side products, herbicides, pesticides to drugs including steroids, and include degradation products from natural sources. The applications involve usually fast and reversible complex formation, due to prevailing non-covalent interactions. This is of importance for sensing as well as for separation techniques, where the often expensive host compounds can then be reused almost indefinitely. Immobilization of host compounds, e.g. on exchange resins or on membranes, and their implementation in smart new materials hold particular promise. The review illustrates how the design of suitable host compounds in combination with modern sensing and separation methods can contribute to solve some of the biggest problems facing chemistry, which arise from the everyday increasing pollution of the environment.


Seeds of Peganum Harmala L. chemical analysis, antimalarial and antioxidant activities, and cytotoxicity against human breast cancer cells.
The present study evaluated the levels of total phenolics, flavonoids, tannins and anthocyanins from Peganum harmala L. seeds and determined their antioxidant, antiplasmodial and anticancer potentials. Antioxidant activity was determined by DPPH and ABTS assays. Extracts of P. harmala seeds from Oudref and Djerba (two places in Tunisia) were obtained by successive extraction solvents: petroleum ether, chloroform, ethyl acetate, ethanol and water. Their composition was evaluated for phenolics (gallic acid equivalent 2.48 to 72.52 g/kg), tannins (catechin equivalent 0 to 25.27 g/kg), anthocyanins (cyanidin equivalent 0 to 20.56 mg/kg) and flavonoids (quercetin equivalent 0 to 3.12 g/kg). Ethanolic extract exerted the highest activities against a chloroquine-resistant strain of Plasmodium falciparum (IC₅₀=23 mg/L), against human breast cancer cells MCF7 (IC₅₀=32 mg/L) and against free radical (IC₅₀=19.09±3.07 mg/L). Correlations were studied between each chemical family and the three activities. Total phenolics content exhibited the highest correlation with antiplasmodial activity (R²=0.92) and with anticancer activity (R²=0.86), respectively.


Long noncoding RNA Chast promotes cardiac remodeling.
Recent studies highlighted long noncoding RNAs (lncRNAs) to play an important role in cardiac development. However, understanding of lncRNAs in cardiac diseases is still limited. Global lncRNA expression profiling indicated that several lncRNA transcripts are deregulated during pressure overload-induced cardiac hypertrophy in mice. Using stringent selection criteria, we identified Chast (cardiac hypertrophy-associated transcript) as a potential lncRNA candidate that influences cardiomyocyte hypertrophy. Cell fractionation experiments indicated that Chast is specifically up-regulated in cardiomyocytes in vivo in transverse aortic constriction (TAC)-operated mice. In accordance, CHAST homolog in humans was significantly up-regulated in hypertrophic heart tissue from aortic stenosis patients and in human embryonic stem cell-derived cardiomyocytes upon hypertrophic stimuli. Viral-based overexpression of Chast was sufficient to induce cardiomyocyte hypertrophy in vitro and in vivo. GapmeR-mediated silencing of Chast both prevented and attenuated TAC-induced pathological cardiac remodeling with no early signs on toxicological side effects. Mechanistically, Chast negatively regulated Pleckstrin homology domain-containing protein family M member 1 (opposite strand of Chast), impeding cardiomyocyte autophagy and driving hypertrophy. These results indicate that Chast can be a potential target to prevent cardiac remodeling and highlight a general role of lncRNAs in heart diseases.


Application of Artificial Intelligence in COVID-19 Pandemic: Bibliometric Analysis.
The application of artificial intelligence (AI) to health has increased, including to COVID-19. This study aimed to provide a clear overview of COVID-19-related AI publication trends using longitudinal bibliometric analysis. A systematic literature search was conducted on the Web of Science for English language peer-reviewed articles related to AI application to COVID-19. A search strategy was developed to collect relevant articles and extracted bibliographic information (e.g., country, research area, sources, and author). VOSviewer (Leiden University) and Bibliometrix (R package) were used to visualize the co-occurrence networks of authors, sources, countries, institutions, global collaborations, citations, co-citations, and keywords. We included 729 research articles on the application of AI to COVID-19 published between 2020 and 2021. PLOS One (33/729, 4.52%), Chaos Solution Fractals (29/729, 3.97%), and Journal of Medical Internet Research (29/729, 3.97%) were the most common journals publishing these articles. The Republic of China (190/729, 26.06%), the USA (173/729, 23.73%), and India (92/729, 12.62%) were the most prolific countries of origin. The Huazhong University of Science and Technology, Wuhan University, and the Chinese Academy of Sciences were the most productive institutions. This is the first study to show a comprehensive picture of the global efforts to address COVID-19 using AI. The findings of this study also provide insights and research directions for academic researchers, policymakers, and healthcare practitioners who wish to collaborate in these domains in the future.


Anterior approach for pure laparoscopic donor right hepatectomy.
Pure laparoscopic donor hepatectomy (PLDH) is being increasingly performed at centers with experienced surgeons [1-6]. This procedure is still developing and is associated with several challenges owing to its technical difficulty [7-9]. Conversely, the anterior approach is sometimes applied to both laparoscopic and open right hepatectomy for management of tumors in the liver [10, 11]. However, there are no reports regarding the use of the anterior approach for PLDH. We found this method to be useful; therefore, we aimed to introduce the novel procedure using a video clip. The donor was placed in the supine position. First, the right side of the inferior vena cava was dissected instead of performing the liver hanging maneuver. The right Glissonean pedicle was encircled and controlled, and the liver parenchyma was completely transected. Thereafter, the ligaments around the liver were dissected, and the graft was mobilized. The hilar vessels were respectively separated. Finally, the right hepatic duct, right hepatic artery, right portal vein, and right hepatic vein were divided, and the graft liver was retrieved. This study was approved by institutional ethics board (MH2019-119), and informed consent was taken from the patient. The overall surgical time was 400 min, the volume of blood loss was 31 mL, the warm ischemic time was 7 min, and no complications were seen. The advantages of the anterior approach for right-sided PLDH might be attribute to reduction of compression injury and incidence of subcapsular hematoma, as liver mobilization is easily performed because of increased liver mobility. However, PLDH is a highly-skilled procedure, and indications for PLDH should be extended in a step-wise manner. Further, the procedure should be performed only by highly proficient surgeons having extensive experience in both laparoscopic liver resection and living donor liver transplantation.


Specific 18F-FDHT Accumulation in Human Prostate Cancer Xenograft Murine Models Is Facilitated by Prebinding to Sex Hormone-Binding Globulin.
Tremendous efforts are currently dedicated to the development of novel therapies targeting the androgen receptor (AR), the major driver of prostate cancer disease and its progression to castration resistance. The ability to noninvasively interrogate AR expression over time in murine models of prostate cancer would permit longitudinal preclinical analysis of novel compounds that could not otherwise be accomplished ex vivo. Although PET imaging with 16β-18F-fluoro-5α-dihydrotestosterone (18F-FDHT) has successfully quantified AR levels clinically, no rodent model of 18F-FDHT imaging has been reported so far. One difference between humans and rodents is the absence in the latter of the sex hormone-binding globulin (SHBG), a glycoprotein that binds to testosterone in the bloodstream, Here, we explore the role of SHBG in developing a working model of rodent AR imaging. Methods: Three human prostate cancer cell lines and xenografts (LNCaP, 22Rv1, and PC3) were used to examine the uptake of free 18F-FDHT and SHBG-bound 18F-FDHT. Both ligands were examined for stability and competitive binding to AR over time in vitro before in vivo studies. PET/CT imaging was used to dynamically measure the uptake of both tracers over 4 h, whereas specificity was determined by competitive binding with the AR antagonist enzalutamide. Results: AR levels correlated with the uptake of both 18F-FDHT and SHBG-18F-FDHT in prostate cancer cell lines. Interestingly, whereas both free and SHBG-bound 18F-FDHT had a similar cellular accumulation at 1 and 2.5 h, SHBG-18F-FDHT accumulated at significantly higher levels after 4 h-evidence that receptor-mediated uptake of SHBG accounted for later time-point differences. This observation was also seen in 22Rv1 tumor-bearing mice, in which SHBG-18F-FDHT exhibited a significantly increased uptake (average tumor-to-background ratio [TBR], 1.62 ± 0.62) in comparison to unbound 18F-FDHT (TBR, 0.81 ± 0.08) at 4 h. Furthermore, the specificity of the SHBG-18F-FDHT accumulation at 4 h was demonstrated by a reduced tumor uptake after AR blockade with enzalutamide (TBR, 1.07 ± 0.13). Conclusion: Prebinding of 18F-FDHT to SHBG allows accurate and quantitative PET imaging of AR levels in murine models of prostate cancer. This procedure may permit the use of PET imaging to study the longitudinal effects of AR-targeting therapies, accelerating novel-drug development.


Prognostic models in predicting outcomes in myelodysplastic syndromes after hypomethylating agent failure.
Myelodysplastic syndromes (MDS) are clonal stem cell disorders marked by bone marrow failure with varying degrees of cytopenias. MDS are characterized by the accumulation of complex genetic alterations that influence disease pathogenesis and outcomes. Given the heterogeneity of MDS patients, multiple prognostic scoring systems have been developed to predict patient outcomes. Most focus primarily on untreated patients in whom outcomes are predicted accurately only at diagnosis; their application dynamically, during the disease course and especially after hypomethylating agent (HMA) failure, may not be accurate. In this focused review, we discuss the utility of established MDS prognostic models and a novel tool at the time of HMA failure, along with the strengths and limitations of each.


Clonal diversity of Staphylococcus aureus originating from the small ruminants goats and sheep.
Staphylococcus aureus is an important pathogen in humans and many animal species. The prevalence of different clonal types in animal species remains largely unknown. We analyzed 267 S. aureus from intramammary infections in goats (47) and sheep (220) by spa typing, multi-locus sequence typing (MLST) and antimicrobial susceptibility. The most frequent spa types in goats were t337 (N=9), t759 (N=6) and t1534 (N=5). Sheep isolates mainly belonged to spa types t1534 (N=72), t2678 (N=29) and t3576 (N=20). Eighteen novel spa-types were observed; two from goat strains, 13 from sheep and three in both species. The majority of the goat strains grouped in MLST CC133 (N=10) and ST522 (N=10), followed by CC9 (N=9), while the majority of the sheep strains were of ST522 (N=108) followed by CC133 (N=86) and CC130 (N=11). Nine new MLST types were detected; three in goat and sheep isolates (ST1739, ST1758 and ST1780), two identified in goats only (ST1740 and ST2061) and four in sheep only (ST1742, ST1743, ST1781 and ST2011). Strains showed resistance below 20% against penicillin and tetracycline; a strong association between CC-types and penicillin resistance was observed. No resistance was detected to cefoxitin, quinupristin-dalfopristin, rifampicin and vancomycin. This study suggests that ST522 is the most common S. aureus clone associated with small ruminants followed by CC133.


Getting the biggest birch for the bang: restoring and expanding upland birchwoods in the Scottish Highlands by managing red deer.
High deer populations threaten the conservation value of woodlands and grasslands, but predicting the success of deer culling, in terms of allowing vegetation to recover, is difficult. Numerical simulation modeling is one approach to gain insight into the outcomes of management scenarios. We develop a spatially explicit model to predict the responses of Betula spp. to red deer (Cervus elaphus) and land management in the Scottish Highlands. Our model integrates a Bayesian stochastic stage-based matrix model within the framework of a widely used individual-based forest simulation model, using data collected along spatial and temporal gradients in deer browsing. By initializing our model with the historical spatial locations of trees, we find that densities of juvenile trees (<3 m tall) predicted after 9-13 years closely match counts observed in the field. This is among the first tests of the accuracy of a dynamical simulation model for predicting the responses of tree regeneration to herbivores. We then test the relative importance of deer browsing, ground cover vegetation, and seed availability in facilitating landscape-level birch regeneration using simulations in which we varied these three variables. We find that deer primarily control transitions of birch to taller (>3 m) height tiers over 30 years, but regeneration also requires suitable ground cover for seedling establishment. Densities of adult seed sources did not influence regeneration, nor did an active management scenario where we altered the spatial configuration of adults by creating "woodland islets". Our results show that managers interested in maximizing tree regeneration cannot simply reduce deer densities but must also improve ground cover for seedling establishment, and the model we develop now enables managers to quantify explicitly how much both these factors need to be altered. More broadly, our findings emphasize the need for land managers to consider the impacts of large herbivores rather than their densities.


Common variable immunodeficiency disorders: division into distinct clinical phenotypes.
The European Common Variable Immunodeficiency Disorders registry was started in 1996 to define distinct clinical phenotypes and determine overlap within individual patients. A total of 7 centers contributed patient data, resulting in the largest cohort yet reported. Patients (334), validated for the diagnosis, were followed for an average of 25.6 years (9461 patient-years). Data were used to define 5 distinct clinical phenotypes: no complications, autoimmunity, polyclonal lymphocytic infiltration, enteropathy, and lymphoid malignancy. A total of 83% of patients had only one of these phenotypes. Analysis of mortality showed a considerable reduction in the last 15 years and that different phenotypes were associated with different survival times. Types of complications and clinical phenotypes varied significantly between countries, indicating the need for large, international registries. Ages at onset of symptoms and diagnosis were shown to have a Gaussian distribution, but were not useful predictors of phenotype. The only clinical predictor was polyclonal lymphocytic infiltration, which was associated with a 5-fold increased risk of lymphoid malignancy. There was widespread variation in the levels of serum immunoglobulin isotypes as well as in the percentages and absolute numbers of B cells, confirming the heterogeneity of these conditions. Higher serum IgM and lower circulating CD8 proportions were found to be predictive markers for polyclonal lymphocytic infiltration and autoimmunity, respectively.


Live vaccine use and safety in DiGeorge syndrome.
Live vaccines are generally contraindicated in patients with DiGeorge syndrome (DGS), a congenital disorder characterized by cellular immune deficiency. Vaccine utilization and safety in this population are not well described. This study examined vaccination patterns and adverse events following live immunization (AEFLI) in these individuals. A multicenter retrospective cohort study was conducted in subjects with DGS confirmed by fluorescence in situ hybridization assay (chromosome 22q11.2 microdeletion). Live vaccine-preventable illnesses, vaccination coverage and timeliness, and AEFLIs in the 56-day window after live vaccination were examined. Bivariate and multivariable analyses assessed the impact of demographics medical history, timing of diagnostic confirmation, and preceding immune function on vaccination patterns and AEFLIs. Of 194 subjects, 77% and 75% received measles-mumps-rubella (MMR) and varicella vaccines, respectively; 58% completed recommended vaccinations by age 19 to 35 months. Adverse events occurred after 14% and 20% of MMR and varicella vaccine doses, respectively. Most events were minor, few were serious, and no deaths were reported in post-live vaccination windows. Although early diagnostic confirmation negatively affected live vaccination coverage and timeliness (P < .001), baseline CD4% did not differ between subjects who did or did not receive live vaccines by 12 to 18 months. Among varicella vaccine recipients, those with a subsequent adverse event had a lower preceding CD4% (24.8% ± 7.3%) than those without (35.5% ± 11.7%) (P < .05); no CD4% differences were observed with MMR vaccination. Fourteen unvaccinated subjects experienced live vaccine-preventable illnesses. Live vaccines were frequently given and generally well-tolerated among patients with DGS with mild-to-moderate immunosuppression.


The case for more cautious, patient-focused antiretroviral therapy.
Many clinicians who care for patients with HIV infection are dissatisfied with the existing recommendations on antiretroviral therapy. Current practice focuses on the early suppression of viremia, yet the outcome of that approach may not be in the best interest of individual patients or populations. The major goal of HIV therapy is to maintain the long-term health of the patient while avoiding drug-related toxicity and preserving viable future treatment options. Recent studies have challenged the principles on which recommendations for early, aggressive treatment were based. Key studies that lead to licensure of antiretroviral medications usually involve short-term results in treatment-naive patients; it is difficult to apply these results to long-term management of therapy-experienced patients. Early, aggressive therapy often prematurely exposes patients to risks for medication-related side effects and resistance. A more cautious, patient-focused, long-term approach to therapy would help foster studies of alternate strategies, such as delayed initiation of therapy, protease-sparing therapy, class-sparing therapy, planned drug interruptions, switches in therapy, and immune-based therapy. It is time for clinicians to rethink their approach to the treatment of HIV infection.


Characteristics and direct costs of academic pediatric subspecialty outpatient no-show events.
Clinic no shows (NS) create a lost opportunity for provider-patient interaction and impose a financial burden to the healthcare system and on society. We aimed to: (1) to determine the clinical and demographic factors associated with increased NS rates at a children's hospital's subsubspecialty clinics and (2) to estimate the direct institutional financial costs associated with NS events. A comprehensive database was generated from all clinic encounters for 15 subspecialty outpatient clinics (five surgical and 10 medical) between September 12, 2005 and December 30, 2010. Multivariate logistic regressions were performed to identify the variables associated with NS events. Direct costs of NS events were estimated using annual revenue for each clinic. A total of 284,275 encounters and 17,024 NS events were available for analysis. Public insurance coverage (Medicaid and Title V), compared to private insurance or self-pay status, was associated with an increased likelihood NS (OR 2.19, 95% CI 2.10-2.28, p < 0.0005 for Medicaid; OR 1.56, 95% CI 1.50-1.62, p < 0.0005 for Title V). Compared to patients 21-30 years of age, patients <12 years (OR 2.08, 95% CI 1.77-2.45, p < 0.0005) had increased likelihood of NS. Scheduled visits with medical subspecialists were more likely than surgical subspecialty visits to result in a NS (OR 1.69, 95% CI 1.63-1.75, p < 0.0005). The predicted annualized lost revenue associated with NS visits was estimated at $730,000 from the 15 clinics analyzed, approximately $210 per NS event. Pediatric subspecialty NS events are common, costly, and potentially preventable.


Physical and Genetic Interactions Between Uls1 and the Slx5-Slx8 SUMO-Targeted Ubiquitin Ligase.
The Slx5-Slx8 complex is a ubiquitin ligase that preferentially ubiquitylates SUMOylated substrates, targeting them for proteolysis. Mutations in SLX5, SLX8, and other SUMO pathway genes were previously identified in our laboratory as genomic suppressors of a point mutation (mot1-301) in the transcriptional regulator MOT1 To further understand the links between the SUMO and ubiquitin pathways, a screen was performed for high-copy suppressors of mot1-301, yielding three genes (MOT3, MIT1, and ULS1). MOT3 and MIT1 have characteristics of prions, and ULS1 is believed to encode another SUMO-targeted ubiquitin ligase (STUbL) that functionally overlaps with Slx5-Slx8. Here we focus on ULS1, obtaining results suggesting that the relationship between ULS1 and SLX5 is more complex than expected. Uls1 interacted with Slx5 physically in to yeast two-hybrid and co-immunoprecipitation assays, a uls1 mutation that blocked the interaction between Uls1 and Slx5 interfered with ULS1 function, and genetic analyses indicated an antagonistic relationship between ULS1 and SLX5 Combined, our results challenge the assumption that Uls1 and Slx5 are simply partially overlapping STUbLs and begin to illuminate a regulatory relationship between these two proteins.


International Conference on Advances in Radiation Oncology (ICARO): outcomes of an IAEA meeting.
The IAEA held the International Conference on Advances in Radiation Oncology (ICARO) in Vienna on 27-29 April 2009. The Conference dealt with the issues and requirements posed by the transition from conventional radiotherapy to advanced modern technologies, including staffing, training, treatment planning and delivery, quality assurance (QA) and the optimal use of available resources. The current role of advanced technologies (defined as 3-dimensional and/or image guided treatment with photons or particles) in current clinical practice and future scenarios were discussed.ICARO was organized by the IAEA at the request of the Member States and co-sponsored and supported by other international organizations to assess advances in technologies in radiation oncology in the face of economic challenges that most countries confront. Participants submitted research contributions, which were reviewed by a scientific committee and presented via 46 lectures and 103 posters. There were 327 participants from 70 Member States as well as participants from industry and government. The ICARO meeting provided an independent forum for the interaction of participants from developed and developing countries on current and developing issues related to radiation oncology.


Nature appropriation and associations with population health in Canada's largest cities.
Earth is a finite system with a limited supply of resources. As the human population grows, so does the appropriation of Earth's natural capital, thereby exacerbating environmental concerns such as biodiversity loss, increased pollution, deforestation and global warming. Such concerns will negatively impact human health although it is widely believed that improving socio-economic circumstances will help to ameliorate environmental impacts and improve health outcomes. However, this belief does not explicitly acknowledge the fact that improvements in socio-economic position are reliant on increased inputs from nature. Gains in population health, particularly through economic means, are disconnected from the appropriation of nature to create wealth so that health gains become unsustainable. The current study investigated the sustainability of human population health in Canada with regard to resource consumption or "ecological footprints" (i.e., the resources required to sustain a given population). Ecological footprints of the 20 largest Canadian cities, along with several important determinants of health such as income and education, were statistically compared with corresponding indicators of human population health outcomes. A significant positive relationship was found between ecological footprints and life expectancy, as well as a significant negative relationship between ecological footprints and the prevalence of high blood pressure. Results suggest that increased appropriation of nature is linked to improved health outcomes. To prevent environmental degradation from excessive appropriation of natural resources will require the development of health promotion strategies that are de-coupled from ever-increasing and unsustainable resource use. Efforts to promote population health should focus on health benefits achieved from a lifestyle based on significantly reduced consumption of natural resources.


Evidence for ordering of Alzheimer disease biomarkers.
To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. Validation sample. Multisite, referral centers. A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Aβ42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. Three AD biomarkers (ie, the CSF Aβ42 level, the CSF total tau level, and the adjusted hippocampal volume). Within each clinical group of the entire sample (n = 401), the CSF Aβ42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Aβ42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Aβ42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. A reduction in the CSF Aβ42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level.


Cohesin interaction with centromeric minichromosomes shows a multi-complex rod-shaped structure.
Cohesin is the protein complex responsible for maintaining sister chromatid cohesion. Cohesin interacts with centromeres and specific loci along chromosome arms known as Chromosome Attachment Regions (CARs). The cohesin holocomplex contains four subunits. Two of them, Smc1p (Structural maintenance of chromosome 1 protein) and Smc3p, are long coiled-coil proteins, which heterodimerize with each other at one end. They are joined together at the other end by a third subunit, Scc1p, which also binds to the fourth subunit, Scc3p. How cohesin interacts with chromosomes is not known, although several models have been proposed, in part on the basis of in vitro assembly of purified cohesin proteins. To be able to observe in vivo cohesin-chromatin interactions, we have modified a Minichromosome Affinity Purification (MAP) method to isolate a CAR-containing centromeric minichromosome attached to in vivo assembled cohesin. Transmission Electron Microscopy (TEM) analysis of these minichromosomes suggests that cohesin assumes a rod shape and interacts with replicated minichromosome at one end of that rod. Additionally, our data implies that more than one cohesin molecule interacts with each pair of replicated minichromsomes. These molecules seem to be packed into a single thick rod, suggesting that the Smc1p and Smc3p subunits may interact extensively.


Residual Peripheral Blood CD26+ Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission.
Chronic myeloid leukemia (CML) patients in sustained "deep molecular response" may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34+/CD38- LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26+ LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45+/CD34+/CD38- stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26+ LSCs (median 19.20/μL, range 0.27-698.6). PB CD26+ LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012-0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006-0.76). Notably, no correlation between BCR-ABL/ABLIS ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that "circulating" CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26+ LSCs during TKI treatment and the role of a "stem cell response" threshold to achieve and maintain TFR are ongoing.


Recurrent EGFR-Mutated Non-Small Cell Lung Cancer Discovered by Abnormal Mammogram: Adjuvant/Frontline Metastatic Management Options.
Breast metastasis from extramammary malignancy is rare, with a reported incidence rate of 0.4% to 1.3% in the published literature. The primary malignancies that most commonly metastasize to the breast are leukemia, lymphoma, and malignant melanoma. Here, we report a very rare case of metastatic EGFR-mutated non-small cell lung cancer (NSCLC) in the breast detected by screening mammography. The patient had initially been diagnosed with a clinical stage IIIA NSCLC and had been treated with neoadjuvant chemoradiation followed by curative-intent surgery. Several interesting aspects of the case, along with a discussion of evolving adjuvant and frontline metastatic management options in EGFR-mutated NSCLC, will be presented.


Heat stroke with multiple organ failure treated with cold hemodialysis and cold continuous hemodiafiltration: a case report.
A 23-year-old comatose man was presented in the emergency room. He had been working inside a building under construction on a hot summer's day. His core body temperature was 42.1 degrees C and he was diagnosed with heat stroke. Urgent cooling procedures, including applying cold vapor to the patient's skin, a gastric lavage with cold water and an intravenous cold saline infusion, were not completely successful and his body temperature remained above 40 degrees C. Because his high temperature was refractory to conventional cooling procedures and we suspected that acute renal failure (ARF) by rhabdomyolysis would develop, we applied hemodialysis (HD) using cold dialysate (initially 30 degrees C and later 35 degrees C), followed by continuous hemodiafiltration (CHDF) with cold dialysate (35 degrees C) at a high flow rate of 18,000 mL per hour. The patient's body temperature fell below 38.0 degrees C within 3 h and was kept below 38.0 degrees C. Continuous hemodiafiltration was continued for one week. During the first week, the patient suffered from multiple organ failure (MOF) involving renal failure, as well as the failure of heart, liver, lung, and central nervous systems. Disseminated intravascular coagulation also developed. However, by virtue of cold CHDF, he almost recovered 3 weeks after the onset, except for remaining mild liver and renal dysfunction. In severe heat stroke, cold HD and high flow, cold CHDF should be a therapeutic choice for cooling and treatment of MOF. Considering mild liver and renal dysfunction still remained, this case suggested these procedures should be initiated at the very beginning of the treatment of severe heat stroke.


Groupwise image registration based on a total correlation dissimilarity measure for quantitative MRI and dynamic imaging data.
The most widespread technique used to register sets of medical images consists of selecting one image as fixed reference, to which all remaining images are successively registered. This pairwise scheme requires one optimization procedure per pair of images to register. Pairwise mutual information is a common dissimilarity measure applied to a large variety of datasets. Alternative methods, called groupwise registrations, have been presented to register two or more images in a single optimization procedure, without the need of a reference image. Given the success of mutual information in pairwise registration, we adapt one of its multivariate versions, called total correlation, in a groupwise context. We justify the choice of total correlation among other multivariate versions of mutual information, and provide full implementation details. The resulting total correlation measure is remarkably close to measures previously proposed by Huizinga et al. based on principal component analysis. Our experiments, performed on five quantitative imaging datasets and on a dynamic CT imaging dataset, show that total correlation yields registration results that are comparable to Huizinga's methods. Total correlation has the advantage of being theoretically justified, while the measures of Huizinga et al. were designed empirically. Additionally, total correlation offers an alternative to pairwise mutual information on quantitative imaging datasets.


Reactivity of canine isolated epicardial collateral coronary arteries. Relation to vessel structure.
To study the relation between structure and vascular reactivity in mature coronary collateral arteries, we prepared 17 dogs with a casein occluder near the origin of the circumflex coronary artery. At least 24 weeks later, we examined the reactivity of surface collateral arteries (approximately 500 micron i.d.) to a range of constrictor and dilator agents and compared them with normal left anterior descending coronary arteries of similar size branching away from the collateral zone. Pairs of normal and collateral arteries 2 mm long were mounted in a double-vessel myograph for isometric force recording. Arteries were contracted by K+ (124 mM) or by cumulative addition of endothelin-1 (1-100 nM) or U46619 (1-300 nM), a thromboxane A2 mimetic drug. In each case, the collateral vessels contracted to approximately half the force generated by the normal arteries. When partially contracted by K+ (25-30 mM), the collateral vessels had a greater range of relaxation and similar sensitivity to acetylcholine, sodium nitroprusside, and cromakalim compared with normal arteries. Morphological and morphometric analyses revealed that the collateral arteries had thickened adventitia, thinner media, ruptured internal elastic laminae, and a thick neointima lined by endothelium. Theoretical calculations of luminal area were made for isotonic conditions in response to constrictor stimuli. Despite the poor contractility of the collateral arteries, the neointimal luminal encroachment further reduced the lumen to zero, an exaggerated response compared with normal arteries. Coronary collateral arteries are thus compromised flow conduits that may play a role in vasospastic angina.


Gastrointestinal Parasites of Vervet Monkeys (Chlorocebus pygerythrus) in a High Latitude, Semi-Arid Region of South Africa.
Given a changing climate and large-scale human migration, understanding infectious diseases in wildlife and the factors that drive the spread of these diseases is becoming increasingly important. Owing to the close phylogenetic relationship between nonhuman primates and humans, primate parasites are of particular interest due to the potential for zoonotic disease transmission and for the study of social transmission within gregarious social groups. There is a wide range of social and environmental factors that influence the prevalence and transmission of pathogens, and identifying these, and their effects, is crucial to understanding the population-level consequences of climate change for animals that live in obligate social groups. Here we investigated gastrointestinal parasite species richness and used fecal egg counts to estimate worm intensities in 3 vervet monkey troops (Chlorocebus pygerythrus) in a high latitude, semi-arid region of South Africa. This region is characterized by unpredictable rainfall and temperature extremes in summer and winter. We identified the gastrointestinal parasites in the population and explored potential demographic predictors, namely sex and troop membership, of parasite species richness and estimated intensity. Additionally, we assessed whether there was short-term intra-individual, inter-sample consistency in egg counts. Six species of gastrointestinal helminths were identified from 3 study troops, with egg counts ranging from 0 eggs/g to 1,100 eggs/g. Neither age nor sex predicted species richness or estimated intensity. This population had the highest prevalence of parasites with an insect vector compared with all other vervet populations studied, and distinctively high prevalences of Trichostrongylus sp. (71%) and Ternidens sp. (27%). Additionally, we found intra-individual egg count consistency in the short term (mean: 32 days).


Disclosing in utero HIV/ARV exposure to the HIV-exposed uninfected adolescent: is it necessary?
The tremendous success of antiretroviral therapy has resulted in a diminishing population of perinatally HIV-infected children on the one hand and a mounting number of HIV-exposed uninfected (HEU) children on the other. As the oldest of these HEU children are reaching adolescence, questions have emerged surrounding the implications of HEU status disclosure to these adolescents. This article outlines the arguments for and against disclosure of a child's HEU status. Disclosure of a child's HEU status, by definition, requires disclosure of maternal HIV status. It is necessary to weigh the benefits and harms which could occur with disclosure in each of the following domains: psychosocial impact, long-term physical health of the HEU individual and the public health impact. Does disclosure improve or worsen the psychological health of the HEU individual and extended family unit? Do present data on the long-term safety of in utero HIV/ARV exposure reveal potential health risks which merit disclosure to the HEU adolescent? What research and public health programmes or systems need to be in place to afford monitoring of HEU individuals and which, if any, of these require disclosure? At present, it is not clear that there is sufficient evidence on whether long-term adverse effects are associated with in utero HIV/ARV exposures, making it difficult to mandate universal disclosure. However, as more countries adopt electronic medical record systems, the HEU status of an individual should be an important piece of the health record which follows the infant not only through childhood and adolescence but also adulthood. Clinicians and researchers should continue to approach the dialogue around mother-child disclosure with sensitivity and a cogent consideration of the evolving risks and benefits as new information becomes available while also working to maintain documentation of an individual's perinatal HIV/ARV exposures as a vital part of his/her medical records. As more long-term adult safety data on in utero HIV/ARV exposures become available these decisions may become clearer, but at this time, they remain complex and multi-faceted.


The last rRNA methyltransferase of E. coli revealed: the yhiR gene encodes adenine-N6 methyltransferase specific for modification of A2030 of 23S ribosomal RNA.
The ribosomal RNA (rRNA) of Escherichia coli contains 24 methylated residues. A set of 22 methyltransferases responsible for modification of 23 residues has been described previously. Herein we report the identification of the yhiR gene as encoding the enzyme that modifies the 23S rRNA nucleotide A2030, the last methylated rRNA nucleotide whose modification enzyme was not known. YhiR prefers protein-free 23S rRNA to ribonucleoprotein particles containing only part of the 50S subunit proteins and does not methylate the assembled 50S subunit. We suggest renaming the yhiR gene to rlmJ according to the rRNA methyltransferase nomenclature. The phenotype of yhiR knockout gene is very mild under various growth conditions and at the stationary phase, except for a small growth advantage at anaerobic conditions. Only minor changes in the total E. coli proteome could be observed in a cell devoid of the 23S rRNA nucleotide A2030 methylation.


Large-scale experiments for microbiological evaluation of measures for safeguarding sulfidic mine waste.
In the framework of a German-Romanian scientific cooperation, experiments were performed to evaluate feasible and cheap techniques for the safe storage of mine waste to prevent acid rock drainage (ARD). A large four-chamber percolator (4CP) was installed in a waste heap at Ilba Mine, Romania, to test the effect of biocides and alkaline layers on the bacteria causing acid rock drainage (ARD). The 4CP consisted of four chambers each containing 65 m3 of sulfidic waste material. The 4CP enabled the transfer of laboratory results to a technical scale. The detergent sodiumdodecylsulfate (SDS) was proved to be active against the leaching bacteria. Organotrophic micro-organisms were not effected by the SDS application. The alkaline layers caused an increase of pH, however, a decrease of cell numbers was measured only in adjacent ore layers, but not in the whole ore body. A rapid evaluation of the effects of these countermeasures on ARD formation became possible by microcalorimetric activity measurements for bioleaching.


Antibodies to IA-2 and GAD65 in type 1 and type 2 diabetes: isotype restriction and polyclonality.
To determine the isotypes and clonality of antibodies to GAD (GADA) and IA-2 (IA-2A) in patients with type 1 and type 2 diabetes. We studied the following consecutive series of patients who attended a diabetes center for antibodies to GADA and IA-2A: 52 newly diagnosed type 1 diabetic patients, 199 type 2 diabetic patients, 200 control patients, and a cohort of 34 nondiabetic identical twins of patients with type 1 diabetes (15 of whom developed diabetes) who were followed prospectively. GADA or IA-2A were detected in 37 (71%) type 1 diabetic patients compared with only 10 (5%) type 2 diabetic patients (P<0.0001). Both GAD and IA-2 antibodies, regardless of the type of diabetes, were usually subclass restricted to IgG1 and were polyclonal. IgM, IgG3, and IgE isotypes were also detected, but all isotypes of GADA and IA-2A were less prevalent than IgG1 (P<0.017 for either antibody). There was no evidence of spreading or switching of isotypes before the onset of type 1 diabetes. These observations suggest that the pathogenesis of antigen-specific antibodies in type 1 and type 2 diabetes is similar and probably involves a chronic nonrandom antigen-driven polyclonal B-cell activation that is consistent with a Th1-type immune response.


KREAP: an automated Galaxy platform to quantify in vitro re-epithelialization kinetics.
In vitro scratch assays have been widely used to study the influence of bioactive substances on the processes of cell migration and proliferation that are involved in re-epithelialization. The development of high-throughput microscopy and image analysis has enabled scratch assays to become compatible with high-throughput research. However, effective processing and in-depth analysis of such high-throughput image datasets are far from trivial and require integration of multiple image processing and data extraction software tools. We developed and implemented a kinetic re-epithelialization analysis pipeline (KREAP) in Galaxy. The KREAP toolbox incorporates freely available image analysis tools and automatically performs image segmentation and feature extraction of each image series, followed by automatic quantification of cells inside and outside the scratched area over time. The enumeration of infiltrating cells over time is modeled to extract three biologically relevant parameters that describe re-epithelialization kinetics. The output of the tools is organized, displayed, and saved in the Galaxy environment for future reference. The KREAP toolbox in Galaxy provides an open-source, easy-to-use, web-based platform for reproducible image processing and data analysis of high-throughput scratch assays. The KREAP toolbox could assist a broad scientific community in the discovery of compounds that are able to modulate re-epithelialization kinetics.


Determination and correction of quadrature fringe measurement errors in interferometers.
The precision and accuracy of interferometers using quadrature fringe detection are often limited not by the interferometer itself but by the detector system. There are three typical errors: unequal gain in the two channels; quadrature phase shift error; and zero offsets. This paper describes a simple method for determining the quadrature errors from experimental data obtained in the interferometer and correcting for them. A numerical example demonstrating the significant improvement in the precision of interferometer data is given.


Rainbows: Mie computations and the Airy approximation.
Efficient and accurate computation of the scattered intensity pattern by the Mie formulas is now feasible for size parameters up to x = 50,000 at least, which in visual light means spherical drops with diameters up to 6 mm. We present a method for evaluating the Mie coefficients from the ratios between Riccati-Bessel and Neumann functions of successive order. We probe the applicability of the Airy approximation, which we generalize to rainbows of arbitrary p (number of internal reflections = p - 1), by comparing the Mie and Airy intensity patterns. Millimeter size water drops show a match in all details, including the position and intensity of the supernumerary maxima and the polarization. A fairly good match is still seen for drops of 0.1 mm. A small spread in sizes helps to smooth out irrelevant detail. The dark band between the rainbows is used to test more subtle features. We conclude that this band contains not only externally reflected light (p = 0) but also a sizable contribution f rom the p = 6 and p = 7 rainbows, which shift rapidly with wavelength. The higher the refractive index, the closer both theories agree on the first primary rainbow (p = 2) peak for drop diameters as small as 0.02 mm. This may be useful in supporting experimental work.


Glutamine administration modulates lung γδ T lymphocyte expression in mice with polymicrobial sepsis.
This study investigated the effects of glutamine (GLN) administration on regulating lung γδ T cells in polymicrobial sepsis. Mice were randomly assigned to normal group (NC), septic saline group (SS), and septic GLN group (SG). All mice were fed with chow diet. Sepsis was induced by cecal ligation and puncture (CLP). The SS and SG groups were, respectively, injected with saline and 0.75 g GLN/kg body weight once via tail vein 1 h after CLP. Mice were killed 12 and 24 h after CLP. Their lungs were collected for further analysis. The results showed that, compared with normal mice, sepsis resulted in higher lung γδ T cell and neutrophil percentages and higher cytokine expressed by γδ T cells. Histopathologic findings showed that the extent of inflammatory lesions of the lung alveolar was less severe in the SG group than the SS group after CLP. The SG group had a higher γδ T cell percentage and lower γδ T cell apoptotic rates as well as lower neutrophil numbers in the lungs. Also, interleukin 17A (IL-17A), interferon γ, and IL-10 expressed by γδ T cells and CXC receptor 2 expressed by neutrophils decreased in the SG group. Moreover, GLN reduced IL-17A, IL-1β, and IL-23 concentrations and myeloperoxidase activity in lung tissues. Our results suggest that GLN administration after initiation of sepsis affects lung γδ T cell percentage and cytokine secretion and prevented apoptosis of γδ T cells and neutrophil infiltration to the lungs, which may partly be responsible for ameliorating acute lung injury induced by sepsis.


Reduced specificity of autobiographical memory: a mediator between rumination and ineffective social problem-solving in major depression?
Depressed individuals display a deficit in effectively solving social problem situations (e.g., []). Recent research suggests that rumination may interfere with such effective problem-solving (e.g., []). However, little is known, as yet, about the mechanisms that are underlying this relation between rumination and poor problem-solving. The present study investigated the role of reduced specificity of autobiographical memories as a mediator of this relationship. 24 depressed patients (15 women) completed the Autobiographical Memory Test (AMT), the Means-Ends Problem-Solving Task (MEPS), the Ruminative Response Scale (RRS) and the Rumination on Sadness Scale (RSS). Consistent with previous studies, rumination, ineffective problem-solving and reduced memory specificity were significantly associated. Regression analyses further extended these findings by showing that reduced memory specificity mediated the association between rumination and problem-solving effectiveness. The correlational nature of this study limits to some extent the conclusions that can be drawn on the directionality of the observed relationships. Results offer support for the idea that lack of autobiographical memory specificity mediates the known relationship between rumination and poor problem-solving.


Electric fields and MAP kinase signaling can regulate early wound healing in lens epithelium.
To use lens epithelial cell monolayer wounds as a model system for the aberrant cell migration underlying posterior capsule opacification (PCO) and to investigate the effects of an applied physiological electric field (EF) on monolayer wound healing. Scratch wounds were made in cultured bovine lens epithelial monolayers, and the wounds were exposed to an EF, with or without U0126 treatment (an inhibitor of active extracellular signal-regulated kinase [ERK 1/2]). Serial wound images were taken and wound areas were measured. Western blot analysis and immunocytochemical staining for ERK 1/2 in the wounded monolayers were performed. An applied EF of a given polarity influenced the healing of lens epithelial monolayer wounds. Wounds facing the anode healed at normal rates, those facing the cathode closed much more slowly. U0126, an inhibitor of mitogen-activated protein kinase (MAPK) signaling, inhibited wound healing, with or without exposure to an EF. Western blot analysis showed that both wounding and application of an EF enhanced the activation of ERK 1/2 independently and that U0126 completely inhibited these activations of ERK 1/2 in monolayers. Immunocytochemical staining showed an asymmetric activation of ERK 1/2 in EF-exposed wounds, with much weaker fluorescence in cathode-facing wounds, which could contribute to differentially directed wound-healing rates in an EF. Exposure to an EF inhibited the healing of lens epithelial monolayer wounds facing the cathode. ERK signaling pathways were involved in healing of lens epithelial monolayer wounds and in the EF-directed migration of the wound edge. It may be possible to use an applied EF to regulate the aberrant migration of lens epithelial cells that results in PCO after cataract surgery.


Adaptation of an enzyme to regulatory function: structure of Bacillus subtilis PyrR, a pyr RNA-binding attenuation protein and uracil phosphoribosyltransferase.
The expression of pyrimidine nucleotide biosynthetic (pyr) genes in Bacillus subtilis is regulated by transcriptional attenuation. The PyrR attenuation protein binds to specific sites in pyr mRNA, allowing the formation of downstream terminator structures. UMP and 5-phosphoribosyl-1-pyrophosphate (PRPP), a nucleotide metabolite, are co-regulators with PyrR. The smallest RNA shown to bind tightly to PyrR is a 28-30 nucleotide stem-loop that contains a purine-rich bulge and a putative-GNRA tetraloop. PyrR is also a uracil phosphoribosyltransferase (UPRTase), although the relationship between enzymatic activity and RNA recognition is unclear, and the UPRTase activity of PyrR is not physiologically significant in B. subtilis. Elucidating the role of PyrR structural motifs in UMP-dependent RNA binding is an important step towards understanding the mechanism of pyr transcriptional attenuation. The 1.6 A crystal structure of B. subtilis PyrR has been determined by multiwavelength anomalous diffraction, using a Sm co-crystal. As expected, the structure of PyrR is homologous to those proteins of the large type I PRTase structural family; it is most similar to hypoxanthine-guanine-xanthine PRTase (HGXPRTase). The PyrR dimer differs from other PRTase dimers, suggesting it may have evolved specifically for RNA binding. A large, basic, surface at the dimer interface is an obvious RNA-binding site and uracil specificity is probably provided by hydrogen bonds from mainchain and sidechain atoms in the hood subdomain. These models of RNA and UMP binding are consistent with biological data. The B. subtilis protein PyrR has adapted the substrate- and product-binding capacities of a PRTase, probably an HGXPRTase, producing a new regulatory function in which the substrate and product are co-regulators of transcription termination. The structure is consistent with the idea that PyrR regulatory function is independent of catalytic activity, which is likely to be extremely low under physiological conditions.


Differences in dietary intakes, food sources and determinants of total flavonoids between Mediterranean and non-Mediterranean countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
A greater adherence to the traditional Mediterranean (MED) diet is associated with a reduced risk of developing chronic diseases. This dietary pattern is based on higher consumption of plant products that are rich in flavonoids. We compared the total flavonoid dietary intakes, their food sources and various lifestyle factors between MED and non-MED countries participating in the EPIC study. Flavonoid intakes and their food sources for 35,628 subjects, aged 35-74 years and recruited between 1992 and 2000, in twenty-six study centres were estimated using standardised 24 h dietary recall software (EPIC-Soft®). An ad hoc food composition database on flavonoids was compiled using analytical data from the United States Department of Agriculture and Phenol-Explorer databases. Moreover, it was expanded to include using recipes, estimations of missing values and flavonoid retention factors. No significant differences in total flavonoid mean intake between non-MED countries (373·7 mg/d) and MED countries (370·2 mg/d) were observed. In the non-MED region, the main contributors were proanthocyanidins (48·2%) and flavan-3-ol monomers (24·9%) and the principal food sources were tea (25·7%) and fruits (32·8%). In the MED region, proanthocyanidins (59·0%) were by far the most abundant contributor and fruits (55·1%), wines (16·7%) and tea (6·8%) were the main food sources. The present study shows similar results for total dietary flavonoid intakes, but significant differences in flavonoid class intakes, food sources and some characteristics between MED and non-MED countries. These differences should be considered in studies about the relationships between flavonoid intake and chronic diseases.


COP9 signalosome controls the degradation of cytosolic misfolded proteins and protects against cardiac proteotoxicity.
Impaired degradation of misfolded proteins is associated with a large subset of heart diseases. Misfolded proteins are degraded primarily by the ubiquitin-proteasome system, but the ubiquitin ligases responsible for the degradation remain largely unidentified. The cullin deneddylation activity of the COP9 signalosome (CSN) requires all 8 CSN subunits (CSN1 through CSN8) and regulates cullin-RING ligases, thereby controlling ubiquitination of a large number of proteins; however, neither CSN nor cullin-RING ligases is known to regulate the degradation of cytosolic misfolded proteins. We sought to investigate the role of CSN8/CSN in misfolded protein degradation and cardiac proteinopathy. Cardiac CSN8 knockout causes mouse premature death; hence, CSN8 hypomorphism (CSN8(hypo)) mice were used. Myocardial neddylated forms of cullins were markedly increased, and myocardial capacity of degrading a surrogate misfolded protein was significantly reduced by CSN8 hypomorphism. When introduced into proteinopathic mice in which a bona fide misfolded protein R120G missense mutation of αβ-crystallin (CryAB(R120G)) is overexpressed in the heart, CSN8 hypomorphism aggravated CryAB(R120G)-induced restrictive cardiomyopathy and shortened the lifespan of CryAB(R120G) mice, which was associated with augmented accumulation of protein aggregates, increased neddylated proteins, and reduced levels of total ubiquitinated proteins and LC3-II in the heart. In cultured cardiomyocytes, both CSN8 knockdown and cullin-RING ligase inactivation suppressed the ubiquitination and degradation of CryAB(R120G) but not native CryAB, resulting in accumulation of protein aggregates and exacerbation of CryAB(R120G) cytotoxicity. (1) CSN8/CSN promotes the ubiquitination and degradation of misfolded proteins and protects against cardiac proteotoxicity, and (2) cullin-RING ligases participate in degradation of cytosolic misfolded proteins.


Building capacity in workplace health promotion: the case of the Healthy Together e-learning project.
The current global economic crisis poses major challenges for workplace health promotion (WHP). Activities that are not perceived to obviously and directly contribute to profits could be sacrificed. This paper argues that WHP must remain centre-stage because of the rights of workers to a healthy, safe working environment but also because of WHP's beneficial financial implications for enterprises. Capacity building for WHP can be developed even within a recessionary environment, particularly if the focus is on the wider workforce, described here as people for whom workplace health promotion may not be their primary function but who have an important role to play in health improvement in workplaces. There is a strong case for the development of the wider workforce based both on the lack of suitably qualified specialists and on the practicalities of having WHP implemented within organizations, particularly for small and medium-sized enterprises (SMEs). SMEs make up a very significant proportion of the global economy and are identified as a priority area for action internationally. An example of an e-learning course, the Healthy Together programme, developed by a partnership of three countries, is discussed as an approach that has potential to develop capacity for WHP in the current climate. The findings of the evaluation of the Healthy Together programme indicate that there is a real potential in developing e-learning materials for training those with a brief for promoting workplace health and safety in SMEs. Although modifications in some aspects of delivery identified in the evaluation of the pilot course need to be considered, the course was well received, and was reported to be relevant to the learning needs of students, to their workplaces and specifically to small businesses in rural areas. Specific features of the e-learning approach increase its potential to address capacity building for WHP.


Seeing the baby: The impact of ultrasound technology.
This paper reports results of a study of prenatal diagnosis patients who underwent ultrasound examinations and lost their pregnancies through miscarriage or elective terminations. The majority of the women felt that viewing the ultrasound image influenced their relationship to the fetus and their coping with the pregnancy loss. The women commented on the power of ultrasound to make their pregnancies more real as well as the painful yet sometimes beneficial consequences of seeing the fetus. Clinical implications are considered for health professionals who provide prenatal diagnostic services or counseling after pregnancy loss.


Variability of facial photographs for use in treatment planning for orthodontics and orthognathic surgery.
Facial photographs are commonly used preoperatively for recording and analyzing skeletofacial and dentofacial deformities prior to orthodontics and/or orthognathic surgery. This study was undertaken to determine the reproducibility of facial photographs over time in any individual patient. Twenty subjects had full-facial frontal and lateral, frontal smile, and lip-to-tooth length (incisor show at rest) photographs taken on 5 different days over a 7- to 14-day period. A total of 18 linear and angular measurements were made on each set of photographs. Standard errors of the 18 measurements over time were generally moderate but varied widely, suggesting that facial photographs have the potential to provide reliable diagnostic information in some cases. In any individual patient, however, there were some variations within measurements that were clinically unacceptable. Measurements made from pictures of the smile were significantly less reliable than those taken at rest, and measurements of vertical head posture and lower lip length were found to be the least reliable. This study suggests that some measurements from facial photographs are generally reproducible over time, but significant individual variations do occur.


E-cadherin immunohistochemical expression as a prognostic factor in infiltrating ductal carcinoma of the breast: a systematic review and meta-analysis.
Multiple studies examining the relationship between loss of E-cadherin expression, a pivotal event for evolving metastatic behavior among epithelially derived cancers, and 5-year survival in infiltrating ductal breast carcinoma have yielded inconclusive and contradictory results. We conducted a systematic review of the PubMed database through August 2005 with no language restrictions to identify cohort studies that evaluated E-cadherin immunohistochemical expression as a prognostic marker for ductal breast carcinoma. 5-year all-cause mortality or 5-year breast cancer-specific mortality were the primary study outcomes. Meta-analysis was conducted using the REVMAN software and summary hazard ratios assuming both fixed effect and random effect models were calculated. Ten retrospective cohort studies were identified. Reduced or absent E-cadherin expression significantly increased the risk of all-cause mortality [combined HR = 1.55; 95% CI = 1.08-2.23] whereas a non-significant association was observed for breast cancer-specific mortality [combined HR = 0.70; 95% CI = 0.39-1.27]. We documented substantial inter-study heterogeneity with respect to all aspects of clinical data collection, immunohistochemical staining and interpretation as well as statistical modeling. These factors could not be formally analyzed but they challenge the robustness of our calculated summary estimates. Loss of E-cadherin expression may be an independent negative prognostic indicator for infiltrating ductal breast carcinoma and randomized, controlled studies evaluating this finding are justified. We encourage standardization of immunohistochemical techniques, data interpretation algorithms across laboratories and use of all-cause mortality to increase data compatibility and facilitate future efforts summarizing the utility of alternate prognostic markers in cancer.


Potentiation of the antidepressant action of clomipramine by tryptophan.
In a double-blind study of 24 patients with endogenous depressiona group treated with clomipramine hydrochloride (chlorimipramine) plus tryptophan was compared with a group treated with clomipramine plus placebo. The sum of the ratings for depressed mood, suicidal intent, depressive thought content, and anxiety showed a more rapid improvement in the former group, the difference being already significant after 12 days of treatment. On the other hand, the ratings for retardation decreased about equally in both groups during the three-week treatment period. Side-effect ratings showed no significant increase but seemed to be partly influenced by the improvement of depressive symptoms. Plasma levels of clomipramine appeared to reach a plateau within a few days, whereas the monodesmethylated metabolite continued to rise for a longer period of time, and reached considerably higher values than the parent compound. In the tryptophan group the degree of improvement seemed to be positively correlated to these levels, suggesting that further improvement might have been reached in some patients by increasing the dose of clomipramine. The levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid appeared to be reduced by clomipramine administration. This effect was prevented by the additional treatment with tryptophan.


Computed Tomography Angiography of Coronary Artery Bypass Grafts: Low Contrast Media Volume Protocols Adapted to Tube Voltage.
The aim of this study was to evaluate the potential of contrast media (CM) reduction in computed tomography angiography (CTA) of coronary artery bypass grafts (CABGs) when adapting CM volume to automatically selected tube voltages. Sixty consecutive patients (mean age, 71 ± 14.5 years) with a total of 176 CABGs (692 bypass segments) underwent contrast-enhanced prospectively electrocardiography-gated high-pitch CTA with automated, attenuation-based tube voltage selection (100 ref. peak kilovoltage [kVp], 200 ref. mAs, tube voltages from 70-150 kVp in 10-kVp steps) using a third-generation 192-slice dual-source computed tomography scanner. Volume and flow of CM (370 mg/mL iodine) was adapted according to the tube voltages using iodine attenuation-curves derived from a foregoing phantom study. In patients, CM volumes ranged from 80 mL (flow rate, 7 mL/s) at 120 kVp to 48 mL (flow rate, 4.2 mL/s) at 80 kVp. Two independent, blinded readers evaluated subjective image quality of the proximal anastomosis, bypass graft, distal anastomosis, and postanastomotic native coronary artery using a 3-point Likert scale. Objective image quality (attenuation of graft and noise) was determined and contrast-to-noise ratio (CNR) was calculated. Volume computed tomography dose index and dose-length product of each CTA examination were noted. Cohen κ was used to define interreader agreement of subjective image quality. Regression analysis was used to determine relationships between tube voltage and vascular attenuation, image noise, and CNR. Using attenuation-based tube voltage selection, 5 patients (8%) were scanned at 80 kVp, 22 (37%) at 90 kVp, 11 (18%) at 100 kVp, 10 (17%) at 110 kVp, and 12 (20%) at 120 kVp. Agreement in subjective image quality between readers was good (κ = 0.678). Diagnostic image quality was achieved in 679 of 692 (98%) bypass segments in 169 of 176 bypass grafts (96%). Thirteen of 692 bypass segments (2%) in 7 of 176 bypass grafts (4%) were rated as nondiagnostic because of severe artifacts caused by motion or beam hardening (2 proximal anastomoses of sequential bypasses, 3 graft bodies, 5 distal anastomoses, and 3 postanastomotic coronary artery segments). Regression analysis revealed no significant relationship between the automatically selected tube voltages and objective image quality parameters (bypass graft attenuation: P = 0.315; noise: P = 0.433; and CNR: P = 0.168), indicating homogenous attenuation, noise, and CNR across tube voltage levels. Mean volume computed tomography dose index was 4.0 ± 0.9 mGy, and mean dose length product was 135.0 ± 29.6 mGy*cm. Adapting CM protocols to automatically selected tube voltage levels allows for low-volume CM CTA examinations of CABG grafts with diagnostic image quality.


Immunohistochemical study of vascular injury in acute multiple sclerosis.
To examine the vascular changes occurring in three archival cases of acute multiple sclerosis, and to provide immunohistochemical evidence of early endothelial cell activation and vascular occlusion in this condition. Central nervous system tissues from three cases of acute active multiple sclerosis and six non-inflammatory controls were stained using the following methods: haematoxylin and eosin, Luxol fast blue, cresyl violet, Bielschowsky's silver, and reticulin. Tissues were also immunostained with specific antibodies against collagen type IV, factor XIIIa, class II antigens, glial fibrillary acidic protein, and fibrinogen. Early vascular endothelial cell activation which may progress to vasculitis and vascular occlusion including class II antigen expression and fibrin deposition were identified. The vascular changes were seen prior to cerebral parenchymal reaction and demyelination, and were not seen in control cerebral tissues. It is proposed that vascular endothelial cell activation may be an early and pivotal event in the evolution of multiple sclerosis, and that demyelination may have an ischaemic basis in this condition. The vascular endothelium may contain an early element in the evolution of multiple sclerosis.


Multiple forms of hotspots of tetrapod biodiversity and the challenges of open-access data scarcity.
The uneven spatial distribution of biodiversity is a defining feature of nature. In fact, the implementation of conservation actions both locally and globally has progressively been guided by the identification of biodiversity 'hotspots' (areas with exceptional biodiversity). However, different regions of the world differ drastically in the availability of fine-scale data on the diversity and distribution of species, thus limiting the potential to assess their local environmental priorities. Within South America-a megadiverse continent-Uruguay represents a peculiar area where multiple tropical and non-tropical eco-regions converge, creating highly heterogeneous ecosystems, but where the systematic quantification of biodiversity remains largely anecdotal. To investigate the constraints posed by the limited access to biodiversity data, we employ the most comprehensive database for tetrapod vertebrates in Uruguay (spanning 664 species) assembled to date, to identify hotspots of species-richness, endemism and threatened species for the first time. Our results reveal negligible spatial congruence among biodiversity hotspots, and that tetrapod sampling has historically concentrated in only a few areas. Collectively, our study provides a detailed account of the areas where urgent biodiversity monitoring efforts are needed to develop more accurate knowledge on biodiversity patterns, offering government and environmental bodies a critical scientific resource for future planning.


Brain metastases from an unknown primary tumour: which diagnostic procedures are indicated?
Seventy two patients presenting with symptomatic brain metastases from undiagnosed primary neoplasms were retrospectively reviewed. Primary malignancies were diagnosed before death in 54 patients and remained unknown in 18 patients. Lung cancer was the most common primary tumour (72%), followed by breast cancer, colon carcinoma, and melanoma. On physical examination, 51 patients had organ specific symptoms or signs providing guidelines to the diagnostic evaluation. In 24 of the 52 patients with a primary lung tumour, and in four of the 20 patients without, organ specific complaints or findings suggested this tumour type, resulting in a positive predictive value of 85%. Overall, radiography and CT of the chest were very useful in detection of primary lung tumours. This could partly be explained by the high prior probability of detecting such tumours. Other diagnostic procedures should be used on indication only. The prognosis of patients with confirmed primary tumour position did not differ from those with unidentified primary tumour.


Microfluidics in structured multimaterial fibers.
Traditional fabrication techniques for microfluidic devices utilize a planar chip format that possesses limited control over the geometry of and materials placement around microchannel cross-sections. This imposes restrictions on the design of flow fields and external forces (electric, magnetic, piezoelectric, etc.) that can be imposed onto fluids and particles. Here we report a method of fabricating microfluidic channels with complex cross-sections. A scaled-up version of a microchannel is dimensionally reduced through a thermal drawing process, enabling the fabrication of meters-long microfluidic fibers with nonrectangular cross-sectional shapes, such as crosses, five-pointed stars, and crescents. In addition, by codrawing compatible materials, conductive domains can be integrated at arbitrary locations along channel walls. We validate this technology by studying unexplored regimes in hydrodynamic flow and by designing a high-throughput cell separation device. By enabling these degrees of freedom in microfluidic device design, fiber microfluidics provides a method to create microchannel designs that are inaccessible using planar techniques.


Decreased short- and long-term swallowing problems with altered radiotherapy dosing used in an organ-sparing protocol for advanced pharyngeal carcinoma.
To determine the effect of a reduced radiotherapy dose on short- and long-term swallowing problems after organ-sparing treatment. Prospective case series. Tertiary care referral center. A consecutive sample of 29 patients with advanced oropharyngeal or hypopharyngeal cancer who were treated with intravenous hydroxyurea and concomitant hyperfractionated, accelerated radiotherapy. Initial experience with 74.4 Gy of radiation demonstrated severe long-term swallowing problems, prompting a dose reduction to 60.0 Gy. Eighteen patients were followed up for this study in the 74.4-Gy group, while 11 were in the 60.0-Gy group. Swallowing variables were assessed in both patient groups at 4 months and at 12 months following completion of therapy. Patient demographics and tumor characteristics were similar in each group, while significant differences were noted in the posttreatment clinical swallowing variables. Persistent severe odynophagia at 4 months (89% [16/18] vs 30% [3/10]) and at 12 months (64% [7/11] vs 11% [1/9]) was greater in the 74.4-Gy group (P =.002). Clinical signs of aspiration were also increased in the 74.4-Gy group, with 81% (13/16) vs 11% (1/9) at 4 months and 60% (6/10) vs 11% (1/9) at 12 months (P<.05). Most striking, however, was the incidence of long-term gastrostomy, with 78% (14/18) of patients receiving 74.4 Gy requiring gastrostomy feedings at 12 months compared with 18% (2/11) in the 60.0-Gy group (P =.002). Local control was unchanged by the altered dosing, with median follow-ups of 43.5 and 24.0 months in the 74.4-Gy and 60.0-Gy groups, respectively. Decreased radiation doses can maintain disease control and reduce treatment-related long-term swallowing complications.


Affective syndromes, psychotic features, and prognosis. I. Depression.
Prognosis is an important issue among patients who have psychotic features and a depressive syndrome; some have outcomes that suggest diagnostic revisions to schizophrenia, and this has far-reaching implications for treatment. To explore this issue, we used biannual evaluations to follow up 103 such individuals for 5 years. Patients with Research Diagnostic Criteria schizoaffective disorder experienced substantially more morbidity of various sorts than did patients with Research Diagnostic Criteria psychotic major depression. Within the group with schizoaffective disorder, patients with the chronic subtype experienced more morbidity than did those with nonchronic schizoaffective disorder; the mainly affective--mainly schizophrenic distinction had less prognostic significance. Factors that predicted sustained delusions at the end of follow-up were exclusively historical and suggested a poor-outcome prototype patient who is single, was socially impaired as an adolescent, and has a history of schizophrenialike psychotic features temporarily dissociated from affective symptoms.


Breast disease in children and adolescents in eastern Nigeria--a five-year study.
(1) To define the spectrum of breast diseases in the children and adolescents in Eastern Nigeria. (2) To provide where possible, an international comparison of statistical variations of both benign and malignant lesions in these age groups. The Morbid Anatomy Department of the University of Nigeria Teaching Hospital (UNTH) Enugu is a referral center for over 30 million people. The laboratory receives around 2,000 surgical pathology specimens per year. Virtually all children and adolescents (4-19) years who complained of a breast mass had a biopsy, and results of all excised breast specimens from children and adolescent age groups from 4 to 19 years were included in the study. The case files of these patients were retrieved and reviewed to ascertain the size and duration of the breast lesions. The number of phyllodes tumors seen in the child and adolescent population was compared to those seen in the adult population at the same period. Two independent pathologists reviewed the slides, and their results compared. A total of 1050 breast specimens were received in the department of morbid anatomy from all age groups, from January 1, 2000 to December 31, 2004, out of which 121 (11.5%) were breast specimens from the children and adolescent age groups. On the average most patients with benign breast lesions presented within 3-5 months of their symptoms, which usually was a palpable lump detected in all cases by either the child or the mother. Their sizes vary from 2-3 cm and only ten were multiple but they were all confined to one breast. Those with phyllodes presented typically within 3 months probably because of the faster rate of growth. Their sizes varied from 5-13 cm and they were all unilateral. Phyllodes tumor in this age group constitute 28.6% of all phyllodes seen in this period and were all benign. The mean age was approximately 11.5 years while the median age was 18 years. Three cases were malignant. Fibro adenoma, fibrocystic breast disease, and low grade phyllodes tumor were the most common breast lesions seen in our children and adolescent population. The three cases of malignancy observed included invasive intraductal carcinoma, a non-hodgkin lymphoma, and metastases involving the lymph nodes from an uncharacterized secondary malignancy. Phyllodes tumors were typically larger in size and tended to present earlier. Genetic characterization of such lesions is recommended for future studies as well as their relationship to lesions seen among other Africans in Diaspora.


Association of Obesity With In-Hospital Mortality of Cardiogenic Shock Complicating Acute Myocardial Infarction.
Several previous studies have shown obesity to be counterintuitively associated with more favorable mortality in patients with acute myocardial infarction (AMI); however, the association of obesity with in-hospital mortality of cardiogenic shock complicating AMI has not been previously examined. We queried the 2004 to 2013 National Inpatient Sample databases to identify all patients ≥18 years hospitalized with the principal diagnosis of AMI. Multivariable regression models adjusting for demographics, hospital characteristics, and co-morbidities were used to examine differences in incidence and in-hospital mortality of cardiogenic shock complicating AMI between obese and nonobese patients. Of 6,097,817 patients with AMI, 290,894 (4.8%) had cardiogenic shock. There was no difference in risk-adjusted incidence of cardiogenic shock between obese and nonobese patients (adjusted odds ratio 1.00, 95% CI 0.98 to 1.01; p = 0.46). Of the patients with cardiogenic shock complicating AMI, 8.9% had a documented diagnosis of obesity. Obese patients were on average 6 years younger and had higher prevalence of most cardiovascular co-morbidities. Obese patients were more likely to receive revascularization (73.0% vs 63.4%, p <0.001) and had lower risk-adjusted in-hospital mortality compared with nonobese patients (28.2% vs 36.5%; adjusted odds ratio 0.89, 95% CI 0.86 to 0.92; p <0.001). Similar findings were seen in subgroups of patients with cardiogenic shock complicating ST elevation or non-ST elevation MI. In conclusion, this large retrospective analysis of a nationwide cohort of patients with cardiogenic shock complicating AMI demonstrated that obese patients were younger, more likely to receive revascularization, and had modestly lower risk-adjusted in-hospital mortality compared with nonobese patients.


Optical polishing pitches: impact frequency responses and indentation depths.
The short-term dynamic properties of a wide range of commercially available optical polishing pitches were determined with an impact frequency response test. A simple dynamic model is presented to evaluate the relevance of the measurement variations across the range of pitches tested. Test results show that harder pitches have higher natural frequencies and lower damping ratios. Strong correlations between pitch hardness (as measured by the indent test) and the natural frequency only existed among pitches from the same series, i.e., the Gugolz or Acculap series. This implies that pitches with similar hardness values from different manufacturers have different dynamic properties.


Structural and Functional Determinants of gamma-Secretase, an Intramembrane Protease Implicated in Alzheimer's Disease.
Alzheimer's disease is the most common form of neurodegenerative diseases in humans, characterized by the progressive accumulation and aggregation of amyloid-beta peptides (Abeta) in brain regions subserving memory and cognition. These 39-43 amino acids long peptides are generated by the sequential proteolytic cleavages of the amyloid-beta precursor protein (APP) by beta- and gamma-secretases, with the latter being the founding member of a new class of intramembrane-cleaving proteases (I-CliPs) characterized by their intramembranous catalytic residues hydrolyzing the peptide bonds within the transmembrane regions of their respective substrates. These proteases include the S2P family of metalloproteases, the Rhomboid family of serine proteases, and two aspartyl proteases: the signal peptide peptidase (SPP) and gamma-secretase. In sharp contrast to Rhomboid and SPP that function as a single component, gamma-secretase is a multi-component protease with complex assembly, maturation and activation processes. Recently, two low-resolution three-dimensional structures of gamma-secretase and three high-resolution structures of the GlpG rhomboid protease have been obtained almost simultaneously by different laboratories. Although these proteases are unrelated by sequence or evolution, they seem to share common functional and structural mechanisms explaining how they catalyze intramembrane proteolysis. Indeed, a water-containing chamber in the catalytic cores of both gamma-secretase and GlpG rhomboid provides the hydrophilic environment required for proteolysis and a lateral gating mechanism controls substrate access to the active site. The studies that have identified and characterized the structural determinants critical for the assembly and activity of the gamma-secretase complex are reviewed here.


Functional connectivity in the prefrontal cortex measured by near-infrared spectroscopy during ultrarapid object recognition.
Near-infrared spectroscopy (NIRS) is a developing technology for low-cost noninvasive functional brain imaging. With multichannel optical instruments, it becomes possible to measure not only local changes in hemoglobin concentrations but also temporal correlations of those changes in different brain regions which gives an optical analog of functional connectivity traditionally measured by fMRI. We recorded hemodynamic activity during the Go-NoGo task from 11 right-handed subjects with probes placed bilaterally over prefrontal areas. Subjects were detecting animals as targets in natural scenes pressing a mouse button. Data were low-pass filtered<1 Hz and cardiac∕respiration∕superficial layers artifacts were removed using Independent Component Analysis. Fisher's transformed correlations of poststimulus responses (30 s) were averaged over groups of channels unilaterally in each hemisphere (intrahemispheric connectivity) and the corresponding channels between hemispheres (interhemispheric connectivity). The hemodynamic response showed task-related activation (an increase∕decrease in oxygenated∕deoxygenated hemoglobin, respectively) greater in the right versus left hemisphere. Intra- and interhemispheric functional connectivity was also significantly stronger during the task compared to baseline. Functional connectivity between the inferior and the middle frontal regions was significantly stronger in the right hemisphere. Our results demonstrate that optical methods can be used to detect transient changes in functional connectivity during rapid cognitive processes.


Randomized trial of diethylstilbestrol vs. tamoxifen in postmenopausal women with metastatic breast cancer. An updated analysis.
One hundred fifty-one postmenopausal women with progressive metastatic breast cancer and no prior hormonal therapy were treated with either diethylstilbestrol (DES) or tamoxifen (TAM). One hundred forty-three eligible patients were followed until death or for a minimum of 14.1 years on the DES arm or 16.7 years on the TAM arm. The overall objective response was 42% for DES and 33% for TAM (p = 0.31) and the median duration of response was 11.8 months for DES and 9.9 months for TAM (p = 0.38). Duration of response and progression-free survival were not found to be significantly different between DES and TAM (p = 0.32 and 0.65, respectively). The median survival was 3.0 years for DES vs. 2.4 years for TAM. The 5-year survival was 35% for the DES arm and 16% for the TAM arm. Survival was significantly better for women on DES than for women on TAM (adjusted p = 0.039). Review of records did not show any difference in pattern of treatment failure or subsequent treatments in the DES and TAM arms. Treatment with DES was more commonly associated with toxicity such as nausea, edema, vaginal bleeding, and cardiac problems, whereas hot flashes were commonly seen with TAM therapy. The initial treatment with DES is associated with increased survival. The basis of this survival advantage is not known. TAM still is the preferred agent in the treatment of metastatic breast cancer, but this trial underscores the fact that estrogens have activity and remain in the armamentarium for treatment of selected patients with metastatic breast cancer.


Image-guided frameless stereotactic needle biopsy in awake patients without the use of rigid head fixation.
Image-guided frameless stereotactic techniques provide an alternative to traditional head-frame fixation in the performance of fine-needle biopsies. However, these techniques still require rigid head fixation, usually in the form of a head holder. The authors report on a series of fine-needle biopsies and brain abscess aspirations in which a frameless technique was used with a patient's head supported on a horseshoe headholder. To validate this technique, they performed an in vitro accuracy study. Forty-eight patients underwent fine-needle biopsy of intracranial lesions that ranged in size from 0.9 to more than 107.7 ml; a fiducial-less, frameless, image-guided technique was used without rigid head fixation. In 1 of the 48 patients a cerebral abscess was drained. The accuracy study was performed with a skull phantom that was imaged with a CT scanner and tracked with a registration mask containing light-emitting diodes. The objective was a skin fiducial marker with a 4-mm circular target to accommodate the 2.5-mm biopsy needle. A series of 50 trials was conducted. Diagnostic tissue was obtained on the first attempt in 47 of 48 brain biopsy cases. In 2 cases small hemorrhages at the biopsy site were noted as a complication on the postoperative CT scan. One of these hemorrhages resulted in hand and arm weakness. The accuracy study demonstrated a 98% success rate of the biopsy needle passing through the 4-mm circular target using the registration mask as the registration and tracking device. This demonstrates a ± 0.75-mm tolerance on the targeting method. The accuracy study demonstrated the ability of the mask to actively track the target and allow navigation to a 4-mm-diameter circular target with a 98% success rate. The frameless, pinless, fiducial-less technique described herein will likely be another safe, fast alternative to frame-based stereotactic techniques for fine-needle biopsy that avoids the potential morbidity of rigid head-pin fixation. Furthermore, it should lend itself to other image-guided applications such as the placement of ventricular catheters for shunting or Ommaya reservoirs.


Mucosal biofilms of Candida albicans.
Biofilms are microbial communities that form on surfaces and are embedded in an extracellular matrix. C. albicans forms pathogenic mucosal biofilms that are evoked by changes in host immunity or mucosal ecology. Mucosal surfaces are inhabited by many microbial species; hence these biofilms are polymicrobial. Several recent studies have applied paradigms of biofilm analysis to study mucosal C. albicans infections. These studies reveal that the Bcr1 transcription factor is a master regulator of C. albicans biofilm formation under diverse conditions, though the most relevant Bcr1 target genes can vary with the biofilm niche. An important determinant of mucosal biofilm formation is the interaction with host defenses. Finally, studies of interactions between bacterial species and C. albicans provide insight into the communication mechanisms that endow polymicrobial biofilms with unique properties.


Impact of Mean Cell Hemoglobin on Hb A1c-Defined Glycemia Status.
Several hematological alterations are associated with altered hemoglobin A1c (Hb A1c). However, there have been no reports of their influence on the rates of exceeding standard Hb A1c thresholds by patients for whom Hb A1c determination is requested in clinical practice. The initial data set included the first profiles (complete blood counts, Hb A1c, fasting glucose, and renal and hepatic parameters) of all adult patients for whom such a profile was requested between 2008 and 2013 inclusive. After appropriate exclusions, 21844 patients remained in the study. Linear and logistic regression models were adjusted for demographic, hematological, and biochemical variables excluded from the predictors. Mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV) correlated negatively with Hb A1c. Fasting glucose, MCH, and age emerged as predictors of Hb A1c in a stepwise regression that discarded sex, hemoglobin, MCV, mean corpuscular hemoglobin concentration (MCHC), serum creatinine, and liver disease. Mean Hb A1c in MCH interdecile intervals fell from 6.8% (51 mmol/mol) in the lowest (≤27.5 pg) to 6.0% (43 mmol/mol) in the highest (>32.5 pg), with similar results for MCV. After adjustment for fasting glucose and other correlates of Hb A1c, a 1 pg increase in MCH reduced the odds of Hb A1c-defined dysglycemia, diabetes and poor glycemia control by 10%-14%. For at least 25% of patients, low or high MCH or MCV levels are associated with increased risk of an erroneous Hb A1c-based identification of glycemia status. Although causality has not been demonstrated, these parameters should be taken into account in interpreting Hb A1c levels in clinical practice.


Teaching undergraduate students in rural general practice: an evaluation of a new rural campus in England.
One approach to facilitating student interactions with patient pathways at Keele University School of Medicine, England, is the placement of medical students for 25% of their clinical placement time in general practices. The largest component is a 15-week 'student attachment' in primary care during the final year, which required the development of a new network of teaching practices in a rural district of England about 90 km (60 mi) from the main campus in North Staffordshire. The new accommodation and education hub was established in 2011-2012 to enable students to become immersed in those communities and learn about medical practice within a rural and remote context. Objectives were to evaluate the rural teaching from the perspectives of four groups: patients, general practice tutors, community hospital staff and students. Learning outcomes (as measured by objective structured clinical examinations) of students learning in rural practices in the final year were compared with those in other practices. Data were gathered from a variety of sources. Students' scores in cohort-wide clinical assessment were compared with those in other locations. Semi-structured interviews were conducted with general practice tutors and community hospital staff. Serial focus groups explored the perceptions of the students, and questionnaires were used to gather the views of patients. Patients reported positive experiences of students in their consultations, with 97% expressing willingness to see students. The majority of patients considered that teaching in general practice was a good thing. They also expressed altruistic ideas about facilitating learning. The tutors were enthusiastic and perceived that teaching had positive impacts on their practices despite negative effects on their workload. The community hospital staff welcomed students and expressed altruistic ideas about helping them learn. There was no significant difference between the rurally placed students' objective structured clinical examination performance and that of their peers in other locations. Some students had difficulty with the isolation from peers and academic activities, and travel was a problem despite their accommodation close to the practices. Students valued the learning opportunities offered by the rural practice placements. The general practice tutors, patients and community hospital staff found teaching to be a positive experience overall and perceived a value to the health system and broader community in students learning locally for substantial periods of time. The evaluation has identified some student concerns about transport times and costs, social isolation, and access to resources and administrative tasks, and these are being addressed.