Dissection of class III major histocompatibility complex haplotypes associated with rheumatoid arthritis.
We have previously identified a single-nucleotide polymorphism (SNP) haplotype involving the lymphotoxin alpha (LTA) and tumor necrosis factor (TNF) loci (termed haplotype LTA-TNF2) on chromosome 6 that shows differential association with rheumatoid arthritis (RA) on HLA-DRB1*0404 and *0401 haplotypes, suggesting the presence of additional non-HLA-DRB1 RA susceptibility genes on these haplotypes. To refine this association, we performed a case-control association study using both SNPs and microsatellite markers in haplotypes matched either for HLA-DRB1*0404 or for HLA-DRB1*0401. Fourteen SNPs lying between HLA-DRB1 and LTA were genotyped in 87 DRB1*04-positive families. High-density microsatellite typing was performed using 24 markers spanning 2,500 kb centered around the TNF gene in 305 DRB1*0401 or *0404 cases and 400 DRB1*0401 or *0404 controls. Single-marker, 2-marker, and 3-marker minihaplotypes were constructed and their frequencies compared between the DRB1*0401 and DRB1*0404 matched case and control haplotypes. Marked preservation of major histocompatibility complex haplotypes was seen, with chromosomes carrying LTA-TNF2 and either DRB1*0401 or DRB1*0404 both carrying an identical SNP haplotype across the 1-Mb region between TNF and HLA-DRB1. Using microsatellite markers, we observed two 3-marker minihaplotypes that were significantly overrepresented in the DRB1*0404 case haplotypes (P = 0.00024 and P = 0.00097). The presence of a single extended SNP haplotype between LTA-TNF2 and both DRB1*0401 and DRB1*0404 is evidence against this region harboring the genetic effects in linkage disequilibrium with LTA-TNF2. Two RA-associated haplotypes on the background of DRB1*0404 were identified in a 126-kb region surrounding and centromeric to the TNF locus.


Prevalence of aflatoxin B1 in liver biopsies of proven hepatocellular carcinoma in India determined by an in-house immunoperoxidase test.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death in the world. The incidence of HCC in India is reportedly low and varies from 0.2 to 1.9 %. Aflatoxins, secondary metabolites produced by Aspergillus flavus and Aspergillus parasiticus, are potent human carcinogens implicated in HCC. The prevalence of aflatoxin B1 (AFB1) as co-carcinogen was analysed using an in-house immunoperoxidase test in 31 liver biopsies and 7 liver-resection specimens from histopathologically proven HCC, and in 15 liver biopsies from cirrhosis patients (control group). Serum was tested for hepatitis B and C serological markers using commercial assays, and for AFB1 using an in-house ELISA with a sensitivity of approximately 1 ng ml(-1) for AFB1. In spite of positive AFB1 immunostaining in HCC cases, all serum specimens, from both HCC and the control groups, were AFB1-negative. There were 18 (58.1 %) HCC cases that revealed AFB1 in liver biopsies; 68.8 % (n=11) of non-B non-C hepatitis cases with HCC and 46.1 % (n=6) of the hepatitis B surface-antigen-positive subjects were positive for AFB1. Out of the two hepatitis B/hepatitis C virus co-infected cases, one was positive for AFB1. Of seven tumour-resection samples, six were positive for AFB1. Only one case revealed AFB1 in the non-tumour area of the resected material. Thus AFB1 staining was significantly associated with tumour tissue (P=0.03). Aflatoxins proved to have a significant association with HCC in this peninsular part of the subcontinent. The impact seems to be a cumulative process, as revealed by the AFB1 deposits in HCC liver tissue, even though the serum levels were undetectable.


Patterns of ambulatory medical care utilization in elderly patients with special reference to chronic diseases and multimorbidity--results from a claims data based observational study in Germany.
In order to estimate the future demands for health services, the analysis of current utilization patterns of the elderly is crucial. The aim of this study is to analyze ambulatory medical care utilization by elderly patients in relation to age, gender, number of chronic conditions, patterns of multimorbidity, and nursing dependency in Germany. Claims data of the year 2004 from 123,224 patients aged 65 years and over which are members of one nationwide operating statutory insurance company in Germany were studied. Multimorbidity was defined as the presence of 3 or more chronic conditions of a list of 46 most prevalent chronic conditions based on ICD 10 diagnoses. Utilization was analyzed by the number of contacts with practices of physicians working in the ambulatory medical care sector and by the number of different physicians contacted for every single chronic condition and their most frequent triadic combinations. Main statistical analyses were multidimensional frequency counts with standard deviations and confidence intervals, and multivariable linear regression analyses. Multimorbid patients had more than twice as many contacts per year with physicians than those without multimorbidity (36 vs. 16). These contact frequencies were associated with visits to 5.7 different physicians per year in case of multimorbidity vs. 3.5 when multimorbidity was not present. The number of contacts and of physicians contacted increased steadily with the number of chronic conditions. The number of contacts varied between 35 and 54 per year and the number of contacted physicians varied between 5 to 7, depending on the presence of individual chronic diseases and/or their triadic combinations. The influence of gender or age on utilization was small and clinically almost irrelevant. The most important factor influencing physician contact was the presence of nursing dependency due to disability. In absolute terms, we found a very high rate of utilization of ambulatory medical care by the elderly in Germany, when multimorbidity and especially nursing dependency were present. The extent of utilization by the elderly was related both to the number of chronic conditions and to the individual multimorbidity patterns, but not to gender and almost not to age.


Network modeling identifies molecular functions targeted by miR-204 to suppress head and neck tumor metastasis.
Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1-22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases.


Using Technology to Facilitate Fidelity Assessments: The Tele-STAR Caregiver Intervention.
Families living with Alzheimer disease and related dementias have more access to support thanks to the development of effective telehealth-based programs. However, as technological science grows, so does the risk that these technology-based interventions will diverge from foundational protocols, diluting their efficacy. Strategies that ensure programs are delivered as intended, with fidelity to guiding protocols, are needed across the intervention spectrum-from development to wide-scale implementation. Few papers address fidelity in their technology-based work. Here, we present our translated telehealth intervention, Tele-STAR, with our fidelity findings. This study aimed to assess the preliminary efficacy of Tele-STAR on reducing family caregiver burden and depression. Across the implementation phases, we assessed the fidelity of a caregiver education intervention, STAR-C, as it was translated into a telehealth option (Tele-STAR). A total of 13 family caregivers consented to participate in an 8-week, videoconference-based intervention (Tele-STAR). Tele-STAR efficacy in reducing the affective burden of caregiving was assessed using pre- and postintervention paired t tests. Content experts assessed program fidelity by reviewing and rating Tele-STAR materials for adherence to the original STAR-C protocol. These experts assessed treatment fidelity by viewing videos of the intervention and rating adherence on a checklist. Tele-STAR reduced caregiver burden and retained good program and treatment fidelity to STAR-C. We found Tele-STAR reduced caregiver burden and had good fidelity to the original protocol. Assessing fidelity is a complex process that requires incorporation of these procedures early in the research process. The technology used in this study facilitated the accrual of informative data about the fidelity of our translated intervention, Tele-STAR.


Flexor tendon repairs: the impact of fiberwire on grasping and locking core sutures.
Immediate surgical repair and early mobilization are essential in preventing adhesion formation and finger stiffness. A new polyethylene-based, braided suture material, Fiberwire (Arthrex, Naples, FL), touting increased strength, presents the potential for stronger repairs and, therefore, earlier active motion after surgery with a greater safety margin. The purpose of this biomechanic study was to investigate the differences in gap formation, tensile strength, and mode of failure for 2 distinct repair techniques using nylon, Ethibond (Ethicon, Somerville, NJ), and Fiberwire. Human cadaver flexor tendons were harvested and repaired in a randomized fashion with either the Strickland or Massachusetts General Hospital (MGH) repairs using either nylon, Ethibond, or Fiberwire. Twelve tendons per group were repaired for each combination of material and method. During load-to-failure testing, 2-mm gap force and maximum tensile strength were statistically analyzed. Strickland repairs failed by suture pull-out in 74% of repairs, whereas 99% of the MGH repairs failed by suture breakage. For MGH repairs, Fiberwire suture provided significantly more tensile strength than Ethibond and nylon. For Strickland repairs, where the mode of failure was more often by suture pull-out rather than breakage, differences between type of suture were not significant. When comparing repair techniques using Fiberwire, the MGH repair was significantly stronger than the Strickland repair. Biomechanic testing shows that Fiberwire outperforms both Ethibond and nylon suture when using a locked flexor tendon repair suture (MGH repair) but not when using a grasping-type, nonlocking repair (Strickland repair).


Genetic Testing Awareness and Attitudes among Latinos: Exploring Shared Perceptions and Gender-Based Differences.
Latinos, whose views are infrequently examined in genomic research, may be at risk of missing out on the benefits of genomic medicine. To explore this possibility, we conducted a qualitative study of awareness and attitudes about genetic testing among Latinos with lower acculturation in New York City. We conducted four focus groups (7 English-speaking men, 5 Spanish-speaking men, 13 English-speaking women and 13 Spanish-speaking women) to explore factors that influence the adoption of new innovations through the discussion of genetic testing in general, and a hypothetical vignette describing a genetic test for skin cancer risk, in particular. Through inductive thematic text analysis of focus group transcripts, our multidisciplinary team identified themes within knowledge and attitudes, communication and sources of information, anticipated responses, factors that may increase adoption, and barriers to adoption of genetic testing. Specifically, a majority of participants expressed some degree of uncertainty regarding the purpose of genetic tests and information these tests provide, rarely discussed genetic testing with others in their social networks, and expressed concerns about the misuse of and possible adverse emotional responses to genetic information. However, participants also expressed high levels of interest in receiving a skin cancer genetic test in response to the vignette and believed that receiving actionable health information was a primary reason to consider testing. Gender-based differences in perceived barriers to testing emerged. The results highlight beliefs and barriers that future interventions could target to help ensure that Latinos have adequate understanding of and access to genomic medicine advances.


Lymphoma immunotherapy: vaccines, adoptive cell transfer and immunotransplant.
Therapy for non-Hodgkin lymphoma has benefited greatly from basic science and clinical research such that chemotherapy and monoclonal antibody therapy have changed some lymphoma subtypes from uniformly lethal to curable, but the majority of lymphoma patients remain incurable. Novel therapies with less toxicity and more specific targeting of tumor cells are needed and immunotherapy is among the most promising of these. Recently completed randomized trials of idiotype vaccines and earlier-phase trials of other vaccine types have shown the ability to induce antitumor T cells and some clinical responses. More recently, trials of adoptive transfer of antitumor T cells have demonstrated techniques to increase the persistence and antitumor effect of these cells. Herein, we discuss lymphoma immunotherapy clinical trial results and what lessons can be taken to improve their effect, including the combination of vaccination and adoptive transfer in an approach we have dubbed 'immunotransplant'.


Undergraduate training in occupational health at Kocaeli University Medical School: a Turkish experience.
Processes and conditions of production may produce unhealthy effects. Both must therefore be included in the education of health care personnel. Vocational training in occupational health at Kocaeli University Medical School, Turkey aims to demonstrate students that occupational health is a specific and important area of work within the context of primary health care. This research is a cross-sectional study. It was planned as a three stage study: 1- reviewing literature and grouping of countries according to their occupational health curricula; 2- reviewing the occupational health programs of medical schools in Turkey, and 3- recommendations for an occupational health curriculum to include an occupational health vocational training period of one week in the two month public health education program for medical interns. During this experience, senior students would be assigned to workplace health units. Of 283 medical schools found on the web, with occupational health teaching, only 20 have a curriculum that includes training in workplace health care units. In Turkey, there is no structured practical education on occupational health. In the third part of this study, we initiated at Kocaeli University School of Medicine's curriculum, a new occupational health education model applied in the workplace health units of factories. Practical experience of occupational health in the workplace is useful in introducing the community-based approach to occupational health in undergraduate medical education and understanding the determinants of health in industry.


Hypochlorous acid stress in Escherichia coli: resistance, DNA damage, and comparison with hydrogen peroxide stress.
We have investigated the mechanisms of killing of Escherichia coli by HOCl by identifying protective functions. HOCl challenges were performed on cultures arrested in stationary phase and in exponential phase. Resistance to HOCl in both cases was largely mediated by genes involved in resistance to hydrogen peroxide (H2O2). In stationary phase, a mutation in rpoS, which controls the expression of starvation genes including those which protect against oxidative stress, renders the cells hypersensitive to killing by HOCl. RpoS-regulated genes responsible for this sensitivity were dps, which encodes a DNA-binding protein, and, to a lesser extent, katE and katG, encoding catalases; all three are involved in resistance to H2O2. In exponential phase, induction of the oxyR regulon, an adaptive response to H2O2, protected against HOCl exposure, and the oxyR2 constitutive mutant is more resistant than the wild-type strain. The genes involved in this oxyR-dependent resistance have not yet been identified, but they differ from those primarily involved in resistance to H2O2, including katG, ahp, and dps. Pretreatment with HOCl conferred resistance to H2O2 in an OxyR-independent manner, suggesting a specific adaptive response to HOCl. fur mutants, which have an intracellular iron overload, were more sensitive to HOCl, supporting the generation of hydroxyl radicals upon HOCl exposure via a Fenton-type reaction. Mutations in recombinational repair genes (recA or recB) increased sensitivity to HOCl, indicative of DNA strand breaks. Sensitivity was visible in the wild type only at concentrations above 0.6 mg/liter, but it was observed at much lower concentrations in dps recA mutants.


Synthetic cells produce a quorum sensing chemical signal perceived by Pseudomonas aeruginosa.
Recent developments in bottom-up synthetic biology (e.g., lipid vesicle technology integrated with cell-free protein expression systems) allow the generation of semi-synthetic minimal cells (in short, synthetic cells, SCs) endowed with some distinctive capacities of natural cells. In particular, such approaches provide technological tools and conceptual frameworks for the design and engineering of programmable SCs capable of communicating with natural cells by exchanging chemical signals. Here we describe the generation of giant vesicle-based SCs which, via gene expression, synthesize in their aqueous lumen an enzyme that in turn produces a chemical signal. The latter is a small molecule, which is passively released in the medium and then perceived by the bacterium Pseudomonas aeruginosa, demonstrating that SCs and bacteria can communicate chemically. The results pave the way to a novel basic and applied research area where synthetic cells can communicate with natural cells, for example for exploring minimal cognition, developing chemical information technologies, and producing smart and programmable drug-producing/drug-delivery systems.


Permanent draft genome sequence of Desulfurococcus mobilis type strain DSM 2161, a thermoacidophilic sulfur-reducing crenarchaeon isolated from acidic hot springs of Hveravellir, Iceland.
This report presents the permanent draft genome sequence of Desulfurococcus mobilis type strain DSM 2161, an obligate anaerobic hyperthermophilic crenarchaeon that was isolated from acidic hot springs in Hveravellir, Iceland. D. mobilis utilizes peptides as carbon and energy sources and reduces elemental sulfur to H2S. A metabolic construction derived from the draft genome identified putative pathways for peptide degradation and sulfur respiration in this archaeon. Existence of several hydrogenase genes in the genome supported previous findings that H2 is produced during the growth of D. mobilis in the absence of sulfur. Interestingly, genes encoding glucose transport and utilization systems also exist in the D. mobilis genome though this archaeon does not utilize carbohydrate for growth. The draft genome of D. mobilis provides an additional mean for comparative genomic analysis of desulfurococci. In addition, our analysis on the Average Nucleotide Identity between D. mobilis and Desulfurococcus mucosus suggested that these two desulfurococci are two different strains of the same species.


Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach.
The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis. A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction. The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal-air interface, forming a 'secretion layer' in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%. The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric 'acid pocket'.


A source of glycosylated human T-cell lymphotropic virus type 1 envelope protein: expression of gp46 by the vaccinia virus/T7 polymerase system.
Heterologous expression of the human T-cell lymphotropic virus type 1 (HTLV-1) envelope surface glycoprotein (gp46) in a vaccinia virus/T7 polymerase system resulted in the production of authentic recombinant gp46. Five differentially glycosylated forms of the surface envelope protein were produced by this mammalian system, as demonstrated by tunicamycin inhibition of N-glycosylation and N-glycan removal with endoglycosidase H and glycopeptidase F. These studies revealed that all four potential N-glycosylation sites in gp46 were used for oligosaccharide modification and that the oligosaccharides were mannose-rich and/or hybrid in composition. Conformational integrity of the recombinant HTLV-1 envelope protein was determined by the ability to bind to various HTLV-1-infected human sera and a panel of conformational-dependent human monoclonal antibodies under nondenaturing conditions. Furthermore, this recombinant gp46 was recognized by a series of HTLV-2-infected human sera and sera from a Pan paniscus chimpanzee infected with the distantly related simian T-cell lymphotropic virus STLVpan-p. Maintenance of highly conserved conformational epitopes in the recombinant HTLV-1 envelope protein structure suggests that it may serve as a useful diagnostic reagent and an effective vaccine candidate.


Issues in health reform: how changes in eligibility may move millions back and forth between medicaid and insurance exchanges.
The Affordable Care Act will extend health insurance coverage by both expanding Medicaid eligibility and offering premium subsidies for the purchase of private health insurance through state health insurance exchanges. But by definition, eligibility for these programs is sensitive to income and can change over time with fluctuating income and changes in family composition. The law specifies no minimum enrollment period, and subsidy levels will also change as income rises and falls. Using national survey data, we estimate that within six months, more than 35 percent of all adults with family incomes below 200 percent of the federal poverty level will experience a shift in eligibility from Medicaid to an insurance exchange, or the reverse; within a year, 50 percent, or 28 million, will. To minimize the effect on continuity and quality of care, states and the federal government should adopt strategies to reduce the frequency of coverage transitions and to mitigate the disruptions caused by those transitions. Options include establishing a minimum guaranteed eligibility period and "dually certifying" some plans to serve both Medicaid and exchange enrollees.


Use of Regional Anesthesia for Outpatient Surgery Within the United States: A Prevalence Study Using a Nationwide Database.
Regional anesthesia is of benefit for outpatient surgery given its demonstrated improvement in analgesia and decrease in complications, resulting in shorter average recovery room times and lower hospital readmission rates. Unfortunately, there are few epidemiological studies outlining the overall utilization of peripheral nerve blocks (PNBs) in this setting. Therefore, the primary objective of this study was to report the overall utilization of several types of PNBs among all candidate cases in the outpatient setting within the United States. We identified all cases from the National Anesthesia Clinical Outcomes Registry that were performed as an outpatient surgery. We reported the frequency of various types of PNBs among all candidate cases, defined as cases that potentially could have received a PNB. Changes in prevalence of PNB utilization from 2010 to 2015 were analyzed by using logistic regression. Of the 12,911,056 outpatient surgeries in the National Anesthesia Clinical Outcomes Registry, 3,297,372 (25.5%) were amenable to a PNB. However, the overall PNB frequency was only 3.3% of the possible cases. The overall utilization for PNB of the brachial plexus, sciatic nerve, and femoral nerve were 6.1%, 1.5%, and 1.9%, respectively. The surgical procedures generating the highest volume of PNBs were shoulder arthroscopies and anterior cruciate ligament reconstruction, in which 41% and 32% received a PNB, respectively. During this time period, there was a significant increase in overall PNB utilization for both single-injection and continuous PNB (P < .0001). However, the proportion of continuous PNB to single-injection PNB did not increase significantly. While the overall frequency of PNB is relatively low, there was a significant increase in its prevalence during the study period. Regional anesthesia offers significant positive impact for perioperative outcomes and hospital efficiency metrics; however, it is not clear what is limiting its widespread use. Future studies are necessary to identify barriers and disparities in care to implement methods to increase regional anesthesia volume nationwide where beneficial and appropriate.


Label consistent K-SVD: learning a discriminative dictionary for recognition.
A label consistent K-SVD (LC-KSVD) algorithm to learn a discriminative dictionary for sparse coding is presented. In addition to using class labels of training data, we also associate label information with each dictionary item (columns of the dictionary matrix) to enforce discriminability in sparse codes during the dictionary learning process. More specifically, we introduce a new label consistency constraint called "discriminative sparse-code error" and combine it with the reconstruction error and the classification error to form a unified objective function. The optimal solution is efficiently obtained using the K-SVD algorithm. Our algorithm learns a single overcomplete dictionary and an optimal linear classifier jointly. The incremental dictionary learning algorithm is presented for the situation of limited memory resources. It yields dictionaries so that feature points with the same class labels have similar sparse codes. Experimental results demonstrate that our algorithm outperforms many recently proposed sparse-coding techniques for face, action, scene, and object category recognition under the same learning conditions.


Rapid identification of pathogenic streptococci isolated from moribund red tilapia (Oreochromis spp.).
Accurate and rapid identification of bacterial pathogens of fish is essential for the effective treatment and speedy control of infections. Massive mortalities in market-sized red tilapia (Oreochromis spp.) were noticed in mariculture concrete ponds in northern Egypt. Histopathological examination revealed marked congestion in the central vein of the liver with the presence of bacterial aggregates inside the lumen and in the vicinity of the central vein. A total of 12 isolates of streptococci were obtained from the moribund fish. This study documented the ability of the MicroSeq 500 16S bacterial sequencing method to accurately identify Streptococcus agalactiae and S. dysgalactiae mixed infections from moribund red tilapia that were difficult to be recognised by the commercial biochemical systems. The continuously decreasing cost of the sequencing technique should encourage its application in routine diagnostic procedures.


TU-E-213AB-02: The Regulatory Path to Achieve QMP Requirement.
Licensure for medical physicists has been pursued for a number of years, with success in some states and failure in others. Lessons from these cases has been used to strengthen the licensure effort, but they have also demonstrated that licensure may not be an option in some states. In such cases, we still need a methodology to achieve credentialing and practice standards. A comprehensive registration approach may provide that methodology. This talk will discuss features of comprehensive registration, along with positive and negative aspects of the approach. It will be demonstrated that comprehensive registration is a viable alternative that can be used when licensure is not achievable. 1. Understand the differences between licensure and the regulatory approach. 2. Learn how the regulatory approach can achieve the goal of requiring se of Qualified Medical Physicists with an appropriate scope of practice. 3. Discuss ways of working with regulators to implement regulatory changes. 4. Discuss potential draft regulatory language.


Modeling emotion in complex stories: the Stanford Emotional Narratives Dataset.
Human emotions unfold over time, and more affective computing research has to prioritize capturing this crucial component of real-world affect. Modeling dynamic emotional stimuli requires solving the twin challenges of time-series modeling and of collecting high-quality time-series datasets. We begin by assessing the state-of-the-art in time-series emotion recognition, and we review contemporary time-series approaches in affective computing, including discriminative and generative models. We then introduce the first version of the Stanford Emotional Narratives Dataset (SENDv1): a set of rich, multimodal videos of self-paced, unscripted emotional narratives, annotated for emotional valence over time. The complex narratives and naturalistic expressions in this dataset provide a challenging test for contemporary time-series emotion recognition models. We demonstrate several baseline and state-of-the-art modeling approaches on the SEND, including a Long Short-Term Memory model and a multimodal Variational Recurrent Neural Network, which perform comparably to the human-benchmark. We end by discussing the implications for future research in time-series affective computing.


FOXM1 confers acquired cisplatin resistance in breast cancer cells.
The transcription factor Forkhead box M1 (FOXM1) is a key regulator of cell proliferation and is overexpressed in many forms of primary cancers, leading to uncontrolled cell division and genomic instability. To address the role of FOXM1 in chemoresistance, we generated a cisplatin-resistant breast cancer cell line (MCF-7-CIS(R)), which had an elevated level of FOXM1 protein and mRNA expression relative to the parental MCF-7 cells. A close correlation was observed between FOXM1 and the expression of its proposed downstream targets that are involved in DNA repair; breast cancer-associated gene 2 (BRCA2) and X-ray cross-complementing group 1 (XRCC1) were expressed at higher levels in the resistant cell lines compared with the sensitive MCF-7 cells. Moreover, cisplatin treatment induced DNA damage repair in MCF-7-CIS(R) and not in MCF-7 cells. Furthermore, the expression of a constitutively active FOXM1 (DeltaN-FOXM1) in MCF-7 cells alone was sufficient to confer cisplatin resistance. Crucially, the impairment of DNA damage repair pathways through the small interfering RNA knockdown inhibition of either FOXM1 or BRCA2/XRCC1 showed that only the silencing of FOXM1 could significantly reduce the rate of proliferation in response to cisplatin treatment in the resistant cells. This suggests that the targeting of FOXM1 is a viable strategy in circumventing acquired cisplatin resistance. Consistently, the FOXM1 inhibitor thiostrepton also showed efficacy in causing cell death and proliferative arrest in the cisplatin-resistant cells through the downregulation of FOXM1 expression. Taken together, we have identified a novel mechanism of acquired cisplatin resistance in breast cancer cells through the induction of FOXM1.


Awareness, attitude and perceived barriers regarding implementation of the Cigarettes and Other Tobacco Products Act in Assam, India.
Tobacco use is a major public health problem in India. The Cigarettes and Other Tobacco Products Act (COTPA) was developed to curb this epidemic. Because no study has been conducted on the awareness, attitude and perceived barriers regarding the implementation of COTPA, this study was undertaken. A community-based cross-sectional survey was conducted among 300 adults (mean age 41 years, 52% men) selected by cluster sampling method from Guwahati Municipal Corporation. Information on awareness, attitude and their predictors and barriers for implementation was collected using a pretested, structured interview schedule. Multivariate analysis was done using SPSS. Adults older than 50 years were 3 times (odds ratio [OR] 3.02, 95% CI 1.44-6.31) and those with more than 10 years of schooling were 4 times (OR 3.60, 95% CI 1.70-7.70) more likely to have good awareness of COTPA compared with their counter parts. Those belonging to the middle socioeconomic status (SES) were 3 times (OR 3.36, 95% CI 1.13-10.01), those who reported secondhand smoking harmful were 3 times (OR 3.32, 95% CI 1.45-7.62), and those with more than 10 years of schooling were 3 times (OR 2.92, 95% CI 1.01-8.45) more likely to have positive attitude toward COTPA compared with their counterparts. Lack of complete information and awareness of the Act, public opposition, cultural acceptance of tobacco use, lack of political support, and less priority for tobacco control were reported as barriers for COTPA implementation. Efforts should be made to increase the awareness of COTPA focusing on younger population, less educated, and those belonging to the low SES.


Robustness and evolvability of the human signaling network.
Biological systems are known to be both robust and evolvable to internal and external perturbations, but what causes these apparently contradictory properties? We used Boolean network modeling and attractor landscape analysis to investigate the evolvability and robustness of the human signaling network. Our results show that the human signaling network can be divided into an evolvable core where perturbations change the attractor landscape in state space, and a robust neighbor where perturbations have no effect on the attractor landscape. Using chemical inhibition and overexpression of nodes, we validated that perturbations affect the evolvable core more strongly than the robust neighbor. We also found that the evolvable core has a distinct network structure, which is enriched in feedback loops, and features a higher degree of scale-freeness and longer path lengths connecting the nodes. In addition, the genes with high evolvability scores are associated with evolvability-related properties such as rapid evolvability, low species broadness, and immunity whereas the genes with high robustness scores are associated with robustness-related properties such as slow evolvability, high species broadness, and oncogenes. Intriguingly, US Food and Drug Administration-approved drug targets have high evolvability scores whereas experimental drug targets have high robustness scores.


Fortunella margarita transcriptional reprogramming triggered by Xanthomonas citri subsp. citri.
Citrus canker disease caused by the bacterial pathogen Xanthomonas citri subsp. citri (Xcc) has become endemic in areas where high temperature, rain, humidity, and windy conditions provide a favourable environment for the dissemination of the bacterium. Xcc is pathogenic on many commercial citrus varieties but appears to elicit an incompatible reaction on the citrus relative Fortunella margarita Swing (kumquat), in the form of a very distinct delayed necrotic response. We have developed subtractive libraries enriched in sequences expressed in kumquat leaves during both early and late stages of the disease. The isolated differentially expressed transcripts were subsequently sequenced. Our results demonstrate how the use of microarray expression profiling can help assign roles to previously uncharacterized genes and elucidate plant pathogenesis-response related mechanisms. This can be considered to be a case study in a citrus relative where high throughput technologies were utilized to understand defence mechanisms in Fortunella and citrus at the molecular level. cDNAs from sequenced kumquat libraries (ESTs) made from subtracted RNA populations, healthy vs. infected, were used to make this microarray. Of 2054 selected genes on a customized array, 317 were differentially expressed (P < 0.05) in Xcc challenged kumquat plants compared to mock-inoculated ones. This study identified components of the incompatible interaction such as reactive oxygen species (ROS) and programmed cell death (PCD). Common defence mechanisms and a number of resistance genes were also identified. In addition, there were a considerable number of differentially regulated genes that had no homologues in the databases. This could be an indication of either a specialized set of genes employed by kumquat in response to canker disease or new defence mechanisms in citrus. Functional categorization of kumquat Xcc-responsive genes revealed an enhanced defence-related metabolism as well as a number of resistant response-specific genes in the kumquat transcriptome in response to Xcc inoculation. Gene expression profile(s) were analyzed to assemble a comprehensive and inclusive image of the molecular interaction in the kumquat/Xcc system. This was done in order to elucidate molecular mechanisms associated with the development of the hypersensitive response phenotype in kumquat leaves. These data will be used to perform comparisons among citrus species to evaluate means to enhance the host immune responses against bacterial diseases.


Nuclear aggregation of olfactory receptor genes governs their monogenic expression.
Gene positioning and regulation of nuclear architecture are thought to influence gene expression. Here, we show that, in mouse olfactory neurons, silent olfactory receptor (OR) genes from different chromosomes converge in a small number of heterochromatic foci. These foci are OR exclusive and form in a cell-type-specific and differentiation-dependent manner. The aggregation of OR genes is developmentally synchronous with the downregulation of lamin b receptor (LBR) and can be reversed by ectopic expression of LBR in mature olfactory neurons. LBR-induced reorganization of nuclear architecture and disruption of OR aggregates perturbs the singularity of OR transcription and disrupts the targeting specificity of the olfactory neurons. Our observations propose spatial sequestering of heterochromatinized OR family members as a basis of monogenic and monoallelic gene expression.


CLUE: a randomized comparative effectiveness trial of IV nicardipine versus labetalol use in the emergency department.
Our purpose was to compare the safety and efficacy of food and drug administration (FDA) recommended dosing of IV nicardipine versus IV labetalol for the management of acute hypertension. Multicenter randomized clinical trial. Eligible patients had 2 systolic blood pressure (SBP) measures ≥180 mmHg and no contraindications to nicardipine or labetalol. Before randomization, the physician specified a target SBP ± 20 mmHg (the target range: TR). The primary endpoint was the percent of subjects meeting TR during the initial 30 minutes of treatment. Of 226 randomized patients, 110 received nicardipine and 116 labetalol. End organ damage preceded treatment in 143 (63.3%); 71 nicardipine and 72 labetalol patients. Median initial SBP was 212.5 (IQR 197, 230) and 212 mmHg (IQR 200,225) for nicardipine and labetalol patients (P = 0.68), respectively. Within 30 minutes, nicardipine patients more often reached TR than labetalol (91.7 vs. 82.5%, P = 0.039). Of 6 BP measures (taken every 5 minutes) during the study period, nicardipine patients had higher rates of five and six instances within TR than labetalol (47.3% vs. 32.8%, P = 0.026). Rescue medication need did not differ between nicardipine and labetalol (15.5 vs. 22.4%, P = 0.183). Labetalol patients had slower heart rates at all time points (P < 0.01). Multivariable modeling showed nicardipine patients were more likely in TR than labetalol patients at 30 minutes (OR 2.73, P = 0.028; C stat for model = 0.72) Patients treated with nicardipine are more likely to reach the physician-specified SBP target range within 30 minutes than those treated with labetalol.


Outcomes of bracing in juvenile idiopathic scoliosis until skeletal maturity or surgery.
Retrospective comparative study. To evaluate the outcome of bracing in patients with juvenile idiopathic scoliosis (JIS) at either skeletal maturity or time of scoliosis surgery. JIS is generally thought to have poor outcomes with high rates of surgical fusion. All patients with JIS between the ages of 4 and 10 years treated with a brace at the Hospital for Sick Children (SickKids) between 1989 and 2011 were eligible. Data were collected from patient health records until either 2 years after skeletal maturity or date of surgery. The average age at diagnosis of 88 patients with JIS was 8.4 ± 1.4 years, with a female to male ratio of approximately 8:1. Pretreatment, Risser score was zero for 80 patients (91%); 72 (92%) of the females were premenarche; and primary Cobb angles ranged from 20° to 71°. Of the 88 patients, 60 (68%) had used a thoracolumbosacral orthosis exclusively; 28 (32%) patients used "other braces" (Milwaukee, Charleston, or a combination of braces), with an average treatment duration of 3.6 ± 1.9 years.As per Scoliosis Research Society definitions, a "non-curve-progression" (≤5° change) group consisted of 25 (28%) patients; and a "curve-progression" group consisted of 63 (72%) patients where the curve had progressed 6° or more.Of the 88 patients, 44 (50%) underwent surgery. The operative rate was higher for patients with curves 30° or more than those with curves 20° to 29° prior to brace treatment (37/58 [64%] vs. 7/30 [23%], respectively; P = 0.001); other braces compared with thoracolumbosacral orthosis (19/28 [68%] vs. 25/60 [42%], respectively; P = 0.02); Lenke I and III curves compared with Lenke VI curves (33/54 [61%] vs. 2/14 [14%], respectively; P = 0.007).


Shape Memory Silk Protein Sponges for Minimally Invasive Tissue Regeneration.
Porous silk protein scaffolds are designed to display shape memory characteristics and volumetric recovery following compression. Two strategies are utilized to realize shape recovery: addition of hygroscopic plasticizers like glycerol, and tyrosine modifications with hydrophilic sulfonic acid chemistries. Silk sponges are evaluated for recovery following 80% compressive strain, total porosity, pore size distribution, secondary structure development, in vivo volume retention, cell infiltration, and inflammatory responses. Glycerol-modified sponges recover up to 98.3% of their original dimensions following compression, while sulfonic acid/glycerol modified sponges swell in water up to 71 times their compressed volume, well in excess of their original size. Longer silk extraction times (lower silk molecular weights) and higher glycerol concentrations yielded greater flexibility and shape fidelity, with no loss in modulus following compression. Sponges are over 95% porous, with secondary structure analysis indicating glycerol-induced β-sheet physical crosslinking. Tyrosine modifications with sulfonic acid interfere with β-sheet formation. Glycerol-modified sponges exhibit improved rates of cellular infiltration at subcutaneous implant sites with minimal immune response in mice. They also degrade more rapidly than unmodified sponges, a result posited to be cell-mediated. Overall, this work suggests that silk sponges may be useful for minimally invasive deployment in soft tissue augmentation procedures.


Electrochemical instability of highly fluorinated tetraphenyl borates and syntheses of their respective biphenyls.
Highly fluorinated tetraphenyl borate anions are of importance as weakly coordinating anions in metalorganic reactions. However, at high positive potentials their electrochemical stability in organic solvents is not sufficient. This was investigated by a comprehensive cyclic voltammetry study and can be used synthetically to generate highly fluorinated biphenyls.


Dynamic expression of Dab2 in the mouse embryonic central nervous system.
Dab2, one of two mammalian orthologs of Drosophila Disabled, has been shown to be involved in cell positioning and formation of visceral endoderm during mouse embryogenesis, but its role in neuronal development is not yet fully understood. In this report, we have examined the localization of the Dab2 protein in the mouse embryonic central nervous system (CNS) at different developmental stages. Dab2 protein was transiently expressed in rhombomeres 5 and 6 of the developing hindbrain between E8.5 and E11.5, and in the floor plate of the neural tube from E9.5 to E12.5, following which it was no longer detectable within these regions. Dab2 protein was also identified within circumventricular organs including the choroid plexus, subcommissural organ and pineal gland during their early development. While Dab2 was still strongly expressed in the adult choroid plexus, immunoreactivity within the subcommissural organ and pineal gland was lost after birth. In addition, Dab2 was transiently expressed within a subpopulation of Iba1-positive mononuclear phagocytes (including presumed microglial progenitors) within the neural tube from E10.0 and was lost by E14.5. Dab2 was separately localized to Iba1 positive cells from E9.5 and subsequently to F4/80 positive cells (mature macrophage/myeloid-derived dendritic cells) positioned outside the neural tube from E12.5 onwards, implicating Dab2 expression in early cells of the mononuclear phagocyte lineage. Dab2 did not co-localize with the pan-neuronal marker PGP9.5 at any developmental stage, suggesting that Dab2 positive cells in the developing CNS are unlikely to be differentiating neurons. This is the first study to demonstrate the dynamic spatiotemporal expression of Dab2 protein within the CNS during development.


U.S. Food and Drug Administration anticancer drug approval trends from 2016 to 2018 for lung, colorectal, breast, and prostate cancer.
This paper aims to describe the clinical and regulatory aspects of new drugs and indications that were approved for lung, breast, prostate, and colorectal cancer, from 2016 to 2018, in order to provide health technology assessment trends in oncology. Data were collected from the US Food and Drug Administration (FDA) online database for new medications and indications approved for the above-mentioned types of cancer. Data regarding clinical study characteristics and regulatory information were collected. From 2016 to 2018, 53 percent of the FDA approvals of new drugs and indications for the most incident cancers were for oral protein kinase inhibitor monotherapy for advanced lung cancer. Since 2018, four drugs were approved as tumor-agnostic therapies. A biomarker was included in 72 percent of indications, and 58 percent of approvals were for targeted therapies, potentially heralding an end to research into conventional cytotoxic agents. A special designation for faster approval was granted in 78 percent of new approvals. The majority of the studies were open label randomized controlled trials (RCTs) (44 percent), followed by blind RCTs, single-arm clinical trials, and cohort studies. Only 14 percent of studies used overall survival as the primary end point; the vast majority used surrogate end points, and did not use patient-important outcomes. Three biosimilars were approved in the period. Advanced lung cancer therapy, mainly targeted drugs, accounted for 53 percent of approvals. Special designations for faster approval were used in 78 percent of FDA approvals, and four drugs were approved for tumor-agnostic treatment-a new form of approval.


The human ZC3H3 and RBM26/27 proteins are critical for PAXT-mediated nuclear RNA decay.
Recruitment of the human ribonucleolytic RNA exosome to nuclear polyadenylated (pA+) RNA is facilitated by the Poly(A) Tail eXosome Targeting (PAXT) connection. Besides its core dimer, formed by the exosome co-factor MTR4 and the ZFC3H1 protein, the PAXT connection remains poorly defined. By characterizing nuclear pA+-RNA bound proteomes as well as MTR4-ZFC3H1 containing complexes in conditions favoring PAXT assembly, we here uncover three additional proteins required for PAXT function: ZC3H3, RBM26 and RBM27 along with the known PAXT-associated protein, PABPN1. The zinc-finger protein ZC3H3 interacts directly with MTR4-ZFC3H1 and loss of any of the newly identified PAXT components results in the accumulation of PAXT substrates. Collectively, our results establish new factors involved in the turnover of nuclear pA+ RNA and suggest that these are limiting for PAXT activity.


The eyespot resistance genes Pch1 and Pch2 of wheat are not homoeoloci.
Phenotyping and mapping data reveal that chromosome intervals containing eyespot resistance genes Pch1 and Pch2 on 7D and 7A, respectively, do not overlap, and thus, these genes are not homoeloci. Eyespot is a stem-base fungal disease of cereals growing in temperate regions. Two main resistances are currently available for use in wheat. Pch1 is a potent single major gene transferred to wheat from Aegilops ventricosa and located on the distal end of chromosome 7D. Pch2, a moderate resistance deriving from Cappelle Desprez, is located at the end of 7AL. The relative positions of Pch1 and Pch2 on 7D and 7A, respectively, suggest that they are homoeoloci. A single seed decent recombinant F7 population was used to refine the position of Pch2 on 7A. New markers designed to 7D also allowed the position of Pch1 to be further defined. We exploited the syntenic relationship between Brachypodium distachyon and wheat to develop 7A and 7D specific KASP markers tagging inter-varietal and interspecific SNPs and allow the comparison of the relative positions of Pch1 and Pch2 on 7D and 7A. Together, phenotyping and mapping data reveal that the intervals containing Pch1 and Pch2 do not overlap, and thus, they cannot be considered homoeloci. Using this information, we analysed two durum wheat lines carrying Pch1 on 7A to determine whether the Ae.ventricosa introgression extended into the region associated with Pch2. This identified that the introgression is distal to Pch2 on 7A, providing further evidence that the genes are not homoeoloci. However, it is feasible to use this material to pyramid Pch1 and Pch2 on 7A in a tetraploid background and also to increase the copy number of Pch1 in combination with Pch2 in a hexaploid background.


Acute promyelocytic transformation in a case of acute myelomonocytic leukemia.
An unusual case of acute myelomonocytic leukemia, with marked bone marrow eosinophilia and basophilia, is described in which there was cytogenetic evidence at presentation of acute promyelocytic transformation, with acquisition of the standard 15;17 translocation.


Mitotic chromosome alignment ensures mitotic fidelity by promoting interchromosomal compaction during anaphase.
Chromosome alignment at the equator of the mitotic spindle is a highly conserved step during cell division; however, its importance to genomic stability and cellular fitness is not understood. Normal mammalian somatic cells lacking KIF18A function complete cell division without aligning chromosomes. These alignment-deficient cells display normal chromosome copy numbers in vitro and in vivo, suggesting that chromosome alignment is largely dispensable for maintenance of euploidy. However, we find that loss of chromosome alignment leads to interchromosomal compaction defects during anaphase, abnormal organization of chromosomes into a single nucleus at mitotic exit, and the formation of micronuclei in vitro and in vivo. These defects slow cell proliferation and are associated with impaired postnatal growth and survival in mice. Our studies support a model in which the alignment of mitotic chromosomes promotes proper organization of chromosomes into a single nucleus and continued proliferation by ensuring that chromosomes segregate as a compact mass during anaphase.


Microglia control neuronal network excitability via BDNF signalling.
Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K⁺-Cl⁻ cotransporter KCC2, dysrupting Cl⁻ homeostasis, and hence the strength of GABA(A)- and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions.


Dig1 protects against cell death provoked by glyphosate-based herbicides in human liver cell lines.
Worldwide used pesticides containing different adjuvants like Roundup formulations, which are glyphosate-based herbicides, can provoke some in vivo toxicity and in human cells. These pesticides are commonly found in the environment, surface waters and as food residues of Roundup tolerant genetically modified plants. In order to know their effects on cells from liver, a major detoxification organ, we have studied their mechanism of action and possible protection by precise medicinal plant extracts called Dig1. The cytotoxicity pathways of four formulations of glyphosate-based herbicides were studied using human hepatic cell lines HepG2 and Hep3B, known models to study xenobiotic effects. We monitored mitochondrial succinate dehydrogenase activity and caspases 3/7 for cell mortality and protection by Dig1, as well as cytochromes P450 1A1, 1A2, 3A4 and 2C9 and glutathione-S-transferase to approach the mechanism of actions. All the four Roundup formulations provoke liver cell death, with adjuvants having stronger effects than glyphosate alone. Hep3B are 3-5 times more sensitive over 48 h. Caspases 3/7 are greatly activated in HepG2 by Roundup at non-cytotoxic levels, and some apoptosis induction by Roundup is possible together with necrosis. CYP3A4 is specifically enhanced by Roundup at doses 400 times less than used in agriculture (2%). CYP1A2 is increased to a lesser extent together with glutathione-S-transferase (GST) down-regulation. Dig 1, non cytotoxic and not inducing caspases by itself, is able to prevent Roundup-induced cell death in a time-dependant manner with an important efficiency of up to 89%, within 48 h. In addition, we evidenced that it prevents Caspases 3/7 activation and CYP3A4 enhancement, and not GST reduction, but in turn it slightly inhibited CYP2C9 when added before Roundup. Roundup is able to provoke intracellular disruption in hepatic cell lines at different levels, but a mixture of medicinal plant extracts Dig1 can protect to some extent human cell lines against this pollutants. All this system constitutes a tool for studying liver intoxication and detoxification.


Changing Face of Family Planning Funding in Kenya: A Cross-Sectional Survey of Two Urban Counties.
As international development partners reduce funding for family planning (FP) programs, the need to estimate the financial resources devoted to FP is becoming increasingly important both at all levels. This cross-sectional assessment examined the FP financing sources, agents, and expenditures in two counties of Kenya for fiscal years 2010/2011 and 2011/2012 to guide local decision-making on financial allocations. Data were collected through a participatory process. This involved stakeholder interviews, review of financial records and service statistics, and a survey of facilities offering FP services. Financing sources and agents were identified, and source amounts calculated. Types of FP provider organizations and the amounts spent by expenditure categories were identified. Overall, five financing sources and seven agents for FP were identified. Total two-year expenditures were KSh 307.8 M (US$ 3.62 M). The government's share of funding rose from 12% to 21% over the two years (p=0.029). In 2010/2011, the largest expense categories were administration, commodities, and labor; however, spending on commodities increased by 47% (p=0.042). This study provides local managers with FP financing and expenditure information for use in budget allocation decision-making. These analyses can be done routinely and replicated in other local counties or countries in a context of devolution.


Orbital volume augmentation after injection of human orbital adipose-derived stem cells in rabbits.
This randomized, controlled animal study investigated the morphologic and histologic properties of rabbit orbital fat following injection of human orbital adipose-derived stem cells (hoADSCs). The efficacy of hoADSCs was compared to that of hyaluronic acid gel (HAG) and human orbital stromal vascular fraction (hoSVF). A total of 30 orbits from 15 New Zealand white rabbits (25 weeks postnatal, 2500-3000 g) underwent injection with HAG (molecular weight [MW] 1,000,000, 0.5 mL, n = 10, HAG only), hoSVF (0.25 mL) mixed with HAG (0.25 mL, n = 10, HAG + hoSVF), or hoADSCs (0.25 mL) mixed with HAG (0.25 mL, n = 10, HAG + hoADSCs). The degree of proptosis, and the time course of changes were determined and compared among groups. The difference between the initial exophthalmometric value and that at 4 weeks after injection was 1.77 mm for HAG only and 2.01 mm for HAG + hoSVF. The difference between the initial value and that at 12 weeks decreased to 0.05 mm for HAG only and 0.24 mm for HAG + hoSVF. In contrast, injection of HAG + hoADSCs increased the exophthalmometric value by 2.43 mm at 4 weeks after injection, and this difference was maintained at 2.56 mm at 12 weeks. Histopathologic examination revealed specific inflammation around the injection materials at 4 weeks after injection, and inflammation subsided 8 weeks after injection in all three groups. Thus, transplantation of hoADSCs with HAG is a safe and effective technique for orbital fat volume expansion. This is a new and promising method for orbital reconstruction and aesthetic orbital volume augmentation.


Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity.
The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background. We used a special study design of "clonal controls," rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean +/- standard deviation (SD) age 25.8 +/- 1.4 y and a body mass index (BMI) difference 5.2 +/- 1.8 kg/m(2). Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults. Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance.


Undisclosed financial ties between guideline writers and pharmaceutical companies: a cross-sectional study across 10 disease categories.
To investigate the proportion of potentially relevant undisclosed financial ties between clinical practice guideline writers and pharmaceutical companies. Cross-sectional study of a stratified random sample of Australian guidelines and writers. Guidelines available from Australia's National Health and Medical Research Council guideline database, 2012-2014, stratified across 10 health priority areas. 402 authors of 33 guidelines, including up to four from each area, dependent on availability: arthritis/musculoskeletal (3); asthma (4); cancer (4); cardiovascular (4); diabetes (4); injury (3); kidney/urogenital (4); mental health (4); neurological (1); obesity (1). For guideline writers with no disclosures, or who disclosed no ties, a search of disclosures in the medical literature in the 5 years prior to guideline publication identified potentially relevant ties, undisclosed in guidelines. Guidelines were included if they contained recommendations of medicines, and writers included if developing or writing guidelines. Proportions of guideline writers with potentially relevant undisclosed financial ties to pharmaceutical companies active in the therapeutic area; proportion of guidelines including at least one writer with a potentially relevant undisclosed tie. 344 of 402 writers (86%; 95% CI 82% to 89%) either had no published disclosures (228) or disclosed they had no ties (116). Of the 344 with no disclosed ties, 83 (24%; 95% CI 20% to 29%) had potentially relevant undisclosed ties. Of 33 guidelines, 23 (70%; 95% CI 51% to 84%) included at least one writer with a potentially relevant undisclosed tie. Writers of guidelines developed and funded by governments were less likely to have undisclosed financial ties (8.1%vs30.6%; risk ratio 0.26; 95% CI 0.13 to 0.53; p<0.001). Almost one in four guideline writers with no disclosed ties may have potentially relevant undisclosed ties to pharmaceutical companies. These data confirm the need for strategies to ensure greater transparency and more independence in relationships between guidelines and industry.


Global health, global surgery and mass casualties. I. Rationale for integrated mass casualty centres.
It has been well-documented recently that 5 billion people globally lack surgical care. Also well-documented is the need to improve mass casualty disaster response. Many of the United Nations (UN) Sustainable Development Goals (SDGs) for 2030-healthcare and economic milestones-require significant improvement in global surgical care, particularly in low-income and middle-income countries. Trauma/stroke centres evolved in high-income countries with evidence that 24/7/365 surgical and critical care markedly improved morbidity and mortality for trauma and stroke and for cardiovascular events, difficult childbirth, acute abdomen. Duplication of emergency services, especially civilian and military, often results in suboptimal, expensive care. By combining all healthcare resources within the ongoing healthcare system, more efficient care for both individual emergencies and mass casualty situations can be achieved. We describe progress in establishing mass casualty centres in Chile and Pakistan. In both locations, planning among the stakeholders (primarily civilian and military) indicates the feasibility of such integrated surgical and emergency care. We also review other programmes and initiatives to provide integrated mass casualty disaster response. Integrated mass casualty centres are a feasible means to improve both day-to-day surgical care and mass casualty disaster response. The humanitarian aspect of mass casualty disasters facilitates integration among stakeholders-from local healthcare systems to military resources to international healthcare organisations. The benefits of mass casualty centres-both healthcare and economic-can facilitate achieving the 2030 UN SDGs.


Epithelial cell identity in hyperplastic precursors of breast cancer.
In the adult human breast, hyperplastic enlarged lobular unit (HELU) and atypical ductal hyperplasia (ADH) are two common abnormalities that frequently coexist with ductal carcinoma in situ (DCIS). For this reason, they have been proposed as the early steps in a biological continuum toward breast cancer. We investigated in silico the expression of 369 genes experimentally recognized as involved in establishing and maintaining epithelial cell identity and mammary gland remodeling, in HELUs or ADHs with respect to the corresponding patient-matched normal tissue. Despite the common luminal origin, HELUs and ADHs proved to be characterized by distinct gene profiles that overlap for 5 genes only. While HELUs were associated with the overexpression of progesterone receptor (PGR), ADHs were characterized by the overexpression of estrogen receptor 1 (ESR1) coupled with the overexpression of some proliferation-associated genes. This unexpected finding contradicts the notion that in differentiated luminal cells the expression of estrogen receptor (ER) is dissociated from cell proliferation and suggests that the establishing of an ER-dependent signaling is able to sustain cell proliferation in an autocrine manner as an early event in tumor initiation. Although clinical evidence indicates that only a fraction of HELUs and ADHs evolve to invasive cancer, present findings warn that exposure to synthetic progestins, frequently administered as hormone-replacement therapy, and estrogens, when abnormally produced by adipose cells and persistently present in the stroma surrounding the mammary gland, may cause these hyperplastic lesions.


Diagnostic value of antibodies against a modified citrullinated vimentin in rheumatoid arthritis.
Antibodies directed against citrullinated vimentin are members of the family of autoantibodies reactive with citrullinated proteins and are among the most specific serological markers for the diagnosis of rheumatoid arthritis (RA). This study was performed to test the diagnostic value of a newly developed enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies against a genetically modified citrullinated vimentin (anti-MCV) in comparison with a second-generation anti-cyclic citrullinated peptides (anti-CCP2) ELISA test system. Blinded sera from 631 patients (409 consecutive out-patients and 222 randomly selected stored sera) with RA (n = 164) and non-RA (osteoarthritis [n = 120], polymyalgia rheumatica/giant cell arteritis [n = 80], spondyloarthritis [n = 36], and other inflammatory rheumatic or non-inflammatory disease [n = 67]) were tested for the presence of anti-MCV and anti-CCP2 antibodies according to the manufacturers' instructions. The diagnostic performance of the anti-MCV was comparable with the anti-CCP2 assay for the diagnosis of RA according to the calculated area under the curve (0.824; 95% confidence interval (CI) 0.778-0.870 versus 0.818; 95% CI 0.767-0.869) as analysed by receiving operating characteristic curve. When categorised with a cutoff value of 20.0 U/ml (as recommended by the manufacturer), sensitivity and specificity of the anti-MCV ELISA were 69.5% (95% CI 61.9%-76.5%) and 90.8% (86.9%-93.8%), respectively, compared with 70.1% (62.5%-77.0%) and 98.7% (96.7%-99.6%) of the anti-CCP2 assay. Using the cutoff values of 19.0 U/ml and 81.5 U/ml for the anti-MCV test to obtain a sensitivity and specificity identical to the anti-CCP2 assay, showed a reduced specificity (89.8%; 85.8%-92.9%) and sensitivity (53.7%; 45.7%-61.5%), respectively, of the anti-MCV ELISA compared with the anti-CCP2 test. In conclusion, the serum ELISA testing for anti-MCV antibodies as well as the anti-CCP-2 assay perform comparably well in the diagnosis of RA. In the high-specificity range, however, the anti-CCP2 assay appears to be superior to the anti-MCV test.


Generalizing self-organizing map for categorical data.
The self-organizing map (SOM) is an unsupervised neural network which projects high-dimensional data onto a low-dimensional grid and visually reveals the topological order of the original data. Self-organizing maps have been successfully applied to many fields, including engineering and business domains. However, the conventional SOM training algorithm handles only numeric data. Categorical data are usually converted to a set of binary data before training of an SOM takes place. If a simple transformation scheme is adopted, the similarity information embedded between categorical values may be lost. Consequently, the trained SOM is unable to reflect the correct topological order. This paper proposes a generalized self-organizing map model that offers an intuitive method of specifying the similarity between categorical values via distance hierarchies and, hence, enables the direct process of categorical values during training. In fact, distance hierarchy unifies the distance computation of both numeric and categorical values. The unification is done by mapping the values to distance hierarchies and then measuring the distance in the hierarchies. Experiments on synthetic and real datasets were conducted, and the results demonstrated the effectiveness of the generalized SOM model.


Efficacy of a near-infrared light device in pediatric intravenous cannulation: a randomized controlled trial.
To determine whether the use of a near-infrared light venipuncture aid (VeinViewer; Luminetx Corporation, Memphis, Tenn) would improve the rate of successful first-attempt placement of intravenous (IV) catheters in a high-volume pediatric emergency department (ED). Patients younger than 20 years with standard clinical indications for IV access were randomized to have IV placement by ED nurses (in 3 groups stratified by 5-year blocks of nursing experience) using traditional methods (standard group) or with the aid of the near-infrared light source (device group). If a vein could not be cannulated after 3 attempts, patients crossed over from one study arm to the other, and study nurses attempted placement with the alternative technique. The primary end point was first-attempt success rate for IV catheter placement. After completion of patient enrollment, a questionnaire was completed by study nurses as a qualitative assessment of the device. A total of 123 patients (median age, 3 years) were included in the study: 62 in the standard group and 61 in the device group. There was no significant difference in first-attempt success rate between the standard (79.0%, 95% confidence interval [CI], 66.8%-88.3%) and device (72.1%, 95% CI, 59.2%-82.9%) groups. Of the 19 study nurses, 14 completed the questionnaire of whom 70% expressed neutral or unfavorable assessments of the device in nondehydrated patients without chronic underlying medical conditions and 90% found the device a helpful tool for patients in whom IV access was difficult. First-attempt success rate for IV placement was nonsignificantly higher without than with the assistance of a near-infrared light device in a high-volume pediatric ED. Nurses placing IVs did report several benefits to use of the device with specific patient groups, and future research should be conducted to demonstrate the role of the device in these patients.


Asian herbal-tobacco cigarettes: "not medicine but less harmful"?
To describe the development and health claims of Asian herbal-tobacco cigarettes. Analysis of international news sources, company websites, and the transnational tobacco companies' (TTC) documents. PubMed searches of herbs and brands. Twenty-three brands were identified, mainly from China. Many products claimed to relieve respiratory symptoms and reduce toxins, with four herb-only products advertised for smoking cessation. No literature was found to verify the health claims, except one Korean trial of an herb-only product. Asian herbal-tobacco cigarettes were initially produced by China by the 1970s and introduced to Japan in the 1980s. Despite initial news about research demonstrating a safer cigarette, the TTC analyses of these cigarettes suggest that these early products were not palatable and had potentially toxic cardiovascular effects. By the late 1990s, China began producing more herbal-tobacco cigarettes in a renewed effort to reduce harmful constituents in cigarettes. After 2000, tobacco companies from Korea, Taiwan, and Thailand began producing similar products. Tobacco control groups in Japan, Taiwan, and Thailand voiced concern over the health claims of herbal-tobacco products. In 2005, China designated two herbal-tobacco brands as key for development. Asian herbal-tobacco cigarettes claim to reduce harm, but no published literature is available to verify these claims or investigate unidentified toxicities. The increase in Asian herbal-tobacco cigarette production by 2000 coincides with the Asian tobacco companies' regular scientific meetings with TTCs and their interest in harm reduction. Asia faces additional challenges in tobacco control with these culturally concordant products that may discourage smokers from quitting.


Cellular inhibitor of apoptosis protein-1 (cIAP1) can regulate E2F1 transcription factor-mediated control of cyclin transcription.
The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein-1) is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-κB signaling pathways in the cytoplasm. However, in some primary cells and tumor cell lines, cIAP1 is expressed in the nucleus, and its nuclear function remains poorly understood. Here, we show that the N-terminal part of cIAP1 directly interacts with the DNA binding domain of the E2F1 transcription factor. cIAP1 dramatically increases the transcriptional activity of E2F1 on synthetic and CCNE promoters. This function is not conserved for cIAP2 and XIAP, which are cytoplasmic proteins. Chromatin immunoprecipitation experiments demonstrate that cIAP1 is recruited on E2F binding sites of the CCNE and CCNA promoters in a cell cycle- and differentiation-dependent manner. cIAP1 silencing inhibits E2F1 DNA binding and E2F1-mediated transcriptional activation of the CCNE gene. In cells that express a nuclear cIAP1 such as HeLa, THP1 cells and primary human mammary epithelial cells, down-regulation of cIAP1 inhibits cyclin E and A expression and cell proliferation. We conclude that one of the functions of cIAP1 when localized in the nucleus is to regulate E2F1 transcriptional activity.


Fibroblast radiosensitivity measured using the comet DNA-damage assay correlates with clonogenic survival parameters.
A study was made of the neutral comet assay as a potential method for measuring normal cell radiosensitivity. Eleven fibroblast strains were studied comprising nine derived from vaginal biopsies from pretreatment cervical cancer patients and two strains from radiosensitive individuals. DNA double strand break (dsbs) dose-response curves for both initial and residual (20-h repair time) damage were obtained over the dose range 0-240 Gy, with slopes varying 3.2 and 8-fold respectively. Clonogenic cell survival parameters were available for all the cell strains following both high- and low-dose rate irradiation. There were no correlations between the dose-response slope of the initial level of DNA dsbs and parameters that mainly describe the initial portion of clonogenic radiation survival curves (SF2, alpha, D). A significant correlation (r = -0.63, P = 0.04) was found between the extent of residual DNA dsbs and clonogenicity for all 11 fibroblast strains. The parameter showing the highest correlation with fibroblast cell killing (D) for the nine normal fibroblasts alone was the ratio of initial/residual DNA dsb dose-response slope (r = 0.80, P = < 0.01). A significant correlation (r = -0.67, P = 0.03) with clonogenic radiosensitivity was also found for all 11 cell strains when using the ratio of initial/residual DNA dsb damage at a single dose of 180 Gy. This study shows that fibroblast radiosensitivity measured using the neutral comet assay correlates with clonogenic radiation survival parameters, and therefore may have potential value in predictive testing of normal tissue radiosensitivity.


Inhibiting protein arginine deiminases has antioxidant consequences.
Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.


Key Features Of Peer Support In Chronic Disease Prevention And Management.
Peer support from community health workers, promotores de salud, and others through community and health care organizations can provide social support and other assistance that enhances health. There is substantial evidence for both the effectiveness and the cost-effectiveness of peer support, as well as for its feasibility, reach, and sustainability. We discuss findings from Peers for Progress, a program of the American Academy of Family Physicians Foundation, to examine when peer support does not work, guide dissemination of peer support programs, and help integrate approaches such as e-health into peer support. Success factors for peer support programs include proactive implementation, attention to participants' emotions, and ongoing supervision. Reaching those whom conventional clinical and preventive services too often fail to reach; reaching whole populations, such as people with diabetes, rather than selected samples; and addressing behavioral health are strengths of peer support that can help achieve health care that is efficient and of high quality. Challenges for policy makers going forward include encouraging workforce development, balancing quality control with maintaining key features of peer support, and ensuring that underresourced organizations can develop and manage peer support programs.


Central nervous system lymphoma: a morphological MRI study.
The aim of the present study was to evaluate morphological MRI findings in histologically-proven central nervous system lymphoma (CNSL) at time of their first appearance, and to describe dynamic changes on repeat MRI before the diagnosis was histologically proven. We retrospectively evaluated the MRI examinations of 74 patients with histologically-proven CNSL (10 secondary CNSL, 64 primary PCNSL; 10 immunocompromised, 54 immunocompetent). In 43 patients, we evaluated the evolution of CNSL on MRI before the diagnosis was proven. Primary CNSL was typically localized supratentorially (63%), with multiple (59%) or infiltrative (36%) lesions showing diffusion restriction (98%), often (87%) reaching the brain surface. In approximately 50% of patients, meningeal, ependymal or cranial nerve involvement was found. We detected significant differences in enhancement patterns between immunocompromised and immunocompetent patients; non-homogenous enhancement present in 50% of immunocompromised patients. We did not find any significant differences in MRI appearance between primary and secondary CNSL. Regression was evident after corticosteroid treatment in 52% of patients; however, in 16% of cases overall progression was observed. CNSL generally presents as an infiltrative lesion or multiple homogenously-enhancing lesions of the brain in contact with the brain surface. Involvement of the corpus callosum, cranial nerves, ependyma or meninges is common. No significant differences between primary and secondary CNSL were detected, however differences in enhancement type between immunocompromised and immunocompetent primary CNSL patients were found. We stress the variability of MRI findings in the course of the disease and also the variable response to corticotherapy.


High coffee consumption and different brewing methods in relation to postmenopausal endometrial cancer risk in the Norwegian women and cancer study: a population-based prospective study.
Coffee and its compounds have been proposed to inhibit endometrial carcinogenesis. Studies in the Norwegian population can be especially interesting due to the high coffee consumption and increasing incidence of endometrial cancer in the country. A total of 97 926 postmenopausal Norwegian women from the population-based prospective Norwegian Women and Cancer (NOWAC) Study, were included in the present analysis. We evaluated the general association between total coffee consumption and endometrial cancer risk as well as the possible impact of brewing method. Multivariate Cox regression analysis was used to estimate risks, and heterogeneity tests were performed to compare brewing methods. During an average of 10.9 years of follow-up, 462 incident endometrial cancer cases were identified. After multivariate adjustment, significant risk reduction was found among participants who drank ≥8 cups/day of coffee with a hazard ratio of 0.52 (95% confidence interval, CI 0.34-0.79). However, we did not observe a significant dose-response relationship. No significant heterogeneity in risk was found when comparing filtered and boiled coffee brewing methods. A reduction in endometrial cancer risk was observed in subgroup analyses among participants who drank ≥8 cups/day and had a body mass index ≥25 kg/m2, and in current smokers. These data suggest that in this population with high coffee consumption, endometrial cancer risk decreases in women consuming ≥8 cups/day, independent of brewing method.


Cell-cycle protein expression in a population-based study of ovarian and endometrial cancers.
Aberrant expression of cyclin-dependent kinase (CDK) inhibitors is implicated in the carcinogenesis of many cancers, including ovarian and endometrial cancers. We examined associations between CDK inhibitor expression, cancer risk factors, tumor characteristics, and survival outcomes among ovarian and endometrial cancer patients enrolled in a population-based case-control study. Expression (negative vs. positive) of three CDK inhibitors (p16, p21, and p27) and ki67 was examined with immunohistochemical staining of tissue microarrays. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between biomarkers, risk factors, and tumor characteristics. Survival outcomes were only available for ovarian cancer patients and examined using Kaplan-Meier plots and Cox proportional hazards regression. Among ovarian cancer patients (n = 175), positive p21 expression was associated with endometrioid tumors (OR = 12.22, 95% CI = 1.45-102.78) and higher overall survival (log-rank p = 0.002). In Cox models adjusted for stage, grade, and histology, the association between p21 expression and overall survival was borderline significant (hazard ratio = 0.65, 95% CI = 0.42-1.05). Among endometrial cancer patients (n = 289), positive p21 expression was inversely associated with age (OR ≥ 65 years of age = 0.25, 95% CI = 0.07-0.84) and current smoking status (OR: 0.33, 95% CI 0.15, 0.72) compared to negative expression. Our study showed heterogeneity in expression of cell-cycle proteins associated with risk factors and tumor characteristics of gynecologic cancers. Future studies to assess these markers of etiological classification and behavior may be warranted.


A pilot study of D-chiro-inositol plus folic acid in overweight patients with type 1 diabetes.
To improve insulin sensitivity, insulin-sensitizing drugs such as metformin are commonly used in overweight and obese T1D patients. Similarly to metformin, D-chiro-inositol (DCI), as putative mediator of intracellular insulin action, can act as insulin sensitizer. The aim of this pilot study was to evaluate the hypothesis that DCI plus folic acid may improve glucose control reducing insulin resistance in overweight or obese T1D patients. A 24-week randomized control trial was carried out in 26 overweight or obese T1D patients, undergoing intensive insulin therapy. Patients were randomized to 1 g DCI plus 400 mcg folic acid once daily (treated group) or to 400 mcg folic acid only once daily (control group). The primary end point was to evaluate the efficacy of DCI on metabolic control as assessed by HbA1c. As secondary endpoints, BMI and insulin requirement (IR) were evaluated. Paired t test (two tailed) and analysis of variance were used to evaluate differences in HbA1c, BMI and IR at different time points. A significant reduction in HbA1c levels in treated group versus control group (7.5% ± 0.9 vs. 7.9% ± 1.7, respectively, p < 0.05) was observed. However, no significant reduction in BMI and IR was observed [(BMI 25.7 ± 2.8 vs. 26.7 ± 1.0, respectively, p NS); (IR 0.52 ± 0.26 vs. 0.52 ± 0.19, respectively, p NS)]. This trial demonstrated for the first time that DCI plus folic acid oral supplementation can improve metabolic control in overweight T1D patients. CLINICALTRIAL. NCT02730949.


Catching the alcohol buzz: an examination of the latent factor structure of subjective intoxication.
The goal of this study was to examine the latent structure among measures of alcohol-induced subjective feelings of intoxication from a behavioral pharmacology perspective. Data on subjective intoxication, measured concomitantly by the Subjective High Assessment Scale, Biphasic Alcohol Effect Scale, and the Short Version of the Profile of Mood States, were collected at 3 levels of breath alcohol concentration during an alcohol administration study in a sample of heavy drinkers (n = 135). Results of exploratory factor analyses supported a 3-factor model which captured the following dimensions of subjective intoxication: (1) stimulation and other pleasant effects, (2) sedative and unpleasant effects, and (3) alleviation of tension and negative mood. The tension-reduction factor was most consistently associated with more frequent drinking and alcohol problems in this sample. These findings support the notion that the neuropharmacological and behavioral effects of alcohol are multifaceted and cannot be simply defined as either positive or negative. Rather, moderate levels of intoxication appear to have concomitant dimensions of positive reinforcement, negative reinforcement, and punishment. This study also suggests that factor scores may be useful in future alcohol administration studies to reduce the number of comparisons and perhaps increase statistical power to detect meaningful effects.


Beneficial actions of melatonin in the management of viral infections: a new use for this "molecular handyman"?
Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional signaling molecule that has a variety of important functions. Numerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein.


Identification of neonatal hearing impairment: evaluation of transient evoked otoacoustic emission, distortion product otoacoustic emission, and auditory brain stem response test performance.
The purpose of this study was to compare the performance of transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), and auditory brain stem responses (ABRs) as tools for identification of neonatal hearing impairment. A total of 4911 infants including 4478 graduates of neonatal intensive care units, 353 well babies with one or more risk factors for hearing loss (Joint Committee on Infant Hearing, 1994) and 80 well babies without risk factor who did not pass one or more neonatal test were targeted as the potential subject pool on which test performance would be assessed. During the neonatal period, they were evaluated using TEOAEs in response to an 80 dB pSPL click, DPOAE responses to two stimulus conditions (L1 = L2 = 75 dB SPL and L1 = 65 dB SPL L2 = 50 dB SPL), and ABR elicited by a 30 dB nHL click. In an effort to describe test performance, these "at-risk" infants were asked to return for behavioral audiologic assessments, using visual reinforcement audiometry (VRA) at 8 to 12 mo corrected age, regardless of neonatal test results. Sixty-four percent of these subjects returned and reliable VRA data were obtained on 95.6% of these returnees. This approach is in contrast to previous studies in which, by necessity, efforts were made to follow only those infants who "failed" the neonatal screening tests. The accuracy of the neonatal measures in predicting hearing status at 8 to 12 mo corrected age was determined. Only those infants who provided reliable, monaural VRA test results were included in the analysis. Separate analyses were performed without regard to intercurrent events (i.e., events between the neonatal and VRA tests that could cause their results to disagree), and then after accounting for the possible influence of intercurrent events such as otitis media and late-onset or progressive hearing loss. Low refer rates were achieved for the stopping criteria used in the present study, especially when a protocol similar to the one recommended in the National Institutes of Health (1993) Consensus Conference Report was followed. These analyses, however, do not completely describe test performance because they did not compare neonatal screening test results with a gold standard test of hearing. Test performance, as measured by the area under a relative operating characteristic curve, were similar for all three neonatal tests when neonatal test results were compared with VRA data obtained at 8 to 12 mo corrected age. However, ABRs were more successful at determining auditory status at 1 kHz, compared with the otoacoustic emission (OAE) tests. Performance was more similar across all three tests when they were used to identify hearing loss at 2 and 4 kHz. No test performed perfectly. Using either the two- or three-frequency pure-tone average (PTA), with a fixed false alarm rate of 20%, hit rates for the neonatal tests, in general, exceeded 80% when hearing impairment was defined as behavioral thresholds > or =30 dB HL. All three tests performed similarly when a two-frequency (2 and 4 kHz) PTA was used as the gold standard; OAE test performance decreased when a three-frequency PTA (adding 1 kHz) was used as the gold standard definition. For both PTA and all three neonatal screening measures, however, hit rate increased as the magnitude of hearing loss increased. Singly, all three neonatal hearing screening tests resulted in low refer rates, especially if referrals for follow-up were made only for the cases in which stopping criteria were not met in both ears. Following a protocol similar to that recommended in the National Institutes of Health (1993) Consensus Conference report resulted in refer rates that were less than 4%. TEOAEs at 80 dB pSPL, DPOAE at L1 = 65, L2 = 50 dB SPL and ABR at 30 dB nHL measured during the neonatal period, and as implemented in the current study, performed similarly at predicting behavioral hearing status at 8 to 12


Changes in the feed intake, pH and osmolality of rumen fluid, and the position of the abomasum of eight dairy cows during a diet-induced left displacement of the abomasum.
During the last six weeks of the dry period, eight Holstein-Friesian cows were fed a restricted amount of grass silage; after calving, a mixture of maize silage and concentrates was offered in a feeding regimen designed to induce a displacement of the abomasum. In the first month after calving, the cows were monitored for the following variables: feed intake and composition, milk production, the position of the abomasum, and the pH and osmolality of the rumen contents. In five of the eight cows, a left displacement of the abomasum occurred between four and 21 days after calving in the absence of other diseases. The displacement was temporary, lasting between five and 36 consecutive hours and one or two days in two of the cows (floaters), and for three or more days in the other three. Before these three cows developed the displacement, their abomasum was 4.3 to 7.9 cm higher, its contents had a higher mean osmolality (+19.2 mosmol/kg), and the ratio of roughage to concentrates in their feed was lower (-0.87) than in the three cows that did not develop clinical signs of a displaced abomasum. There were no significant differences in these variables between the floaters and the healthy cows.


Potential Effects of CXCL9 and CCL20 on Cardiac Fibrosis in Patients with Myocardial Infarction and Isoproterenol-Treated Rats.
The chemokines CXCL9 and CCL20 have been reported to be associated with ventricular dysfunction. This study was aimed to investigate the effects of CXCL9/CCL20 on cardiac fibrosis following myocardial infarction (MI). Blood samples of patients with MI were obtained to determine the serum CXCL9, CCL20, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β). The expression of CXCL9 and CCL20 in hypoxia-incubated H9c2 cells and TNF-α/TGF-β-activated peripheral blood mononuclear cells (PBMCs) were examined. The experimental MI of rats was produced by the intraperitoneal injection of isoproterenol (ISO) (85 mg/kg/day) for two consecutive days. The growth and migration of CXCL9/CCL20-incubated cardiac fibroblasts in vitro were evaluated. TNF-α/TGF-β-activated PBMCs showed an enhanced expression of CXCL9 and CCL20, while hypoxic H9c2 cells did not. Patients with MI had significantly enhanced levels of serum TGF-β and CXCL9 compared to healthy subjects. ISO-treated rats had increased serum CXCL9 levels and marked cardiac fibrosis compared to control rats. The trend of increased serum CCL20 in patients with MI and ISO-treated rats was not significant. CXCL9-incubated cardiac fibroblasts showed enhanced proliferation and migration. The findings of this study suggest that an enhanced expression of CXCL9 following MI might play a role in post-MI cardiac fibrosis by activating cardiac fibroblasts.