cssi/SciSciGPT-SciSciNet huggingface dataset:
Publish or perish: Success with publication in pharmacy residency training.

Abstract Background and purpose Pharmacy residency training standards require development of medical writing skills. These skills are fundamental to pharmacy clinicians and scholars alike. Despite this requirement, new practitioners and seasoned clinicians frequently struggle with scholarly development and manuscript generation for a variety of reasons, ranging from lack of experience or familiarity with the process of peer-review submission to time constraints. Educational activity and setting We describe a process for fostering pharmacy resident scholarship and publication utilized at Robert Wood Johnson University Hospital, including the stages of the project development process and corresponding responsibilities during each phase of the manuscript submission process. From identification of interest, to project and manuscript development, review, submission, revision, and reflection, our postgraduate pharmacy residents receive guidance and structure from a preceptor mentor to usher them through this experience for the first time. Findings The program has had success utilizing this structured approach to supporting residency publication efforts, with the preparation of 23 manuscripts that have resulted in peer-reviewed publications from 28 residents graduating between 2013 and 2017. This results in a resident authorship rate of 82%. Summary Although medical writing and manuscript development may not be an intuitive process, it is imperative that preceptors and individuals interacting with postgraduate pharmacy trainees consider exposing their trainees to this process, with foresight into thinking about a structured approach to publication at the onset of project development.
Chromatic stereopsis

One approach to developing faster, more robust stereo algorithms is to seek a more complete and efficient use of information available in stereo images. The use of chromatic (color) information has been largely neglected in this regard. Motivations for using chromatic information are discussed, including strong evidence for the use of chromatic information in the human stereo correspondence process in the form of a novel psychophysical experiment which we have performed. Specifically, we measured the minimum disparity needed to produce a reversal in apparent depth in ambiguous chromatic "wallpaper" stereograms. Our results indicate that chromatic information plays an important role in the stereo correspondence process when luminances variations are present. To investigate the potential role of chromatic information in computational stereo algorithms, a novel chromatic matching constraint -- the chromatic gradient matching constraint -- is presented. Then, a thorough analysis of the utility of this constraint in the PMF Algorithm is performed for a large range of sizes of the matching strength support neighborhood, and the performances of the algorithm with and without these constraints are directly compared in terms of disambiguation ability, matching accuracy and algorithm speed. The results demonstrate that chromatic information can gready reduce the matching ambiguity, while significantly increasing both matching accuracy and algorithm speed.
“Do not Disturb the Peace!” Identities, Livelihoods and the Politics of Post-War Discontent in Sierra Leone:

Although the collective memory of war is frequently invoked in post-war societies, who chooses to invoke it and to what effect has been less studied relative to other aspects of such societies. In ...
Sickle Cell Disease Promotes Dysregulation of Hepatic Iron Homeostasis By Regulating Hepcidin Expression

Sickle cell disease (SCD) is an autosomal-recessive-genetic disorder that affects millions of people worldwide. Although hepatic crisis affects 10-40% of hospitalized SCD patients and can progress to fatal liver failure, the current treatment is primarily supportive and the molecular pathophysiology remains largely unknown. We found that transgenic, humanized SCD mice developed liver injury with age, manifested by increased inflammation, necrosis and hepatic iron accumulation. The presence of iron particles in SCD liver was confirmed by transmission electron micrograph (TEM) analysis and prussian blue staining which revealed increased iron accumulation in the central and midzonal region of the SCD liver tissue. An increase in aggregates of iron pigment reminiscent of hemosiderin-laden macrophages was also observed in SCD liver tissue. Interestingly, the SCD mice also showed significant enrichment of both hepatic (p=0.02) and serum iron (p=0.04) compared to control AS mice. We determined the expression level of genes commonly involved in iron homeostasis by RT-PCR. Interestingly, a significantly lower expression level of hepcidin transcripts was observed in the liver of SCD mice compared to control mice (AS) (p=0.01). In order to define the pathways controlling hepcidin transcription in SCD, we performed an RNA-seq analysis in the liver of SCD mice. Remarkably, our data showed significant misexpression of hypoxia signaling pathways. Further analysis revealed a significant increase in hypoxia-inducible factor (HIF)-2α levels in the liver of SCD mice by western blot. Reduced levels of Hepcidin were also confirmed in serum samples from SCD patients compared to controls. Work is currently underway to understand how HIF2α might hypothetically regulate hepcidin expression in the liver. This is particularly relevant because HIF2a translation is known to be regulated by iron through an iron response element at the 5' end of its transcript. In summary, our results reveal a significant defect in iron homeostasis in the liver of SCD mice, suggesting that impaired iron homeostasis may contribute to hepatobiliary injury in SCD independent of blood transfusions. Our study also highlights the importance of hepcidin as potential therapeutic target in regulation of hepatic injury in SCD. Disclosures Gladwin: Bayer Pharmaceuticals: Other: Co-investigator; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases ; Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning. Kato: Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.
Chapter 11 – Structural Colors

Prospectus Structural colors originate in the scattering of light from ordered microstructures, thin films, and even irregular arrays of electrically small particles, but they are not produced by pigments. Examples include the flashing sparks of colors in opals and the brilliant hues of some butterflies such as Morpho rhetenor. Structural colors can be implemented industrially to produce structurally colored paints, fabrics, cosmetics, and sensors.
A Novel HCI Reliability Model for RF/mmWave Applications in FDSOI Technology

Although technology scaling to deep submicron enable higher degrees of semiconductor integration, highly integrated circuit have become increasingly sensitive to the slightest parameter drift. One of the main causes of parameter degradation in recent technologies is the Hot Carrier Injection (HCI), a progressive wear out phenomenon whose understanding and modeling has become mandatory in new CMOS nodes. Therefore, we present in this paper a new HCI reliability model for Fully Depleted Silicon On Insulator (FDSOI) MOSFETs which covers the RF/mmWave (Radiofrequency /millimeter wave) applications taking into account back bias operation.
Grace in Our Place? The Concept of Representation in the Theology of Karl Rahner:

How does Jesus bring about human salvation? Throughout his career, Karl Rahner expressed deep suspicion of answers that portray Christ as “stepping in” for us (Stellvertretung) and performing a gre...
Optical Properties of Alloyed Noble Metal Nanoparticles: A Nanotechnology Experiment for Chemistry and Engineering Students

Nanoscale phenomena are under increasingly intense investigation both in academia and industry. The unique physical and chemical properties stemming from their high surface area and confined space ...
Estimating Wealth Effects Without Expenditure Data—Or Tears: An Application to Educational Enrollments in States of India

This paper has an empirical and overtly methodological goal. The authors propose and defend a method for estimating the effect of household economic status on educational outcomes without direct survey information on income or expenditures. They construct an index based on indicators of household assets, solving the vexing problem of choosing the appropriate weights by allowing them to be determined by the statistical procedure of principal components. While the data for India cannot be used to compare alternative approaches they use data from Indonesia, Nepal, and Pakistan which have both expenditures and asset variables for the same households. With these data the authors show that not only is there a correspondence between a classification of households based on the asset index and consumption expenditures but also that the evidence is consistent with the asset index being a better proxy for predicting enrollments--apparently less subject to measurement error for this purpose--than consumption expenditures. The relationship between household wealth and educational enrollment of children can be estimated without expenditure data. A method for doing so - which uses an index based on household asset ownership indicators- is proposed and defended in this paper. In India, children from the wealthiest households are over 30 percentage points more likely to be in school than those from the poorest households.
Genetic Sex Effects of Polycystic Ovary Syndrome Reveal Distinct Metabolic Etiology

Females with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). High-risk groups or individuals with a family history are more likely to have a greater genetic susceptibility to these diseases, which drastically increases their risk of developing other chronic health conditions. In this study, we systematically evaluated the bidirectional genetic burden of PCOS and its comorbidities among females and males. First, we analyzed the pleiotropic effects of the PCOS polygenic risk score (PRS), a measurement of genetic liability to PCOS, across 1,857 medical conditions recorded in the Vanderbilt University Medical Center electronic health record. We conducted a phenome-wide association study (PheWAS) adjusted for median age, sex, and genetic ancestry. In the European sex-combined model (n = 72,824), we observed that PCOS PRS was significantly (Bonferroni corrected p < 7.86e-06) associated with T2D (OR = 1.11, p = 8.75e-08) and hypertension (OR = 1.06, p = 1.13e-07) in addition to polycystic ovaries (OR = 1.11, p = 1.91e-07). In the sex-stratified model, we found that males (n = 32,022) with a higher PRS for PCOS were more likely to develop cardiovascular diseases (CVD) compared to females (n = 40,802) who had higher odds of developing T2D. Although we were underpowered to detect any phenome-wide significant effects in our African descent sample (n=15,283), uterine leiomyoma (OR = 1.24, p = 3.79e-03), osteoarthritis (OR = 1.21, p = 3.94e-03), and benign neoplasm of uterus (OR = 1.24, p = 4.00e-03) were the top three nominal significant results (p < 0.05) in females (n = 9,418). To understand the genetic relationships observed in the PheWAS, we used LD score regression to determine the genetic correlation between the phenotypes. We found that PCOS was positively correlated with T2D (rg = 31%), systolic blood pressure (rg = 12%), and pulse pressure (rg = 15%). However, we found no significant associations between the genetic risk of CVD and PCOS diagnosis in the European or African descent samples. Our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but the genetic risk of those comorbidities is not predictive of a PCOS diagnosis. This suggests that other drivers are contributing to the endocrine and cardiovascular comorbid signatures that underlie PCOS.
Preliminary Evidence on the Effects of Exercise on Tumor Biology: a Potential Guide for Prescribing Exercise

This report reviews the preliminary evidence of how exercise may alter the tumor microenvironment and tumor biology in animal and human studies and how to incorporate this information in clinical practice of oncology rehabilitation. Potential mechanisms explaining the impact of exercise on the tumor microenvironment include activating and mobilizing immune cells, reducing inflammation, and modifying tumor vasculature which enhances the delivery of anticancer therapies. Pre-clinical data translates to promising preliminary data in human studies; however, randomized, controlled trials in patients are limited. Despite the paucity of robust data demonstrating the beneficial effects of exercise on tumor biology, the strong observational and epidemiological data and limited interventional trials encourage the continued prescribing of exercise by rehabilitation professionals for cancer survivors.
Transcriptional activation of p21 by phenethyl isothiocyanate via chromatin remodeling and c-myc de-repression in prostate cancer cells.

Proc Amer Assoc Cancer Res, Volume 47, 2006 5591 The isothiocyanates, present naturally in cruciferous vegetables are potent chemopreventive agents for carcinogen-induced cancers in rodents. The major action is thought to be cytoprotection by inhibiting the metabolism of procarcinogens and inducing phase 2 enzymes to block the initiation of carcinogenesis. We have demonstrated that the isothiocyanates are also growth regulators, inhibiting the cell cycle cdk activity and/or up-regulating the inhibitor p21WAF1 (p21) in cancer cells. The up-stream mechanism to modulate cell cycle progression remained to be elucidated. Here we demonstrate that exposure of human prostate cancer cells LNCaP to phenethyl isothiocyanate (PEITC) resulted in G1 arrest and p21 induction. The hypothesis that PEITC inhibits cell growth via chromatin remodeling was investigated. We demonstrated with a cell-free assay, that PEITC inhibited the activity of histone deacetylases (HDAC), the enzyme acetylates the histones. Additionally the level of HDAC was reduced. The PEITC-exposed LNCaP cells were shown to have reduced HDAC activity. Analyses of the status of histone acetylation revealed a significant enhancement of global acetylation, including the acetylation of histones H3 and H4, and selective acetylation of H3K14. These are marks consistent to transcription competent chromatins. To further examine the relationship between acetylated histones and p21 activation, ChIP assay was performed. Using an anti-acetylated histone H3 antibody, we demonstrated for the first time that the chromatins from cells exposed to PEITC contained more p21 DNA in the precipitates of hyperacetylated histones, as compared with cells without PEITC. This indicates the possible increases of accessibility of transcriptional machinery to the p21 promoter after chromatin unfolding. The investigation further revealed that the c-myc expression was significantly down-regulated by PEITC that paralleled the inhibition of HDAC. The decreased expression of c-myc may further release p21 transcription otherwise repressed by the c-myc oncogene. The experimental results indicate that although PEITC affects multiple molecular pathways, regulation of the epigenetic targets may be important mechanisms leading to the up-regulation of p21, thereby mediating cell cycle arrest in prostate cancer cells. Thus, our observations have provided a critical aspect for further investigating PEITC and other isothiocyantes in chemoprevention and inhibiting the growth of malignant cells.
Optimization and Analytical Applications of the Technique of Dynamic Introduction of Liquids into Centrifugal Analyzers

The technique of dynamically introducing a measured volume of liquid into the spinning rotor of a miniature Centrifugal Fast Analyzer where it is subsequently apportioned into equal aliquots [C. D. Scott and J. C. Mailen, Clin. Chem. 18, 749 (1972)] has been further developed and improved. Several important structural and operational factors have been identified and investigated, including rotor design and geometry, rotor speed, injection volume and rate, and probe diameter. To determine the effect of these factors on the precision and accuracy with which a liquid may be dynamically introduced and apportioned, we developed a dye-dilution procedure. These studies demonstrate that liquid volumes ranging from 10 to 50 µl per cuvet can be dynamically loaded with an accuracy and precision (expressed as standard deviation) of 1 to 2% and 0.5 to 1.1 µl per cuvet, respectively. Several analytical applications of this technique have been investigated: ( a ) measurement of true sample-blank absorbance before dynamic reagent introduction, ( b ) sequential reagent addition, ( c ) correlation studies involving discrete versus dynamic loading of reagent, and ( d ) reconstitution of lyophilized reagents.
Differential Misclassification Arising from Nondifferential Errors in Exposure Measurement

Misclassification into exposure categories formed from a continuous variable arises from measurement error in the continuous variable. Examples and mathematical results are presented to show that if the measurement error is nondifferential (independent of disease status), the resulting misclassification will often be differential, even in cohort studies. The degree and direction of differential misclassification vary with the exposure distribution, the category definitions, the measurement error distribution, and the exposure-disease relation. Failure to recognize the likelihood of differential misclassification may lead to incorrect conclusions about the effects of measurement error on estimates of relative risk when categories are formed from continuous variables, such as dietary intake. Simulations were used to examine some effects of nondifferential measurement error. Under the conditions used, nondifferential measurement error reduced relative risk estimates, but not to the degree predicted by the assumption of nondifferential misclassification. When relative risk estimates were corrected using methods appropriate for nondifferential misclassification, the "corrected" relative risks were almost always higher than the true relative risks, sometimes considerably higher. The greater the measurement error, the more inaccurate was the correction. The effects of exposure measurement errors need more critical evaluation.
Influenza Vaccination of Pregnant Women: Attitudes and Behaviors of Oregon Physician Prenatal Care Providers

In spite of increased risk of influenza complications during pregnancy, only half of US pregnant women get influenza vaccination. We surveyed physician prenatal care providers in Oregon to assess their knowledge and behaviors regarding vaccination of pregnant women. From September through November 2011, a state-wide survey was mailed to a simple random sample (n = 1,114) of Oregon obstetricians and family physicians. The response rate was 44.5 %. Of 496 survey respondents, 187 (37.7 %) had provided prenatal care within the last 12 months. Of these, 88.5 % reported that they routinely recommended influenza vaccine to healthy pregnant patients. No significant differences in vaccine recommendation were found by specialty, practice location, number of providers in their practice, physician gender or years in practice. In multivariable regression analysis, routinely recommending influenza vaccine was significantly associated with younger physician age [adjusted odds ratio (AOR) 2.01, 95 % confidence interval (CI) 1.29–3.13] and greater number of pregnant patients seen per week (AOR 1.95, 95 % CI 1.25–3.06). Among rural physicians, fewer obstetricians (90.3 %) than family physicians (98.5 %) had vaccine-appropriate storage units (p = 0.001). Most physician prenatal care providers understand the importance of influenza vaccination during pregnancy. To increase influenza vaccine coverage among pregnant women, it will be necessary to identify and address patient barriers to receiving influenza vaccination during pregnancy.
Postmarketing surveillance: accuracy of patient drug attribution judgments.

Data from two samples of ambulatory patients participating in a postmarketing surveillance study, one receiving antibiotics and another receiving tricyclic antidepressant agents, are presented, indicating that patients appear to be capable of correctly discriminating probable adverse drug reactions from other adverse clinical events. However, attribution accuracy depended both on the surveillance method and on how reports of the adverse clinical events were obtained. Discrimination was better when patients were reporting adverse clinical events spontaneously than when the interviewer probed for recall in a systematic inquiry. Discrimination was also better when the adverse clinical events were obtained from a staff-initiated surveillance method than from a self-monitoring, patient-initiated telephone-reporting method–probably because the latter method generates an excessively strong tendency to report mainly those adverse clinical events suspected of being drug related. Clinical Pharmacology and Therapeutics (1990) 48, 102–107; doi:10.1038/clpt.1990.123
Experimental intradermal granuloma formation.

Experimental induction of an intradermal granulomatous hypersensitivity reaction in the primarily immunized guinea pig was studied by means of tight microscopy during the course of the immune response. Animals were sensitized to dinitrophenylated human serum albumin (DNP 10 -HSA), and challenged with this antigen covalently linked to Sepharose 2B beads by the cyanogen bromide reaction. At appropriate intervals, the dermal changes produced by this complex antigen were compared with those produced by DNP 10 -HSA or soluble antigen. Sepharose 2B beads atone, and DNP 10 -HSA plus Sepharose 2B in the same animal. The complex antigen produced lesions characteristic of granulomatous hypersensitivity 5 and 11 days beyond the time of the skin test. The others showed the characteristic responses of hypersensitivity, foreign-body reaction, and a mixture of delayed-hypersensitivity and foreign-body reaction, but the intensity of the reactions had diminished by 5 days and had disappeared after 11 days. These results indicate that a dermal granulomatous hypersensitivity reaction may be differentiated from a foreign-body reaction. They also suggest that locally retained antigen interacts with sensitized lymphocytes to contribute to granuloma formation.
EXTENT OF GERONTOLOGY INSTRUCTION IN AMERICAN INSTITUTIONS OF HIGHER EDUCATION

Gerontology instruction in American institutions of higher education has increased rapidly over the past 20 years. A number of studies have reported this growth in single professions, various types of institutions, geographic regions, or individual states. However, there have been few comprehensive surveys that collected data from of all colleges, community colleges, and universities in this country. This report of a 1985 survey by the Association for Gerontology in Higher Education and the Andrus Gerontology Center at the University of Southern California indicates that the number of campuses offering at least one credit course in gerontology has nearly doubled in the past nine years. Courses are now available at most large campuses and those that offer graduate degrees. Small campuses, especially those of community colleges, are still not likely to offer gerontology instruction. Course work is not evenly distributed among the states. In some states, 75% of campuses offer gerontology courses while in oth...
The Biosocial Perspective and Environmental Communication Research

Cet article affirme que la recherche en communication environnementale doit s'interesser aux relations relatives a la communication qui existent entre la societe et l'environnement, et argumente que la theorie biosociale presente un cadre conceptuel utile aux specialistes de la communication de masse qui s'interessent a l'etude de ces relations. L'article presente une selection de resultats probants issus d'une etude de cas realisee sur une zone sauvage a la frontiere de l'Ontario et du Minnesota, qui mettent en evidence cinq propositions generalisables et reciproques presentant des caracteristiques de ces relations relatives a la communication
Managed Care Under Siege

Managed Care Organizations (MCOs) are frequently criticized for their marketing mistakes. Often that criticism is leveled against an implicit benchmark of an ideal competitive market or an ideal system of government provision. But any accurate assessment in the choice of health care organizations always requires a comparative measure of error rates. These are high in the provision of health care, given the inherent uncertainties in both the cost and effectiveness of treatment. But the continuous and rapid evolution of private health care mechanisms is, in the absence of regulation, more likely to secure access and contain costs than any system of government regulation. State regulation is subject to the risk of capture and to the sluggish and acquisitive behavior of state run monopolies. The proposed fixes for the MCOs (rights to specialists, access to physicians outside the network, guaranteed emergency room access) are likely, when imposed from without, to cost more than they are worth. The long-term risk is that markets will fail under regulation, paving the way for greater losses from massive government control of the health care delivery system.
Development of an unattended ground sensor for ultraviolet laser-induced fluorescence detection of biological agent aerosols

A prototype of an unattended ground sensor has been developed for detection of biological agent aerosols. This point sensor uses ultraviolet laser induced fluorescence (UV LIF) to detect aerosol biological microorganisms collected on filter media. The concept can be designed to be compact, low power, and hardened to survive harsh delivery environments such as airdrop. The prototype consists of an air sampling system, a filter exchange mechanism, an Nd:YAG microlaser that is frequency tripled and quadrupled to generate 355-nm and 266-nm excitation wavelengths, a spectrometer, an intensified CCD detector, and a data acquisition and control system. The analysis utilizes a spectral database of fluorescence signatures of biological organisms and common interferents measured by Sandia for the Army's Edgewood Research and Development Engineering Center (ERDEC) and the Department of Energy's Chemical and Biological Non-proliferation (DOE CBNP) program. The analysis algorithms are based on algorithms developed by Sandia for an airborne UV LIF lidar system.
Bone mineral content and density of the lumbar spine of infants and toddlers: Influence of age, sex, race, growth, and human milk feeding

Little is known about factors that affect bone mass and density of infants and toddlers and the means to assess their bone health owing to challenges in studying this population. The objectives of this study were to describe age, sex, race, growth, and human milk feeding effects on bone mineral content (BMC) and areal density (aBMD) of the lumbar spine, and determine precision of BMC and aBMD measurements. We conducted a cross-sectional study of 307 healthy participants (63 black), ages 1 to 36 months. BMC and aBMD of the lumbar spine were measured by dual-energy X-ray absorptiometry. Duplicate scans were obtained on 76 participants for precision determination. Age-specific Z-scores for aBMD, weight, and length (BMDZ, WAZ, LAZ) were calculated. Information on human milk feeding duration was ascertained by questionnaire. Between ages 1 and 36 months, lumbar spine BMC increased about fivefold and aBMD increased twofold (p < 0.0001). BMC was greater (5.8%) in males than in females (p = 0.001), but there was no difference in aBMD (p = 0.37). There was no difference in BMC or aBMD between whites and blacks (p ≥ 0.16). WAZ and LAZ were positively associated with BMDZ (r = 0.34 and 0.24, p < 0.001). Duration of human milk feeding was negatively associated with BMDZ in infants <12 months of age (r = −0.42, p < 0.001). Precision of BMC and aBMD measurements was good, 2.20% and 1.84%, respectively. Dramatic increases in BMC and aBMD of the lumbar spine occur in the first 36 months of life. We provide age-specific values for aBMD of healthy infants and toddlers that can be used to evaluate bone deficits. Future studies are needed to identify the age when sex and race differences in aBMD occur, and how best to account for delayed or accelerated growth in the context of bone health assessment of infants and toddlers. © 2013 American Society for Bone and Mineral Research
Carbon Dioxide Laser abrasion: A New Approach to Management of Familial Benign Chronic Pemphigus (Hailey-Hailey Disease)

Familial benign chronic pemphigus (FBCP), or Hailey-Hailey disease, can be a debilitating condition. Treatment is palliative and only excision of lesional skin followed by split-thickness grafting may be curative. The success of surgery is attributed to the removal of adnexal structures and a decrease in sweating and maceration. This is the first report of successful carbon dioxide (CO2) laserabrasion of a patient with FBCP. The procedure spared the underlying adnexae which contributed to the reepithelialization of the epidermis. The selective destructive property of the CO2 laser may contribute to understanding the pathophysiology of FBCP.
Regiospecificity determinants of human heme oxygenase: differential NADPH- and ascorbate-dependent heme cleavage by the R183E mutant.

The ability of the human heme oxygenase-1 (hHO-1) R183E mutant to oxidize heme in reactions supported by either NADPH-cytochrome P450 reductase or ascorbic acid has been compared. The NADPH-dependent reaction, like that of wild-type hHO-1, yields exclusively biliverdin IXα. In contrast, the R183E mutant with ascorbic acid as the reductant produces biliverdin IXα (79 ± 4%), IXδ (19 ± 3%), and a trace of IXβ. In the presence of superoxide dismutase and catalase, the yield of biliverdin IXδ is decreased to 8 ± 1% with a corresponding increase in biliverdin IXα. Spectroscopic analysis of the NADPH-dependent reaction shows that the R183E ferric biliverdin complex accumulates, because reduction of the iron, which is required for sequential iron and biliverdin release, is impaired. Reversal of the charge at position 183 makes reduction of the iron more difficult. The crystal structure of the R183E mutant, determined in the ferric and ferrous-NO bound forms, shows that the heme primarily adopts the same orientation as in wild-type hHO-1. The structure of the Fe(II)·NO complex suggests that an altered active site hydrogen bonding network supports catalysis in the R183E mutant. Furthermore, Arg-183 contributes to the regiospecificity of the wild-type enzyme, but its contribution is not critical. The results indicate that the ascorbate-dependent reaction is subject to a lower degree of regiochemical control than the NADPH-dependent reaction. Ascorbate may be able to reduce the R183E ferric and ferrous dioxygen complexes in active site conformations that cannot be reduced by NADPH-cytochrome P450 reductase.
A preliminary investigation on time perception and autonomic self-regulation.

This study sought to examine how perception of time duration was affected by two autonomic self-regulation treatment procedures: a biofeedback/self-regulation treatment program and a relaxation response treatment program. Time experience was assessed in two ways: time interval estimation during an actual treatment session (N=5, in each of the two groups) and subjective reporting (all 10 subjects in each group were evaluated). During an actual relaxation/self-regulation session, patients overestimated time duration and, retrospectively, patients in the group that learned to reduce blood pressure experienced time as slowing, whereas participants in the other treatment program experienced time as passing “normally” during the treatment sessions. All subjects reported that they usually experienced time as passing “normally” or corresponding to clock time. These results raise the question as to whether the experience of temporal slowing may be an important component of the psychological experience of the patients that allows autonomic learning to occur. Further research in this area is recommended and briefly discussed.
Treatment of osteopenia and osteoporosis in anorexia nervosa: A systematic review of the literature

Objective: To systematically review the evidence supporting treatment of osteopenia and osteoporosis in patients with anorexia nervosa (AN). Data sources: We identified controlled clinical studies of interventions for low bone mass in AN via searches of MEDLINE; the Cochrane Library; EMBASE; PsycINFO; and cumulative index to nursing and allied health literature. Outcomes of interest were changes in bone mineral density and fracture incidence. Results: Six randomized controlled trials (RCTs) and two cohort trials examined five classes of medical therapy on bone mineral density outcomes. One RCT of bisphosphonates showed no benefit and a second flawed RCT showed some benefit; one RCT showed a benefit of insulin-like growth factor-I; none of the five trials evaluating estrogen therapy showed benefit. Discussion: Although patients with AN are often losing bone mass when they should be optimizing bone growth, there is no good evidence to guide medicinal interventions. Therefore, early detection and weight restoration are of utmost importance whereas ongoing trials define effective therapies.
Probes for narcotic receptor mediated phenomena. 40. N-Substituted cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols

A series of N-substituted rac-cis-4a-ethyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-8-ols have been prepared using a simple synthetic route previously designed for synthesis of related cis-2methyl-4a-alkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols. The new phenolic compounds, where the aromatic hydroxy moiety is situated ortho to the oxygen atom in the oxidebridged ring, do not interact as well as the pyridin-6-ols with opioid receptors. The N-parafluorophenethyl derivative had the highest μ-opioid receptor affinity of the examined compounds (Ki = 0.35 μM).
Endomorphin-1 induces antinociception without immunomodulatory effects in the rat

Rationale: Although there is evidence that central opioid receptors are involved in immunomodulation, it has been only recently that an endogenous agonist, designated endomorphin-1, possessing high selectivity and affinity for the mu opioid receptor has been identified. Objective: The present study assesses the immunomodulatory effects of endomorphin-1 in the rat and provides further evaluation of the antinociceptive effects of endomorphin-1. Methods: Rats were surgically implanted with cannulae directed at the lateral cerebral ventricle. Animals received vehicle or endomorphin-1 at doses of 31.63 or 56.23 µg (ICV) and were tested for antinociception in two different assays, the warm water tail withdrawal procedure and the hotplate assay. Additional studies assessed the effect of naltrexone on the antinociception produced by endomorphin-1 in both antinociceptive assessments. Assessments of immune status following endomorphin-1 treatment included measurements of splenic natural killer cell activity, production of interferon-γ, and lymphocyte proliferative responses to mitogenic stimulation by Con-A, LPS, and the microbial superantigen, TSST-1. Results: Endomorphin-1 induced significant and naltrexone reversible antinociception 30 and 60 min following drug administration, as measured by the hotplate assay and warm water tail withdrawal procedure. In marked contrast, endomorphin-1 did not produce immunomodulatory effects up to 120 min following ICV administration. Conclusions: Endomorphin-1 produces antinociception but does not induce immunomodulatory effects in the rat. These findings suggest that it is possible to develop therapeutic strategies for separating antinociception and immunomodulatory properties through the mu opioid receptor.
Molecular organisation of cell–matrix contacts: essential multiprotein assemblies in cell and tissue function

The adhesion of cells to their surrounding extracellular matrix has vital roles in embryonic development, inflammatory responses, wound healing and adult tissue homeostasis. Cells attach to extracellular matrix by specific cell-surface receptors, of which the integrins and transmembrane proteoglycans are major representatives. The engagement of adhesion receptors triggers assembly of functional matrix contacts, in which bound matrix components, adhesion receptors and associated intracellular cytoskeletal and signalling molecules form large, localised multiprotein complexes. This review discusses the functional categories of matrix contacts, examples of the biological roles of matrix contacts in normal physiology, and examples of the ways in which abnormalities of matrix contacts are associated with major human diseases.
A mutation-created novel intra-exonic pre-mRNA splice site causes constitutive activation of KIT in human gastrointestinal stromal tumors

We report a new mechanism of aberrant pre-mRNA splicing resulting in constitutive activation of a mis-spliced oncoprotein (KIT) leading to malignancy (gastrointestinal stromal tumor) in contrast to loss of function of mis-spliced proteins resulting in diverse human diseases in the literature. The mechanisms of three consecutive molecular events, deletion of noncoding and coding regions encompassing the 3' authentic splice site, creation of a novel intra-exonic pre-mRNA 3' splice acceptor site leading to in-frame loss of 27 nucleotides (nine amino acids; Lys550-Lys558), and the mechanism of constitutive activation of the mis-spliced KIT are elucidated. Loss of a peptide in a critical location unleashed the protein from autoinhibition (as evidenced by three-dimensional structural analysis), causing KIT to become constitutively activated and resulting in the GIST phenotype. We also demonstrated that only one of the following two exonic splicing enhancers is sufficient for inclusion of the KIT exon 11 in vivo: AACCCATGT (nucleotides 2-10 from the 5' end, which are recognized by SC35, SRp55, and SF2/ASF) or GGTTGTTGAGG (nucleotides 27-37 from the 5' end, which are recognized by SC35 and SRp55), suggestive of exonic enhancer redundancy.
Surgical decision making in necrotizing enterocolitis and focal intestinal perforation: Predictive value of radiologic findings

Abstract Background/Purpose: Given the current controversy over the appropriate surgical management (peritoneal drainage versus exploratory laparotomy) of advanced necrotizing enterocolitis and focal intestinal perforation, the authors examined the predictive value of radiologic findings. Methods: The medical records of 80 infants undergoing exploratory laparotomy for presumed advanced necrotizing enterocolitis (NEC) or focal intestinal perforation (FIP) were reviewed. Radiologic criteria were evaluated as predictors of NEC (pneumatosis intestinalis, portal venous gas) or perforation (free air, gasless abdomen). The standard epidemiologic measures were calculated for each criterion. Results: For pneumatosis intestinalis, the sensitivity was 44% (n = 27) and specificity, 100% (n = 19). For portal venous gas, the sensitivity was 13% (n = 8) and specificity, 100% (n = 19). The sensitivity and specificity calculated for free air was 52% (n = 23) and 92% (n = 33), respectively. The sensitivity and specificity calculated for a gasless abdomen was 32% (n = 14) and 92% (n = 33), respectively. Conclusions: While demonstrating high specificity, the radiologic signs traditionally associated with NEC and FIP have unexpectedly low sensitivities. Although positive radiologic findings are of great predictive value, negative radiologic findings acquired while determining the need for and specific type of surgical intervention in suspected NEC or FIP must be interpreted with extreme caution. J Pediatr Surg 37:1688-1691. Copyright 2002, Elsevier Science (USA). All rights reserved.
Glycogen storage disease of the muscles. Report of a case with unusual features.

A case of glycogen storage disease of the muscle in a 2 1/2-year-old child is reported. This may represent a fourth type of glycogen disease of striated muscle although, with the data available, a severe form of McArdle's disease with the onset in infancy cannot be excluded. The clinical findings consisted of hypotonia and palatal paralysis without cardiomegaly or hepatomegaly. Blood lactate concentration failed to rise normally following epinephrine administration. Striated muscle contained massive deposits of glycogen of normal molecular structure. Amylo-1, 6-glucosidase was normal. Phosphorylase was not assayed. A summary of the types of glycogen storage disease of muscle is presented. Muscle biopsy in early cases of muscle dystrophy is urged as a means of discovering further examples of glycogen disease of striated muscle.
A Comparative Study of Sandbathing Behavior in Heteromyid Rodents

The movement patterns found in sandbathing were studied in selected species from all five genera of the rodent family Heteromyidae. The primitive subfamily Heteromyinae has a stereotyped pattern for spreading scent consisting of rubbing the ventrum on the substrate. There is no sandbathing in the functional sense. The Perognathinae and Dipodomyinae have both the ventral-rub and side-rub components and often combine these acts into a complex sandbathing pattern. These last two subfamilies have adapted to arid habitats and secrete copiously from their sebaceous glands. Evidence is given for the chemical communicatory nature of the places were sandbathing and ventral-rubbing have taken place. It is suggested that sandbathing has evolved secondarily as a pelage dressing motor pattern while still retaining a function as a means of chemical communication which is the only function of the simple ventral-rubbing found in the Heteromyinae. From a discussion of sandbathing in other rodent families it is proposed that the convergently-evolved sandbathing behavior has originated from different motor patterns.
Identification of two populations of biogenic amine-containg cells in the mouse lung.

Two distinct populations of fluorogenic amine-containing cells were observed in the lungs of nine-week old mice: one with an intense yellow emission, which possibly indicates the presence of serotonin; and one emitting a yellow-green fluorescence, which probably indicates the presence of a catecholamine such as dopamine or norepinephrine. Simultaneous identification of two different fluorogenic amine-containing cells, without pre-administration of a precursor to that amine, has not previously been reported. Such evidence of amine-containing cells demonstrated the success of the perfusion-freezing technique and established that cellular storage of fluorogenic amines does occur in vivo under normal physiological conditions. The function of such amine-containing cells has not been established; however, their location and the known physiological effects of amines would suggest regional control of ventilation/perfusion of the lung.
The Major Dimerization Determinants of the Nitrogen Regulatory Protein NTRC from Enteric Bacteria Lie in Its Carboxy-terminal Domain

The NTRC protein (nitrogen regulatory protein C) of enteric bacteria is an enhancer-binding protein that activates transcription by the sigma54-holoenzyme form of RNA polymerase. NTRC is a homodimeric protein that binds to a dyad-symmetrical site in DNA. To activate transcription NTRC must be phosphorylated and must form an appropriate oligomeric species at an enhancer. In order to study subunit exchange between NTRC dimers, we constructed a fusion of the maltose-binding protein (MBP) to the amino-terminal end of NTRC (MBP-NTRC) and visualized the formation of heterodimers between MBP-NTRC and wild-type NTRC by a gel-mobility shift assay for DNA-binding. When MBP-NTRC is mixed with wild-type NTRC at 37 degrees C, subunit exchange occurs rapidly. The apparent half-life for dissociation of homodimers of NTRC is two to three minutes at 37 degrees C and is not changed by phosphorylation. The isolated carboxy-terminal domain of NTRC (91 amino acid residues) forms heterodimers with both wild-type NTRC and MBP-NTRC, indicating that the C-terminal domain is sufficient for dimerization. The apparent rate of dissociation of homodimers of the C-terminal domain is essentially the same as that of full-length NTRC, indicating that the major dimerization determinants of the protein lie in its C-terminal domain. Congruent with this, a truncated form of NTRC from which the last 58 amino acid residues were removed is a monomer in solution. Moreover, truncated forms of NTRC from which the last 16 or 26 amino acid residues were removed are predominantly monomeric in solution, as is a mutant form with the amino acid substitution A410E in its C-terminal domain. Monomerization of the above mutant forms of NTRC can be rationalized on the basis of homology between the C-terminal region of NTRC and a 50 amino acid residue region of the factor for inversion stimulation (FIS) protein.
Preparation of Active Proteins, Vaccines and Pharmaceuticals as Fine Powders using Supercritical or Near-Critical Fluids

Supercritical or near-critical fluid processes for generating microparticles have enjoyed considerable attention in the past decade or so, with good success for substances soluble in supercritical fluids or organic solvents. In this review, we survey their application to the production of protein particles. A recently developed process known as CO2-assisted nebulization with a Bubble Dryer® (CAN-BD) has been demonstrated to have broad applicability to small-molecule as well as macromolecule substances (including therapeutic proteins). The principles of CAN-BD are discussed as well as the stabilization, micronization and drying of a wide variety of materials. More detailed case studies are presented for three proteins, two of which are of therapeutic interest: anti-CD4 antibody (rheumatoid arthritis), α1-antitrypsin (cystic fibrosis and emphysema), and trypsinogen (a model enzyme). Dry powders were formed in which stability and activity are maintained and which are fine enough to be inhaled and reach the deep lung. Enhancement of apparent activity after CAN-BD processing was also observed in some formulation and processing conditions.
A technique for rapid, reliable assessment of thermal-pain threshold in humans

A simple and reliable method of assessing pain threshold in humans may be useful in a number of research areas, such as in examining acute antinociceptive effects of drugs. We have developed a low-cost, computer-controlled method to reliably assess thermal-pain threshold using radiant heat focused from a slide projector and applied to a small area of skin. An electronic shutter is attached to the projector opening to provide precise onset and offset of heat. A computer keypad allows for subject response at the point of pain onset (i.e., threshold), with latency to threshold determined by computer timer. The details of the apparatus setup, subject preparation, and instructions to subjects are presented. The development of the method is described, and sources of unreliability are identified. Coefficients of variation (CVs) are calculated to provide a measure of variability within subjects across trial exposures and across sessions. Results indicate that the method is reliable for determining pain threshold, especially within sessions, and can be employed with relatively minimal expense and subject preparation.