Medical education scholarship: an introductory guide: AMEE Guide No. 89.
Abstract This AMEE Guide provides an overview of medical education scholarship for early career scholars, based upon a summary of the existing literature and pragmatic advice derived from the experience of its authors. After providing an introduction to the principles of scholarship and describing questions that the Guide addresses, the authors offer a conceptual description of the complementary traditions of teaching and educational discovery, and advocate for the development of educational scholars with both traditions. They then describe the attributes of effective mentor-mentee relationships and how early career scholars can identify potential mentors who can fulfill this role. In the subsequent sections, they describe the appropriate development of scholarly questions and other components of a complete scholarly plan, including how to use conceptual frameworks in guiding such plans. From here, they describe methods that align with both the teaching and discovery traditions and provide concrete examples of each. They then provide guidelines for assessing the impact of scholarship, identify the various opportunities for sharing it, and how to effectively interpret and describe it. Additionally, they provide practical advice on how appropriately to demonstrate the scholarship in a promotional packet, including the principle of reflectivity in scholarship. Finally, they address the principles of applied research ethics for educational scholarship and when to consider soliciting approval for scholarly activities by a human research board.


Paraneoplastic hyperthyroidism.
The authors describe a 31-year-old male with a metastatic germ cell tumour and massively elevated human chorionic gonadotrophin (HCG) levels who presented with hyperthyroidism. As HCG is structurally closely related to thyroid stimulating hormone (TSH), it can activate the TSH receptor; grossly elevated levels may result in hyperthyroidism. After initiation of chemotherapy, HCG levels decreased and hyperthyroidism resolved.


Suicidality, Depression, and the FDA: Health Inequities and the Ethical Conduct of Research.
Persons with mental health disorders, including suicidality, are underrepresented in clinical trials, undermining the generalizability of results and possibly contributing to health inequities. This report (1) documents the exclusion of persons with suicidality in trials used to secure US Food and Drug Administration (FDA) approval for antidepressants, (2) describes barriers to inclusion, and (3) identifies possible steps for overcoming barriers. Inclusion and exclusion criteria for efficacy trials for depression or major depressive disorder described on FDA labels for 14 antidepressants approved from 1991 through 2013 were studied by reading the FDA labels, publications described on labels, and ClinicalTrials.gov entries for registered trials. Labels for drugs approved in or before 1998 were obtained through a Freedom of Information Act request filed June 26, 2018. For drugs approved after 1998, labels are on the FDA website. Publications based on the trials described on FDA labels were identified through a PubMed search on October 23, 2018, using each drug name and trial or study as the keywords and setting no date limit. For drugs approved from 1991 to 2000, of 36 publications identified, 26 did not mention suicidality, 7 excluded persons with suicidality but did not describe assessing suicidality with an instrument, 2 excluded persons with suicidality and described assessing suicidality using at least 1 instrument, and 1 included persons with suicidality. For drugs approved from 2000 through 2013, of 28 publications identified, 4 did not mention suicidality, 12 reported excluding persons with suicidality but did not describe assessing suicidality with an instrument, 12 excluded persons with suicidality and described assessing suicidality using at least one instrument, and none included persons with suicidality. More stringent criteria for assessing and excluding based on suicidality very likely were applied for drugs approved post-2000. The exclusion of persons with suicidality from antidepressant trials is common, creating uncertainty about medication safety and efficacy in parts of the target population. Information about study populations can be beneficial for prescribing clinicians, but it is not always readily available.


A Multisource Approach to Assessing Child Maltreatment From Records, Caregivers, and Children.
Practitioners and researchers alike face the challenge that different sources report inconsistent information regarding child maltreatment. The present study capitalizes on concordance and discordance between different sources and probes applicability of a multisource approach to data from three perspectives on maltreatment-Child Protection Services (CPS) records, caregivers, and children. The sample comprised 686 participants in early childhood (3- to 8-year-olds; n = 275) or late childhood/adolescence (9- to 16-year-olds; n = 411), 161 from two CPS sites and 525 from the community oversampled for psychosocial risk. We established three components within a factor-analytic approach: the shared variance between sources on presence of maltreatment (convergence), nonshared variance resulting from the child's own perspective, and the caregiver versus CPS perspective. The shared variance between sources was the strongest predictor of caregiver- and self-reported child symptoms. Child perspective and caregiver versus CPS perspective mainly added predictive strength of symptoms in late childhood/adolescence over and above convergence in the case of emotional maltreatment, lack of supervision, and physical abuse. By contrast, convergence almost fully accounted for child symptoms for failure to provide. Our results suggest consistent information from different sources reporting on maltreatment is, on average, the best indicator of child risk.


Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke.
We examined expression of vascular endothelial growth factor (VEGF), phosphorylation of mitogen activated protein kinase (MAP) kinase (ERK1 and ERK2) and tyrosine phosphorylation in 19 patients (aged 58-90 years; mean 75) who died 1-44 days after acute ischaemic stroke. In the grey matter penumbra, 13 of 19 patients showed an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 8-fold, ERK2; 2.2- to 11-fold) compared with normal contralateral tissue. In almost all cases, ERK-2 phosphorylation was higher than ERK1. Of these 13 patients, 11 also showed a general increase in tyrosine kinase phosphorylation, and eight expressed increased levels of VEGF protein (2.5- to 5-fold). In tissue examined directly from the infarct core, activation of the above proteins was not observed in the, majority of patients. In the white matter, seven of 19 patients (penumbra), and nine of 19 patients (stroke) had an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 4.6-fold and ERK-2; 2.3- to 5.4-fold respectively) compared with normal contralateral tissue. There was no relationship between activation of MAP kinase and expression of VEGF. Examination of phosphorylated MAP kinase by immunohistochemistry revealed an increase in immunoreactivity in neurones, astroglial cells, reactive microglia and endothelial cells in areas surrounding infarcts, especially in areas with the highest density of microvessels. In conclusion, chronic activation of tyrosine phosphorylated events, in particular redistribution and phosphorylation of MAP kinase (ERK1/ERK2) occurs consistently in the grey matter penumbra of brain tissue following ischaemic stroke, and may be associated with increase in expression of VEGF. These signal transduction events could be important determinants of the extent of neuronal survival and/or angiogenic activity in the recovering brain tissue.


Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging.
Our goal is to develop minimally invasive biomarkers for predicting radiation-induced lung injury before symptoms develop. Currently, there are no biomarkers that can predict radiation pneumonitis. Radiation damage to the whole lung is a serious risk in nuclear accidents or in radiologic terrorism. Our previous studies have shown that a single dose of 15 Gy of x-rays to the thorax causes severe pneumonitis in rats by 6-8 wk. We have also developed a mitigator for radiation pneumonitis and fibrosis that can be started as late as 5 wk after radiation. We used 2 functional SPECT probes in vivo in irradiated rat lungs. Regional pulmonary perfusion was measured by injection of (99m)Tc-macroaggregated albumin. Perfused volume was determined by comparing the volume of distribution of (99m)Tc-macroaggregated albumin to the anatomic lung volume obtained by small-animal CT. A second probe, (99m)Tc-labeled Duramycin, which binds to apoptotic cells, was used to measure pulmonary cell death in the same rat model. The perfused volume of lung was decreased by about 25% at 1, 2, and 3 wk after receipt of 15 Gy, and (99m)Tc-Duramycin uptake was more than doubled at 2 and 3 wk. There was no change in body weight, breathing rate, or lung histology between irradiated and nonirradiated rats at these times. Pulmonary vascular resistance and vascular permeability measured in isolated perfused lungs ex vivo increased at 2 wk after 15 Gy of irradiation. Our results suggest that SPECT biomarkers have the potential to predict radiation injury to the lungs before substantial functional or histologic damage is observed. Early prediction of radiation pneumonitis in time to initiate mitigation will benefit those exposed to radiation in the context of therapy, accidents, or terrorism.


X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.


Advances and issues in flow cytometric detection of immunophenotypic changes and genomic rearrangements in acute pediatric leukemia.
Flow cytometry with its rapidly increasing applications has been using to aid the diagnosis of hematological disorders for more than two decades. It is also the most commonly used technology in childhood leukaemia diagnosis, characterization, prognosis prediction and even in the decision making of targeted therapy. Leukemia cells can be recognized by virtue of unique cell marker combinations, visualized with monoclonal antibodies conjugated and detected by flow cytometry. Currently, such instruments allow the detection of eight or more markers by providing a comprehensive description of the leukemic cell phenotype to facilitate their identification, especially in detecting and monitoring of minimal residual disease (MRD) during treatment. Additionally, the flow cytometric DNA index (DI) can identify biclonality at diagnosis and distinguish persistent aneuploid leukemia during induction therapy, when the standard cytogenetic and morphologic techniques fail to do so. This review focuses on the latest advances and application issues about some of flow cytometric diagnostic and prognostic applications for acute pediatric leukemia.


Creating an α7 nicotinic acetylcholine recognition domain from the acetylcholine-binding protein: crystallographic and ligand selectivity analyses.
Determining the structure of the ligand-binding domain of the nicotinic acetylcholine receptor (nAChR) has been a long standing goal in the design of selective drugs useful in implicated diseases for this prevalent receptor family. Acetylcholine-binding proteins have proven to be valuable surrogates with structural similarity and sequence identity to the extracellular domain of the nicotinic receptor, yet these soluble proteins have their unique features and do not serve as exact replicates of the nAChRs of interest. Here we systematically modify the sequence of these proteins toward the homomeric human α7 nAChR. These chimeric proteins exhibit a shift in affinities to reflect α7 binding characteristics yet maintain expression levels and stability conducive for crystallization. We also present a pentameric humanoid nAChR extracellular domain with the structural determination of the α7 nAChR glycosylation site.


Comparative beta-adrenoreceptor-blocking effects and pharmacokinetics or propranolol and pindolol in hypertensive Africans.
1. The beta-adrenoreceptor-blocking effects of pindolol were compared with those of propranolol and a placebo in a double-blind cross-over trial involving nine hypertensive African patients. 2. Heart rate, systolic blood pressure and diastolic blood pressure were measured at rest and immediately after exercise before and at intervals up to 6 h after oral administration of the drugs. In addition, plasma pindolol and propranolol concentrations were determined at the same intervals. 3. Pindolol diminished systolic blood pressure at rest and after exercise and antagonized exercise-induced tachycardia, but had no effect on resting heart rate. Propranolol diminished systolic blood pressure predominantly after exercise and reduced both resting and exercise heart rate. Both drugs had no effect on diastolic pressure. 4. The mean plasma concentration reached a peak at 2 h for each drug and this coincide with the interval at which maximal beta-adrenoreceptor-blocking effect was observed.


A Systematic Scoping Review of How Healthcare Organizations Are Facilitating Access to Fruits and Vegetables in Their Patient Populations.
There is compelling evidence on the impact of diet as preventative medicine, and with rising health care costs healthcare organizations are attempting to identify interventions to improve patient health outcomes. The purpose of this systematic scoping review was to characterize existing healthcare organization-based interventions to improve access to fruits and vegetables (F&V) for their patient populations. In addition, we aimed to review the impact of identified interventions on dietary intake and health outcomes. Titles and abstracts were searched in PubMed® (MEDLINE®), Embase®, CINAHL®, and the Cochrane Library® from 1 January 1990 to 31 December 2019. To be selected for inclusion, original studies must have included a healthcare organization and have had a programmatic focus on increasing access to or providing fresh F&V to patients in an outpatient, naturalistic setting. The Effective Public Health Practice Project tool was used to assess study quality in 6 domains (selection bias, study design, confounders, blinding, data collection methods, and withdrawals and dropouts). A total of 8876 abstracts were screened, yielding 44 manuscripts or abstracts from 27 programs. Six program models were identified: 1) a cash-back rebate program, 2) F&V voucher programs, 3) garden-based programs, 4) subsidized food box programs, 5) home-delivery meal programs, and 6) collaborative food pantry-clinical programs. Only 6 of 27 studies included a control group. The overall quality of the studies was weak due to participant selection bias and incomplete reporting on data collection tools, confounders, and dropouts. Given the heterogeneity of outcomes measured and weak study quality, conclusions regarding dietary and health-related outcomes were limited. Healthcare-based initiatives to improve patient access to F&V are novel and have promise. However, future studies will need rigorous study designs and validated data collection tools, particularly related to dietary intake, to better determine the effect of these interventions on health-related outcomes.


In vivo Activity of Copper(II), Manganese(II), and Silver(I) 1,10-Phenanthroline Chelates Against Candida haemulonii Using the Galleria mellonella Model.
Candida haemulonii is an emerging opportunistic pathogen resistant to most antifungal drugs currently used in clinical arena. Metal complexes containing 1,10-phenanthroline (phen) chelating ligands have well-established anti-Candida activity against different medically relevant species. This study utilized larvae of Galleria mellonella, a widely used model of in vivo infection, to examine C. haemulonii infection characteristics in response to different copper(II), manganese(II), and silver(I) chelates containing phen, which had demonstrated potent anti-C. haemulonii activity in a previous study. The results showed that C. haemulonii virulence was influenced by inoculum size and incubation temperature, and the host G. mellonella immune response was triggered in an inoculum-dependent manner reflected by the number of circulating immune cells (hemocytes) and observance of larval melanization process. All test chelates were non-toxic to the host in concentrations up to 10 μg/larva. The complexes also affected the G. mellonella immune system, affecting the hemocyte number and the expression of genes encoding antifungal and immune-related peptides (e.g., inducible metalloproteinase inhibitor protein, transferrin, galiomycin, and gallerimycin). Except for [Ag2(3,6,9-tdda)(phen)4].EtOH (3,6,9-tddaH2 = 3,6,9-trioxoundecanedioic acid), all chelates were capable of affecting the fungal burden of infected larvae and the virulence of C. haemulonii in a dose-dependent manner. This work shows that copper(II), manganese(II), and silver(I) chelates containing phen with anti-C. haemulonii activity are capable of (i) inhibiting fungal proliferation during in vivo infection, (ii) priming an immune response in the G. mellonella host and (iii) affecting C. haemulonii virulence.


Importance of lipids in the nutritional treatment of inflammatory diseases.
Over the last decades, scientific advances in the knowledge of anti-inflammatory properties of lipids have lead to the development of new formulas for enteral and parenteral nutrition. These products have been utilised as a treatment for a variety of inflammatory diseases. In this review we expose the effects of lipids used in enteral nutriton on different inflammatory pathologies such as inflammatory bowel disease, atherosclerosis, lung fibrosis, rheumatoid arthritis, and others. During inflammatory diseases, eicosanoids are produced from polyunsaturated fatty acids present in cellular membranes. Inflammatory activity of these molecules depends on the nature of their precursors: when arachidonic acid (n-6) is present, pro-inflammatory molecules are released, whereas eicosapentaenoic acid (n-3)-derived eicosanoids are weakly inflammatory. In this way, fish oils, rich in n-3 polyunsaturated fatty acids, increase the content of eicosapentaenoic-eicosanoids and decrease arachidonic acid in immune and endothelial cells leading to a lower inflammatory activity. Likewise, oleic acid exhibits anti-inflammatory effects by preventing the release of particular chemotactic molecules. In summary, enteral diets supplemented with n-3 polyunsaturated fatty acids and oleic acid benefits the treatment of patients with inflammatory pathologies, leading to better outcomes, and decreasing the doses of anti-inflammatory drugs, which exhibit important secondary effects.


Autophagy is activated to protect renal tubular epithelial cells against iodinated contrast media‑induced cytotoxicity.
With the steady increase in the use of various contrast‑related technologies in recent years, contrast‑induced nephropathy has received significant attention from clinicians and researchers. The present study aimed to determine the potential role of autophagy in iodinated contrast media (CM)‑induced cell injury and apoptosis in human proximal renal tubular epithelial HK‑2 cells. The present study used the iodinated CM iohexol (200 mg iodine/ml) to treat HK‑2 cells for 6 h, in order to establish a damaged cell model. The autophagy inhibitor 3‑methyladenine (3‑MA; 10 mM) was used to inhibit the formation of autophagosomes. Immunofluorescence assay and transmission electron microscopy (TEM) were used to observe the formation of autophagosomes in the cytoplasm. The protein expression levels of microtubule‑associated protein 1A/1B‑light chain 3 (LC3)‑II and autophagy‑related protein 7 (Atg7) were detected by western blotting. The cytotoxicity of CM was evaluated by MTT assay and lactate dehydrogenase release, and cell apoptosis was detected by flow cytometry. Increased formation of autophagosomes and autophagic vesicles was observed under TEM in HK‑2 cells following iohexol treatment for 6 h. Immunofluorescence assay demonstrated that iohexol increased LC3‑II expression in HK‑2 cells. Furthermore, the expression levels of LC3‑II and Atg7 in HK‑2 cells were significantly upregulated by iohexol administration; however, LC3‑II and Atg7 expression was decreased by 3‑MA treatment. These results provided evidence to suggest that autophagy is activated in response to iohexol‑induced cell injury and apoptosis, and may exert a renoprotective role in HK‑2 cells.


Characteristic features of granular deposit formation in granular corneal dystrophy type 2.
To describe the characteristic features of white granular deposits associated with granular corneal dystrophy type 2 (GCD2). Five patients with GCD2 associated with the R124H mutation (2 homozygous GCD2 and 3 heterozygotes) were examined. The corneal deposits of all patients were assessed and reviewed by slit-lamp photographs. Density line profiles of corneal surfaces were evaluated around the discrete corneal deposits using Image J software. A Fourier-domain optical coherence tomography with cornea anterior module was used to visualize the characteristic surrounding features of these granular deposits. A histopathological study of the homozygous corneal specimen obtained after keratoplasty was performed. Slit-lamp images and densitometry line profiles showed that discrete granules were surrounded by relatively clear areas in all patients. The Fourier-domain optical coherence tomography image clearly showed highly reflective lesions, corresponding to the corneal deposits, surrounded by lower reflective areas. Histopathological study revealed comparable findings to the optical coherence tomography image. Serial comparison of slit-lamp photographs demonstrated a recurrence pattern after penetrating keratoplasty in a homozygous patient and natural progression in a heterozygote patient. They were similar in that diffuse fine granules gradually increased in density and discrete granular deposits also enlarged or were newly formed. In GCD2, discrete white granular deposits were surrounded by rather lucid areas and fine granular haze. These findings suggest that white granular deposits may be formed by aggregation of surrounding fine granules.


Causation, compulsion, and involuntariness.
This article first addresses the persistent confusion between causation and excuse. It demonstrates that causation is not the equivalent of compulsion and that causation per se is not an excusing condition. Then the article examines the conceptual and practical difficulties presented by the excuse that is variously labeled "compulsion," "involuntariness," "volitional problems," "irresistible impulse," and the like. It concludes that this excuse, when produced by internal causes, is far less well understood and assessed than forensic clinicians usually assume and that most such excusing conditions are better understood and assessed in terms of rationality problems.


Optical detection of singlet oxygen from single cells.
The lowest excited electronic state of molecular oxygen, singlet molecular oxygen, O(2)(a (1)Delta(g)), is a reactive species involved in many chemical and biological processes. To better understand the roles played by singlet oxygen in biological systems, particularly at the sub-cellular level, optical tools have been developed to create and directly detect this transient state in time- and spatially-resolved experiments from single cells. Data obtained indicate that, contrary to common perception, this reactive species can be quite long-lived in a cell and, as such, can diffuse over appreciable distances including across the cell membrane into the extracellular environment. On one hand, these results demonstrate that the behavior of singlet oxygen in an intact cell can be significantly different from that inferred from model bulk studies. More generally, these results provide a new perspective for mechanistic studies of intra- and inter-cellular signaling and events that ultimately lead to photo-induced cell death.


Effectiveness of electronic fetal monitoring with additional ST analysis in vertex singleton pregnancies at >36 weeks of gestation: an individual participant data metaanalysis.
The purpose of this study was to assess the effectiveness of electronic fetal monitoring (EFM) alone and with additional ST analysis (EFM + ST) in laboring women with a singleton term pregnancy that is in cephalic presentation in the prevention of metabolic acidosis by the application of individual patient data metaanalysis. We conducted an individual patient data metaanalysis using data from 4 randomized trials, which enabled us to account for missing data and investigate relevant subgroups. The primary outcome was metabolic acidosis, which was defined as an umbilical cord-artery pH <7.05 and a base deficit that had been calculated in the extra cellular fluid compartment >12 mmol/L. We performed 8 explanatory subgroup analyses for 8 different endpoints. We analyzed data from 12,987 women and their newborn infants. Metabolic acidosis was present in 57 women (0.9%) in the EFM + ST group and 73 women (1.1%) in the EFM alone group (relative risk [RR], 0.76; 95% CI, 0.53-1.10). Compared with EFM alone, the use of EFM + ST resulted in a reduction in the frequency of instrumental vaginal deliveries (RR, 0.90; 95% CI, 0.83-0.99) and fetal blood samples (RR, 0.49; 95% CI, 0.44-0.55). Cesarean delivery rates were comparable between both groups (RR, 0.99; 95% CI, 0.91-1.09). Subgroup analyses showed that EFM + ST resulted in fewer admissions to a neonatal intensive care unit for women with a duration of pregnancy of >41 weeks (RR, 0.61; 95% CI, 0.39-0.95). EFM + ST does not reduce the risk of metabolic acidosis, but it does reduce the need for instrumental vaginal deliveries and fetal blood sampling.


Self-Organization of Microcircuits in Networks of Spiking Neurons with Plastic Synapses.
The synaptic connectivity of cortical networks features an overrepresentation of certain wiring motifs compared to simple random-network models. This structure is shaped, in part, by synaptic plasticity that promotes or suppresses connections between neurons depending on their joint spiking activity. Frequently, theoretical studies focus on how feedforward inputs drive plasticity to create this network structure. We study the complementary scenario of self-organized structure in a recurrent network, with spike timing-dependent plasticity driven by spontaneous dynamics. We develop a self-consistent theory for the evolution of network structure by combining fast spiking covariance with a slow evolution of synaptic weights. Through a finite-size expansion of network dynamics we obtain a low-dimensional set of nonlinear differential equations for the evolution of two-synapse connectivity motifs. With this theory in hand, we explore how the form of the plasticity rule drives the evolution of microcircuits in cortical networks. When potentiation and depression are in approximate balance, synaptic dynamics depend on weighted divergent, convergent, and chain motifs. For additive, Hebbian STDP these motif interactions create instabilities in synaptic dynamics that either promote or suppress the initial network structure. Our work provides a consistent theoretical framework for studying how spiking activity in recurrent networks interacts with synaptic plasticity to determine network structure.


Correlative study of fluoride content in urine, serum and urinary calculi.
Fluoride content was measured in 100 urinary stones retrieved by open surgery of stone formers admitted at PGIMS Rohtak and their respective urine and serum and compared with those of healthy individuals. The concentration of fluoride was also measured in the sources of drinking water of these stone formers. The concentration of fluoride was definitely significantly higher in serum (p>0.01) and highly significantly higher in urine (p>-0.001) of stone formers compared to those of healthy individuals. The content of oxalate in serum and 24 h urine of the stone formers was also measured, which was increased significantly (p<0.005 and p<0.001) compared to healthy individuals. The concentration of fluoride was probably significantly higher in drinking water of these stone formers than the normal ones. There was a positive correlation between the content of fluoride of urinary stones and urine of stone patients (r=.88); stone and serum (r=.62); drinking water and stone (r=.85) and their urine and serum (r=.54); urine and drinking water (r=.83) and serum and water (r=.51). These results indicate a definite role of fluoride in urinary stone formation.


The role of needle exchange programs in HIV prevention.
Injecting drug users (IDUs) are at high risk for infection by human immunodeficiency virus (HIV) and other blood-borne pathogens. In the United States, IDUs account for nearly one-third of the cases of acquired immunodeficiency syndrome (AIDS), either directly or indirectly (heterosexual and perinatal cases of AIDS where the source of infection was an IDU). IDU also account for a substantial proportion of cases of hepatitis B (HBV) and hepatitis C (HCV) virus infections. The primary mode of transmission of HIV among IDUs is parenteral, through direct needle sharing or multiperson use of syringes. Despite high levels of knowledge about risk, multiperson use of needles and syringes is due primarily to fear of arrest and incarceration for violation of drug paraphernalia laws and ordinances that prohibit manufacture, sale, distribution, or possession of equipment and materials intended to be used with narcotics. It is estimated that in 1997 there were approximately 110 needle exchange programs (NEPs) in North America. In part, because of the ban on the use of Federal funds for the operation of needle exchange, it has been difficult to evaluate the efficacy of these programs. This chapter presents data from the studies that have evaluated the role of NEPs in HIV prevention. Evidence for the efficacy of NEPs comes from three source: (1) studies originally focused on the effectiveness of NEPs in non-HIV blood-borne infections, (2) mathematical modeling of data on needle exchange on HIV seroincidence, and (3) studies that examine the positive and negative impact of NEPs on HIV and AIDS. Case-control studies have provided powerful data on the positive effect of NEPs on reduction of two blood-borne viral infections (HBV and HCV) For example, a case-control study in Tacoma, Washington, showed that a six-fold increase in HBV and a seven-fold increase in HCV infections in IDUs were associated with nonuse of the NEP. The first federally funded study of needle exchange was an evaluation of the New Haven NEP, which is legally operated by the New Haven Health Department. Rather than relying on self-report of reduced risky injection drug use, this study utilized mathematical and statistical modeling, using data from a syringe tracking and testing system. Incidence of HIV infection among needle exchange participants was estimated to have decreased by 33% as a result of the NEP. A series of Government-commissioned reports have reviewed the data on positive and negative outcomes of NEPs. The major reports are from the National Commission on AIDS; the U.S. General Accounting Office; the Centers for Disease Control/University of California; and the National Academy of Sciences. The latter two reports are used in this chapter. The aggregated results support the positive benefit of NEPs and do not support negative outcomes from NEPs. When legal restrictions on both purchase and possession of syringes are removed, IDUs will change their syringe-sharing behaviors in ways that can reduce HIV transmission. NEPs do not result in increased drug use among participants or the recruitment of first-time drug users.


OncoKB: A Precision Oncology Knowledge Base.
With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.


Hepatitis C virus transmission by intravenous immunoglobulin.
The polymerase chain reaction was used to detect hepatitis C virus infection in patients who had previously been reported to have developed non-A, non-B hepatitis after intravenous immunoglobulin infusion. Of the 33 patients with intravenous immunoglobulin associated non-A, non-B hepatitis studied, HCV RNA could be detected in 15 out of 17 patients (88%) who were HCV RNA negative prior to the development of non-A, non-B hepatitis after implicated intravenous immunoglobulin batches. Similarly, eight out of nine patients (89%) in whom no sample was available for polymerase chain reaction testing prior to intravenous immunoglobulin therapy, had detectable HCV RNA after intravenous immunoglobulin therapy with intravenous immunoglobulin batches implicated in non-A, non-B hepatitis transmission. Two of the three intravenous immunoglobulin preparations implicated in non-A, non-B hepatitis transmissions that were available for polymerase chain reaction testing also had detectable HCV RNA, confirming that hepatitis C virus is the implicated virus in intravenous immunoglobulin-associated non-A, non-B hepatitis.


Factors associated with onset, relapses or progression in multiple sclerosis: A systematic review.
Multiple sclerosis (MS) is a chronic disease of the central nervous system with an unidentified etiology. We systematically reviewed the literature on the possible risk factors associated with MS disease onset, relapses and progression from 1960 to 2012 by accessing six databases and including relevant systematic reviews, meta-analyses, case-control or cohort studies. The focus was on identifying modifiable risk factors. Fifteen systematic reviews and 169 original articles were quality assessed and integrated into a descriptive review. Best evidence, which included one or more prospective studies, suggested that lower exposure to sunlight and/or lower serum vitamin D levels were associated with an increased risk of developing MS onset and subsequent relapses, but a similar quality of evidence was lacking for disease progression. Prospective studies indicated that cigarette smoking may increase the risk of MS as well as accelerate disease progression, but whether smoking altered the risk of a relapse was largely unknown. Infections were implicated in both risk of developing MS and relapses, but data for progression were lacking. Specifically, exposure to the Epstein-Barr virus, particularly if this manifested as infectious mononucleosis during adolescence, was associated with increased MS risk. Upper respiratory tract infections were most commonly associated with an increase in relapses. Relapse rates typically dropped during pregnancy, but there was no strong evidence to suggest that pregnancy itself altered the risk of MS or affected long-term progression. Emerging research with the greatest potential to impact public health was the suggestion that obesity during adolescence may increase the risk of MS; if confirmed, this would be of major significance.


Reasons for non-adherence to antiretroviral therapy: patients' perspectives provide evidence of multiple causes.
The objective of the study was to define common reasons for non-adherence (NA) to highly active antiretroviral therapy (HAART) and the number of reasons reported by non-adherent individuals. A confidential questionnaire was administered to HIV-seropositive patients taking proteinase inhibitor based HAART. Median self-reported adherence was 95% (n = 178, range = 60-100%). The most frequent reasons for at least 'sometimes' missing a dose were eating a meal at the wrong time (38.2%), oversleeping (36.3%), forgetting (35.0%) and being in a social situation (30.5%). The mean number of reasons occurring at least 'sometimes' was 3.2; 20% of patients gave six or more reasons; those reporting the lowest adherence reported a significantly greater numbers of reasons (rho = - 0.59; p < 0.001). Three factors were derived from the data by principal component analysis reflecting 'negative experiences of HAART', 'having a low priority for taking medication' and 'unintentionally missing doses', accounting for 53.8% of the variance. On multivariate analysis only the latter two factors were significantly related to NA (odds ratios 0.845 and 0.849, respectively). There was a wide spectrum of reasons for NA in our population. The number of reasons in an individual increased as adherence became less. A variety of modalities individualized for each patient are required to support patients with the lowest adherence.


Evaluation of the efficacy of therapeutic ultrasound in the treatment of migraine.
This study aims to evaluate the efficacy of therapeutic pulsed ultrasound (US) applied to the occipital nerve distribution area in chronic migraine patients. This prospective, randomized, double-blind, placebo-controlled, study was conducted on 58 patients diagnosed with migraine at the University of Health Sciences Bursa Yüksek Ihtisas Training and Research Hospital, Department of Physical Medicine and Rehabilitation between January 2018 and October 2018. The patients were randomly divided into two groups as sham and pulsed US group. Pulsed US was applied in Group 1 (n=29), and sham US was used in Group 2 (n=29) for 5 min for a total of 10 sessions in each group. The evaluation was made at pre-treatment, post-treatment first month (week six) and third month (week 14) using the numeric rating scale, and the Migraine Disability Assessment Scale (MIDAS). The final analysis was conducted with 52 patients (7 males, 45 females; mean age: 38.3±7.9 years; range, 20 to 65 years) due to drop-outs, with 27 patients in Group 1 and 25 patients in Group 2. A statistically significant improvement was found in all parameters at week six and week 14 compared to pre-treatment values in Group 1. A statistically significant worsening was detected in MIDAS 1, 4, 5, total questions, and a significant improvement was found in MIDAS A and B at week six compared to pre-treatment values in Group 2. A statistically significant worsening was found only in MIDAS total score at week 14 compared to pre-treatment values. In the comparison of the difference scores of the two groups, all parameters in Group 1 showed significant improvement at week six and week 14. The findings obtained in this study show that pulsed US applied to the occipital nerve distribution region in migraine patients can be effective on headache frequency, severity, and disability.


Increased energy expenditure in gastric bypass rats is not caused by activated brown adipose tissue.
To investigate whether gastric bypass induces a higher activity of brown adipose tissue and greater levels of the brown adipose tissue-specific protein uncoupling protein-1 (UCP-1) in rats. Gastric bypass rats and sham-operated controls (each n = 8) underwent whole body (1)H-MR spectroscopy for analysis of body composition and (18)F-fluorodeoxyglucose positron emission tomography combined with computed tomography ((18)F-FDG PET/CT) imaging for measurement of the metabolic activity of brown adipose tissue. Brown adipose tissue was harvested and weighed, and UCP-1 mRNA content was measured by Northern Blot technique. Gastric bypass rats had a significantly lower percentage of whole body adipose tissue mass compared to sham-operated rats (p = 0.001). There was no difference in brown adipose tissue activity between the two groups (standardised uptake value sham 2.81 ± 0.58 vs. bypass 2.56 ± 0.46 ; p = 0.73). Furthermore, there was no difference in the UCP-1 mRNA content of brown adipose tissue between the two groups (sham 49.5 ± 13.2 vs. bypass 43.7 ± 13.1; p = 0.77). Gastric bypass does not increase the activity of brown adipose tissue in rats suggesting that other mechanisms are involved to explain the increased energy expenditure after bypass surgery. Our results cannot justify the radiation dose of (18)F-FDG PET/CT studies in humans to determine potential changes in brown adipose tissue after gastric bypass surgery.


Rod bipolar cells in the macaque monkey retina: immunoreactivity and connectivity.
Rod bipolar cells in the macaque monkey retina were labeled by three antibodies: an antibody against the alpha- and beta-subspecies of protein kinase C (PKC), a polyclonal antiserum against the L7 protein from mouse cerebellum, and a monoclonal antibody against rabbit olfactory bulb (MAb 115A 10). The MAb 115A10 antibody also labeled some cone bipolar and some amacrine cells. The antibody against PKC was used to study the synaptic connectivity of rod bipolar cells. Reconstructions of 28 rod spherules showed that usually two and up to four rod bipolar processes invaginate each rod spherule. Six rod bipolar axons in the inner plexiform layer were reconstructed; they all showed the same pattern of connectivity. Synaptic output at rod bipolar dyads usually was onto two amacrine cell profiles: one that resembled the All amacrine cell and another that frequently made a reciprocal synapse. Rod bipolar cells did not contact ganglion cells. Synaptic input to rod bipolar cells came from reciprocal amacrine cells at dyads and other amacrine cells. In these respects, the rod pathway in the monkey is very similar to that described in cat and rabbit. The density of rod bipolar cells was determined and compared with the density of rods. There is a maximum of 15,000-20,000 rod bipolar cells/mm2 at 1-3 mm eccentricity, close to where rod density is maximum. Rod density is 10 times higher than rod bipolar cell density within 2 mm of the fovea, and 30 times higher at 15 mm eccentricity. This change in relative density is compensated by an increase in the number of rods contacted by individual rod bipolar cells (seen in Golgi-stained whole-mount retina) so that the number of rod bipolar terminal boutons in each rod photoreceptor remains relatively constant with changing eccentricity. We estimate that each rod bipolar cell is contacted by about 20 rods at 2-4 mm eccentricity and about 60 rods at 6-7 mm eccentricity.


Thresholds for health and thresholds for illness: panic disorder versus subthreshold panic disorder.
There is increasing evidence that subthreshold forms of psychopathology are both common and clinically relevant. To enable classification of these subthreshold forms of psychopathology, it may be useful to distinguish not only a threshold for illness but also for health. Our aim was to investigate this with regard to panic. Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), which is based on a large representative sample of the adult general population (18-65 years) of The Netherlands (n=7076). The Composite International Diagnostic Interview was used as a diagnostic instrument. By defining two thresholds, three groups were formed: panic disorder, subthreshold panic disorder and no-panic. These groups were compared using multinomial regression analysis, chi2 and analysis of variance. The 12-month prevalence of panic disorder was 2.2% while that of subthreshold panic disorder was 1.9%. Symptom profiles and risk indicators associated with panic disorder and subthreshold panic disorder were similar, and half of the risk indicators were more strongly associated with panic disorder than with subthreshold panic disorder. Subthreshold panic disorder occupied an intermediate position between panic disorder and no-panic with regard to the number of symptoms, the percentage of subjects with co-morbidity, and functioning. Subthreshold panic disorder is common, and seems clinically relevant, but is milder than panic disorder. These results thus support the use of a double threshold in panic. Further research should focus on the positioning of the thresholds, the course of subthreshold panic disorder and its treatment options.


Analysis of epididymal proteins during sexual maturation in male albino mice.
Androgen dependent epididymal proteins act as antigen to produce autoantibodies and affect normal fertility. In the present study, epididymal proteins were analyzed during the time of sexual maturation and their androgen dependency was studied in male albino mice. Epididymis of 21 days (Pre-pubertal), 45 days (Pubertal), 60 days (Post-pubertal), orchidectomized (15 days after surgery) and orchidectomized with testosterone-treated (15 days after treatment) mice were dissected out and analyzed. Caput, corpus and cauda epididymidis were separated and the protein extract was prepared with 0.1 M PBS for 10% SDS-PAGE analysis. Testosterone assay was performed in the experimental groups except the testosterone treated group. The electrophoretic analysis of proteins in caput, corpus and cauda epididymidis of orchidectomized animals showed the disappearance of several proteins as compared to the adult. However, the disappeared proteins started to reappear in testosterone treated animals. The results suggest that removal of testis depletes the testosterone level and causes significant alteration in epididymal proteins. These proteins need further investigation for the purpose of immunocontraception by using them as antigens.


Evaluation of the smear layer and hybrid layer in noncarious and carious dentin prepared by air abrasion system and diamond tips.
To analyze the smear layer and the hybrid layer in noncarious and carious dentin prepared by different cutting instruments and restored with composite resin. Cavities were randomly prepared in 160 specimens (noncarious and artificial carious dentin) by high-speed diamond tips (KG Sorensen 1013), air abrasion system (Prepstart, Danville Engineering), ultrasonic tip (CVDentus 8.3231-1), and ultrasonic tip associated with ultrasonic cavitation by water for 10 s. Half of the cavities in each group were conditioned with 37% phosphoric acid for 15 s. The amount of smear layer and dentinal tubules present were analyzed using scanning electron microscopy and graded from 0 to 3. Cavities were prepared in another 20 noncarious specimens and 20 carious specimens and restored with adhesive composite resin system. The restorations were hemisected longitudinally and analyzed using scanning electron microscopy to evaluate the hybrid layer and resinous prolongation characteristics, using scores ranging from 1 to 6. The data were statistically analyzed using Kruskal-Wallis and Dunn tests at 5% of significance level. There was evidence that the most efficient smear layer removal was the acid etching in the noncarious dentin and the water ultrasonic cavitation in the carious dentin. The hybrid layer formed on the noncarious and carious dentin prepared by the ultrasonic tip was more regular than in the specimens prepared by high-speed diamond tip, with many resinous prolongations. The ultrasonic tip seems to be a promising tool for carious dentin cavity preparation.


Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis.
Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual.


Premature mortality in children aged 6-9 years with neurological impairments in rural Kenya: a cohort study.
Neurological impairments might significantly contribute to reduced life expectancy in low-income and middle-income countries (LMICs). There are no empirical studies of premature mortality in children with neurological impairments in Africa. This study estimated the risk of premature mortality in children with neurological impairments and identified risk factors and causes of death. We did a cohort study based on a two-stage epidemiological survey in the Kilifi Health and Demographic Surveillance System (Kilifi, Kenya). Study participants were children aged 6-9 years. In the first stage, five trained field workers administered a low-cost screening tool to a random sample of households. In the second stage, we assessed for neurological impairments in five domains (epilepsy, cognitive impairments, vision impairments, hearing impairments, and motor impairments) using comprehensive clinical evaluation and extensive neuropsychological assessments. From the two-stage survey we identified a cohort of children with neurological impairment and a cohort of matched controls. We also enrolled an age-matched sample from the general population. The primary outcome was all-cause mortality. Mortality rates, standardised mortality ratio (SMR), and hazard ratios (HR) for risk factors were estimated and causes of death identified. We enrolled 306 children with neurological impairment, 9912 survey controls, and 22 873 age-matched participants from the general population, and followed up the cohorts between June 1, 2001, and Aug 31, 2018. Median follow-up was 14·5 years (IQR 8·6-17·2). 11 (3·9%) of 284 children with neurological impairment, 92 (1·0%) of 9009 controls, and 272 (1·2%) of 22 873 participants in the general population sample died during the follow-up. Overall mortality rates were 309·8 per 100 000 person-years of observation (95% CI 126·7-492·9) in children with neurological impairment, 80·8 per 100 000 person-years of observation (64·3-97·3) in controls, and 98·8 per 100 000 person-years of observation (87·1-110·6) in the general population sample (mortality rate ratio 3·83, 95% CI 2·05-7·16, p<0·001, compared with controls; 3·13, 1·71-5·72, p<0·001, compared with the general population). Mortality risk in children with neurological impairment was not dependent on the severity of impairment (p=0·291) nor on a specific neurological impairment domain (p=0·205). The overall risk of death adjusted for age and sex was higher in children with neurological impairment compared with controls (HR 4·24, 95% CI 2·26-7·94, p=0·002). An SMR of 3·15 (95% CI 1·66-5·49) was obtained after using the general population sample as the reference for indirect standardisation. In multivariable risk factor analysis, developmental delay (adjusted HR 18·92, 95% CI 2·23-160·44, p=0·007) and severe malnutrition (20·92, 3·14-139·11, p=0·002) increased the risk of mortality in children with neurological impairment. Infections such as HIV/AIDS and accidents were common among all decedents. The risk of premature mortality was higher in children diagnosed with neurological impairments compared with the general population and was increased by developmental delay and severe malnutrition. Child development and nutritional status should be assessed in all children in LMICs and tailored interventions started to improve outcomes. Wellcome Trust, DELTAS Africa Initiative.


Modeling the effect of transient populations on epidemics in Washington DC.
Large numbers of transients visit big cities, where they come into contact with many people at crowded areas. However, epidemiological studies have not paid much attention to the role of this subpopulation in disease spread. We evaluate the effect of transients on epidemics by extending a synthetic population model for the Washington DC metro area to include leisure and business travelers. A synthetic population is obtained by combining multiple data sources to build a detailed minute-by-minute simulation of population interaction resulting in a contact network. We simulate an influenza-like illness over the contact network to evaluate the effects of transients on the number of infected residents. We find that there are significantly more infections when transients are considered. Since much population mixing happens at major tourism locations, we evaluate two targeted interventions: closing museums and promoting healthy behavior (such as the use of hand sanitizers, covering coughs, etc.) at museums. Surprisingly, closing museums has no beneficial effect. However, promoting healthy behavior at the museums can both reduce and delay the epidemic peak. We analytically derive the reproductive number and perform stability analysis using an ODE-based model.


Technical-efficiency analysis of end-of-life care in long-term care facilities within Europe: A cross-sectional study of deceased residents in 6 EU countries (PACE).
An ageing population in the EU leads to a higher need of long-term institutional care at the end of life. At the same time, healthcare costs rise while resources remain limited. Consequently, an urgency to extend our knowledge on factors affecting efficiency of long-term care facilities (LTCFs) arises. This study aims to investigate and explain variation in technical efficiency of end-of-life care within and between LTCFs of six EU countries: Belgium (Flanders), England, Finland, Italy, the Netherlands and Poland. In this study, technical efficiency reflects the LTCFs' ability to obtain maximal quality of life (QoL) and quality of dying (QoD) for residents from a given set of resource inputs (personnel and capacity). Cross-sectional data were collected by means of questionnaires on deceased residents identified by LTCFs over a three-month period. An output-oriented data-envelopment analysis (DEA) was performed, producing efficiency scores, incorporating personnel and capacity as input and QoL and QoD as output. Scenario analysis was conducted. Regression analysis was performed on explanatory (country, LTCF type, ownership, availability of palliative care and opioids) and case mix (disease severity) variables. 133 LTCFs of only one type (onsite nurses and offsite GPs) were considered in order to reduce heterogeneity. Variation in LTCF efficiency was found across as well as within countries. This variation was not explained by country, ownership, availability of palliative care or opioids. However, in the 'hands-on care at the bedside' scenario, i.e. only taking into account nursing and care assistants as input, Poland (p = 0.00) and Finland (p = 0.04) seemed to be most efficient. Efficiency of LTCFs differed extensively across as well as within countries, indicating room for considerable efficiency improvement. Our findings should be interpreted cautiously, as comprehensive comparative EU-wide research is challenging as it is influenced by many factors.


Carbon source recovery from excess sludge by mechanical disintegration for biological denitrification.
The goal of the study was to evaluate the possibility of carbon source recovery from excess sludge by mechanical disintegration for biological denitrification. The total efficiency of denitrification, unit demand for organic compounds for denitrification, unit volume of disintegrated sludge and unit cost of nitrogen removal as a function of energy density used for excess sludge disintegration (70, 140 and 210 kJ/L) were analyzed. In the study a full-scale disc disintegrator was used (motor power: 30 kWh, motor speed: 2,950 rpm). It was shown that the amounts of organic compounds released from the activated sludge flocs at all tested levels of energy density are high enough to be used to intensify the removal of nitrogen compounds from wastewater. It was also documented that the energy density provided during process of disintegration was an important factor determining the characteristics of organic compounds obtained under the disintegration for their use in order to intensify the process of denitrification. The highest value of total efficiency of denitrification (50.5 ± 3.1 mg N/L) was obtained for carbon source recovery from excess sludge at 70 kJ/L, but the lowest unit cost of nitrogen removal occurred for 140 kJ/L (0.0019 ± 0.0011 EUR/g N).


Beta-3 adrenoceptor selectivity of the dioxolane dicarboxylate phenethanolamines.
The beta-1, beta-2 and beta-3 adrenergic properties of several benzodioxole-containing phenethanolamines were determined in vitro in both functional and binding assays. In addition, two of the compounds were evaluated for their effects on radioligand binding and cyclic AMP (cAMP) production in stably transfected Chinese Hamster Ovary (CHO) cells expressing the cloned rat or human beta-3 adrenoceptor or the human beta-2 or beta-1 adrenoceptor. The (+/-)-R*,R*-racemate, CL 314,514, and the pure (-)-R,R enantiomer, CL 316,243, stimulated rat adipocyte lipolysis (beta-3 effect) with EC50 values in the low nanomolar range, while having no effect on the rate of contraction of guinea pig atria (beta-1 effect) and little or no ability to prevent the insulin-stimulated incorporation of [14C]glucose into rat soleus muscle glycogen (beta-2 effect) with concentrations as great as 100 microM. The lack of beta-1 and beta-2 adrenergic activity was confirmed by the low affinity of the compounds for beta-1 or beta-2 adrenoceptors in plasma membranes from rat heart or rat soleus muscle, respectively. In CHO cells expressing each human beta adrenoceptor subtype, CL 314,514 bound to beta-3-CHO cells with a Ki of 2 microM and stimulated cAMP production with an activation constant (Kact) of 1 microM, whereas it did not bind to either beta-1- or beta-2-CHO cells at 100 microM. CL 316,243 bound to membranes from rat beta-3-CHO cells with a Ki of 1 microM and stimulated cAMP production in beta-3-CHO cells with a Kact of 0.7 nM.(ABSTRACT TRUNCATED AT 250 WORDS)


Monotremes provide a key to understanding the evolutionary significance of epididymal sperm maturation.
It has been widely accepted that mammalian spermatozoa are infertile when they leave the testes and require a period of maturation in both the epididymis and the female reproductive tract before acquiring the ability to fertilize an oocyte. However, the necessity for such a complex process of posttesticular sperm maturation appears to be unique to mammals because it is well established that these processes do not directly influence the fertilizing ability of the spermatozoa of birds, reptiles, and other lower vertebrates. Because of their key evolutionary position and form of reproduction, we contend that monotremes (platypus and echidna) provide a unique model for resolving why these processes are necessary. In the present review, we examine evidence that the epididymal maturation of monotreme spermatozoa is far less complex than in other mammals. However, a unique feature of the monotreme epididymis lies in its ability to promote the formation of elaborate sperm bundles that serve to greatly enhance the cells' motility. It is suggested that this intriguing cooperative strategy used by monotreme sperm represents an early form of epididymal maturation that appears to have been elaborated upon during the evolution of higher mammals, possibly as an adaptation for sperm competition.


Discovery of candidate genes and pathways regulating oviduct development in chickens.
Estrogen is a key regulator in the development of the female reproductive system. It also stimulates oviduct development in immature chicks. We identified candidate genes and pathways associated with the development of chicken oviducts. A pellet containing the synthetic estrogen analog diethylstilbestrol (DES) was implanted subcutaneously in 1-wk-old female chicks for 10 days. The pellet was removed from half the group for 10 days, and an additional dose was given for a further 10 days. Total RNA was extracted from the oviducts of DES-treated and untreated chicks and subjected to an Affymetrix chicken GeneChip analysis. We found differential expression of 2290 and 1745 transcripts from the oviducts that were treated with DES once and twice, respectively. We also found a twofold or greater change in the expression of 77 and 390 transcripts between the two control and DES-treated time points, respectively, while we found a change in the expression of 10 transcripts that were common to all groups. Analyses of real-time PCR and in situ hybridization of selected genes confirmed the validity of the gene expression patterns observed in the microarray analysis. In particular, CCRN4L, FAM26F, HAS2, NELF, and NTM were up-regulated in the DES-treated chicken oviducts. High-throughput analysis revealed that the differentially expressed genes were related to tubular formation, epithelial differentiation, hormone interactions, nerve development, and tissue remodeling in the chicken oviduct. This study provides novel insights into candidate genes regulating oviduct development and differentiation via estrogen. The identified genes may serve as biomarkers of reproductive tract development in chicks.


Identification of small-molecule inhibitors of the XendoU endoribonucleases family.
The XendoU family of enzymes includes several proteins displaying high sequence homology. The members characterized so far are endoribonucleases sharing similar biochemical properties and a common architecture in their active sites. Despite their similarities, these proteins are involved in distinct RNA-processing pathways in different organisms. The amphibian XendoU participates in the biosynthesis of small nucleolar RNAs, the human PP11 is supposed to play specialized roles in placental tissue, and NendoU has critical function in coronavirus replication. Notably, XendoU family members have been implicated in human pathologies such as cancer and respiratory diseases: PP11 is aberrantly expressed in various tumors, while NendoU activity has been associated with respiratory infections by pathogenic coronaviruses. The present study is aimed at identifying small molecules that may selectively interfere with these enzymatic activities. Combining structure-based virtual screening and experimental approaches, we identified four molecules that specifically inhibited the catalytic activity of XendoU and PP11 in the low micromolar range. Moreover, docking experiments strongly suggested that these compounds might also bind to the active site of NendoU, thus impairing the catalytic activity essential for the coronavirus life cycle. The identified compounds, while allowing deep investigation of the molecular functions of this enzyme family, may also represent leads for the development of new therapeutic tools.


Contraceptive and condom use adoption and maintenance: a stage paradigm approach.
The Transtheoretical Model of Behavior Change was examined for its applicability to contraceptive and condom use adoption and maintenance using N = 248 heterosexually active college-age men and women. The model posits that individuals do not go directly from old behaviors to new behaviors to new behaviors, but progress through a sequence of stages: precontemplation, contemplation, preparation, action, and maintenance. The stages of change offer a temporal dimension that provides information regarding when a particular shift in attitudes, intentions, and behavior may occur. The model also postulates a set of or outcome variables--the pros and cons of change and self-efficacy. The results demonstrated that individuals were furthest along in the stages of change for general contraceptive use, followed closely by condom use with other (e.g., casual) partners, and then condom use with main partners. Although no sex differences were found for the stages for the three separate contraceptive behaviors, males and females differed on the pros and cons and levels of self-efficacy when engaging in intercourse with the two types of partners. MANOVA/ANOVA results indicated that the relationship between stages and other constructs follows predicted patterns suggesting that the transtheoretical model may provide a useful framework or paradigm for understanding contraceptive and condom use behavior.


Nutrition assessment of the critically ill child.
Nutrition assessment is an integral part of the evaluation of the critically ill child. The goal of nutrition assessment is to identify those children who are malnourished and those who are at risk of becoming malnourished. Malnutrition is known to affect wound healing, infection rate, mortality, and morbidity, making early identification of children at risk essential. An initial assessment consists of a complete history and physical examination. The history and physical examination findings are then evaluated in conjunction with appropriate laboratory and anthropometric measurements. Through vigilant nutrition assessment, prompt, appropriate nutrition support can be provided to the critically ill child.


Why are Latinos the most uninsured racial/ethnic group of US children? A community-based study of risk factors for and consequences of being an uninsured Latino child.
Latinos continue to be the most uninsured racial/ethnic group of US children, but not enough is known about the risk factors for and consequences of not being insured in Latino children. [corrected] The objective of this study was to identify the risk factors for and consequences of being uninsured in Latino children. A cross-sectional survey was conducted of parents at urban, predominantly Latino community sites, including supermarkets, beauty salons, and laundromats. Parents were asked 76 questions on access and health insurance. Interviews were conducted of 1100 parents, 900 of whom were Latino. Uninsured Latino children were significantly more likely than insured Latino children to be older (mean age: 9 vs 7 years) and poor (89% vs 72%) and to have parents who are limited in English proficiency (86% vs 65%), non-US citizens (87% vs 64%), and both employed (35% vs 27%). Uninsured Latinos were significantly less likely than their insured counterparts to have a regular physician (84% vs 99%) and significantly more likely not to be brought in for needed medical care because of expense, lack of insurance, difficulty making appointments, inconvenient office hours, and cultural issues. In multivariable analyses, parents who are undocumented or documented immigrants, both parents working, the child's age, and the $4000 to $9999 and $15000 to $19999 family income quintiles were the only factors that were significantly associated with a child's being uninsured; neither Latino ethnicity nor any other of 6 variables were associated with being uninsured. Compared with insured Latino children, uninsured Latino children had 23 times the odds of having no regular physician and were significantly more likely not to be brought in for needed medical care because of expense, lack of health insurance, difficulty making appointments, and cultural barriers. After adjustment, parental noncitizenship, having 2 parents work, low family income, and older child age are associated with being an uninsured child, but Latino ethnicity is not. The higher prevalence of other risk factors seems to account for Latino children's high risk for being uninsured. Uninsured Latino children are significantly more likely than insured Latino children to have no regular physician and not to get needed medical care because of expense, lack of health insurance, difficulty making appointments, and cultural barriers. These findings indicate specific high-risk populations that might benefit most from targeted Medicaid and State Child Health Insurance Program outreach and enrollment efforts.


Elderly patients undergoing major vascular surgery: risk factors and medication associated with risk reduction.
This study assesses risk factors in elderly vascular surgery patients and to evaluate whether perioperative cardiac medication can reduce postoperative mortality rate. In a cohort study, 1693 consecutive patients > or =65 years undergoing major non-cardiac vascular surgery were preoperatively screened for cardiac risk factors and medication. During follow-up (median: 8.2 years), mortality was noted. Hospital mortality occurred in 8.1% and long-term mortality in 28.5%. In multivariate analysis, age, coronary artery disease, heart failure, cerebrovascular disease, renal failure and diabetes were significantly associated with increased hospital and long-term mortality. Perioperative aspirin (OR: 0.53, 95% confidence interval: 0.34-0.83), beta-blockers (OR: 0.32, 95% CI: 0.19-0.54) and statins (OR: 0.35, 95% CI: 0.18-0.68) were significantly associated with reduced hospital mortality. In addition, aspirin (HR: 0.65, 95% CI: 0.53-0.81), angiotensin-converting enzyme (ACE)-inhibitors (HR: 0.74, 95% CI: 0.59-0.92), beta-blockers (HR: 0.61, 95% CI: 0.48-0.76) and statins (HR: 0.65, 95% CI: 0.49-0.87) were significantly associated with reduced long-term mortality. Heterogeneity tests revealed a gradient decrease of mortality risk in patients from low to high age using statins (p=0.03). In conclusion, age is an independent predictor of hospital and long-term mortality in elderly patients undergoing major vascular surgery. Aspirin, ACE-inhibitors, beta-blockers and statins reduce long-term mortality risk. Especially the very elderly may benefit from statin therapy.


Reconstructing evolution from eukaryotic small-ribosomal-subunit RNA sequences: calibration of the molecular clock.
The detailed descriptions now available for the secondary structure of small-ribosomal-subunit RNA, including areas of highly variable primary structure, facilitate the alignment of nucleotide sequences. However, for optimal exploitation of the information contained in the alignment, a method must be available that takes into account the local sequence variability in the computation of evolutionary distance. A quantitative definition for the variability of an alignment position is proposed in this study. It is a parameter in an equation which expresses the probability that the alignment position contains a different nucleotide in two sequences, as a function of the distance separating these sequences, i.e., the number of substitutions per nucleotide that occurred during their divergence. This parameter can be estimated from the distance matrix resulting from the conversion of pairwise sequence dissimilarities into pairwise distances. Alignment positions can then be subdivided into a number of sets of matching variability, and the average variability of each set can be derived. Next, the conversion of dissimilarity into distance can be recalculated for each set of alignment positions separately, using a modified version of the equation that corrects for multiple substitutions and changing for each set the parameter that reflects its average variability. The distances computed for each set are finally averaged, giving a more precise distance estimation. Trees constructed by the algorithm based on variability calibration have a topology markedly different from that of trees constructed from the same alignments in the absence of calibration. This is illustrated by means of trees constructed from small-ribosomal-subunit RNA sequences of Metazoa. A reconstruction of vertebrate evolution based on calibrated alignments matches the consensus view of paleontologists, contrary to trees based on uncalibrated alignments. In trees derived from sequences covering several metazoan phyla, artefacts in topology that are probably due to a high clock rate in certain lineages are avoided.


Efficacy of the lithotripsy in treating lower pole renal stones.
Use of extracorporeal lithotripsy is declining in North America and many European countries despite international guidelines advocating it as a first-line therapy. Traditionally, lithotripsy is thought to have poor efficacy at treating lower pole renal stones. We evaluated the success rates of lithotripsy for lower pole renal stones in our unit. 50 patients with lower pole kidney stones ≤15 mm treated between 3/5/11 and 19/4/12 were included in the study. Patients received lithotripsy on a fixed-site Storz Modulith SLX F2 lithotripter according to a standard protocol. Clinical success was defined as stone-free status or asymptomatic clinically insignificant residual fragments (CIRFs) ≤3 mm at radiological follow-up. The mean stone size was 7.8 mm. The majority of stones (66 %) were between 5 and 10 mm. 28 % of stones were between 10 and 15 mm. For solitary lower pole stones complete stone clearance was achieved in 63 %. Total stone clearance including those with CIRFs was achieved in 81 % of patients. As expected, for those with multiple lower pole stones the success rates were lower: complete clearance was observed in 39 % and combined clearance including those with CIRFs was 56 %. Overall, complete stone clearance was observed in 54 % of patients and clearance with CIRFs was achieved in 72 % of patients. Success rate could not be attributed to age, stone size or gender. Our outcome data for the treatment of lower pole renal stones (≤15 mm) compare favourably with the literature. With this level of stone clearance, a non-invasive, outpatient-based treatment like lithotripsy should remain the first-line treatment option for lower pole stones. Ureteroscopy must prove that it is significantly better either in terms of clinical outcome or patient satisfaction to justify replacing lithotripsy.


Interleukin 2 inhibits in vitro growth of human T cell lines carrying retrovirus.
Four human T cell lines, TL-Mor, TL-Su, TL-TerI, and TL-OmI, carrying human T cell leukemia virus (HTLV), were established previously. TL-Mor, TL-Su, and TL-TerI were derived from interleukin 2 (IL-2)-dependent parental cell lines cloned from peripheral blood leukocytes (PBL) of three healthy HTLV carriers, while TL-OmI was directly established from PBL of a patient with adult T cell leukemia. These four TL cell lines grow autonomously without IL-2. When they were cultured in the presence of IL-2, their growth was inhibited after a few days. This growth inhibition depended on the dose of IL-2, and the effective dose significantly promoted growth of their parental IL-2-dependent cell lines. The growth inhibition is demonstrated to be due to specific binding of IL-2 to receptors on the TL cells.


Improving efficacy and efficiency through the implementation of a new organisational model in a Radiation Oncology Department.
To evaluate a new organisational model, "process management" (PM), implemented in the Hospital Universitario Virgen de la Victoria (HUVV) compared with traditional models used in other Radiation Oncology Departments (RODs), in terms of efficacy and efficiency. The study period ranged from September 2011 to August 2012. Efficacy was assessed, comparing the number of patients attended in first consultation and treated per month, average waiting time from referral to first visit and average waiting time from first visit to treatment. Data were collected from two public hospitals in Andalusia: the HUVV and another Public Hospital in Andalusia (PHA1). Efficiency was assessed comparing the costs per patient attended in first visit and treated at HUVV in 2012 compared with those of a second Public Hospital in Andalusia (PHA2) for 2008. The number of sessions saved using hypofractionation versus classical schemes during the year 2012 in HUVV was estimated, and the money saved was calculated. In the efficacy analysis, we found significant differences in the average waiting time for first visit, start of treatment, and the number of patients seen and treated annually. After calculating the total cost generated in the ROD, the efficiency analysis showed a lower cost per patient attended in first visit (EUR 599.17) and per patient treated (EUR 783.50), with a saving of 6035 sessions using hypofractionated schemes. Process management in an ROD reduces time, both to first medical visit and to treatment initiation, allowing an optimisation of linear accelerator (LINAC) capacity.


Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma.
Thirteen patients with recurrent medulloblastoma were treated with cyclophosphamide in association with Sargramostim. Cyclophosphamide was given at doses ranging between 1.0-2.5 g/m2 daily for two doses. Sargramostim was given at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the ANC was more than 1,000 cells/microliters for two consecutive days. A total of 33 courses were given with toxicity consisting of grade 4 neutropenia in all courses and grade 3-4 thrombocytopenia in 10 of 13 patients. There were no deaths related to infection or bleeding. Four patients were taken off study because of prolonged myelosuppression. Three of these patients were at the 2.5 g/m2 level, and of these three, two developed lung toxicity (grades 2 and 4, respectively). One patient developed an allergic reaction following the first injection of Sargramostim and was also taken off study. Of 10 evaluable patients, there were 9 PR and 1 SD. We conclude that cyclophosphamide at a dose of 2.0 g/m2/day x 2 days q 4 weeks in association with Sargramostim demonstrates marked activity with acceptable toxicity in patients with recurrent medulloblastoma.


Building community-based participatory research partnerships with a Somali refugee community.
The U.S. has become home to growing numbers of immigrants and refugees from countries where the traditional practice of female genital cutting (FGC) is prevalent. These women under-utilize reproductive health care, and challenge healthcare providers in providing culturally appropriate care. This study examined Somali immigrant women's experiences with the U.S. healthcare system, exploring how attitudes, perceptions, and cultural values, such as FGC, influence their use of reproductive health care. A mixed-method community-based participatory research (CBPR) collaboration with a Somali refugee community was conducted from 2005 to 2008 incorporating surveys, semi-structured focus groups, and individual interviews. Providers caring for this community were also interviewed to gain their perspectives and experiences. The process of establishing a partnership with a Somali community is described wherein the challenges, successes, and lessons learned in the process of conducting CBPR are examined. Challenges obtaining informed consent, language barriers, and reliance on FGC self-report were surmounted through mobilization of community social networks, trust-building, and the use of a video-elicitation device. The community partnership collaborated around shared goals of voicing unique healthcare concerns of the community to inform the development of interventional programs to improve culturally-competent care. Community-based participatory research using mixed-methods is critical to facilitating trust-building and engaging community members as active participants in every phase of the research process, enabling the rigorous and ethical conduct of research with refugee communities.


Comparing patient access to pharmaceuticals in the UK and US.
The debate on access to new drugs has focused on the time lag between applications for approval and granting of marketing authorisation. This delay was identified as the first barrier with respect to patient access to new drugs, encompassing the hurdles of safety, efficacy and quality. Additional barriers have since been identified. These pertain to reimbursement and pricing of approved drugs, the so-called fourth and fifth hurdles. We reviewed 38 National Institute for Health and Clinical Excellence (NICE) guidance appraisals carried out between April 1999 and April 2005. These appraisals included 71 recently approved drugs considered to have either high clinical or cost impact. For each drug we first determined its marketing approval date by the British Medicines Healthcare Products Agency (MHRA) or European Medicines Evaluation Agency (EMEA). Secondly, we determined if each drug was approved by the US FDA for marketing and, if so, the date when it was approved. Thirdly, we considered whether and when each drug was recommended for reimbursement and use by NICE, and whether conditions of reimbursement applied. Fourthly, for the subset of FDA-approved drugs, we examined formulary placement, cost sharing and conditions of reimbursement on three-tier formularies used by seven leading US third-party payers serving Medicare beneficiaries. Fifthly, we reviewed each NICE recommendation to determine if cost-effectiveness data were referred to either in the appraisal documentation or in the final recommendation. Sixthly, we asked a spokesperson from each US payer whether cost-effectiveness assessments or rebates played a role in determining formulary placement of drugs in our sample, and whether there was a lag between marketing approval and reimbursement for any of the covered drugs. Of the 71 drugs contained in 38 NICE guidance appraisals, the US FDA approved 64. On average, the subset of 64 drugs received marketing authorisation in the US prior to the UK. On average, US plans covered 87% of the 64 drugs, the same percentage of drugs recommended for NHS reimbursement and use. Cost sharing in the US was significantly higher than in the UK, with wider variation across plans. On average, drugs covered in the US had fewer conditions of reimbursement (15%) than the percentage of drugs given conditions by NICE (46%). US plans were quicker to decide to reimburse drugs following marketing approval than NICE. The US provides faster, more flexible access to most, but not all, of the UK-approved pharmaceuticals in our sample. However, US patients have higher cost sharing than the UK and coverage is less evenly spread across the population. From a policy perspective, our study findings confirm the need to bolster the NICE fast-track initiative to decrease the amount of time it takes to appraise certain new pharmaceuticals. Also, the study findings point to the need in the US for careful monitoring of plan compliance with regulations pertaining to the Medicare drug benefit, particularly with respect to formulary restrictions and limits on cost sharing.


Individual Uncertainty About Longevity.
This article presents an assessment of individual uncertainty about longevity. A survey performed on 3,331 French people enables us to record several survival probabilities per individual. On this basis, we compute subjective life expectancies (SLE) and subjective uncertainty regarding longevity (SUL), the standard deviation of each individual's subjective distribution of her or his own longevity. It is large and equal to more than 10 years for men and women. Its magnitude is comparable to the variability of longevity observed in life tables for individuals under 60, but it is smaller for those older than 60, which suggests use of private information by older respondents. Our econometric analysis confirms that individuals use private information-mainly their parents' survival and longevity-to adjust their level of uncertainty. Finally, we find that SUL has a sizable impact, in addition to SLE, on risky behaviors: more uncertainty on longevity significantly decreases the probability of unhealthy lifestyles. Given that individual uncertainty about longevity affects prevention behavior, retirement decisions, and demand for long-term care insurance, these results have important implications for public policy concerning health care and retirement.


Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.
Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.


Effective antigen presentation by dendritic cells is NF-kappaB dependent: coordinate regulation of MHC, co-stimulatory molecules and cytokines.
Antigen presentation is a key rate-limiting step in the immune response. Dendritic cells (DC) are the most potent antigen-presenting cells for naive T cells, due to their high expression of MHC and co-stimulatory molecules, but little is known about the biochemical pathways that regulate this function. We here demonstrate that monocyte-derived mature DC can be infected with adenovirus at high efficiency (>95%) and that this procedure can be used to dissect out which pathways are essential for inducing DC antigen presentation to naive T cells. Using adenoviral transfer of the endogenous inhibitor of NF-kappaB, IkappaBalpha, we show that DC antigen presentation is NF-kappaB dependent. The mechanism for this is that NF-kappaB is essential for three aspects of antigen-presenting function: blocking NF-kappaB coordinately down-regulates HLA class II, co-stimulatory molecules like CD80, CD86 and CD40, and immuno-stimulatory cytokines like IL-12 and tumor necrosis factor-alpha. In contrast adhesion molecules are up-regulated after infection with the adenovirus transferring IkappaBalpha, indicating that NF-kappaB also regulates the duration of T cell-DC interaction. These results establish NF-kappaB as an effective target for blocking DC antigen presentation and inhibiting T cell-dependent immune responses, and this finding has potential implications for the development of therapeutic agents for use in allergy, autoimmunity and transplantation.


The use of dual phase 201Tl SPECT for differentiating pulmonary malignancies from benign lesions.
This study examines the usefulness of thallium-201 single photon emission computed tomography ((201)Tl SPECT) in differentiating pulmonary malignancies from benign lesions by using dual phase (201)Tl scintigraphy. One hundred and six patients with thoracic lesions and confirmed diagnoses were assessed by (201)Tl chest SPECT examinations; of these 106 enrolled thoracic lesions, 59 were malignancies and 47 were benign lesions. Dual phase (201)Tl SPECT was performed with an early image acquired at 10-20 min and a delayed image at 2-3 h after intravenous injection of 2-3 mCi of (201)Tl. The results of (201)Tl SPECT images were classified as either malignant or benign lesions by visual interpretation: the lesion was interpreted as positive for malignancy if the uptake of (201)Tl in the lung lesion in the delayed phase was increased or persistent as compared with that in the early phase image; otherwise, it was considered as a benign lesion. Simultaneously, the traditional method of retention index (RI) was also calculated to help in the differential diagnosis of pulmonary lesions. Then, both methods of dual phase (201)Tl SPECT, visual reading and traditional RI, were compared to differentiate pulmonary malignancies from benign lesions. Analyzing the image results, we found that dual phase (201)Tl SPECT could differentiate pulmonary malignancies from benign lesions with a sensitivity of 83%, a specificity of 91% and an accuracy of 87%. Moreover, by using the traditional RI method of (201)Tl SPECT, it could differentiate pulmonary malignancy from benign lesions with a sensitivity of 79.3%, a specificity of 80.8% and an accuracy of 80%. We conclude that using dual phase (201)Tl SPECT with visual interpretation is a simpler and potentially more effective method for differentiating pulmonary malignancies from benign lesions, with results compatible with the traditional RI method of (201)Tl SPECT.


The seismic analyzer: interpreting and illustrating 2D seismic data.
We present a toolbox for quickly interpreting and illustrating 2D slices of seismic volumetric reflection data. Searching for oil and gas involves creating a structural overview of seismic reflection data to identify hydrocarbon reservoirs. We improve the search of seismic structures by precalculating the horizon structures of the seismic data prior to interpretation. We improve the annotation of seismic structures by applying novel illustrative rendering algorithms tailored to seismic data, such as deformed texturing and line and texture transfer functions. The illustrative rendering results in multi-attribute and scale invariant visualizations where features are represented clearly in both highly zoomed in and zoomed out views. Thumbnail views in combination with interactive appearance control allows for a quick overview of the data before detailed interpretation takes place. These techniques help reduce the work of seismic illustrators and interpreters.


Developing through relationships: an embodied coactive systems framework.
In recent decades, the developmental sciences have undergone a relational turn. Epigenetic (Gottlieb & Lickliter, 2007), embodied (Thompson, 2007), relational (Lerner & Overton, 2008) and systems (Kelso, 2003) approaches are transforming the ways in which we think about the nature and origins of psychological structures. At their most basic level, relational and systems approaches analyze the developmental origins of order and variability not in terms of sets of separable causal forces but instead in analyses of relations between causal systems. From this view, genes and environment, biology and culture, cognition and emotion, self and other, and so forth are inseparable as causal processes in the development of action and experience. Drawing on these principles, this paper contains an outline of an embodied coactive systems framework for understanding how individual psychological structures develop as a product of socially distributed coactions that occur among elements of the extended person-environment system. Based on these principles, a system for the Developmental Analysis of Joint Action is described. This system provides a set of conceptual and empirical tools for making precise assessments of dynamic structure of jointly constructed patterns of thinking, feeling and acting. By tracking developmental changes in joint action, the system allows researchers to track the origins of higher order psychological structures through particular sequences of coconstructive activity. The holistic analytic system is illustrated through microdevelopmental analyses of (1) the joint construction of shoe-tying skill between a 5-year-old boy and a caregiver, and (2) socioemotional organization developing representations of self in a young adult over the course of a single session of psychotherapy.


[Evaluation of the Sentinel Surveillance Program in Occupational Health in Navarra (1998-2007)].
To evaluate the Sentinel Surveillance Program in Occupational Health in Navarre for the 1998-2007 period, identify factors that facilitate its implementation and describe the socioeconomic characteristics of the notified cases. An analysis was made of all occupational sentinel events reported by primary care between 1998 and 2005. All of these were followed through to 2007. In the whole period 2,055 cases were notified; 1,223 with personal identifications and 832 without (59.5% and 40.5%). These included 1,192 elbow tendinitis, 354 carpal tunnel and 417 dermatitis cases. This represents an incidence rate of 332.8 per 100,000 workers in 2005. Only 21% took sick leave and 10.5% had come to primary care after being refused attention by occupational medical insurers. The positive predictive value was 70% (confirmed as occupational). 41% of those work-related diseases were officially notified, 51% received official notification first and the remaining 49% received notification after being seen by a doctor in the public health system. The Sentinel Surveillance Program in Occupational Health in Navarra is a good experience in obtaining an information system that connects the public health system and the occupational compensation system in Spain, but it requires close monitoring and coordination.


Detection of analyte binding to microarrays using gold nanoparticle labels and a desktop scanner.
Microarray hybridization or antibody binding can be detected by many techniques, however, only a few are suitable for widespread use since many of these detection techniques rely on bulky and expensive instruments. Here, we describe the usefulness of a simple and inexpensive detection method based on gold nanoparticle labeled antibodies visualized by a commercial, office desktop flatbed scanner. Scanning electron microscopy studies showed that the signal from the flatbed scanner was proportional to the surface density of the bound antibody-gold conjugates, and that the flatbed scanner could detect six attomoles of antibody-gold conjugates. This detection system was used in a competitive immunoassay to measure the concentration of the pesticide metabolite 2,6-dichlorobenzamide (BAM) in water samples. The results showed that the gold labeled antibodies functioned comparably with a fluorescent based immunoassay for detecting BAM in water. A qualitative immunoassay based on gold-labeled antibodies could determine if a water sample contained BAM above and below 60-70 ng L(-1), which is below the maximum allowed BAM concentration for drinking water (100 ng L(-1)) according to European Union legislation.