A new measure to understand the role of science in US Congress: lessons learned from the Legislative Use of Research Survey (LURS).

Background: There is growing interest in and recognition of the need to use scientific evidence to inform policymaking. However, many of the existing studies on the use of research evidence (URE) have been largely qualitative, and the majority of existing quantitative measures are underdeveloped or were tested in regional or context-dependent settings. We are unaware of any quantitative measures of URE with national policymakers in the US. Aims and objectives: Explore how to measure URE quantitatively by validating a measure of congressional staff's attitudes and behaviors regarding URE, the Legislative Use of Research Survey (LURS), and by discussing the lessons learned through administering the survey. Methods: A 68-item survey was administered to 80 congressional staff to measure their reported research use, value of research, interactions with researchers, general information sources, and research information sources. Confirmatory factor analyses were conducted on each of these five scales. We then trimmed the number of items, based on a combination of poor factor loadings and theoretical rationale, and ran the analyses on the trimmed subscales. Findings: We substantially improved our model fits for each scale over the original models and all items had acceptable factor loadings with our trimmed 35-item survey. We also describe the unique set of challenges and lessons learned from surveying congressional staff. Discussion and conclusions: This work contributes to the transdisciplinary field of URE by offering a tool for studying the mechanisms that can bridge research and policy and shedding light into best practices for measuring URE with national policymakers in the US.

[Rethinking the place of primary healthcare in France--role of general practice]. / Repenser la place des soins de santé primaires en France--Le rôle de la médecine générale.

Primary healthcare is poorly structured in France while it is well defined at the international level: it is the point of first medical contact of the population with the healthcare system. General practice is the clinical specialty oriented to primary healthcare. Data in the scientific literature highlight the need of refocusing the health system on primary care known to improve both morbi-mortality and care efficiency. In France, health authorities acknowledge general practitioners as playing a key role in the health care system: its time to move from intention to action. Structural changes are needed to achieve this reinforcement of primary healthcare: to re-orientate medical studies towards primary care; to develop research in primary care; to promote cooperation between care providers; to ease the daily workload of practitioners; to diversify methods of payment; to propose a guide for patient's use of primary care. The transformation of the healthcare system in France requires a real strategy of primary healthcare implementation. Regardless of financial constraints, it is possible to redistribute the resources towards ambulatory care. Strengthening the role of general practice and favoring its societal recognition will be the major stages of this change.

Lumbar stenosis rates in symptomatic patients using weight-bearing and recumbent magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of lumbar stenosis detected via magnetic resonance imaging (MRI) in patients with symptomatic foraminal stenosis, lateral recess stenosis, or central stenosis. METHODS: A retrospective review was performed on 1983 MRI scans from a 2-year period on 1486 symptomatic patients. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II; Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright sitting position using midfield (0.6 T) open Upright MRI (Fonar Corp, Melville, NY). In total, 986 serial scans (recumbent) and 997 serial scans (weight-bearing) were performed. RESULTS: Of scans performed in the recumbent position, stenoses were identified in 382 scans (38.8%), central stenosis in 119 scans (12%), lateral recess stenosis in 91 scans (9.2%), and foraminal stenosis in 327 scans (33.2%). Of scans performed in a weight-bearing position, stenoses were identified in 565 scans (56.7%), central stenosis in 136 scans (13.6%), lateral recess stenosis in 206 scans (20.7%), and foraminal stenosis in 524 scans (52.6%). CONCLUSIONS: The stenosis rates as indicated by MRI interpretation ranged between 38.5% (recumbent) and 56.7% (weight-bearing). These rates are higher than those reported in the medical literature for asymptomatic patients. Further study is needed to determine whether weight-bearing, compared with recumbent, MRI better informs the clinician in the diagnosis of spinal stenosis.

Lumbar disk protrusion rates of symptomatic patients using magnetic resonance imaging.

OBJECTIVE: The purpose of this study was to determine the rate of disk protrusions detected via magnetic resonance imaging (MRI) in patients symptomatic for spine pain, radiculopathy, or other spine-related pain. METHODS: A retrospective review of 1983 MRI scans was performed over a 2-year period on 1486 patients, each of whom was symptomatic for spine pain, radiculopathy, or other noncancer, spine-related pain. Of these patients, 761 were scanned in the recumbent position using low-field (0.3 T, Airis II, Hitachi, Twinsburg, Ohio) MRI, and 725 were scanned in an upright, sitting position using mid-field (0.6 T) open Upright MRI (Fonar, Melville, NY). In total, 986 serial scans were performed on patients in the recumbent position and 997 serial scans on patients in the weight-bearing position. RESULTS: One or more disk protrusions were identified in 73.3% of scans performed in the sitting position and in 50.1% of scans performed in the recumbent position. Most disk protrusions occurred at L5-S1 (52.3% and 29.8%), L4-L5 (42.6% and 26.7%), and L3-L4 (26.7% and 13.1%) in upright and recumbent positions, respectively. CONCLUSIONS: The disk protrusion rate in this group of patients ranged between 50.1% (recumbent) and 73.3% (weight-bearing). These rates are higher than rates reported in the medical literature for asymptomatic patients, a finding that supports the decision to further evaluate patients with persistent spine-related pain.

[E-cigarette use among cannabis users and multi-users of psychoactive products: A cohort study]. / L'usage d'e-cigarette chez les usagers de cannabis et les polyconsommateurs : étude de cohorte.

INTRODUCTION: There is no evidence in the literature relating to the evolution of e-cigarette use among cannabis users and multi-users (of alcohol, tobacco or cannabis). OBJECTIVE: To describe the evolution over 12 months of e-cigarette use in cannabis users and multi-users. METHODS: A prospective observational cohort study in general practice, between 2015 and 2016. RESULTS: A total of 4.8% of monitored cannabis users remained or became current users of e-cigarettes by the end of the monitoring period versus 4.5% among non-users of cannabis, with no statistically significant difference. A total of 5.1% of monitored multi-users remained or became current users of e-cigarettes by the end of the monitoring period versus 2.4% among the non-multi-users, with no statistically significant difference. Cannabis users and multi-users reported more e-cigarette experimentation through curiosity and following someone's suggestion, compared to non-cannabis users or non multi-users. No statistically significant association was found between cannabis or multi-drug use and staying or becoming a current e-cigarette user over 12 months. CONCLUSION: Cannabis users and multi-users would tend to experiment with e-cigarettes more than other patients but this use would not be sustained.

An evaluation of a computer based education program for the diagnosis and management of dementia in primary care. An international study of the transcultural adaptations necessary for European dissemination.

OBJECTIVES: The aim of this study is to make an inventory of the changes that are needed to make an interactive computer based training program (ICBT) with a specific educational content, acceptable to professional communities with different linguistic,cultural and health care backgrounds in different European countries. METHODS: Existing educational software, written in two languages was reviewed by GPs and primary care professionals in three different countries. Reviewers worked through the program using a structured critical reading grid. RESULTS: A 'simple' translation of the program is not sufficient. Minor changes are needed to take account of linguistic differences and medical semantics. Major changes are needed in respect of the existing clinical guidelines in every country related to differences in the existing health care systems. CONCLUSIONS: ICTB programs cannot easily be used in different countries and cultures. The development of a structured educational program needs collaboration between educationalists, domain experts, information technology advisers and software engineers. Simple validation of the content by local expert groups will not guarantee the program's exportability. It is essential to involve different national expert groups at every phase of the development process in order to disseminate it in other countries.

The validity of clinical diagnoses of dementia in a group of consecutively autopsied memory clinic patients.

BACKGROUND: Epidemiological studies show that up to 10% of individuals aged 65 years and older suffer from dementia, most commonly from dementia of the Alzheimer Type (DAT) (1). Clinicopathological studies are critical to our understanding of this disease and improving the accuracy of clinical diagnoses. OBJECTIVES: Our objectives were to examine the validity of clinical diagnoses of DAT, to determine the prevalence of different forms of dementia in this sample, and to investigate the relationship between age at death and polymorbidity. SUBJECTS AND METHOD: Clinical data were available from 221 patients who had been examined at the Basel Memory Clinic between 1986 and 1996. From this population, 34% (75 patients) were autopsied in the Department of Pathology, University Hospital Basel, and neuropathological examinations were additionally performed on 62 (83%) of these patients. Clinical and neuropathological data were retrospectively compared. RESULTS: 67.8% of the neuropathologically examined patients received a definitive diagnosis of AD (Alzheimer's disease), vascular dementia (VaD) or mixed dementia (AD and VaD). AD alone or with other histopathological hallmarks of dementia was the most prevalent neuropathological diagnosis (63%). VaD was deemed the only cause of dementia in only 4.8% of patients. The sensitivity for DAT was 75.9%, the specificity 60.6%. Increasing age was associated with an increasing number of clinical and neuropathological diagnoses. CONCLUSION: The sensitivity and specificity of the clinical diagnoses of DAT found in our study are similar to previous reports (2-5). Older patients had more etiologies of their dementia than younger patients. This study reaffirms the need for internationally accepted criteria for clinical and neuropathological diagnoses, as well as further clinical-neuropathological investigations to further refine the clinical diagnostic process.

ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner.

The different epidermal growth factor (EGF)-related peptides elicit a diverse array of biological responses as the result of their ability to activate distinct subsets of ErbB receptor dimers, leading to the recruitment of different intracellular signaling networks. To specifically examine dimerization-dependent modulation of receptor signaling, we constructed NIH 3T3 cell lines expressing ErbB-1 and ErbB-2 singly and in pairwise combinations with each other ErbB family member. This model system allowed the comparison of EGF-activated ErbB-1 with ErbB-1 activated by Neu differentiation factor (NDF)-induced heterodimerization with ErbB-4. In both cases, ErbB-1 coupled to the adaptor protein Shc, but only when activated by EGF was it able to interact with Grb2. Compared to the rapid internalization of EGF-activated ErbB-1, NDF-activated ErbB-1 showed delayed internalization characteristics. Furthermore, the p85 subunit of phosphatidylinositol kinase (PI3-K) associated with EGF-activated ErbB-1 in a biphasic manner, whereas association with ErbB-1 transactivated by ErbB-4 was monophasic. The signaling properties of ErbB-2 following heterodimerization with the other ErbB receptors or homodimerization induced by point mutation or monoclonal antibody treatment were also analyzed. ErbB-2 binding to peptides containing the Src homology 2 domain of Grb2 or p85 and the phosphotyrosine binding domain of Shc varied according to the mode of receptor activation. Finally, tryptic phosphopeptide mapping of both ErbB-1 and ErbB-2 revealed that receptor phosphorylation is dependent on the dimerization partner. Differential receptor phosphorylation may, therefore, be the basis for the differences in the signaling properties observed.

Recovery of homogeneous and functional beta 2-adrenergic receptors from extracellular baculovirus particles.

Expression in baculovirus-infected insect cells allows sufficient production of G-protein coupled receptor for structural studies. An important drawback of this expression system comes from the presence of unprocessed and biologically inactive receptors that have to be eliminated during receptor purification steps. We show that viral particles released from Sf9 cells infected with a recombinant baculovirus coding for the human beta 2-adrenergic receptor (beta 2AR) cDNA contain glycosylated and biologically active beta 2AR. In addition, post-translational modifications known to modulate receptor activity were found to occur in these particles.

Structural basis for the high affinity of amino-aromatic SH2 phosphopeptide ligands.

An anthranyl moiety placed at the N terminus of a phosphotyrosine peptide potentiates the inhibitory effect of this small peptide on the binding of the Grb2 SH2 domain to the EGF receptor. Using molecular modeling procedures based on the Lck SH2 domain structure, this observation was rationalized in terms of a suitably favorable pi-pi stacking interaction between the anthranyl moiety and the arginine alphaA2 (ArgalphaA2) residue side-chain of Grb2 SH2. The crystal structure of the Grb2 SH2 domain in complex with the inhibitor 2-Abz-EpYINQ-NH2 (IC50 26 nM) has been solved in two different crystal forms at 2.1 and 1.8 A resolution. This structure confirms the modeling based on the Lck SH2 domain. The ArgalphaA2 residue is conserved in most SH2 domains. Thus, as expected, the anthranyl group also confers high affinity to small peptide ligands of other SH2 domains such as Lck-, PLC-gamma-amino-terminal and p85 amino-terminal SH2 domains as demonstrated by structure affinity relationships (SAR) data. These potent peptides with an amino-terminal surrogate group and the structure of Grb2 SH2 domain in complex with one such peptide represent good starting points for the design and optimization of new inhibitors of many SH2 domains.

Sequence requirement for the nucleolar localization of human I-mfa domain-containing protein (HIC p40).

The human I-mfa domain-containing protein (HIC) mRNA produces two protein isoforms, HIC p32 and p40, synthesized from alternative translational initiations. p32 translation is initiated from a standard AUG codon and p40 is an N-terminal extension of p32 generated from an upstream GUG codon. The two isoforms show different subcellular localization: p32 is distributed throughout the cytoplasm whereas p40 can be found both in the cytoplasm and the nucleolus. To investigate the possibility that p40 contains a nucleolus targeting sequence in its N-terminal region, COS cells were transfected with an eukaryotic expression vector coding for green fluorescent protein (GFP) fused to the p40 N terminus. The localization of this fusion protein in the nucleolus indicated that the N-terminal amino acids of p40 probably contain a nucleolar localization signal (NoLS). To find the structural motifs required for nucleolar localization of p40, deletion mutants were expressed in COS cells as fusion polypeptides with GFP. We defined a domain of 19 amino acids near the N terminus that contains an arginine-rich subdomain that conforms to other known NoLS. To demonstrate that this sequence is an authentic NoLS, the sequence was fused to GFP. This fusion protein was observed to migrate into the nucleolus. Taken together, our studies demonstrate that p40 contains a NoLS.

Structure-based design, synthesis, and X-ray crystallography of a high-affinity antagonist of the Grb2-SH2 domain containing an asparagine mimetic.

Previous efforts in the search for molecules capable of blocking the associations between the activated tyrosine kinase growth factor receptors and the SH2 domain of Grb2 had resulted in the identification of 3-amino-Z-pTyr-Ac6c-Asn-NH2, a high-affinity and selective antagonist of this SH2 domain. In the present paper, we report the successful replacement of asparagine in this compound by a beta-amino acid mimetic, which brings us closer to our objective of identifying a Grb2-SH2 antagonist suitable for pharmacological investigations.

Structure-based design and synthesis of high affinity tripeptide ligands of the Grb2-SH2 domain.

The X-ray structure of the Grb2-SH2 domain in complex with a specific phosphopeptide ligand has revealed the existence of an extended hydrophobic area adjacent to the primary binding site of the ligand on the SH2 domain. This has been exploited to design hydrophobic C-terminal groups that improve the binding affinity of the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain. The most significant increase in affinity (25-fold compared to that of the reference peptide having a nonsubstituted carboxamide C-terminus) was obtained with a 3-naphthalen-1-yl-propyl group which was predicted to have the largest contact area with the SH2 domain hydrophobic region. This modification combined with replacement of the minimal sequence isoleucine residue by 1-aminocyclohexane carboxylic acid to stabilize the beta-turn conformation required for recognition by the Grb2-SH2 domain resulted in the high affinity (47 nM in an ELISA assay) and selective phosphopeptide Ac-pTyr-Ac6c-Asn-NH(3-naphthalen-1-yl-propyl).

Discovery of 3-aminobenzyloxycarbonyl as an N-terminal group conferring high affinity to the minimal phosphopeptide sequence recognized by the Grb2-SH2 domain.

The observation that anthranilic acid as N-terminal group produces a dramatic increase of the binding affinity of the phosphopeptide sequence Glu-pTyr-Ile-Asn for the Grb2-SH2 domain was rationalized by molecular modeling. The model, which invokes a stacking interaction between the N-terminal group and the SH2 domain residue Arg alpha A2, was subsequently used to design the 3-aminobenzyloxycarbonyl N-terminal group. The latter confers high affinity (IC50 = 65 nM in an ELISA assay) to the minimal sequence pTyr-Ile-Asn recognized by the Grb2-SH2 domain.

Immunoreactive domains and integrin-binding motifs in adenovirus penton base capsomer.

A panel of nine independent mouse monoclonal antibodies (MAbs) against penton base capsomers of subgenus C adenovirus serotypes 2 (Ad2) and 5 (Ad5) were isolated and characterized. Two of them (1D2 and 5A5), raised against Ad5 virion as the immunogen, bound to sodium dodecyl sulfate (SDS)-resistant and subgenus C-specific epitopes that were not present in subgenus B Ad3 penton base. The 1D2 and 5A5 epitopes were mapped to two distinct regions that did not belong to the main variable region carrying the integrin-binding RGD motif at position 340. For the other seven MAbs, raised against recombinant Ad2 penton base protein (9S-pentamers), the epitopes were sensitive to SDS-denaturation, but reacted with native Ad2, Ad5, and Ad3 penton base. The epitopes recognized by the nine MAbs and by polyclonal antipenton base antibodies defined three major immunoreactive regions. One (I) mapped to the N-terminal domain (residues 116-165); the other two regions were almost symmetrically disposed on both sides of the integrin-binding RGD motif at position 340, within residues 248-270 (II), and within residues 368-427 (III) in the C-terminal domain. Region II overlapped the fiber-binding site in penton base (residues 254-260). None of the MAbs showed any detectable virus neutralization effect, but they all slightly augmented the efficiency of Ad-mediated gene transfer. Although none of their epitopes included the RGD-340 tripeptide, substitutions of the arginine residue in the RGD motif abolished the reactivity of six individual and distant epitopes, suggesting a major conformational role for the RGD-containing domain.

In vitro and in vivo effects of indomethacin on phytohemagglutinin-stimulated lymphocyte mitogenesis.

The in vitro and in vivo effects of indomethacin on blastogenesis of rat splenic lymphocytes in response to phytohemagglutinin (PHA) were investigated. Direct addition of indomethacin to lymphocyte cultures was found to have both a stimulatory effect at low concentrations (less than or equal to 0.003 microM) and an inhibitory effect at higher concentrations (greater than or equal to 0.01 microM). The in vitro stimulation was significant only at submaximal and supramaximal concentrations of PHA, whereas the inhibitory response was observed with a wide range of mitogen concentrations. When indomethacin was administered to animals twice daily for 3 days, similar dose-dependent stimulatory and inhibitory effects were observed. Again the stimulatory effects were associated with lower doses (0.1 microgram/kg) and were found to be significant only with submaximal PHA concentrations. The inhibition with higher doses of indomethacin (IC50 = 0.20 mg/kg) was accompanied by a dose-dependent decrease in the maximal response and an increase in the EC50 to PHA in indomethacin-treated animals. These inhibitory effects of indomethacin administration on lymphocyte proliferation were found to occur at doses which closely approximate those required for the anti-inflammatory effects of the drug.

Exposure to halogenated hydrocarbons in the indoor environment.

The indoor environment has frequently been ignored as a significant source of exposure to air pollutants. To date there are a number of documented examples of levels of indoor air pollutants greatly exceeding those levels which commonly occur in the outdoor environment. Among these instances are airborne buildup of polynuclear aromatics and cadmium from cigarette smoke, lead from burning candles, and vinyl chloride from use of aerosols containing this substance as a propellant. These examples suggest that there may be additional sources of indoor air pollutants, particularly halogenated hydrocarbons from aerosol products, which have heretofore not been generally recognized as important. The present paper endeavors to review those instances where halogenated hydrocarbons in the indoor air environment may build up to concentrations of potential public health concern. These considerations may be especially relevant in future years as increasing efforts are being made to insulate buildings more efficiently as a means to conserve energy. The available data strongly suggest that halogenated hydrocarbons are an important class of air pollutants in the indoor environment and that their presence in the outdoor environment should also be carefully examined. In this regard, halogenated hydrocarbons in the outdoor environment may also contaminate indoor air spaces.

Is early adulthood a critical developmental stage for psychosis proneness? A survey of delusional ideation in normal subjects.

It has been hypothesized that late adolescence and early adulthood might be a brain developmental stage favoring the clinical expression of psychotic symptoms in psychiatric or neurological diseases. The aim of the present survey was to examine the relationship between age and delusional ideation in a sample of subjects with no psychiatric disorder. The survey was carried out with the Aquitaine Sentinel Network of general practitioners. Consecutive practice attenders were invited to complete the PDI-21 (Peters Delusional Inventory 21 items), a self-report questionnaire designed to measure delusional ideation in the normal population. The study concerned 444 patients who had no lifetime history of psychiatric disorder and who completed the PDI-21. A principal component analysis of the PDI-21 items was performed in order to identify delusional dimensions. An age-related decrease in the likelihood to report delusional ideas was found, younger subjects scoring higher on most dimensions of delusional ideation, such as 'persecution', 'thought disturbance', 'grandiosity' and 'paranormal beliefs'. 'Religiosity' was the only dimension positively associated with age. The results suggest that there may be a physiological neurodevelopmental stage favouring the expression of psychosis proneness in normal subjects, and support the hypothesis that the association between age and positive psychotic symptoms in functional and organic psychoses may be linked to the interaction between normal brain maturational processes and cerebral abnormalities involved in the aetiology of functional and organic psychoses.

Radiologic evaluation of the nontraumatized child with respiratory distress.

The radiologic examination of the chest is an essential part of the evaluation of the pediatric patient presenting to the emergency room with respiratory distress. In many cases the chest radiograph will be diagnostic of a specific cause for the distressful symptom. Opaque foreign bodies are readily visualized in the tracheobronchial tree. The presence of massive atelectasis or severe obstructive emphasema may be visualized. Large pleural fluid collections or tension pneumothoraces can be localized and immediately treated by proper drainage. The presence of pneumonia, acute pulmonary edema, and pulmonary hemorrhage may be identified. Complications associated with bronchial asthma (pneumomediastinum, pneumothorax, and atelectasis) may be manifested radiographically before clinical signs are obvious. Lung compression by large mediastinal tumors and delayed congenital hernias may be readily demonstrated by chest radiography.

Comparative pharmacokinetics of free muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and liposomal MTP-PE.

The comparative pharmacokinetics of free MTP-PE (muramyl tripeptide phosphatidyl ethanolamine) and MTP-PE entrapped in negatively charged multilamellar liposomes (liposomal MPT-PE) was evaluated in rats at a bolus intravenous (i.v.) dose of 0.2 mg/kg and in dogs at a bolus i.v. dose of 0.1 mg/kg. Additional studies were performed with the free form in rats (1.4 mg/kg, bolus i.v.) and dogs (1 mg/kg, bolus i.v.) and with the liposomal form in dogs (0.5 mg/kg, bolus i.v.). Plasma samples were obtained at various times up to 48 h postinjection and assayed for the drug by a chemiluminescence immunoassay. The pharmacokinetic data regarding liposomal MTP-PE describe the distribution of free drug released from liposomes and total drug concentrations. The present studies demonstrate that the distribution characteristics of MTP-PE changed dramatically depending on the dosage form. The elimination kinetics of free MTP-PE from blood is substantially slower than that of the liposomal drug. For liposomal MTP-PE, free drug levels in plasma are very low compared with free MTP-PE. In rats at a dose of 0.2 mg/kg, 96% of MTP-PE contained in liposomes is removed from the plasma compartment 10 min after injection, and in dogs at a dose of 0.1 mg/kg, 100% of MTP-PE contained in liposomes is removed in the same time period. This rapid phase of liposome clearance is followed by a slower rate of clearance for the remainder of the liposomes in rats at a dose of 0.2 mg/kg and in dogs at a dose of 0.5 mg/kg.