julilili42/papers huggingface dataset:
Estimation of the time‐dependent vaccine efficacy from a measles epidemic
2002-07-26

Abstract We present a method to estimate the time‐dependent vaccine efficacy from the cohort‐specific vaccination coverage and from data on the vaccination status of cases and apply it to a measles epidemic in Germany which involved 529 cases, 88 of whom were vaccinated and 370 unvaccinated (for the remaining 71 cases the vaccination status is unknown). Our epidemiological model takes into account that maternal antibodies prevent successful vaccination and that vaccine immunity may be lost over time. Model parameters are estimated from the data using maximum likelihood. Vaccination coverage, as determined in school surveys, ranged from 27.6 per cent for the cohort born in 1974 to 85 per cent for the 1986 cohort, which is far too low to prevent measles transmission. Cohorts for which no school surveys were performed are omitted from analysis. Thus, sufficient data are available for only 282 cases, 69 of whom are vaccinated. According to our estimates, measles vaccinations provided no immunity before 1978 (95 per cent CI: 0 to 47 per cent), for the period 1978‐1982, the estimated vaccine efficacy was 80per cent (95 per cent CI: 67 to 89 per cent), and for 1982–1990 it was 97 per cent (95 per cent CI: 93 to 99 per cent). After 1990, the estimated value dropped to 89 per cent, but its confidence interval widely overlaps with that of the previous period (95 per cent CI: 74 to 97 per cent). Loss of immunity was estimated to be zero (95 per cent CI: 0 to 0.003/year). Several sensitivity analyses were performed with respect to the model assumptions. A modified model which assumed constant efficacy at all vaccination times yielded a high estimate of 96 per cent (95 per cent CI: 92 to 98 per cent) for primary vaccine efficacy but also a high loss rate of immunity of 0.007/year (95 per cent CI: 0.001 to 0.012) to explain the high fraction of vaccinated cases among older individuals. The likelihood score value is however significantly inferior compared to the score value of the model with time‐dependent vaccine efficacy. Copyright © 2002 John Wiley &amp; Sons, Ltd.
Clindamycin as an Antimalarial Drug: Review of Clinical Trials
2002-07-28

Clinical trials from the 1970s and 1980s have shown the efficacy, safety, and practicability of the treatment of Plasmodium falciparum malaria with clindamycin. Two reviews from the early 1990s have summarized these studies in detail ([24][1], [25][2]). Since then, interest in clindamycin as an
Psychophysiology of Anxiety Disorders
2002-07-30

This chapter contains sections titled: Introduction Phobias Specific Phobia Social Phobia Agoraphobia Direct Comparison of Phobias Panic Disorder with or Without Agoraphobia Discrepant Findings in Resting Heart Rate as an Example for Different Explanations Theoretical Models for the Development of Panic Disorder and Psychophysiological Response Patterns Respiratory Psychophysiology and Its Explanatory Capacity in Panic Disorder Is Regional Brain Asymmetry Associated with (Different) Anxiety Disorders? Hemisphere Asymmetry and General Negative Emotional Dispositions Generalized Anxiety Disorder Post-traumatic Stress Disorder (PTSD) Psychophysiological Responses to External Stimuli Psychophysiological Responses to Mental Imagery Psychophysiological Responses to Intense but Neutral Stimulation (Auditory Startle) Summary Event-related Electroencephalographic Potentials (ERPs) Obsessive–Compulsive Disorder (OCD) EEG Studies ANS Activity References
The Peroxisome Proliferator-Activated Receptor-γ2 Pro12Ala Polymorphism
2002-08-01

Peroxisome proliferator-activated receptor (PPAR)-γ is a transcription factor with a key role in adipocyte differentiation. The Ala allele of the common Pro12Ala polymorphism in the isoform PPAR-γ2 is associated with reduced risk for type 2 diabetes. The effect on the individual is weak, but because of a prevalence of &amp;gt;75% of the high-risk Pro allele, the population-attributable risk is enormous. The in vivo effects of the polymorphism are secondary to alterations in adipose tissue, where PPAR-γ2 is predominantly expressed. Moderate reduction in transcriptional activity of PPAR-γ as a result of the polymorphism modulates production and release of adipose-derived factors. Both decreased release of insulin-desensitizing free fatty acids, tumor necrosis factor-α, and resistin and increased release of the insulin-sensitizing hormone adiponectin result in secondary improvement of insulin sensitivity of glucose uptake and suppression of glucose production. The population effect of this polymorphism may be modulated by environmental or genetic factors such as obesity, ethnicity, ratio of unsaturated to saturated fatty acids, and genetic background. Once diabetes has developed, the protective effect of the Ala allele may be lost, since increased vascular complications and more pronounced β-cell dysfunction have been reported. These observations, however, are currently unexplained. In conclusion, the Pro12Ala polymorphism in PPAR-γ2 represents the first genetic variant with a broad impact on the risk of common type 2 diabetes. The precise understanding of its mechanism may lead to novel diagnostic, preventive, and therapeutic approaches for improving the management of type 2 diabetes.
Microbial siderophore-mediated transport
2002-08-01

Microbial iron chelates, called siderophores, are synthesized by bacteria and fungi in response to low iron availability in the environment. The present review summarizes structural details of siderophore ligands with respect to their transport properties. This presentation is largely centred on the occurrence and function of siderophores in the various bacterial and fungal genera.
Neuroprotection by Hypoxic Preconditioning Requires Sequential Activation of Vascular Endothelial Growth Factor Receptor and Akt
2002-08-01

Hypoxic preconditioning provides protection against ischemic brain lesions in animal models of cerebral ischemia-hypoxia. To analyze the underlying molecular mechanisms, we developed an in vitro model of hypoxic neuroprotection in cerebellar granule neurons (CGN) by reducing the oxygen tension to 1-5% for 1-24 hr. Exposure to 5% O2 for 9 hr resulted in reduction of cell death after potassium deprivation, treatment with 100 microm glutamate, or 500 microm 3-nitroproprioninc acid (3-NP) by 46, 22, and 55%, respectively. Shorter (1 or 3 hr) or longer (>12 hr) intervals or pretreatment with lower oxygen tension failed to rescue CGN from death. In contrast, toxicity of four different chemotherapeutic drugs [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, cisplatine, topotecane, and vincristine] was unaffected by hypoxic preconditioning. The induction of protective effects was dependent on new protein synthesis. Protein levels of B-cell lymphoma protein-2 (BCL-2), BCL-x(L/S), heat shock protein 70/90, and BCL-2-associated death protein remained unaltered. CGN incubated at 5% O2 for 9 hr showed increased levels of the vascular endothelial growth factor (VEGF), the VEGF receptor-2 (VEGFR-2), phosphorylated Akt/protein kinase B (PKB), and extracellular signal-regulated kinase 1 (ERK1). Incubation with a neutralizing anti-VEGF antibody, a monoclonal antibody to VEGFR-2, wortmannin, or antisense-Akt/PKB, but not treatment with U0126, an ERK-inhibitor, reverted the resistance acquired by hypoxic preconditioning. Inhibition of VEGFR-2 blocked the activation of Akt/PKB. Finally, pretreatment with recombinant VEGF resulted in a hypoxia-resistant phenotype in the absence of hypoxic preconditioning. Our data are indicating a sequential requirement for VEGF/VEGFR-2 activation and Akt/PKB phosphorylation for neuronal survival mediated by hypoxic preconditioning and propose VEGF as a hypoxia-induced neurotrophic factor.
Spectral types of planetary host star candidates: Two new transiting planets?
2002-08-01

\\n Recently, 46 low-luminosity object transits were reported from\\n the Optical Gravitational Lensing Experiment. Our follow-up spectroscopy\\n of the 16 most promising candidates provides a spectral classification of the\\n primary. Together with the radius ratio from the transit measurements, we\\n derived the radii of the low-luminosity companions. This allows to\\n examine the possible sub-stellar nature of these objects. Fourteen of them\\n can be clearly identified as low-mass stars. Two objects,\\n <ext-link ext-link-type="aoi">OGLE-TR-03</ext-link> and <ext-link ext-link-type="aoi">OGLE-TR-10</ext-link> have companions with radii of\\n 0.15 which is very similar to the radius of the transiting planet\\n HD 209458 B. The planetary nature of these two objects should therefore\\n be confirmed by dynamical mass determinations.\\n \\n
Dendritic Cell Immunogenicity Is Regulated by Peroxisome Proliferator-Activated Receptor γ
2002-08-01

Abstract Dendritic cells (DC) are the most potent APCs known that play a key role for the initiation of immune responses. Ag presentation to T lymphocytes is likely a constitutive function of DC that continues during the steady state. This raises the question of which mechanism(s) determines whether the final outcome of Ag presentation will be induction of immunity or of tolerance. In this regard, the mechanisms controlling DC immunogenicity still remain largely uncharacterized. In this paper we report that the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ), which has anti-inflammatory properties, redirects DC toward a less stimulatory mode. We show that activation of PPAR-γ during DC differentiation profoundly affects the expression of costimulatory molecules and of the DC hallmarker CD1a. PPAR-γ activation in DC resulted in a reduced capacity to activate lymphocyte proliferation and to prime Ag-specific CTL responses. This effect might depend on the decreased expression of costimulatory molecules and on the impaired cytokine secretion, but not on increased IL-10 production, because this was reduced by PPAR-γ activators. Moreover, activation of PPAR-γ in DC inhibited the expression of EBI1 ligand chemokine and CCR7, both playing a pivotal role for DC migration to the lymph nodes. These effects were accompanied by down-regulation of LPS-induced nuclear localized RelB protein, which was shown to be important for DC differentiation and function. Our results suggest a novel regulatory pathway for DC function that could contribute to the regulated balance between immunity induction and self-tolerance maintenance.
Epstein-Barr Nuclear Antigen 1-Specific CD4+ Th1 Cells Kill Burkitt’s Lymphoma Cells
2002-08-01

Abstract The γ-herpesvirus, EBV, is reliably found in a latent state in endemic Burkitt’s lymphoma. A single EBV gene product, Epstein-Barr nuclear Ag 1 (EBNA1), is expressed at the protein level. Several mechanisms prevent immune recognition of these tumor cells, including a block in EBNA1 presentation to CD8+ killer T cells. Therefore, no EBV-specific immune response has yet been found to target Burkitt’s lymphoma. We now find that EBNA1-specific, Th1 CD4+ cytotoxic T cells recognize Burkitt’s lymphoma lines. CD4+ T cell epitopes of EBNA1 are predominantly found in the C-terminal, episome-binding domain of EBNA1, and ∼0.5% of peripheral blood CD4+ T cells are specific for EBNA1. Therefore, adaptive immunity can be directed against Burkitt’s lymphoma, and perhaps this role for CD4+ Th1 cells extends to other tumors that escape MHC class I presentation.
Cerebellum and Speech Perception: A Functional Magnetic Resonance Imaging Study
2002-08-01

Abstract A variety of data indicate that the cerebellum participates in perceptual tasks requiring the precise representation of temporal information. Access to the word form of a lexical item requires, among other functions, the processing of durational parameters of verbal utterances. Therefore, cerebellar dysfunctions must be expected to impair word recognition. In order to specify the topography of the assumed cerebellar speech perception mechanism, a functional magnetic resonance imaging study was performed using the German lexical items “Boden” ([bodn], Engl. “floor”) and “Boten” ([botn], “messengers”) as test materials. The contrast in sound structure of these two lexical items can be signaled either by the length of the wordmedial pause (closure time, CLT; an exclusively temporal measure) or by the aspiration noise of wordmedial “d” or “t” (voice onset time, VOT; an intrasegmental cue). A previous study found bilateral cerebellar disorders to compromise word recognition based on CLT whereas the encoding of VOT remained unimpaired. In the present study, two series of “Boden—Boten” utterances were resynthesized, systematically varying either in CLT or VOT. Subjects had to identify both words “Boden” and “Boten” by analysis of either the durational parameter CLT or the VOT aspiration segment. In a subtraction design, CLT categorization as compared to VOT identification (CLT VOT) yielded a significant hemodynamic response of the right cerebellar hemisphere (neocerebellum Crus I) and the frontal lobe (anterior to Broca's area). The reversed contrast (VOT CLT) resulted in a single activation cluster located at the level of the supra-temporal plane of the dominant hemisphere. These findings provide first evidence for a distinct contribution of the right cerebellar hemisphere to speech perception in terms of encoding of durational parameters of verbal utterances. Verbal working memory tasks, lexical response selection, and auditory imagery of word strings have been reported to elicit activation clusters of a similar location. Conceivably, representation of the temporal structure of speech sound sequences represents the common denominator of cerebellar participation in cognitive tasks acting on a phonetic code.
Analytical techniques for volatiles: A case study using intermediate (andesitic) glasses
2002-08-01

Small-scale analyses of volatiles in minerals and glasses provide information on how volatiles influence high-temperature geologic processes and low-temperature alteration processes. Four techniques for determining the C-O-H volatile contents of andesitic glasses are compared: manometry, secondary ion mass spectrometry, micro-Fourier transform infrared spectroscopy, and a technique where the H2O content is calculated using the difference between electron microprobe analysis totals and 100% sum. We present a method to determine the H content of a wide range of glass and mineral compositions using secondary ion mass spectrometry and a model for calibration factors. The extinction coefficients for H-O volatile contents in intermediate composition synthetic glasses are determined, and it is demonstrated that C-O speciation changes as total H2O content increases, with molecular CO2 decreasing, CO32- increasing, and carbonate peak splitting increasing. For glasses with low H2O content and oxy-substituted minerals, the methods of choice for volatile analysis are secondary ion mass spectrometry or micro-Fourier transform infrared spectroscopy.
Clustering of CD40 Ligand Is Required to Form a Functional Contact with CD40
2002-08-01

Receptor clustering is a key event in the initiation of signaling by many types of receptor molecules. Here, we provide evidence for the novel concept that clustering of a ligand is a prerequisite for clustering of the cognate receptor. We show that clustering of the CD40 receptor depends on reciprocal clustering of the CD40 ligand (gp39, CD154). Clustering of the CD40 ligand is mediated by an association of the ligand with p53, a translocation of acid sphingomyelinase (ASM) to the cell membrane, an activation of the ASM, and a formation of ceramide. Ceramide appears to modify preexisting sphingolipid-rich membrane microdomains to fuse and form ceramide-enriched signaling platforms that serve to cluster CD40 ligand. Genetic deficiency of p53 or ASM or disruption of ceramide-enriched membrane domains prevents clustering of CD40 ligand. The functional significance of CD40 ligand clustering is indicated by the finding that clustering of CD40 on B lymphocytes upon co-incubation with CD40 ligand-expressing T cells depends on clustering of the CD40 ligand and is abrogated by inhibition of CD40 ligand clustering.
Glibenclamide binding to sulphonylurea receptor subtypes: dependence on adenine nucleotides
2002-08-01

ATP‐sensitive K + channels are composed of pore‐forming subunits Kir6.2 and of sulphonylurea receptors (SURs); the latter are the target of the hypoglycaemic sulphonylureas like glibenclamide. Here, we report on the negative allosteric modulation by MgATP and MgADP of glibenclamide binding to SUR1 and to SUR2 mutants with high glibenclamide affinity, SUR2A(Y1206S) and SUR2B(Y1206S). ATP, in the presence of an ATP‐regenerating system to oppose hydrolysis during incubation, inhibited glibenclamide binding to SUR1 and SUR2B(Y1206S) by ∼60%, to SUR2A(Y1206S) by 21%). Inhibition curves for the SUR2(Y1206S) isoforms were monophasic with IC 50 values of 5–10 μ M ; the curve for SUR1 was biphasic (IC 50 values 4.7 and 1300 μ M ). Glibenclamide inhibition curves for ADP, performed in the presence of an ATP‐consuming system to oppose ATP formation from ADP, were generally shifted rightwards and showed positive cooperativity, in particular with the SUR2(Y1206S) isoforms. In the absence of the coupled enzyme systems, inhibition curves of MgATP or MgADP were generally shifted leftwards. This indicated synergy of MgATP and MgATP in acting together. Coexpression of SUR1 and SUR2B(Y1206S) with Kir6.2 reduced both potency and efficacy of ATP in inhibiting glibenclamide binding; this was particularly marked for Kir6.2/SUR1. The data show (a) that the inhibitory effects of ATP and ADP on glibenclamide binding differ from one another, (b) that they depend on the SUR subtype, and (c) that they are weakened by coexpression with Kir6.2. British Journal of Pharmacology (2002) 136 , 995–1004. doi: 10.1038/sj.bjp.0704801
Proteasome inhibition leads to NF-κB-independent IL-8 transactivation in human endothelial cells through induction of AP-1
2002-08-01

IL-8 is an important mediator of leukocyte trafficking and activation, participating in tumor angiogenesis, inflammatory processes and coronary atherosclerosis. Under flow conditions IL-8, in conjunction with MCP-1, triggers the firm adhesion of monocytes to the vascular endothelium. While previous studies have suggested the requirement of NF-kappaB for IL-8 secretion by endothelial cells, we investigated the possibility of IL-8 transactivation under conditions of NF-kappaB suppression. Inhibition of the proteasome by MG-132 or lactacystin completely blocked TNF-alpha-induced IkappaBalpha degradation as well as NF-kappaB activity in human arterial endothelial cells. Surprisingly, basal secretion of IL-8 protein was eight- to tenfold induced by proteasome inhibitors, while MCP-1 expression was, as expected, completely down-regulated. IL-8 was up-regulated at the transcriptional level, and promoter studies proved a more than ninefold induction of transcription factor AP-1 activity to be the cause of increased IL-8 transcription. Mutation of the AP-1 binding site in an IL-8 promoter construct completely abrogated this effect, while mutation of the NF-kappaB motif did not influence IL-8 transactivation by proteasome inhibitors. With DNA binding assays we found a seven- to eightfold induction of phosphorylated c-Jun and hence JNK kinase activity under MG-132 treatment. Induction of JNK kinase appeared independent of the cell type, even in tumor cell lines not responding to proteasome inhibitors. Since neither inactivation of p53 in wild-type p53 cells nor reintroduction of functional p53 into p53(-/-) cells affected MG-132-inducible IL-8 secretion, a direct influence of p53 on IL-8 regulation could be excluded. These results show that proteasome inhibitors can not only lead to functional AP-1 induction by enhanced c-Jun phosphorylation, but also transactivate the IL-8 gene in human endothelial cells despite complete suppression of NF-kappaB activity.
Affinities of Dihydrocodeine and its Metabolites to Opioid Receptors
2002-08-01

Abstract: Dihydrocodeine is metabolized to dihydromorphine, dihydrocodeine‐6‐ O ‐, dihydromorphine‐3‐ O ‐ and dihydromorphine‐6‐ O ‐glucuronide, and nordihydrocodeine. The current study was conducted to evaluate the affinities of dihydrocodeine and its metabolites to μ‐, δ‐ and κ‐opioid receptors. Codeine, morphine, d,l‐methadone and levomethadone were used as controls. Displacement binding experiments were carried out at the respective opioid receptor types using preparations of guinea pig cerebral cortex and the specific opioid agonists [ 3 H]DAMGO (μ‐opioid receptor), [ 3 H]DPDPE (δ‐opioid receptor) and [ 3 H]U69,593 (κ‐opioid receptor) as radioactive ligands at concentrations of 0.5, 1.0 and 1.0 nmol/l, respectively. All substances had their greatest affinity to the μ‐opioid receptor. The affinities of dihydromorphine and dihydromorphine‐6‐ O ‐glucuronide were at least 70 times greater compared with dihydrocodeine (K i 0.3 μmol/l), whereas the other metabolites yielded lower affinities. For the δ‐opioid receptor, the order of affinities was similar with the exception that dihydrocodeine‐6‐ O ‐glucuronide revealed a doubled affinity in relation to dihydrocodeine (K i 5.9 μmol/l). In contrast, for the κ‐opioid receptor, dihydrocodeine‐6‐ O ‐ and dihydromorphine‐6‐ O ‐glucuronide had clearly lower affinities compared to the respective parent compounds. The affinity of nordihydrocodeine was almost identical to that of dihydrocodeine (K i 14 μmol/l), whereas dihydromorphine had a 60 times higher affinity. These results suggest that dihydromorphine and its 6‐ O ‐glucuronide may provide a relevant contribution to the pharmacological effects of dihydrocodeine. The O ‐demethylation of dihydrocodeine to dihydromorphine is mediated by the polymorphic cytochrome P‐450 enzyme CYP2D6, resulting in different metabolic profiles in extensive and poor metabolizers. About 7% of the caucasian population which are CYP2D6 poor metabolizers thus may experience therapeutic failure after standard doses.
Anorectal functional disorders in the absence of anorectal inflammation in patients with Crohn's disease
2002-08-01

Abstract Background Histological alterations in the enteric nervous system (ENS) have been described in patients suffering from Crohn's disease (CD). The aim of this study was to investigate whether patients with CD without rectal inflammation have abnormal anorectal function compared with healthy volunteers. Methods Fifty-four patients with CD and 26 healthy volunteers were examined by anorectal manometry and answered a standardized questionnaire. No patient had active CD in the rectum as determined by endoscopy. Results Maximum anal resting and squeeze pressures did not differ between patients and healthy volunteers. The rectoanal inhibitory reflex was absent in 24 of 54 patients and two of 26 healthy volunteers (P &amp;lt; 0·05). The first sensation to distension of the rectal balloon was reported at mean(s.e.m.) 57·9(4·4) ml by patients and 37·5(2·2) ml by healthy volunteers (P &amp;lt; 0·01). The standardized interview revealed additional disorders of anorectal function in patients with CD. Conclusion Anorectal function appears to be altered in many patients with CD even in the absence of macroscopic anorectal disease. This may be due to a disorder of the ENS.