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Biomedical subjects

G Langer

Publications and source records attributed to G Langer.

At least 19 recordsLinked to original sources

Self-cooling of a micromirror by radiation pressure.

Cooling of mechanical resonators is currently a popular topic in many fields of physics including ultra-high precision measurements, detection of gravitational waves and the study of the transition between classical and quantum behaviour of a mechanical system. Here we report the observation of self-cooling of a micromirror by radiation pressure inside a high-finesse optical cavity. In essence, changes in intensity in a detuned cavity, as caused by the thermal vibration of the mirror, provide the mechanism for entropy flow from the mirror's oscillatory motion to the low-entropy cavity field. The crucial coupling between radiation and mechanical motion was made possible by producing free-standing micromirrors of low mass (m approximately 400 ng), high reflectance (more than 99.6%) and high mechanical quality (Q approximately 10,000). We observe cooling of the mechanical oscillator by a factor of more than 30; that is, from room temperature to below 10 K. In addition to purely photothermal effects we identify radiation pressure as a relevant mechanism responsible for the cooling. In contrast with earlier experiments, our technique does not need any active feedback. We expect that improvements of our method will permit cooling ratios beyond 1,000 and will thus possibly enable cooling all the way down to the quantum mechanical ground state of the micromirror.

Journal Article↗

SPINE workshop on automated X-ray analysis: a progress report.

The Structural Proteomics In Europe (SPINE) consortium contained a workpackage to address the automated X-ray analysis of macromolecules. The aim of this workpackage was to increase the throughput of three-dimensional structures while maintaining the high quality of conventional analyses. SPINE was able to bring together developers of software with users from the partner laboratories. Here, the results of a workshop organized by the consortium to evaluate software developed in the member laboratories against a set of bacterial targets are described. The major emphasis was on molecular-replacement suites, where automation was most advanced. Data processing and analysis, use of experimental phases and model construction were also addressed, albeit at a lower level.

Algorithms↗

Modeling parameter dependence from time series.

Two approaches for modeling of parameter dependence of dynamical systems from time series are investigated and applied to different examples. For both methods it is assumed that a few time series are available that have been measured for different (known) parameter values of the underlying (experimental) dynamical system. The objective is to model the changing dynamics of the system as a function of its parameters and to use this for experimental bifurcation analysis. Using parametrized families the tasks of modeling the dynamics and of modeling its parameter dependence are separated. Technical difficulties that may occur with this approach are discussed and illustrated. An alternative are extended state space models where both modeling tasks are treated simultaneously. To obtain reliable models from a few time series only, ensembles of models are employed that show very good extrapolation and generalization properties.

Journal Article↗

Spectral encoding of the polarization state of light in multiplexed polarization-sensitive lasing structures.

We report the experimental demonstration of spectral encoding of the polarization state of light by use of multiplexed distributed-feedback lasers in a dye-doped organic thin film by exploiting the pump polarization selectivity of the superimposed resonators. Measurement of the Stokes parameters of the pump light without a priori knowledge of the lasing properties of the structure is discussed.

Journal Article↗

Nutritional interventions for preventing and treating pressure ulcers.

BACKGROUND: Pressure ulcers affect 10% of people in hospitals and older people are at highest risk. The correlation between nutritional intake and the development of pressure ulcers is suggested by several studies, but the results are inconsistent. OBJECTIVES: To evaluate the effectiveness of enteral and parenteral nutrition on the prevention and treatment of pressure ulcers. SEARCH STRATEGY: The Cochrane Wounds Group Specialised Trials Register and the Cochrane Central register of Controlled Trials were searched in September 2002. An additional search of PubMed and Cinahl and hand search of conference proceedings and journals was performed, bibliographies of relevant articles were examined and experts in the field as well as manufacturers were contacted in order to find additional literature that may be relevant. SELECTION CRITERIA: Randomised controlled trials evaluating the effectiveness of enteral or parenteral nutrition on the prevention and treatment of pressure ulcers by measuring the incidence of new ulcers, ulcer healing or changes in pressure ulcer severity. There were no restrictions on patients, setting, date, publication status or language. DATA COLLECTION AND ANALYSIS: Abstracts were independently inspected and full articles were obtained of potentially relevant studies. In case of disagreement advice was sought from a third person (AK). Data extraction and assessment of quality were undertaken by the three reviewers independently. MAIN RESULTS: Only 8 randomised controlled trials out of 16 potentially relevant articles were included. However, most of the 8 trials included are small and of poor methodological quality. PREVENTION: Four studies compared a combination of nutritional supplements, consisting of a minimum of energy and protein in different dosages, for the prevention of pressure ulcers. The largest study found that nutritional supplements reduced the number of new pressure ulcers (Bourdel-M 2000). The three smaller studies lacked power. TREATMENT: Four studies evaluated the effects of nutritional supplements for the treatment of existing pressure ulcers: one trial examined mixed nutritional supplements, one trial examined zinc, another the effect of proteins, and two studies compared ascorbic acid. The trials included are heterogeneous with regard to participants, interventions and outcomes; therefore it was considered inappropriate to perform a meta-analysis. REVIEWER'S CONCLUSIONS: It was not possible to draw any firm conclusions on the effect of enteral and parenteral nutrition on the prevention and treatment of pressure ulcers. Further trials of high methodological quality are necessary.

Aged↗

[TFF peptides. New mucus-associated secretory products of the conjunctiva].

The molecular architecture of the human ocular mucus is not yet completely understood. Recently, TFF peptides (formerly known as trefoil factors or P-domain peptides) could be identified as new constituents of this delicate mucus. Members of the TFF-peptide family are typical secretory products of mucous epithelia and three are known in humans and designated as TFF1, TFF2 and TFF3. They enhance cell migratory processes (motogenic effect), they show anti-apoptotic effects and are inflammatory modulators Both TFF1 and TFF3 expression could be monitored by the reverse transcription-polymerase chain reaction (RT-PCR) in the human conjunctiva; in contrast, TFF2 transcripts were not detectable. Using immunohistochemistry, TFF1 and TFF3 peptides were found in varying concentrations solely in secretory vesicles of conjunctival goblet cells. This localisation matches precisely that of the secretory mucin MUC5AC. Thus, conjunctival TFF1 and TFF3 have to be considered as typical mucin-associated peptides probably modulating the rheological properties of the ocular mucus and the tear fluid. Future investigations are in progress to elucidate the role of TFF-peptides during pathological conditions of the eye as well as their diagnostic and therapeutic potential.

Conjunctiva↗

Hsp70-RAP46 interaction in downregulation of DNA binding by glucocorticoid receptor.

Receptor-associating protein 46 (RAP46) is a cochaperone that regulates the transactivation function of several steroid receptors. It is transported into the nucleus by a liganded glucocorticoid receptor where it downregulates DNA binding and transactivation by this receptor. The N- and C-termini of RAP46 are both implicated in its negative regulatory function. In metabolic labelling experiments, we have shown that the N-terminus of RAP46 is modified by phosphorylation, but this does not contribute to the downregulation of glucocorticoid receptor activity. However, deletion of a sequence that binds 70 kDa heat shock protein (Hsp70) and the constitutive isoform of Hsp70 (Hsc70) at the C-terminus of RAP46 abrogated its negative regulatory action. Surface plasmon resonance studies showed that RAP46 binds the glucocorticoid receptor only when it has interacted with Hsp70/Hsc70, and confocal immunofluorescence analyses revealed a nuclear transport of Hsp70/Hsc70 by the liganded receptor. Together these findings demonstrate an important contribution of Hsp70/Hsc70 in the binding of RAP46 to the glucocorticoid receptor and suggest a role for this molecular chaperone in the RAP46-mediated downregulation of glucocorticoid receptor activity.

Amino Acid Sequence↗

Secretory peptides TFF1 and TFF3 synthesized in human conjunctival goblet cells.

PURPOSE: The objective of this study was to determine whether human conjunctival epithelium synthesizes TFF-peptides (formerly P-domain peptides, trefoil factors), a family of mucin-associated secretory peptides of the gastrointestinal tract. METHODS: Expression of TFF-peptides in human conjunctiva was monitored by reverse transcription-polymerase chain reaction analysis. Antisera specific for TFF-peptides were used for immunohistochemistry to determine the presence and distribution of TFF-peptides in human conjunctiva. RESULTS: mRNA expression of TFF1 and TFF3, but not TFF2, was detected in human conjunctiva. TFF1 and TFF3 but not TFF2 are stored in conjunctival goblet cells only as revealed by immunofluorescence. CONCLUSIONS: Goblet cells of the human conjunctiva synthesize TFF1 and TFF3. These peptides, together with the secretory ocular mucin MUC5AC, may contribute to the rheological properties of the tear film. They also may influence healing of corneal wounds due to their motogenic properties.

Aged↗

Evolution of gilled mushrooms and puffballs inferred from ribosomal DNA sequences.

Homobasidiomycete fungi display many complex fruiting body morphologies, including mushrooms and puffballs, but their anatomical simplicity has confounded efforts to understand the evolution of these forms. We performed a comprehensive phylogenetic analysis of homobasidiomycetes, using sequences from nuclear and mitochondrial ribosomal DNA, with an emphasis on understanding evolutionary relationships of gilled mushrooms and puffballs. Parsimony-based optimization of character states on our phylogenetic trees suggested that strikingly similar gilled mushrooms evolved at least six times, from morphologically diverse precursors. Approximately 87% of gilled mushrooms are in a single lineage, which we call the "euagarics." Recently discovered 90 million-year-old fossil mushrooms are probably euagarics, suggesting that (i) the origin of this clade must have occurred no later than the mid-Cretaceous and (ii) the gilled mushroom morphology has been maintained in certain lineages for tens of millions of years. Puffballs and other forms with enclosed spore-bearing structures (Gasteromycetes) evolved at least four times. Derivation of Gasteromycetes from forms with exposed spore-bearing structures (Hymenomycetes) is correlated with repeated loss of forcible spore discharge (ballistospory). Diverse fruiting body forms and spore dispersal mechanisms have evolved among Gasteromycetes. Nevertheless, it appears that Hymenomycetes have never been secondarily derived from Gasteromycetes, which suggests that the loss of ballistospory has constrained evolution in these lineages.

Basidiomycota↗

Expression of the vitamin D and the retinoid X receptors in Saccharomyces cerevisiae: alternative in vivo models for ligand-induced transactivation.

The transcription factors of the nuclear hormone receptor family regulate gene expression via a complex network of macromolecular interactions. The ligand dependent activity of the vitamin D receptor is of particular interest because it modulates gene expression by the heterodimeric interaction with retinoid X receptors. We report here that individual functions of the vitamin D receptor including DNA-binding, homo- and heterodimerization and transactivation can be reconstituted in the yeast Saccharomyces cerevisiae. Interestingly, the simultaneous expression of the native vitamin D receptor and the retinoid X receptor beta resulted in a ligand independent transactivation of the lacZ reporter gene coupled to a mouse osteopontin vitamin D response element. However, homodimerization of the vitamin D receptor and heterodimerization were strongly enhanced upon ligand binding, when the receptors were expressed as fusion proteins with the Gal4 transcription factor in a yeast two-hybrid system. Furthermore, transactivating activity of a Gal4-fused vitamin D receptor was induced by vitamin D in a one-hybrid system devoid of retinoid X receptors. In addition, both Gal4-based systems behaved similar with regard to their dose-dependent response to vitamin D and related compounds when compared to the transcriptional activity of the vitamin D receptor in transiently transfected MCF-7 cells. Our results point out that specific ligands strongly enhanced receptor dimerization and induced transactivation in yeast and in MCF-7 cells. The constitutive transactivation by vitamin D receptor-retinoid X receptor heterodimers in yeast, depending on DNA binding of the receptors, strongly argues for the existence of cofactors, which are absent in yeast, but play a fundamental role in gene regulation in higher eukaryotic organisms.

Animals↗

Biperiden and haloperidol plasma levels and extrapyramidal side effects in schizophrenic patients.

Anticholinergic drugs such as biperiden are used for the treatment of extrapyramidal side effects (EPS) induced by neuroleptics such as haloperidol. The effects of biperiden and haloperidol plasma levels on EPS were studied in 29 chronically ill schizophrenics. The results show relationships between biperiden dose and biperiden plasma levels (BPL), and between BPL and haloperidol plasma levels (HPL). Neither BPL nor HPL seem to influence EPS.

Adult↗

Correlation between vasopressin baseline and TSH-blunting in depressives.

A blunted thyrotropin (TSH) response is a predictor of a good response to antidepressant drug treatment in depressives and neuroleptic treatment in paraphrenic patients (Larger et al 1986). The aim of the following study was to elucidate possible relationships between different endocrine systems and to shed light on the pathogenetic hypotheses of TSH-blunting. In order to evaluate especially hypothalamic activity in severe depression we were interested in the vasopressin system as another hormonal system underlying hypothalamic control. Thirty-four patients who met the criteria for major depression according to DSM-III-R were subjected to the thyrotropin-releasing hormone (TRH) test. We also took baseline readings of the cortisol, neurophysinI (hNpI, reflecting vasopressin plasma levels), and neurophysinII (hNpII, reflecting oxytocin plasma levels) levels. Likelihood ratio tests were done with logistic regression models to analyze the phenomenon of TSH-blunting. We observed that the likelihood of a blunted TSH response increases with higher levels of hNpI and low levels of cortisol, but is unrelated to hNpII levels.

Adult↗

Low-M(r) urokinase-type plasminogen activator as a reporter protein.

A reporter plasmid coding for the low-molecular-weight (low-M(r)) form of single-chain urokinase-type plasminogen activator (low-M(r) u-PA; Leu144-Leu411) has been constructed and used to analyze promoter activity. Vectors containing the low-M(r) u-PA cDNA coupled to hormone-responsive promoters were introduced to mammalian cells. Following hormone treatment, the activity of the secreted reporter protein was determined in aliquots of cell culture supernatants. The assay is based on plasminogen activation by low-M(r) u-PA and subsequent cleavage of the plasmin-specific tripeptide substrate, S-2251. The resulting chromophore, p-nitroanilide, was quantified colorimetrically at 405 nm. Transient and stable expression of the low-M(r) u-PA reporter gene in different eukaryotic cells demonstrates the suitability of the system for the quantification of the activity of eukaryotic promoter elements in a rapid and highly sensitive manner, while maintaining cell integrity.

Animals↗

Three-month efficacy and safety of once-daily diltiazem in chronic stable angina pectoris.

The 3-month efficacy and safety of a once-daily controlled formulation of diltiazem (180 to 360 mg/day) were assessed in a study of 54 patients with angina pectoris. This multicenter study was a nonrandomized, placebo run-in, open-label, 3-month trial followed by a 1-week, double-blind, randomized period during which most patients (89%) received placebo. There were only minimal changes in the time to termination (mean change +/- SEM -5.8 +/- 9.6 seconds), time to onset of angina (10.5 +/- 12.2 seconds), and the time to 1 mm ST-segment depression (2.9 +/- 12.5 seconds) from the end of the titration phase to the end of the open-label study. There were, however, statistically significant differences between the end of the 3-month treatment phase and the end of the 1-week randomized placebo phase for those 3 efficacy parameters (-37.3 +/- 11.2, -58.6 +/- 13.6, and -45.6 +/- 16.4 seconds, respectively). Diltiazem significantly decreased the frequency of anginal attacks and nitroglycerin use at the end of the 3-month treatment phase compared with results at the end of the randomized double-blind placebo phase. No new or unusual adverse events were reported during treatment. The present results suggest that there is no loss of efficacy of once-a-day diltiazem when administered for a long period to patients with chronic stable angina pectoris.

Aged↗

Production of vampire bat plasminogen activator DSPA alpha 1 in CHO and insect cells.

Salivary plasminogen activator from the vampire bat Desmodus rotundus (DSPA alpha 1) is a promising new thrombolytic agent. Continuous growth of a stably transfected, methotrexate amplified, dhfr- CHO cell line yields up to 60 mg l-1 of DSPA alpha 1. Utilizing an engineered baculovirus 10 mg l-1 were produced in batches of Sf9 insect cells. Recombinant DSPA alpha 1 is purified from both sources using a one-step purification protocol. Although differences in glycosylation were detected, enzymatic activity and fibrin cofactor dependency are unaffected when DSPA alpha 1 derived from the two expression systems is compared.

Animals↗

Hypothalamic-pituitary-gonadal axis in depressed premenopausal women: elevated blood testosterone concentrations compared to normal controls.

To assess the function of the hypothalamic-pituitary-gonadal (HPG) axis in major depression, a multihormonal study was carried out in 20 depressed premenopausal women. Serum concentrations of LH, FSH, estradiol, progesterone, testosterone, and GnRH-stimulated LH and FSH were measured before initiation of treatment (on the first day after menstruation) and during clomipramine treatment (same time one menstrual cycle later). Significantly higher blood concentrations of testosterone were found in untreated patients compared to normal controls. Furthermore, there was a significant negative correlation between Hamilton depression scores and estradiol concentrations of patients. The efficacy of clomipramine treatment was not related to hormonal parameters.

Adult↗

Isoflurane narcotherapy in depressive patients refractory to conventional antidepressant drug treatment. A double-blind comparison with electroconvulsive treatment.

This is the first report on a controlled study comparing the therapeutic and non-therapeutic (side) effects of electroconvulsive treatment (ECT) and isoflurane narcotherapy (ISONAR; deep anesthesias with the inhalation of anesthetic isoflurane) in drug-refractory, severely depressed women, who had been randomly allocated either to ECT (n = 10) or ISONAR (n = 10). Patients from each group were subjected to a total of six treatment sessions (two sessions per week) and maintained on a fixed antidepressant drug dose. The antidepressant efficacy of either treatment was evaluated for each treatment session (in search of a 'rapid antidepressant effect') and at weekly intervals. Cognitive functions or signs of an organic brain syndrome were evaluated by means of psychological tests and extensive EEG analyses. Rapid antidepressant effects of the first treatment session were only significant in patients on ISONAR; in the subsequent treatment sessions, ECT also induced rapid antidepressant effects. Antidepressant effects during the treatment period were comparable, and patients on ISONAR improved further during follow-up, whereas patients on ECT tended to relapse. ISONAR-treated patients improved in most psychometric variables, whereas patients on ECT deteriorated. Finally, the EEG patterns of the ISONAR-treated patients remained normal or augmented (dominant alpha power), whereas patients on ECT developed an increase in abnormalities in EEG patterns and theta/delta power. This indicates an organic brain syndrome in patients on ECT.

Adult↗