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Biomedical subjects

T Lange

Publications and source records attributed to T Lange.

At least 19 recordsLinked to original sources
PubMed2026

Esketamine multi-omic biomarker evaluation in major depressive disorder (EMBER-MDD): concept, objectives and methodologies of a non-clinical investigator-initiated study.

Treatment resistance (TR) in major depressive disorder (MDD) affects a substantial minority of patients and is hard to recognize early, delaying intensified care. The Esketamine multi-omic biomarker evaluation in MDD (EMBER-MDD) is a non-interventional, investigator-initiated, in-vitro study within the EU Psych-STRATA programme, analyzing biospecimens collected in the randomized INTENSIFY study and the mirror OBS-TR cohort after participants complete treatment. EMBER-MDD aims to discover individual-omic and integrated multi-omic (hypothesis-free) biomarkers and signatures associated with TR risk, and molecular correlates of clinical response to esketamine nasal spray versus treatment as usual (TAU). Biomaterials will derive from approximately 420 adults with MDD (estimated n = 210 esketamine; n = 210 TAU) and include whole blood, RNA-stabilized whole blood, plasma and serum, sampled at baseline and, when feasible, during and after treatment (up to ~ 5,040 aliquots stored at - 80 °C). Genomics will use baseline DNA genotyping on Illumina Infinium GSA v3.0+MD arrays; epigenomics will profile genome-wide DNA methylation across time points using MethylationEPIC v2.0; transcriptomics will employ mRNA-seq (NovaSeq X/ X Plus); and proteomics/ metabolomics will be generated using high-throughput Olink and/ or Biocrates platforms. Each layer will undergo state-of-the-art preprocessing and analyses (e.g., GWAS/ PRS, EWAS, differential expression, WGCNA, pathway and network analyses), followed by integrative strategies including QTL mapping (meQTL/ eQTL/ pQTL/ mQTL) and intermediate-fusion machine learning with nested cross-validation, explainable AI (SHAP/ LIME) and treatment-effect modelling. All outputs are research-only and will not support individual efficacy, tolerability, or clinical decision-making. The study will deliver robust biosignatures and mechanistic hypotheses to guide future validation and inform stratified, molecularly guided intervention strategies in subsequent prospective trials. Trial registration number: 2023-506617-21-00 and 2025-178-f-S.

Humans↗
PubMed2001

Total asymmetric synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin a and of the authentic natural sclerophytins A and B.

An enantioselective synthetic route to the thermodynamically most stable diastereomer of the structure assigned to sclerophytin A (5) has been realized. The required tricyclic ketone 33 was prepared by sequential Tebbe-Claisen rearrangement of lactones 29 and 30, which originated from the Diels-Alder cycloaddition of Danishefsky's diene to (5S)-5-(d-menthyloxy)-2(5H)-furanone (14). An allyl and a cyano group were introduced into the resulting adduct by means of stereocontrolled allylindation under aqueous Barbier-like conditions and by way of cyanotrimethylsilane, respectively. Following stereocontrolled nucleophilic addition of a methyl group to 33, ring A was elaborated by formation of the silyl enol ether, ytterbium triflate-catalyzed condensation with formaldehyde, O-silylation, and Cu(I)-promoted 1,4-addition of isopropylmagnesium chloride. The superfluous ketone carbonyl was subsequently removed and the second ether bridge introduced by means of oxymercuration chemistry. Only then was the exocyclic methylene group unmasked via elimination. An alternative approach to the alpha-carbinol diastereomer proceeds by initial alpha-oxygenation of 37 and ensuing 1,2-carbonyl transposition. Neither this series of steps nor the Wittig olefination to follow induced epimerization at C10. Through deployment of oxymercuration chemistry, it was again possible to elaborate the dual oxygen-bridge network of the target ring system. Oxidation of the organomercurial products with O(2) in the presence of sodium borohydride furnished 72, which was readily separated from its isomer 73 after oxidation to 61. Hydride attack on this ketone proceeded with high selectivity from the beta-direction to deliver (-)-60. Comparison of the high-field (1)H and (13)C NMR properties and polarity of synthetic 5 with natural material required that structural revision be made. Following a complete spectral reassessment of the structural assignments to many sclerophytin diterpenes, a general approach to sclerophytin A, three diastereomers thereof, and of sclerophytin B was devised. The presence of two oxygen bridges as originally formulated was thereby ruled out, and absolute configurations were properly determined. Key elements of the strategy include dihydroxylation of a medium-ring double bond, oxidation of the secondary hydroxyl in the two resulting diols, unmasking of an exocyclic methylene group at C-11, and stereocontrolled 1,2-reduction of the alpha-hydroxy ketone functionality made available earlier.

Antineoplastic Agents↗
PubMed2001

Chemotherapy for mobilisation of Ph-negative progenitor cells from patients with CML: impact of different mobilisation regimens.

Mobilised peripheral blood stem cells are widely used for autografting in patients with chronic myeloid leukaemia (CML) and it is generally thought that a high proportion of Ph-negative progenitor cells in the graft is desirable. We report here the results of 91 stem cell mobilisations performed with various chemotherapy regimens followed by G-CSF. We show that mobilisation of Ph-negative cells is possible after diagnosis as well as in advanced stages of the disease. The yield of Ph-negative cells is highly dependent on the chemotherapy regimen: while the combination of idarubicin and cytarabin for 3-5 days (IC3-5) mobilised Ph-negative cells in most patients, high-dose cyclophosphamide was ineffective. Mobilisation of Ph-negative progenitor cells after IC3 was at least as effective as after IC5; however, less apheresis sessions were required, and toxicity was much reduced after IC3. Compared to historical controls, IC was equally effective as the widely used ICE/miniICE (idarubicin, cytarabin, etoposide) protocol. No correlation was found between graft quality and the cytogenetic response to subsequent treatment with interferon-alpha. We conclude that IC3 is an effective and well-tolerated regimen for mobilising Ph-negative cells that compares well with more aggressive approaches such as IC5 and ICE/miniICE.

Adolescent↗
PubMed2001

Production of dwarf lettuce by overexpressing a pumpkin gibberellin 20-oxidase gene.

We investigated the effect of overexpressing a pumpkin gibberellin (GA) 20-oxidase gene encoding an enzyme that forms predominantly biologically inactive products on GA biosynthesis and plant morphology in transgenic lettuce (Lactuca sativa cv Vanguard) plants. Lettuce was transformed with the pumpkin GA 20-oxidase gene downstream of a strong constitutive promoter cassette (El2-35S-Omega). The transgenic plants in which the pumpkin gene was detected by polymerase chain reaction were dwarfed in the T(2) generation, whereas transformants with a normal growth phenotype did not contain the transgene. The result of Southern-blot analysis showed that the transgene was integrated as a single copy; the plants segregated three dwarfs to one normal in the T(2) generation, indicating that the transgene was stable and dominant. The endogenous levels of GA(1) and GA(4) were reduced in the dwarfs, whereas large amounts of GA(17) and GA(25), which are inactive products of the pumpkin GA 20-oxidase, accumulated in these lines. These results indicate that a functional pumpkin GA 20-oxidase is expressed in the transgenic lettuce, resulting in a diversion of the normal pathway of GA biosynthesis to inactive products. Furthermore, this technique may be useful for controlling plant stature in other agricultural and horticultural species.

Cucurbitaceae↗
PubMed2000

Interferon-alpha acutely impairs sleep in healthy humans.

We investigated the effects of two low doses of interferon-alpha (IFN-alpha) on nocturnal sleep in 18 healthy men by means of polysomnographic sleep recordings. At 1900h, human recombinant IFN-alpha (1000 or 10000 U/kg body weight) or placebo was administered subcutaneously. Between 2300h and 0700h subjects were allowed to sleep. In general effects were stronger at the dose of 10000 than 1000 U/kg body weight of IFN-alpha. Although, after IFN-alpha subjects experienced increased fatigue, the cytokine impaired the quality of nocturnal sleep. The higher dose of IFN-alpha suppressed slow wave sleep (17.8 +/- 2.0% vs 25.2 +/- 2.6% following placebo, P<0.003) but increased time spent in shallow sleep (P<0.05) during the first half of sleep time. Rapid eye movement (REM) sleep latency was postponed (P<0.02) and time spent in REM sleep was significantly decreased after IFN-alpha (P<0.04). The impairing influence of IFN-alpha on sleep in humans is in contrast with findings of sleep promoting effects of this cytokine in animals. Our data suggest that endogenous IFN-alpha may be a factor responsible for alterations of sleep, e.g. in the course of viral infections.

Adrenocorticotropic Hormone↗
PubMed2000

Characteristic distribution pattern of Helicobacter pylori in dental plaque and saliva detected with nested PCR.

The precise mode of transmission and the natural reservoir for Helicobacter pylori are unknown. PCR assays have proved to be highly sensitive and specific and are regarded as the method of choice for detecting H. pylori DNA in the oral cavity. The aim of this study was to investigate the prevalence and distribution of H. pylori in the oral cavity. Forty-two patients undergoing gastroscopy were investigated for the presence of H. pylori in dental plaque and saliva by nested PCR, and in the stomach by the 13C-urea breath test. Samples tested comprised dental plaque from molars, premolars and incisors and saliva. Two sets of primers homologous to the 860-bp fragment of H. pylori DNA, which have been shown previously to be highly sensitive and specific, were used for nested PCR. Eleven patients (26.2%) were infected with H. pylori in the stomach. H. pylori DNA was identified in dental plaque samples from 41 patients (97%) and in 23 saliva samples (55%). The prevalence in dental plaque from molars, premolars and incisors was 82%, 64% and 59%, with an odds ratio of 3.18, 1.24 and 1 (reference), respectively. In conclusion, H. pylori was present in the oral cavity of 97% of tested patients, with a characteristic distribution that was independent of the infection status of the stomach. Thus H. pylori may belong to the normal oral microflora.

Adult↗
PubMed2000

Virtual reality in surgical training.

Virtual reality in surgery and, more specifically, in surgical training, faces a number of challenges in the future. These challenges are building realistic models of the human body, creating interface tools to view, hear, touch, feel, and manipulate these human body models, and integrating virtual reality systems into medical education and treatment. A final system would encompass simulators specifically for surgery, performance machines, telemedicine, and telesurgery. Each of these areas will need significant improvement for virtual reality to impact medicine successfully in the next century. This article gives an overview of, and the challenges faced by, current systems in the fast-changing field of virtual reality technology, and provides a set of specific milestones for a truly realistic virtual human body.

Computer Simulation↗
PubMed1999

Surgical versus medical care for postoperative cardiac surgical patients at the general ward.

OBJECTIVES: To shorten hospital stay after cardiac surgery, several risk factors have been defined to identify patients who can be discharged early. These risk factors are dependant on the patient; no studies exist on the influence of the treating physician himself on postoperative patient stay. METHODS: In a university affiliated cardiac surgical clinic we investigated patients who were postoperatively treated either on medical wards with no cardiac surgeon's presence or on a cardiac surgical ward; at both types of wards physicians had several years experience with cardiac surgical patients. Taking several risk factors for postoperative morbidity into account, postoperative length of stay and incidence of wound healing complications have been compared. RESULTS: Within a 3-month period, 84 patients were treated at the cardiac surgical ward, 102 patients at the medical wards. Risk factors for postoperative morbidity were present in 87% of patients, statistically independent of postoperative wards. Although demographic data and median ICU-stay of both patient groups was comparable, the median post-ICU stay was 9 days at the surgical and 13 days at the medical wards (P < 0.0001). Incidence of wound healing complication was higher (19.6%) at the medical wards than at the surgical ward (10.7%), without reaching statistical significance. CONCLUSION: As patients at the respective wards were statistically not different, the difference in post-ICU stay, infection and costs must depend on the treating physicians. As a consequence, postoperative care for cardiac surgical patients in all cases should include direct cardiac surgical participation.

Aged↗
PubMed1999

Gibberellin Biosynthesis in Maize. Metabolic Studies with GA(15), GA(24), GA(25), GA(7), and 2,3-Dehydro-GA(9).

[17-(14)C]-Labeled GA(15), GA(24), GA(25), GA(7), and 2,3-dehydro-GA(9) were separately injected into normal, dwarf-1 (d1), and dwarf-5 (d5) seedlings of maize (Zea mays L.). Purified radioactive metabolites from the plant tissues were identified by full-scan gas chromatography-mass spectrometry and Kovats retention index data. The metabolites from GA(15) were GA(44), GA(19), GA(20), GA(113), and GA(15)-15,16-ene (artifact?). GA(24) was metabolized to GA(19), GA(20), and GA(17). The metabolites from GA(25) were GA(17), GA(25) 16alpha,17-H(2)-17-OH, and HO-GA(25) (hydroxyl position not determined). GA(7) was metabolized to GA(30), GA(3), isoGA(3) (artifact?), and trace amounts of GA(7)-diene-diacid (artifact?). 2,3-Dehydro-GA(9) was metabolized to GA(5), GA(7) (trace amounts), 2,3-dehydro-GA(10) (artifact?), GA(31), and GA(62). Our results provide additional in vivo evidence of a metabolic grid in maize (i.e. pathway convergence). The grid connects members of a putative, non-early 3,13-hydroxylation branch pathway to the corresponding members of the previously documented early 13-hydroxylation branch pathway. The inability to detect the sequence GA(12) --> GA(15) --> GA(24) --> GA(9) indicates that the non-early 3,13-hydroxylation pathway probably plays a minor role in the origin of bioactive gibberellins in maize.

Journal Article↗
PubMed1998

Reduction of wound healing problems after median sternotomy by use of retention sutures.

Obese people have a higher risk of sternal wound dehiscence resulting from traction of suprasternal tissue. In such patients we recommend the use of retention sutures with extracorporeal plates to improve tissue connection and to disburden fascia and skin sutures. This augmented closure is simple and effective and, since 1996, has prevented wound healing problems in more than 50 patients with a body mass index greater than 27.

Body Mass Index↗
PubMed1998

Microhemodynamics and leukocyte sequestration after pulmonary ischemia and reperfusion in rabbits.

OBJECTIVE: Investigation of leukocyte sequestration in alveolar capillaries and of microhemodynamic changes after pulmonary ischemia/reperfusion injury. METHODS: The kinetics of leukocyte passage and the hemodynamics in pulmonary microcirculation were investigated in 16 rabbits by intravital microscopy. Mean red blood cell velocity and the number of sticking leukocytes were measured in pulmonary arterioles, venules, and capillaries after 1 hour of tourniquet ischemia and 10 minutes and 1 hour after reperfusion. RESULTS: The decrease of red blood cell velocity after reperfusion was associated with a largely increased heterogeneity of blood flow. Immediately after the onset of blood flow, sequestered leukocytes were found in all microvascular segments. An increased number of leukocytes was present in arterioles, venules, and alveolar capillaries 10 minutes and 1 hour after reperfusion. Concomitantly, width of alveolar septa was increased while arterial oxygen tension was reduced, indicating the development of interstitial pulmonary edema. CONCLUSION: Leukocytes are sequestered after pulmonary ischemia and reperfusion not only in alveolar capillaries but also in arterioles and venules, and they may contribute to the development of reperfusion edema.

Animals↗
PubMed1997

Dissimilarity in aflatoxin dose-response relationships between DNA adduct formation and development of preneoplastic foci in rat liver.

Earlier work in this laboratory and that carried out by others demonstrated that after a single dose of aflatoxin B1 (AFB) the resulting liver AFB-DNA adduct levels were directly proportional to dose. Earlier work also showed that after ten daily doses the AFB dose-response relationship with gamma-glutamyl transpeptidase (GGT) positive preneoplastic foci measured at 3 months was sublinear, with a threshold at a dose of about 150 micrograms/kg body weight/day. The objective of this study is to determine the factors influencing the shift in AFB dose-response between AFB-DNA adducts and GGT foci. Male Fisher 344 weanling rats were orally administered one or ten doses of AFB ranging from 50 to 350 micrograms/kg body weight/day. The animals were killed 2 or 24 h after the first AFB dose, or after the tenth AFB dose. The first and tenth doses were tritiated in these animals and 3H-AFB-guanine adducts isolated from liver DNA were measured by HPLC. Another group was killed 3 months after receiving ten doses in order to measure GGT foci development. AFB-guanine adduct levels were directly proportional to dose after the first dose, but after the tenth dose were much lower in the 200-350 micrograms/kg groups than after a single dose. The GGT foci response confirmed earlier work concerning a sublinear response. Among the individual animals in the 200-350 micrograms/kg groups there was a positive relationship, after controlling for dose, between GGT foci development and weight gained both during dosing (P = 0.018) and also to a lesser extent during the early promotional period (P = 0.066). Enzyme activity levels of GGT in liver homogenates were higher in the highest dose groups and reflected biliary proliferation rather than histological GGT stained foci. Urinary levels of AFB metabolites changed proportions in the high dosage multiply dosed animals reflecting alteration in AFB metabolism or excretion. The differences between the linear adduct and the sublinear foci dose-response curves may be the result of non-adduct effects of higher multiple AFB doses on foci formation including acute cytotoxicity, altered AFB metabolism and disposition, enhanced weight gains, or shortened foci latency but not through enhanced guanine adduct levels. Other studies that showed a linear relationship between AFB dose and liver tumor development used continuous feeding of maximal doses an order of magnitude less than the lowest dose in this study and thus avoided acutely toxic effects. We hypothesize that liver tumor development may mirror foci response in a 10-dose AFB regimen with doses above 100 micrograms/kg due to acute toxicity effects.

Administration, Oral↗
PubMed1997

Relationships between myocardial bioenergetic and left ventricular function in hearts with volume-overload hypertrophy.

BACKGROUND: Left ventricular (LV) hypertrophy secondary to volume overload can result in alterations in myocardial bioenergetics and LV dysfunction. This study examined whether bioenergetic abnormalities contribute to the pump dysfunction. METHODS AND RESULTS: Severe mitral regurgitation (MR) was produced in 10 dogs by disruption of the chordal apparatus. Hemodynamics and ventricular function were examined 11.7 months later under baseline conditions and during treadmill exercise. Myocardial high-energy phosphates were measured by using magnetic resonance spectroscopy at rest, during coronary vasodilation with adenosine, and during oxidative stress induced by rapid pacing and dobutamine. Chronic MR caused a 30% increase in LV mass and a 65% increase in LV volume. In MR animals, the hemodynamic and LV function were normal at rest, but abnormalities developed during beta-blockade and exercise. Myocardial creatine phosphate-to-ATP ratios were significantly lower in each layer across the LV wall in MR hearts than normal hearts. Myocardial blood flow and coronary reserve were normal in MR hearts. Moreover, hyperperfusion did not correct the abnormal bioenergetics. Despite altered bioenergetics at rest, the MR hearts tolerated rapid pacing and dobutamine infusion well. CONCLUSIONS: In volume-overloaded LV hypertrophied hearts, alterations in myocardial high-energy phosphate levels do not induce abnormal mechanical performance at rest but may be related to a decreased contractile reserve during exercise.

Adenosine Triphosphate↗
PubMed1997

Cloning gibberellin dioxygenase genes from pumpkin endosperm by heterologous expression of enzyme activities in Escherichia coli.

Gibberellin (GA) plant hormones are biosynthesized via complex pathways, the final steps of which are catalyzed by 2-oxoglutarate-dependent dioxygenases. Here, the cloning of two such enzymes, the GA 7-oxidase and the GA 20-oxidase, is reported using a novel approach, namely, by screening for GA dioxygenase activities expressed as T7 gene 10 fusion proteins in recombinant Escherichia coli. In vitro translation products of mRNA from endosperm of immature pumpkin seeds contained three GA dioxygenase activities, including 7-oxidase, 20-oxidase, and 3beta-hydroxylase. A cDNA expression library was prepared from the endosperm mRNA in lambdaMOSElox. An aliquot of the amplified library was converted to plasmids in vivo and used for transformation of E. coli BL21(DE3), which thereafter expressed recombinant fusion proteins containing 7-oxidase, 20-oxidase, and 3beta-hydroxylase activities. By screening for specific GA dioxygenase expression, clones harboring 7-oxidase and 20-oxidase cDNA were isolated. The ORF of the 7-oxidase cDNA is 945 bp long, encoding for 314 amino acid residues with a calculated Mr of 35,712 and pI of 5.7. Recombinant GA 7-oxidase oxidizes GA12-aldehyde to GA12 and GA14-aldehyde to GA14. Evidence was obtained for further metabolism of GA12 by the 7-oxidase to four products, two of which are monohydroxylated GA12. The ORF of the 20-oxidase is-apart from seven changes, resulting in four amino acid substitutions-identical to the 20-oxidase cDNA previously cloned from pumpkin cotyledon mRNA; both 20-oxidases have the same catalytic properties.

Amino Acid Sequence↗