Biomedical subjects

M Schindler

Publications and source records attributed to M Schindler.

At least 19 recordsLinked to original sources

PubMed2006

[Trigeminal neuralgia: how often are trigeminal nerve-vessel contacts found by MRI in normal volunteers].

PURPOSE: To assess prospectively how often contacts are found between the trigeminal nerve and arteries or veins in the perimesencephalic cistern via MRI in normal volunteers. MATERIALS AND METHODS: 48 volunteers without a history of trigeminal neuralgia were examined prospectively (MRI at 1.5 T; T2-CISS sequence, coronal orientation, 0.9 mm slice thickness). Two radiologists decided by consensus whether there was a nerve-vessel contact in the perimesencephalic cistern. RESULTS: In 27 % of the volunteers, no contact was found between the trigeminal nerve and regional vessels, while in 73 %, such a contact was present. In 61 % of the cases, the offending vessel was an artery, in 39 %, it was a vein. In 2 volunteers, a deformation of the nerve was noted. CONCLUSION: Contrary to what has been suggested by retrospective studies, the majority of normal volunteers, if studied prospectively, do show a contact between the trigeminal nerve and local vessels. A close proximity between the nerve and regional vessels is thus normal and is not necessarily proof of a pathological nerve-vessel conflict.

Adult↗

PubMed2005

Development of a multipoint model for sulfur in proteins: a new parametrization scheme to reproduce high-level ab initio interaction energies.

To properly represent weak hydrogen bonds to sulfur in biological systems, a new multipoint model of atomic sulfur for the amino acid methionine is introduced. This is of particular importance for the description of ligand-protein interactions. The parametrization is performed by fitting the nonbonding parameters of dimethyl sulfide to high level ab initio interaction energy surfaces of the dimethyl sulfide-methanol system and incorporating them in the GROMACS force field. Two examples demonstrate the performance of the new model, the molecular dynamics simulations of the hRAR receptor and of alpha-lytic protease. In hRAR the origin of the discrimination between the R- and S-enantiomers of the synthetic ligand BMS 184394 is explained, and in the simulation of the alpha-lytic protease it is shown that no artificial long range disorders are introduced by the new parametrization.

Binding Sites↗

PubMed2005

Influence of the cyclooctadepsipeptides PF1022A and PF1022E as natural products on the design of semi-synthetic anthelmintics such as emodepside.

The 24-membered cyclooctadepsipeptide (CODP) PF1022A, the active metabolite of the fungus imperfectus Mycelia sterilia (Rosellinia sp.) isolated from the plant Camellia japonica in Japan, is described as a powerful broad-spectrum anthelmintic natural product with low toxicity in animals. Further CODPs such as PF1022B, C, D and E have been isolated from the same culture and their structures have been established. Both PF1022A and PF1022E serve as valuable starting materials for the synthesis of semi-synthetic CODP derivatives with improved intrinsic anthelmintic potency and broad-spectrum activity. It was found that in most cases the di-substituted PF1022A derivatives showed a greater (or equal) activity by oral application against the gastrointestinal nematode Haemonchus contortus compared to the corresponding mono-substituted PF1022A analogues as exemplified by emodepside. In order to get additional information on the bioactive conformation, emodepside was transformed into its mono- and tetra-thionated derivatives by isosteric replacement. In the light of the increased efficacy of these derivatives against H. contortus or Trichostrongylus colubriformis, it has been suggested that the asymmetric conformation clearly influences the anthelmintic activity of CODPs. Although useful synthetic pathways are available today for the preparation of the semi-synthetic CODP emodepside, the fermentative production of its bis-para-nitro and bis-para-amino precursors could be the process used for its industrial-scale production in the future.

Animals↗

PubMed2005

Cyclohexadepsipeptides (CHDPs) with improved anthelmintical efficacy against the gastrointestinal nematode (Haemonchus contortus) in sheep.

Besides 24-membered cyclooctadepsipeptides (CODPs) with the most prominent member of this class emodepside, the structurally related 18-membered cyclohexadepsipeptides (CHDPs) were of interest with regard to their efficacy against the nematode H. contortus in sheep.The CHDPs prepared by a simple total synthesis represent enniatin derivatives with strong in vivo activity against H. contortus in sheep. The correlation between the nature of the CHDP major conformers and their anthelmintic activities was studied in detail. All CHDPs with strong in vivo activity exists in deuterochloroform solution as conformers with restricted flexibility which was found by 2D-NMR spectroscopic analysis. This reduced flexibility of the major conformer can be exemplified by CHDPs containing e.g.: (i) an unsymmetrically folded conformation with no cis-amide bound, (ii) an internal hydrogen bond or (iii) one cis-amide bond, respectively.The strong in vivo anthelmintic activity against H. contortus in sheep indicates that the stereochemistry in 2-position of CHDPs is less important for their high inding affinity. It may be assumed that the identified inflexible region of the major conformers might mimic the active conformation of these CHDPs, which could be helpful for rational design of anthelmintics with less complicated structures.

Animals↗

PubMed2005

PYY3-36 as an anti-obesity drug target.

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.

Animals↗

PubMed2004

Flow profiling of a surface-acoustic-wave nanopump.

The flow profile in a capillary gap and the pumping efficiency of an acoustic micropump employing surface acoustic waves is investigated both experimentally and theoretically. Ultrasonic surface waves on a piezoelectric substrate strongly couple to a thin liquid layer and generate a quadrupolar streaming pattern within the fluid. We use fluorescence correlation spectroscopy and fluorescence microscopy as complementary tools to investigate the resulting flow profile. The velocity was found to depend on the applied power approximately linearly and to decrease with the inverse third power of the distance from the ultrasound generator on the chip. The found properties reveal acoustic streaming as a promising tool for the controlled agitation during microarray hybridization.

Acoustics↗

PubMed2004

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Animals↗

PubMed2004

[Minimally invasive, safe treatment of the neurogenic bladder with botulinum-A-toxin in children with myelomeningocele].

PURPOSE: The efficacy and durability of botulinum-A toxin in the treatment of detrusor hyperreflexia in myelomeningocele (MMC) children was evaluated prospectively. MATERIALS AND METHODS: A total of 15 children (10 male and 5 female, mean age 5.8 years), all on clean intermittent catheterisation (CIC) due to MMC, were "non responders" to orally and intravesically administered anticholinergic medication. Pretreatment assessment included a videourodynamic evaluation, incontinence scoring and a mercaptoacetyltriglycine-3 renal scan. We injected from 10 U/kg up to a maximum of 360 U botulinum-A toxin at 25-40 sites of the detrusor, sparing the trigone. Follow-up was 24 months. All children had a urodynamic reevaluation with assessment of bladder capacity and incontinence score at 3, 9 and 12 months. RESULTS: Mean bladder reflex volume increased from 72.00 +/- 28.12 ml to 298 +/- 32.45 ml (p < 0.001). The maximal detrusor pressure decreased from 78.76 +/- 23.14 cm H(2)O to 42.76 +/- 24.34 cm H(2)O (p < 0.001). Maximal bladder capacity increased from 136.34 +/- 45.71 ml to 297.02 +/- 87.17 ml (p < 0.001). Detrusor compliance increased from 18.29 +/- 27.19 ml/cm H(2)O to 51.17 +/- 38.17 ml/mmH(2)O (p < 0.001). While 10 patients became completely dry between CIC, the remaining 2 patients improved from score 3 to 1. Results at 9 months were similar to the ones at 3 months. The mean efficacy and durability of the toxin was 10.5 months after the first intravesical injection. CONCLUSIONS: Botulinum-A toxin is a safe alternative in the management of detrusor hyperreflexia in MMC children. Preliminary results are promising concerning urodynamic parameters and continence.

Botulinum Toxins, Type A↗

PubMed2004

Cardiac ECMO for biventricular hearts after paediatric open heart surgery.

OBJECTIVE: To delineate predictors of hospital survival in a large series of children with biventricular physiology supported with extracorporeal membrane oxygenation (ECMO) after open heart surgery. RESULTS: 81 children were placed on ECMO after open heart surgery. 58% (47 of 81) were transferred directly from cardiopulmonary bypass to ECMO. Hospital survival was 49% (40 of 81) but there were seven late deaths among these survivors (18%). Factors that improved the odds of survival were initiation of ECMO in theatre (64% survival (30 of 47)) rather than the cardiac intensive care unit (29% survival (10 of 34)) and initiation of ECMO for reactive pulmonary hypertension. Important adverse factors for hospital survival were serious mechanical ECMO circuit problems, renal support, residual lesions, and duration of ECMO. CONCLUSIONS: Hospital survival of children with biventricular physiology who require cardiac ECMO is similar to that found in series that include univentricular hearts, suggesting that successful cardiac ECMO is critically dependent on the identification of hearts with reversible ventricular dysfunction. In our experience of postoperative cardiac ECMO, the higher survival of patients cannulated in the operating room than in the cardiac intensive care unit is due to early effective support preventing prolonged hypoperfusion and the avoidance of a catastrophic cardiac arrest.

Cardiopulmonary Bypass↗

PubMed2003

CL/RAMP2 and CL/RAMP3 produce pharmacologically distinct adrenomedullin receptors: a comparison of effects of adrenomedullin22-52, CGRP8-37 and BIBN4096BS.

Adrenomedullin (AM) has two known receptors formed by the calcitonin receptor-like receptor (CL) and receptor activity-modifying protein (RAMP) 2 or 3: we report the effects of the antagonist fragments of human AM and CGRP (AM22-52 and CGRP8-37) in inhibiting AM at human (h), rat (r) and mixed species CL/RAMP2 and CL/RAMP3 receptors transiently expressed in Cos 7 cells or endogenously expressed as rCL/rRAMP2 complexes by Rat 2 and L6 cells. AM22-52 (10 microM) antagonised AM at all CL/RAMP2 complexes (apparent pA2 values: 7.34+/-0.14 (hCL/hRAMP2), 7.28+/-0.06 (Rat 2), 7.00+/-0.05 (L6), 6.25+/-0.17 (rCL/hRAMP2)). CGRP8-37 (10 microM) resembled AM22-52 except on the rCL/hRAMP2 complex, where it did not antagonise AM (apparent pA2 values: 7.04+/-0.13 (hCL/hRAMP2), 6.72+/-0.06 (Rat2), 7.03+/-0.12 (L6)). On CL/RAMP3 receptors, 10 microM CGRP8-37 was an effective antagonist at all combinations (apparent pA2 values: 6.96+/-0.08 (hCL/hRAMP3), 6.18+/-0.18 (rCL/rRAMP3), 6.48+/-0.20 (rCL/hRAMP3)). However, 10 microM AM22-52 only antagonised AM at the hCL/hRAMP3 receptor (apparent pA2 6.73+/-0.14). BIBN4096BS (10 microM) did not antagonise AM at any of the receptors. Where investigated (all-rat and rat/human combinations), the agonist potency order on the CL/RAMP3 receptor was AM approximately betaCGRP>alphaCGRP. rRAMP3 showed three apparent polymorphisms, none of which altered its coding sequence. This study shows that on CL/RAMP complexes, AM22-52 has significant selectivity for the CL/RAMP2 combination over the CL/RAMP3 combination. On the mixed species receptor, CGRP8-37 showed the opposite selectivity. Thus, depending on the species, it is possible to discriminate pharmacologically between CL/RAMP2 and CL/RAMP3 AM receptors.

Adrenomedullin↗

PubMed2003

Genotyping of Clostridium perfringens isolated from domestic and exotic ruminants and swine.

Clostridium perfringens types A, B, C, D and E are known to cause severe enteritis/enterotoxaemia and diseases (especially caused by type A) belonging to the gas oedema complex in many species. Samples from the small intestine as well as faeces of domestic and exotic animals suffering from enterotoxaemic signs or having died within days after first occurance of toxaemia were submitted for typing C. perfringens toxovars by multiplex PCR. The following species have been investigated: domestic sheep (Ovis ammon; n = 10), domestic goat (Capra aegagrus hircus; n = 26), Japanese serow (Capricornis sumatraensis; n = 4), lechwe waterbuck (Hydrotragus leche; n = 1), blackbuck (Antilope cervicapra; n = 1), European reindeer (Rangifer tarandus tarandus; n = 4), domestic swine (Sus scrofa; n = 52), and collared peccary (Tayassu albirostris; n = 1). Interestingly, the predominant C. perfringens toxovar in domestic sheep was type A. This toxovar could also be diagnosed in all reindeer, in three Japanese serows, one lechwe waterbuck and most pigs (n = 47), the majority of those being at suckling age. Type D was the most prevalent toxovar (n = 18) in domestic goats, but also types A and E could be identified as pathogens in this species. Type C could only be found in domestic swine (n = 5) and in one case of clostridiosis in a Japanese serow. Two cases of enterotoxaemia in goats, one case in reindeer, and a single case in blackbuck and collared peccary were caused by C. perfringens type E. Genotyping of C. perfringens is recommended before starting vaccination programmes as it could be shown, that the importance of specific toxovars has been underestimated in specific species and/or age groups.

Animals↗

PubMed2002

Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis.

Somatostatin receptors (SSTRs) have been extensively mapped in human tumors by means of autoradiography, reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). We analyzed the SSTR type 1-5 expression by means of RT-PCR and/or IHC in a series of 81 functioning and non-functioning gastroenteropancreatic (GEP) endocrine tumors and related normal tissues. Moreover, we compared the results with clinical, pathological and hormonal features. Forty-six cases (13 intestinal and 33 pancreatic) were studied for SSTR 1-5 expression using RT-PCR, IHC with antibodies to SSTR types 2, 3, 5 and ISH for SSTR2 mRNA. The vast majority of tumors expressed SSTR types 1, 2, 3 and 5, while SSTR4 was detected in a small minority. Due to the good correlation between RT-PCR and IHC data on SSTR types 2, 3, and 5, thirty-five additional GEP endocrine tumors were studied with IHC alone. Pancreatic insulinomas had an heterogeneous SSTR expression, while 100% of somatostatinomas expressed SSTR5 and 100% gastrinomas and glucagonomas expressed SSTR2. Pre-operative biopsy material showed an overlapping immunoreactivity with that of surgical specimens, suggesting that the SSTR status can be detected in the diagnostic work-up. It is concluded that SSTRs 1-5 are heterogeneously expressed in GEP endocrine tumors and that IHC is a reliable tool to detect SSTR types 2, 3 and 5 in surgical and biopsy specimens.

Adult↗

PubMed2002

Development and potential of non-peptide antagonists for calcitonin-gene-related peptide (CGRP) receptors: evidence for CGRP receptor heterogeneity.

Calcitonin-gene-related peptide (CGRP) is a 37-amino-acid vasodilatory peptide, of which two isoforms, alpha CGRP and beta CGRP, have been described. The use of C-terminal fragments of CGRP peptide, such as human alpha CGRP-(8-37), has led to the pharmacological subdivision of CGRP receptors into CGRP-1 [high potency for binding of human alpha CGRP-(8-37)] and CGRP-2 (lower potency) receptors. We have recently developed BIBN4096BS, the first non-peptide CGRP antagonist, which has sub-nanomolar affinity for primate CGRP receptors. The use of BIBN4096BS has led to the discovery of further functional CGRP receptor heterogeneity in rat tissues. To further exploit BIBN4096BS as a pharmacological tool, we used BIBN4096BS in pig left anterior descending coronary vessels and cerebral basilar arteries, and compared functional with molecular data, characterizing CGRP receptor components. Our data show that, apart from a subdivision into CGRP-1 and -2 receptors, BIBN4096BS reveals additional functional differences between the actions of alpha CGRP and beta CGRP. However, evidence for CGRP receptor heterogeneity on a molecular level is scarce.

Animals↗

PubMed2001

Mosses share mitochondrial group II introns with flowering plants, not with liverworts.

Extant bryophytes are regarded as the closest living relatives of the first land plants, but relationships among the bryophyte classes (mosses, liverworts and hornworts) and between them and other embryophytes have remained unclear. We have recently found that plant mitochondrial genes with positionally stable introns are well suited for addressing questions of plant phylogeny at a deep level. To explore further data sets we have chosen to investigate the mitochondrial genes nad4 and nad7, which are particularly rich in intron sequences. Surprisingly, we find that in these genes mosses share three group II introns with flowering plants, but none with the liverwort Marchantia polymorpha or other liverworts investigated here. In mitochondria of Marchantia, nad7 is a pseudogene containing stop codons, but nad7 appears as a functional mitochondrial gene in mosses, including the isolated genus Takakia. We observe the necessity for strikingly frequent C-to-U RNA editing to reconstitute conserved codons in Takakia when compared to other mosses. The findings underline the great evolutionary distances among the bryophytes as the presumptive oldest division of land plants. A scenario involving differential intron gains from fungal sources in what are perhaps the two earliest diverging land plant lineages, liverworts and other embryophytes, is discussed. With their positionally stable introns, nad4 and nad7 represent novel marker genes that may permit a detailed phylogenetic resolution of early clades of land plants.

Amino Acid Sequence↗

PubMed2001

Presence of sst2(a) receptor immunoreactivity in rat ependyma and tanycytes.

Somatostatin sst2(a) receptor was observed, by immunofluorescence, in ependymal cells and in tanycytes of the wall of the ventricle and the hypothalamic recess of the male rat median eminence. Strong immunoreactivity for the receptor protein was observed in lateral tanycytes (alpha-type) while a moderate signal was seen in medial tanycytes (beta-type). In high magnification the immunoreactive material, of moderate intensity, had a coarse granular appearance. Only few of the alpha-tanycytes also displayed immunoreactive GFAP. The apical portion of the ependymal cells as well as of tanycytes contained immunoreactive S-100 (alphabeta). Since rather high levels of somatostatin are demonstrated to occur in the cerebrospinal fluid of the third ventricle, it is suggested that somatostatin via the sst2(a) receptor may regulate the physiology of tanycytes.

Animals↗

PubMed2001

Immunohistochemical localization of adenosine A1 receptors in human brain regions.

Adenosine exerts its physiological actions by binding to G-protein coupled receptors, four of which have been identified and cloned to date (A1, A2a, A2b and A3). Here we report the development of anti-human adenosine A1, receptor anti-peptide polyclonal antibodies and their use to define the distribution of A1, receptors in human brain regions, spinal cord and trigeminal ganglia by an immunohistochemical approach. Although the distribution of adenosine A1, receptor and its mRNA in the human brain has been investigated in the past by autoradiography and in situ hybridization, this is the first demonstration of localization of the A1, receptors by immunohistochemical means. Our localization data broadly agree with immunohistochemical data published for the human brain obtained using other experimental approaches. Furthermore, we have demonstrated the novel finding that abundant expression of the adenosine A1, receptor protein occurs in the trigeminal ganglia, which may be suggestive of a role of this receptor in analgesia.

Adult↗

PubMed2001

Expression of somatostatin receptor types 2, 3 and 5 in biopsies and surgical specimens of human lung tumours. Correlation with preoperative octreotide scintigraphy.

The increasingly popular use of somatostatin analogs in clinical practice for both diagnostic and therapeutic purposes prompted extensive investigations on somatostatin receptor (sst) expression in human tumors by autoradiography, nucleic acid analysis and, recently, immunohistochemistry (IHC). The currently employed radiotracer for scintigraphy (Octreoscan) is octreotide, a somatostatin analog having a high affinity for sst types 2, 3, and 5. In this study on 25 patients, we compared sst 2, 3, and 5 expression in surgical and biopsy specimens of lung tumors, as revealed by immunohistochemical and reverse transcriptase polymerase chain reaction (RT-PCR), with the octreoscan outcome (which was positive in 20/25 cases). By IHC, the tumors mainly expressed sst2 (17/25, 68%) at the cell membrane level, while sst 3 and 5 were detected in a fraction of cases (24% and 20%, respectively). Comparing RT-PCR and IHC data, a correlation was found in 83.3% of cases, while octreoscan findings and sst expression were correlated in 22/25 cases (88%). In addition, cytological and biopsy specimens expressed the same sst type found in the corresponding surgical sample, thus indicating that a cell membrane sst immunoreactivity in a biopsy reliably predicts the tumor-receptor profile before its resection. Finally, sst expression was not restricted to neuroendocrine lung tumors, but was also a feature of some non-neuroendocrine carcinomas, although to a lesser extent. The occasional expression of sst subtypes in intratumoral lymphocytes, endothelia and necrotic areas is an additional feature to be considered in the interpretation of Octreoscan findings, since the in vivo procedure does not allow to define the sst cellular distribution. IHC can therefore be usefully coupled to radionuclear investigations to better characterize the sst cellular location and subtype in lung tumors.

Adenocarcinoma↗

PubMed2001

Effect of delayed sternal closure after cardiac surgery on respiratory function in ventilated infants.

OBJECTIVE: Studies examining the effect of sternal closure on respiratory function have not been published, and currently there is little evidence to guide ventilation management immediately after closure. The aim of this study was to establish the impact of delayed sternal closure on expired tidal volume, respiratory system compliance, and CO2 elimination immediately after the procedure in infants who had undergone open heart surgery. DESIGN: Prospective study of respiratory function before and after delayed sternal closure. SETTING: Cardiac intensive care unit, Great Ormond Street Hospital, London. PATIENTS: Seventeen infants (median age, 2 wks) with open median sternotomy incisions after cardiac surgery. Data were collected between August 1998 and March 2000. INTERVENTIONS: Respiratory function was measured continuously for 30 mins before and after delayed sternal closure in paralyzed ventilated infants. MEASUREMENTS AND RESULTS: Four babies were excluded from the study because they required either immediate increase in ventilation after delayed sternal closure (n = 3) or removal of pericardial blood collection (n = 1). In the remaining 13 infants, expired tidal volume and CO2 elimination decreased significantly (p < .005) by a mean of 17% and 29%, respectively, after sternal closure. In five of the remaining 13 patients, the magnitude of tracheal tube leak increased by > or = 10% after delayed sternal closure, thereby invalidating recorded changes in respiratory system compliance. Of the eight infants in whom there was a minimal change in leak, respiratory system compliance decreased significantly (p < .05) by a mean of 19%. CONCLUSIONS: This study supports the hypothesis that respiratory function may be compromised after delayed sternal closure and that ventilatory support should be increased to counteract the anticipated decrease in tidal volume. Extra vigilance should be applied in monitoring blood gases after delayed sternal closure to assess clinical responses to sternal closure or changes in ventilatory support. Accurate assessment of change in respiratory system compliance after any therapeutic intervention may be precluded by changes in tracheal tube leak during the procedure.

Critical Care↗