[Circularly arrayed peripheral spots on the iris].
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Diagnosis, Differential↗
Biomedical subjects
J Reinhard
Publications and source records attributed to J Reinhard.
[Unclear atrophy of the optic nerve].
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Adult↗
Effect of visual restitution training on absolute homonymous scotomas.
The authors examined 16 patients with stable homonymous visual field defects (HVFDs) with static automated perimetry (SAP). Training effect E was defined as difference of the proportions of absolutely defective locations in all test locations, before and after visual restitution training (VRT). E was 0.05 +/- 0.05 (mean +/- SD). The authors observed a relevant training effect (E >or= 0.12) in two subjects, but only monocularly. VRT has little effect on absolute HVFDs in SAP.
Adult↗
Development of a single unit extended release formulation for ZK 811 752, a weakly basic drug.
ZK 811 752, a potent candidate for the treatment of autoimmune diseases, demonstrated pH-dependent solubility. The resulting release from conventional matrix tablets decreased with increasing pH-values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Three different polymers were used as matrix formers, the partly water-soluble and poorly swellable mixture of polyvinylacetate/polyvinylpyrrolidone, the water-insoluble and almost unswellable ethylcellulose (EC) and the water-soluble and highly swellable hydroxypropyl methylcellulose (HPMC). To solve the problem of pH-dependent solubility different organic acids, such as fumaric, tartaric, adipic, glutaric and sorbic acid were added to the drug-polymer system. The addition of organic acids to all three matrix formers was found to maintain low pH-values within the tablets during release of ZK 811 752 in phosphate buffer pH 6.8. Thus, the micro-environmental conditions for the dissolution of the weakly basic drug were kept almost constant. An extended release matrix tablet for ZK 811 752 consisting of drug, polymer and organic acid providing the desired pH-independent drug release has been developed.
Chemistry, Pharmaceutical↗
Does visual restitution training change absolute homonymous visual field defects? A fundus controlled study.
AIM: To examine whether visual restitution training (VRT) is able to change absolute homonymous field defect, assessed with fundus controlled microperimetry, in patients with hemianopia. METHODS: 17 patients with stable homonymous visual field defects before and after a 6 month VRT period were investigated with a specialised microperimetric method using a scanning laser ophthalmoscope (SLO). Fixation was controlled by SLO fundus monitoring. The size of the field defect was quantified by calculating the ratio of the number of absolute defects and the number of test points; the training effect E was defined as the difference between these two ratios before and after training. A shift of the entire vertical visual field border by 1 degrees would result in an E value of 0.14. RESULTS: The mean training effect of all right eyes was E = 0.025 (SD 0.052) and all left eyes E = 0.008 (SD 0.034). In one eye, a slight non-homonymous improvement along the horizontal meridian occurred. CONCLUSIONS: In one patient, a slight improvement along the horizontal meridian was found in one eye. In none of the patients was an explicit homonymous change of the absolute field defect border observed after training.
Adult↗
Monosaccharide-linked inhibitors of O(6)-methylguanine-DNA methyltransferase (MGMT): synthesis, molecular modeling, and structure-activity relationships.
A series of potential inhibitors of the human DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) were synthesized, characterized in detail by NMR, and tested for their ability to deplete MGMT activity in vitro. The new compounds, omega-[O(6)-R-guan-9-yl]-(CH(2))(n)-beta-d-glucosides with R = benzyl or 4-bromothenyl and omega = n = 2, 4,. 12, were compared with the established inhibitors O(6)-benzylguanine (O(6)-BG), 8-aza-O(6)-benzylguanine (8-aza-BG), and O(6)-(4-bromothenyl)guanine (4-BTG), which exhibit in an in vitro assay IC(50) values of 0.62, 0.038, and 0.009 microM, respectively. Potential advantages of the glucosides are improved water solubility and selective uptake in tumor cells. The 4-BTG glucosides with n = 2, 4, 6 show moderate inhibition with an IC(50) of ca. 0.5 microM, while glucosides derived from BG and 8-aza-BG showed significantly poorer inhibition compared to the parent compounds. The 4-BTG glucosides with n = 8, 10, 12 were effective inhibitors with IC(50) values of ca. 0.03 microM. To understand this behavior, extensive molecular modeling studies were performed using the published crystal structure of MGMT (PDB entry: ). The inhibitor molecules were docked into the BG binding pocket, and molecular dynamics simulations with explicit water molecules were carried out. Stabilization energies for the interactions of specific regions of the inhibitor and individual amino acid residues were calculated. The alkyl spacer is located in a cleft along helix 6 of MGMT. With increasing spacer length there is increasing interaction with several amino acid residues which play an important role in the proposed nucleotide flipping mechanism required for DNA repair.
Cell-Free System↗
Inactivation of O(6)-methylguanine-DNA methyltransferase by glucose-conjugated inhibitors.
The DNA-repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a decisive determinant of resistance of tumor cells to methylating and chloroethylating anti-cancer drugs. Therefore, selective inhibition of MGMT in tumors is expected to cause tumor sensitization. Several inhibitors of MGMT have been developed which function in both tumors and normal tissue. To deplete MGMT preferentially in tumors, strategies to target the inhibitor to the tumor tissue need to be developed. Here, we report on the properties of glucose-conjugated MGMT inhibitors that might be useful for tumor targeting since tumor cells frequently over-express glucose transporter. O(6)-Benzylguanine (O6BG), 8-aza-O(6)-benzylguanine, O(6)-(4-bromothenyl)-guanine (O6BTG) and the corresponding spacer-linked beta-D-glucose conjugates were analyzed comparatively for MGMT-inhibitory activity. Substitution at the N9 position of the purine moiety resulted generally in a reduction in the efficiency with which the inhibitors blocked MGMT. However, the inhibitory activity of the O6BTG conjugates increased with increasing spacer length, and O6BTG conjugated with a C8 spacer with beta-D-glucose was nearly as effective as O6BTG on its own. MGMT was inhibited by the conjugates both in crude cell extracts and upon treatment of intact HeLa cells, indicating efficient uptake of the glucose conjugates into cells. Since the O6BTG-C8-D-glucose conjugate 8-[O(6)-(4-bromothenyl)-guan-9-yl]-octyl-beta-D-glucoside was highly efficient at MGMT inhibition in a non-toxic concentration range, the drug might be a useful tool for specific tumor sensitization.
Enzyme Inhibitors↗
The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.
Animals↗
Inter-hospital transportation of patients with severe acute respiratory failure on extracorporeal membrane oxygenation--national and international experience.
OBJECTIVE: To evaluate the experiences and results from inter-hospital transportation of patients with acute respiratory failure on extracorporeal membrane oxygenation (ECMO). DESIGN: Observational, descriptive study. SETTING: Tertiary referral center in a University Hospital. SUBJECTS AND METHODS: When standard ECMO criteria were fulfilled and the patient considered too unstable for a conventional transport, the mobile ECMO team cannulated the patient for ECMO at the referring hospital. The patients were then transported to our ECMO center by ground ambulance, helicopter or fixed-wing vehicle. Patients were also transported on ECMO from our ECMO center to other centers due to shortage of available ECMO beds. RESULTS: 29 patients (15 neonates, seven pediatric, and seven adult patients) with acute respiratory failure were transported on ECMO on a total of 30 occasions. Median time from arrival of the ECMO team at the referring hospital until the patient was on ECMO (28 patients) was 2.2 h (range 1.25-4.25 h). The median time that the transport team was out was 10 h (range 5.5-36.5 h) and the median time with the patient was 6 h (range 3-30.5 h). The distance of transport ranged from 4-1,500 km. Six transports were international. No patient complications occurred during the transports. Two technical complications related to the transport vehicle were encountered. One ambulance compressor malfunctioned. During one helicopter transport, one out of two electric supply circuits malfunctioned. The patients were not affected. Twenty-one of the 29 patients survived to discharge (72%). None of the deaths was transport related. CONCLUSIONS: Tertiary intensive care units and ECMO centers require a dedicated transport team. ECMO transports can be performed safely for all age groups for long distances, probably throughout most of Europe.
Acute Disease↗
Food exploitation in termites: indication for a general feeding-stimulating signal in labial gland secretion of isoptera.
The paired labial glands are located in all termite species in the thorax. During food exploitation workers of the French termite Reticulitermes santonensis and the African termite Schedorhinotermes lamanianus release the secretion of their labial glands directly onto the food. The secretion carries a water-soluble, heat-resistant, nonvolatile signal that stimulates gnawing and feeding and leads to aggregations of feeding workers. In a feeding bioassay, extracts of the labial glands of 11 termite species from five families all proved to have this feeding-stimulating effect both on R. santonensis and S. lamanianus. The heat resistance of the feeding-stimulating signal also could be shown for selected species from all termite families tested. A combined thin layer chromatography-feeding bioassay on cellulose TLC plates showed that after chromatography of labial gland secretion, the feeding-stimulating signal is located in all 11 species in the same area from Rf 0.46 to 0.88. An extract of labial glands of cockroaches stimulated feeding in R. santonensis and S. lamanianus as well, but was not active after heat treatment and after TLC. This points towards a general feeding-stimulating signal having evolved only in the labial gland secretion of termites.
Animals↗
Thin-layer chromatography assessing feeding stimulation by labial gland secretion compared to synthetic chemicals in the subterranean termite Reticulitermes santonensis.
The labial gland of the French subterranean termite Reticulitermes santonensis De Feytaud contains a polar, heat-resistent, and persistent chemical signal that is released onto the food during food exploitation and stimulates feeding in nestmates. Separation of the labial gland secretion by thin-layer chromatography on cellulose plates revealed that the secretion contains components with reducing and amino groups. In feeding bioassays conducted on the cellulose plate after TLC, termites preferred the area between Rf 0.46 and 0.88 (biologically active zone) for feeding, indicating the location of the feeding-stimulating signal. Thirty-five synthetic chemicals with similar chemical properties as the feeding-stimulating signal were analyzed with TLC. None of them covered the biologically active zone. Therefore, all chemical classes tested, such as sugars, amino acids, and salts, are unlikely as possible sources for the signal structure. In feeding choice tests with synthetic chemicals, termites showed clear feeding preference only for sugarlike components with physiologically excessive concentrations of 10 mmol and 100 mmol. Amino acids induced only light feeding preference. The intensity of feeding stimulation by the natural signal from the labial gland as compared to synthetic phagostimulants is discussed.
Animals↗
Evaluation of the rhodopsin knockout mouse as a model of pure cone function.
PURPOSE: To determine a time window in the rhodopsin knockout (Rho(-/-)) mouse during which retinal function is already sufficiently developed but cone degeneration is not yet substantial, thus representing an all-cone retina. METHODS: Electroretinograms (ERGs) were obtained from 14 homozygous Rho(-/-) mice and eight C57Bl/6 control mice. The same individuals were tested every 7 days, beginning as early as postnatal day (P)14. The ERG protocols included flash and flicker stimuli, both under photopic and scotopic conditions. Retinal and choroidal morphology was observed in animals of comparable age. RESULTS: Functionally, the developmental phase lasted until postnatal week (PW)3 in both the Rho(-/-) mice and the control animals. During PW4 to 6, the Rho(-/-) mice showed a plateau in ERG parameters with normal or even supernormal cone responses and complete absence of rod contributions. At PW7, there was a marked onset of degeneration, which progressed so that no ERG signals were left at PW13, when the control eyes still had normal ERG responses. Microscopically, cone degeneration paralleled the functional changes, beginning at approximately PW6 and almost complete at PW13, whereas retinal pigment epithelium (RPE) and choroid did not show any abnormalities. CONCLUSIONS: From PW4 to 6, Rho(-/-) mice appear to have normal cone and no rod function. Despite the missing rod outer segment (OS), the structure of retina, RPE, and choroid remained unchanged. Therefore, the Rho(-/-) mice can serve during this age period as a model for pure cone function. Such a model is particularly useful to evaluate rod-cone interaction and to dissect rod- from cone-mediated signaling pathways in vivo.
Animals↗
Clonal culture of fetal cells from maternal blood.
Successful isolation and genetic testing of fetal cells obtained from maternal blood could eliminate the risks associated with invasive prenatal testing. We used clonal in-vitro expansion of fetal haemopoietic cells and micromanipulation and fluorescent PCR of single colonies to obtain pure fetal colonies from peripheral blood of 12 healthy pregnant women. Of 2966 randomly selected colonies, 42 contained fetal and other cells and, for four women, two to four colonies each contained purely fetal cells. Detection of fetal cells has been hampered by rarity in maternal blood, but with our approach many cells are available for analysis.
Cells, Cultured↗
High survival in adult patients with acute respiratory distress syndrome treated by extracorporeal membrane oxygenation, minimal sedation, and pressure supported ventilation.
OBJECTIVES: To evaluate the results of treatment of severe acute respiratory distress syndrome (ARDS) with extracorporeal membrane oxygenation (ECMO), minimal sedation, and pressure supported ventilation. DESIGN AND SETTING: Observational study in a tertiary referral center, Intensive Care Unit, Astrid Lindgren Children's Hospital at Karolinska Hospital, Stockholm, Sweden. SUBJECTS AND METHODS: Seventeen adult patients with ARDS were treated with venovenous or venoarterial ECMO after failure of conventional therapy. The Murray score of pulmonary injury averaged 3.5 (3.0-4.0) and the mean PaO2/FIO2 ratio was 46 (31-65). A standard ECMO circuit with nonheparinized surfaces was used. The patients were minimally sedated and received pressure-supported ventilation. High inspiratory pressures were avoided and arterial saturation as low as 70% was accepted on venovenous bypass. RESULTS: In one patient a stable bypass could not be established. Among the remaining 16 patients 13 survived (total survival rate 76%) after 3-52 days (mean 15) on bypass. Major surgical procedures were performed in several patients. The cause of death in the three nonsurvivors was intracranial complications leading to total cerebral infarction. CONCLUSION: A high survival rate can be obtained in adult patients with severe ARDS using ECMO and pressure-supported ventilation with minimal sedation. Surgical complications are amenable to surgical treatment during ECMO. Bleeding problems can generally be controlled but require immediate and aggressive approach. It is difficult or impossible to decide when a lung disease is irreversible, and prolonged ECMO treatment may be successful even in the absence of any detectable lung function.
Adolescent↗
Image analysis method to assess adhesion of Helicobacter pylori to gastric epithelium using confocal laser scanning microscopy.
We have used confocal scanning microscopy of FITC-labelled bacteria to assess binding of Helicobacter pylori to stomach sections and to assess the effect of inhibitors on binding to the Lewis antigens. We have quantified the binding using an image manipulation package that is readily available on the web. Our results demonstrate heterogeneity of binding of Helicobacter pylori to tissue sections and that binding can be inhibited using synthetic Lewis B oligosaccharide.
Bacterial Adhesion↗
Continuous monitoring of the stimulated area in multifocal ERG.
INTRODUCTION: Multifocal electroretinography (MF-ERG) is widely used in the detection of local retinal dysfunction. However, the position of the stimulus on the retina and the stability of fixation are usually not directly accessible. Thus, devices have been designed for a continuous fundus visualization during recording. METHODS: MF-ERGs were recorded with a RetiScan system connected to two different Scanning-laser ophthalmoscopes (SLOs) that use either a red (633 nm) or green (415 nm) laser for stimulation, and a VERIS 4 system connected to a piggyback stimulator prototype that added the stimulus to the optical pathway of the SLO by means of a wavelength-sensitive mirror. Fundus visualization was achieved with the infrared lasers of the SLOs (780 and 835 nm). RESULTS: The most extensive study so far with a green laser stimulus in a cat model of retinal degeneration demonstrated the capability of the device to detect retinal landmarks and the different stages of degeneration. Also, the advantages of exactly reproducible stimulus positioning for averaging within and comparison between disease groups became apparent. The results with the same setup in transgenic mice suggest a pure cone origin of the responses. In humans, recordings show that fixation is sufficiently good in most subjects. It is not clear yet whether red or green laser stimulation (or both) is preferable. The results with the prototype were very similar to the MF-ERGs obtained with a standard CRT screen. CONCLUSIONS: All three devices allowed us to record MF-ERGs with continuous fundus monitoring. Although further refinements are necessary, it is obvious that fundus controlled methods will improve the reliability of MF-ERG in future research on glaucoma, transplantation studies, and evaluation of gene therapy.
Journal Article↗
Density correlations in lattice gases in contact with a confining wall
A discrete version of classical density functional theory applicable to lattice gases or Ising spin systems is proposed, which accounts for the requirement of particle-hole symmetry in the presence of pairwise forces. Results of our theory for density profiles and two-particle correlation functions in two-dimensional strip geometries compare favorably with Monte Carlo simulations. Some problems with standard "weighted-density" approximation schemes, when applied to lattice gases, are pointed out.
Journal Article↗
Continuous monitoring of the stimulated area in multifocal ERG.
INTRODUCTION: Multifocal electroretinography (MF-ERG) is widely used in the detection of local retinal dysfunction. However, the position of the stimulus on the retina and the stability of fixation are usually not directly accessible. Thus, devices have been designed for a continuous fundus visualization during recording. METHODS: MF-ERGs were recorded with a RetiScan system connected to two different Scanning-laser ophthalmoscopes (SLOs) that use either a red (633 nm) or green (415 nm) laser for stimulation, and a VERIS 4 system connected to a piggyback stimulator prototype that added the stimulus to the optical pathway of the SLO by means of a wavelength-sensitive mirror. Fundus visualization was achieved with the infrared lasers of the SLOs (780 and 835 nm). RESULTS: The most extensive study so far with a green laser stimulus in a cat model of retinal degeneration demonstrated the capability of the device to detect retinal landmarks and the different stages of degeneration. Also, the advantages of exactly reproducible stimulus positioning for averaging within and comparison between disease groups became apparent. The results with the same setup in transgenic mice suggest a pure cone origin of the responses. In humans, recordings show that fixation is sufficiently good in most subjects. It is not clear yet whether red or green laser stimulation (or both) is preferable. The results with the prototype were very similar to the MF-ERGs obtained with a standard CRT screen. CONCLUSIONS: All three devices allowed us to record MF-ERGs with continuous fundus monitoring. Although further refinements are necessary, it is obvious that fundus controlled methods will improve the reliability of MF-ERG in future research on glaucoma, transplantation studies, and evaluation of gene therapy.
Animals↗