Pemetrexed: mRNA expression of the target genes TS, GARFT and DHFR correlates with the in vitro chemosensitivity of human solid tumors.
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Biomedical subjects
Publications and source records attributed to L Schulz.
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INTRODUCTION: The purpose was to evaluate the effects of levetiracetam (LEV) in routine therapy in learning disabled patients with therapy-resistant epilepsy. METHODS: In an open observational add-on study design, 46 patients (residents of the Bethel Epilepsy Centre) with severe therapy-resistant epilepsy and different degrees of learning disabilities, who were treated with LEV between its introduction in Autumn 2000 and February 2002, were evaluated retrospectively. Information on monthly seizure frequencies, seizure severity and psychiatric status was extracted from the current patient case records. A 3 months baseline and a 3 months LEV treatment period (after 3 months of titration) were compared. Responders were defined as having a 50% reduction in seizure frequency and being evaluated as good or very good in an ad hoc global clinical efficacy scale. When only one criterion was positive, a careful individual decision was made based on the impact on the patients' daily activities. RESULTS: The responder rate was 41.3% (34.8 for 50% seizure reduction). It was higher in focal and multifocal epilepsy as compared to symptomatic generalised epilepsy/Lennox Gastaut Syndrome (P<0.05). Antiepileptic response occurred in doses between 500 and 4000 mg/day. Changes in seizure severity were rare. Nine patients experienced positive psychotropic effects (mostly improved vigilance and mood); six of these patients had antiepileptic effects as well. Twelve patients had adverse effects, mostly mild; in three cases, however, more severe effects led to discontinuation. CONCLUSIONS: LEV is an effective and generally well-tolerated drug for this patient group, especially in focal and multifocal epilepsy.
Crop species experienced strong selective pressure directed at genes controlling traits of agronomic importance during their domestication and subsequent episodes of selective breeding. Consequently, these genes are expected to exhibit the signature of selection. We screened 501 maize genes for the signature of selection using microsatellites or simple sequence repeats (SSRs). We applied the Ewens-Watterson test, which can reveal deviations from a neutral-equilibrium model, as well as two nonequilibrium tests that incorporate the domestication bottleneck. We investigated two classes of SSRs: those known to be polymorphic in maize (Class I) and those previously classified as monomorphic in maize (Class II). Fifteen SSRs exhibited some evidence for selection in maize and 10 showed evidence under stringent criteria. The genes containing nonneutral SSRs are candidates for agronomically important genes. Because demographic factors can bias our tests, further independent tests of these candidates are necessary. We applied such an additional test to one candidate, which encodes a MADS box transcriptional regulator, and confirmed that this gene experienced a selective sweep during maize domestication. Genomic scans for the signature of selection offer a means of identifying new genes of agronomic importance even when gene function and the phenotype of interest are unknown.
The inhibition of growth and development resulting from surgical treatment of the cleft lip and palate is a widely discussed topic. Various studies have been conducted in search of answers as to how the untreated upper jaw develops, focusing on individuals with untreated cleft lip and palate as found in so-called Third World countries. This study offers the opportunity to compile literature dealing with the research and description of untreated unilateral cleft lip and palate. The focus was to take a closer look at groups of individuals with complete unilateral cleft lip and palate, who had received no surgical treatment at all, as well as groups who had received surgical treatment of only the cleft lip. The upper jaw of untreated cleft lip and palate patients most often adopts a protruded position without enlarging the maxilla itself. The horizontal dimension tends to be reduced, whereas the vertical dimension is normal. The upper jaw of patients with unilateral cleft lip and palate who received surgical treatment of the lip more often adopted a retruded position. The model analysis showed no clear-cut tendencies. There seemed to be a degree of regional variation. Considering the relatively small number of recruitable individuals with untreated cleft lip and palate, the introduction of a standard method of evaluation is desirable. This would significantly facilitate the comparison of different studies with each other in the future. The first steps in this direction have already been initiated.
An algorithm for assessments of fuzzy molecular structural characteristics has been presented, and its chemical relevance is approved for numerous evidences of reaction mechanisms. Empirical rules pervading the results of chemical synthesis are continuously the source of information efficiently used by experimental chemists and technologists. Approaching them theoretically to broaden areas of applicability and to make them more precise for better prediction is of great importance to reach progress in the chemical information recognition and to steer and control technological processes. Fuzzy sets called splitting and overlapping have been applied for assessments of the reaction hazards. The mathematically grounded properties turned out to underlie well-known empirical rules for preliminary estimations of organic reaction tendencies. Informative quantitative data shown are revealing new ways of understanding basic chemical reaction mechanisms.
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Although skeletal muscle abnormalities have been described in association with human immunodeficiency virus (HIV), the effects of HIV infection on respiratory muscle function have not been well characterized. We hypothesized that HIV+ individuals may develop respiratory muscle weakness and that respiratory muscle dysfunction may contribute to the unexplained dyspnea that occurs in the setting of HIV. To test this hypothesis we studied maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), inspiratory muscle endurance, and respiratory symptoms in 23 HIV+ male outpatients who had no history of acquired immune deficiency syndrome (AIDS)-related pulmonary complications, with a CD4+ T-lymphocyte count of 331.6 +/- 62.1 (mean +/- SEM). Respiratory muscle endurance was measured with an incremental threshold loading (ITL) protocol. We compared these results to those for 14 HIV- males matched for age and weight. Compared with the controls, HIV+ subjects had a significantly lower mean MIP (98.7 +/- 7.4 versus 121.4 +/- 9.3 cm H2O, p < 0.05) and MEP (115.0 +/- 9.3 versus 152.1 +/- 14.8 cm H2O, p < 0.05). Furthermore, during ITL, the mean load at task failure in the HIV+ group was 295.7 +/- 36.2 g, versus 405.8 +/- 52.2 g in the control group (p < 0.05). In the HIV+ subjects there was no relationship between muscle performance and CD4+ count or azidothymidine (AZT) use. There was, however, a highly significant relationship between respiratory muscle dysfunction and symptoms of dyspnea. We conclude that HIV seropositivity is associated with a decline in respiratory muscle performance. This impairment in respiratory muscle function may contribute to the feeling of breathlessness that has been well described in this patient population.
Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) is a deoxycytidine (dCyd) analog that extensively modulates intracellular CTP and dCTP metabolism. In Chinese hamster ovary (CHO) cells, a 4-hour exposure to gemcitabine (100 mumol/L) reduced cellular CTP and dCTP concentrations to 5.9% and 50%, respectively. Intracellular UTP concentrations increased, indicating a metabolic block at CTP synthetase. Pool-sizes of ATP and GTP remained unaffected. In contrast, a CHO mutant deficient in deoxycytidine kinase, and thus unable to accumulate dFdCTP, maintained its CTP pools under identical conditions, suggesting that the CTP pool depletion was dependent on dFdC phosphorylation. Neither 100 mumol/L arabinosylcytosine nor 5 mmol/L hydroxyurea affected CTP levels, indicating that inhibition of DNA synthesis by analog incorporation or by depletion of dNTP pools were not the causes of the CTP pool perturbation. Metabolic studies demonstrated that incorporation of [3H]uridine into the UTP pool was not impaired by dFdC treatment, whereas the specific activity of the CTP pools decreased as a function of increasing gemcitabine concentration and time of exposure. Comparable results were obtained using 3-deazauridine, a known inhibitor of CTP synthetase. We conclude that high cellular concentrations of dFdCTP deplete cellular CTP concentrations by inhibition of the dCTP pool and also may be a limiting factor for RNA synthesis.
A similar plaque inhibition by was found after daily topical application of CHX or AmF/SnF2 in comparison with a placebo on rats. The fluoride combination exhibited a significant caries protective influence which was equal to AmF when the last was used in the same concentration. More concentrated AmF has shown a higher caries reducing effect and higher fluoride accumulation in the enamel surface layer of teeth. AmF/SnF2 could been recommended to individual plaque control with parallel caries protective effect.
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In parallel with the study on the correlation between increased mucosal permeability and the secretagogue effect of deoxycholate on the perfused rat colon, we examined the mucosal morphology by scanning and transmission electron microscopy. Dependent on concentration (2, 4, and 8 mmol/l), the treated mucosa showed structurally altered 'ballooned' absorptive cells, severely injured sloughing cells, and exfoliated cells lying on the surface. In spite of these changes, the continuity of the epithelial lining was maintained. Patchy defects exposing the lamina densa of the basement membrane could be observed only in specimens artificially altered by cell loss through vigorous rinsing. Clusters of extruded cells were still seen attached to the mucosal surface in the region between the openings of neighbouring crypts when net transfer of fluid and permeability after a period of recovery had returned to control levels. These findings support the hypothesis that fluid filtration during perfusion with deoxycholate occurs via a paracellular pathway through a leaky, damaged epithelium.
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1. The effect of deoxycholate and cholera toxin on the transfer of water, sodium, potassium and chloride and on mucosal permeability was studied in perfusion experiments on rat colon in vivo. The influence of both secretagogues on surface morphology was assessed by scanning electron microscopy. 2. Deoxycholate turned the absorption of water, sodium and chloride to secretion and enhanced potassium secretion. Cholera toxin induced water and sodium secretion, inhibited chloride absorption and enhanced potassium secretion. 3. Deoxycholate increased reversibly the mucosal permeability as measured by the colonic clearance of 51CrEDTA and glucose, whereas cholera toxin decreased the colonic 51CrEDTA clearance. 4. Deoxycholate caused protrusion of the luminal cell surface and an increase of exfoliation of epithelial cells. The epithelial continuity was preserved. The only change induced by cholera toxin was an enhanced mucus extrusion. 5. Our results are consistent with the view that deoxycholate causes fluid secretion by filtration whereas cholera toxin enhances the secretory activity of the epithelium.
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The ependymal surface of the area postrema (rabitt) was examined by scanning and transmission electron microscopy. The flattened ependymal cells show few microvilli. Towards the central canal, the ependymal cells change gradually to a columnar shape; the number of microvilli increases concomitantly. The area postrema ependymal cell surface mostly bears a single cilia. In contrast, a region immediately adjacent to the area postrema, which has been named area subpostrema (Gwyn and Wolstencroft 1968), shows cilia arranged in bunches. These cilia are regularly covered with colloid -- like droplets. A period-acid-bisulfit-aldehydthionine method (Specht 1970) permits to identify these droplets with glyproteids.it has been suggested that the droplets might derive from the area subpostrema ependymal cells. Above the ependymal surface of the area postrema, a great number of fine unmyelinated neuronal processes and thicker processes are observed. Some of them show bulb-like endings. These terminals contain small vesicles, dense cored vesicles (400...800 A), and mitochondria which are mostly characterized by a single central prismatic tubule. The plasmalemma of some bulbs is in a synaptic contact with the apical plasmalemma of the ependyma, while other bulbs see to end freely in the ventricle. Some neuronal processes penetrate between ependymal cells of the area postrema into the ventricular lumen.
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