[Side-effects in nitrothiamidazole (Ambilihar) therapy].
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Angina Pectoris↗
Biomedical subjects
C Roth
Publications and source records attributed to C Roth.
L-lactate protects in vitro acetylcholinesterase (AChE) from inhibition by paraoxon (E 600).
Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Oximes are the only enzyme reactivators clinically available. Recent work has shown that lactate is able to reduce in vitro the POX effects on butyrylcholinesterase (BChE). Most of the acute clinical symptoms, however, are caused by inhibition of acetylcholinesterase (AChE). Effects of lactate on the inhibition of AChE by POX were assessed in vitro in plasma of 12 (six male, six female) healthy human volunteers. The determinations were repeated using different lactate and different POX concentrations. The AChE activity determinations were performed in the following settings: (BL) baseline (untreated plasma); (a) after addition of POX to plasma (pl + POX); (b) after POX and plasma were incubated and then lactate was added (pl + POX/lact); (c) after addition of lactate to plasma (pl + lact); (d) after lactate and plasma were incubated and then POX was added (pl + lact/POX); (e) after lactate and POX were incubated and then added to plasma (lact + POX/pl). In the micro- and millimolar ranges, lactate is able to protect in vitro AChE from inhibition by POX when added to human plasma prior to POX or when incubated with POX prior to addition to plasma. Lactate added to plasma after POX has no protective effect. In a second set of experiments, the effect of lactate on AChE activity was determined. At high millimolar concentrations, lactate itself inhibits AChE non-competitively (mixed inhibition) to an extent comparable to POX (inhibition constant K(I) = 254 mM).
Acetylcholinesterase↗
Pralidoxime and l-lactate effects in vitro on the inhibition of acetylcholinesterase by paraoxon: pralidoxime does not confer superior protection.
Intoxication with the organophosphorus compound paraoxon (POX), an inhibitor of serine hydrolases, is frequent. Although oximes are the only enzyme reactivators presently available, clinical experience with their use was rather disappointing. Recent work has shown that under certain conditions l-lactate is also able to reduce in vitro the POX inhibition of butyrylcholine- and acetylcholineesterase (BChE and AChE). To assess the practical relevance, if any, of these findings, the protective effects of pralidoxime (PRX) and those of lactate had to be compared in the same in vitro model. Effects of PRX on the inhibition of AChE by POX were assessed in vitro in plasma of 12 (six male and six female) healthy human volunteers. The determinations were repeated using different oxime and different POX concentrations. The AChE activity determinations were performed using the following sampler: sample BL-baseline (or untreated plasma); sample a-after addition of POX to plasma (pl + POX); sample b-after POX and plasma were incubated and then oxime was added (pl + POX/PRX); sample c-after addition of oxime to plasma (pl + PRX); sample d-after oxime and plasma were incubated and then POX was added (pl + PRX/POX); sample e-after oxime and POX were incubated and then added to plasma (PRX + POX/pl). Results were corrected for spurious enzyme 'pseudo-activity' due to interaction between PRX and substrate (acetylthiocholine) in the absence of enzyme. In the micro- and millimolar ranges, PRX is able to protect in vitro AChE from inhibition by POX when added to human plasma prior to POX or when incubated with POX prior to addition to plasma. Adding PRX to plasma after POX has no protective effect. The PRX results were compared statistically with historical lactate data (obtained under identical conditions) using the Wilcoxon matched pairs test, with significance assumed for p = 0.01. No difference between PRX and lactate's protective effect on the AChE inhibition by POX was found in the in vitro model used. We therefore conclude that in vivo testing of lactate as a POX protective agent is warranted.
Acetylcholinesterase↗
Characterization of amphotericin B aerosols for inhalation treatment of pulmonary aspergillosis.
In recent years, the incidence of invasive pulmonary aspergillosis has increased in patients receiving immunosuppressive therapy and/or organ transplantation. For prophylaxis against Aspergillus infections, amphotericin B may be a useful drug when inhaled as aerosol. In this study, the aerosolization of amphotericin B was investigated using eight different medical nebulizers under various operating conditions and with different amphotericin B concentrations in the solution. The output of each nebulizer was characterized by the mass flow of spray (drug) leaving the mouthpiece and by the size distribution of the droplets. An effective prevention of pulmonary aspergillosis via amphotericin B inhalation requires a high pulmonary deposition of the drug within an acceptable time of administration associated with a low deposition in the oropharyngeal region. To evaluate the dosages of drug delivered by various types of nebulizers to different regions of the respiratory tract, a semi-empirical deposition model was applied which is based on experimental aerosol deposition data from over 20 normal adults. The main results of the study are: Solutions with amphotericin B concentrations up to 10 mg/ml can be converted into sprays by means of medical nebulizers without any problems. For most nebulizers, the slight foaming of the amphotericin B solution has no effect on the production of the aerosol. To optimize amphotericin B treatment of the lungs via inhalation, sprays with mass flows above 100 mg/min and with mass median aerodynamic diameters (MMAD) below 3 microns should be slowly inhaled by the subject. Applying these criteria to the nebulizers investigated, three out of eight devices have proved suitable for amphotericin B treatment via inhalation.
Administration, Inhalation↗
A novel approach to the induction of specific cytolytic T cells in vivo.
The induction of specific cytotoxic T lymphocytes (CTL) is one component in the immune response which can effectively protect the host against the progression of many viral infections. CTL are also known to play an important role in immune defence against tumour growth. CTL induction is dependent the presence of the specific antigen, appropriately presented, and interleukin-2 (IL2), provided by T helper lymphocytes. We studied the specific CTL response induced by tumour cells transfected with murine IL2. Our results show that tumour cells manipulated to secrete IL2 induce an improved specific anti-tumour response which results in tumour rejection in mice. To further investigate the effect of IL2 on the CTL response to different antigens, we introduced synthetic peptides into IL2-secreting tumour cells and determined the specific CTL induction in syngeneic mice immunized with these cells. We report here that such IL2-secreting cells can effectively prime peptide-specific CTL in vivo. Our data are relevant to immunotherapy and vaccine development and open up the possibility that autologous cells, manipulated to secrete IL2 and located with one or a cocktail of peptides, could be used to stimulate a specific CTL response.
Animals↗
Antigenic variation in Trypanosoma equiperdum.
Trypanosoma equiperdum is an African trypanosome that causes dourine in horses. Like the other African trypanosomes, T. equiperdum escapes elimination by the immune system of its host by using an elaborate system of antigenic variant. The trypanosomes are covered by a coat consisting of a single protein called the variable surface glycoprotein (VSG) that acts as the major trypanosome immunogen. As the host responds to one VSG, trypanosomes covered with another VSG become dominant. There is a loose order of appearance of these VSG during the infection. The factors that affect the timing of VSG expression and the effective size of the VSG repertoire in T. equiperdum are reviewed. The VSG genes are generally activated by a process of duplicative transposition involving the duplication of a silent VSG gene and inserting a copy of the gene into an expression site. The order of VSG expression is related to the amount of homology between the silent gene and the expression site. The genes expressed late in infection lack extensive homology with the expression site and depend on homology with the gene in the expression site. The genes coding for VSG expressed late in infection are hybrid genes because of this mode of transfer. This transfer mechanism allows the trypanosome to create complex VSG genes from parts of several different silent genes that are each pseudogenes. Additionally, data are presented showing that only a limited portion of the VSG is actually seen by the host immune system. These factors indicate that the effective VSG repertoire is greater than the number of VSG genes in the trypanosome genome.
Animals↗
Public idiotopes and/or internal images in the anti-poly(Glu60Ala30Tyr10) response: analysis by monoclonal antibodies.
From BALB/c mice immunized with BALB/c polyclonal anti-GAT antibodies, we have obtained monoclonal antiidiotypic antibodies directed against public idiotopes expressed following GAT (Glu60Ala30Tyr10) immunization in all individuals of all mouse strains tested. Nine monoclonal anti-Id antibodies were studied in detail. One of these monoclonals recognizes only polyclonal anti-GAT antibodies; the other eight recognize polyclonal anti-GAT antibodies and monoclonal anti-GAT antibodies. The distribution of the structures recognized by the different monoclonal anti-Id on a battery of twenty monoclonal anti-GAT antibodies allows a definition of two families of public idiotopes. The significance of the existence of these two families is discussed in light of the hypothesis recently proposed by Jerne et al. (EMBO J., 1982, 1, 243-247) who consider that the induction of internal images of antigen during immunization leading to the production of antiidiotypic reagents is responsible for the existence of public idiotopes. Our present results may be interpreted to indicate that even though certain monoclonal anti-Id reagents could be internal images of the antigen, the others do, in fact, recognize public idiotopes. Therefore, the notion of internal image does not exclude the existence of public idiotypic specificities.
Animals↗
The internal image and the structural idiotypic network (Ab1, Ab2, Ab3) in the GAT system.
The GAT repertoire expressed at the different levels of the classical idiotypic cascade Ag----Ab1----Ab2----Ab3 has been analysed by direct nucleotide sequencing of H- and L-enriched mRNA. Ab1 and Ab3 expressing the major public idiotypes used similar, if not identical, VH and VK genes. The VH Ab3 of the Ab1 type (Ab1') appeared highly conserved. Ab2 also use a small number of germ-line genes. The D region of Ab2 is of particular interest since it contains either a Tyr-Tyr-Glu or a Glu-Glu-Tyr sequence, characteristic of the GAT major determinants. It is therefore suggested that this D region contains the internal image of the antigen. A large number of VH germ-line genes have been isolated and sequenced. They all pertain to the VH-II family, which contains a large number of members, some of them being very close in sequence.
Amino Acid Sequence↗
Is there a germ-line network? The "GAT" case.
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Animals↗
Cancer immunotherapy by direct in vivo transfer of immunomodulatory genes.
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Adenoviridae↗
Stable expression of two variable surface glycoproteins by cloned Trypanosoma equiperdum.
African trypanosomes are thought to evade the host immune system by periodically changing their variable surface glycoprotein (VSG). VSG genes are activated by a complex process involving the duplicative transposition of silent basic copy genes to one of several expression sites. These expression-linked copies (ELCs) of the VSG genes are also subject to regulation within expression sites by as yet unknown mechanisms. It is generally assumed that trypanosomes can express only one VSG gene at a time. Nevertheless, the finding that they contain multiple VSG gene expression sites suggests that multiple expression is possible. We show here that Trypanosoma equiperdum can stably express two VSG genes in a simple axenic culture system and that both antigens are present on the cell surface. The two antigens do not co-cap or form heterodimers. Their corresponding genes show no cross-hybridization and are situated in different telomere-linked expression sites. Northern blot analysis reveals that both genes are active in the double expressors.
Animals↗
[Cranial irradiation induces premature activation of the gonadotropin-releasing-hormone].
BACKGROUND: CNS-irradiation in prepubertal children with leukemia or brain tumors can lead to precocious or in high doses to delayed puberty. The underlying mechanisms of these disorders are unknown. METHODS: A new animal model of experimentally induced pubertal disorders by cranial irradiation has been developed. In infantile or juvenile (12 - 23 days old) female rats precocious or delayed puberty have been induced by selective cranial Co60-irradiation (4 - 18 Gy). At age of 32 - 38 days or 3 months relevant hormone parameters have been studied basal and after stimulated conditions. RESULTS: Low radiation doses (5 or 6 Gy) led to accelerated onset of puberty as well as elevated LH- and estradiol levels. High radiation doses (9 - 18 Gy) caused retardation of sexual development, lower gonadotropin levels and growth retardation associated with growth hormone deficiency. After cranial irradiation with 5 Gy the release rates of the inhibitory neurotransmitter gamma-aminobutyric-acid (GABA) from hypothalamic explants were significantly lower (p < 0,05). The gonadotropin-releasing-hormone (GnRH) expression in the hypothalamic preoptic area of irradiated animals (5 Gy) was significantly higher than in controls (p < 0,05). CONCLUSION: The GnRH-pulse generator is very radiosensitive as low dose irradiation causes precocious puberty, whereas high dose irradiation is associated with delayed sexual maturation. Radiation induced precocious puberty might be caused by damage to inhibitory GABAergic neurons leading to desinhibition and premature activation of GnRH neurons. Our animal model of cranial irradiation seems to be suitable to study neurotransmitter disorders, molecular mechanisms and potential preventive intervention of radiation induced pubertal changes.
Abnormalities, Radiation-Induced↗
Obesity after childhood craniopharyngioma--German multicenter study on pre-operative risk factors and quality of life.
BACKGROUND: Craniopharyngiomas are tumorous embryogenic malformations. As the survival rate after craniopharyngioma is high (92 %), prognosis and quality of life (QoL) in survivors mainly depend on adverse late effects such as obesity. PATIENTS AND METHODS: We analyzed 214 children and adolescents with craniopharyngioma. The records of 185 patients (86 %) were available for retrospective analysis of weight profiles and risk factors for obesity. Quality of life (QoL) was measured in 145 patients by the Fertigkeitenskala Münster/Heidelberg score (FMH) and in 77 patients by PEDQOL questionnaire. RESULTS: Eighty-two of 185 patients (44 %) developed severe obesity (body mass index [BMI] > 3 SD). Obese patients were compared with 79 patients (43 %) who kept normal weight (BMI < 2 SD). No differences between obese and normal weight patients were found in terms of gender distribution, age at diagnosis and follow-up period. However, the BMI SDS at the time of diagnosis was higher (p < 0.0001) in patients who developed obesity than in those who did not. Furthermore, obese patients presented with bigger tumors (p < 0.05) and a higher rate of a hydrocephalus requiring a shunt (p < 0.05) and hypothalamic involvement (p < 0.05). The mothers of patients who developed severe obesity had a higher BMI (p < 0.001) at the time of diagnosis. Obese patients had a higher height-SDS at diagnosis (p < 0.05) and at the time of last follow-up (p < 0.05) when compared with normal weight patients. A prediction model for severe obesity after craniopharyngioma was calculated by logistic regression based on the risk factors: patient's BMI > 2 SD at diagnosis (p < 0.05; odds ratio: 16.4), hypothalamic involvement (p < 0.05; odds ratio: 3.4) and maternal BMI > 25 kg/m(2) (p < 0.05; odds ratio: 4.6). Significant increases in BMI (p < 0.001) occurred during the early post-operative period especially during the first three years after diagnosis. FMH percentiles correlated negatively with BMI SDS (Spearman r: - 0.37; p < 0.001). Children with craniopharyngioma rated their QoL more negative (p < 0.05) in regard to physical abilities, cognitive functioning and social functioning when compared with healthy children of the same age group. Severely obese patients with craniopharyngioma estimated their QoL lower (p < 0.05) for all domains except for autonomy, cognition and familial integration in comparison with non-obese patients. CONCLUSION: Hypothalamic tumor involvement and familial disposition for obesity are risk factors for the development of severe obesity in patients with craniopharyngioma. As weight gain starts early after diagnosis and severe obesity causes a reduction in QoL, early therapeutic efforts should be considered in patients at risk. To confirm our results the prospective multicenter study Kraniopharyngeom 2000 on children and adolescents with craniopharyngioma was initiated (www.kraniopharyngeom.com).
Adolescent↗
Some genetic aspects of idiopathic and symptomatic absence seizures: waking and sleep EEGs in siblings.
Epileptic activity was recorded in the waking and sleep EEG of 62.5% of 80 siblings of 38 patients with absence seizures. Epileptic discharges were noted in waking only in 8.7%, in waking as well as sleep in 28.8%, and in sleep only in 25%. Generalized, partly irregular, and slow spike-wave complexes were found, twice with lateral emphasis. Spike-wave complexes were recorded in 72% of 50 siblings of patients with idiopathic absence and in 46.7% of 30 siblings of patients with symptomatic absence. One epileptic discharge was observed every 108.6 s on the average, without striking differences between siblings of patients with idiopathic (99.7 s) and symptomatic absence (119.3 s). Without any differences between siblings of children with idiopathic and symptomatic absence, the most epileptic discharges were activated in sleep stages C and D, followed by stages A and B. The highest activation rate was observed in the 7-14-year-old group (73.5%) and to a somewhat lesser degree in the group between 15 and 20 years of age (66.7%); fewer epileptic discharges were recorded in younger (25%) and older patients (28.6%). The higher activation rates in the male sex were significant only in siblings of patients with idiopathic absence. Although only five patients (13.2%) were photosensitive, a photosensitivity was found in 24% of siblings of children with idiopathic absence and in 20% of siblings of patients with symptomatic absence. Three siblings of patients with idiopathic absence also had absence seizures; in one of them a febrile seizure occurred at an earlier age. All of them showed generalized spike wave discharges in waking as well as sleep. Occipital theta delta activity with generalization was observed more frequently in siblings of patients with idiopathic absence (82.2%) than in those of patients with symptomatic absence (63.6%). Our waking and sleep EEG recordings prove that concerning etiology-genetic factors play a striking role in idiopathic absence, but are also of considerable significance in the symptomatic types.
Adolescent↗
Modification of visceral sensitivity and pain in irritable bowel syndrome by 5-HT3 antagonism (ondansetron).
Intrinsic neurons containing serotonin (5-HT) are involved in the regulation of gastrointestinal motor function and are also thought to be important in the modulation of visceral sensory function. We have evaluated the effect of a specific 5-HT3 antagonist (ondansetron, O) on visceral sensation and rectal compliance in a randomized, double-blind, cross-over, placebo (P) controlled study of O 16 mg 3 times/day, in healthy volunteers and patients with irritable bowel syndrome (IBS). Symptoms were also evaluated in the latter group. A 2-week run-in period was followed by two 2-week treatment arms of P and O, separated by a 2-week wash-out period. Twelve healthy subjects and 9 patients with IBS were recruited. Assessment was by daily symptom and bowel function diary, and physiological tests of anal manometry, rectal sensory testing to distension and electrical stimulation, and rectal compliance. Ten healthy subjects completed the entire study, and 6 IBS patients completed the diary card evaluation, including 5 who also completed the physiological evaluation. O caused significantly (p < 0.01) firmer stools when considering both subject groups together. In the healthy subjects no physiological parameters were altered by O. In IBS patients the rectal sensory threshold to electrical stimulation tended to increase with O (20 vs. 28 mA, P vs. O, median, p = 0.06) while the urge (80 vs. 60 ml, p = 0.05) and maximum tolerated volumes (130 vs. 90, p = 0.03) to distension tended to decrease with O. Patients with IBS experienced significantly fewer daily episodes of pain while on O (2 vs. 1, p = 0.03). Serotonin-3 antagonism (O) causes firmer bowel actions in all subjects, and may affect gut sensitivity and pain in patients with IBS.
Adult↗
Midwives' Journal. HIV and pregnancy.
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Acquired Immunodeficiency Syndrome↗