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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 685 records · Page 38Linked to original sources
PubMed1988

Drug input rate from the GI-tract. Michaelis-Menten kinetics and the bioavailability of slow release verapamil and nifedipine.

We present evidence, from studies with slow release verapamil and nifedipine, for Michaelis-Menten metabolism during first pass through the liver. Drug input rate from the GI-tract after an oral dose appears to be a determinant of bioavailability. Highest oral bioavailabilities are observed with standard release formulations at high dosage. The bioavailability of slow release formulations with a zero order release kinetic is lower than standard release formulations and related to the dissolution rate in vitro. In addition, (a) the presence of non-linear absorption kinetics offers a further explanation for the considerable inter-patient variability in AUC since the ability of drug to cross the liver is a function of the concentrations attained in portal blood which will be dependent on dissolution conditions prevailing in the GI-tract, (b) depending on the choice of the dose and dosage interval of the conventional release formulation used for comparison and as a consequence of Michaelis-Menten first pass metabolism it is possible to obtain relative bioavailability data showing superiority, equivalence or bioavailability loss with the slow release form. This may explain the discrepancies in bioavailability data for slow release drugs reported in the literature, (c) 'true' estimates of relative bioavailability of a slow release formulation can only be achieved if steady state conditions are present, and the dose and dosage interval of the slow and conventional release formulation are the same, (d) since a slower dissolution rate is 'ipso facto' associated with a lower bioavailability, slow release formulations of verapamil and nifedipine cannot be classified as being 'inferior' or of poorer quality on the basis of bioavailability alone.

Biological Availability↗
PubMed1988

[Immunodeficiencies and lymphoma].

Primary immunodeficiencies (ID) lead to a high incidence of cancer, particularly of lymphomas. The risk excess varies according to the type of ID. Cellular IDs carry a very high risk, tumoral IDs have an intermediate risk while deficiencies of non-specific immunity bear no risk. Acquired IDs are also associated with an increased risk of lymphomas. The physiopathogeny of ID-associated lymphomas remains unknown, although several hypotheses have been proposed, including a defective immunological surveillance, repeated viral and antigenic stimulations and DNA repair anomalies.

DNA Repair↗
PubMed1987

Gastric stump carcinoma.

Earlier studies report an increased risk of gastric cancer following B II. The present study performed a complete follow up of 1000 patients after B II in the years 1948-1956. The observed incidence of gastric stump carcinoma was 19. This is not significantly different from the expected number of 12.5, the risk being 1.52. From this result it is assumed that after a B II resection the risk of gastric cancer is not increased.

Follow-Up Studies↗
PubMed1987

Graft vs graft reaction resulting in the elimination of maternal cells in a SCID patient with maternofetal GVHd after an HLA identical bone marrow transplantation.

In a young girl with a severe combined immunodeficiency, the presence of circulating maternal T lymphocytes was proven by HLA typing. Manifestations of skin graft vs host disease were associated with the persistence of maternal cells. The patient received an HLA identical bone marrow transplantation from her brother without any conditioning. The bone marrow transplantation was quickly followed by a transient and dramatic increase in skin lesions associated with fever and the finding of a high number of circulating lymphocytes and eosinophils. Lymphocytes were shown to be of donor origin and exerted a spontaneous cytotoxic activity toward maternal cells. This activity progressively disappeared within 90 days, whereas maternal cells were no longer detected in patient's blood, and skin graft vs host disease was resolved within 8 wk. Cytotoxic activity was proven to be mediated by donor T lymphocytes specific for the mother's HLA antigens. The cytotoxic activity was demonstrated to be specific for the HLA class I molecules of the mother not shared with her daughter (HLA A1, B17) as shown by the use of a series of HLA typed cells as targets. In addition, cold K562 target cells did not block the cytotoxic activity, and the kinetics of the cytotoxic activity did not correlate with that of natural killer activity emergence after the bone marrow transplantation. Patient's serum did not contain antibodies toward maternal specific HLA class I antigen. Cytotoxic activity was totally blocked by anti-T3 monoclonal antibodies and partially by anti-T8 and anti-T4. It is thus likely that donor origin cytotoxic T lymphocytes were promptly activated after bone marrow transplantation and provoked the elimination of the maternal graft after a transient exacerbation of graft vs host disease manifestations. This observation represents one of the first examples of the possible role in vivo of allogeneic cytotoxic lymphocytes in humans.

Bone Marrow Transplantation↗
PubMed1987

LFA-1 beta-chain synthesis and degradation in patients with leukocyte-adhesive proteins deficiency.

The defective membrane expression of the adhesive protein family (LFA-1, Mo1 and p150,93) on leukocytes from certain patients with recurrent bacterial infections was shown to be secondary to the absence of synthesis of mature beta chain that is common to all three antigens (Springer et al., 1984, Lisowska-Grospierre et al., 1986). In all patients, studies of beta-chain biosynthesis that lead to this conclusion were performed using the monoclonal anti-beta chain antibody to isolate the beta subunit. Since this antibody detects the mature form of beta chain only, the potential presence of a precursor or of an abnormal beta chain in the patient's cells could not be tested. The availability of the polyclonal antibody to the purified beta subunit allowed us to re-examine the biosynthesis of the LFA-1 subunits in 3 affected children. In all 3 patients, the absence of membrane expression of the LFA-1, CR3 and p150,95 proteins was confirmed. The LFA-1 alpha-chain precursor of 170 kDa was detected in the lysates of PHA blasts of two children, but was not detected in the third. The beta-chain precursor of 85 kDa was isolated by the polyclonal anti-beta chain antiserum from the cytoplasm of phytohemagglutinin and Epstein-Barr virus-induced blasts of one patient. The same antibody precipitated some peptides of smaller mol. wt. from the cell lysates of 2 other patients. These results suggest that in this disorder the membrane nonexpression of the adhesive proteins is probably due to the structural abnormality of beta chain which, although synthesized, is rapidly degradated.

Antibodies, Monoclonal↗
PubMed1987

Close linkage of random DNA fragments from Xq 21.3-22 to X-linked agammaglobulinaemia (XLA).

Linkage analysis of 15 families affected by X-linked agammaglobulinaemia (XLA) showed close linkage with three probes located towards the centre of the long arm of the X chromosome. No cross-overs were found using pXG12 (DXS94) lod 6.6 or S21 (DXS17) lod 4.4. One cross-over was found with 19.2 (DXS3). This confirms and extends a previous linkage study (Kwan et al. 1986) which demonstrated linkage with S21 and 19.2. Of the families 14 were informative for either pXG12 or S21 and these probes should thus be of great diagnostic value. No evidence of heterogeneity was found in the XLA families but several cross-overs within this region were detected in a family with the X-linked hyper-IgM syndrome confirming this disease as a separate clinical entity.

Agammaglobulinemia↗
PubMed1987

Mannan-specific and mannan-induced T-cell suppressive activity in patients with chronic mucocutaneous candidiasis.

We have studied T- and B-cell responses to antigens of Candida albicans in 18 patients suffering from chronic mucocutaneous candidiasis. We have shown that in vitro production of antibody to one of these antigens, mannan, was absent during the active phase of the disease and that this absence was consequent to the activation of specific CD8(+) and CD8(-) suppressor T lymphocytes. Such activation was also observed when control T lymphocytes were incubated in the presence of monocytes and a high concentration of mannan. This suppressive effect was specific to antigens of Candida albicans, was radiosensitive, and was not consequent to the secretion of prostaglandin E2. It appeared as well that the induction of these suppressor T cells was HLA-DQ restricted. The suppressor T-cell activity induced by antigens of Candida albicans in vitro is thus comparable to the suppressor T-cell activity observed in vivo in patients affected with chronic mucocutaneous candidiasis. Defective handling of mannan by monocytes could result in the accumulation of mannan, resulting in the activation of specific T suppressor cells and in the consequent cellular immunodeficiency specific to Candida albicans. Successful treatment of the candidiasis resulted in complete correction of the immune abnormalities.

Adolescent↗
PubMed1987

Gastrin and partial gastrectomy in duodenal ulcer patients 25 years postoperatively.

Serum gastrin concentrations were measured in 26 patients (Group A) who underwent partial gastrectomy for duodenal ulcer disease at least 25 years previously. The basal serum gastrin level was 31.6 +/- 1.5 pg/ml, increasing significantly after food stimulation to 36.8 +/- 2.4 pg/ml (p less than 0.05). In 16 of these patients (Group B), endoscopic biopsy specimens were taken from the minor and major curvatures of the stomach, from the jejunal part of the gastrojejunostomy, and from the duodenum. Mucosal gastrin concentrations measured were 0, 20.4 +/- 3 ng/g, and 30 +/- 7.1 ng/g, respectively. Ten of these patients (Group C) had a repeated gastroscopy with food stimulation of the duodenal pouch, using a balloon catheter in the lower duodenum. Serum gastrin concentrations after pouch stimulation did not differ significantly compared with basal values. No changes in the mucosal gastrin concentrations during pouch stimulation were seen. In conclusion, since no gastrin could be detected in the gastric mucosa and the mucosal gastrin concentration in the duodenum was 50 times lower than reported in other studies, the gastrin release measured after food stimulation could have been of extragastric or extraduodenal origin.

Aged↗
PubMed1987

Human diseases associated with C3 receptor deficiencies.

Genetic deficiencies of complement receptors have recently been described. CR1 expression is reduced on erythrocytes, leucocytes and podocytes of many patients with systemic lupus erythematosus because of both genetic and acquired mechanisms. CR1 deficiency is also found in AIDS and AIDS-related syndromes and correlates with clinical subpopulations of HIV-infected patients. The pathogenic significance of CR1 deficiency relates to the functions of CR1 in clearance of immune complexes, phagocytosis and immune regulation. CR3 deficiency occurs as an autosomal recessive inherited disease characterized by the lack of or severe reduction in expression of the leucocyte antigens CR3, LFA1, p150,95 and their common chain. The disease is associated with severe defects in neutrophil and lymphocyte functions and recurrent bacterial infections. The in vivo effects of C3 receptor deficiencies emphasize the critical role of these membrane molecules in immunity.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11-q13.

The gene for X chromosome-linked severe combined immunodeficiency (SCID), a disease characterized by a block in early T-cell differentiation, has been mapped to the region Xq11-q13 by linkage analysis with restriction fragment length polymorphisms. High logarithm of odds (lod) scores were obtained with the marker 19.2 (DXS3) (z = 5.51 at a recombination fraction theta = 0.11) and with the marker cpX73 (DXS159) that showed complete cosegregation with the disease locus in the informative families analyzed (z = 5.27 at theta = 0.00). Other significant linkages were obtained with several markers from Xq11 to q22. With the help of a recently developed genetic map of the region, it was possible to perform multipoint linkage analysis, and the most likely genetic order is DXS1-(SCID, DXS159)-DXYS1-DXYS12-DXS3, with a maximum multipoint logarithm of odds score of 11.0. Our results demonstrate that the SCID locus (gene symbol IMD4) is not closely linked to the locus of Bruton's agammaglobulinemia (a defect in B-cell maturation). They also provide a way for a better estimation of risk for carrier and antenatal diagnosis.

Female↗
PubMed1987

Megaloblastic anemia and immune abnormalities in a patient with methionine synthase deficiency.

We report a case of methionine synthase deficiency associated with cellular immune deficiency discovered in a 14-year-old boy. Principal findings were: developmental delay, recurrent upper and lower respiratory tract infections, megaloblastic anemia, discovered at 3 months of age, unresponsive to cyanocobalamin and poorly responsive to folinic acid. Biochemical studies showed: an abnormal deoxyuridine suppression test despite normal serum folate, cobalamin and transcobalamin levels; a normal intracellular uptake of these two coenzymes; and an absolute requirement of methionine for fibroblast growth, suggestive of defective methionine synthesis. An absence of methionine synthase activity in the patient's bone marrow and a profound depression of this activity in lymphocytes and liver were found. Hypergammaglobulinemia with variable lymphopenia, depressed lymphocyte transformation after lectin or recall-antigen stimulation, defective delayed-type hypersensitivity and decreased natural killer activity were noted as well. The patient died at the age of 14.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1987

Protein C and antithrombin III in polytransfused thalassemic patients.

Seventy-four patients with beta-thalassemia major were studied to test the hypothesis that a deficiency of protein C (PC) and antithrombin III (AT III), both antithrombotic proteins, could contribute to the pathogenesis of CNS thromboembolic lesions. In 70 patients, PC levels were found to be significantly lower than normal, whereas AT III activity was found to be lower only in 41 patients. The lowest values of PC and AT III were found in older splenectomized patients, a low PC value only was found in chronic hepatitis patients. Prothrombin time and fibrinogen were found to be particularly abnormal in patients with chronic hepatitis and without spleen. A relatively poor correlation was observed between PC and AT III (p less than 0.02). PC correlated with age (p less than 0.001), transfusional iron (p less than 0.001) and ferritin (p less than 0.001). It also correlated with serum albumin (p less than 0.001), prothrombin time (p less than 0.001) and fibrinogen (p less than 0.02) and with serum transaminases (GPT) (p less than 0.001). The same indexes correlated less significantly with AT III activity. Nevertheless, only 2 of our patients had CNS thromboembolic complications. It is probable that low clotting factors, hyperfibrinolysis and thrombocytopenia (which are common in chronic liver disease) could have the opposite effect on hemostasis from that of low levels of anticoagulant proteins such as PC and AT III.

Adult↗
PubMed1987

Urothelial atypia concomitant with primary bladder tumour. Incidence in a consecutive series of 500 unselected patients.

A consecutive series of 500 primary bladder tumours from a single clinic is presented, with distribution of the tumours according to T category and histologic type and grade. Mucosal biopsies were obtained from pre-selected sites at initial cystoscopy or initial transurethral resection of the tumour in 396 cases. In 54% of the patients with grade III tumour there was concomitant urothelial atypia, either carcinoma in situ (urothelial atypia grade III, 30%) or urothelial atypia grade II (24%). In 30% of the patients with invasive grade II bladder tumour and in 14% of those with noninvasive grade II tumour there was concomitant urothelial atypia, mostly grade II. Since concomitant urothelial atypia predicts new tumour growth after successful transurethral surgery or radiotherapy, mucosal biopsies should be performed at preselected sites during initial cystoscopy or transurethral tumour resection in order to identify high-risk patients.

Adenocarcinoma↗