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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 127 records · Page 7Linked to original sources
PubMed2001

Factors V leiden and II 20210A in patients with symptomatic pulmonary embolism and deep vein thrombosis.

PURPOSE: Factor V Leiden and factor II 20210A are inherited disorders of the clotting system that occur frequently in patients with deep vein thrombosis. We conducted this study to determine whether these factors are also common in patients with pulmonary embolism. SUBJECTS AND METHODS: We determined the prevalence of factor V Leiden and factor II 20210A in 773 consecutive patients with objectively documented symptomatic deep vein thrombosis or symptomatic pulmonary embolism, or with a combination of these disorders. RESULTS: Isolated symptomatic deep vein thrombosis occurred in 345 patients; isolated symptomatic pulmonary embolism occurred in 236; and both anomalies occurred in 192. Factor V Leiden was present in 21 (9%) of the patients with isolated symptomatic pulmonary embolism, in 30 (16%) with both manifestations, and in 63 (18%) with isolated symptomatic deep vein thrombosis (P = 0.007). Factor V Leiden was more common among patients with deep vein thrombosis (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.2 to 3.7; P = 0.006) or both pulmonary embolism and deep vein thrombosis (OR = 1.8; 95% CI: 1.0 to 3.3; P = 0.07) than among patients with isolated pulmonary embolism. Factor V Leiden was less common in massive pulmonary embolism (5% [7 of 127]) than in submassive pulmonary embolism (13% [21 of 155], P = 0.03). We found no significant difference in the prevalence of factor II 20210A among the three groups. CONCLUSION: Factors V Leiden and II 20210A vary in prevalence among patients with pulmonary embolism and deep vein thrombosis, suggesting that the risk of pulmonary embolization may vary among patients who have different causes of venous thromboses.

Adult↗
PubMed2001

Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake.

Pulmonary delivery of peptidomimetic antibiotics is frequently used for local drug therapy in pulmonary infections. Identification of transport pathways into airway epithelia can lead to new strategies of therapy. Here we describe the distribution of the beta-lactam-transporting high-affinity proton-coupled peptide transporter PEPT2 in mammalian lungs. Using reverse transcriptase-polymerase chain reaction and Northern blot analysis, PEPT2-mRNA was detected in lung extracts. The expression of PEPT2-mRNA and protein was localized to alveolar type II pneumocytes, bronchial epithelium, and endothelium of small arteries of rat lung by nonisotopic in situ hybridization and immunohistochemistry. In addition, transport studies using murine whole-organ preparations revealed transporter-mediated uptake of a fluorophore-conjugated dipeptide derivative into bronchial epithelial cells and type II pneumocytes. This transport was competitively inhibited by cephalosporins and dipeptides that are reported as PEPT2-carried substrates. Cell specificity of the PEPT2-mediated uptake pattern was confirmed by double labeling with Lycopersicon esculentum lectin. Together these data suggest that PEPT2 is the molecular basis for the transport of peptides and peptidomimetics in pulmonary epithelial cells. In conclusion PEPT2 may be an interesting target for pulmonary delivery of peptides and peptidomimetics.

Animals↗
PubMed2001

Neural regulation of airway smooth muscle tone.

Airway smooth muscle is innervated by sympathetic and parasympathetic nerves. When activated, airway nerves can markedly constrict bronchi either in vivo or in vitro, or can completely dilate a precontracted airway. The nervous system therefore plays a primary role in regulating airway caliber and its dysfunction is likely to contribute to the pathogenesis of airways diseases. The predominant contractile innervation of airway smooth muscle is parasympathetic and cholinergic in nature, while the primary relaxant innervation of the airways is comprised of noncholinergic (nitric oxide synthase- and vasoactive intestinal peptide-containing) parasympathetic nerves. These parasympathetic nerves are anatomically and physiologically distinct from one another and differentially regulated by reflexes. Sympathetic-adrenergic nerves play little if any role in directly regulating smooth muscle tone in the human airways. Activation of airway afferent nerves (rapidly adapting receptors, C-fibers) can evoke increases in airway smooth muscle parasympathetic nerve activity, or decreases in parasympathetic nerve activity (through activation of slowly adapting receptors). Extrapulmonary afferents can also modulate nerve mediated regulation of airway smooth muscle tone. In guinea pigs and rats, peripheral activation of tachykinin-containing airway afferent nerves evokes bronchospasm via release of substance P and neurokinin A. This effect of airway afferent nerve activation appears to be unique to guinea pigs and rats. The actions and interactions between the components of airway innervation are discussed.

Animals↗
PubMed2001

[Gene therapy of X-linked severe combined immunologic deficiency (SCID-X1)].

X-linked severe combined immunodeficiency (SCID-X1) is a recessive hereditary disorder in which early T and Natural Killer (NK) lymphocyte development is blocked. The genetic disorder results from mutations in the common gamma c chain that participates in several cytokine receptors including the interleukin-2 (Il-2), Il-4, Il-7, Il-9, Il-15 receptors. SCID-X1 offers a reliable model for gene therapy as it is a lethal condition that is, in many cases, curable by allogeneic bone marrow transplantation. We have shown that retrovirus-mediated transfer of the gamma c cDNA induced gamma c chain expression and restored the function of the high-affinity IL-2 receptor on SCI-X1 EBV-transformed B-cell lines. We have the designed culture conditions to study NK-cell and T-cell development of CD34+ hematopoietic progenitor cells. In the culture systems, gamma c transduced CD34+ marrow cells from two SCID-X1 patients were able to mature into CD56+ and/or CD16+ NK cells and into CD4+ TCR alpha beta+ T cells. These preclinical results set the basis for a clinical study of ex-vivo gamma c gene transfer into CD34+ cells from SCID-X1 patients.

Antigens, CD34↗
PubMed2001

The role of cytotoxicity in lymphocyte homeostasis.

Several human inherited immune disorders lead to the same fatal lymphoproliferative syndrome, called the hemophagocytic syndrome. Through defective perforin expression or transport, these disorders highlight the determinant role of the secretory cytotoxic pathway in the regulation of the immune response and in lymphocyte homeostasis. In addition, new effectors of this secretory pathway have been identified.

Animals↗
PubMed2001

Active cooling during open repair of thoraco-abdominal aortic aneurysms improves outcome.

OBJECTIVE: Evaluate impact of active cooling with partial cardiopulmonary bypass (CPB) and low systemic heparinization during open repair of thoracoabdoninal aortic aneurysms. METHODS: Prospective analysis of 100 consecutive patients undergoing surgical repair of thoracoabdominal aortic aneurysms. Partial CPB and normothermic (36 degrees C) or hypothermic (29 degrees C) perfusion was selected in accordance to the surgeons preference. In the hypothermic group, aortic cross clamp was applied when the target temperature of the venous blood was achieved and rewarming was started after declamping. RESULTS: 52/100 patients (62.2+/-10.9 years) received normothermic and 48/100 patients hypothermic perfusion (63.8+/-10.6 years: NS). Emergent procedures accounted for 18/52 (35%) with normothermia vs. 21/48 (44%: NS) with hypothermia. The number of aortic segments (eight = maximum including arch and bifurcation) replaced was 3.9+/-1.5 with normothermia vs. 4.1+/-1.5 with hypothermia (NS); Crawford type II aneurysms accounted for 21/52 patients (40%) for normothermia vs. 20/48 (42%:NS) for hypothermia. Total clamp time was 38+/-21 min with normothermia vs. 47+/-28 min with hypothermia (P=0.05). Pump time was 55+/-28 min with normothermia vs. 84+/-34 min with hypothermia (P=0.001). Mortality at 30 days was 8/52 patients (15%) with normothermia vs. 2/48 (4%) with hypothermia (P=0.06; odds ratio = 4.1). Parapareses/plegias occurred in 4/52 patients (8%) with normothermia vs. 4/48 (8%) with hypothermia (NS). Revisions for bleeding were required in 4/52 patients (8%) with normothermia vs. 2/48 patients (4%) with hypothermia (P=0.38). Revisions for distal vascular problems were necessary in 5/52 patients (10%) with normothermia vs. 2/48 (4%) with hypothermia (P=0.25). Freedom from death, paraplegia, and surgical revision was 89.9% with normothermia vs. 94.8% with hypothermia (P=0.04; odds ratio 2.0). CONCLUSIONS: Active cooling during repair of thoracoabdominal aortic aneurysms allows for longer cross-clamp times, more complex repairs and improves outcome.

Aged↗
PubMed2001

Expression of immediate early genes in sensory ganglia.

C-Jun and c-Fos belong to the family of immediate early genes. Apart from their role as transcription factors, a basal expression was shown for them in central nervous system tissues. The expression of c-Jun and c-Fos in sensory ganglia of guinea pig, rat and murine sensory ganglia was examined under normal, unstimulated conditions by quantitative double-immunohistochemistry. 4.6 +/- 2.8% of neuron-specific protein gene-product 9.5 -positive cells in nodose ganglia, 51.6 +/- 2.1% in jugular ganglia, 46.4 +/- 3.0% in trigeminal ganglia and 42.5 +/- 1.3% of cervical dorsal root ganglia neurons were positive for c-Jun in the guinea pig (less than 1% for c-Fos). In rat and mouse, less than 1% of the sensory neurons exhibited c-Jun and c-Fos-immunoreactivity. The high basal expression of c-Jun in guinea pig sensory neurons suggests that in this species the presence of c-Jun does not only depend on specific stimulation and is not exclusively associated with neuronal plasticity of gene expression and functional changes.

Animals↗
PubMed2001

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Adolescent↗
PubMed2001

Expression and distribution of vasoactive intestinal polypeptide receptor VPAC(2) mRNA in human airways.

SUMMARY: Vasoactive intestinal polypeptide (VIP) is a putative neurotransmitter of the inhibitory non-adrenergic non-cholinergic nervous system and influences many aspects of mammalian airway function. VIP binds to two G-protein-coupled VPAC receptors that are highly homologous structurally but distinguished by their different affinities for peptide analogues of VIP. As VIP binding sites in the respiratory tract have only been examined by ligand binding and cytochemical techniques, we studied the distribution of the mRNA that encodes the inducible receptor subtype VPAC(2) in the human respiratory tract. Northern blots demonstrated the expression of VPAC(2) mRNA in human airways and other tissues. A human-specific VPAC(2) cRNA probe was used to detect VPAC(2) mRNA expression in human lung by nonradioactive in situ hybridization. In larger airways, positive VPAC(2) mRNA signals were localized to tracheal and bronchial ciliated epithelial cells. There was also marked staining of mucous and serous cells of submucosal glands. No signals were obtained in airway and vascular smooth muscle myocytes and endothelial cells. In peripheral lung tissues, VPAC(2) mRNA expression was localized to epithelial cells of the bronchioles. Specific staining was detected in immune cells and alveolar macrophages. In summary, VPAC(2) is localized in airway epithelial, glandular, and immune cells of the lung but not in airway and vascular smooth muscle. The absence of VPAC(2) mRNA in vascular and airway smooth muscle myocytes may indicate that the effects of VIP on vasodilation and bronchodilation are mediated by VPAC(1) or undefined receptors. However, a paracrine modulation of the two most prominent effects of VIP in the respiratory tract by VPAC(2) cannot be excluded.

Binding Sites↗
PubMed2001

Chimaeric anti-CD20 monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children.

Post-transplant lymphoproliferative disorder (PTLD) after haemopoietic stem cell transplantation is a serious complication that occurs in 8-22% of patients with high-risk factors. We retrospectively investigated tolerance and efficacy of humanized anti-CD20 monoclonal antibody (rituximab) as first-line treatment in 12 children with B-cell PTLD. At diagnosis, eight patients had tumoral involvement. The other four patients had fever, associated with raised Epstein-Barr virus (EBV) viral load and monoclonal gammopathy. Rituximab was given at the dose of 375 mg/m2 once a week by intravenous infusion (1-9 infusions). Only 1/48 infusions was associated with a grade 2 clinical adverse event. Eight out of 12 (66%) patients responded to the treatment and were in complete remission. All patients without tumoral involvement responded to the treatment. A rapid decrease in fever within 1 week was observed in all responders. Non-responders did not show any clinical response during the first week. Tumoral involvement and immunodepression seemed to be more marked in non-responders. Rituximab was an effective and well-tolerated treatment of B-cell PTLD. Early treatment before tumoral involvement seemed to be the most effective approach. Lack of rapid response should lead to intensification of PTLD treatment. Pre-emptive treatment should be considered and evaluated in further longitudinal multicentre studies.

Antibodies, Monoclonal↗
PubMed2001

Regulation of HEMA1 expression by phytochrome and a plastid signal during de-etiolation in Arabidopsis thaliana.

The synthesis of 5-aminolevulinic acid (ALA) is the rate-limiting step for the formation of all plant tetrapyrroles, including chlorophyll and heme, and regulation of ALA synthesis is therefore critical to plant development. Glutamyl-tRNA reductase (GluTR) is the first committed enzyme of this pathway and is encoded by a small family of nuclear HEMA genes. Here, we have used transgenic Arabidopsis (Arabidopsis thaliana L. Col) lines expressing chimeric HEMA1 promoter:gusA fusion genes, combined with RNA gel blot analyses, to characterise the light-mediated regulation of the Arabidopsis HEMA1 gene during de-etiolation. HEMA1 was expressed strongly, but not exclusively, in photosynthetic tissues and was shown to be light regulated at the transcriptional level by the phytochrome family of photoreceptors acting in both the far-red high irradiance and low fluence response modes. The HEMA2 gene, which is expressed only in roots of seedlings, was not light regulated. Analysis of truncated HEMA1 promoter constructs demonstrated that a -199/+252 promoter fragment was sufficient to confer full light-responsiveness to gusA expression. This fragment contained GT-1/I-box and CCA-1 binding sites that are implicated as the light-responsive cis elements. Both the full-length and truncated HEMA1 promoters required the presence of intact chloroplasts for full expression, consistent with previous indications that light and plastid factor signals converge to co-ordinately regulate expression of photosynthesis-related nuclear genes. These results provide the most comprehensive analysis to date of the light-regulation of a tetrapyrrole biosynthetic gene and support a direct link between regulation of HEMA1 transcription and chlorophyll accumulation during seedling de-etiolation.

Aldehyde Oxidoreductases↗
PubMed2001

Combined benefits of annual mass treatment with ivermectin and cattle zooprophylaxis on the severity of human onchocerciasis in northern Cameroon.

We studied the effect of 10 annual distributions of ivermectin for control of human onchocerciasis on the reduction of Onchocerca volvulus transmission by Simulium vector flies. Prevalence and infection load in the human population decreased, whilst the annual biting rates (ABR) of the vector remained unchanged. The annual transmission potential of infective larvae of O. volvulus fell to 40% of the pre-intervention level, but was still sufficient to maintain endemicity. However, recent immigration of herds of nomadic cattle into the study area has diverted the flies from man to cattle, creating an additional zooprophylactic effect. The predominant transmission of the bovine filaria O. ochengi to man also provides some concomitant cross-protective immunity against further infestations with O. volvulus. The effects of ivermectin on O. volvulus, combined with the zooprophylactic effects of the increased cattle population, have produced a complex beneficial influence on the transmission of human onchocerciasis.

Animals↗
PubMed2001

Increased trypanolytic activity in sera of sleeping sickness patients after chemotherapy.

We tested sera from patients previously treated for human African trypanosomiasis, from patients infected with trypanosomes, and from individuals never diagnosed with African trypanosomiasis living in the Trypanosoma brucei gambiense sleeping sickness focus of Mbini in Equatorial Guinea for their trypanolytic activity against bloodstream forms of T. b. rhodesiense expressing a metacyclic and bloodstream variant surface glycoprotein (VSG). Nearly 80% of the sera from treated patients showed high trypanolytic activity against trypanosomes expressing a metacyclic VSG. The trypanolytic activity of part of these sera was mediated by IgM while that of the other part was antibody-independent. On the other hand, only 40% of the sera exhibited high trypanolytic activity against trypanosomes expressing a bloodstream VSG which also was almost completely abolished by heat-inactivation. In contrast, most sera from infected and negative individuals displayed only low to moderate trypanolytic activity against either trypanosomes expressing a metacyclic or a bloodstream VSG. These results suggest that trypanolytic activity of sera increases after African sleeping sickness and is directed against trypanosomes expressing metacyclic VSG.

Animals↗
PubMed2001

Immunohistochemical detection of calcitonin gene-related peptide receptor (CGRPR)-1 in the endothelium of human coronary artery and bronchial blood vessels.

The potent vasodilatory peptide, calcitonin gene-related peptide (CGRP) is present in the innervation of vascular tissue. The actions of CGRP occur via a receptor, CGRP receptor(R)-1, which is also a target for the cardioprotective peptide adrenomedullin. The human version of the pharmacologically-defined CGRPR-1 has been cloned but its distribution and cellular location is unknown. A rabbit antibody was generated to a synthetic peptide that corresponds to the C-terminus of human CGRPR-1 Immunochemical analysis of the human cell-line, SK-N-MC, which exhibits functional expression of the CGRPR-1 confirmed the antibody's specificity. The antiserum revealed specific staining in the endothelium of human coronary arteries. The vascular smooth muscle and ventricular myocardium were not immunoreactive. In bronchial blood vessels CGRPR-1-immunoreactivity was detected in the endothelium of the venules and not in the arterioles, which is particularly relevant for elucidating the putative role of CGRP in inflammation in this tissue.

Antibody Specificity↗
PubMed2001

[Vault fixation by fascial sling (Williams-Richardson technique) or sacrospinous/sacrotubed fixation (Amreich-Richter technique) - Is there a difference in indications?].

There are many techniques in the treatment of female genital descent. We analysed sacrospinous/sacrotuberal fixation in comparison to abdominal fixation using fascial slings. One of the aims of the study presented was to determine whether there is a differentiation in indications in the use of either technique. There was no difference in recurrence rates, stress incontinence did not occur in a significant number of cases postoperatively. Recovery was different in both techniques. Apparently the fascial sling technique is effective in cases where intraabdominal surgery has to be performed at the same time and descent is limited to the upper third of the vagina. The use of sacrospinous/sacrotuberal fixation is only limited by simultaneous appearance of excessive lateral detachment defect. It seems to be most effective in cases where larger recto-enteroceles have to be treated at the same time. A lateral defect has to be approached differently in all cases.

Adult↗