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Biomedical subjects

T Harder

Publications and source records attributed to T Harder.

At least 19 recordsLinked to original sources
PubMed2007

Immediate and long-term outcomes in children with prenatal diagnosis of selected isolated congenital heart defects.

OBJECTIVES: To compare the immediate postinterventional and long-term outcomes of children with a prenatal and those with a postnatal diagnosis of isolated congenital heart defects. METHODS: This was a retrospective study of 257 children admitted over a 10-year period to our pediatric cardiology unit with one of four different cardiac lesions: transposition of the great arteries, atrioventricular canal defect, tetralogy of Fallot and pulmonary atresia; 208 were diagnosed postnatally and 49 prenatally. Management was identical in the two patient groups. RESULTS: The median age at admission was 22 days in the postnatal group and 10 days in the prenatal group. In the prenatal group there was a higher median preoperative O2 saturation level (P=0.07), fewer cases of preoperative cardiac failure (P=0.03), fewer cases of preoperative closure of the duct (P=0.04), a shorter median duration of postoperative mechanical ventilation (P=0.03), less need for resurgery (P=0.02) and a shorter median duration of stay in the intensive care unit (P=0.05). Postoperative survival was 96% in the prenatal group and 90% in the postnatal group. Assessment of long-term survival revealed a longer catheter intervention-free interval in the prenatal group (P=0.03). At the 1-year follow-up, residual impaired cardiac function was less frequent in the prenatal than in the postnatal group (P=0.04). Overall survival at maximum follow-up was 92% in the prenatal and 84% in the postnatal group. CONCLUSIONS: Prenatal diagnosis of isolated congenital heart defects allows admission for surgery in a more stable condition and is associated with lower short-term and long-term morbidity and mortality.

Child↗
PubMed2006

Neurotropism of highly pathogenic avian influenza virus A/chicken/Indonesia/2003 (H5N1) in experimentally infected pigeons (Columbia livia f. domestica).

This investigation assessed the susceptibility of experimentally infected pigeons to the highly pathogenic avian influenza virus (HPAIV) H5N1 that caused recent outbreaks of avian influenza in birds and humans in several countries of Asia. For this purpose 14 pigeons were infected ocularly and nasally with 10(8) EID50 and clinical signs were recorded and compared with five chickens infected simultaneously as positive controls. The chickens demonstrated anorexia, depression, and 100% mortality within 2 days postinoculation. Three of the pigeons died after a history of depression and severe neurological signs consisting of paresis to paralysis, mild enteric hemorrhage, resulting in a mortality of 21%. Gross lesions in these pigeons were mild and inconsistent. Occasionally subcutaneous hyperemia and hemorrhage and cerebral malacia were observed. Microscopic lesions and detection of viral antigen were confined to the central nervous system of these pigeons. In the cerebrum and to a minor extent in the brain stem a lymphohistiocytic meningoencephalitis with disseminated neuronal and glial cell necrosis, perivascular cuffing, glial nodules, and in one bird focally extensive liquefactive necrosis could be observed. The remaining nine pigeons showed neither clinical signs nor gross or histological lesions associated with avian influenza, although seroconversion against H5 indicated that they had been infected. These results confirm that pigeons are susceptible to HPAIV A/chicken/Indonesia/2003 (H5N1) and that the disease is associated with the neurotropism of this virus. Although sentinel chickens and most pigeons did not develop disease, further experiments have to elucidate whether or not Columbiformes are involved in transmission and spread of highly pathogenic avian influenza.

Animals↗
PubMed2003

Chlamydia pneumoniae infection and restenosis in patients with coronary heart disease.

BACKGROUND: The aim of this study was to establish whether Chlamydia pneumoniae is implicated in the development of restenosis in patients with coronary heart disease (CHD) after percutaneous transluminal coronary angioplasty (PTCA). PATIENTS AND METHODS: 67 patients were selected for study after they underwent control angiography after PTCA. Sera were tested for anti-chlamydial antibodies with a genus specific ELISA and a species-specific microimmunofluorescence test (MIFT). Oropharyngeal specimens were examined for the presence of antigen with a Chlamydia immunofluorescence test (IFT), C. pneumoniae IFT and semi-nested PCR. In addition, anamnestic findings were also included. To determine the general level of antibodies, an age- and sex matched control group of 180 persons was also examined for Chlamydia and C. pneumoniae serology. RESULTS: Coronary angiography revealed that 31 of the 67 patients had developed a restenosis. There was no significant correlation between serological and angiographic findings. However, the MIFT showed a higher positive rate, especially in IgA, in the restenosis group. C. pneumoniae was detected in the oropharynx by PCR and/or IFT in 20.8% and 16.0% of the cases in patients with and without a restenosis. PCR found more C. pneumoniae-positive cases in the restenosis patients than IFT. No association was found between the detection of Chlamydia antigen and serology. The women with restenosis were more frequently smokers (p = 0.012). Men with restenosis were significantly older (p = 0.015). C. pneumoniae serology based on the rELISA or the MIFT did not show any correlation with restenosis. CONCLUSION: No evidence was found to suggest that positive C. pneumoniae serology is a risk factor for the development of restenosis. However, whether the species-specific serological test, especially for IgA-antibodies, and the detection of C. pneumoniae in oropharyngeal specimens by PCR might be reliable diagnostic markers in these cases remains to be determined.

Age Distribution↗
PubMed2001

Immunoisolation of TCR signaling complexes from Jurkat T leukemic cells.

The formation of multimolecular assemblies of signaling molecules at the plasma membrane is key to triggering signaling cascades following activation of transmembrane receptors at the plasma membrane. We have developed a method to immunoisolate activated T cell receptors (TCRs) and associated signaling molecules in plasma membrane subdomains from Jurkat T leukemic cells. The immunoisolation procedure for the signaling complexes uses magnetic beads, which are coupled to TCR-activating antibodies. Following mechanical cellular disruption using nitrogen cavitation, conjugates of these beads with Jurkat cells are formed and isolated. TCR-signaling complexes within plasma membrane fragments associate with the antibody-coupled beads and are retrieved along with the beads using a magnet. We found that the immunoisolated plasma membrane fragments are highly enriched for activated TCRs and associated signaling proteins. This isolation procedure allows a detailed and precise biochemical analysis of the assembly of signaling proteins in plasma membrane subdomains.

Antibodies, Monoclonal↗
PubMed2001

Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring.

Exposure to a diabetic intrauterine environment leads to diabetogenic disturbances throughout later life in rats. This is accompanied by a fetally acquired dysplasia of the ventromedial hypothalamic nucleus (VMN) which is decisively involved in the regulation of metabolism. We investigated whether malformation of the VMN is preventable by normalization of gestational hyperglycaemia. Correction of hyperglycaemia in pregnant streptozotocin-diabetic rats was achieved by pancreatic islet transplantation. The number of neurons in the VMN was significantly reduced in adult offspring of non-treated, sham-transplanted mother rats (P<0.05), but did not differ between offspring of islet-transplanted mother rats and offspring of control mothers. In conclusion, prevention of VMN malformation in offspring of islet-transplanted diabetic mothers might be co-responsible for normalization of their glucose homeostasis during life.

Animals↗
PubMed2001

Raft membrane domains: from a liquid-ordered membrane phase to a site of pathogen attack.

While the existence of cholesterol/sphingolipid (raft) membrane domains in the plasma membrane is now supported by strong experimental evidence, the structure of these domains, their size, their dynamics, and their molecular composition remain to be understood. Raft domains are thought to represent a specific physical state of lipid bilayers, the liquid-ordered phase. Recent observations suggest that in the mammalian plasma membrane small raft domains in ordered lipid phases are in a dynamic equilibrium with a less ordered membrane environment. Rafts may be enlarged and/or stabilized by protein-mediated cross-linking of raft-associated components. These changes of plasma membrane structure are perceived by the cells as signals, most likely an important element of immunoreceptor signalling. Pathogens abuse raft domains on the host cell plasma membrane as concentration devices, as signalling platforms and/or entry sites into the cell. Elucidation of these interactions requires a detailed understanding raft structure and dynamics.

Animals↗
PubMed2001

Perinatal 'programming' of insulin resistance in childhood: critical impact of neonatal insulin and low birth weight in a risk population.

AIM: Low birth weight may predispose to later insulin resistance and hyperinsulinaemia, but the pathophysiological mechanisms are unclear. The perinatal endocrine situation may play an important role, but has been little studied. Children of mothers with diabetes during pregnancy are an important risk population for later insulin resistance and hyperinsulinaemia. We therefore examined relationships between birth weight, insulin and insulin resistance at birth, and insulin secretion and insulin resistance in infancy in these children. METHODS: We studied 104 infants of mothers with Type 1 diabetes mellitus during pregnancy. Oral glucose tolerance tests (area under the curve of glucose, AUCG) with determination of insulin (area under the curve of insulin, AUCI) were performed at 1-5 years of age. Using correlation and regression analysis, birth data were related to insulin secretion (AUCI) and stimulated insulin/glucose ratio (AUCI/AUCG) in childhood. RESULTS: Children with an AUCI in the highest tertile of distribution had the lowest birth weights. Birth weight was negatively correlated to AUCI in childhood (P = 0.03). Insulin/glucose ratio at birth was raised in infants with an AUCI in the upper tertile, accompanied by a positive correlation between insulin/glucose ratio at birth and AUCI (P = 0.02). Insulin and insulin/glucose ratio at birth were both positively correlated to AUCI/AUCG (P = 0.04 and P = 0.02 respectively), while the correlation between birth weight and AUCI/AUCG was not significant (P = 0.12). In a stepwise regression analysis, insulin/glucose ratio contributed as much as birth weight to AUCI in childhood. Birth weight, however, was significantly negatively related to AUCI/AUCG only when the insulin/glucose ratio at birth was included in the regression model. CONCLUSIONS: Insulin and insulin resistance at birth show a positive relation to insulin secretion and insulin resistance in later life, in addition to the influence of a low birth weight, but independent of it. Perinatal and neonatal insulin, known to be of critical importance for long-term outcome, should be evaluated in future studies on the 'small baby syndrome'.

Age of Onset↗
PubMed2001

Maternal and paternal family history of diabetes in women with gestational diabetes or insulin-dependent diabetes mellitus type I.

Animal studies have shown that prenatal exposure to a diabetic intrauterine milieu leads to an increased risk in the female offspring of developing gestational diabetes (GD). In the present study, the family history of non-insulin-dependent diabetes mellitus type II (NIDDM) and insulin-dependent diabetes mellitus type I (IDDM) was evaluated in 106 women with GD, as compared to 189 women with IDDM. In GD patients, the prevalence of diabetes was significantly greater in mothers than in fathers (p = 0.03). This was mainly due to a greater prevalence of NIDDM in the mothers (p = 0.05). Furthermore, a significant aggregation of NIDDM was also observed in the maternal-grandmaternal line of GD women, as compared to the paternal-grandpaternal side (p = 0.02). In patients with IDDM no significant difference concerning the prevalence of any type of diabetes between mothers and fathers was observed. In conclusion, an aggregation of NIDDM in mothers and grandmothers of women with GD is reported here. A history of NIDDM on the maternal side of pregnant women should be considered as a particular risk factor for GD and, hence, for intergenerative transmission of NIDDM, which therefore might be prevented, at least in part, by strict avoidance of GD.

Adult↗
PubMed2000

Selective accumulation of raft-associated membrane protein LAT in T cell receptor signaling assemblies.

Activation of T cell antigen receptor (TCR) induces tyrosine phosphorylations that mediate the assembly of signaling protein complexes. Moreover, cholesterol-sphingolipid raft membrane domains have been implicated to play a role in TCR signal transduction. Here, we studied the assembly of TCR with signal transduction proteins and raft markers in plasma membrane subdomains of Jurkat T leukemic cells. We employed a novel method to immunoisolate plasma membrane subfragments that were highly concentrated in activated TCR-CD3 complexes and associated signaling proteins. We found that the raft transmembrane protein linker for activation of T cells (LAT), but not a palmitoylation-deficient non-raft LAT mutant, strongly accumulated in TCR-enriched immunoisolates in a tyrosine phosphorylation-dependent manner. In contrast, other raft-associated molecules, including protein tyrosine kinases Lck and Fyn, GM1, and cholesterol, were not highly concentrated in TCR-enriched plasma membrane immunoisolates. Many downstream signaling proteins coisolated with the TCR/LAT-enriched plasma membrane fragments, suggesting that LAT/TCR assemblies form a structural scaffold for TCR signal transduction proteins. Our results indicate that TCR signaling assemblies in plasma membrane subdomains, rather than generally concentrating raft-associated membrane proteins and lipids, form by a selective protein-mediated anchoring of the raft membrane protein LAT in vicinity of TCR.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Induction of caveolae in the apical plasma membrane of Madin-Darby canine kidney cells.

In this paper, we have analyzed the behavior of antibody cross-linked raft-associated proteins on the surface of MDCK cells. We observed that cross-linking of membrane proteins gave different results depending on whether cross-linking occurred on the apical or basolateral plasma membrane. Whereas antibody cross-linking induced the formation of large clusters on the basolateral membrane, resembling those observed on the surface of fibroblasts (Harder, T., P. Scheiffele, P. Verkade, and K. Simons. 1998. J. Cell Biol. 929-942), only small ( approximately 100 nm) clusters formed on the apical plasma membrane. Cross-linked apical raft proteins e.g., GPI-anchored placental alkaline phosphatase (PLAP), influenza hemagglutinin, and gp114 coclustered and were internalized slowly ( approximately 10% after 60 min). Endocytosis occurred through surface invaginations that corresponded in size to caveolae and were labeled with caveolin-1 antibodies. Upon cholesterol depletion the internalization of PLAP was completely inhibited. In contrast, when a non-raft protein, the mutant LDL receptor LDLR-CT22, was cross-linked, it was excluded from the clusters of raft proteins and was rapidly internalized via clathrin-coated pits. Since caveolae are normally present on the basolateral membrane but lacking from the apical side, our data demonstrate that antibody cross-linking induced the formation of caveolae, which slowly internalized cross-linked clusters of raft-associated proteins.

Alkaline Phosphatase↗
PubMed2000

Hypothalamic neuropeptide Y levels in weaning offspring of low-protein malnourished mother rats.

Maternal low-protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Hypothalamic neuropeptides are decisively involved in the central nervous regulation of body weight and metabolism. We investigated neuropeptide Y (NPY) in distinct hypothalamic nuclei in the offspring of LP mother rats at the end of the critical hypothalamic differentiation period (20th day of life). Weanling LP offspring were underweight (P< 0.001) and hypoinsulinaemic (P< 0.05), while leptin levels were unchanged. NPY was significantly increased in the paraventricular hypothalamic nucleus (PVN) (P< 0.01) and lateral hypothalamic area (P< 0.05) in LP offspring. In contrast, NPY was unchanged in the ventromedial hypothalamic nucleus (VMN). These observations indicate a leptin-independent stimulation of the orexigenic ARC-PVN axis in undernourished LP rats at weaning. Furthermore a disturbed NPYergic regulation of the VMN is suggested, possibly contributing to alterations of the hypothalamic regulation of body weight and metabolism in LP offspring during life.

Animals↗
PubMed2000

Hypothalamic nuclei are malformed in weanling offspring of low protein malnourished rat dams.

Maternal low protein malnutrition during gestation and lactation (LP) is an animal model frequently used for the investigation of long-term deleterious consequences of perinatal growth retardation. Both perinatal malnutrition and growth retardation at birth are risk factors for diabetic and cardiovascular disturbances in later life. The pathophysiologic mechanisms responsible are unknown. Hypothalamic nuclei are decisively involved in the central nervous regulation of food intake, body weight and metabolism. We investigated effects of a low protein diet (8% protein; control diet, 17% protein) during gestation and lactation in rat dams on the organization of hypothalamic regulators of body weight and metabolism in the offspring at weaning (d 20 of life). LP offspring had significantly lower body weight than control offspring (CO; P: < 0.001), associated with hypoglycemia and hypoinsulinemia (P: < 0. 005) on d 20 of life. This was accompanied by a greater relative volume of the ventromedial hypothalamic nucleus (P: < 0.01) and a greater numerical density of Nissl-stained neurons in this nucleus (P: < 0.01) as well as in the paraventricular hypothalamic nucleus (PVN; P: < 0.001). In contrast, no significant differences in neuronal densities were observed generally in the lateral hypothalamic area, arcuate hypothalamic nucleus (ARC), and dorsomedial hypothalamic nucleus between LP offspring and CO offspring. On the other hand, LP offspring displayed fewer neurons immunopositive for neuropeptide Y in the ARC (P: < 0.05), whereas in the PVN, lower neuronal densities of neurons immunopositive for galanin were found in LP offspring compared with CO offspring (P: < 0.001). On the contrary, in the PVN, no significant group difference in the numerical density of cholecystokinin-8S-positive neurons was present. A long-term effect of these specific hypothalamic alterations on body weight and metabolism in LP offspring during later life is suggested.

Animals↗