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Biomedical subjects

K Schulze

Publications and source records attributed to K Schulze.

At least 73 records · Page 4Linked to original sources
PubMed1997

Adenine nucleotide translocator in dilated cardiomyopathy: pathophysiological alterations in expression and function.

Several findings pointed to an insufficient energy supply in heart muscle tissue of patients suffering from dilated cardiomyopathy (DCM). We found a lowered ANT transport capacity of the adenine nucleotide translocator (ANT), the only transport system for ATP and ADP in eucaryotic cells, in explanted hearts of DCM patients. The reduced ANT transport rate was accompanied by a marked elevation in total ANT protein caused by an increase in ANT 1 isoform protein. Simultaneously, a reduction in ANT 2 transcripts and an unchanged ANT 3 expression was observed. In contrast, patients with ischemic or valvular heart disease showed no alteration in ANT function or expression, which indicates the disease-specificity of these findings. With regard to autoimmunological and viral processes, which are thought to play an important role in the pathogenesis of DCM, we could show that the ANT function is reduced in the hearts of A.SW/Sn-J mice infected with the enterovirus Cox-sackie B3, and in those of guinea pigs immunized with purified myocardial ANT. Both treatments led to autoimmunological reactions against the ANT protein, that reduce the myocardial ANT transport capacity, thus disturbing energy metabolism and consequently depressing heart function. In contrast to these animal models, no restriction in ANT capacity was observed in hypoxic hearts of guinea pigs, which corresponds to the findings of unaffected ANT function in ischemic human hearts.

Animals↗
PubMed1996

Radioiodination of nicotine with specific activity high enough for mapping nicotinic acetylcholine receptors.

A novel radiochemical method is presented to synthesize 5-[123I/125I/131I]-dL-nicotine by radioiodination of 5-bromonicotine. Radioiodination of the precursor 5-dL-bromonicotine was achieved using a copper (I)-assisted nucleophilic exchange reaction in the presence of reducing agent. The reaction conditions were optimized by varying pH, concentration of Sn(II) salt, ascorbic acid, Cu(I)chloride and reaction temperature. After purification by high-performance liquid chromatography the radiochemical purity of the product exceeded 98%, with a radiochemical yield of 55% and a specific activity > or =5 GBq/micromol. Specific binding of the iodinated nicotine was demonstrated in rat brain by autoradiography. The radioactivity from the specific structures was displaced by an excess of non-radioactive nicotine (10(-3)M) with KD and Bmax of 13.1+/-7.8 nM and 22+/-2.7 fmol/mg protein and unspecific binding of about 40%. The in vivo distribution of 5-[131I]iodonicotine was determined in 20 female Wistar rats at various time intervals of 15s to 90 min post injection (p.i.) by well counting and autoradiography. Brain activity peaked within 0.5 min p.i., and then showed a biexponential washout. Initially, activity within the cerebral cortex exceeded that of the cerebellum by a factor of 1.5-2.0. It was also increased in the striatum and thalamus. However, as soon as 15 min p.i. activity was almost homogeneously distributed. In conclusion, synthesis of 5-iodo-dL-nicotine (labelled with 131I, 125I or 123I, respectively) with appropriately high specific activity for receptor studies was achieved and specific binding to nicotine receptors in rat brain was demonstrated; following intravenous injection, however, there is considerable unspecific binding, obviously due to highly flow-dependent tissue retention.

Animals↗
PubMed1996

The role of sensitized T-cells in myocarditis and dilated cardiomyopathy.

Enteroviruses like coxsackie are known to cause myocarditis both in animals and humans and enteroviral genom was found in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. However, subsequent to the initial viral infection, immune mechanisms seem to play an important role in the pathogenesis of both diseases. Using synthetic peptides, it was possible to identify T-cell epitopes of coxsackie B3 virus and to test their significance in the pathogenesis of myocarditis in the animal model. The T-cell response against coxsackie virus and autoantigens like the adenine nucleotide translocator is also present in the human disease, since sensitized T-cells can be cultured from about 50% of endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. The significance of the cellular immune responses in the human disease can be demonstrated by the transfer of peripheral blood leukocytes of patients with chronic myocarditis into severe combined immune deficiency mice that develop human cellular infiltrates of the myocardium and an impairment of the left ventricular function within 60 days. Thus, these results show the presence and importance of cellular immune responses in the pathogenesis of myocarditis and dilated cardiomyopathy.

Animals↗
PubMed1996

Hemoquant determination of hookworm-related blood loss and its role in iron deficiency in African children.

Iron deficiency remains the most prevalent form of human malnutrition, and current interventions to control it have not decreased the global prevalence. Hookworm control activities are becoming more widely implemented, but the importance of these efforts to prevent anemia in populations is not well-defined. We studied the relationships among hookworm infection, intestinal blood loss, and iron status of 203 Zanzibari school children. Helminth infection intensity was quantified by fecal egg counts, and iron deficiency anemia was defined by low hemoglobin and serum ferritin concentrations. Intestinal blood loss was quantified by measuring fecal heme and heme breakdown products as porphyrin, a noninvasive method that has not been used previously to assess hookworm blood loss. Intestinal blood loss was strongly and linearly related to hookworm egg counts. The degree of degradation of fecal heme indicated that blood loss occurred in the upper gastrointestinal tract, compatible with the behavior of hookworms. Trichuris trichiura and Ascaris lumbricoides infections were also common, but did not contribute significantly to intestinal blood loss in this population. The prevalence of iron deficiency anemia increased steadily as hookworm infection intensity and intestinal blood loss increased. In the context of a poor diet, as exists in Zanzibar and many tropical countries, hookworm-related blood loss contributes dramatically to anemia. In such contexts, hookworm control is a feasible and essential component of anemia control. Determination of fecal heme is relatively simple and noninvasive and may be a useful tool for measuring the impact of hookworm control activities.

Anemia, Iron-Deficiency↗
PubMed1996

[A Q-fever pneumonia epidemic in Dusseldorf].

There was an unusually high incidence of atypical pneumonias in the catchment area of the Rhine river near the university of Düsseldorf in July 1994 during a long period of hot and dry weather. The 18 patients described in this paper (5 women and 13 men) complained of sudden onset of fever up to over 40 degrees C, often associated with severe headache and dry cough. Almost all of these patients had previously been healthy and active and of young to middle age (average 38 years) without any bronchopulmonary anamnesis. Radiology revealed that all the patients had in most cases defined pulmonary infiltrates without any specific preference for a particular site. Serology was initially negative, but four weeks later the complement fixation reaction titre was positive for Coxiella burnetii antibodies in 14 patients (78%). All patients became symptom-free within a few days'time when treated with a combination of antibiotics which included doxycycline, whereas the infiltrates receded completely only after several weeks. The occurrence of pulmonary Q-fever in a large northern German conurbation had been rare at that time. Such epidemics, however, were also noted in Berlin (1992) and in Dortmund (1993). The epidemic reported in this article probably originated from one of the frequent flocks of sheep grazing along the banks of the Rhine river near Düsseldorf. The infections were probably acquired by inhalation of airborne organisms in infected aerosols derived from infected sheep, promoted by the long-term very hot and dry weather which was at the same time very windy, leading to an unusually extensive spreading of the pathogens throughout a very large infected aerosol area.

Adult↗
PubMed1995

Impairment of left ventricular function in combined immune deficiency mice after transfer of peripheral blood leukocytes from patients with myocarditis.

Autoimmune mechanisms are suspected to play an important role in the pathogenesis of human myocarditis. In order to evaluate the significance of autoimmune leukocytes for the development of human myocarditis (MC) and subsequent heart failure, we transferred 15 x 10(6) or 50 x 10(6) peripheral blood leukocytes (PBLs) from patients with immunohistologically proven MC and impaired left ventricular function into severe combined immune deficiency (SCID) mice that possess neither B nor T lymphocytes. PBLs from seven patients and five healthy controls were transferred into three SCID mice each by intraperitoneal injection. After 60 days human PBLs could be demonstrated in the peripheral blood of SCID mice, representing up to 10% of peripheral blood mononuclear cells. Likewise, human immunoglobulins were present in all transfused SCID mice (up to 3 mg.ml-1 IgG and IgM); however, autoantibodies against the adenine nucleotide translocator, a myocardial autoantigen, were only present in the mice receiving PBLs from patients with MC. Infiltrating human lymphocytes were also only found in the hearts of SCID mice having received PBLs from MC patients, but not in those receiving PBLs from normal controls. When we measured the slope of the left ventricular pressure pulse by direct puncture under ether anaesthesia, we found it to be decreased (dp/dt = 1750 +/- 194 mmHg.s-1 in mice receiving PBLs from MC patients, compared with mice receiving PBLs from controls (dp/dt = 2456 +/- 92 mmHg.s-1 or receiving no transfusion (dp/dt = 2576 +/- 142 mmHg.s-1. These results demonstrate that the impairment of the ventricular function seen in patients with MC can be transferred to SCID mice by transfer of PBLs. This proves the significance of autoimmune mechanisms for the pathogenesis of MC.

Animals↗
PubMed1995

The role of the ADP/ATP carrier in the pathogenesis of viral heart disease.

The ADP/ATP carrier is an autoantigen in myocarditis and dilated cardiomyopathy, both of which are diseases related to virus infections. Sera of these patients bear carrier-specific autoantibodies inhibiting transmembrane nucleotide transport on isolated mitochondria. To further assess the role of the ADP/ATP carrier in viral heart disease, guinea pigs were immunized with the isolated ADP/ATP carrier protein and A-strain mice were infected with coxsackie B3 virus. Both species generated specific and carrier-inactivating antibodies after immunization/infection. The transport activity of the ADP/ATP carrier-estimated from the cytosolic-mitochondrial difference of the phosphorylation potential of ATP (delta G[cyt-mit])-markedly declined in guinea pig and mice hearts. A close relationship was observed between the magnitude of reduction of delta G(cyt-mit) and the decrease of cardiac function. Therefore, it seems plausible that carrier dysfunction induced by viral infection creates an imbalance in myocardial energy metabolism, and is responsible for the impairment of cardiac function. The underlying mechanism might be an autoimmune reaction triggered via molecular mimicry or a modulation of the expression of ADP/ATP carrier isoforms changing the overall transport capacity of the cardiac ADP/ATP carrier.

Animals↗
PubMed1995

Antibody-mediated imbalance of myocardial energy metabolism. A causal factor of cardiac failure?

The ADP-ATP carrier of the inner mitochondrial membrane is an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain carrier-specific autoantibodies that inhibit the transmembrane nucleotide transport on isolated mitochondria. Guinea pigs immunized with the isolated ADP-ATP carrier protein also generate specific carrier-inactivating antibodies. In this study, we measured the cardiac function of guinea pigs immunized with the ADP-ATP carrier by determining the external heart work (EHW) of their isolated perfused spontaneously beating hearts stimulated by 4.0 mmol/L calcium and aortic ligature. Further, the electrogenic transport activity of the ADP-ATP carrier was estimated by calculating the cytosolic-mitochondrial difference of the phosphorylation potential of ATP [delta G(cyt-mit)] in the freeze-clamped isolated hearts by nonaqueous fractionation. The EHW of immunized guinea pigs was seen to be reduced by 54% (P < .005) compared with nonimmunized control guinea pigs, and delta G(cyt-mit) declined from 4.9 kJ/mol ATP in nonimmunized control hearts to 2.3 kJ/mol ATP in the hearts of the immunized guinea pigs (P < .005). The decisive result of this study, however, is the close relation observed between the magnitude of reduction of delta G(cyt-mit) and the size of the decrease in EHW (r = .87). Therefore, it seems plausible that antibody-mediated carrier dysfunction (creating the observed imbalance in myocardial energy metabolism) is responsible for the impairment of cardiac function. Our data support the hypothesis that immunopathic mechanisms in myocarditis and dilated cardiomyopathy can trigger subsequent heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1995

Cutaneous presentations of lymphoma in human immunodeficiency virus disease. Predominance of T cell lineage.

BACKGROUND AND DESIGN: Most non-Hodgkin's lymphomas in patients with human immunodeficiency virus infection are of B-cell lineage. Cutaneous lymphoma in the human immunodeficiency virus disease has not been systematically reviewed. We studied 25 patients with both human immunodeficiency virus infection and cutaneous presentations of lymphoma, using immunohistochemistry and in situ hybridization for Epstein-Barr virus. RESULTS: Two groups of patients were discerned: (1) those with conditions similar to mycosis fungoides or Sézary syndrome with an indolent course (n = 8) and (2) those with nodules or papules, greater immunosuppression, a rapid clinical course, and large cell lymphoma seen on biopsy specimens (n = 17). The epidermotropic lymphomas were T-cell lineage and CD30-. Thirteen of the large cell lymphomas were also of the T-cell type, and 71% were CD30+. Epstein-Barr virus was absent in the epidermotropic lymphomas, but it was present in 73% of the nonepidermotropic cases. CONCLUSIONS: Two forms of human immunodeficiency virus-associated cutaneous lymphoma were found: indolent disease resembling mycosis fungoides or Sézary syndrome and large cell lymphomas with a poor prognosis, whose cells often had a CD30+ T-cell phenotype and harbored the Epstein-Barr virus.

Adult↗
PubMed1994

Alteration of the cytosolic-mitochondrial distribution of high-energy phosphates during global myocardial ischemia may contribute to early contractile failure.

Depending on its duration, temporary myocardial ischemia leads to a disturbance of myocardial function before irreversible cellular necrosis is developed. Mechanical, electrical, and metabolic disturbances were suggested to be possible mechanisms accounting for the altered mechanical performance in ischemic hearts. To further investigate the alteration of myocardial energy metabolism on the subcellular level, we determined, by means of nonaqueous fractionation, the cytosolic-mitochondrial distribution of high-energy phosphates and other metabolites (ATP, ADP, phosphocreatine, creatine, and inorganic phosphate) in ischemic (zero-flow) guinea pig hearts after isolated perfused working heart preparation. Additional experiments using 31P nuclear magnetic resonance spectroscopy were performed to determine pHi and [Mg2+]i changes during global ischemia. The total ATP content of myocardial tissue dropped only slowly to 76% of control ATP at 10 minutes and to 51% at 30 minutes and reached almost zero at 60 minutes of ischemia. However, striking differences were observed on the subcellular level: While cytosolic phosphocreatine was almost completely consumed after 3 minutes of ischemia (from 19.1 +/- 1.6 to 3.3 +/- 0.5 mmol/L), ATP concentration in the cytosol decreased within 30 minutes from 8.4 +/- 0.6 to only 5.4 +/- 0.9 mmol/L. Mitochondrial ATP was rapidly and linearly reduced to 60% after 5 minutes of ischemia and was nearly unmeasurable after a further 20 minutes. Thus, in contrast to the breakdown of phosphocreatine in cytosol, the only slight alteration of cytosolic ATP reveals a reduction in cytosolic ATP utilization. Moreover, the unaffected cytosolic-mitochondrial difference in the phosphorylation potential of ATP demonstrates the intact function of the ADP/ATP carrier during early ischemia. These results might indicate a disturbance of the functional coupling between carrier and phosphocreatine kinase (phosphocreatine shuttle), which could be of importance for the early contractile failure in myocardial ischemia.

Adenosine Diphosphate↗
PubMed1993

Mutational analysis of Drosophila synaptotagmin demonstrates its essential role in Ca(2+)-activated neurotransmitter release.

Synaptotagmin (syt), a synaptic vesicle-specific protein known to bind Ca2+ in the presence of phospholipids, has been proposed to mediate Ca(2+)-dependent neurotransmitter release. We have addressed the role of syt in neurotransmitter release in vivo by generating mutations in synaptotagmin (syt) in the fruitfly and assaying the subsequent effects on neurotransmission. Most embryos that lack syt fail to hatch and exhibit very reduced, uncoordinated muscle contractions. Larvae with partial lack-of-function mutations show almost no evoked excitatory junctional potentials (EJPs) in 0.4 mM Ca2+ and a 15-fold reduction in EJP amplitude in 1.0 mM Ca2+ when compared with heterozygous controls. In contrast, we observe an increase in the frequency of spontaneous miniature EJPs in the mutants. These results provide in vivo evidence that syt plays a key role in Ca2+ activation of neurotransmitter release and indicate the existence of separate pathways for evoked and spontaneous neurotransmitter release.

Alleles↗
PubMed1993

Severe anaphylactic shock due to repeated application of aprotinin in patients following intrathoracic aortic replacement.

Aprotinin is known to significantly reduce the incidence of perioperative bleeding complications in cardiac, thoracic and vascular surgery. Despite the wide use of this medication in other surgical fields, there are only a few reports of serious adverse side effects. In this paper we report on two patients with severe anaphylactic shock due to repeated administration of aprotinin, who both required cardiopulmonary resuscitation.

Adolescent↗
PubMed1993

Cardiorespiratory costs of growth in low birth weight infants.

The energy cost of growth includes two components: the energy stored in new tissues and the energy expended in all energy requiring steps associated with nutrient intake and net tissue accretion. Most of the energy expended in growth is accounted for by the energy cost of tissue anabolism: peptide bonds, lipogenesis, substrate transport, etc. However, to the extent that additional work is required of the heart and lungs for growth-related increases in O2 and CO2 transport, increased energy is also expended in cardiorespiratory work. Indirect estimates of these costs can be gained by examining the effects of diet and weight gain on heart rate and respiratory frequency. We studied 66 healthy low birth weight infants, mean study weight = 2010 g, fed constant intakes of protein (2.25-3.9 g/kg per day) and energy (100-150 kcal/kg per day). These diets led to rates of weight gain ranging from 13.9 to 21.7 g/kg per day, among the diet groups. Bi-weekly 6-h assessments of energy expenditure, heart rate, respiratory frequency and state of sleep were made after full enteral intake was achieved. After adjustment of heart rate for the effect of postnatal age, heart rate during active sleep was related to weight gain (y = 0.97 x + 144, r2 = 0.15), nitrogen-energy ratio of the diet (y = 5.9 x + 139,2 r2 = 0.22), and energy expenditure (y = 0.53 x + 129, r2 = 0.13). Multiple regression analysis revealed that age-adjusted heart rate during active and quiet sleep was significantly related to a combination of the same three variables (r2 = 0.31).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Alteration of endotoxin fever and release of arginine vasopressin by dehydration in the guinea pig.

Arginine vasopressin (AVP), synthesized in hypothalamic neurons, is transported in axons either to the pituitary for release into the circulation or to different brain areas. In our previous experiments we documented central antipyretic AVP pathways from the hypothalamus to the ventrolateral septal area in the limbic system. In the present study we investigated if osmotic stimulation is able to activate peripheral and central release of AVP concurrently and if the antipyretic pathways are influenced by this kind of stimulation. In dehydrated animals (24 h water deprivation) the arterial blood plasma level of AVP doubled causing antidiuretic effects. Also the concentration of AVP in push-pull perfusates of the limbic septal area was significantly higher in dehydrated (5.6 pg AVP/ml perfusate) than in control animals (2.6 pg AVP/ml perfusate). The febrile response to bacterial endotoxin was reduced by 50% in dehydrated guinea pigs compared to controls, statistically significant between 30 and 180 min after pyrogen application. A microinfusion of AVP antiserum into the limbic septal area enhanced the fever reaction of dehydrated guinea pigs compared to the effects of a microinfused preimmune serum, in this case statistically significant between 180 and 360 min after application. From these data we assume a simultaneous activation of peripheral and central release of AVP with antidiuretic and antipyretic effects by dehydration.

Animals↗
PubMed1990

The effect of ACE inhibition on myocardial energy metabolism.

There are several indications that the oxygen supply to the myocardium is inadequate in chronic heart failure. This is due to an increased intramyocardial vascular resistance, elevated filling pressures, and a shortened diastolic perfusion time. In parallel, the myocardial oxygen demand is heightened due to elevated wall stress, heart rate and contractility. This imbalance between myocardial oxygen supply and demand might be the cause of the adaptive metabolic changes seen in severe chronic heart failure. We showed increased LDH 5, decreased LDH 1 and increased ADP/ATP-carrier concentration in the myocardium from patients with chronic heart failure. After ACE-inhibitor treatment in 33 patients with chronic heart failure, LDH 1 increased from 38.7 +/- 6.7% to 42.3 +/- 5.5% (P less than 0.005) paralleled by a decrease in LDH 5 from 20.8 +/- 7.0% to 15.8 +/- 4.7% (P less than 0.001). The ADP/ATP-carrier concentration also decreased significantly within the normal range. This shift in the LDH isoenzyme pattern and decrease in the ADP/ATP-concentration can be interpreted as an indication for an improvement of myocardial energy balance in chronic heart failure under ACE-inhibitor therapy. This might help interrupt the self-perpetuation of chronic heart failure which is partially caused by a progressive subendocardial perfusion deficit.

Cardiac Output, Low↗
PubMed1990

Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac function.

The adenosine diphosphate (ADP)-adenosine triphosphate (ATP) carrier of the inner mitochondrial membrane is identified as an autoantigen in myocarditis and dilated cardiomyopathy. Sera of patients with these diseases contain autoantibodies to the ADP-ATP carrier capable of inhibiting nucleotide transport in vitro. Recently, an antibody-related infringement of energy metabolism was shown in intact perfused hearts isolated from guinea pigs immunized with the ADP-ATP carrier. A decreased cytosolic-mitochondrial difference of the phosphorylation potential of ATP was measured that originated from a reduction in mitochondrial-cytosolic nucleotide transport. Nonimmunized animals did not show these changes in energy metabolism, despite being in a comparable metabolic state and performing equal external heart work. To establish whether antibodies to the ADP-ATP carrier can also alter cardiac function, hemodynamic parameters of isolated hearts of guinea pigs that were preimmunized with the carrier protein were measured. Cardiac metabolism was stimulated by exposing the hearts to a high calcium concentration in conjunction with a maximum elevation of the afterload. Mean aortic pressure, stroke volume, stroke work, and external heart work were found to be lowered significantly (p less than 0.005). The external heart work of the immunized hearts reached only about 20% of the level performed by control hearts. Myocardial oxygen consumption was lowered 2.5-fold, whereas the extent of lactate production was found to be more than doubled. These results show a diminished cardiac performance of hearts from animals immunized with the ADP-ATP carrier. Our findings demonstrate that autoimmunity to the ADP-ATP carrier may contribute to the pathophysiology of dilated cardiomyopathy as a subsequent stage of myocarditis by causing an autoantibody-mediated reduction in cardiac function on the basis of an imbalance between energy delivery and demand.

Animals↗