PubMed Health⌕ Search

Biomedical subjects

C Richter

Publications and source records attributed to C Richter.

At least 19 recordsLinked to original sources
PubMed1996

Stimulation of Ca2+ release from rat liver mitochondria by the dithiol reagent alpha-lipoic acid.

Rat liver mitochondria contain a Ca(2+)-specific release pathway stimulated by Ca(2+)-dependent hydrolysis of oxidized intramitochondrial pyridine nucleotides to ADP ribose and nicotinamide. We have previously shown that NAD+ hydrolysis and subsequent Ca2+ release are inhibited by cyclosporine A and that they are only possible when some critical thiols are cross-linked or oxidized, e.g. by phenylarsine oxide, gliotoxin, or peroxynitrite. We now report that the antioxidant alpha-lipoic acid stimulates Ca2+ release from intact mitochondria, i.e. with preservation of the mitochondrial membrane potential and without large-amplitude swelling. The release stimulated by alpha-lipoic acid is inhibited by cyclosporine A and is more effective when the pyridine nucleotides are oxidized. The results strongly suggest that alpha-lipoic acid stimulates the Ca(2+)-specific release pathway from intact mitochondria by oxidizing some vicinal thiols, thereby stimulating hydrolysis of oxidized pyridine nucleotides. These observations further corroborate that intact rat liver mitochondria contain a specific Ca2+ release pathway stimulated by modification of vicinal thiols. Prolonged stimulation of Ca2+ release by lipoic acid followed by its re-uptake (Ca2+ "cycling") may contribute to the detrimental, prooxidant-like effects seen with higher concentrations of lipoic acid.

Animals↗
PubMed1996

Direct observation of iron-induced conformational changes of mitochondrial DNA by high-resolution field-emission in-lens scanning electron microscopy.

When respiring rat liver mitochondria are incubated in the presence of Fe(III) gluconate, their DNA (mtDNA) relaxes from the supercoiled to the open circular form dependent on the iron dose. Anaerobiosis or antioxidants fail to completely inhibit the unwinding. High-resolution field-emission in-lens scanning electron microscopy imaging, in concert with backscattered electron detection, pinpoints nanometer-range iron colloids bound to mtDNA isolated from iron-exposed mitochondria. High-resolution field-emission in-lens scanning electron microscopy with backscattered electron detection imaging permits simultaneous detailed visual analysis of DNA topology, iron dose-dependent mtDNA unwinding, and assessment of iron colloid formation on mtDNA strands.

Animals↗
PubMed1996

Peroxynitrite stimulates the pyridine nucleotide-linked Ca2+ release from intact rat liver mitochondria.

Rat liver mitochondria contain a specific Ca2+ release pathway which operates when oxidized mitochondrial pyridine nucleotides are hydrolyzed in a Ca2+-dependent manner to ADP-ribose and nicotinamide. We have previously shown that NAD+ hydrolysis is inhibited by cyclosporin A and is possible only when some vicinal thiols are cross-linked. Here we report that the thiol oxidant peroxynitrite (ONOO-), which can form from nitric oxide (nitrogen monoxide, NO.) and superoxide anion (O2-), at low concentrations stimulates the specific Ca2+ release pathway. Both peroxynitrite-induced pyridine nucleotide hydrolysis and Ca2+ release are inhibited by cyclosporin A, and peroxynitrite is ineffective when pyridine nucleotides are kept reduced. Ca2+ release induced by peroxynitrite occurs with maintenance of the mitochondrial membrane potential and is not accompanied by entry of sucrose into mitochondria. The results suggest that peroxynitrite stimulates the specific Ca2+ release from intact mitochondria by modifying critical mitochondrial thiols other than glutathione in such a way that hydrolysis of oxidized pyridine nucleotides is achieved. These findings provide further insight into the regulation of Ca2+ release from mitochondria by nitric oxide and its congeners.

Animals↗
PubMed1996

Control of apoptosis by the cellular ATP level.

Apoptosis is a physiological form of cell death. Its causes and execution mechanisms are not clearly understood. Oxidative stress, nitric oxide and its congeners, Ca2+, proteases, nucleases, and mitochondria are considered mediators of apoptosis. At present their importance and exact role are elusive but it is clear that mitochondria are both the target and the source of oxidative stress, nitric oxide, and Ca2+. The mitochondrial membrane potential (delta psi), which is the driving force for mitochondrial ATP synthesis, declines during apoptosis, and maintenance of delta psi prevents apoptosis. Since apoptosis is highly regulated and involves the activity of hydrolytic enzymes, chromatin condensation and vesicle formation apoptosis is likely to have a high energy demand. We propose that the cellular ATP level is an important determinant for cell death. This hypothesis is supported by circumstantial evidence, is consistent with the available data, has a corrolary in aging, and is amenable to direct experimental testing particularly with flow cytometry as a promising tool.

Adenosine Triphosphate↗
PubMed1996

PCR detection of mycobacteraemia in tanzanian patients with extrapulmonary tuberculosis.

In 191 Tanzanian patients admitted to hospital with suspected extrapulmonary tuberculosis (TB), TB was diagnosed in 158 patients; the remaining 33 patients had neither microbiological nor clinical evidence of TB. Mycobacterium tuberculosis was detected in the blood of 25 patients, in 92% by a polymerase chain reaction (PCR) technique and in 52% by culture of buffy coat cells. The presence of mycobacterial DNA or Mycobacterium tuberculosis bacteria in peripheral blood (positive culture) was significantly associated with HIV infection; it was detected in 22 (21.4%) of 103 HIV-seropositive patients compared to only 3 (3.5%) of 55 HIV-seronegative patients (p < 0.009). In two-thirds of the patients with mycobacteraemia, TB can be detected by simple smears from other organ sites. In patients with suspected extrapulmonary tuberculosis in whom smears from the infected site are negative or not available, PCR on blood will confirm the diagnosis within 24 hours in one third of the cases.

Adult↗
PubMed1996

Control of the pyridine nucleotide-linked Ca2+ release from mitochondria by respiratory substrates.

Oxidation of mitochondrial pyridine nucleotides followed by their hydrolysis promotes Ca2+ release from intact liver mitochondria. In most of the previous studies oxidation was achieved with pro-oxidants which were added to mitochondria respiring on succinate in the presence of rotenone, a site I-specific inhibitor of the respiratory chain. Here we investigate pro-oxidant dependent and independent Ca2+ release from mitochondria when respiration is supported either by the NAD(+)-linked substrate beta-hydroxybutyrate, or by succinate. In the presence, as well as in the absence, of the pro-oxidant t-butylhydroperoxide mitochondria retain Ca2+ much better with succinate than with beta-hydroxybutyrate as respiratory substrate. When Ca2+ release is induced by t-butylhydroperoxide succinate-supported Ca2+ retention is impeded by rotenone. Ca2+ release (pro-oxidant dependent or independent) is paralleled by oxidation and hydrolysis of intramitochondrial pyridine nucleotides, and Ca2+ retention is paralleled by reduction of pyridine nucleotides. It is concluded that the pyridine nucleotide-linked Ca2+ release from mitochondria can be controlled by respiratory substrates which regulate the intramitochondrial hydrolysis of oxidized pyridine nucleotides.

3-Hydroxybutyric Acid↗
PubMed1995

Nitric oxide (nitrogen monoxide, NO) stimulates insulin secretion by inducing calcium release from mitochondria.

Nitric oxide (nitrogen monoxide, NO) acts as messenger molecule in a variety of cells and may also be involved in the insulin secretory pathway of islet beta-cells. We report here that NO at a low micromolar concentration stimulates epinephrine-sensitive insulin secretion from cells of the beta-cell line, INS-1. Insulin secretion is paralleled by a reversible decrease of the mitochondrial membrane potential and by an increase of the cytosolic calcium. Chelation of intracellular, but not of extracellular calcium prevents the NO-induced insulin secretion. These data indicate that NO can stimulate insulin secretion by deenergizing mitochondria and thereby triggering mitochondrial calcium release.

Animals↗
PubMed1995

Oxidants in mitochondria: from physiology to diseases.

Reactive oxygen species (ROS: superoxide radical, O2.-; hydrogen peroxide, H2O2; hydroxyl radical, OH.), which arise from the univalent reduction of dioxygen are formed in mitochondria. We summarize here results which indicate that ROS, and also the radical nitrogen monoxide ('nitric oxide', NO), act as physiological modulators of some mitochondrial functions, but may also damage mitochondria. Hydrogen peroxide, which originates in mitochondria predominantly from the dismutation of superoxide, causes oxidation of mitochondrial pyridine nucleotides and thereby stimulates a specific Ca2+ release from intact mitochondria. This release is prevented by cyclosporin A (CSA). Hydrogen peroxide thus contributes to the maintenance of cellular Ca2+ homeostasis. A stimulation of mitochondrial ROS production followed by an enhanced Ca2+ release and re uptake (Ca2+ 'cycling') by mitochondria causes apoptosis and necrosis, and contributes to hypoxia/reperfusion injury. These kinds of cell injury can be attenuated at the mitochondrial level by CSA. When ROS are produced in excessive amounts in mitochondria nucleic acids, proteins, and lipids are extensively modified by oxidation. Physiological (sub-micromolar) concentrations of NO potently and reversibly deenergize mitochondria at oxygen tensions that prevail in cells by transiently binding to cytochrome oxidase. This is paralleled by mitochondrial Ca2+ release and uptake. Higher NO concentrations or prolonged exposure of cells to NO causes their death. It is concluded that ROS and NO are important physiological reactants in mitochondria and become toxic only when present in excessive amounts.

Animals↗
PubMed1995

Perioperative management in thoracic surgery.

The quality of perioperative treatment for patients undergoing thoracic surgery is of the utmost importance for postoperative morbidity and mortality. Hence, it was the purpose of this study to examine various aspects of our own procedure. The clinical course following 812 successive thoracotomies in 792 patients over a period of 3 years was documented and analysed. The overall complication rate was found to be 19.7%, with a mortality of 3.8% over a 30-day period. Secretostasis, atelectasis and pneumonia were the most common complications. Owing to the predeposition of autologous blood, the percentage of patients requiring allogeneic blood transfusion was reduced from 27% to 9%. There was no evidence suggesting an increase in the complication rate or a longer stay in hospital. Perioperative antibiotic prophylaxis has reduced postoperative wound infection significantly. Similar reductions in the FEV1 are recorded following thoracic surgery, irrespective of the amount of lung tissue resected. This observation indicates that the remaining lung tissue is severely compromised throughout the postoperative period and that the surgical trauma alone is a major factor influencing postoperative pulmonary function for at least 2 weeks.

Adolescent↗
PubMed1995

Clinical features of HIV seropositive and HIV seronegative patients with tuberculous lymphadenitis in Dar es Salaam.

SETTING: The medical wards of a referral hospital in Dar es Salaam, Tanzania. OBJECTIVE: To investigate the impact of HIV infection on clinical features in tuberculous lymphadenitis. DESIGN: A prospective clinical study of HIV seropositive and HIV seronegative patients with lymphadenopathy. RESULTS: Of 128 patients with peripheral lymphadenopathy, 24 had no tuberculosis (TB) and in 10 patients TB was found only in other organs. The remaining 94 patients, of whom 76% were HIV seropositive, formed our study population. TB lymphadenitis was considered proven in 89 and probable in 5 patients. Disseminated TB (both TB adenitis and TB in other organs) was diagnosed more often in HIV seropositive than in HIV seronegative patients (52% versus 26%, P < 0.03). 59% of the 71 HIV-infected patients compared to only 4% of the 23 patients without HIV infection were over 30 years of age (P < 0.02). The following clinical features were significantly associated with HIV infection: dyspnoea, respiratory rate > 20/min, low motility score (bedridden), neurological abnormalities, hepatomegaly, splenomegaly, lymph node size < 2.5 cm, negative PPD skin test, lymphopenia (< 1000/cm3) and presence of pleural fluid. CONCLUSION: Co-infection with HIV influences several clinical and laboratory features in patients with tuberculous lymphadenitis.

Adult↗
PubMed1995

Predictive markers of survival in HIV-seropositive and HIV-seronegative Tanzanian patients with extrapulmonary tuberculosis.

SETTING: Prediction of survival in Tanzanian patients with extrapulmonary tuberculosis (TB). OBJECTIVE: To evaluate the prognostic value of clinical and laboratory parameters on survival in human immunodeficiency virus (HIV) seropositive and HIV seronegative patients with extrapulmonary TB. DESIGN: Over an 8-month period 192 consecutive patients with extrapulmonary TB, admitted to a major referral centre in Tanzania, were enrolled in the study. Their symptoms, signs and PPD skin test were noted. Their sera were tested for HIV and analyzed for beta-2-microglobulin content. Univariate risk factors for 12 months' survival after the start of anti-TB chemotherapy were entered into a stepwise Cox regression model. Survival probabilities were estimated according to the number of risk factors. RESULTS: Of the 192 patients 126 (65%) were HIV-infected, and 29.7% had disseminated TB. Thirty-five patients, of whom 24 (68.6%) were HIV-positive, withdrew from the study immediately after hospital discharge. For survival analysis 157 patients remained. Within 12 months' follow-up after initiation of anti-TB therapy, the case fatality rate of the 102HHIV-infected patients was 22% and of the 55 HIV seronegative patients 2% (P < 0.001). In the HIV seropositive patients the following independent risk factors were significantly associated with a decreased probability of survival: peripheral lymphadenopathy (Hazard Rate Ratio (HRR) 5.2, 95% Confidence Interval [CI] 1. 7-16.2), a decreased activity score (bedridden > 50%/day (HRR 4.5, 95% CI 1.7-11.7), lymphopenia of < 1000/microL (HRR 4.4, 95% CI 1.7-11.8), and mycobacteraemia (HRR 4.0, 95% CI 1.2-13-.1). An anergic PPD skin test reaction proved to be another independent risk factor when the analysis was performed on 89 patients with available Mantoux test results. In the HIV seropositive patients, the 12 months' survival probabilities were 93%, 86%, 54% and 0% for presence of 0, 1, 2, and > 2 risk factors respectively. CONCLUSION: Estimation of survival probabilities in patients with extrapulmonary TB may be possible without performing CD4 cell counts.

Adolescent↗
PubMed1995

Humoral response to Mycobacterium tuberculosis-specific antigens in African tuberculosis patients with high prevalence of human immunodeficiency virus infection.

SETTING: The applicability of serodiagnosis of tuberculosis using Mycobacterium tuberculosis-complex-specific antigens in a Tanzanian population with high prevalence of HIV. OBJECTIVE: This study was performed to evaluate the usefulness, sensitivity and specificity of serology using M. tuberculosis-specific antigens in the diagnosis of tuberculosis in patients with and without HIV co-infection. DESIGN: Patients with proven pulmonary and extrapulmonary tuberculosis at a major referral centre in Tanzania were enrolled in the study. The control group consisted of patients without a history of previous tuberculosis admitted to the trauma ward and of healthy volunteers. Sera were analysed by an enzyme linked immunoassay (ELISA) using two M. tuberculosis specific proteins as antigen: the 38 kDa protein [3T] and a 17 kDa protein. In addition was recorded presence or absence of BCG scar and tuberculin sensitivity and the sera were tested for HIV and analysed for beta-2-microglobulin content. RESULT: Sensitivity and specificity were markedly reduced in tuberculosis patients with HIV co-infection compared to patients without this disease (73% and 70% versus 52% and 50% respectively). CONCLUSION: Serology for diagnosis of tuberculosis is not feasible in an HIV endemic region.

Antibodies, Bacterial↗
PubMed1995

Oxidative damage to mitochondrial DNA and its relationship to ageing.

Mitochondria are the most important intracellular source of reactive oxygen species and are protected against them by enzymatic and nonenzymatic antioxidants. Nevertheless, mitochondrial DNA (mtDNA) is subject to severe oxidative damage, and much more so than nuclear DNA (nDNA). Damage is indicated by the detection of various base modifications, particularly 8-hydroxydeoxyguanosine (8OHdG), which can lead to point mutations because of mispairing. MtDNA is also fragmented to some extent. Conceivably, such fragmentation relates to the deletions found in mtDNA. Several hypotheses suggest that defective mitochondria contribute to, or are responsible for, ageing. Recent observations indicate that mitochondria in an old organism differ in many respects from those in a young organism. Thus, with ageing there is an increased production of reactive oxygen species, a decrease in certain antioxidants, a decreased transcription, translation, and cytochrome oxidase content, and an increase in the extent of DNA modifications. Major unresolved questions concerning the role of mtDNA changes in ageing are addressed: is there a causal relationship; what is the true extent of DNA damage; what are significance and functional consequences of mtDNA oxidation; are reactive oxygen species the cause of the DNA modifications found in vivo; what is the relationship between DNA damage and alterations of RNAs and proteins? Future studies promise to clarify the possible causal relationship between mitochondrial dysfunction, reactive oxygen species production, mtDNA modifications, and ageing.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1995

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality.

Adult↗
PubMed1995

rhEPO treatment of postpartum anemia.

Postpartum hemorrhage is a continuing problem occurring in 5-10% of all deliveries. Due to recent problems with blood transfusion, heterologous blood is nowadays restricted to life-threatening indications. As a consequence the clinician is faced with many patients suffering from overt symptoms of anemia. We therefore investigated the effect of recombinant human erythropoietin (rhEPO) in combination with adequate iron supplementation as an alternative for blood transfusion in postpartum anemia. In a pilot study we could show that rhEPO can enhance the effect of endogenous erythropoietin on erythropoiesis. These data could be confirmed in a larger randomized trial. In another study we could show that rhEPO given s.c. is as effective as i.v. Measurement of the iron stores, however, demonstrated low values at the end of pregnancy indicating that iron is a limiting factor for erythropoiesis in postpartum anemia. In a next study i.v. iron combined with rhEPO showed a greater increase in Hb compared to i.v. iron alone. The chosen dose of i.v. iron, however, was too small as shown by the low ferritin levels. We concluded from these previous studies that rhEPO enhances endogenous erythropoiesis, but so far the effect was only slight (ca 1 g/dl within 14 days); all treated patients developed overt iron deficiency in terms of low ferritin levels despite oral and i.v. iron supplementation; no major side-effects were seen. A further study in healthy non pregnant volunteers demonstrated an effect on erythropoiesis lasting for 3-4 days after a single dose of 300 U/kg rhEPO.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia↗
PubMed1995

Erythropoiesis in the postpartum period.

The puerperium is a time of immense physiological changes for the female organism. Erythropoiesis plays one of the central roles in these processes. The aim of this investigation was to describe physiological erythropoiesis in healthy women during the puerperium. Blood samples were taken just before delivery and on days 1, 2, 3, 4 and 14 postpartum. In addition to the usual parameters such as hemoglobin, hematocrit, platelets, leucocytes, ferritin, CRP, endogenous erythropoietin, etc., the absolute and the percentage reticulocyte counts-both the total and for the subpopulations-were determined by flow cytometry. The mean Hb values decreased in the first 24 hours postpartum by 0.8 g/dl and then rose to 0.2 g/dl more than the initial value on day 14. The reticulocytes reflected erythropoietic stimulation with an increase from day 0 to day 1 of 2.1% (79.1 x 10(9)/1) and a continual decrease thereafter. The hematological parameters followed a characteristic course in the puerperium. For the reticulocytes and the subpopulations, a definite erythropoietic stimulation was evident even before delivery, as was an increase in the erythropoietic activity in the early puerperium.

Adult↗
PubMed1995

Recombinant human erythropoietin and parenteral iron in the treatment of pregnancy anemia: a pilot study.

Our aim was to correct severe iron deficiency anemia during pregnancy by using a combination therapy of recombinant human erythropoietin and parenteral iron. Eleven anemic pregnant women were treated once weekly until a hemoglobin value of 11.0 g/dl was reached. Red blood cell production was monitored by reticulocyte flow cytometry and hemoglobin increase. Iron status was assessed by serum ferritin values and transferrin saturation values. 8/11 patients showed an immediate response, noted by a continuous increase of reticulocytes, high fluorescent reticulocyte ratio and hemoglobin levels. Three patients who had lower serum ferritin values, low transferrin saturation and a lower reticulocyte count before treatment showed little response. The combination of rhEPO and parenteral iron is effective in stimulating erythropoiesis and in treating certain pregnancy anemias. This therapy could be an alternative for patients refusing blood transfusions or who are resistant to iron alone. Poor response to the treatment can be due to insufficient iron supplementation during therapy with rhEPO or due to factors that inhibit erythropoiesis during pregnancy, such as undetected infections.

Anemia↗