CD4/CXCR4-mediated cell death in AIDS.
Explore the source record for details and available documents.
Acquired Immunodeficiency Syndrome↗
Biomedical subjects
R Breitkreutz
Publications and source records attributed to R Breitkreutz.
Prehospital ultrasound imaging improves management of abdominal trauma.
BACKGROUND: Blunt abdominal trauma with intra-abdominal bleeding is often underdiagnosed or even overlooked at trauma scenes. The purpose of this prospective, multicentre study was to compare the accuracy of physical examination and prehospital focused abdominal sonography for trauma (PFAST) to detect abdominal bleeding. METHODS: Six rescue centres took part in the study from December 2002 to December 2003, including 230 patients with suspected abdominal injury. The accuracy of physical examination at the scene and PFAST were compared. Later examinations in the emergency department (ultrasonography and/or computed tomography) were used as the reference standard. RESULTS: The complete protocol and follow-up was obtained in 202 patients. The sensitivity, specificity and accuracy of PFAST were 93 per cent, 99 per cent and 99 per cent, respectively, compared with 93 per cent, 52 per cent and 57 per cent for physical examination at the scene. Scanning with PFAST occurred a mean(s.d.) 35(13) min earlier than ultrasound in the emergency department. Abdominal bleeding was detected in 14 per cent of patients. Using PFAST led to a change in either prehospital therapy or management in 30 per cent of patients, and a change to admitting hospital in 22 per cent. CONCLUSION: In this study, PFAST was a useful and reliable diagnostic tool when used as part of surgical triage at the trauma scene.
Abdominal Injuries↗
Flux of amino acids and energy substrates across the leg in weight-stable HIV-infected patients with acute opportunistic infections: indication of a slow protein wasting process.
Increased whole-body proteolysis with muscle protein net degradation has been suggested as one of the causes of weight loss in patients infected with human immunodeficiency virus (HIV). We studied the exchange rates of amino acids and energy substrates across the lower extremity in 16 HIV patients and 16 age-matched controls with similar body cell mass. The patients had either opportunistic infections or chronic diarrhea but no signs of clinical malnutrition. The following findings were obtained in the HIV patients: an augmented peripheral net release of arginine and lysine; an increase in both the negative arterial-venous difference and the efflux of the nitrogen contained in nonmetabolized amino acids; diminished export of 3-methylhistidine; lowered plasma and erythrocyte amino acid concentrations; reduced output of glycerol and furthermore; and neither a net release nor a net uptake of free fatty acids. The findings concerning nitrogen metabolism support the hypothesis that, in the presence of a reduction in protein breakdown, peripheral protein synthesis is severely depressed, making a slow protein wasting process likely to occur. The balances of glycerol and free fatty acids are due not only to the leg tissues but perhaps also in part to increased net retention of these substrates by skeletal muscle.
AIDS-Related Opportunistic Infections↗
Influence of N-acetylcysteine on hepatic amino acid metabolism in patients undergoing orthotopic liver transplantation.
Experimental treatment with the antioxidant and glutathione precursor N-acetylcysteine (NAC) has been performed in orthotopic liver transplantation (OLT) to reduce reperfusion injury. To investigate the effect of NAC on the hepatic and intestinal amino acid metabolism, intraoperative amino acid exchange rates were studied in liver transplant recipients with high dose NAC treatment (n = 10) and in control patients (n = 9). Treatment with NAC was found to cause a loss of amino acids and increased urea nitrogen release from the liver graft. The net balance of most amino acids was shifted to increased hepatic release or decreased hepatic uptake. The initial cumulative splanchnic release of all proteinogenic amino acids in the NAC treated group was significantly higher than in the control group. These findings are tentatively explained by an increased net protein catabolism in the liver. The increased hepatic urea and glutamine production rate of the NAC treated patients is expected to increase the energy and oxygen demand of the liver in this critical situation. Thus, NAC may have caused marked metabolic disturbances in the freshly implanted graft. The dosage of NAC should therefore be modified to avoid these disadvantages.
Acetylcysteine↗
N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients.
OBJECTIVE: The antioxidant N-acetylcysteine (NAC) has been shown to attenuate septic tissue injury. To evaluate whether NAC affects host defense mechanisms in critically ill patients, thus predisposing to increased risk of infection, the current study focuses on neutrophil phagocytotic and burst activity after treatment with NAC. DESIGN: Prospective, randomized, clinical trial. SETTING: Twelve-bed operative intensive care unit in a university hospital. PATIENTS: Thirty patients diagnosed with sepsis/systemic inflammatory response syndrome, or multiple trauma. INTERVENTIONS: Patients were randomly assigned to receive either NAC (n = 15) for 4 days in increasing dosages (day 1: 6 g; day 2: 12 g; days 3 and 4: 18 g) or a mucolytic basis dosage of NAC (3 x 300 mg/day [control]; n = 15), respectively. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken before NAC high-dose infusion (day 1), after increasing doses of NAC (days 3 and 5) and 4 days after the last high-dose treatment (day 8). Neutrophil oxidative burst activity after stimulation with Escherichia coli and polymorphonuclear phagocytosis were determined in a flow cytometric assay. Baseline values of polymorphonuclear functions were comparable in both groups. NAC high-dose treatment resulted in a significantly improved phagocytosis activity compared with control patients. In contrast to this, polymorphonuclear burst activity was significantly reduced in the NAC high-dose treated group on day 3. CONCLUSION: These findings suggest that infusion of NAC in high doses affects granulocyte functions in critically ill patients. Antimicrobial host defense requires the effective sequence of cell adhesion, phagocytosis, and bactericidal respiratory burst. The enhanced phagocytotic activity might be a compensatory mechanism in states of impaired respiratory burst to maintain tissue sterility. For certain mechanisms of disease, the effects observed might be favorable (e.g., ischemia/reperfusion, endothelial cell activation), for others (infection) this might be detrimental.
APACHE↗
Hepatitis B virus nucleic acids circulating in the blood: distinct patterns in HBs carriers with hepatocellular carcinoma.
Circulating nucleic acids in serum and plasma are common in a variety of disease conditions. Here, we focus (i) on our approach for the detection of various hepatitis B virus (HBV)-related nucleic acids in liver tissue and in serum, (ii) on the progression of the chronic HBV infection, (iii) on the relation of HBV-specific nucleic acids circulating in the blood of patients with hepatocellular carcinoma, and in general (iv) on the diagnostic potential of circulating HBV nucleic acids.
Amino Acid Sequence↗
Metabolic encephalopathies: liver disease, renal failure, critical illness.
Explore the source record for details and available documents.
Animals↗
Circulating hepatitis B virus nucleic acids in chronic infection : representation of differently polyadenylated viral transcripts during progression to nonreplicative stages.
PURPOSE: Beside the established maturation of hepatitis B virus (HBV) transcripts at a polyadenylation signal downstream of the HBV x protein open reading frame, maturation at an internal polyadenylation signal has been observed in the chronically infected liver. In the present study, it was the aim to identify the respective circulating full-length and truncated transcripts in plasma/serum of carriers. EXPERIMENTAL DESIGN: Nucleic acids extracted from sera were analyzed using established PCR and reverse transcription-PCR procedures targeted to HBV x protein gene regions. Amplification products were cloned and sequenced. RESULTS: Base substitution patterns were determined, which indicated infection stages advanced to different degrees regardless of the transcript type analyzed. HBV full-length RNA (fRNA) showed a high correlation with hepatitis B e antigen and viral DNA, indicative for a replicative infection. In contrast, truncated RNA (trRNA) appeared to be independent of hepatitis B e antigen and showed only a weak association with circulating viral DNA. No correlation was observed between the levels of trRNA and the apparent liver damage as reflected by alanine transaminase levels. An age-dependent representation of fRNA and trRNA was observed: fRNA decreased progressively to low levels, whereas trRNA remained at comparably high values. trRNA and RNA not polyadenylated at either of the two polyadenylation signals were detected even in the absence of any other conventional HBV seromarker, including viral DNA. This was shown for patients with cryptogenic cirrhosis and hepatitis C virus carriers. CONCLUSIONS: The identification of HBV RNA in human serum has a diagnostic potential for apparent and for inapparent infection stages.
Adolescent↗
Enhancement of T cell receptor signaling by a mild oxidative shift in the intracellular thiol pool.
Exposure of T cells to the macrophage products hydrogen peroxide (HP) or L-lactate (LAC) was previously shown to enhance IL-2 production and to modulate glutathione (GSH) status. We now found that 50 microM HP and 30 mM LAC enhanced strongly the transcription from the IL-2 promoter in Jurkat T cells after stimulation with anti-CD28 together with or without anti-CD3 but not with anti-CD3 Abs alone. Therefore, we used anti-CD3 plus anti-CD28-stimulated cells to investigate the effect of the GSH reductase inhibitor 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) on the signal cascade. BCNU enhanced the transcription to a similar extent as HP or LAC. Lowering the intracellular GSH/GSH disulfide ratio by BCNU, HP, or NO resulted in all cases in the fulminant enhancement of Jun-N-terminal kinase and p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2. Jun-N-terminal kinase and NF-kappaB activation was enhanced through pathways involving Rac, Vav1, PKCTheta, p56(lck), p59(fyn), and IkappaB kinases. In a cell-free system, the autophosphorylation of rFyn was stimulated by GSH disulfide but not by HP. These findings suggest that the oxidation of the cellular thiol pool may play a role as an amplifying mechanism for TCR/CD3 signals in immune responses.
Antibodies, Monoclonal↗
Thiol-mediated redox regulation of intestinal lamina propria T lymphocytes.
Intestinal lamina propria T lymphocytes (LP-Ts) have a markedly low proliferative potential both in vivo and in vitro. Here, we have identified that the capacity of antigen-presenting cells to release cysteine upon receptor-ligand interactions represents a critical parameter for proliferation of LP-Ts. The availability of cysteine is limiting for the intracellular production of glutathione, which in turn is essential for cell cycle progression. When cysteine is provided either directly or by addition of the reducing agent 2-mercaptoethanol to cystine-containing culture medium, proliferation of LP-T is fully restored. Importantly, coculture with peripheral blood monocytes that easily take up cystine, reduce cystine, and secrete cysteine also restores reactivity of LP-Ts to T cell receptor/CD3 stimulation. In marked contrast, lamina propria macrophages lack this capacity to elaborate cysteine, and thereby secure physiological unresponsiveness to antigen exposure in the intestinal microenvironment. The well-documented local recruitment of blood monocytes in inflammatory bowel disease (IBD) may thus represent an important parameter underlying hyperresponsiveness of T cells, an essential component of the pathogenesis of IBD.
Antigen-Presenting Cells↗
Glutathione is a factor of resistance of Jurkat leukemia cells to nitric oxide-mediated apoptosis.
We have previously reported that nitric oxide (NO) stimulates apoptosis in different human neoplastic lymphoid cell lines through mitochondrial damage (including degradation of cardiolipin, a major mitochondrial lipid) followed by activation of caspases. Here we demonstrate that Jurkat human leukemia cells which survive after 24 h treatment with NO form subpopulations with higher and lower cardiolipin content (designated as NAO(high) and NAO(low), respectively). Sorted NAO(high) cells were found to survive in culture whereas sorted NAO(low) cells died. Moreover, NAO(high) cells acquired an increased resistance to the exposure to NO donors which remained unchanged during long-term culture. These cells showed a similar cardiolipin content and expressed the same level of anti-apoptotic proteins Bcl-2 and Bcl-x(L) as APO-S unsorted cells but contained significantly higher concentration of the antioxidant glutathione. Depletion of glutathione in these cells with buthionine-sulfoximine (BSO) correlated with a significant stimulation of NO-mediated apoptosis whereas the exposure of NO-sensitive APO-S cells to the glutathione precursor N-acetylcysteine (NAC) resulted in a substantial suppression of this effect. Our data suggest a complex mechanism of the resistence to NO-induced apoptosis in Jurkat human leukemia cells in which glutathione plays an important role.
Acridine Orange↗
Massive loss of sulfur in HIV infection.
Skeletal muscle tissue from SIV-infected macaques was previously found to contain abnormally high sulfate and low glutathione levels indicative of an excessive cysteine catabolism. We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit. The comparison of the sulfate concentrations of the arterial and venous blood from the lower extremities of 16 symptomatic HIV+ patients and 18 HIV- control subjects (study 1) revealed (1) that the peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and (2) that plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. A complementary investigation of 64 asymptomatic HIV+ patients and 65 HIV- subjects (study 2) revealed increased plasma sulfate levels in the asymptomatic patients. The analysis of the daily urinary excretion of sulfate and urea of another group of 19 HIV+ patients and 22 healthy HIV- subjects (study 3) confirmed (1) that HIV+ patients experience a massive loss of sulfur and (2) that this loss is not ameliorated by HAART. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to an alarming negative balance of approximately 2 kg of cysteine per year under the assumption that the normal sulfate excretion equivalent to approximately 3 g of cysteine per day is balanced by a standard Western diet. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool.
Adult↗
Improvement of immune functions in HIV infection by sulfur supplementation: two randomized trials.
To determine the therapeutic effect of sulfur amino acid supplementation in HIV infection we randomized 40 patients with antiretroviral therapy (ART; study 1) and 29 patients without ART (study 2) to treatment for 7 months with N-acetyl-cysteine or placebo at an individually adjusted dose according to a defined scheme. The main outcome measures were the change in immunological parameters including natural killer (NK) cell and T cell functions and the viral load. Both studies showed consistently that N-acetyl-cysteine causes a marked increase in immunological functions and plasma albumin concentrations. The effect of N-acetyl-cysteine on the viral load, in contrast, was not consistent and may warrant further studies. Our findings suggest that the impairment of immunological functions in HIV+ patients results at least partly from cysteine deficiency. Because immune reconstitution is a widely accepted aim of HIV treatment, N-acetyl-cysteine treatment may be recommended for patients with and without ART. Our previous report on the massive loss of sulfur in HIV-infected subjects and the present demonstration of the immunoreconstituting effect of cysteine supplementation indicate that the HIV-induced cysteine depletion is a novel mechanism by which a virus destroys the immune defense of the host and escapes immune elimination.
Acetylcysteine↗
Glutathione and immune function.
The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation. This factor has been studied most extensively in the case of human immunodeficiency virus (HIV)-infected patients who were found to experience, on average, a massive loss of S equivalent to a net loss of approximately 4 g cysteine/d. Two randomized placebo-controlled trials have shown that treatment of HIV-infected patients with N-acetyl-cysteine caused in both cases a significant increase in all immunological functions under test, including an almost complete restoration of natural killer cell activity. It remains to be tested whether cysteine supplementation may be useful also in other diseases and conditions that are associated with a low mean plasma cystine level and impaired immunological functions.
Acetylcysteine↗
Effect of carnitine on muscular glutamate uptake and intramuscular glutathione in malignant diseases.
Abnormally low intramuscular glutamate and glutathione (GSH) levels and/or a decreased muscular uptake of glutamate by the skeletal muscle tissue have previously been found in malignant diseases and simian immunodeficiency virus (SIV) infection and may contribute to the development of cachexia. We tested the hypothesis that an impaired mitochondrial energy metabolism may compromise the Na+-dependent glutamate transport. A randomized double-blind clinical trial was designed to study the effects of L-carnitine, i.e. an agent known to enhance mitochondrial integrity and function, on the glutamate transport and plasma glutamate level of cancer patients. The effect of carnitine on the intramuscular glutamate and GSH levels was examined in complementary experiments with tumour-bearing mice. In the mice, L-carnitine treatment ameliorated indeed the tumour-induced decrease in muscular glutamate and GSH levels and the increase in plasma glutamate levels. The carnitine-treated group in the randomized clinical study showed also a significant decrease in the plasma glutamate levels but only a moderate and statistically not significant increase in the relative glutamate uptake in the lower extremities. Further studies may be warranted to determine the effect of L-carnitine on the intramuscular GSH levels in cancer patients.
Adult↗
N-acetyl-cysteine in the therapy of HIV-positive patients.
Randomly selected asymptomatic HIV-positive persons reveal, on average, a massive daily loss of sulphur, which appears to represent in first approximation the mean loss throughout the asymptomatic stage, and may explain the widely observed decrease in cyst(e)ine and glutathione levels. This sulphur loss is reasonably expected to lead, within a few years, to a life-threatening condition and may, therefore, contribute decisively to disease progression. Importantly, the rate of sulphur loss is not ameliorated by highly active antiretroviral therapy and may contribute to antiretroviral treatment failure. Several clinical trials on N-acetyl-cysteine treatment of HIV-positive patients have revealed various therapeutic effects, but did not meet the rigorous standards for approval by the health authorities.
Acetylcysteine↗
[Prenatal care of a HIV-1-positive pregnancy and birth].
Mother-to-child (vertical) transmission of the human immunodeficiency virus type-1 (HIV-1) is now the main route of infection in HIV-positive children. Without any medical measures and avoiding breastfeeding the rate of vertical HIV-1-transmission is 15-20% in Europe. The rate of vertical HIV-transmission in the German centers is today approximately 2%. This low risk is the result of interdisciplinary prenatal care, antiretroviral therapy according to the individual risk profile as well as cesarean section before onset of labor, and antiretroviral treatment of neonates in the centers.
Anti-HIV Agents↗
The redox state as a correlate of senescence and wasting and as a target for therapeutic intervention.
The loss of body cell mass (bcm) in senescence and wasting is poorly understood. We now show that the plasma cystine/acid soluble thiol ratio, ie, an indicator of the redox state, is increased in old age and cancer patients and correlated with a decrease in bcm and plasma albumin. A cause/effect relationship was suggested by two independent studies with N-acetyl-cysteine (NAC). NAC caused an increase in the bcm of healthy persons with high plasma cystine/thiol ratios, and treatment of cancer patients with NAC plus interleukin-2 caused an increase in bcm, plasma albumin, and functional capacity. Albumin levels below 680 micromol/L were associated with an increase in body water. Our studies suggest that the shift in the redox state may contribute to the loss of bcm and may provide a quantitative guideline for therapeutic intervention. Treatment of cancer patients with thiol-containing antioxidants may improve the quality of life.
Acetylcysteine↗