[Hepatitis C and serum IgM concentration].
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Hepatitis C, Chronic↗
Biomedical subjects
H Hartmann
Publications and source records attributed to H Hartmann.
Small-angle X-ray scattering reveals differences between the quaternary structures of oxygenated and deoxygenated tarantula hemocyanin.
Small-angle X-ray scattering (SAXS) curves have been recorded for the oxygenated and deoxygenated states of the 4 x 6-meric hemocyanin from the tarantula Eurypelma californicum. A comparison of the curves shows that the quaternary structures of the two states are different by three criteria, which all indicate that the hemocyanin is less compact in the oxygenated compared to the deoxygenated form: (a) The radius of gyration is 8.65 +/- 0.05 nm for the deoxy- and 8.80 +/- 0.05 nm for the oxy-form. (b) The maximum particle dimension amounts to 25.0 +/- 0.5 nm for the deoxy- and to 27.0 +/- 0.5 nm for the oxy-form. (c) A dip in the intramolecular distance distribution function p(r) is more pronounced and shifted to larger distances in the oxy-form. The p(r) functions based on SAXS measurements were compared to p(r) functions deduced from published electron microscopical images of three different 4 x 6-meric hemocyanins from closely related species. The p(r) functions of SAXS and electron microscopy were similar in one case, whereas in the other two cases the distance between the two 12-meric half-molecules had to be changed by 1-1.5 nm to obtain good agreement. The differences between the p(r) functions of oxygenated and deoxygenated 4 x 6-meric tarantula hemocyanin are much larger than one would expect from a comparison of X-ray structures of the oxygenated and deoxygenated states of a closely related 6-meric hemocyanin. Thus, the conformational changes upon oxygenation occur at various levels of the quaternary structure, as postulated by hierarchical theories of allosteric interactions.
Animals↗
X-ray structure determination of a metastable state of carbonmonoxy myoglobin after photodissociation.
The x-ray structure of carbon monoxide (CO)-ligated myoglobin illuminated during data collection by a laser diode at the wavelength lambda = 690 nm has been determined to a resolution of 1.7 A at T = 36 K. For comparison, we also measured data sets of deoxymyoglobin and CO-ligated myoglobin. In the photon-induced structure the electron density associated with the CO ligand can be described by a tube extending from the iron into the heme pocket over more than 4 A. This density can be interpreted by two discrete positions of the CO molecule. One is close to the heme iron and can be identified to be bound CO. In the second, the CO is dissociated from the heme iron and lies on top of pyrrole ring C. At our experimental conditions the overall structure of myoglobin in the metastable state is close to the structure of a CO-ligated molecule. However, the iron has essentially relaxed into the position of deoxymyoglobin. We compare our results with those of Schlichting el al. [Schlichting, I., Berendzen, J., Phillips, G. N., Jr., & Sweet, R. M. (1994) Nature 317, 808-812], who worked with the myoglobin mutant (D122N) that crystallizes in the space group P6 and Teng et al. [Teng, T. Y., Srajer, V. & Moffat, K. (1994) Nat. Struct. Biol. 1, 701-705], who used native myoglobin crystals of the space group P2(1). Possible reasons for the structural differences are discussed.
Animals↗
Free intracellular calcium in aging and Alzheimer's disease.
Brain cells of aged mice exhibit distinct alterations of [Ca2+]i regulation resulting in lower levels of [Ca2+]i after stimulation. These alterations are probably more related to disturbances of mechanisms regulating transmembraneous Ca2+ fluxes than to mechanisms of intracellular Ca2+ release and storage. Comparable although not identical disturbances of [Ca2+]i regulation are present in mouse, rat, and human lymphocytes. Accordingly, one is tempted to speculate that in the human brain similar alterations of [Ca2+]i regulation might be present in aging as found in the aged mouse and rat brain. Since the downregulation of [Ca2+]i levels in aged brain cells seems to be accompanied by an enhanced intracellular sensitivity for changes of [Ca2+]i, both divergent alterations might compensate each other under normal conditions. However, it seems quite conceivable that the ability of the Ca2+ signal transduction pathway to adopt to periods of over-or understimulation (e.g., hypoxia, stress) might be disturbed in the aging brain. One of those conditions of additional alterations of [Ca2+]i regulation might be AD. Although we did not see AD-specific changes of [Ca2+]i regulation per se, the effect of beta A4 on cellular [Ca2+]i regulation was significantly and specifically disturbed in AD. It is not unlikely that a small, but long lasting (years or even decades) alterations of cellular [Ca2+]i regulation by beta A4, which is a product of normal brain metabolism, might finally contribute to the severe neuronal damage seen during the disease.
Age Factors↗
Preferential virological response to interferon-alpha 2a in patients with chronic hepatitis C infected by virus genotype 3a and exhibiting a low gamma-GT/ALT ratio.
Hepatitis C virus infection causes acute and often chronic hepatitis. Therapy with interferon-alpha has been shown to induce remission of the inflammatory process within the liver and also elimination of the virus. However, only about 50% of treated patients respond in terms of at least a transient disappearance of viral RNA from the circulation below the limit of detection. In order to find prognostic factors for responsiveness, patients with chronic hepatitis C virus infection were analyzed for virus genotype and pretreatment biochemical liver parameters including serum AST, ALT, and gamma-GT activities. Whereas the initial biochemical response to interferon-alpha 2a was found not to be related to virus genotype, the initial virological response was found to be closely related to infection by genotype 3a and to a low pretreatment ratio of serum gamma-GT/ALT activity. These data confirm and extend the importance of virus genotype for responsiveness to interferon-alpha therapy and introduce an additional, host-specific parameter with a potential predictive value, namely the pretreatment ratio of serum gamma-GT/ALT activity.
Adult↗
Down-regulation of free intracellular calcium in dissociated brain cells of aged mice and rats.
Age-related changes in resting levels of the free intracellular calcium concentration ([Ca2+]i) as well as alterations of the rise in [Ca2+]i following depolarization have been investigated in acutely isolated cells of the mouse brain and of various regions of the rat brain. Resting [Ca2+]i as well as Ca2+ responses after depolarization were lower in brain cells of aged mice and in hippocampus and cortex cells, but not striatum or cerebellum cells of aged rats. It is concluded that the Ca2+ homeostasis is specially susceptible to the aging process in some brain regions only, resulting in a down regulation of [Ca2+]i probably as a consequence of an enhanced sensitivity of mechanisms regulating [Ca2+]i. This speculation was confirmed by an enhanced sensitivity of Ca(2+)-stimulated phospholipase C activity in the aging mouse brain. The alterations of the central Ca2+ homeostasis in the mouse and the rat were paralleled by comparable changes of [Ca2+]i in spleenocytes of both species in aging. The rise of [Ca2+]i after stimulation with the mitogen phytohemagglutinin (PHA) was significantly reduced in the plateau phase, which is maintained by Ca2+ influx mechanisms. Moreover, a reduced Ca2+ response was also found after stimulation of the cells with the Ca2+ ionophore A23187. The data may indicate that comparable disturbances of the Ca2+ homeostasis occur in central and peripheral cells and that these alterations mainly affect transmembraneous Ca2+ fluxes rather than Ca2+ release from intracellular stores. These alterations may be compensated under normal conditions. However, in situations of additional stress like ischemia or hypoglycemia, the preexisting alterations of Ca2+ homeostasis may result in a reduced capacity for adaptation. This assumption was supported by observations indicating that the down-regulation of [Ca2+]i after subchronic treatment with nimodipine (20 mg/kg, 14 days) was less in brain cells of aged than of young mice.
Aging↗
Lymphocytes and neutrophils as peripheral models to study the effect of beta-amyloid on cellular calcium signalling in Alzheimer's disease.
According to the calcium hypothesis of brain aging, disturbances of free intracellular calcium homeostasis ([Ca2+]i) play a key role in pathology of Alzheimer's disease (AD). Recent data from neuronal tissue culture support the contribution of the beta-amyloid peptide (beta A) to neurodegeneration in AD, probably by disruption of the intracellular Ca2+ regulation. On the basis of this premise, we used peripheral blood cells to examine the role of beta A on Ca2+ signalling, not only to obtain an experimental approach to investigate these effects of beta A in man, but also to search for AD-specific alterations of the effects of beta A on Ca2+ signalling. This approach is based on observations indicating that the phytohemagglutinin (PHA)-induced Ca2+ response in circulating human lymphocytes of healthy volunteers is affected by beta A and its fragment 25-35 in a fashion similar to its effects on central neurons, whereas we found no effect of beta A on receptor-activated Ca2+ response in neutrophils. Therefore, we used human blood lymphocytes as peripheral model systems to search directly for AD-related abnormalities of Ca2+ regulation, for alterations of beta A effects on Ca2+ signalling and on membrane fluidity, and for possible changes of potassium channels. In accordance with our data in neutrophils, we were unable to identify any relevant change of the PHA-induced Ca2+ elevations in lymphocytes, which is not supporting the assumption of general alterations of cellular Ca2+ regulation in AD. On the other hand, the amplifying effect of beta A on Ca2+ signalling was significantly reduced in lymphocytes from AD patients. Moreover, Ca2+ responses to beta A25-35 were not different between early- and late-onset AD patients. Our findings indicate that the sensitivity of the lymphocyte for the effects of beta A is reduced in a high percentage of patients with probable or possible AD. As possible explanation we observed a similar reduction of the sensitivity of the lymphocyte membrane for the fluidity-decreasing properties of beta A. Finally, the inhibition of the PHA-induced Ca2+ response by tetraethylammonium (TEA) was lower in the AD group compared to aged controls. This could suggest the presence of a K+ channel dysfunction on AD lymphocytes, as it has been shown on skin fibroblasts of AD patients.
Alzheimer Disease↗
A reevaluation of the association of hepatitis C virus replicative intermediates with peripheral blood cells including granulocytes by a tagged reverse transcription/polymerase chain reaction technique.
BACKGROUND/AIMS: Persistence of hepatitis C virus at extrahepatic sites is of both basic and clinical interest. The clinical interest arises mainly from the occurrence of reinfections of the hepatic allograft following transplantation. Therefore, any extrahepatic association of virus, e.g. with peripheral blood cells, appears relevant. METHODS: In this study we employed for the first time the recently developed tagged reverse transcription/polymerase chain reaction procedure to determine the presence of genomic HCV RNA and antigenomic replicative intermediates in RNA preparations from sera, peripheral blood mononuclear cells, and polymorphonuclear granulocytes of 29 patients with chronic hepatitis C virus infection. RESULTS: All sera were found to contain both genomic and antigenomic HCV RNA. In addition to peripheral blood mononuclear cells, viral nucleic acids were found to be associated with polymorphonuclear granulocytes, too. CONCLUSIONS: In individual patients different patterns were observed for the distribution of hepatitis C virus genomes and antigenomes among peripheral blood mononuclear cells and polymorphonuclear granulocytes, apparently neither related to pretreatment biochemical parameters, nor to response following interferon-alpha 2a treatment, nor to hepatitis C virus genotype.
Base Sequence↗
Insulin-like growth factor-I serum concentrations and patterns of insulin-like growth factor binding proteins in patients with chronic liver disease.
BACKGROUND/AIMS: Serum concentrations of insulin-like growth factor-I are decreased in liver cirrhosis. However, this growth factor is bound for the most part to specific binding proteins that are known to modulate biological actions. Plasma insulin-like growth factor binding proteins are predominantly synthesized in the liver. METHODS: The effect of liver disease on basal and on growth hormone-stimulated serum concentrations of total and "free" insulin-like growth factor-I and on insulin-like growth factor binding protein patterns is reported. Sera were obtained from 20 patients with non-cirrhotic chronic liver diseases and from 20 patients with cirrhosis before and 24 h after a single subcutaneous dose of growth hormone. Samples were analyzed using radioimmunoassays, gel chromatography, ligand blotting and immunoblotting. RESULTS: In cirrhosis, serum concentrations of total and "free" insulin-like growth factor-I were decreased, the binding protein pattern was changed profoundly showing a reduction in the 150 kD complex and an increase in the 30-40 kD complexes. Concentrations of binding protein-1 and -2 were increased, while that of binding protein-3 was decreased in cirrhosis. The response to growth hormone was blunted. These changes were related to the degree of liver dysfunction as assessed by the Child-Pugh classification. CONCLUSIONS: A pathogenetic link of altered bio-availability of insulin-like growth factor-I to clinical characteristics of advanced liver disease, e.g. insulin resistance or skeletal muscle wasting, may be suggested by the present data.
Adult↗
Reform, not rhetoric: a critique of welfare policy and charting of new directions.
Current changes in welfare policy are examined, and the likelihood that they will be unworkable or counterproductive is discussed. Based on knowledge and data from the articles in this special section, as well as other relevant research, policy and program recommendations are offered for welfare reform that would most effectively help poor women support themselves and their families.
Aid to Families with Dependent Children↗
Synthesis of insulinlike growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: regulation by insulin, insulinlike growth factor, and growth hormone.
The adult liver is the main source of circulating insulinlike growth factors (IGFs) and their serum binding proteins (IGFBPs) including the acid-labile subunit (ALS), a component of the ternary binding protein complex. Within the liver, the biosynthesis of individual proteins has been attributed to different cell populations, e.g., that of ALS to hepatocytes and that of IGFBP-3 to nonparenchymal cells. Ligand and immunoblotting as well as Northern blotting analyses were used to study synthesis of IGFBPs and their hormonal regulation in cultured adult rat hepatocytes, Kupffer cells (KCs), and cocultures. In hepatocytes, synthesis of IGFBP-1, -2, and -4 was observed; insulin and IGF-I decreased that of IGFBP-1, and -2 while increasing that of IGFBP-4. KCs synthesized IGFBP-2, and -3, insulin and IGF-I showing no effect. In cocultures, however, synthesis of IGFBP-3 was stimulated by insulin and IGF-I. By immunocytochemistry IGFBP-3 biosynthesis was localized to KCs exclusively. When pore membranes were used for separation of hepatocytes and KCs in coculture, this insulin-stimulatory action on IGFBP-3 synthesis was preserved. Growth hormone (GH) did not affect biosynthesis of IGFBPs. Expression of ALS was localized in hepatocytes only. Insulin, IGF-I, and GH increased ALS expression. It can be concluded that biosynthesis of individual IGFBPs and of ALS are compartmentalized in adult rat liver and are distinctly regulated by insulin, IGF-I, and GH. The insulin-dependent stimulation of IGFBP-3 synthesis in KCs appears to require a diffusable mediator derived from hepatocytes.
Animals↗
Active syphilis in HIV infection: a multicentre retrospective survey. The German AIDS Study Group (GASG).
OBJECTIVE: To study syphilis in HIV infection focusing on immunocompromised patients with an atypical or aggressive clinical course of syphilis, inappropriate serological reactions or an unreliable response to therapy. STUDY DESIGN: A multicentre retrospective chart review using a standardised questionnaire for all patients with active syphilis. SETTINGS: Thirteen dermatological and medical centres throughout Germany, all members of the German AIDS Study Group (GASG). PATIENTS: Clinical data of 11,368 HIV infected patients have been analysed for cases of active syphilis requiring treatment. Asymptotic patients with reactive serological parameters indicating latent syphilis without a need for treatment were excluded. RESULTS: Active syphilis was reported in 151 of 11,368 HIV infected patients (1.33%, range per centre 0.3%-5.1%). Most of the 151 syphilis patients were male (93%) and belonged to the homosexual or bisexual exposure category for HIV infection (79%); another 6% were iv drug users. Among the 151 syphilis patients primary syphilis was diagnosed in 17.2%, maculopapular secondary syphilis in 29.1%, ulcerating secondary syphilis in 7.3%, neurosyphilis in 16.6% and latent seropositive syphilis without clinical symptoms but serological abnormalities indicating active syphilis in 25.2%. A history of prior treatments for syphilis was reported in 50%. At the time of syphilis diagnosis 26.5% of the patients were in CDC stage II, 33.8% in stage III and 24.5% in stage IV of HIV disease (CDC classification 1987). CD4 cell count was lowest in those with ulcerating secondary syphilis (mean 307, SD 140/microliters) and neurosyphilis (351, SD 235/ microliters). The highest CD4 count was found in patients with early primary and early secondary syphilis (444, SD 163/microliters and 470, SD 355/microliters). Inappropriate serological response to syphilis infection was found in 81 of 151 patients (54%). Remarkable findings were false negative VDRL titres (11 patients with non primary syphilis), false negative TPHA (1) or 19S-IgM-FTA-ABS-tests (16), and strongly reactive VDRL (> or = 512, 8) or TPHA titres (> or = 10 240, 47). Treatment failures were reported in at least 6 of 151 cases (4%). CONCLUSIONS: Atypical clinical and serological courses of syphilis were observed in HIV infected patients. Ulcerating secondary syphilis with general symptoms ("malignant syphilis") was 60 times more frequent than in historic syphilis series. Neurosyphilis was found in one sixth of those with active syphilis. Therefore lumbar puncture should be considered a routine in coinfections with HIV and syphilis. Treatment efficacy should be monitored carefully.
Adult↗
[The calcium hypothesis of brain aging].
The "calcium hypothesis of brain aging" assumes that a small increase in free intra-cellular calcium concentration ([Ca2+]i) over years or decades finally leads to brain lesions similar to the short [Ca2+]i overload following one acute event (e.g., stroke). Recent data are reviewed that disprove the hypothesis in this rather simple form. Studies on brain cells of experimental animals as well as on animal and human blood cells suggest that [Ca2+]i is reduced rather than elevated in brain aging. However, probably as compensation, aging seems to lead to enhanced sensitivity of the brain (or of calcium-dependent mechanisms in the brain) to changes in [Ca2+]i. Under normal conditions, both alterations seem to compensate each other. However, under situations of additional stress leading to elevated [Ca2+]i (hypoxia, hypoglycemia), aged brain cells might be more vulnerable because of a reduced ability to down-regulate [Ca2+]i. In contrast to these typical changes in the aging, very little evidence exists that [Ca2+]i is also changed in Alzheimer's disease. On the other hand, recent evidence suggests that the modulation of [Ca2+]i by beta-amyloid is specifically altered in this disease, but the pathogenetic significance of this observation is not yet finally understood.
Aged↗
Measurement of charged and neutral current e-p deep inelastic scattering cross sections at high Q2.
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Journal Article↗
The amplifying effect of beta-amyloid on cellular calcium signalling is reduced in Alzheimer's disease.
The amplifying effect of beta-amyloid fragment 25-35 (beta A25-35) on the mitogen-induced rise of free intracellular calcium in circulating lymphocytes was strongly reduced in 24 patients with Alzheimer's disease when compared with elderly, non-demented controls. Low beta-amyloid responses were significantly correlated with the presence of the apolipoprotein E epsilon 4 allele, suggesting a dose effect.
Adult↗
beta-Amyloid peptide decreases membrane fluidity.
The beta-amyloid peptide-25-35 (beta A25-35) decreases the fluidity of mouse brain membranes in a concentration-depending fashion. First effects were already seen at a beta A25-35 concentration of 100 nmol/1. beta-Amyloid peptide(1-40) was similarly active. beta A25-35 also decreases the fluidity of human lymphocyte membranes and of membranes from the cortex, hippocampus, striatum, and cerebellum of the rat, although the effects in the rat cerebellum are only weak. Scrambled beta A25-35 when investigated under similar conditions showed no effects on membrane fluidity. It is suggest that the effect on cellular calcium-signalling but also the neurotoxic properties of beta-amyloid might be the result of its concentration depending effects on membrane properties.
Amino Acid Sequence↗
Recurrent episodes of acute hepatitis associated with LKM-1 (cytochrome P450 2D6) antibodies in identical twin brothers.
BACKGROUND/AIMS: Liver/kidney microsomal antibodies have been noted in liver disease of different etiology, e.g. in autoimmune hepatitis, chronic hepatitis C and D virus infection and in drug-induced liver disease. Unlike these, acute hepatitis of unknown etiology associated with high-titer liver/kidney microsomal-1 antibodies (cytochrome P450 2D6) is reported in identical twin brothers. METHODS: Patients were studied using clinical, biochemical, serological and immunological methods, as well as liver biopsy. RESULTS: The acute icteric episodes were followed by spontaneous remission with complete normalization of liver function tests and liver histology. During the acute phase, serum titer for liver/kidney microsomal-1 antibodies (detected by indirect immunofluorescence, ELISA and Western blot analysis) was exceedingly high and decreased gradually thereafter. Hepatitis C and D virus infection were excluded by repeated serological testing; exposure to drugs or chemicals was not evident. Concomitant autoimmune disease was not detectable. HLA typing for class 1 and 2 antigens was positive for the HLA haplotype DQ2, but negative for HLA B4, B8, DR3 and DR4. CONCLUSIONS: The present observations might suggest a hitherto unreported form of acute hepatitis of unknown etiology, distinct from other liver diseases in which liver/kidney microsomal antibodies have been described so far.
Acute Disease↗
Synthesis of insulin-like growth factor binding proteins and of the acid-labile subunit of the insulin-like growth factor ternary binding protein complex in primary cultures of human hepatocytes.
BACKGROUND/AIMS: The liver is the main source of circulating insulin-like growth factor binding proteins. In man, the cellular origin of insulin-like growth factor binding proteins has remained obscure. METHODS: Human hepatocytes isolated from surgical specimens were purified and cultured using a collagen gel immobilization technique. Gene expression of individual insulin-like growth factor binding proteins and of the acid-labile subunit of the insulin-like growth factor binding proteins by Western ligand blotting and immunoblot analysis. Neutral size chromatography of medium samples was used to detect insulin-like growth factors binding protein complexes. RESULTS: In cultured hepatocytes transcripts for insulin-like growth factor binding protein-1, -2, -3, -4 and for acid labile subunit could be demonstrated. Ligand blotting revealed the secretion of insulin-like growth factor binding proteins of molecular weights of 24 kD, 30 kD, 34 kD, 43 kD and 46 kD, respectively. Using polyclonal antisera, these proteins were identified as insulin-like growth factor binding protein-1, -2 and the insulin-like growth factor binding protein-3 doublet. Neural size chromatography of culture supernatants showed the presence of an insulin-like growth factor binding protein complex of approximately 40 kD, but absence of the high molecular weight ternary complex of 150 kD. CONCLUSIONS: It is concluded that in man parenchymal liver cells have to be regarded as a source of acid-labile subunit and of circulating insulin-like growth factor binding proteins including insulin-like growth factor binding protein-3.
Blotting, Northern↗