Biomarkers of connective tissue aging: biosynthesis of fibronectin, collagen type III, and elastase.
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Aging↗
Biomedical subjects
P Kern
Publications and source records attributed to P Kern.
[Lemierre's syndrome with splenic abscesses].
A week after onset of a pharyngo-tonsillitis a previously healthy 23-year-old man developed high fever (41.4 degrees C), leukocytosis (12,200/microliters) with marked shift to the left, thrombocytopenia (86,000/microliters) and increased transaminases (GOT 83 U/l, GPT 113 U/l). Chest x-ray film suggested intrapulmonary abscesses with left-sided pleural effusion. The suspected diagnosis of "post-tonsillitis" septicaemia (Lemierre's syndrome) was confirmed by demonstrating anaerobic, fusiform, gram-negative bacteria (Fusobacterium nucleatum and necrophorum) in several blood cultures. Despite antibacterial treatment (amoxicillin/clavulanic acid, imipenem/cilastatin, clindamycin) he had recurrent pain referred to the kidney region and persisting fever. Repeated ultrasound and radiological examinations revealed new foci in the spleen, which were enlarging. Laparotomy with splenectomy performed on day 17 after the begin of treatment confirmed multiple splenic abscesses, but abscess pus and splenic tissue were sterile. After altogether 6 weeks of antibiotic treatment, finally with chloramphenicol, the patient was discharged in a good general state.
Abscess↗
[Clinical diagnosis and neuropathologic examination findings in 20 AIDS patients].
Disorders of the central nervous system (CNS) associated with HIV infections are becoming increasingly important in the area of clinical diagnosis and treatment of patients with AIDS. The aim of this retrospective analysis of 20 patients with AIDS who died in 1989 was to compare clinical diagnosis, neuroradiological findings and treatment with the results of neuropathological studies. The neuropathological examinations revealed primary CNS lymphoma (high-grade non-Hodgkin's lymphoma) in seven cases, cerebral toxoplasmosis in four cases, haemorrhagic infarction in three cases, cerebral cryptococcosis in three cases, and one case each of infiltration of the dura by a peripheral Burkitt's lymphoma, cytomegalovirus encephalitis and bacterial meningitis. A remarkably high percentage of CNS lymphomas with no distinct clinical or neuroradiological differentiation criteria were found in this study. On the basis of these data, we conclude that stereotactic biopsy and histological diagnosis should be recommended for patients with focal intracerebral lesions who fail to respond to suitable anti-parasitic treatment.
AIDS Dementia Complex↗
UVA- and UVB-induced changes in collagen and fibronectin biosynthesis in the skin of hairless mice.
The modifications induced in hairless mouse skin by chronic UV irradiation were investigated. Skin explant cultures were used to study UVA- and UVB-induced changes occurring in interstitial collagen (type I and type III) and fibronectin biosynthesis. To study the long-term effects, albino hairless mice were irradiated with UVA radiation alone from two sources with different spectral qualities or with UVB. UVA and UVB radiation produced a significant increase in the ratio of type III to type I collagen (more than 100% for UVA-irradiated skin and about 60% for UVB-irradiated skin) accompanied by a significantly increased fibronectin biosynthesis (50% or more in all irradiated groups). Irradiation with either UVA or UVB alone had no significant effect on the total collagen synthesis and resulted in only a slight decrease in the total collagen content of the skin determined as hydroxyproline. This decrease was significant only in the case of the group irradiated with UVA (xenon) (decrease of 25%, expressed as micrograms of hydroxyproline per milligram wet weight). A significant decrease in collagen hydroxylation (expressed as radioactive hydroxyproline/radioactive hydroxyproline plus proline in neosynthesized collagen) was observed of about 50% in skin irradiated with UVA (xenon) but not in UVB-treated skin. Several of the above modifications (increased fibronectin biosynthesis, increased collagen type III to type I ratio) correspond to the modifications observed during the aging of non-irradiated hairless mice. Therefore it appears that UV irradiation accelerates the modifications of extracellular matrix biosynthesis observed during aging.
Amino Acids↗
[Long-term therapy of cystic liver echinococcosis with mebendazole].
Surgery is the therapy of choice in the treatment of infestations with Echinococcus (E.) granulosus and E. multilocularis. Chemotherapy with mebendazole, a benzimidazole derivative, introduced 1976 in the therapy of human echinococcosis, showed good results only in cases of infestation with E. multilocularis. In the cases of liver cysts, caused by E. granulosus, the treatment with mebendazole did not succeed as well. Between 1977 and 1986, 44 patients, suffering from infestations with E. granulosus, were referred to the Clinical Department of the Bernhard-Nocht-Institut. In a retrospective study, the data of seven patients had been evaluated: They had not undergone surgery because of the size of the lesions or because they refused the operative treatment. Receiving mebendazole as the only therapy, they had been treated and followed up for more than four years. Mebendazole was given in a dosage of 50 mg/kg body weight in repeated cycles of one month's duration followed by a treatment-free interval of two months. After a median of 55 months (median 13 effective treatment months) six of the seven patients presented a therapeutical success as demonstrated by ultrasound and computed tomography. The cystic lesions had dissolved or decreased in size considerably. One case showed unaltered findings of the liver lesion. Mebendazole treatment was well tolerated by all patients. If the size of the cystic liver-lesions excludes a curative operative treatment or if the patient refuses surgery, the indication for chemotherapy with mebendazole is given.
Adult↗
[Malaria tropica].
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Exchange Transfusion, Whole Blood↗
Prevalence of antibodies to recombinant virion infectivity factor in the sera of prospectively studied patients with HIV-1 infection.
Two hundred twenty-four sera were collected from 34 HIV-1 infected patients during an observation period of up to 4.5 years (109 patient years of observation). The sera were tested for the presence of antibodies against the HIV-1 virion infectivity factor (vif) protein. Thirty sera from 6 HIV-1 seronegative individuals served as negative controls. The sera were immunoblotted against a recombinant, prokaryotically expressed vif protein. The prevalence of anti-vif antibodies increased significantly with progression of the disease from 18% to 81% (P less than 0.0001) which suggests a possible role of vif in HIV-1 replication and pathogenicity.
Biomarkers↗
Soluble tumor necrosis factor receptors correlate with parasitemia and disease severity in human malaria.
Elevated serum or plasma concentration of immunoreactive tumor necrosis factor (TNF) is consistently detected in patients with malaria. TNF levels correlate with high parasitemia and clinical severity but not always with outcome. Since the effects of TNF may be neutralized by soluble TNF receptors, sera of 30 nonimmune patients with malaria were analyzed before and during antimalarial therapy. High concentrations of receptors R1 (55 kDa) and R2 (75 kDa) were detected immunologically in all sera of untreated patients. Levels of immunoreactive TNF correlated closely with levels of soluble TNF R1 and R2 (r = .75 and .59, respectively). In contrast, sera lacked cytotoxic activity against target cells in the TNF bioassays. Soluble TNF receptor levels remained elevated for days after treatment. These results suggest that excessive release of TNF induced by the asexual stage of malaria parasites is controlled by a subsequent shedding of soluble TNF receptors that may bind and deactivate biologically functional TNF.
Adolescent↗
In vivo evaluation of photoprotection against chronic ultraviolet-A irradiation by a new sunscreen Mexoryl SX.
In a previous study on the hairless mouse it was shown that sub-erythemal doses of pure UV-A enhanced the numerous changes normally observed during chronological aging. A new sunscreen (a bis-benzylidene campho sulfonic acid derivative) has been synthesized in our research laboratory (lambda max: 345 nm, epsilon: 47,000). Its photoprotective properties against UV-A induced damages were assessed in our mouse model. Three month old albino hairless mice were exposed for 1 y to suberythemal doses (35 J/cm2) of UV-A obtained from a xenon source filtered through a WG 345 filter. One group of animals was exposed untreated, the other received a formulation containing 5% of the sunscreen prior to irradiation. At the end of the study the cutaneous properties of protected mice were compared to those of unprotected animals and to 3 and 15 month old unirradiated controls. We found that the visible changes induced by UV-A irradiation were mainly sagging and wrinkling. Histological and electron microscopic alterations consisted of hyperkeratosis, increased density of elastic fibers with alteration of fiber orientation and increased glycosaminoglycan deposits. Biochemical changes consisted of decreases in total collagen and collagen hydroxylation and increases in both collagen III/I + III ratio and fibronectin biosynthesis. All these changes were reduced or abolished by the sunscreen.
Animals↗
Relative rates of biosynthesis of collagen type I, type V and type VI in calf cornea.
The biosynthesis of type I, type V and type VI collagens was studied by incubation of calf corneas in vitro with [3H]proline as a marker. Pepsin-solubilized collagen types were isolated by salt fractionation and quantified by SDS/PAGE. Expressed as proportions of the total hydroxyproline solubilized, corneal stroma comprised 75% type I, 8% type V and 17% type VI collagen. The rates of [3H]proline incorporation, linear up to 24 h for each collagen type, were highest for type VI collagen and lowest for type I collagen. From pulse-chase experiments, the calculated apparent half-lives for types I, V and VI collagens were 36 h, 10 h and 6 h respectively.
Animals↗
Progression of HIV-1 infection. Monitoring of HIV-1 DNA in peripheral blood mononuclear cells by PCR.
We present data on the distribution of human immunodeficiency virus (HIV-1) proviral DNA in different subsets of peripheral blood mononuclear cells (PBMCs) over an observation period of eight months. Eleven patients with well documented HIV-1 infection were studied. The PBMCs were obtained at two intervals and purified by fluorescence-activated cell sorting (FACS) after staining with FITC-labelled monoclonal antibodies. Varying numbers of FACS-sorted CD4+ cells, CD8+ cells and peripheral monocytes were assayed for HIV-1 proviral DNA (env and gag region) by PCR. Samples from patients at CDC stages II or III had to contain 10(3)-10(4) cells in order to allow detection of proviral HIV-1 DNA. At CDC stage IV, however, HIV-1 DNA was detected in as few as 100 CD4+ T-lymphocytes. In contrast, in peripheral monocytes HIV-1 DNA was not regularly found. CD8+ cells did not harbor detectable amounts of proviral DNA. During an observation period of eight months, the rate of infected CD4+ T-lymphocytes increased significantly in three patients while staying constant in the remaining eight patients. This increase of the infection rate was paralleled by clinical progression in one patient and by a decrease of the absolute number of CD4+ cells in another patient. The percentage of CD4+ cells harboring the viral genome increases in the course of the disease. These results may help to explain the decrease in CD4+ T-lymphocyte counts during HIV-1 infection.
Acquired Immunodeficiency Syndrome↗
Activation of the host response in human Plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels.
PURPOSE: Hemostatic alterations and elevated tumor necrosis factor/cachectin (TNF alpha) serum levels may contribute to the pathogenesis of organ complications in human Plasmodium falciparum malaria. Therefore, we examined whether altered protein C (PC) and thrombin-antithrombin III (TAT) plasma levels correlated with TNF alpha serum concentrations, parasitemia, and the clinical course of human P. falciparum malaria. PATIENTS AND METHODS: Forty-seven patients with P. falciparum malaria were evaluated prospectively before and during antiparasitic therapy. TNF alpha serum levels were determined by immunoradiometric assay, PC and TAT plasma antigen by enzyme-linked immunosorbent assay, and PC and PC inhibitor-1 (PCI-1) activity levels by functional tests. Cultured endothelial cells were incubated with serum from four patients with malaria and from healthy control subjects and then assayed for procoagulant activity. Northern blot hybridization was used to detect tissue factor mRNA. RESULTS: In vivo, TNF alpha serum concentrations were elevated (median: 38.6 pg/mL; n = 47) while plasma levels of PC (antigen 55.4%; activity 39.0%; n = 47) and PCI-1 (0.56 U/L) were decreased in almost all patients before antiparasitic treatment. At the same time, TAT concentrations were high. These alterations correlated significantly (p less than 0.01) both with the severity of the disease (as defined by organ impairment) and with the number of circulating parasitized erythrocytes. Low PCI-1 activity correlated with low PC activity (p less than 0.001) and antigen (p less than 0.05) levels. The plasma level of coagulation factor IX, another vitamin K-dependent protein, was not significantly changed. In vitro, incubation of endothelial cells with patient serum (severe P. falciparum malaria) increased both endothelial cell procoagulant activity and cytoplasmic tissue factor mRNA levels. CONCLUSION: Elevated levels of TNF alpha and TAT, decreased plasma levels of anticoagulant PC, and the induction of procoagulant activity in endothelial cells by patient serum indicate a shift in the balance of hemostatic activity towards a procoagulant state in P. falciparum malaria. The alterations in TNF alpha, TAT, and PC levels may be a response to infection, since they correlate with parasitemia and are reversed during antiparasitic treatment.
Animals↗
Age-dependent variations of the biosyntheses of fibronectin and fibrous collagens in mouse skin.
Skin explant cultures from hairless mice of increasing age were incubated with radioactive precursors in order to determine the age-dependent variations of the biosyntheses of fibronectin and fibrous collagens (types I and III). Total collagen synthesis expressed as a percentage of total protein synthesis did not vary with age but, if expressed as micrograms hydroxyproline per mg wet weight of skin, decreased by about 30% between 2 and 22 months of age. Hydroxylation of collagen, expressed as the ratio of 3H-hypro over 3H (pro + hypro) incorporated in freshly synthesized collagen, decreased with age by about 40% between 2 and 22 months of age. The proportion of type III collagen expressed as % of type I + type III collagens increased progressively with age by about 25% at 12 months to 60% at 22 months of age. Fibronectin biosynthesis, determined by immunoprecipitation of 35S-methionine labeled peptides in SDS-extracts of skin increased progressively with age from about 2% of total incorporated radioactivity in fibronectin at 2 months to 4% at 22 months. Plasma fibronectin, of hepatic origin, was shown already to increase with age in humans. It appears thus that the expression of genes coding for extracellular matrix macromolecules is under age-dependent regulation. This regulation appears to be different for the investigated macromolecules.
Aging↗
Characterization of monoclonal antibodies against alpha-hemolysin of Escherichia coli.
Monoclonal antibodies (MAbs) were raised against native and denatured alpha-hemolysin (HlyA) of Escherichia coli. Binding of the MAbs to native, denatured, and erythrocyte-complexed active wild-type hemolysin and mutant derivatives was tested. All 15 MAbs analyzed bound to native hemolysin, even when the toxin was complexed with human erythrocytes. While some MAbs were unable to bind to a specific native mutant hemolysin, others could not even bind to mutant hemolysin carrying deletions remote from their actual binding sites. A rough determination of the binding sites of 15 MAbs on HlyA was performed by Western immunoblot analysis using CNBr fragments of HlyA and mutant hemolysin proteins. Interestingly, the binding sites of the MAbs against native hemolysin seem to be more randomly distributed on HlyA than are those of MAbs against denatured hemolysin. Three MAbs inhibited the hemolytic activity significantly. Two of these MAbs bound to the hydrophobic region, and the other one bound to the repeat domain of HlyA. The use of synthetic peptides from these regions allowed determination of the linear epitopes for two of these MAbs.
Animals↗
Neither heparin nor acetylsalicylic acid influence the clinical course in human Plasmodium falciparum malaria: a prospective randomized study.
Procoagulant alterations and thrombocytopenia in falciparum malaria correlate with parasitemia, serum levels of tumor necrosis factor alpha (TNF alpha), and clinical severity. Thus, heparin or acetylsalicylic acid (ASA), which are used frequently to prevent thrombosis and (in the case of ASA) to control fever, could be potentially beneficial. We randomized 97 patients with falciparum malaria into three groups: 33 patients received low-dose heparin subcutaneously, 31 received ASA intravenously, and 33 did not receive either drug. All patients received appropriate antiparasitic treatment. Eighteen of 97 patients (seven receiving heparin, five receiving ASA, and 6 in the control group) had complications upon admission. During therapy, elevated TNF alpha and lactate dehydrogenase levels and decreased platelet counts returned to normal values. Except for a minimal partial thromboplastin time prolongation with heparin, heparin or ASA did not affect any laboratory parameter, duration of parasitemia, fever clearance, or the length of hospitalization. Thus, it appears that ASA and heparin do not influence the course of falciparum malaria. Hence, in view of possible side effects, these substances should not be recommended for routine use in the treatment of human malaria.
Aspirin↗
Classification of histopathological changes of lymph nodes in HIV-1 infection. Significance of Castleman's disease-like lymph node lesion concerning the diagnosis of HIV-1-related Kaposi's sarcoma.
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Acquired Immunodeficiency Syndrome↗
[Recombinant interferon alpha-2A in the treatment of HIV-associated Kaposi sarcoma. Long-term results].
47 HIV-positive male patients with cutaneous Kaposi's sarcoma (KS) were treated with recombinant interferon alpha-2A (IFN) in an open, prospective study. 45 patients received 18 million I.U. IFN s.c. daily for the first three months. From the fourth month, the patients received 18 million I.U. IFN s.c. three times weekly. Four of the 45 patients withdrew from therapy because of side effects during the first weeks (weeks 2 to 6) of treatment. The remaining 41 patients were treated for a minimum period of two years or until their death. Two further patients received 36 million I.U. IFN daily for three months. After three months of IFN therapy we observed complete remission (CR) in five of the 41 patients (12%), partial remission (PR) in seven patients (17%), stable disease in seven patients (17%) and progressive disease (PD) in 22 patients (54%). The mean survival time from the beginning of IFN therapy to date is 26 months for the 19 responders (patients with CR, PR or SD; six are still alive) and nine months for the 22 non-responders (patients with PD; all died). Recurrence of tumor progression occurred in 15 of the 19 responders after an average of ten months of continuous IFN therapy. The longest time of survival in this group is 54 months up to now. Of the four remaining patients, all in the CR group, two died after 24 and 26 months of IFN therapy, without any recurrence of KS growth (causes of death: Burkitt's lymphoma and unknown). The two other patients, both still alive, have not suffered any recurrence of tumor progression after 40 and 41 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
CD34+ hematopoietic progenitor cells are not a major reservoir of the human immunodeficiency virus.
Hematologic abnormalities occur in the majority of patients with acquired immunodeficiency syndrome (AIDS). Infection of the hematopoietic progenitor cells has been proposed as a potential explanation. In this study, different bone marrow cell populations, including the CD34+ hematopoietic progenitor cells, were purified by a fluorescence-activated cell sorter (FACS) and analyzed for the presence of human immunodeficiency virus-1 (HIV-1) proviral DNA using the polymerase chain reaction. A group of 14 patients with AIDS or AIDS-related complex (ARC) was studied (11 with peripheral blood cytopenias). The CD4+ helper cells in the bone marrow were found positive for HIV-1 DNA in all patients. In contrast, CD34+ progenitor cells were positive in only one patient. Two monocyte samples and two samples of CD4-/CD34- lymphocytes/blasts (mainly B and CD8 lymphocytes) were positive. Proviral DNA could not be detected in granulocytes. FACS analysis showed that the percentage of CD34+ hematopoietic progenitor cells was not altered in the bone marrow of AIDS patients in comparison with the HIV-1 seronegative controls. In contrast, the number of CD4+ lymphocytes was markedly reduced in the bone marrow of AIDS patients. These results show that the hematologic abnormalities in AIDS patients are neither explained by direct infection of the hematopoietic progenitor cells with HIV-1 nor by a depletion of progenitor cells.
Antigens, CD34↗