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Biomedical subjects

P Kern

Publications and source records attributed to P Kern.

At least 109 records · Page 6Linked to original sources
PubMed1996

Expression of laminin and type IV collagen by basement membrane-producing EHS tumors in streptozotocin-induced diabetic mice: in vivo modulation by low-molecular-weight heparin fragments.

The biosynthesis of basement membrane components in Engelberth Holm Swarm-bearing mice with or without streptozotocin-induced diabetes and the effect of low-molecular-weight heparin derivatives (CY222, Sanofi Recherche/Institut Choay) on the relative rates of these synthetic activities were studied. In diabetic mice, the laminin mRNA level increased, whereas type IV collagen mRNA decreased. In vivo treatment with heparin fragments decreased the mRNA level of laminin to control values without altering the mRNA level of collagen IV. Biosynthetic studies with radiolabeled precursors ([3H]-proline for collagen and [35S]-methionine for laminin) confirmed these results. Laminin protein biosynthesis increased in diabetic mice. Treatment with CY222 corrected this alteration. Our results suggested an increased labeling of polymeric forms of collagen IV in diabetic mice. In addition, we showed that biosynthesis of acid-extractable collagen IV decreased in diabetic mice and that CY222 treatment corrected this disturbance. These experiments suggest that low-molecular-weight heparin fragments CY222 can modulate the biosynthesis of extracellular matrix macromolecules altered in diabetic animals by different pathways, including pretranslational and posttranslational steps.

Animals↗
PubMed1996

A pseudo-particle approach for studying protein-ligand models truncated to their active sites.

A molecular dynamics method has been developed to describe the structural and dynamic properties of protein-ligand complexes that are truncated to their active sites. The active site is comprised of the ligand and discontinuous, positionally unrestrained peptide chains. This truncated active-site complex is surrounded by big unspecific pseudo-particles representing the complete protein and the solvent. Thus, knowledge of the folding of the outer parts of the protein is not required, and the method can be applied to protein models, derived from homology modeling. The method has been tested using ligand complexes of adenylate kinase, retinol binding protein, HIV-1 protease, and human leucocyte antigen. Comparisons with their crystal structures and with results from time-demanding simulations of the whole complexes in explicit water solvent show that the ligand binding properties are conserved. Most of the hydrogen bonds between the ligand and the active-site residues are reproduced and, furthermore, the simulation time is reduced.

Amino Acid Sequence↗
PubMed1996

Collagen synthesis by vascular smooth muscle cells in the presence of antiproliferative polysaccharides.

Production of various components of the extracellular matrix (ECM) modulates biological functions of the vascular tissue. This process is generally amplified in pathologic states as atherosclerosis. Atheroma originates from smooth muscle cells (SMC) which have migrated and proliferated in the vascular intima. In this study we investigated protein synthesis, collagen synthesis, and types I, III, and V collagen distribution by SMC in the presence of three families of watersoluble polysaccharides, heparin, fucans, and derivatized dextrans. We observed that fucan and derivatized dextran were able, as was heparin, to inhibit rat aortic SMC growth in culture. We then analyzed collagen modulation by measuring the incorporation of the radiolabeled precursor (3H)-proline into vascular SMC. Our results showed uncoupling of the antiproliferative capacity with collagen biosynthesis. However, fucan, the most antiproliferative polysaccharide, was also the most active in inhibiting protein and collagen synthesis. In addition, compounds that decreased total collagen synthesis preferentially increased the proportion of cell-associated collagen. Interestingly, only the antiproliferative polysaccharides inhibited significantly type V collagen biosynthesis. These new biomaterials appear to be valuable tools to study and control extracellular-matrix interactions with cells from the vascular walls.

Animals↗
PubMed1996

Levels of cytokines and cytokine inhibitors in the neutropenic patient with alpha-hemolytic streptococcus shock syndrome.

The pathogenesis of alpha-hemolytic streptococcus shock syndrome (SS), a life-threatening complication in neutropenic patients following aggressive chemotherapy that is caused by viridans streptococci, is unknown. We measured serum concentrations of proinflammatory and antiinflammatory cytokines and T cell activation markers in two patients with lethal alpha-hemolytic streptococcus SS. The results were compared with those for controls, two neutropenic patients with uncomplicated bacteremia due to gram-positive organisms and four patients with neutropenia and bacteremia due to gram-negative organisms (two of whom had lethal septic shock). In patients with alpha-hemolytic streptococcus SS, levels of interleukin (IL) 1 were undetectable, levels of tumor necrosis factor (TNF) alpha were only slightly elevated, and IL-6 was the only proinflammatory cytokine that was found in high concentrations and had a late peak level at the time of clinical deterioration. IL-6 levels were much higher in patients with alpha-hemolytic streptococcus SS than in controls with uncomplicated bacteremia due to gram-positive organisms but were comparable with those in controls with bacteremia due to gram-negative organisms. Soluble TNF receptor fragments and IL-1 receptor antagonist apparently were not protective despite high serum concentrations.

Adult↗
PubMed1996

Release of soluble tumor necrosis factor receptors in Mediterranean spotted fever rickettsiosis.

Tumor necrosis factor alpha (TNF) is a key cytokine in the defense against many intracellular pathogens, including Rickettsia conorii, the causative agent of Mediterranean spotted fever (MSF). The levels of two soluble TNF receptors (sTNFR-p55 and sTNFR-p75), the extracellular domains of the two cell surface receptors for TNF, were elevated in the acute-stage plasma samples from 20 patients with serologically confirmed MSF. The median values were 3.1 and 7.8 ng/ml for sTNFR-p55 and sTNFR-p75, respectively. sTNFR values correlated significantly with plasma TNF concentrations. Patients with severe MSF had higher values for both receptor fragments than patients with nonsevere disease. The differences were statistically significant for sTNFR-p55 (median, 5.8 versus 2.0 ng/ml; P = 0.008). Given the proportionately higher values for both TNF and sTNFR-p55 in patients with severe MSF, the sTNFR-p55/TNF ratios for the two patient subgroups did not differ (P = 0.5), while the sTNFR-p75/TNF ratios were significantly different (P = 0.01), with disproportionately lower values in patients with severe disease.

Boutonneuse Fever↗
PubMed1996

Alveolar echinococcosis of the liver: percutaneous stent therapy in Budd-Chiari syndrome.

BACKGROUND AND AIMS: Infiltration of the hepatic veins in the alveolar echinococcosis can lead to the development of the Budd-Chiari syndrome. The medical and surgical treatment of this condition is generally unsatisfactory. The results of successful interventional treatment with percutaneous stent implantation in the hepatic veins are reported. METHODS: Using a transjugular approach, metal mesh stents (Boston Scientific, Medi-Tech Accuflex 8/60 mm) were placed in the median and left hepatic veins of a 53 year old woman. After the intervention, oral chemotherapy with albendazole (2 x 400 mg/day) was continued, but no anticoagulants were given. RESULTS: Stent placement was performed without complications. The clinical picture improved rapidly: normalisation of portal blood flow was confirmed by Doppler ultrasound and there was improvement of liver function, reduction of oesophageal varices, and disappearance of ascites. A follow-up examination at 15 months showed no evidence of stent occlusion. CONCLUSIONS: Treatment of portal hypertension in alveolar echinococcosis of the liver is problematic. In selected patients with portal hypertension secondary to hepatic vein stenoses but no cirrhosis, percutaneous stent placement in the hepatic veins represents a promising treatment alternative.

Albendazole↗
PubMed1995

Derivatized dextrans modulate collagen synthesis in aortic smooth muscle cells.

The effect of specifically derivatized dextrans, with or without antiproliferative activity on smooth muscle cells (SMC), was investigated on type I and type III collagen biosynthesis and mRNA levels in post-confluent SMC cultures. Our results indicate that dextran derivatives decreased total protein and collagen synthesis independently of their antiproliferative activities. However, the most substituted dextran, the one exhibiting the strongest antiproliferative activity towards SMC, was the most active in modulating type III collagen expression. In addition, only the two dextran derivatives bearing benzylamide groups inhibited collagen excretion.

Animals↗
PubMed1995

Expression of fibronectin and interstitial collagen genes in smooth muscle cells: modulation by low molecular weight heparin fragments and serum.

The effect of low M(r) heparin fragments (CY222) and fetal calf serum (FCS) on the level of fibronectin and fibrillar collagen mRNAs was investigated in smooth muscle cells (SMC) in culture. In the absence of FCS, addition of CY222 (100 micrograms/10(6) cells) to postconfluent early passage SMC resulted in a decrease in mRNA level of type III collagen. In contrast, mRNA levels coding for type I collagen, fibronectin and GAPDH (used as control of cellular activity) were not modified. Addition of 5% FCS (without CY222) to the culture medium did not affect mRNA levels of type I and type III collagens nor that of GAPDH. The level of fibronectin mRNA, however, increased in the presence of 5% FCS. In the presence of both 5% FCS and CY222, we observed a decrease in type III collagen mRNA and fibronectin mRNA levels (this level remained, however, above the control value without FCS and the level with CY222 alone). Our results demonstrate that low M(r) heparin fragments can modulate the steady-state levels of type III collagen and fibronectin mRNAs.

Animals↗
PubMed1995

Diagnosis of Echinococcus multilocularis infection by reverse-transcription polymerase chain reaction.

Alveolar echinococcosis is a life-threatening parasitosis occurring in countries in the Northern hemisphere. The diagnosis of an Echinococcus multilocularis infection is routinely performed by radiological techniques and by the detection of specific antibodies in the sera of infected patients. However, because serodiagnosis fails in 5%-10% and radiological techniques are difficult to interpret in some cases, we developed a polymerase chain reaction for the detection of echinococcal-specific messenger RNA from fine-needle biopsy specimens. This technique was applied to the diagnosis of alveolar echinococcosis in a 20-year-old seronegative woman. Detection of messenger RNA not only allowed the diagnosis of echinococcal disease but also proved to be a reliable measure for determining the efficacy of an antiparasitic therapy.

Adult↗
PubMed1995

Secondary structure prediction of adenylate kinase by circular dichroism spectroscopy of synthetic peptides.

The synthesis of 13 segments of porcine adenylate kinase (AK 1) consisting each of 15 residues and covering the whole sequence of AK 1 is reported. The peptides were obtained by multiple peptide synthesis applying Fmoc/tert. butyl strategy. For the conformational analysis by circular dichroism spectroscopy different mixtures of phosphate buffer (pH 7), trifluoroethanol and methanol were used. Ten peptides showed alpha-helical conformation in all solvents except of pure buffer. The conformation of these peptides correlated well with the secondary structure obtained by homology modelling and even more striking with the X-ray structure of adenylate kinase, which was published recently. In contrast, three peptides, which were suggested to adopt no helical conformation did not show any content of alpha-helicity in any of the solvents that we investigated. One peptide, which contains a beta-sheet according to the X-ray analysis revealed a high content of beta-conformation by CD in buffer and in mixtures with trifluoroethanol. The two other peptides revealed mainly random coil in all solvents which we investigated. Therefore, we conclude that synthetic peptides are suitable tools to investigate the secondary structure of protein segments and that this conformation is frequently preserved in the intact protein.

Adenylate Kinase↗
PubMed1995

Interleukin-5 is the predominant cytokine produced by peripheral blood mononuclear cells in alveolar echinococcosis.

An involvement of cellular immunity in alveolar echinococcosis is strongly suggested by the intense granulomatous infiltrations observed around the hepatic parasite lesions. However, the basis of cellular immunoregulation in patient with alveolar echinococcosis is poorly understood. The present report shows a comparative analysis of lymphoid cell function in peripheral blood mononuclear cells (PBMC) of 16 patients with alveolar echinococcosis and of healthy individuals. Our in vitro restimulation studies with crude Echinococcus multilocularis antigen demonstrated that PBMC from patients with alveolar echinococcosis were responsive to challenge with parasitic antigen as measured by lymphoid cell proliferation. In this system, we also evaluated cytokine expression at the gene and protein levels after stimulation with E. multilocularis antigen. Analysis of cytokine mRNA expression revealed distinct patterns of cytokine expression in patients and normal donors. By using reverse transcriptase PCR, we could demonstrate that the TH1 cytokine transcripts interleukin-2 (IL-2) and gamma interferon (IFN-gamma) are present in PBMC from patients with alveolar echinococcosis. Moreover, it was found that stimulation with E. multilocularis antigen induced or enhanced the expression of the TH2 cytokine IL-3, IL-4, IL-10, and especially IL-5 mRNAs in PBMC from 13 of 16 patients with alveolar echinococcosis. Two patients who were examined after radical surgery, as well as another patient with a stable course of the disease under continuous chemotherapy, were not able to generate the same pattern of cytokine response and had no evidence of IL-5 mRNA synthesis. In contrast to the frequent expression of TH2 cytokine mRNAs observed in patients with alveolar echinococcosis, PBMC cultures from normal donors showed prominent IL-2 and IFN-gamma mRNA expression but weak IL-3, IL-4, and IL-10 mRNA expression. Most interestingly, IL-5 mRNA was substantially absent in PBMC from healthy individuals. In accordance with the mRNA studies, it was found that E. multilocularis antigen induced the secretion of large amounts of IL-5 and intermediate amounts of IFN-gamma in patients with alveolar echinococcosis, whereas large amounts of IFN-gamma and no or threshold amounts of IL-5 were detected in supernatants from healthy individuals. Collectively, the present study provides the first evidence that a TH2 immune response is gradually activated during the course of E. multilocularis infection, indicating a critical role for IL-5 in the manifestation of human alveolar echinococcosis.

Adult↗
PubMed1995

Intestinal cytomegalovirus disease in immunocompromised patients may be ruled out by search for cytomegalovirus DNA in stool samples.

Cytomegalovirus (CMV) PCR from stool specimens was adopted as a diagnostic tool for patients with suspected CMV colitis. After being established, the method was evaluated in 17 AIDS patients and 19 other immunocompromised patients by comparison of PCR results with clinical, histological, and microbiological or virological data. CMV PCR was positive in 4 symptomatic patients with proven CMV colitis and negative in 15 of 16 patients without characteristic histopathology. Neither CMV immunoglobulin G seropositivity nor intestinal symptoms alone were significantly associated with positive PCR results, but severe active systemic CMV infection may lead to a positive PCR. Absence of CMV DNA in stool samples may prove useful in ruling out CMV related colitis.

Acquired Immunodeficiency Syndrome↗
PubMed1995

[Alveolar echinococcosis of the liver--computerized tomography findings].

In order to ascertain the typical computed tomographic findings of hepatic alveolar echinococcosis, 24 computed tomograms of 19 patients were evaluated. The liver was involved in all cases whereas the diaphragma was infiltrated in 32%, and the retroperitoneal area in 42%. The right liver lobe was affected in 65%. Both before and after intravenous bolus contrast medium administration, the lesions were mainly inhomogeneous and of low density; a masking of the lesions due to the contrast medium administration was not observed; the enhancement pattern was irregular. Calcifications were detected in 96% of the cases, cystic structures in 50%, and cholestasis in 54%. On the basis of the crucial finding of calcifications in combination with the other typical observations, CT seems to be very suitable for the evaluation of hepatic alveolar echinococcosis.

Adult↗
PubMed1994

Nucleotide-binding properties of adenylate kinase from Escherichia coli: a molecular dynamics study in aqueous and vacuum environments.

The complex of adenylate kinase with its transition-state inhibitor has been studied by molecular dynamics simulations in water and in vacuum environments with the GROMOS force field over a period of 300 ps. The adenylate kinase, a member of the nucleotide-binding protein family, was exemplarily chosen for the inspection of the nucleotide-binding properties in the active site. The ligand binding and the domain movements have been studied in detail over the simulation period and compared with the crystal structure. Secondary structure transitions and domain closures defined those parts of the structure which are involved in an induced-fit movement of the enzyme. The presence of more stable hydrogen bonds on the substrate side leads to the assumption that substrate binding is more specific than cosubstrate binding. Reliable results were achieved only if water was explicitly included in the stimulation.

Adenylate Kinase↗
PubMed1994

Liposomal doxorubicin in AIDS-related Kaposi's sarcoma: long-term experiences.

Treatment of AIDS-related Kaposi's sarcoma with cytotoxic chemotherapy is limited by toxicities of the various agents. Liposomal doxorubicin is a new treatment option for patients with Kaposi's sarcoma with potentially reduced toxicity. Three AIDS patients with different stages of tumor risk were enrolled in a study evaluating the safety and efficacy of liposomal doxorubicin at a dose of 10-20 mg/m2 every 2-4 weeks. Maximal duration of treatment was 86 weeks with a cumulative dose of 560 mg/m2. Criteria proposed by the AIDS Clinical Trials Group were used to define tumor stages and response to therapy. All patients showed partial responses after 40-100 mg/m2 total dose with reduction of tumor-associated edema and flattening of more than 50% of previously nodular or plaque-like lesions. One patient showed progressive disease after discontinuation of treatment for 8 weeks; Kaposi's sarcoma responded again partially on retreatment. Progression was also seen in one patient after dose reduction due to granulocytopenia and again during treatment of active cytomegalovirus retinitis. Serial measurements of cutaneous target lesion surface area did not indicate response. Increases in surface area, however, correlated with progressive disease. Toxicities included moderate leukopenia, aphthous stomatitis, and transient alopecia. Liposomal doxorubicin may well be valuable for long-term treatment of AIDS-associated Kaposi's sarcoma, especially in patients with extensive disease. However, controlled comparison with conventional treatment regimens is mandatory.

Acquired Immunodeficiency Syndrome↗
PubMed1994

An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy.

A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well-controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions.

Adolescent↗
PubMed1994

A randomized trial of roxithromycin in patients with acute leukemia and bone marrow transplant recipients receiving fluoroquinolone prophylaxis.

Fluoroquinolone prophylaxis in patients with profound neutropenia may be useful for preventing gram-negative bacterial infection, but it is ineffective against gram-positive bacterial infections in the bloodstream, particularly those caused by streptococci and coagulase-negative staphylococci, which appear to have emerged as significant causes of morbidity, decreased treatment efficacy, and the increased costs of empiric antimicrobial therapy. In a prospective, randomized, open trial, we evaluated the efficacy and safety of oral roxithromycin (150 mg twice daily) as additional antibacterial prophylaxis in 131 adult patients with acute leukemia and bone marrow transplant recipients receiving oral ofloxacin. In comparison with patients given ofloxacin alone, fewer patients receiving ofloxacin plus roxithromycin developed bacteremia caused by viridans group streptococci (incidence, 9 versus 0%; P = 0.03), while the incidence of bacteremia caused by other organisms, the incidence of febrile episodes from any cause, the risk of infection-associated complications (including prolonged or secondary fever, pneumonia, septic shock, need for mechanical ventilation, and/or infection-related death), and antimicrobial usage for therapy were comparable between both groups. Adverse events possibly related to the study drugs were slightly more common among the patients receiving the combination treatment (P = 0.05). Although effective for the prevention of streptococcal bacteremia, the addition of roxithromycin to a fluoroquinolone should not be used routinely as a prophylactic regimen in patients with profound neutropenia, but it might be considered and may be useful for cancer patients with a particularly high risk of streptococcal infection and related complications.

Acute Disease↗