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Biomedical subjects

A Heim

Publications and source records attributed to A Heim.

At least 19 recordsLinked to original sources
PubMed2025

Habitat Specialisation Impacts Clownfish Demographic Resilience to Pleistocene Sea-Level Fluctuations.

Habitat fragmentation and loss are key threats to biodiversity, yet their impacts on marine species remain poorly understood. Clownfishes, which rely on sea anemones for shelter and reproduction, provide an interesting model to explore how ecological specialisation mediates species responses to habitat perturbations. We used whole-genome data from 382 individuals across 10 species with varying host specialisations to reconstruct demographic histories and infer spatial genetic structure to assess the impact of Pleistocene sea-level fluctuations. Generalist species, associated with multiple hosts, maintained stable effective population sizes () and population connectivity during habitat fragmentation, reflecting resilience to environmental instability. In contrast, specialists experienced severedeclines and genetic structuring, driven by their dependence on specific hosts, without signs of population recovery following habitat reconnection. Spatial genomic analyses identified the Indonesian Through-Flow as a key dispersal corridor and the Coral Triangle as a critical hub of genetic diversity, while continental shelves and extensive open ocean regions appeared as barriers to gene flow. Our findings reveal how host specialisation shapes clownfish population dynamics, emphasising the importance of incorporating ecological dependencies into conservation assessments and deepening our understanding of species responses to ecological constraints and environmental changes over evolutionary timescales.

Animals↗
PubMed1999

More than reason

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Journal Article↗
PubMed1999

Gide's solution

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Journal Article↗
PubMed1999

Evaluation of serological screening of cadaveric sera for donor selection for cornea transplantation.

Human corneas are explanted for grafting as late as 72 h after death, for example, from medical examiner cases. Currently, infection of the donor with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) is excluded in most cornea banks by serological testing of the cadaveric serum only. The reliability of this strategy was investigated by testing paired cadaveric and premortem sera of 33 potential donors. Results were discordant in 17 of 33 donors by at least one assay. Most frequently, HBsAg enzyme-linked immunosorbent assay (ELISA) yielded false-positive results with the cadaveric serum (16 of 33 serum pairs). Virus safety of the graft was affected in a single case, which was HCV antibody negative in the cadaveric serum, but positive in the premortem serum (confirmed by HCV-RIBA strip immunoassay). Forensic DNA profiling by polymerase chain reaction (PCR) of both serum samples confirmed that these were derived from the same individual. In conclusion, the results indicate that serological testing of cadaveric sera is not a reliable method for screening of potential cornea donors, and may not be sufficient for the virus safety of cornea grafts. Therefore, other screening strategies such as detection of viral nucleic acids by PCR should be evaluated.

Adult↗
PubMed1999

Activation of the Jak-Stat pathway in cells that exhibit selective sensitivity to the antiviral effects of IFN-beta compared with IFN-alpha.

We determined whether selective activation of components of the Jak-Stat pathway by different type I interferons (IFN) occurs in human myocardial fibroblasts that exhibit much higher sensitivity to the antiviral effects of IFN-beta than of IFN-alpha. Similar levels of activation of the Tyk2 kinase and the Stat3 transcription factor were induced in response to either IFN-beta or IFN-alpha treatment. However, activation of the Jak1 tyrosine kinase was detectable only in IFN-beta-treated but not IFN-alpha-treated cells. Consistent with this, tyrosine phosphorylation of Stat1 and Stat2 and formation of the IFN-stimulated gene factor 3 (ISGF3) complex occurred to a much higher degree in response to IFN-beta stimulation. These findings demonstrate that differential activation of distinct components of the Jak-Stat pathway by different type I IFN can occur. Furthermore, they strongly suggest that such selective activation accounts for the occurrence of differences in the antiviral properties of distinct type I IFN in certain cell types.

Antiviral Agents↗
PubMed1999

Adenoviruses and enteroviruses as pathogens in myocarditis and dilated cardiomyopathy.

BACKGROUND: Enteroviruses were detected in up to 50% in myocardium of patients with myocarditis and dilated cardiomyopathy, the latter being considered as a result of a prior subclinical myocarditis. A wide range of other infectious agents are being discussed as pathogens, often only based on reports of single cases. Adenovirus genome was recently identified in a significant number in the myocardium of paediatric patients with myocarditis. However, data on the role of adenoviruses for the aetiopathogenesis of myocarditis in adult patients is missing so far. Therefore, we studied the prevalence of adenoviral and enteroviral genome in myocardium of adults with myocarditis and dilated cardiomyopathy. METHODS: 15 patients were diagnosed at baseline with myocarditis, 16 patients with dilated cardiomyopathy according to clinical and histological criteria. Endomyocardial biopsies of these patients and 8 control patients with non-infectious heart diseases were evaluated by polymerase chain reactions for enterovirus and adenovirus genome. RESULTS: Enteroviral genome was detected in 27.3% patients with myocarditis or dilated cardiomyopathy, whereas adenoviral genome was not identified in any patient. Samples from control subjects systematically yielded negative results. CONCLUSIONS: From our data, it seems doubtful that adenoviruses are major pathogens of myocarditis or DCM, whereas enterovirus genome was identified in a significant number of patients with both diseases.

Adenovirus Infections, Human↗
PubMed1998

Highly sensitive detection of gene expression of an intronless gene: amplification of mRNA, but not genomic DNA by nucleic acid sequence based amplification (NASBA).

NASBA is an isothermal nucleic acid amplification reaction that amplifies mRNA in a dsDNA background. Although similar to the sensitive reverse transcription/polymerase chain reaction (RT-PCR) in mRNA detection, NASBA is not prone to give false positive results caused by genomic dsDNA. Therefore, NASBA is unique for sensitive detection of transcription of intronless genes, which preclude strategies such as intron spanning primer pairs to control false positive results in RT-PCR. Using NASBA, mRNA of the intronless human interferon-beta gene was demonstrated with a sensitivity of 10 copies, whereas 100 ng genomic DNA gave a negative result.

False Positive Reactions↗
PubMed1998

Antiviral activity of WIN 54954 in coxsackievirus B2 carrier state infected human myocardial fibroblasts.

Persistent infections with a cardiotropic enterovirus, e.g. coxsackievirus B2 (CVB2), cause chronic myocarditis and eventually congestive heart failure. Therefore, the antiviral activity of WIN 54954, a capsid binding antiviral agent that inhibits enterovirus uncoating, was studied in persistently CVB2-infected cultures of human myocardial fibroblasts. Cultures displayed a typical carrier state infection with virus titers of 3.9 +/- 1.6 x 10(5) plaque forming units (PFU)/ml and 0.99% infected cells. WIN 54954 (0.025-1 microg/ml) application was started 7 days after infection of the cultures. Compared to the WIN 54954 concentration resulting in a 90% plaque number reduction (EC90 = 0.197 microg/ml) in acutely infected Vero cells, WIN 54954 reduced virus yields of myocardial fibroblast cultures more efficiently, e.g. more than 100 fold (99%) with 0.025 microg/ml after 4 days of application. Antiviral effects of WIN 54954 increased with application time and at 0.025 microg/ml Win 54954 completely inhibited infectious virus progeny after 16 days. Increasing the WIN 54954 concentration up to 1 microg/ml did not cause a greater inhibition of virus replication. In situ hybridization demonstrated that at 0.1 microg/ml WIN 54954 reduced the number of infected cells from 0.99 to 0.18%, although a complete eradication of CVB2-infected cells was not achieved at concentrations as high as 1 microg/ml. In conclusion, the results indicate that low concentrations of WIN 54954 are effective in treating persistent enterovirus infections of myocardial fibroblasts, although a complete eradication of the infection is not achieved with WIN 54954 as a single antiviral agent.

Animals↗
PubMed1998

Molecular characterization of hemagglutination domains on the fibers of subgenus D adenoviruses.

The adenovirus fiber mediates the agglutination of erythrocytes. Based on differential hemagglutinating properties, subgenus D adenoviruses can be subdivided into clusters DI, DII, and DIII. While subgenus DI adenoviruses agglutinate rat and human erythrocytes, DII adenoviruses simply agglutinate rat erythrocytes and DIII adenoviruses display no or only weak rat erythrocyte agglutination. Amino acid sequence comparisons revealed distinct domains on the fiber knob which could be involved in hemagglutination. In order to localize and characterize the domains responsible for the interaction with rat and human erythrocytes, potential hemagglutination domains of the adenovirus type 9 (Ad9) (subgenus DI) fiber knob were introduced into Ad17 (subgenus DII) and Ad28 (subgenus DIII) fiber knobs by primer-directed mutagenesis. Furthermore, rat erythrocyte hemagglutination domains were also introduced into the Ad3 (subgenus B) fiber knob, which only agglutinated monkey erythrocytes. Altogether, 27 chimeric and mutated fiber proteins were expressed in Escherichia coli and subsequently tested for hemagglutination activity. The hemagglutination tests revealed that at least two domains can mediate the agglutination of rat erythrocytes. While one domain is located on the GH loop, the other domain extends from the C beta strand to the CD loop. The domain on the GH loop was partially conserved in all adenoviruses showing an incomplete hemagglutination pattern with rat erythrocytes. The domains involved in the agglutination of human erythrocytes are located on the CD and HI loops of the subgenus DI fiber knob.

Adenoviruses, Human↗
PubMed1998

Coxsackievirus genome in myocardium of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Enteroviruses are known as major infectious agents for inflammatory heart diseases such as myocarditis and dilated cardiomyopathy (DCM). Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by replacement of right ventricular myocardium by fatty and fibrous tissue. In about 65% of patients inflammatory infiltrates suggest an inflammatory or infectious etiopathogenesis. To test this hypothesis, we investigated endomyocardial biopsies of patients with ARVC, with myocarditis or DCM, and from patients with non-inflammatory cardiac disorders for the presence of enteroviral genome. Enteroviral RNA with homology to coxsackieviruses type B was detected in 3 of 8 patients with ARVC (37.5%), in 7 of 23 patients with myocarditis or DCM (30.4%), but in none of 5 patient with non-infectious myocardial diseases (p < 0.05 compared to ARVC patients). These results support earlier suggestions that coxsackievirus infection of the myocardium is possibly related to the pathogenesis of ARVC.

Adult↗
PubMed1997

Enterovirus heart disease of adults: a persistent, limited organ infection in the presence of neutralizing antibodies.

Detection of enterovirus RNA in endomyocardial biopsies (EMB) by reverse transcription/polymerase chain reaction (RT-PCR) is currently the preferred diagnostic procedure in suspected enterovirus heart disease (EHD), which can present clinically as myocarditis, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). EMB and peripheral blood mononuclear cells (PBMC) of 44 patients with suspected EHD were examined by nested RT-PCR to investigate whether the myocardial enterovirus infection is limited to the heart or is generalized. Enterovirus RNA was detected in EMB, but not in PBMC, of 8 patients (3 of these suffered from ARVC), whereas EMB of 16 controls and PBMC of 45 controls were negative. In addition, enterovirus RNA was demonstrated in PBMC, but not in EMB, of a single patient with suspected EHD. A high sequence homology of the amplicons to coxsackievirus B3 was demonstrated in 7 patients, and to coxsackievirus B2 in two patients. In order to evaluate whether the myocardial enterovirus infection was acute or persistent, neutralization and complement fixation tests were performed for antibodies against the serotypes indicated by the nucleic acid sequences. Neutralizing antibodies were detected in the sera of all 9 patients, but complement fixing antibodies were demonstrated only in one EHD patient and in the patient positive for enterovirus RNA in PBMC. In conclusion, the molecular and serological data demonstrate that CVB3 predominates as cardiotropic enterovirus, and that the enterovirus replication is limited to the heart in EHD. Serological results support the hypothesis of myocardial enterovirus RNA persistence in spite of neutralizing antibodies.

Adult↗
PubMed1997

Conserved sequences in the fibers of epidemic keratoconjunctivitis associated human adenoviruses.

The fiber gene sequences of the human adenovirus types 19 and 37 were determined. The predicted polypeptides exposed a high homology. Ad8, Ad19, and Ad37 can cause epidemic keratoconjunctivitis (EKC), whereas Ad9 only infrequently causes acute follicular conjunctivitis. Comparison of the fiber knobs of Ad8, Ad9, Ad19, Ad37, and other previously published fiber sequences revealed that only two amino acid residues were conserved in the fiber knobs of Ad8, Ad19, and Ad37. Since the knob is responsible for interaction with the cell receptor, these two amino acid residues could play an important role in the pathogenicity of EKC causing adenoviruses.

Adenoviridae↗
PubMed1997

Inhibition of coxsackievirus B3 carrier state infection of cultured human myocardial fibroblasts by ribavirin and human natural interferon-alpha.

As enterovirus infections of the heart cause myocarditis and eventually congestive heart failure, the antiviral activity of ribavirin was studied in coxsackie virus B3 (CVB3)-infected carrier cultures of human myocardial fibroblasts. Cultures were infected 7 days before application of ribavirin and effects were evaluated over a period of 16 days by plaque assays and in situ hybridization. Compared to the low antiviral activity in HeLa cells, ribavirin was highly active in reducing infectious virus yields in human myocardial fibroblasts, for example, to 2.0 x 10(3) pfu/ml with 25 microg/ml and to 1.3 x 10(2) pfu/ml with 50 microg/ml (4.3 x 10(4) pfu/ml in infected controls). Moreover, 100 microg ribavirin/ml completely suppressed infectious virus progeny in two of three cultures, and reduced the number of infected cells from 14.3 to 0.3% as determined by in situ hybridization, whereas up to 3200 microg ribavirin/ml did not result in a significant cytotoxic effect. Interaction with interferon-alpha (IFN-alpha) was additive to slightly synergistic in reducing the number of infected cells and virus yields. In conclusion, our results suggest a cell-specific high activity of ribavirin in human myocardial fibroblasts and indicate the importance of using organ-specific cells for testing antiviral agents in myocarditis. Furthermore, the usefulness of in situ hybridization for determining the long term effects of antivirals in carrier state cell cultures was demonstrated.

Antiviral Agents↗
PubMed1996

Recombinant Interferons beta and gamma have a higher antiviral activity than interferon-alpha in coxsackievirus B3-infected carrier state cultures of human myocardial fibroblasts.

We compared the antiviral activities of three recombinant human interferons (IFN-alph2a, IFN-beta, and IFN-gamma) in cultured human myocardial fibroblasts to select a candidate for trial in heart disease induced by cardiotropic enterovirus, e.g., coxsackievirus B3 (CVB3). Cells were exposed to CVB3, and after 7 days, when a persistent infection had developed, IFN was added. Virus yields were measured on alternate days for the next 7 or 16 days, and IFN activity was assessed as the percentage reduction in yield. IFN-gamma and IFN-beta were both highly active and reduced virus yields by 2 log (EC(99)) at concentrations of 23.4 IU/ml (SD = 8.6) and 10.1 IU/ml (SD = 3.2), respectively; with 250 IU/ml of either IFN, no infectious virus was formed. Unexpectedly, IFN-alpha2a (EC(99)> 1250 IU/ml) was at least 120 times less active than IFN-beta; after use for 8 days or more, the minor effects it produced were no longer related to the concentration applied. Despite the pharmacokinetic advantages of IFN-alpha2a, our data suggest that IFN-beta should in preference be evaluated in the clinic.

Antiviral Agents↗
PubMed1996

General pharmacology of insulin lispro in animals.

[Lys(B28),Pro(B29)]-human insulin (insulin lispro, CAS 133107-64-9, LY275585, Humalog) is a quick acting insulin analog which is currently undergoing clinical evaluation for the treatment of diabetes. The potential secondary pharmacological activity of insulin lispro was profiled in studies for the evaluation of effects on the central and autonomic nervous system, the cardiovascular system, urine and electrolyte excretion, and gastrointestinal function. In vivo doses ranged from 0.03 to 10 U/kg, administered by the subcutaneous route, while pharmacologic activity in vitro was examined in smooth and cardiac muscle at concentrations of 1 x 10(-9) to 1 x 10(-5) mol/l. Insulin lispro exhibited secondary pharmacological activity in central nervous system tests only at higher doses with the most prominent observations being sedation and decreased responsiveness. Insulin lispro was essentially inactive in tests of autonomic (smooth and cardiac muscle), cardiovascular (mean arterial pressure, heart rate, systolic pressure, diastolic pressure, and pulse pressure), renal (urine and electrolyte excretion) and gastrointestinal (motility) function. In summary, insulin lispro had minimal effect in these pharmacodynamic studies indicating that insulin lispro has minimal potential to produce adverse pharmacological side effects at clinically relevant doses.

Animals↗
PubMed1995

Myocardial enterovirus infection with left ventricular dysfunction: a benign disease compared with idiopathic dilated cardiomyopathy.

OBJECTIVES: Endomyocardial biopsy samples from patients with idiopathic dilated cardiomyopathy were screened for the presence of enterovirus genome. Patients with enterovirus-positive samples were further studied with regard to disease course, histologic variables and response to interferon-alpha treatment. BACKGROUND: Studies of patients with idiopathic dilated cardiomyopathy have reported widely divergent clinical outcomes, suggesting that there is no unique underlying pathogenetic mechanism. METHODS: Five left ventricular endomyocardial biopsy samples were screened for the presence of the enterovirus genome by an established in situ hybridization technique in combination with a histologic, histomorphometric and immunohistologic workup. The course of the disease was then prospectively followed for up to 50 months. Virus-positive patients whose condition deteriorated were treated with interferon-alpha. RESULTS: Of 77 patients, 20 (26%) had enterovirus-positive and 57 (74%) enterovirus-negative biopsy samples. During a mean follow-up period of 25.8 +/- 13.7 months, 1 patient in the enterovirus-positive group and 11 in the enterovirus-negative group died. Four patients in the enterovirus-negative group underwent heart transplantation (p < 0.05). The surviving 19 enterovirus-positive patients had a decrease in mean left ventricular end-diastolic diameter from 66 to 61 mm (p < 0.05) and a mean increase in left ventricular ejection fraction from 0.35 to 0.43 (p < 0.05). In contrast, enterovirus-negative patients had no significant change in end-diastolic diameter or left ventricular ejection fraction. Four patients in the enterovirus-positive group whose condition deteriorated were treated with a 6-month course of subcutaneous interferon-alpha (3 x 10(6) U every second day). This treatment induced hemodynamic improvement in all four patients and eliminated the persistent enteroviral infection in two. CONCLUSIONS: Enterovirus-positive patients have a better heart transplantation-free survival rate and hemodynamic course, with fewer histologic changes, than do enterovirus-negative patients. In addition, enterovirus-positive patients respond favorably to interferon-alpha treatment. These observations indicate that myocardial enteroviral infection with associated left ventricular dysfunction is a distinct disease entity with a benign course.

Cardiac Catheterization↗
PubMed1995

Cultured human myocardial fibroblasts of pediatric origin: natural human interferon-alpha is more effective than recombinant interferon-alpha 2a in carrier-state coxsackievirus B3 replication.

Cultured human myocardial fibroblasts of pediatric origin seem to be a useful species-specific model for studying various heart diseases which involve the myocardial interstitium, for example enterovirus heart disease. Cells were propagated from small samples of human ventricular tissues (0.2 g) obtained from standard surgical procedure for the correction of Fallot-tetralogy. Cultured cells exhibited typical fibroblastoid morphology over a period of 4 months and were uniformly immunoreactive with a monoclonal antibody directed against prolyl-4-hydroxylase, a marker enzyme of fibroblasts. Infection of cell cultures with coxsackievirus B3, a cardiotropic enterovirus, resulted in a typical carrier-state type of virus persistence. Average virus titers of 2.3 x 10(5) plaque-forming units/ml (SD = 9.9 x 10(4)) were maintained over a period of up to 10 weeks by productive infection of about 8-10% of the cell population. Coxsackievirus B3 carrier cultures of human myocardial fibroblasts were used to evaluate in vitro the long-term antiviral effects of recombinant interferon alpha-2a and natural human interferon-alpha. Recombinant interferon-alpha reduced virus yields by 90% with a concentration of 423 IU/ml, whereas with natural interferon-alpha a 90% reduction of virus yields was achieved with concentrations as low as 21 IU/ml. Antiviral effects of both recombinant and natural interferon-alpha were highly specific and not related to inhibition of cell-proliferation (< 50% with interferon-alpha concentrations as high as 6250 IU/ml). Since effective concentrations of interferon-alpha can be easily attained in vivo with subcutaneous application, interferon-alpha (in particular: natural interferon-alpha) may become useful in the treatment of patients with enterovirus myocarditis and enterovirus induced dilated cardiomyopathy.

Antiviral Agents↗