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Biomedical subjects

J Fohlman

Publications and source records attributed to J Fohlman.

At least 37 records · Page 2Linked to original sources
PubMed1993

Therapy of coxsackie virus B3-induced myocarditis with WIN 54954 in different formulations.

The antiviral efficacy of WIN 54954 was demonstrated in vivo in a Coxsackie B 3 virus (Woodruff strain) induced myocarditis mouse model. The model was selected because of the high mortality rate during the first week, which was convenient for antiviral therapy regimen studies. The antiviral component WIN 54954 was found to inhibit the early virus-induced mortality almost completely if treatment was started at the same time as virus was inoculated. However, there was still a late mortality, occurring at 1-2 months after virus inoculation. Non-infected mice which were treated with the drug did not show any such late effects. However, drug treatment in non-infected mice did not cause any mortality. When therapy was delayed for one day, 85% survived for 3 weeks as compared to 100% mortality after just over 3 weeks in the infected control group (p < 0.05). With a delay of 4 days after viral inoculation, a therapeutic effect was still noted. Thus, mortality was virtually abrogated when the compound was given early, but the effect vanished with time of delay. Different preparations of the WIN 54954 substance were tried, and it was found that a fat emulsion containing several nutrients (Nutrodrip) was superior to other used formulations. We conclude that the use of the antiviral drug WIN 54954 in treatment of enteroviral associated diseases is of great value if therapy is started early. Thus therapy is almost fully effective within 24 hours of infection, but the beneficial effects decline with time. Nutrodrip oil emulsion was found superior as vehicle as compared to other formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Ionophoric interaction with the myocyte sarcolemma: a new insight into the pathophysiology of degenerative myocardial disease.

A certain group of compounds often derived from microbes known as ionophores function as ion channels when incorporated in biological membranes. Different ionophores have a relative specificity for certain cations such as Ca2+ or K+. When such compounds are integrated in the cell membrane of a host cell a leakage of the ion in question is induced and the physiologic ion gradient will be dissipated. This will activate ion pumps at the expense of ATP in order to restore the physiologic ion gradient. This effect is seen for a number of different viruses including Coxsackie B3. Based on own experiments we suggest that this ionophoric effect is important in the pathophysiology of myocarditis. We have shown that mice with Coxsackie B3 myocarditis have low myocardial ATP and high ADP and AMP levels. This pattern of abnormal energy metabolism is also seen in patients with Syndrome X. It is suggested that the ECG and thallium perfusion scintigram suggestive of ischemia in such patients is rather due to the effect of an ionophore leading to an extracellular potassium shift.

Adenine Nucleotides↗
PubMed1993

Genotypic and serotypic profile in dilated cardiomyopathy.

Eighteen consecutive patients, admitted with a diagnosis of dilated cardiomyopathy (DCM), to the Cardiology Section, Department of Internal Medicine, University Hospital, Uppsala, Sweden were enrolled into the study. All patients suffered signs of cardiac incompensation of variable duration. Patients were defined by conventional clinical investigations including chest X-ray, ultrasound, g-camera, catheterization and endomyocardial biopsy with histological evaluation by a specially trained pathologist. Angiography was performed to exclude ischemic heart disease. Several patients were diagnosed as having a specific reason for the cardiac insufficiency, like pheochromocytoma, SLE, ethylism, ischemic heart disease and hypertrophic cardiomyopathy. In this group all 7/7 had negative serology against Coxsackie B viruses. In the other group of idiopathic CM, no other etiology could be found. Serological analysis in this group showed high IgM titres against Coxsackie viruses in 6/8 patients. EDTA-blood was taken for tissue-typing using DNA probe hybridisation. 6/12 patients had DQB1:4 using the newest nomenclature, vs 17% in the control population. The reversed picture was observed for DQB1:2, occurring in 1/12 patients, vs 19% in the normal population, thus indicating a protective value of this genotype, which to our knowledge has not been described before. The results indicate a dual dependence of (host) genotype and (virus) serotype according to the Doherty-Zinkernagel hypothesis. Thus, it would also be in agreement with the virus-immune hypothesis suggested more than 20 years ago to explain the enigmatic pathogenesis of DCM.

Adult↗
PubMed1993

Altered distribution of heavy metals and lipids in coxsackievirus B3 infected mice.

This report presents evidence that a micro-organism common in our environment, coxsackievirus B3 (CB3) and the host responses it causes, can change the body distribution of heavy metals and lipids. The present results show that the distributions of intravenously injected 109Cd, 63Ni and 14C-Cholesterol are changed during infection, in a way that is specific for each of the studied compounds. Increased accumulation of 109Cd in the spleen and kidneys, 63Ni in the pancreas and ventricular myocardium, and 14C-Cholesterol in the heart and pancreas was observed during CB3 infection. This may affect the development of inflammatory lesions and subsequently result in altered and/or increased target organ toxicity as well as lipid accumulation. Thus, risk assessment in exposed populations may have to be evaluated depending on individual nutritional and exposure status.

Animals↗
PubMed1993

The epidemiology of viral heart disease.

The enteroviruses, especially the Coxsackie B viruses, predominate as causative agents in myopericarditis and may be involved in the pathogenesis of dilated cardiomyopathy. Some studies suggest that these and other viruses might be implicated even in atherosclerosis and myocardial infarction. True incidence data of myopericarditis in the population at large are hardly feasible, since the disease is most often mild or subclinical. The long-term prognosis is favorable even in a majority of hospital-treated patients. A recent histopathological study of unselected autopsy cases employing the "Dallas criteria" for a diagnosis shows a myopericarditis incidence of 1.06 per cent. A link between myopericarditis and dilated cardiomyopathy is supported by findings of enteroviral RNA in biopsies and explanted hearts in the latter condition. A partly new panorama of viral heart disease is emerging in heart transplant recipients and AIDS patients.

Humans↗
PubMed1992

Coxsackie B virus IgM in children at onset of type 1 (insulin-dependent) diabetes mellitus: evidence for IgM induction by a recent or current infection.

Thirty-five children with newly-diagnosed Type 1 (insulin-dependent) diabetes mellitus and their 47 siblings were investigated for the presence of IgM antibodies to Coxsackie B virus serotypes 1-5 (CBV 1-5) with the aid of mu-antibody-capture radioimmunoassays. When a high cut-off value was used, 16 (46%) diabetic children and 16 (34%) siblings showed CBV-IgM. Of the siblings of diabetic patients positive for CBV-IgM, 11 (44%) were CBV-IgM-positive; the corresponding figure for the siblings of negative patients was five (26%). With a lower cut-off value, leading to a "borderline titre", the frequency of IgM positivity increased in both the patients and siblings. When the borderline titres were included, the number of IgM-positive patients was 19 (54%) and the corresponding number of siblings was 29 (62%). Of the siblings of positive patients, 27 (93%) showed CBV-IgM, and of the siblings of the negative patients, two (11%) were CBV-IgM-positive. Sixteen (89%) siblings of IgM-negative patients remained negative. Regarding the serotypes of CBV to which IgM was directed, CBV 4 was most frequent, followed by serotypes CBV 3, CBV 2, CBV 5 and CBV 1. There was a striking similarity between the individual diabetic child and his or her sibling(s) concerning this specificity of IgM. It is concluded that within most families with a newly-diagnosed diabetic child positive for CBV-IgM the same serotype(s) of the virus circulates and that the intrafamilial spread of virus is considerable. The results strongly indicate that the IgM detected was CBV-specific and caused by a recent or current CBV infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

A common viral infection can change nickel target organ distribution.

The autoradiographic distribution of the toxic heavy metal nickel (Ni) was studied at 4 and 7 days post-coxsackievirus B3 (CB3) infection in Balb/c mice. The distribution of the iv injected 63Ni was studied 10 min, 4 hr, and 24 hr after administration. Results clearly show that the site of 63Ni accumulation is greatly changed during this viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in the pancreas and the wall of the ventricular myocardium. Healthy animals showed almost no 63Ni accumulation in these tissues. These results for the first time show that an invading microorganism can change the distribution of an environmental pollutant.

Animals↗
PubMed1992

Altered distribution of 109cadmium in mice during viral infection.

The distribution of the toxic heavy metal cadmium (Cd) was studied in Coxsackie virus B3 (CB3)-infected Balb/c mice by whole-body autoradiography and gamma-counting. The distribution of 109Cd was studied 4 days post CB3-inoculation and 10 min after intravenous injection of 0.21 microgram of Cd/kg body weight. Whole-body autoradiography results showed that the distribution of 109Cd is greatly changed during this viral infection. This newly discovered distribution was mainly visible as a greatly increased accumulation in the renal and adrenal cortices. After impulse counting of selected organs it was found that the normal accumulation of 109Cd in the kidneys (184,354 +/- 30,961 c.p.m.) was increased by 47% (P less than 0.05) during CB3 infection (270,503 +/- 54,780 c.p.m.). In contrast to healthy animals, some infected mice showed accumulation of 109Cd in the spleen. These results show for the first time that an invading micro-organism can change the distribution of an environmental pollutant.

Adrenal Cortex↗
PubMed1990

Vaccination of Balb/c mice against enteroviral mediated myocarditis.

A non-virulent strain of Coxsackie B3 (CB3) virus was used to produce a subunit vaccine. It contains the capsid proteins VP1, 2, 3 and probably 4 and can be made RNA-free. It is based on the ISCOM technology ensuring non-toxic properties and good adjuvant effect. Vaccinated animals at doses above 16 ng were completely protected from mortality when challenged with a myocarditic strain of CB3. Histologically no inflammatory lesions were found in the heart. This was corroborated using immune histological techniques with monoclonal antibodies against lymphocyte subsets. Even at a dose of 0.16 ng a delayed mortality was observed. Neutralizing antibody titres rose to 512, thus ensuring a circulating level well above that considered protective. It is suggested that vaccination might be a possible way of prophylaxis for myocarditis and even dilated cardiomyopathy, the latter presently being the chief cause of heart transplantation. By persistence or triggering of autoimmune phenomena Coxsackie virus is incriminated as the first step in pathogenesis.

Animals↗
PubMed1990

A qualitative and quantitative method for in situ characterization of the inflammatory response in experimental myocarditis.

Coxsackie virus B3 causes myocarditis in Balb/c inbred mice. In this model mortality is about 60% on day 7 and 95% on day 12 after inoculation. Significant inflammatory infiltrates appear on day 7. Recent research has focused on the immune response to explain the ensuing tissue damage. Thus we were interested in mapping cellular interaction and time course to understand the development of a possible autoimmune attack. By a newly developed immunohistochemical staining technique single lymphocytes could be visualized and different lymphocyte subpopulations enumerated. Stained cells were easily detectable and readily distinguishable from non-stained cells. Before day 7 Th cells could only occassionally be seen. The number of pan T lymphocytes increased almost 10-fold from day 7 to 12. The T helper/T killer ratio did not change significantly but indicated a predominant increase in Tk-cells. The B cell population also increased, roughly about ten times. The number of class II positive cells was constant. No expression of Il-2 receptor was found. In preliminary studies, exercise and methylprednisolone treatment tended to influence the expression of class II antigens. Cyclophosphamide and cyclosporine A reduced the number of inflammatory cells more than 10-fold. No clear concurrent reduction in mortality was observed.

Animals↗
PubMed1990

Cardiovascular lipid accumulation with Coxsackie B virus infection in mice.

The authors used a myocarditic coxsackievirus B3 infection in Balb/c mice to investigate cardiovascular lipid accumulation and whether a cholesterol-enriched diet influences the development of the myocardial inflammatory reaction. It was found that, seven days after CB3 infection, the accumulation of 14C-cholesterol increased by 75% (P less than 0.001) in the heart and by 92% (P less than 0.001) in the aorta. This infection also caused extensive inflammatory lesions (4.5% of tissue section area) and lipid accumulation in the myocardium seven days after inoculation. Seven weeks on a 1% cholesterol-enriched diet did not affect the myocardial area damaged (3.9%), the lethality, or immune cell activity (T, B, and natural killer [NK] cells). The response pattern of myocardial lymphocyte subpopulations was studied with an immune histochemical staining technique. The number of Mac 2+ (macrophages), class II expressing cells, or the T cytotoxic, suppressor/T helper cell ratio was not changed by the cholesterol diet. The number of class II cells tended to increase (38%) with cholesterol and was positively correlated (P less than 0.001) with the Mac 2 expression regardless of the cholesterol diet. Although moderate diet-induced hypercholesterolemia did not alter host response to viral infection, these results support the idea that virus and immune cells may cooperate and play a role in arterial and myocardial lipid accumulation, possibly acting as initiating factors for atherosclerosis.

Animals↗
PubMed1989

Effects of the immunomodulator LS 2616 on lymphocyte subpopulations in murine Coxsackievirus B3 myocarditis.

Quinoline-3-carboxamide (LS 2616) is a broadly acting immunostimulator with anti-inflammatory effects in Coxsackie virus B3-induced myocarditis in female BALB/c mice. This infection caused extensive inflammatory and necrotic lesions in the myocardium 7 days after inoculation (6.8% of tissue section area). The damaged area was reduced (to 3.7% (p less than 0.05] and the lethality decreased when LS 2616 was administered over 14 days, starting 7 days before the inoculation. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was elucidated by a newly developed immune histochemical staining technique. LS 2616 increased the number of class II-expressing cells 3-fold (p less than 0.01) and the CTL, Ts:Th cell ratio by 55% (p less than 0.05), whereas Lyt-1+ and TIB+ cells were unaffected. After 7 days of LS 2616 treatment, spleen lymphocyte activity tended to increase (T cells by 21% (NS) and B cells by 60% (p less than 0.05), respectively). The activity of NK cells increased by 51% (p less than 0.01). LS 2616 may thus have potential in therapy of human inflammatory disorders, such as myocarditis.

Adjuvants, Immunologic↗
PubMed1989

Exercise in coxsackie B3 myocarditis: effects on heart lymphocyte subpopulations and the inflammatory reaction.

To investigate whether exercise in coxsackie B3 virus infection is detrimental to the myocardium, Balb/c mice were inoculated with the virus and exercised to exhaustion on a motor-driven treadmill up to 48 hours after the inoculation. This infection evokes myocarditis. The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered 4.32% of the tissue section area in the nonexercised group. Exercise at 0 hours did not affect this myocardial damage (4.77%), whereas exercise at 48 hours after the inoculation increased the lesion to 7.85% (p less than 0.05). Lethality was not influenced by exercise. The response pattern of myocardial lymphocyte subpopulations was studied with an immune histochemical staining technique. The number of T cytotoxic, T suppressor cells increased threefold (p less than 0.01), and the T cytotoxic, suppressor/T helper cell ratio increased twofold (p less than 0.01) with exercise at 48 hours but was unchanged with exercise at 0 hours. The number of class II expressing cells decreased with exercise at 48 hours (p less than 0.05) and was negatively correlated (p less than 0.01) with the size of the inflammatory reaction. The development of myocardial inflammatory and necrotic lesions seems to be dependent on the presence and cooperation of class II expressing cells and T killer cells. Furthermore, failure to restrict physical activity in the acute phase of this infection may well contribute to the progression of the disease.

Animals↗
PubMed1988

The anti-inflammatory effect of LS 2616 and poly I:C in coxsackievirus B3 induced murine myocarditis.

We have studied the effects of immunotherapy in coxsackievirus B3-induced myocarditis in male BALB/c mice. A single i.p. injection of the synthetic interferon inducer poly I:C conferred an almost total protection from lethality when administered at 0 h or 24 h after infection. Poly I:C treatment at 48 h after infection, as well as daily i.p. injections of the quinoline-3-carboxamide LS 2616, a new stimulator of NK-cell activity, gave no protection from lethality. The inflammatory lesions and necrosis in the ventricular myocardium 7 days after virus inoculation (3.1% of section area) were reduced in the poly I:C (24 h) treated group (1.0% of tissue section area). A less pronounced reduction was seen in the LS 2616 and poly I:C (48 h) treated groups (1.7 and 1.9% of tissue section area, respectively). The response patterns of the studied lymphocyte subpopulations were different with these two compounds, TIB+ (pre-B)-cells increased with poly I:C treatment (49%), but decreased with the LS 2616 treatment (65%). The Lyt 1+ (pan T)-cells responded similarly. Poly I:C (24 h) and LS 2616 treatment tended to increase the number of class II expressing cells (1.9- and 2.9-fold, respectively). The titer of neutralizing antibodies to coxsackievirus B3 was significantly increased in the LS 2616 treated group (1:80) but not significantly so in the poly I:C treated groups (1:40) as compared to the infected and non-infected control groups (1:20 and less than 1:5, respectively).

Adjuvants, Immunologic↗
PubMed1987

Matching of host genotype and serotypes of Coxsackie B virus in the development of juvenile diabetes.

Thirty-six consecutive paediatric patients (0-16 years old) with recently contracted juvenile diabetes (IDDM) during 1982-84 were included in the study. Sera were assayed for recent or current Coxsackie B virus (CBV) infection using a specific and sensitive IgM RIA. Eighteen patients (50%) had IgM against CBV 1-5. The patients were also assayed for restriction fragment length polymorphism (RFLP) patterns with DNA probes coding for HLA-DR and DQ beta chains. The CBV-positive patients (n = 18) had either RFLP patterns associated with HLA-DR 3 or 4 or HLA-DQ patterns III or IV beta. Two of the CBV negative patients had neither HLA-DR 3 nor DR 4 and four of them had neither DQ patterns III nor IV. Eleven out of 18 CBV-positive patients had HLA-DQ III and DR 3 (61%) versus 5 out of 18 (28%) of the CBV-negative patients. All 11 patients with serology positive for CBV 2, 3, and 5 had HLA-DR 4 and DQ IV patterns. This was significantly (P less than 0.01) different from all five CBV 4-positive patients, who in contrast all had HLA-DR 3 or HLA-DQ III patterns. CBV 1-positive patients (n = 2) all had HLA-DR 3, 4, and HLA-DQ III, IV patterns. Thus CBV 4 seems to be significantly associated with a different host genetic constitution from at any rate CBV 2, 3, and 5, and possibly CBV 1.

Adolescent↗
PubMed1987

The complete amino acid sequence of human serum retinol-binding protein.

The complete amino acid sequence of human serum Retinol-binding protein (RBP) including the distribution of its three disulfide bridges, has been determined. The protein consists of 182 amino acid residues, the order of which was determined following the isolation of five CNBr-fragments. Direct amino acid sequence analysis in an automatic liquid phase sequencer provided almost the entire sequences of the five CNBr-fragments. Several sets of enzymatically derived peptides of RBP were also used to elucidate the primary structure. RBP displays significant homology to bovine beta-lactoglobulin, human alpha 1-microglobulin and rat alpha 1-microglobulin. RBP contains an internal homology. Thus, residues 36 to 83 display statistically significant homology with residues 96 to 141.

Alpha-Globulins↗
PubMed1985

Comparison of 252californium plasma desorption and fast atom bombardment mass spectrometry for analysis of small peptides.

The data obtained with 252Cf plasma desorption (PD) and fast atom bombardment mass spectrometry of eight tri-, tetra- and pentapeptides were compared. Good spectra were obtained with 1-10 nmol of peptide. In both techniques molecular weight information was obtained. The PD mass spectra are often dominated by the cationized molecular ions in contrast to the fast atom bombardment (FAB) mass spectra, where cationization is rarely observed. Amino acid content is reflected in the immonium ions equally well in both techniques. The fragmentation patterns observed with the two techniques are almost identical. However, practical sequencing of peptides based on either FAB or PD mass spectrometry of underivatized peptides alone is difficult. This is due to the unpredictable and sometimes absent cleavage yield at certain peptide bonds. Another difficulty is the many simultaneous fragmentation pathways. However, for many peptides enough information is present to allow sequence determination for at least a major part of the molecule.

Californium↗