Göran Friman

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.

SummaryThirty-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 (CBV1-5) with the aid of μ-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 CB V 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. It is highly probable that the same strain of virus was present in different members of the same family. Therefore, if diabetogenic CBV strains do in fact exist, additional factors must be of importance for the development of Type 1 diabetes in children infected with such a CBV strain but remaining non-diabetic.

The possible role of Coxsackie A and echo viruses in the pathogenesis of type I diabetes mellitus studied by IgM analysis

IgM antibodies to Coxsackie B virus (CBV) have recently been observed in the serum of a relatively high proportion of children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). In the present study, 108 IDDM patients below the age of 15 years, diagnosed during the period 1976 to 1985, were investigated at the onset of their disease by mu-antibody-capture radioimmunoassay (RIA) of IgM against seven different enterovirus antigens, namely virions of CBV serotypes 1-5 (CBV 1-5) and procapsids of CBV 3 and CBV 5. As has been shown the RIAs with virions give type-specific or narrow type-specific reactions, whereas procapsids react with IgM against both homotypic and heterotypic enteroviruses. The annual frequency of IgM against virions varied between 15 and 76% (mean 38%). IgM against CBV3 and CBV2 predominated, but IgM against the other serotypes was also observed. When procapsids were used as antigen, the frequency of IgM varied between 11 and 86% (mean 63%). With virions and procapsids, the corresponding variation was 44-100% (mean 70%). The total number of patients exhibiting virion-IgM was 41, whereas procapsid-IgM alone [indicating an infection with Coxsackie A virus (CAV) and/or echo virus (EV)] was detected in 36 patients. For 2 of the years, samples of serum from control groups were included. These showed a significantly lower frequency of IgM in both the virion and the procapsid RIAs. It is concluded that not only infection with CBV but also that with other enteroviruses, such as CAV and/or EV, may be involved in the pathogenesis of IDDM in children.

High incidence of Chlamydia pneumoniae in sclerotic heart valves of patients undergoing aortic valve replacement

Chlamydia pneumoniae has previously been demonstrated in the atherosclerotic lesions of various arteries, including the coronary arteries, and has been proposed to play a role in the pathogenesis of atherosclerosis. A prospective study of the incidence of C. pneumoniae in the sclerotic valves of patients undergoing aortic valve replacement because of aortic stenosis and in the aortic valves of cases dying of non-cardiac reasons and undergoing forensic autopsy was undertaken. The results were correlated to serological markers of past (IgG) or persistent (IgA) C. pneumoniae infection. C. pneumoniae, as determined by the polymerase chain reaction (PCR), was detected in the aortic valve in 19/39 (49%) patients and in 1/11 (9%) autopsy controls (p = 0.018) and confirmed by electron microscopy in one patient. There was no significant difference in the incidence rate of IgG or IgA antibody positivity between PCR-positive and PCR-negative cardiac patients. These results extend the hypothesis of a pathogenic role of C. pneumoniae in atherosclerosis to include also aortic valve sclerosis.

Infections and exercise in high-performance athletes

The elite athlete has a potentially increased sensitivity to respiratory infections, rendering protective measures particularly important. Some other infections that may appear in clusters in the sports setting, such as gastroenteritis, leptospirosis, herpes simplex and viral hepatitis, also require special precautionary attention. Strenuous exercise during ongoing infection and fever may be hazardous and should always be avoided. In addition, early symptoms of infection warrant caution until the nature and severity of the infection become apparent. Because myocarditis may or may not be accompanied by fever, malaise or catarrhal symptoms, athletes should be informed about the symptoms suggestive of this disease. Although sudden unexpected death resulting from myocarditis is rare, exercise should be avoided whenever myocarditis is suspected. Guidelines are suggested for the management and counselling of athletes suffering from infections, including recommendations on when to resume training. Acute febrile infections are associated with decreased performance resulting from muscle wasting, circulatory deregulation and impaired motor coordination, which require variable amounts of time to become normalized once the infection is over.

Effects of methyl mercury on cytokines, inflammation and virus clearance in a common infection (Coxsackie B3 myocarditis)

A myocarditic coxsackievirus B3 (CB3) infection in Balb/c mice was used to investigate the effects of 12 weeks of methyl mercury (MeHg) exposure (3.69 mg/g diet) on inflammatory heart lesions, virus in the heart, the cytokine response, i.e. cachectin/TNF-alpha and gamma-interferon (IFN-gamma) levels in plasma, and on disease complications and mortality. This dose of MeHg did not influence mortality in this infection model. The inflammatory and necrotic lesions in the ventricular myocardium 7 days after the inoculation covered 2.2% of the tissue section area in infected control mice. This damage was increased (n.s.) by 50% (to 3.3% of the tissue section area) in MeHg-treated mice. The response pattern of lymphocyte subsets in situ in myocardial inflammatory lesions was corroborated using an immune histological technique. MeHg treatment tended to increase (2.2-fold, n.s.) the number of Mac 2+ cells (macrophages) in the heart muscle in this infection. Plasma levels of both TNF-alpha and IFN-gamma increased on day 3 of the infection in MeHg-treated as well as in non-MeHg-treated mice, but the mean IFN-gamma response was more pronounced in the MeHg-treated mice. On day 7 of the infection, when most animals still showed clinical signs of disease, cytokine levels were back to normal. MeHg-exposure in non-infected mice did not affect cytokine levels. In situ hybridization of virus RNA in myocardial tissue showed remaining virus in those mice who had the lowest plasma IFN-gamma levels. A 20% increased (P < 0.05) lymphoproliferative response to the T cell mitogen Con A was observed as a result of the MeHg treatment. Even heart tissue lesions and virus persistence tended to be influenced by MeHg in a direction compatible with the development of chronic disease.

Splanchnic and peripheral release of 3-methylhistidine in relation to its urinary excretion in human infection☆

The present investigation was undertaken in order to determine the release of 3-methylhistidine (3MH) from the splanchnic region and from the leg, and the contributions these make to the increase in urinary 3MH excretion in infection. Thirteen febrile patients with infection were investigated. After an overnight fast, hepatic vein, femoral vein, and radial artery catheterizations were performed. Splanchnic and leg blood flows were determined by dye dilution technique. Plasma 3MH was analyzed by a modified HPLC method. The release of 3MH from the leg was 0.064 +/- 0.007 mumol/min (+/- SE) and from the splanchnic region 0.012 +/- 0.013 mumol/min. These releases of 3MH constitute 27% +/- 2% and 8% +/- 6% of the individual urinary excretions, respectively. With increasing degree of catabolism, measured as individual 3MH increase above baseline excretion or as the 3MH to creatinine ratio (3MH:Cr), the relative contribution to urinary excretion from the leg was increased (individual increase, P = 0.08; 3MH:Cr, P less than 0.01). Since this contribution was not decreased in the more catabolic patients, as would have been expected if the increase in urinary 3MH originated elsewhere, it is concluded that skeletal muscle is the source, and these results thus validate the use of urinary 3MH excretion as a marker of myofibrillar protein catabolism in infected patients.

The Swedish childhood diabetes study III: IgM against coxsackie B viruses in newly diagnosed Type 1 (insulin-dependent) diabetic children — no evidence of increased antibody frequency

SummarySera from essentially all Swedish children aged 0–14 years with Type 1 (insulin-dependent) diabetes mellitus with onset during an autumn period (October–December 1985) and a late spring period (May–June 1986) were selected. In all, 98 patients were analysed for IgM antibodies against coxsackie B virus serotypes 1 through 5 by a μ-antibody capture radio immunoassay technique. Sera from 94 referent children matched for age, sex and residential area, collected during the same period, were also analysed. During the autumn period, 10 out of 67 (15%) diabetic children were IgM positive while 14 out of 75 (19%) of the healthy referent children demonstrated positivity. During the late spring period only one out of 31 (3%) children with diabetes and two out of 19 (10%) referent children were IgM positive. In the diabetic patients, five were coxsackie B2 positive while coxsackie B1, 3, 4 and 5 were represented by one to three patients each. Eight referent children were coxsackie B4 positive, six were B3 positive and two B2 positive, while no referent children were positive against coxsackie B1 and 5. During these two periods in late 1985 and early 1986 these data demonstrate no evidence of increased antibody frequency against coxsackie B virus 1 through 5 at the onset of childhood diabetes in Sweden.

Swedish guidelines for diagnosis and treatment of infective endocarditis

Swedish guidelines for diagnosis and treatment of infective endocarditis (IE) by consensus of experts are based on clinical experience and reports from the literature. Recommendations are evidence based. For diagnosis 3 blood cultures should be drawn; chest X-ray, electrocardiogram, and echocardiography preferably transoesophageal should be carried out. Blood cultures should be kept for 5 d and precede intravenous antibiotic therapy. In patients with native valves and suspicion of staphylococcal aetiology, cloxacillin and gentamicin should be given as empirical treatment. If non-staphylococcal etiology is most probable, penicillin G and gentamicin treatment should be started. In patients with prosthetic valves treatment with vancomycin, gentamicin and rifampicin is recommended. Patients with blood culture negative IE are recommended penicillin G (changed to cefuroxime in treatment failure) and gentamicin for native valve IE and vancomycin, gentamicin and rifampicin for prosthetic valve IE, respectively. Isolates of viridans group streptococci and enterococci should be subtyped and MIC should be determined for penicillin G and aminoglycosides. Antibiotic treatment should be chosen according to sensitivity pattern given 2–6 weeks intravenously. Cardiac valve surgery should be considered early, especially in patients with left-sided IE and/or prosthetic heart valves. Absolute indications for surgery are severe heart failure, paravalvular abscess, lack of response to antibiotic therapy, unstable prosthesis and multiple embolies. Follow-up echocardiography should be performed on clinical indications.

Urinary excretion of 1-methylhistidine a qualitative indicator of exogenous 3-methylhistidine and intake of meats from various sources

In order to investigate whether the urinary excretion of 1-methylhistidine (1MH) might serve as an objective indicator of meat ingestion and exogenous 3-methylhistidine (3MH) intake, healthy subjects were fed an ovolactovegetarian diet. At five-day intervals they were given meat of different origin and 24-hour urinary excretions of 1MH and 3MH were determined. After beef intake there was a marked increase of 3MH and 1MH excretion. The elimination curves were found to follow first-order kinetics and to indicate similar elimination rates. 1MH was present in ten different types of meat analyzed. A strong linear relationship was found between increase in 3MH and 1MH excretion and the amount of chicken, pork, or plaice ingested. IMH may serve as an objective indicator of meat and exogenous 3MH intake, since it is present in meat, and, regardless of source, shows similar dose-independent kinetics, and has similar half-life to 3MH.

Subacute bartonella infection in Swedish orienteers succumbing to sudden unexpected cardiac death or having malignant arrhythmias.

During the period 1979-92, an increasing number of sudden unexpected cardiac deaths (SUCD) occurred in young, Swedish, male elite orienteers. Myocarditis was the most common diagnosis in the 16 victims, and in 4 cases was also associated with fatty infiltration mimicking arrhythmogenic right ventricular cardiomyopathy (ARVC). Tissues from autopsies of 5 orienteers were tested for Bartonella by PCR targeting the gltA (citrate-synthase) gene. The products were then sequenced. Antibodies to B. henselae, B. quintana and B. elizabethae were measured by indirect fluorescence antibody assay. Bartonella spp. DNA was detected in the hearts of 4 deceased orienteers, and in the lung of a fifth deceased case. The sequences were close to B. quintana in 2 cases and identical to B. henselae in 3. Four of these 5 cases, as well as 2 additional cases of elite orienteers with ARVC, indicated antibodies to Bartonella. It is suggested that Bartonella-induced silent subacute myocarditis, eventually leading to electric instability, caused the increased SUCD rate among the Swedish orienteers. It is further suggested that Bartonella infection may be a major pathogenetic factor in the development of ARVC-like disease. Although the mode of transmission is unknown, both zoonotic/vector-borne and parenteral person-to-person transmission may be involved.During the period 1979-92, an increasing number of sudden unexpected cardiac deaths (SUCD) occurred in young, Swedish, male elite orienteers. Myocarditis was the most common diagnosis in the 16 victims, and in 4 cases was also associated with fatty infiltration mimicking arrhythmogenic right ventricular cardiomyopathy (ARVC). Tissues from autopsies of 5 orienteers were tested for Bartonella by PCR targeting the gltA (citrate-synthase) gene. The products were then sequenced. Antibodies to B. henselae, B. quintana and B. elizabethae were measured by indirect fluorescence antibody assay. Bartonella spp. DNA was detected in the hearts of 4 deceased orienteers, and in the lung of a fifth deceased case. The sequences were close to B. quintana in 2 cases and identical to B. henselae in 3. Four of these 5 cases, as well as 2 additional cases of elite orienteers with ARVC, indicated antibodies to Bartonella. It is suggested that Bartonella-induced silent subacute myocarditis, eventually leading to electric instability, caused the increased SUCD rate among the Swedish orienteers. It is further suggested that Bartonella infection may be a major pathogenetic factor in the development of ARVC-like disease. Although the mode of transmission is unknown, both zoonotic/vector-borne and parenteral person-to-person transmission may be involved.