From a longitudinal prospective study, 160 women with spontaneous menopause and without steroid medication were followed during the transition from pre- to postmenopause. After 12 years 152 women were still participating in the study. Blood samples were drawn every 6 months until 1 year after the menopause and every 12 months thereafter. Measurements of bone mineral density (BMD) on the forearm were performed every second year. All women routinely completed a questionnaire concerning symptoms frequently attributed to the climacteric period. All data were grouped around the onset of the menopause, thereby allowing longitudinal evaluation of the changes in the variables from the premenopausal to the postmenopausal period. The beginning of the perimenopausal period was characterized by transitory elevations of follicle-stimulating hormone (FSH). A significant increase in serum levels of gonadotropins was observed for both FSH and luteinizing hormone (LH) from about 5 years before the menopause. Within the 6 month period around the menopause there was a further increase which culminated within the first postmenopausal year for LH and 2-3 years postmenopause for FSH. Thereafter, a continuous decrease in LH occurred over the following 8 years. With respect to FSH, there was a slight decline starting about 4 years postmenopause. During the premenopausal period an increasing frequency of inadequate luteal function or anovulation occurred and, in the postmenopausal years, the serum levels of progesterone (P) were invariably low. Gradually, the ratio between estrone (E1) and 17-beta-estradiol (E2) increased, reflecting the declining follicular steroidogenesis. A marked decrease in estrogen levels occurred during the 6 month period around the menopause, most pronounced in E2. During the next 3 years, the levels of E2 and E1 showed an essentially parallel, moderate decline. Around the menopause, serum levels of testosterone (T), delta 4-androstenedione (A) and sex hormone-binding globulin (SHBG) showed small but significant decreases. From about 3 years postmenopause, the levels were relatively constant over the following 5 years. A decrease in BMD was observed in the postmenopause, and from about 3 years postmenopause, estradiol correlated positively with BMD. Before, as well as after the menopause, body mass index (BMI) showed an inverse correlation with SHBG. Postmenopausal androstenedione correlated positively with E1, E2 and T. BMI correlated positively with E1 and E2. The concentrations of the free fraction of E2 and T are dependent on the levels of SHBG, which in turn has a negative correlation with BMI. The impact of this will influence the severity of symptoms, the degree of bone loss and the need for supplementary therapy.

Type I (insulin-dependent) diabetes mellitus is a multifactorial disease that develops after exposure to unknown environmental factors in children with specific HLA susceptibility genes. At the time of clinical diagnosis, the majority of the insulin-producing cells in the pancreatic islets have been eradicated in association with autoimmune phenomena including insulitis [1 ,2, 3], lymphocyte proliferation abnormalities [4,5,6] and autoantibodies to islet cell antigens [7±9]. Studies in first-degree relatives [7,8], twins [9], pregnant mothers [10,11] and school children [12,13,14] have found that islet autoantibodies can be present years before clinical diagnosis. Some [15±17], but not Diabetologia (1999) Summary Islet autoantibodies are early markers for Type I (insulin-dependent) diabetes mellitus. The aim of this study was to establish whether islet autoantibodies were present at birth in children who developed Type I diabetes before 15 years of age. Cord blood sera from 81 children who developed Type I diabetes between 10 months and 14.9 years of age were tested for glutamic acid decarboxylase autoantibodies (GAD65Ab), islet cell antigen 512 autoantibodies (ICA512Ab), insulin autoantibodies (IAA) all by quantitative radioligand binding assays and islet cell autoantibodies (ICA) by indirect immunofluorescence. Cord blood sera from 320 randomly selected matched children were controls. The children who developed Type I diabetes had an increased frequency of cord blood islet autoantibodies compared with control subjects: Glutamic acid decarboxylase autoantibodies were detected in 6 % (5/81) patients and 2 % (5/320) control subjects (p = 0.03); islet cell antigen 512 autoantibodies in 5 % (4/73) patients and 1 % (4/288) control subjects (p = 0.06); insulin autoantibodies (IAA) in 0 % (0/79) patients and 0.3 % (1/320) control subjects (p = 0.36); and islet cell autoantibodies in 10 % (8/81) patients compared with 0.6 % (2/320) control subjects (p = 0.0001). Taken together, 17 % (14/81) patients had one or more islet autoantibody compared with 4 % (12/320) control subjects (p = 0.0001). Whereas none of the control children had more than one antibody, 4 % (3/81) children who later developed Type I diabetes were double positive (p = 0.002). Although glutamic acid decarboxylase autoantibodies' concentrations in cordblood correlated to those in the mothers' blood at the time of delivery, no corresponding correlation was found for the other two types of autoantibodies. The increased frequency of cord blood islet autoantibodies suggests that the Type I diabetes process could already be initiated in utero. [Diabetologia (1999)

Capillary blood samples from 63 infants collected 3-7 days after birth, and thereafter stored on filter papers for 12-18 y, were tested for the presence of CMV DNA by the polymerase chain reaction (PCR) method. Of 16 infants with proven congenital CMV infection (positive virus isolation test in urine sampled within 1 week of age), 13 (81%) had a positive CMV PCR test and 3 (19%) a negative PCR test. All blood samples from 16 control infants without congenital CMV infection (negative virus isolation test in urine sampled within 1 week of age) were CMV PCR-negative. When 31 samples on filter papers stored above or below the samples of the infected infants were tested, 6 (19%) had a weak reactivity. This suggests that CMV DNA can be transferred from one filter paper to another during storage. We conclude that PCR performed on dried blood stored on filter paper is a useful method in the retrospective diagnostics of congenital CMV infection. Consideration must be given, however, to the possibility of transfer of CMV DNA from blood samples stored nearby.

Summary In a population-based setting, we traced serum samples collected at time of birth from 55 mothers whose children later developed insulin-dependent diabetes (IDDM) and .matched them pairwise to control subjects who gave birth at the same hospital during the same month. The sera were analysed for IgM antibodies to coxsackie B virus serotypes 2, 3 and 4 (CBV-2, 3 and 4) using a type-specific w-antibody-capture radioimmunoassay. Despite a decreased power due to the close matching by time of birth we found a significantly higher frequency of CBV-3 IgM at delivery in mothers whose children later became diabetic compared to their matched control subjects. When using the presence of CBV-3 IgM as a risk factor the Mantel-Haenszel odds ratio estimate (95 % confidence limits) was 2.57 (1.02; 7.31), p = 0.043. For CBV-2 and CBV-4, respectively no significant difference was found between mothers of patients and control subjects. According to the odds ratio estimate for CBV-3 and the proportion of exposed mothers among patients estimated in this study the aetiological fraction for this risk determinant would be 27 %. In conclusion, this study indicates that children of mothers who expressed CBV IgM at delivery are at increased risk for developing childhood onset IDDM. A fetal infection with CBV similar to rubella virus may initiate autoimmunity or cause persistent infection that may lead to progressive beta-cell destruction. [Diabetologia (1995[Diabetologia ( ) 38: 1371[Diabetologia ( -1373 Key words Pregnancy; Coxsackie B virus viral infections; Childhood IDDM. Viral infections, especially due to picornaviruses, have long been suspected to be associated with insulin-dependent diabetes (IDDM) and evidence for such a mechanism has been collected in a large number of animal experiments. Viruses may directly infect and destroy the beta cells, as indicated from one case report where coxsackie B4 virus (CBV-4) was isolated from the pancreas of a child who died a few days after the onset of IDDM. Viruses may also more unspecifically precipitate disease onset by increasing the work load of an already damaged beta- cell, a mechanism which is suggested by the discovery of a dose-response relationship between the risk for IDDM and the frequency of recent infections. In humans, the most convincing evidence of virus as an early initiator of IDDM was the discovery of a very high prevalence of diabetes in a cohort of children who were followed-up because of fetal rubella embryopathy syndrome [1]. The rubella embryopathy syndrome is now virtually eradicated in Sweden due to vaccination programmes but other fetal virus infections might also affect the vulnerable immature immune system and thereby initiate autoimmunity to the beta cell.In a recent population-based case-control study we found that mothers whose children later became diabetic had higher titres of group-specific enterovirus antibodies at time of giving birth when compared to mothers whose children were healthy, whereas no difference was found in antibody titres to herpes,

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