Absorption,effectiveness and side effects of highly purified porcine NPH-insulin preparations (Leo®)

Summary The clinical characteristics of highly purified porcine NPH-insulin (Insulin Retard RI^®) were investigated, including absorption from the subcutaneous tissue, blood glucose-lowering effect, stability of mixtures of NPH and regular insulin and measurement of circulating porcine proinsulin and insulin antibodies in diabetics. The absorption of NPH-insulin followed first order kinetics. The half time was 6.9±2.6 h, with an intraindividual coefficient of variation of 26% and an interindividual coefficient of variation of 55%. After 24 h 90% of the injected insulin had disappeared from the subcutaneous tissue. The plasma insulin concentration was maximal 4–5 h after the injection and 24 h after the injection it was not significantly higher than before the injection. The blood glucose-lowering effect was significant 2.5 h after subcutaneous injection of NPH-insulin and was maximal after 5.5 h. The blood glucose-lowering effect of a pre-prepared mixture of 70% NPH and 30% regular insulin was not significantly different from the effect of 70% NPH and 30% regular insulin injected separately, which indicates the stability of mixtures of NPH and Regular insulin. Porcine proinsulin disappeared from the serum of patients switched to treatment with highly purified porcine NPH insulin and the insulin antibody titer fell. It was concluded that insulin Retard RI^® has a well-defined, reproducible effect with a clinically useful time course.With the technical assistance of Birthe Lørup, Hanne Richter-Olesen, and Knud Jørgensen, Finsen Laboratoriet, Copenhagen, Denmark.     

Familial risk of multiple sclerosis: a nationwide cohort study

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk=7.1, 95% confidence interval: 5.8, 8.8) (n=90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among first-degree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood.     

Detection of a highly toxic clone of Actinobacillus actinomycetemcomitans (JP2) in a Moroccan immigrant family with multiple cases of localized aggressive periodontitis

The JP2 clone of Actinobacillus actinomycetemcomitans, a high-leukotoxin-producing strain, characterized by a 530-basepair (bp) deletion in the promoter region of the leukotoxin gene operon and mainly found among individuals with African origin, is associated with localized aggressive periodontitis. The objective of the study was to examine the occurrence of periodontal disease in a Moroccan immigrant family living in Denmark in which the oldest son (14 year) was referred and treated for localized aggressive periodontitis. Further, the potential occurrence of the JP2 clone of A. actinomycetemcomitans in the family was examined. Here we present the clinical, radiographic, and microbiological findings from the family. Clinical and radiographic examination of the other family members revealed that 3 of 5 younger siblings had localized aggressive periodontitis, one had gingivitis and the mother had chronic periodontitis. Despite scaling followed by intensive maintenance therapy several family members, including the sibling with gingivitis, had further attachment loss at the 1-year examination. The JP2 clone of A. actinomycetemcomitans was isolated from subgingival plaque samples from 4 children with periodontitis. In contrast, it was not detected in plaque from the oldest boy, who had been treated for localized aggressive periodontitis by surgery combined with antibiotic therapy. The 4 children with periodontitis and colonized with the JP2 clone were treated by scaling and antibiotic administration. One month later the JP2 clone could still be detected in plaque samples. In conclusion, it is confirmed that members of immigrant families with African origin are potential carriers of the JP2 clone and that those families often have multiple family members with localized aggressive periodontitis. It is proposed that those families are given periodontal examination frequently to benefit from early diagnosis and treatment of the disease.     

Breastfeeding and risk of atopic dermatitis, by parental history of allergy, during the first 18 months of life

The role of breastfeeding in allergic diseases remains controversial. The authors studied the association between breastfeeding and development of atopic dermatitis during the first 18 months of life among children with and without a parental history of allergy. A cohort study of 15,430 mother-child pairs enrolled in The Danish National Birth Cohort was carried out between 1998 and 2000. Data on breastfeeding, atopic dermatitis, and potential confounders was obtained from telephone interviews conducted during pregnancy and when the children were 6 and 18 months of age. The cumulative incidence of atopic dermatitis was 11.5% at 18 months of age. Overall, current breastfeeding was not associated with atopic dermatitis (incidence rate ratio (IRR) = 0.91, 95% confidence interval (CI): 0.80, 1.04). Exclusive breastfeeding for at least 4 months was associated with an increased risk of atopic dermatitis in children with no parents with allergies (IRR = 1.29, 95% CI: 1.06, 1.55) but not for children with one (IRR = 1.11, 95% CI: 0.94, 1.31) or two (IRR = 0.88, 95% CI: 0.69, 1.13) parents with allergies (test for homogeneity, p = 0.03). The authors found no overall effects of exclusive or partial breastfeeding on the risk of atopic dermatitis. However, the effect of exclusive breastfeeding for 4 months or more depended on parental history of allergic diseases.     

Identification, synthesis, and characterization of new glycogen phosphorylase inhibitors binding to the allosteric AMP site

Inhibition of glycogen phosphorylase (GP) has attracted considerable attention during the last five to 10 years as a means of treating the elevated hepatic glucose production seen in patients with type 2 diabetes. Several different GP inhibitors binding to various binding sites of the GP enzyme have been reported in the literature. In this paper we report on a novel class of compounds that have been identified as potent GP inhibitors. Their synthesis, mode of binding to the allosteric AMP site as well as in vitro data on GP inhibition are shown. The most potent inhibitor was found to be 4-[2,4-bis-(3-nitrobenzoylamino)phenoxy]phthalic acid (4j) with an IC(50) value of 74 nM. This compound together with a closely related analogue was further characterized by enzyme kinetics and in primary rat hepatocytes.     

Perinatal and maternal complications related to postterm delivery: a national register-based study, 1978-1993

OBJECTIVE: This study was undertaken to estimate the risk of fetal and maternal complications associated with postterm delivery in Denmark. STUDY DESIGN: A cross-sectional study that used records from the Danish Medical Birth Registry from 1978 to 1993 was performed. All women with registered prolonged pregnancy (n = 78022) and a 5% random sample of all women who gave birth (n = 47021) were linked to the Danish National Discharge Register. We established a postterm group of 77956 singleton deliveries and a term group of 34140 singleton spontaneous deliveries. Logistic regression models were used to analyze data. RESULTS: The risk of perinatal and obstetric complications was high in postterm delivery compared with term delivery (adjusted odds ratios between 1.2 and 3.1). The risk of perinatal death was 1.33 (1.05-1.68). CONCLUSION: Postterm delivery was associated with significantly increased risks of perinatal and maternal complications in Denmark in the period from 1978 to 1993.     

Second-trimester maternal serum alpha-fetoprotein and risk of adverse pregnancy outcome(1)

OBJECTIVE: To determine the risk of adverse pregnancy outcome by maternal serum alpha-fetoprotein (MSAFP) level. METHODS: We followed 77,149 pregnant women and their infants from MSAFP screening in the 15th to 20th week of gestation until 1 year after birth. Information on pregnancy outcome was obtained from national registries. The relative risks (RRs) and 95% confidence intervals (CIs) for adverse pregnancy outcome were estimated according to the level of MSAFP, with adjustment for confounders. RESULTS: A total of 638 pregnancies resulted in spontaneous abortion, 289 in stillbirth, and 437 in infant death. Compared with women with MSAFP levels at 0.75-1.24 multiples of the median (MoM), those with MSAFP levels greater than or equal to 2.5 MoM had an increased risk of spontaneous abortion (RR 12.5; 95% CI 9.7, 16.1), preterm birth (RR 4.8; 95% CI 4.1, 5.5), small for gestational age (RR 2.8; 95% CI 2.4, 3.2), low birth weight (RR 5.8; 95% CI 5.0, 6.6), and infant death (RR 1.9; 95% CI 1.2, 2.8). Women with MSAFP levels below 0.25 MoM had an increased risk of spontaneous abortion (RR 15.1; 95% CI 9.3, 24.8), preterm birth (RR 2.2; 95% CI 1.3, 3.8), and stillbirth (RR 4.0; 95% CI 1.0, 16.0); those with levels less than 0.5 MoM had an increased risk of infant death (RR 1.9; 95% CI 1.2, 3.0). The increased risk of infant death remained after the subtraction of recognized conditions associated with extreme MSAFP values. CONCLUSION: Pregnant women with extreme MSAFP values in the second trimester have an increased risk of fetal and infant deaths. Obstet Gynecol 2001;97:277-82.     

Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies

Evidence has emerged that childhood leukemia is initiated in utero. High birth weight is one of the few birth-related factors that has been associated with childhood leukemia, albeit not consistently. The authors conducted a meta-analysis of studies of the association between birth weight and childhood leukemia risk. Study-specific odds ratios for leukemia were calculated, using a cutoff at 4,000 g of birth weight. The authors also evaluated whether the association between birth weight and leukemia followed a log-linear dose-response-like pattern. They calculated summary estimates using weighted averages of study-specific odds ratios from dichotomous and trend analyses. Eighteen studies (published between 1962 and 2002) were included, encompassing 10,282 children with leukemia. Children weighing 4,000 g or more at birth were at higher risk of acute lymphoblastic leukemia than children weighing less (odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.17, 1.37). Furthermore, data were consistent with a dose-response-like effect (OR = 1.14/1,000-g birth weight increase, 95% CI: 1.08, 1.20). Studies of acute myeloid leukemia indicated a similar increase in risk for children weighing 4,000 g or more at birth (OR = 1.27, 95% CI: 0.73, 2.20) and a dose-response-like effect (OR = 1.29/1,000 g, 95% CI: 0.80, 2.06), but results varied across studies. Our findings support a relation between birth weight and childhood acute lymphoblastic leukemia risk and emphasize the need for additional studies of the biologic mechanisms underlying this association.     

Specific assay for pregnancy-specific-beta 1-glycoprotein (Sp1-beta). Preparation of antiserum specific for SP1-beta by absorption with a crossreacting high molecular weight serum protein

Two pregnancy-associated proteins reacting with antibody against pregnancy-specific beta 1-glycoprotein (PS beta G or SP1) were separated by means of ammonium sulphate precipitation, size chromatography and preparative zone electrophoresis. The antibody preparation was made monospecific to the beta-mobile protein by liquid phase cross-absorption of anti-SP1 immunoglobulin preparation with the isolated alpha2-mobile high molecular weight protein. The specificity of the absorbed antibody was tested in line immunoelectrophoresis, rocket immunoelectrophoresis and crossed immunoelectrophoresis.