Pubertal development in Danish children: comparison of recent European and US data.

Two recent epidemiological studies (PROS and NHANES III) from the USA noted earlier sexual maturation in girls, leading to increased attention internationally to the age at onset of puberty. We studied the timing of puberty in a large cohort of healthy Danish children in order to evaluate differences between USA and Denmark, as well as to look for possible secular trends in pubertal development. Healthy Caucasian children from public schools in Denmark participated in the study which was carried out in 1991-1993. A total number of 826 boys and 1,100 girls (aged 6.0-19.9 years) were included, and pubertal stages were assessed by clinical examination according to methods of Tanner. In boys testicular volume was determined using an orchidometer. We found that age at breast development 2 (B2) was 10.88 years, and mean menarcheal age was 13.42 years. Girls with body mass index (BMI) above the median had significantly earlier puberty (age at B2 10.42 years) compared with girls with BMI below the median (age at B2 11.24 years, p < 0.0001). Similarly, menarcheal age was significantly lower in girls with BMI above the median compared with girls with BMI below the median (13.12 vs. 13.70 years, p = 0.0012). In Danish boys we found that age at genital stage 2 (G2) was 11.83 years. Both sexes were significantly taller compared with data from 1964, but timing of pubertal maturation seemed unaltered. Finally, puberty occurred much later in Denmark compared with recent data from USA. We could not detect any downwards secular trend in the timing of puberty in Denmark between 1964 and 1991-1993 as seen in the US. Obesity certainly plays a role in the timing of puberty, but the marked differences between Denmark and USA cannot be attributed exclusively to differences in BMI. A possible role of other factors like genetic polymorphisms, nutrition, physical activity or endocrine disrupting chemicals must therefore also be considered. Therefore, we believe it is crucial to monitor the pubertal development closely in Denmark in the coming decades.

Bone mineral status in 134 patients with cystic fibrosis.

AIM: To investigate bone mineral status in patients with cystic fibrosis (CF). PATIENTS AND METHODS: Whole body bone mineral content (BMC), projected bone area, and bone mineral density (BMD) were determined by dual energy x ray absorptiometry in 134 patients with CF and compared with 396 healthy controls. RESULTS: In patients 19 years of age, BMD and BMC for age were significantly reduced. CONCLUSION: Short and narrow bones were the main reasons for reduced BMC for age in patients

Secular changes in anthropometric data in cystic fibrosis patients.

The aim of this study was to study the secular changes in anthropometric data over calendar time in patients with cystic fibrosis (CF). Growth curves were constructed for 270 patients based on height and weight registrations from the medical files. Height, body mass index (BMI), magnitude of pubertal peak height velocity (PHV) and age at PHV were analysed for possible secular changes from the 1960s to the 1990s. There was a significant change in height over calendar time in only 1 of 12 age groups. BMI showed a significant increase in 10- and 15-y-old boys and girls and in 5-y-old girls. The magnitude of PHV changed significantly over time, whereas age at PHV was constant. No significant changes in height and age at PHV over calendar time were observed; this was probably due to a selection bias since the oldest patients, who survived to be part of the present investigation, represented milder forms of the disease. The increase in BMI and change in magnitude of PHV over calendar time may reflect the improvement in treatment leading to a better survival and clinical status through puberty. The increase in BMI and change in magnitude of PHV were sufficient to overcome the selection bias from older patients with milder disease.

Normal spontaneous and stimulated GH levels despite decreased IGF-I concentrations in cystic fibrosis patients.

OBJECTIVE: The aim of the present study was to investigate whether patients with cystic fibrosis (CF) are GH resistant with increased GH release and decreased concentrations of IGF-I as a result of malabsorption, increased catabolism and impaired glucose tolerance. DESIGN: Twenty CF patients were included, ten with normal glucose tolerance (five male, five female, median age 25.5 years (range 20-31)) and ten with diabetes mellitus (five male, five female, median age 25.3 years (range 17-45). Twenty healthy individuals served as controls (ten male, ten female, median age 28.4 years (range 18-36)). METHODS: GH status was evaluated by 12h spontaneous GH release during the night time, arginine-stimulated GH release and the basal concentrations of IGF-I and insulin-like growth factor-binding protein-3 (IGFBP-3). Twelve hour spontaneous GH profiles were estimated using a constant blood withdrawal technique with sampling every 30min and the Pulsar method was used for the analysis of profiles. RESULTS: No significant differences were found in spontaneous and stimulated GH release in CF patients compared with healthy controls, whereas IGF-I and IGFBP-3 were significantly decreased in CF patients compared with healthy controls. The combination of reduced IGF-I and IGFBP-3 with normal GH release points to a relative GH resistance or a disturbance in the pituitary axis in patients with CF. The spontaneous GH release, the stimulated GH release and the basal concentrations of IGF-I and IGFBP-3 were not significantly different in diabetic CF patients compared with CF patients with normal glucose tolerance and the presence of diabetes mellitus was not consistent with increased GH resistance in CF patients. CONCLUSION: CF patients with normal glucose tolerance and diabetic CF patients had normal GH release and decreased concentrations of IGF-I indicating a relative GH resistance.

The acid-labile subunit of human ternary insulin-like growth factor binding protein complex in serum: hepatosplanchnic release, diurnal variation, circulating concentrations in healthy subjects, and diagnostic use in patients with growth hormone deficiency.

Circulating insulin-like growth factor-I (IGF-I) is predominantly bound in the trimeric complex comprised of IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS). Circulating concentrations of IGF-I, IGFBP-3 and ALS are believed to reflect the GH secretory status, but the clinical use of ALS determination is not known. We therefore, determined the: 1) hepatosplanchnic release of ALS by liver vein catheterization (n=30); 2) 24-h diurnal variation of ALS (n=8); 3) normal age-related ranges of circulating ALS (n=1158); 4) diagnostic value of ALS in 108 patients with childhood-onset GH deficiency (GHD). We found: 1) no significant arteriovenous gradient over the liver ofALS, IGF-I, and IGFBP-3; 2) the diurnal variation of ALS was 12% (mean coefficient of variation percent); 3) ALS levels increased throughout childhood with maximal levels in puberty, with a subsequent decrease with age in adults; and 4) ALS levels were below -2 SD in 57 of 79 GHD patients (sensitivity 72%) and above 2 SD in 22 of 29 patients with normal GH response (specificity 76%), which was similar, compared with the diagnostic utility of IGF-I and IGFBP-3. Finally, our findings indicate that hepatic ALS production is not measurable by this approach or, alternatively, that the liver is not the primary source of circulating ALS, IGF-I, or IGFBP-3 in humans. In conclusion, we have provided extensive normal data for a novel ALS assay and found that circulating ALS levels exhibit minor diurnal variation. We suggest that ALS determination may be used in future classification of adults suspected of GHD.

Central precocious puberty in girls: internal genitalia before, during, and after treatment with long-acting gonadotropin-releasing hormone analogues.

Pelvic ultrasonography was systematically performed on 33 girls with idiopathic central precocious puberty to investigate the impact of treatment with gonadotropin-releasing hormone analogues on female internal genitalia. All girls were treated with a long-acting gonadotropin-releasing hormone analogue (Decapeptyl Depot; Ferring Co., Copenhagen, Denmark) 75 micrograms/kg every 4 weeks. Before, during, and after treatment, pelvic ultrasonography was performed and ovarian and uterine volumes were calculated. The size of follicles > 5 mm were accurately measured. The results were related to a normative study of healthy Danish schoolgirls. Our data demonstrated that ovaries and uterus are enlarged in a significant number of girls (50%) with the diagnosis of central precocious puberty at the time of diagnosis. Median ovarian volume at time of diagnosis was 1.1 standard deviation scores (range -0.6 to 3.2 SD), median uterine volume was 1.8 standard deviation scores (range 0.0 to 3.5 SD). Within 3 months of treatment, both ovarian and uterine volumes decreased significantly (p < 0.01) to normal values appropriate for age. Median ovarian volume after 3 months of treatment was 0.0 SD (range -2.4 to 1.5 SD); median uterine volume was 0.7 SD (range -0.6 to 4.1 SD). Ovarian and uterine volume remained within normal range (< 2 standard deviation scores) after discontinuation of treatment. Follicles and macrocysts regressed during treatment. None of the girls' ovaries had a polycystic appearance during or after treatment with the gonadotropin-releasing hormone analogue. Our results confirmed pelvic ultrasonography as a reliable tool for investigation of internal genitalia in girls with precocious puberty and as a valid method for evaluation of the efficacy of treatment with gonadotropin-releasing hormone analogues. We suggest that repeated investigations be performed when evaluating treatment because the morphologic changes, including follicular maturation or regression, reflect ovarian stimulation or suppression. We found no evidence that girls with precocious puberty treated with long-acting gonadotropin-releasing hormone analogues have enlarged polycystic ovaries develop.

Controlled trial of inhaled budesonide in patients with cystic fibrosis and chronic bronchopulmonary Psuedomonas aeruginosa infection.

The efficacy and safety of anti-inflammatory treatment with inhaled glucocorticosteroids in patients with cystic fibrosis (CF) and complicating chronic Pseudomonas aeruginosa (P.a.) lung infection was studied in a placebo-controlled, parallel, double-blind single center trial. Active treatment consisted of budesonide dry powder, 800 microg twice daily, delivered from a Turbuhaler. The study period covered two successive 3-mo intervals between elective courses of intravenous anti-Pseudomonas antibiotics. Fifty-five patients entered the study, with a mean age of 20 yr and a mean FEV1 of 63% of predicted. Analysis of all patients entered, irrespective of trial adherence ("intention to treat"), showed a decrease in FEV1 in the first period of -0.032 L in patients on budesonide versus -0.187 L in patients on placebo (p = 0.08). The corresponding figures for the patients adhering to the protocol during the first period were -0.017 L versus -0.198 L (p < 0.05, confidence interval of the difference: -0.035 to +0.327 L). For all patients entered, as well as for patients adhering to the trial, there was always a trend in favor of budesonide, as judged by changes in FEV1 and FVC in both 3-mo periods. None of the patients had asthma, but the patients on budesonide had a mean improvement in histamine reactivity of +1.15 dose steps over the entire 6-mo period, as opposed to +0.017 dose steps in patients on placebo (p < 0.05). There was also a significant (p = 0.01) correlation between pre-trial histamine reactivity and the change in FEV1 in the first period in patients on budesonide. We conclude that inhaled glucocorticosteroids can be of short-term benefit in patients with CF and chronic P.a. infection and that those patients most likely to benefit from this treatment are patients with hyperreactive airways. Prolonged studies in larger number of patients are necessary to determine the long-term efficacy of this treatment.

Toward understanding insulin fibrillation.

Formation of insulin fibrils is a physical process by which partially unfolded insulin molecules interact with each other to form linear aggregates. Shielding of hydrophobic domains is the main driving force for this process, but formation of intermolecular beta-sheet may further stabilize the fibrillar structure. Conformational displacement of the B-chain C-terminal with exposure of nonpolar, aliphatic core residues, including A2, A3, B11, and B15, plays a crucial role in the fibrillation process. Recent crystal analyses and molecular modeling studies have suggested that when insulin fibrillates this exposed domain interacts with a hydrophobic surface domain formed by the aliphatic residues A13, B6, B14, B17, and B18, normally buried when three insulin dimers form a hexamer. In rabbit immunization experiments, insulin fibrils did not elicit an increased immune response with respect to formation of IgG insulin antibodies when compared with native insulin. In contrast, the IgE response increased with increasing content of insulin in fibrillar form. Strategies and practical approaches to prevent insulin from forming fibrils are reviewed. Stabilization of the insulin hexameric structure and blockage of hydrophobic interfaces by addition of surfactants are the most effective means of counteracting insulin fibrillation.

Doppler assessment of flow velocity in the uterine artery during pubertal maturation.

The aim of this study was to investigate the possible changes in uterine artery flow velocity during puberty and young adulthood. In a cross-sectional study, 133 healthy volunteers aged 6.7 to 25.4 years were investigated. Pubertal development according to the Tanner classification was recorded in each subject. Uterine arteries were visualized by transabdominal color-coded ultrasound. Maximum, minimum and time averaged maximum flow velocities were measured and the pulsatility index (PI) was calculated electronically. When flow velocity was compared between patients at different rates of pubertal development, we found that the average velocity increased from Tanner breast stages I and II to V, followed by a slight decrease in adults (p < 0.0001). The PI varied significantly from stage I to adult (p < 0.0001). The PI was similar in breast stage I, stage II and in adults, with median 4.7 (range 2.7-8.5), 6.1 (range 3.0-7.8) and 4.3 (range 1.9-8.1), respectively. The PI decreased in stages III and IV to 2.6 (1.8-8.4) and 2.8 (1.2-7.9), respectively, whereas stage V was intermediate, at 3.7 (1.1-6.3). The variance of PI was independent of age. In summary, we demonstrated a significant increase in the uterine artery flow velocity during puberty. Furthermore, a significant decline in vascular resistance expressed by the PI was observed in the mid-pubertal period, reflecting increasing blood flow to the rapidly growing uterus.

[Reduced concentration of insulin-like growth factor I in patients with cystic fibrosis]. / Nedsatte koncentrationer af insulin-like growth factor I hos patienter med cystisk fibrose.

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function and linear growth. Using radioimmunoassay we measured IGF-I once in 235 of our 240 patients (114 males, 121 females, median age 16.2 years, range 0.1-44.0 years). IGF-I was significantly reduced compared with a healthy Scandinavian control population: Mean (-2SD to +2SD) IGF-I-SD score -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females, both values were significantly different from zero (p < 0.001). Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females (p < 0.001). The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

[Vibrio vulnificus infections in Denmark during the summer of 1994]. / Vibrio vulnificus-infektioner i Danmark sommeren 1994.

The clinical manifestations and epidemiological data of 11 patients infected with Vibrio vulnificus found in Denmark during the unusually warm summer of 1994 are reported. All patients had been exposed to seawater prior to illness, but none had consumed seafood. Nine patients, including four with bacteraemia, developed skin manifestations of various degrees of severity. One patient died of septic shock despite surgery and treatment with relevant antibiotics. Four patients contracted the disease while fishing. High seawater temperature increases the risk of V. vulnificus infections even in temperate climates such as the Danish. Exposure to seawater, including handling of fresh seafood, during warm periods carries a risk of infection with V. vulnificus.

[Landfill gas]. / Lossepladsgas.

In a landfill mixture of gases, consisting principally of methane and carbon dioxide, may be produced by microbial degradation of organic waste under anaerobic conditions. Methane is explosive at concentrations between 5 and 15% by volume. Other gases, for instance hydrogensulphide, mercury and ethane, may be emitted at low concentrations, but usually do not represent a health hazard following normal atmospheric dilution. Indoor climate may be affected, though, in cases of accumulation in closed spaces. A case is presented where two persons died following an explosion caused by lighting a cigarette in their house which was surrounded on three sides by a landfill. The explosion occurred after heavy precipitation on a day with low atmospheric pressure. Methane measurements showed values consistent with risk of explosion.

Pubertal maturation of the internal genitalia: an ultrasound evaluation of 166 healthy girls.

Pelvic ultrasound is an important tool in the management of children with disturbances of pubertal development; interpretation requires an understanding of the normal relationship between maturation of internal genitalia and the appearance of secondary sex characteristics. We performed pelvic ultrasound examinations in 166 healthy females aged 6.4-25.4 years, and related uterine and ovarian volumes and size of follicles to age and pubertal stage. We demonstrated growth of the uterus and ovaries before the appearance of breast development and pubic hair growth. In prepubertal girls, uterine and ovarian growth was related to height (p = 0.008 and p = 0.010, respectively). From breast stages 1-5, median uterine and ovarian volumes increased from 1.6 ml to 43 ml, and from 1.2 ml to 7.3 ml, respectively (p < 0.0001). Uterine growth continued several years after menarche. Postmenarcheal uterine growth was related to the number of years after menarche (p < 0.001), but not to height, weight or age. Follicles were seen in 86% of prepubertal girls and in 99% of pubertal girls. Follicles up to 8 mm in diameter were observed in prepubertal girls. Maturation of the internal genitalia begins before the onset of clinical puberty, and extends well into the second decade.

Socio-economic status of AIDS patients.

The charts of 187 patients diagnosed at Hvidovre University Hospital, Copenhagen from 1981 through 1989 as having AIDS were reviewed retrospectively in order to examine the extent of their employment and alternative sources of income during the first 2 years after diagnosis. At the time of diagnosis, 50% were actively employed, 15% were on sick leave, and 19% were receiving a pension. The remaining 16% were either receiving unemployment benefits, on welfare, students, or supported by family or friends. The proportion of patients actively employed declined to 22% one month after the time of diagnosis. After 2 years, only 6% still worked, while 22% had a pension. Sixty-seven percent had died. The major source of income during these first 2 years after diagnosis was a pension, most often a disability pension. During this period the total average disbursement of public allowances per patient amounted to US$16,150. As shown here, the work capacity of AIDS patients is quite low, and alternative sources of income must be provided.

[Contamination of a water system with sewage]. / Forurening af et vandvaerk med kloakvand.

The purpose of the study was to examine the extent of illness caused by contamination of a waterworks with waste water due to overflow. Structured questionnaires were mailed to all 703 households (the main study group) and four day-care centers supplied by the waterworks as well as a group of 200 randomly chosen households in neighbouring communities with a different water supply. Fourteen hundred and fifty-five persons (88% of respondents in the main study group) reported that they had had symptoms of gastroenteritis, particularly diarrhoea (83%) and vomiting (55%). In the control group, 10% of respondents had had symptoms of gastroenteritis. Onset of diarrhoea correlated well with precipitation (Spearman's correlation coefficient: 0.75; p = 0.0002). No pathogens were found. It is important to be aware of the possibility of water contamination when an increased number of cases of gastroenteritis are observed in a local area and to report even a suspicion of waterborne diseases to the county public health office.

Diminished concentrations of insulin-like growth factor I in cystic fibrosis.

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r = 0.28, p < 0.001) was found. The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

Gastroenteritis: a waterborne outbreak affecting 1600 people in a small Danish town.

STUDY OBJECTIVE: To examine (i) the extent of illness caused by contamination of a waterworks with waste water due to overflow, and its correlation with precipitation; (ii) the potential secondary spread; (iii) economic losses due to sick leave. DESIGN: A historical follow up study with structured postal questionnaires. SETTING: A small community on the outskirts of greater Copenhagen at the end of 1991 and the beginning of 1992. PARTICIPANTS: The main study group comprised all 703 households supplied by the waterworks (response rate: 89% of households). There was a control group of 200 randomly chosen households in neighbouring communities with a different water supply source (response rate: 64% of households). A day care group of all 149 children (response rate: 78%) and 30 teachers (response rate: 83%) who lived in central Copenhagen, but spent the day in four day care centres supplied by the waterworks, and members of their household was also studied. MEASUREMENTS AND MAIN RESULTS: Altogether 1455 people (88% of respondents in the main study group) reported having had symptoms of gastroenteritis, particularly diarrhoea (83%) and vomiting (55%). In the control group, 10% had had symptoms of gastroenteritis. The onset of episodes with diarrhoea correlated well with precipitation (Spearman's correlation coefficient: 0.75; p = 0.0002). The secondary attack rate in household contacts was 12%. No pathogens were found. Affected people stayed home from work for a total of 1658 days. The cost of loss of production because of sick leave amounted to 1,600,000 Danish kroner (180,000 pounds). CONCLUSIONS: The outbreak caused extensive illness correlated with precipitation, showed secondary spread, and was associated with major economic losses. Increased awareness among local physicians and waterworks personnel of the possibility of contamination of the water could have led to earlier intervention and reduced the extent of illness. Outbreaks are often caused by several factors, many of a technical nature, which in this case acted together. It is recommended that attention be paid to each factor.

Serum ferritin in children and adolescents. Results from population surveys in 1979 and 1986 comprising 1312 individuals.

Iron stores were assessed by measurement of serum ferritin in a population survey comprising 436 randomly selected urban Danish schoolchildren (219 boys, 217 girls) 7 to 17 years old. Median ferritin values were similar in boys and girls 7 to 13 years old, while 14- to 17-year-old boys had significantly higher values than girls of similar age (p < 0.0001). Boys had stable median ferritin values from 7 to 15 years of age, after which a significant rise was found from 16 to 17 years of age (p < 0.01). Girls had unchanged median ferritin values from 7 to 11 years of age, after which a significant decrease was found from 12 to 17 years of age (p < 0.01). The frequencies of low ferritin values < 16 micrograms/l (indicating absent iron stores) were: Children 7 to 11 years, 1.0%. Boys 12 to 15 years, 4.5%; 16 to 17 years, 0%. Girls 12 to 15 years, 7.6%; 16 to 17 years, 16.7%. Ferritin levels in the reported 1986 survey were significantly higher than those obtained in a similar survey in the same area in 1979. The results indicate an overall increase in iron stores in Danish schoolchildren and adolescents during 1979-1986, possibly due to an increase in the consumption of meat, and in the use of vitamin-mineral supplements containing iron.