Phenotypic and genotypic characterization of 10 Finnish patients with von Willebrand disease type 3: discovery of two main mutations.

Severe von Willebrand's disease (VWD) type 3 is a rare autosomal-recessively inherited bleeding disorder, showing considerable genotypic heterogeneity. We investigated the phenotype in correlation with the genotype in Finnish type 3 VWD patients. Ten patients previously diagnosed with VWD type 3 treated at the Coagulation Disorder Unit in Helsinki University Hospital were re-evaluated for bleeding tendency and treatment. Phenotypic characterization included coagulation and platelet function testing confirming the diagnosis. The genotype was assessed by initial screening for the common c.2435delC mutation and subsequently if needed, by analysing all 51 coding exons of the von Willebrand factor gene. Our result confirmed the diagnosis of type 3 VWD for all 10 patients. We discovered two common mutations: nine of the 20 alleles (45%) were found to carry the c.2435delC frameshift mutation, previously described to be frequent in countries surrounding the Baltic Sea. The nonsense mutation c.4975C>T (p.R1659X) was found on 8/20 (40%) of the alleles. In addition, three novel mutations, a potential splice site mutation (c.874+2T>C) and two frameshift mutations (c.1668delC and c.2072delCCinsG) were found. Seven patients were homozygous and three compound heterozygous for the reported mutations. This study indicates that mainly two mutations (c.2435delC and p.R1659X) cause the majority of type 3 VWD in Finland. This result sets future standards for the genetic testing among the Finnish type 3 VWD population.

A population-based study on epilepsy in mentally retarded children.

PURPOSE: This study presents data on cumulative risk of seizures, cause, comorbidity, and remission of epilepsy among mentally retarded (MR) children followed until the age of 22 years. METHODS: A total of 151 MR children were identified at the age of 8 or 9 years by screening four birth cohorts of 12,882 children born from 1969 to 1972 in the Finnish province of Kuopio. Information about epilepsy was gathered longitudinally when children were 9 to 10, 17, and 22 years old. The guidelines for epidemiological studies on epilepsy proposed by the International League Against Epilepsy were followed. RESULTS: By the age of 10 years, 29 of the 151 MR children (19%) had epilepsy. The cumulative risk for epilepsy at 22 years was 21%. The probability of developing epilepsy was increased fivefold in severely MR children compared with mildly MR children, i.e., in 27 of the 77 severely MR children (35%) versus 5 of the 74 mildly MR children (7%). Postnatal causes of mental retardation or association with cerebral palsy increased the risk for epilepsy, especially in the mildly MR children. When these risk factors were not present, the mildly MR children exhibited only a 3% risk for epilepsy, whereas the respective risk was about 10-fold in severe mental retardation. The cumulative probability of epilepsy being in remission for 5 years by the age of 22 was 32%. CONCLUSIONS: The cumulative risk of epilepsy varies according to the severity and the cause of the retardation as well as the presence of additional disabilities. The cumulative probability of epilepsy remission tended to increase with age.

Determinants of bronchial responsiveness at school age in prematurely born children.

The bronchial challenge test using isocapnic hyperventilation of cold air (IHCA) was used to evaluate bronchial responsiveness in 63 offspring of multiple pregnancies when they were 8-15 years old. At birth, 27 (43%) children had had intrauterine growth retardation (IUGR, birth weight <-2 SD, or birth weight difference between twin pairs >1.3 SD). The median birth weight was 2,050 g (range, 800-3, 150), and the median gestational age was 35 weeks (range, 28-38). None of the children had asthma or suffered from asthma-like symptoms. In the interpretation of the IHCA test, a fall of 9% or more in the forced expiratory volume in 1 sec (FEV(1)) was considered as abnormal, and these children were classified as "cold air responders." The number of responders was 16 (25%); their baseline FEV(1)/forced vital capacity ratio (FEV(1)/FVC) and forced expiratory flow between 25-75% FVC (FEF(25-75)), but not FEV(1) were significantly lower than the corresponding values in nonresponders. No differences were found in perinatal or neonatal factors between responders or nonresponders. Eight (30%) of the 27 IUGR and 8 (22%) of the 36 appropriate for gestational age (AGA) children were IHCA responders. In particular, IUGR was not correlated with maximal FEV(1) falls following the IHCA test. Respiratory infections after the neonatal period were equally common in IUGR and AGA children; but infections were associated with subsequent IHCA responsiveness. Adenoidectomy, tonsillectomy, and/or myringotomy had been performed significantly more often in the responders than in the nonresponders. At least one of the above invasive procedures had been performed in 20 (32%) of the children; this group was termed the "ENT (ear, nose, throat) surgery group." Fifty-six percent of the responders, but only 26% of the nonresponders, belonged to the ENT surgery group (P = 0.02). We conclude that intrauterine growth retardation or prematurity is not associated with abnormal cold air responsiveness in the IHCA test.

Multiple fetuses, growth deviations and mortality in a very preterm birth cohort.

The associations between deviant fetal growth and fetal to 1st year mortality were analysed using univariate and multivariate techniques in a very preterm birth cohort (N = 355; 285 live births; 70 stillbirths) born at or before 32 weeks' gestation in the province of Kuopio, Finland, in 1978-86. Regional fetal growth norms were obtained from non-malformed preterm singletons live-born during a separate five-year period to mothers without chronic diseases or pregnancy complications. Both small and large for gestational age preterms (SGAs and LGAs) showed significantly higher fetal to 1st year mortality (66% and 53%, respectively) than the appropriately-grown group (35%). However, the mortality risk increased markedly if deviant growth (either SGA or, in particular, LGA) was present in multiple fetuses. In such cases, careful follow-up of fetal and neonatal well-being is indicated through the remaining perinatal period. Interactions between perinatal variables should also be taken into account as determinants of outcome both in interventional studies and quality assessments of the care of mid-pregnancy fetuses and preterm infants.

Risk factors associated with cervical human papillomavirus infections: a case-control study.

As a part of the long-term prospective follow-up study conducted for women with genital human papillomavirus (HPV) infections in Kuopio University Hospital, Finland, since 1981, a case-control study was designed to assess risk factors for genital HPV infections. The cases (n = 691) were women who had been invited to attend the follow-up program on the basis of an abnormal cervical smear consistent with HPV-induced cytopathic changes, i.e., had a clinical HPV infection. The controls (n = 706) were a randomly selected group of women who had normal smears in the screening. Both groups were asked to fill in an extensive questionnaire focusing on detailed epidemiologic data on previous gynecologic and obstetric history, sexual practices, sexual partners, and smoking habits. In the multivariate analysis, eight variables emerged as independent risk factors for prevalent HPV infection. These variables could explain over 80% of the risk for infection. The risk for the infection varied with age, being highest in the age group 20-29 years, thereafter declining in the following 10-year age groups. The strongest independent risk factor was the number of sexual partners during the past 2 years (adjusted odds ratio = 12.1; 95% confidence interval 4.3-33.8 for five or more vs. one or no partners). Among the independent risk factors that increased the risk were also current smoking (adjusted odds ratio = 2.7; 95% confidence interval 1.7-4.3), warts in sexual partner(s) (adjusted odds ratio = 3.2; 95% confidence interval 1.6-6.5), and increasing frequency of sexual intercourse per week. Independent risk factors with a protective effect included a normal result in the last Papanicolaou smear, regular use of an intrauterine device as a contraceptive method, and good personal hygiene. No significant association between oral contraceptive use and risk for HPV infection was found. Condom use did not result in protection from the infection. The results of this study support the concepts that sexual intercourse is the main form of transmission among adults and that sexual promiscuity is the most important determinant for genital HPV infections.

Impact of regular relaxation training on the cardiac autonomic nervous system of hospital cleaners and bank employees.

The work-related strain of 50 female hospital cleaners and 48 female bank employees was recorded during a period of rationalization in the workplace, and the effect of daily relaxation to help the workers cope was tested. The subjects were arranged into age-matched pairs and randomly allocated into intervention and reference groups. The intervention period lasted six months. The relaxation method was brief and easily introduced as an alternative break in the workplace. Each training session lasted 15 min. A microcomputer-based system was used to record heart rate variability in response to quiet breathing, the Valsalva maneuver, deep breathing, and active orthostatic tests. Cardiac reflexes indicated that occupational strain (especially of a mental nature) caused the functioning of the autonomic nervous system to deteriorate. Regular deep relaxation normalized the function and improved the ability to cope.

[Sexuality of the aged--attitudes of nurses and physicians]. / Iäkkäiden seksuaalisuus--hoitohenkilökunnan käsityksiä ja asenteita.

The purpose of this study was to describe attitudes of the nurses and the physicians and their knowledge towards the sexuality of the hospitalized and non-hospitalized aged patients. The study was carried out in a small health centre near Turku involving a total of 70 persons of the medical staff, nurses and doctors. The questionnaire was returned by 53 of those involved. According to the participants, aged people only rarely express their wish to discuss their sexual needs during the care. Neither do the nurses or physicians bring up the matter themselves. Most of the attendants in the study would be ready to discuss with the patients matters dealing with the sexuality of the aged. The participants had knowledge of the sexual needs of the elderly and their attitudes were acceptive. This might mean that the member of the staff is willing to try to help the patient in matters usually difficult to handle.

Survival of the smallest. Time trends and determinants of mortality in a very preterm population during the 1980s.

In a regionally representative preterm birth cohort, the fetal to first year survival of very preterm infants born at 32 weeks' gestation or less increased from 54% to 66% between 1978 and 1986. This improvement was due to a fall in numbers of stillbirths while neonatal mortality either declined or remained the same. Only among extremely immature preterm babies born at 26 weeks or less was improvement in fetal survival counteracted by an increase in neonatal mortality. Fewer than 5% of complete fetal to first year deaths occurred postneonatally. After the age of 26 gestational weeks, intrauterine growth retardation was a major unfavourable factor, associated with a 3-fold increase in neonatal mortality.

Prematurity-associated morbidity during the first two years of life. A population-based study.

Two-year patterns of postneonatal morbidity, both chronic and non-chronic, reported for all liveborn preterm infants (n = 612; malformations excluded) delivered in the province of Kuopio, Finland, between 1978 and 1982. The overall readmission rate was 30%, the commonest cause being respiratory infections, surgical disorders (inguinal hernias) and neurological problems. The higher readmission rate in preterms born at less than or equal to 33 weeks of gestation was due to a large proportion of children being admitted with chronic prematurity-associated conditions; preterms without chronic disabilities had similar rates of readmission irrespective of gestational age. Neonatal treatment variables were of little help in the identification of children requiring readmission after neonatal care. Instead, intrauterine growth retardation (IUGR) or being of the male sex significantly increased the risk of subsequent readmission.

Occurrence, predictive factors and associated morbidity of bronchopulmonary dysplasia in a preterm birth cohort.

The occurrence, predictive factors and associated morbidity of bronchopulmonary dysplasia (BPD) was examined in a preterm birth cohort of 712 children, born before 37 weeks of gestation to residents of a geographically defined area between 1978-82. All cases of BPD (N = 16) were born at or before 32 weeks of gestation. The incidence of BPD, based on status at the age of 28 days, was 1 per 1000 live births, but 135 per 1000 live preterms born at or before 32 weeks. Most cases of BPD developed following respiratory distress syndrome (RDS), only one case developing after minimal respiratory symptoms was observed. BPD infants had higher neonatal morbidity, even when compared with preterms of equal gestational maturity, but only a few variables had predictive value with respect to the future development of BPD. Radiologic grading of RDS and associated early cardiologic signs did not increase their predictivity regarding the subsequent development of BPD. Two (12.5%) of the 16 BPD infants died postneonatally. The unfavorable effects of BPD on the health status of preterm infants extended far beyond the neonatal period. The BPD group, which consisted only of 18% of neonatal survivors born at less than or equal to 32 weeks, consumed 53% of all hospital days used by these preterms during the first two years of life. In particular, BPD survivors had markedly more respiratory infections (63%), more neurologic sequelae (37%) and more cases of retrolental fibroplasia (12%) than their non-BPD counterparts.

Neurodevelopmental screening of in utero growth-retarded prematurely born children before school age.

As part of a prospective follow-up study of two premature cohorts (gestational age less than or equal to 36 weeks) born between 1976 and 1977, designed to evaluate the effects of IUGR on morbidity, mortality and neurological development in prematurely born children, 71 prematurely born children (48 AGA, 23 IUGR) without major neurological handicaps were subjected to detailed assessment of their neurological and psychological status at the age of 4 years. Thirty-six healthy full-term children formed a control group. The socioeconomic status of the families of the premature groups was similar to that of the families of the control group. The assessment consisted of a neurodevelopmental screening test and four psychological tests. Validation of the NDS test in relation to proven cognitive problems (sensitivity 96%, specificity 64%, relative risk 16.74) and determination of normal ranges were based on findings in the control group. There were significantly more children with moderate to high risk scores (greater than or equal to 10) among the IUGR group than among the AGA group. The neurodevelopmental profile of the preterm IUGR group was characterized by complex deviations of motor, visual and perceptual functions from normal. Preterm AGA children had only slightly higher risk scores in relation to fine motor, upper motor and perceptive functions than control children. Of the various perinatal factors studied, IUGR (especially in relation to boys who needed respirator therapy) was the most likely to be associated with abnormal NDS scores before school age.

Antenatal screening for congenital nephrosis in Finland by maternal serum alpha-fetoprotein.

In the Kuopio and North-Karelia districts of Finland 10724 pregnancies were screened for congenital nephrosis by maternal serum alpha-fetoprotein (AFP) measurement. Outcome was known for 10504 (98%) pregnancies, of which 509 (4 X 8%) had a serum AFP level greater than or equal to 2 X 5 multiples of the normal median (MoM) at 15-18 weeks gestation. After exclusion of those women who had a normal serum AFP level (less than 2 X 5 MoM) in a second sample, 'wrong dates' or multiple pregnancy, 267 (2 X 5%) remained with a high serum AFP level. Amniocentesis was carried out in 225 (2 X 1%) and 16 women had an amniotic fluid AFP level greater than 10 SD above the normal mean. In this group there were six fetuses with congenital nephrosis (four confirmed and two suspected), six other serious malformations (including an intrauterine death) and four without obvious abnormality. In the 98% pregnancies followed up there were no infants with congenital nephrosis that had been missed. Babies with congenital nephrosis require permanent hospitalization and have a mean survival of 8 months. In Finland, within certain areas, the birth prevalence is as high as 1 in 2600 per year. In such areas maternal serum AFP measurement appears to be a useful method of screening for congenital nephrosis. The service was also well accepted since 94% of the women with raised serum AFP levels wished to be screened again in a future pregnancy.