The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL). Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up. The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level. Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters. In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.

An in vitro method was developed for measuring aromatase, based on binding of competitive aromatase inhibitor [11C]vorozole to the active site of the enzyme. [11C]Vorozole displayed high, specific binding in vitro to human placenta and human granulosa cells (GC), both fresh and frozen/thawed cells, provided correct procedures were used. High, specific binding was also observed in pig and rat ovaries, whereas binding in other tissues was unspecific and usually low. Aromatase concentrations measured by [11C]vorozole binding correlated well to aromatase activity measured by [3H]water release from 1β[3H]androstenedione. In human GC in vitro, low concentrations of 5α-dihydrotestosterone (DHT), but not of other androgens, stimulated aromatase activity measured by [3H]water release but had no effects on aromatase concentration measured by [11C]vorozole binding. DHT may interact with aromatase differently than other androgens, perhaps by changing aromatase affinity to precursor. In the rat estrous cycle, aromatase activity in ovarian homogenate, measured by [3H]water release, together with serum androstenedione and estradiol-17β, peaked between 6 and 13 h after onset of the light period of proestrus, the former activity being independent of radioactive substrate concentration. [11C]Vorozole binding characteristics changed more rapidly than de novo synthesis of the enzyme. [11C]Vorozole binding Kd showed close inverse correlation to aromatase activity in ovarian homogenate and to serum estradiol-17β. Rapid changes in substrate affinity rather than changes in substrate concentration or de novo synthesis of the enzyme may thus be important for regulation of ovarian aromatase. The [11C]vorozole in vivo technique yields additional information compared with traditional in vitro techniques.

The overall aim of this thesis was to examine the adoption of emergency contraceptive pills (ECP) in Sweden. Two cross-sectional surveys and two quasi-experimental studies were used. Reasons for induced abortion, contraceptive practices and contraceptive failure were examined in a group of abortion applicants with a waiting-room questionnaire (I) and knowledge, use and practices of ECP were assessed with a postal questionnaire in a population-based sample of young women (II). One community-based information campaign was evaluated with a repeated postal questionnaire (III) and a school-based education intervention was evaluated with repeated class-room questionnaires (IV). Abortion applicants had inadequate contraceptive practices and a low use of ECP. One year after the deregulation of ECP women were highly aware of the method and preferred the pharmacy for the purchase of ECP. Correct knowledge and positive attitudes influenced the willingness to use ECP in the future. The information campaign was noticed by two-thirds of the women and there was an overall trend towards better knowledge, improved attitudes and increased use among all women at follow-up. The school-based intervention improved the students’ knowledge of, and attitudes to, ECP without jeopardizing condom use. The adoption of ECP in Sweden seems to have gone through the first stages of diffusion of an innovation, i.e., developement, dissemination, and adoption, and has reached the stage of implementation since the studies indicated a general awareness of more than 90%, an intention to use in case of need of more than 70%, and womens’ own experience of use of around 30%. The most cited information channels were media, friends and the local Youth Clinic. ECP is gradually becoming a more widely known, accepted and used contraceptive method in Sweden, but must be considered as being only one of many tools in the prevention of unintended pregnancies.

Different modes of assisted ventilation were investigated in cats before and after lung lavage and after instillation of surfactant. The activity of single units of slowly adapting pulmonary stretch receptors (PSRs) in the vagal nerve and the integrated phrenic nerve activity were recorded. The instantaneous impulse frequency (fimp) of PSRs was calculated and related to transpulmonary pressure (Ptp), tidal volume (Vt) and the calculated energy storage of the lung (ΣP*ΔV). Respiratory rate (RR), inspiratory and expiratory time, and Vt were measured, and their coefficients of variation were calculated. During assist control (A/C) ventilation with different pressure waveforms, PNA was shorter and lower in amplitude with squarewave pressure waveform than with linear and sinusoidal pressure waveforms in cats with normal lungs, concomitantly with earlier peak fimp during inspiration and prolonged fimp during expiration. The type of pressure waveform can thus influence the spontaneous breathing effort during A/C ventilation. Proportional assist ventilation (PAV) is a new mode of assisted ventilation which servo-controls the applied airway pressure continuously in proportion to the breathing effort. After lung lavage and surfactant instillation, PAV improves ventilation markedly, with lower PNA and oesophageal pressure deflection and higher RR and variability of breathing, compared to CPAP. In addition, an earlier and higher maximal fimp was observed during PAV. Under conditions of low work and maintained control of breathing, PAV seems to be an attractive mode of ventilatory support. Low-threshold (LT) and high-threshold (HT) PSRs respond to the surfactant content of the lung partly independent of Ptp and Vt in spontaneously breathing cats, implying a possible effect of surfactant on PSRs. The PSR fimp normalized to ΣP*ΔV confirmed these findings and showed that LT and HT PSRs are intrinsically the same. After instillation of surfactant, compliance and PSR activity increased, but the breathing still remained shallow and rapid, suggesting a control of breathing less dominated by PSR activity.

This investigation was undertaken to examine effects of motor skill intervention in children with motor difficulties consistent with developmental co-ordination disorder (DCD) diagnosed in child health care before school entrance, to analyse the parents' descriptions of their children, and to follow up the children's motor status in a short-term perspective. Thirteen studies on the effects of motor skill intervention were submitted to a meta-analysis (Study I). Thirty-seven children who at age 5 to 6 years were diagnosed as having motor difficulties consistent with DCD were enrolled in an experimental investigation of effects of group motor skill intervention on motor skills (Study II) and on self-perceived competence (Study III). The parents' descriptions of their children were obtained at an interview (Study IV). The children's motor status was re-examined when they were 7 to 8 years old (Study V). Motor skill intervention, using the Specific Skills approach, in a group setting or in a home programme, 3 to 5 times per week, was found beneficial for children with DCD who were older than 5 years of age. The non-specific group motor skill intervention influenced the number of children with borderline motor difficulties who changed to having no motor difficulties, and seemed to enhance awareness of motor competence. Parents whose children had definite motor difficulties were more inclined to support their children in physical activity, and reported worry and uncertainty. The children had not changed their motor status at the age of 7 to 8 years. The children with definite motor difficulties, in particular, continued to have these difficulties. Children who when 5 to 6 years old have motor difficulties and who score at the 5th percentile or below at the Movement ABC motor test, seem to need active support in joyful motor learning situations to reduce unwillingness and displeasure.

In this study 165 Swedish parents of young children with Downs’s syndrome (DS) were investigated regarding their perception of the quality of the first information and support received after the birth of the child. The parents’ opinions were compared with clinical routines at the paediatric clinics regarding these issues. Strong clinical ambitions fell short, however, since 70 % of the parents felt insufficiently informed; 56 % felt unsupported, and the timing of the disclosure varied between 0 hour to >5 days. On the basis of a grounded theory analysis the parents’ written narratives regarding the quality of the first information and support were analysed to better understand the reasons underlying the parental dissatisfaction. Criticisms were raised by the parents concerning: the low communication skills by professionals; the lack of privacy; too much negative information; and an unmet desire to early meet other DS parents. The implications of being DS parents regarding their daily life were examined by measuring parental health, stress, sense of coherence, employment and sick leave rates. Results were compared with those in a randomly selected group of parents of healthy age-matched children. The similarities between the DS and control parents were more pronounced than the differences regarding divorce rates, siblings in the family, time spent on child care, employment and sick leave rates, and their self-perceived health, stress, and sense of coherence. However, self-perceived health of the DS mothers was impaired and stress was increased. A small group of DS parents (5 mothers and 1 father) had an extremely high rate of sick leave and no such group was seen in the control parents. In addition, the DS mothers stayed at home because of the child’s sickness most frequently and the DS fathers stayed at home for this reason more than control mothers. Conclusions: Existing guidelines for optimal first information and support of new parents of children with DS are not always followed in Sweden. Qualitative clinical improvements from the parents’ perspective are proposed. Most DS parents live an ordinary family life in respect to the measured parameters, but the risk for health deterioration, particularly in DS mothers, might need attention.

2-Methoxyestradiol (2-ME), a metabolite of 17β-estradiol, is a potent antitumor and antiangiogenesis agent in vitro and in vivo. This study aimed to investigate the effects of 2-ME on human cervical and endometrial cancers in vitro and in vivo. Human cervical cancer HeLaS3 cells, endometrial cancer HEC-1-A and RL-95-2 cells, and severe combined immune deficient (SCID) mice were used. On cervical cancer HeLaS3 cells, 2-ME inhibited the cell growth which is accompanied by apoptosis via iNOS pathway and by G2/M cell cycle arrest. 2-ME had slight effects on normal cervical epithelial cells. In vivo on SCID mice, 2-ME (75 mg/kg p.o.) inhibited the growth of human cervical carcinoma by 34% (p < 0.05) and showed slight side effects to liver and spleen. On human endometrial cancer cells (HEC-1-A and RL-95-2 cells), 2-ME inhibited the growth by blocking cell cycle progress in S- and G2/M-phase in both cell types, and by inducing apoptosis in HEC-1-A cells and by causing necrosis in RL-95-2 cells. 2-ME had no effects on normal endometrial cells. The apoptotic effect, in HEC-1-A cells, was prevented by iNOS-inhibitor 1400W and eliminated by Caspase-inhibitor Z-VAD-FMK. The necrosis, on RL-95-2 cells, was due to a severe disruption of the mitochondrial membrane potential. Unfortunately, 2-ME had no significant effects on endometrial cancer xenografts. It showed slight toxicity to liver, spleen and proliferative effect on uterus. In conclusion, 2-ME inhibits the growth of human cervical and endometrial cancer cells in vitro. However, a weaker anti-tumor effect was observed in our animal model and 2-ME was slightly toxic to liver and spleen. Considering the proliferative effect on uterus, 2-ME might not be a suitable therapeutic agent in gynecological tumors.

The experience of pregnancy and childbirth is a central life event with special implications for women at high risk. This thesis describes the meaning of pregnancy, childbirth and midwifery care in four qualitative interview studies based on the lifeworld theory. Women were interviewed during pregnancy and within one week after childbirth. Midwives were interviewed concerning midwifery care for women at high risk. In an intervention study, childbirth experience as reported through a post partum questionnaire was compared between women receiving standard care and women who had formulated a birth plan preceded by a questionnaire on their expectations and feelings about childbirth. The findings emphasise that childbearing women at high risk live in an extremely vulnerable situation. The vulnerability is obvious in the use of an individual birth plan, where negative feelings become more frequent in women at high risk than in those with normal pregnancy and childbirth. During pregnancy the women feel a moral commitment towards the child, including feelings of objectification and of exaggerated responsibility. During an obstetrically complicated childbirth the essential meaning is the women’s desire to be recognised and affirmed as individual persons. Like women with normal pregnancy and childbirth, they need an emotionally present midwife who sees, give trust and supports. Good midwifery care of childbearing women at high risk is synthesised as "genuine caring in caring for the genuine". The ethos of caring constitutes the basis of caring. Women’s transition during pregnancy and childbirth is described as a genuinely natural process. Midwives have a special responsibility to encourage and preserve this process within women at high risk. The caring relationship is the core and the most essential tool in the care. Distinctive features in the midwifery care are embodied knowledge, physical as well as emotional presence, sensitivity, a mutual dialogue including shared control between midwife and woman, and confirmation and support of the genuine in each woman. The midwifery care is a struggle and a balance between natural and medical perspectives.

<p>The aim with this thesis was to assess the impact of prenatal ultrasound exposure on psychotic illness, childhood brain tumors (CBT) and school achievement, and to evaluate prenatal X-ray exposure and the risk of CBT.</p><p>In a cohort study, children born in Malmö 1973-1978, where prenatal ultrasound was used routinely, were considered exposed (n=13, 212) and children born at hospitals with no use of ultrasound, were considered unexposed (n=357,733). Exposed men had a tendency toward a higher risk of schizophrenia. For other psychoses there were no differences between groups. Other factors related to place of birth might have influenced the results. </p><p>In a case control study, children born 1975-1984 with a diagnosis of CBT (n=512), and randomly selected control children (n=524) were included. Exposure data on X-ray and ultrasound from antenatal records was completed with information from the Medical Birth Register. We found no overall increased risk for CBT after prenatal X-ray exposure. When stratifying by histological subgroups, primitive neuroectodermal tumors had the highest risk estimates. For ultrasound exposure, no increased risk for CBT was seen and numbers of examinations or gestational age at exposure had no substantial impact on the results. </p><p>In a follow-up of a randomized trial on prenatal ultrasound scanning 1985-87, we assessed the children’s school grades when graduating from primary school (15-16 years of age). We performed analyses according to randomization, ultrasound exposure in the second trimester and exposure at any time during pregnancy. There were no differences in school performance for boys or girls according to randomization or exposure in the second trimester. Boys exposed to ultrasound any time during fetal life had a reduced mean score in physical education and small, non-significant increased risk of poor school performance in general.</p>

<p><strong>ABSTRACT</strong></p><p><strong>Background</strong></p><p>Postpartum depression (PPD) occurs in 10% of women who have recently given birth. Postpartum depression is treatable but unidentified and untreated it could lead to serious consequences. There are multiple instruments for screening available. The Edinburgh Postnatal Depression Scale is the most frequently used and is regarded as the best instrument.</p><p><strong> </strong><strong>Aim</strong></p><p>The aim of this study was to analyze to what extent and how midwifes and primary care nurses identify mothers with symptoms of depression respectively PPD. A further aim was to enquire if there are routines for follow up and if there is any collaboration among the professions?</p><p><strong>Method</strong></p><p>A descriptive and comparative design with collection of quantitative and qualitative data was chosen. Midwifes (n=20) and primary care nurses (n=26) at 9 primary care centres answered a questionnaire concerning PPD.</p><p><strong>Results</strong></p><p>Almost all of the primary care nurses reported that they used EPDS as a screening instrument. They also described signs of depression/PPD. Midwifes and primary care nurses had some education in PPD, but there was a need for more education. Even if there was some collaboration among the professions there still was a wish for an increase of co-working.</p><p><strong>Conclusion</strong></p><p>EPDS-screening and referrals to psychologist, physicians and psychiatrists are routines used to identify PPD and also for follow-ups. The midwifes have not received education and does not use EPDS-screening in the same extension as the primary care nurses.</p><p><strong> </strong></p><p><strong></strong></p>