(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent.

Here we describe for the first time the distinctive pharmacological profile for (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 µmol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypoactivity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to ∼250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to ∼250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptamine 7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT: This report describes the distinctive preclinical profile of (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.

Measurement of iron absorption from compositite meals.

In earlier studies using the recently introduced extrinsic tag technique meals were carefully minced and mixed with the extrinsic tracer to ensure complete isotopic exchange. In the present paper the validity of simpler and more realistic techniques to label and serve composite meals was evaluated. Equal or almost equal absorption figures were found when mixing the label homogenously into a meal, adding it dropwise, or mixing it into the most bulky component of the meal. The necessity of serving the meals in a realistic way was underlined by the finding of higher absorption from a meal in which the components were served separately than from meals mixed before serving. The results of the present study indicate that the validity of using the reference dose as a basis for comparison of absorption data in different groups, was higher when serving the reference dose and the meals on consecutive days than when serving 2 weeks apart. This was true especially in women. The present findings imply that it is both necessary and possible to design simple labeling techniques that allow valid measurements of iron absorption from composite meals. Moreover, when determining the schedule of serving the meals and the reference doses the findings in the present paper must be carefully considered.

Isolation of differentially expressed mRNA in ovaries after estrogen withdrawal in hypophysectomized diethylstilbestrol-treated rats: increased expression during apoptosis.

Ovarian follicular atresia occurs throughout follicular development and involves apoptosis. In addition to regulation by various hormones and growth factors, ovarian granulosa cell apoptosis was shown to be dependent on transcription and translation since the spontaneous onset of DNA degradation in incubated rat granulosa cells was inhibited by actinomycin-D or cycloheximide. Using differential display of mRNA, five transcriptionally upregulated cDNA clones were isolated in the ovary after withdrawal of the anti-apoptotic factor, estrogen. Two of these estrogen-regulated genes, designated ARG-33 and ARG-40, were further characterized using Northern blot hybridizations. ARG-40 showed increased mRNA expression during apoptosis after estrogen withdrawal in the ovary, and after androgen withdrawal in the prostate, while ARG-33 was upregulated during apoptosis only after estrogen withdrawal. This suggests that the two cDNA clones are regulated by steroids, and may be involved in apoptosis in these tissues. ARG-40 showed high homology to cytochrome b, while ARG-33 was novel.

Isolation of differentially expressed aldose reductase in ovaries after estrogen withdrawal from hypophysectomized diethylstilbestrol treated rats: increased expression during apoptosis.

More than 99% of the follicles are eliminated by apoptosis before reaching ovulation. Several growth factors and hormones inhibit apoptosis in the ovary, including estrogen. Using differential display of mRNA, aldose reductase was shown to increase in the ovary of diethylstilbestrol treated hypophysectomized rats after estrogen withdrawal, inducing apoptosis. The aldose reductase mRNA expression was confirmed to be 2.2 +/- 0.2-fold higher after estrogen withdrawal using northern blot analysis. In addition, untreated immature rats showed a 1.7 +/- 0.3-fold higher expression of ovarian aldose reductase mRNA compared to ovaries 24 h after pregnant mare's serum gonadotropin treatment, decreasing apoptosis in the ovary. In the prostate, the level of aldose reductase was increased 3.1 +/- 1.1-fold 2 days after castration induced apoptosis. Although the physiological role of aldose reductase in the ovary is not known, these data suggest that aldose reductase may be part of a hormonally regulated apoptotic pathway in the ovary and prostate.

The use of contraceptive methods among women seeking a legal abortion.

In a simple random sample study of 404 women 20 to 29 years of age, 201 applying for abortion and 203 continuing their pregnancies, all were interviewed personally and requested to complete a questionnaire. The aim of the study was to analyse the use and experience of contraceptives among the abortion applicants in this age group, and to compare their experience with that of women in a matched control group. The most important reasons given for desisting in the use of contraceptives were the experience of side effects, worry about the side effects, and the "human failure" factor involved even with methods of contraception such as pills, which generally are regarded as safe. This study demonstrates that women living alone without any permanent relationship, having a strained economy or having previously had an abortion, need particular and detailed contraceptive advice plus continued close follow-up. To improve the continuation rate, precise contraception counselling focusing on both positive and adverse effects to reduce worry seems essential.

PIP: A 1988 study in Sweden compared the experiences of contraceptives among 201 women, 20-29 years old, electing to undergo legal abortion with those of 203 age- and residence-matched pregnant controls. The researchers also wanted to study the contraceptive experiences of 20-29 year old women choosing abortion. All study subjects attended the family planning clinic of the University Hospital or maternity centers in Goteborg. Cases who had undergone at least 1 other previous legal abortion (A2) were more likely to report side effects from their chosen contraceptive than the controls (51% vs. 29%; p .01). Both these women and those undergoing their first legal abortion (A1) experienced contraceptive side effects more frequently than controls (p = or .01). Women in the abortion groups who had side effects were more likely to discontinue their current contraceptive method than those in the control group who had side effects (90.8% vs. 20.3%). The abortion groups were more likely to have side effects and fear side effects from the use of oral contraceptives (OCs) than the control group (33% for A1 and 45% for A2 vs. 22%; p .01). The most popular contraceptive used by all groups was OCs (79-84%). Among all 404 women, 77 (19%) became pregnant despite contraception use. Women in the abortion groups were more likely to be using a contraceptive when they conceived than controls (33.6% for A1 and 32.8% for A2 vs. 4.9%). Controls were more likely to be married or living together and had longer relationships than the abortion groups (95% vs. 33-44% and 5 vs. 1.5-2.5 years, respectively). Women in the abortion groups tended to have a poor economic situation (39-42% vs. 17% for controls). These findings show that family planning practitioners need to provide individualized and detailed contraceptive counseling, with continued follow-up, to women not in a permanent relationship, in a poor economic situation, or with a history of previous abortion.

Reduction of back and posterior pelvic pain in pregnancy.

STUDY DESIGN: This study analyzed an education and training program concerning back and pelvic problems among pregnant women. OBJECTIVE: The program was aimed at reducing back and pelvic posterior pain during pregnancy. SUMMARY OF BACKGROUND DATA: Low back and posterior pelvic pain accounts for the majority of sick leave among pregnant women. No previous study has suggested any type of solution to this problem. METHODS: Four hundred and seven consecutive pregnant women were included in the study and randomly assigned into three groups. Group A served as controls while different degrees of interventions were made in groups B and C. RESULTS: Serious back or posterior pelvic pain developed in 47% of all women. Pain-related problems were reduced in groups B and C (P < 0.05), and sick-leave frequency was reduced in group C (P < 0.01). For some of the women in this group, pain intensity was also reduced 8 weeks post partum (P < 0.05). Weekly physical exercise before pregnancy reduced the risk for back pain problems in pregnancy (P < 0.05). A non-elastic sacro-iliac belt offered some pain relief to 82% of the women with posterior pelvic pain. CONCLUSIONS: An individually designed program reduced sick leave during pregnancy. Working with groups was less effective. Differentiation between low back and posterior pelvic pain was essential. Good physical fitness reduced the risk of back pain in a subsequent pregnancy. Reduction of posterior pelvic pain by a non-elastic pelvic support was experienced by 82% of the women with posterior pelvic pain.

Evaluation of stated motives for legal abortion.

In a study of 404 women (simple random sample), 20-29 years of age, 201 (group A) applying for abortion and 203 (group B) continuing their pregnancies, the women were given a questionnaire and in addition were interviewed. The aim of the study was to evaluate the spontaneous personal motives of women for abortion at a time when age is not supposed to be a common reason. The results showed that more than half of the women expressed that a bad relationship with the partner in one way or another was a motive for the abortion. Other important motives included characteristics of the women and their partners, mainly immaturity, work/studies and unsuitable life situation for having a child. Less common motives seemed to be economy, dwelling and medical and health factors. It is obvious that women in this study wanted to have a stable relationship to the child's father before they dared or wanted to have a child. Social networks in modern society seem to be too weak. The women do not want to face social and emotional problems as lonely mothers. Political decisions in the society, for example with parental benefit according to your income discourage women from continuing their pregnancies during their studies. It also seems important for the woman to feel mature enough to have a child. The provision and encouragement of methods for safer sex may be a possible way by which to reduce the number of abortions.

Repeat abortion: a comparative study.

In a study of 404 women (simple random sample) 20-29 years of age, 201 women (group A) applying for abortion and 203 women (group B) continuing their pregnancies were given a questionnaire and were also interviewed. The aim of the study was to describe women applying for repeat abortion and to compare them with women having their first abortion and with women continuing their pregnancies. Variables measured were socio-economic, psychological and social problems, relationship with the partner, earlier pregnancies, how the present pregnancy was experienced and decision-making. For presentation of the results, the data have been divided into four subgroups: pregnant women applying for their first abortion (A1, n = 137), women applying for repeat abortion (A2, n = 64), women continuing their pregnancies who have never applied for abortion (B1, n = 142), and women continuing their pregnancies who had previously applied for one or more abortions (B2, n = 58). Women who had had previous abortion/abortions had experienced more psychological problems during their lifetime than the other groups studied. They had more contact with the social welfare service and evaluated their relationship with the partner as less harmonious than women having a first abortion, also in comparison with women continuing their pregnancies with no earlier applications for abortion. Women who have had previous abortion/abortions seem to have a need for special attention. This involves not only being provided with efficient and acceptable contraception, but also with social and psychological support based on the experiences of the women.

[Better advice is needed both before and after abortion]. / Förbättrad rådgivning motiverad såväl före som efter abort.

PIP: 202 women seeking legal abortions were interviewed. 117 attended the follow-up after 3 months; 79% used the pill or IUD. Legal abortion was the solution to an unwanted pregnancy for those women who had not found an appropriate method of contraception. 1 in 4 women were ambivalent about their decision to have an abortion. This group had more psychological problems; 57% as compared to 39% in the overall group. Continuation rates for the pill and IUD were approximately 80% after 3 months. A recommendation is given for follow-up after abortion to give repeated advice on contraception and provide psychological support. (author's modified)^ieng

Smoking during pregnancy. Possibilities of prevention in antenatal care.

Prevention of smoking in pregnancy is a mission of utmost importance since the fetal outcome is improved when the mother quits smoking. Methods to prevent smoking have to consider maternal attitudes and characteristics and be based on pedagogical and behavioral principles. A well-motivated staff, a self-help manual accepted by most women, and special support to those who want it are minimal requirements.

Iron absorption in early pregnancy - a study of the absorption of non-haeme iron and ferrous iron in early pregnancy.

The absorption of non-haeme iron in the food and from a 3 mg reference dose of ferrous iron in solution was measured in 17 healthy women before the 12th week of gestation and in 13 of the women two months after legal abortion. The absorption of ferrous iron in solution was calculated from determinations of the 55Fe activity in blood samples. The food iron absorption was measured from 59Fe-labelled test meals using a highly sensitive whole-body counter. In addition bone-marrow smears and other haematological parameters were studied. The median value of the absorption from the non-haeme food iron was 2.5% and from the ferrous iron salt 10.0 % in early pregnancy in women with storage iron. Two months after abortion the absorption increased to 12.6 and 42.6 % respectively. In early pregnancy the absorption of iron was higher in women without stainable iron in bone-marrow smears. The present results confirm previous observations that the absorption of food iron in early pregnancy is lower than the basal daily requirements. The low absorption is only partly explained by the reduced requirements of iron in early pregnancy. Some other factors related to pregnancy seem also to be involved.

Studies of dietary habits in pregnancy - with special reference to the intake of iron.

The dietary habits of 94 pregnant women (median age 26 years) were studied by means of four-day dietary records. Twenty-seven women were followed longitudinally and were observed in the 10-15th, the 24-27th and the 34-37th week of gestation (L-series). The remaining 67 women comprised the A-series, of which 20, 32, and 15 made their records during the 10-15th, 24-27th, and 34-37th week of gestation, respectively. There were no significant differences between the results from these two series. The mean daily energy intake was 2360 kcal and remained unchanged during pregnancy, exceeding by 250 kcal the average intake in non-pregnant women in Gothenburg, studied earlier. The iron intake comprised 1-2 mg of haeme iron, about 10 mg of native non-haeme iron and 5-6 mg of fortificiation iron. The mean iron intake was 7.2 mg/1000 kcal, which is below the recommendation, but it was distributed over the food groups in a manner more favourable for iron absorption than in the average Swedish population. Further effects to improve the diet so as to increase the content of iron and factors known to favour iron absorption are desirable. The results justify the normal practice of prescribing supplement iron in late pregnancy.

Stopping smoking in pregnancy: effect of a self-help manual in controlled trial.

For medical reasons, encouraging women to stop smoking during pregnancy and post partum has high priority. Many smokers want to stop smoking but decline clinical treatment when it is offered. The aim of this study was to find a method which was accepted by a large number of smokers, had a high success rate and, at the same time, required little involvement from personnel. For one year, all pregnant smokers attending 13 of the 14 public health maternity clinics in Gothenburg for their first appointment were invited to participate in this study. Inclusion criteria were daily smoking, a gestational age of less than 12 weeks and ability to understand Swedish. A total of 745 women was registered, but 22 of them stopped smoking before the treatment. The remaining women were randomized to a treatment group (n = 492) and a control group (n = 231). Of the 492 women in the treatment group 417 (85%) accepted the idea of using the self-help manual written especially for pregnant women and given to each woman in the treatment group by the obstetrician. Overall 10.4% of the treatment group stopped smoking up to 8 weeks after delivery compared with 5.2% of the control group (odds ratio 0.5, 95% CI 0.2-0.9). The ex-smoking status was verified by measurement of thiocyanate in blood. The self-help manual had a high acceptance rate and a success rate that was double the rate in the control group.

Prediction of preterm birth.

The aim of this study was to assess the value of screening of cervical status in normal as well as in pregnancies with risk factors. 1327 pregnancies were studied prospectively; 16% had a medical history of earlier obstetrical or gynecological complications (group I) and 6% had complications during the first 24 weeks of the current pregnancy (group II). The remainder were considered low-risk pregnancies and randomly divided into groups III and IV. In groups I, II and III cervical scoring in accordance with Westin was performed in weeks 24, 28 and 32. The incidence of births before 37 weeks of gestation was 5.6% in group I, 8.8% in group II, 1.5% in group III and 0.7% in group IV. In presence of the risk factors, 61% of the spontaneous preterm deliveries were predicted early in pregnancy. The predictive value of a normal cervical score was high (about 95%) in all groups. In uncomplicated pregnancies the predictive value of a pathological score was only 4% and for cervical dilatation, 6%. In the risk groups the predictive value of a pathological cervix was 3-5-fold higher. Cervical examination in low-risk pregnancies does not improve prediction of preterms but is a complement in a system for indication for preterm delivery in women with defined risk factors.

Dietary iron absorption in pregnancy - a longitudinal study with repeated measurements of non-haeme iron absorption from whole diet.

In 22 healthy women the non-haeme iron absorption (bone-marrow smears and haematological parameters) was studied at the 12th, the 24th and the 36th week of gestation and two months after delivery. In eight non-pregnant women and in seven pregnant women (at the 36th week of gestation) the absorption of food iron was measured from different types of meals. The iron absorption was measured from radioiron-labelled test meals using a whole-body counter with a very high sensitivity. During pregnancy the non-haeme iron absorption increased continuously from less than 1 % in early pregnancy to almost 15 % in late pregnancy. Calculations indicated that the amount of iron absorbed from the diet covered only about half of the demands. The increasing absorption of food iron during pregnancy seems to be related to the still more increasing demands. However, the very low absorption values in early pregnancy was quite unexpected. The amount of iron absorbed was actually below the basal demands, which means that even in early pregnancy, for reasons unknown, there is a negative iron balance. Further studies are necessary to elucidate the significance of this finding. Two months after delivery the absorption of iron from the diet was increased compared to in non-pregnant women and exceeded the demands at that phase thus indicating that a positive iron balance was achieved.

Absorption of supplemental iron during pregnancy - a longitudinal study with repeated bone-marrow studies and absorption measurements.

Iron absorption, bone-marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women. The same studies were repeated two months after delivery. The material was randomly divided into two groups. Twenty-four women were treated with 200 mg of ferrous iron daily while 26 were given placebo. The iron absorption was measured from radioiron-labelled test doses of 100 mg ferrous iron in a whole-body counter with high sensitivity. In the placebo group the iron absorption increased throughout pregnancy from an average of 6.5 % at the 12th week to 14.3 % at the 35th week of gestation. Two months after delivery the absorption was higher than initially. In the iron-treated group the absorption increased between the 24th and 35th week of gestation from 6.0 to 8.6 %. After delivery 5.5 % of the test dose was absorbed. The haemosiderin iron in the bone-marrow was mobilized during pregnancy. In the placebo group no woman had more than trace of haemosiderin in the bone-marrow smears at the 35th week of gestation. In the iron-treated group 65 % had the same bone-marrow findings. The amount of bone-marrow haemosiderin at term seems not to have the same significance for the diagnosis of iron deficiency in pregnancy as in non-pregnant subjects. Two months after delivery about 50 % of the women in the placebo group had restored their iron deposits. In the iron-group the haemosiderin content in the bone-marrow smears was enhanced in most women compared to early pregnancy. In the placebo group haematological data indicated a high frequency of iron deficiency in late pregnancy while in the iron-treated group iron deficiency was prevented.

Decision-making about unwanted pregnancy.

BACKGROUND: The aim of the study was to focus on aspects of the decision-making process among women having first and repeat abortion, in comparison with women continuing their pregnancies with or without having experienced abortions. METHODS: In a study of 401 pregnant women, (simple random sample) 20-29 years of age, 137 having first abortion (A1), 64 repeat abortion (A2), 142 continuing their pregnancies with no experience of abortion (B1) and 58 continuing, having experienced abortion(s) (B2), were given a questionnaire and were interviewed. RESULTS: The pregnancy evoked ambivalent feelings in all groups. One third of the women in the A-groups and about 25% of those in the B-groups had ambivalent feelings. More than half of the women decided to have an abortion upon first finding out they were pregnant, and after a few weeks of thought most of them had decided to have the abortion. More than half of the women having an abortion said it was rather or very difficult to make a decision. Among these subjects, women having had contact with social services found it significantly harder to make this decision. A majority agreed with their partners on having an abortion. A majority did not feel influenced by someone else when deciding about the abortion. However, 10% in the A1-group and 6% in the A2-group felt much or comparatively much influenced by someone else. CONCLUSIONS: Counselling seems to be important among a considerable number of women finding it hard to make a decision about abortion. Special attention is required for women feeling influenced by someone else and/or having pronounced social problems.

Prevalence of iron deficiency in Swedish adolescents.

The prevalence of iron deficiency was determined in Göteborg, Sweden, in a sample of 15- to 16-y-old girls (n = 220) and boys (n = 207) using serum ferritin (SF). In a recent study in women on the relationship between SF and stainable bone marrow iron, it was established that at a cutoff value for SF of < 16 micrograms/L in 75% of women with no iron stores SF concentration was below this value (sensitivity 75%), whereas in 98% of iron-replete women it was above this cutoff value (specificity 98%). The present study showed that in 40% of the girls and 15% of the boys SF was below this cutoff value, indicating iron deficiency. Low SF concentration was associated with significant decreases in transferrin saturation, Hb concentration, mean corpuscular Hb, and mean corpuscular volume. The results from this cross-sectional study showed that, with decreasing SF, the decrease of values for these parameters occurred already before SF had reached the level 16 micrograms/L, suggesting that SF can be validly used as a single criterion of iron deficiency. Using the cutoff value SF < 16 micrograms/L, the figures for the prevalence of iron deficiency in adolescents in different countries were compared and found to be rather similar in Australia, Canada, the United States, and Sweden. High iron requirements combined with the present low-energy life-style leading to an insufficient supply of dietary iron may be a reasonable main explanation for the paradoxical, high prevalence of iron deficiency in adolescents in affluent societies.