Current uncertainties and challenges of publicly available pharmaceutical environmental risk assessment data.

Pharmaceutical residues are widely detected in aquatic environment worldwide mainly arising from human excretions in sewage systems. Presently, publicly available, high quality environmental risk assessment (ERA) data for pharmaceuticals are limited. However, databases like the Swedish Fass offer valuable resources aiding healthcare professionals and environmental scientists in identifying substances of significant concern. In this review, we provide a concise overview of the regulatory ERA process for medicinal products intended for human use. We explore its key assumptions and uncertainties using a subset of 37 pharmaceuticals. First, we compare the consistency of their predicted no-effect concentrations reported in the Fass database with those by marketing authorisation holders. Second, we compare the predicted environmental concentrations (PEC) calculated based on sales data between European and national drug consumption statistics as well as with measured environmental concentrations (MEC), to demonstrate their impact on the regional risk quotients. Finally, we briefly discuss the prevailing uncertainties and challenges of current ecotoxicity testing, especially outcomes of chronic and nonlethal effects.

Ionization of acids on the quasi-liquid layer of ice.

The ice quasi-liquid layer (QLL) forms on ice surfaces below the bulk ice melting temperature. It is abundant in the atmosphere, and its importance for atmospheric chemistry is recognized. In the present work, we have studied the microscopic mechanisms of acid ionization on the QLL using ab initio molecular dynamics. The model system QLL is established by nanosecond time scale simulations with empirical force fields, while the reactivity of the QLL is studied using ab initio molecular dynamics. Our ab initio simulations reveal that QLL is reactive, exhibiting stable crystalline point defects, which contribute to efficient acid solvation, ionization, and proton transfer. We study in detail deuterated hydrogen iodide (DI) and nitric acid (DNO3). Ionization in both cases benefits from the abundance of weakly bonded hydrogen-bond single-acceptor double-donor water molecular species available on the QLL in high relative concentration. Picosecond time scale ionization is demonstrated for both molecular species. Our results suggest efficient reactivity of acid ionization and proton transfer at temperature ranges appropriate for the upper troposphere and lower stratosphere.

Configurational Entropy in Ice Nanosystems: Tools for Structure Generation and Screening.

Recently, a number of experimental and theoretical studies of low-temperature ice and water in nanoscale systems have emerged. Any theoretical study trying to model such systems will encounter the proton-disorder problem, i.e., there exist many configurations differing by water-molecule rotations for a fixed oxygen atom structure. An extensive search within the allowed proton-disorder space should always be perfomed to ensure a reasonable low-energy isomer and to address the effect of proton-configurational entropy that may affect experimental observables. In the present work, an efficient general-purpose program for finite, semiperiodic, and periodic systems of hydrogen-bonded molecules is presented, which can be used in searching and enumerating the proton-configurational ensemble. Benchmarking tests are performed for ice nanotubes and finite slabs. Finally, the program is applied to experimentally appropriate ice nanosystems. A boron nitride film supported ice nanodot is studied in detail. Using a systematic generation of its proton-configurational ensemble, we find an isomer that is ∼1 eV lower in total energy than one previously studied. The present isomer features a considerable dipole moment and implies that ice nanodots are inherently ferroelectric parallel to the surface. We conclude by demonstrating how the so-called hydrogen-bond connectivity parameters can be used to screen low-energy isomers.

(H2O)20 water clusters at finite temperatures.

We have performed an exhaustive study of energetics of (H2O)20 clusters. Our goal is to study the role that various free-energy terms play in this popular model system and see their effects on the distribution of the (H2O)20 clusters and in the infrared spectrum at finite temperatures. In more detail, we have studied the electronic ground-state structure energy and its long-range correlation (dispersion) part, vibrational zero-point corrections, vibrational entropy, and proton configurational entropy. Our results indicate a delicate competition between the energy terms; polyhedral water clusters are destabilized by dispersion interaction, while vibrational terms (zero-point and entropic) together with proton disorder entropy favor them against compact structural motifs, such as the pentagonal edge- or face-sharing prisms. Apart from small water clusters, our results can be used to understand the influence of these energy terms in water/ice systems in general. We have also developed energy expressions as a function of both earlier proposed and novel hydrogen-bond connectivity parameters for prismatic water clusters.

Ionization of Nitric Acid on Crystalline Ice: The Role of Defects and Collective Proton Movement.

Ionization of nitric acid (HNO3) on a model ice surface is studied using ab initio molecular dynamics at temperatures of 200 and 40 K with a surface slab model that consists of the ideal ice basal plane with locally optimized and annealed defects. Pico- and subpicosecond ionization of nitric acid can be achieved in the defect sites. Key features of the rapid ionization are (a) the efficient solvation of the polyatomic nitrate anion, by stealing hydrogen bonds from the weakened hydrogen bonds at defect sites, (b) formation of contact ion pairs to stable "presolvated" molecular species that are present at the defects,

Global minima of protonated water clusters (H2O)20H+ revisited.

A graph-theoretical analysis is performed on the (H(2)O)(20) "edge-sharing pentagonal prism" cluster to find proton configurations that yield the lowest cluster total energies. Using the low-energy structures, we create models for protonated (H(2)O)(20)H(+) clusters that compete energetically with "cage-like" structures proposed earlier in the literature. We perform benchmarking between different theoretical methods and observe significant stabilization of compact versus polyhedral clusters due to long-range electron correlation effects, which make the comparison between different cluster morphologies difficult using density functional theory only. All methodologies that we used (up to the second level of Møller-Plesset perturbation theory (MP2)) agree that for protonated clusters, the cage-like morphology proposed in [ Chem. Phys. Lett. 2000, 324, 279-288] is the most stable one. We study in detail several (H(2)O)(20)H(+) cluster structures and suggest that the energetics in small protonated water clusters is dominated by the competition of open polyhedral structures, favored by the Eigen H(9)O(4)(+) species, against van der Waals interaction and "ice rules", which both favor compact structural motifs such as the prismatic particle. We demonstrate this tendency using ab initio calculations for prismatic, dodecahedral, and cage-like clusters, while the "magic number" cluster (H(2)O)(n)H(+), n = 21, is observed to minimize all competing energy contributions simultaneously. We emphasize the utility of the cage-like cluster as a model template for ice-related atmospheric reactions and benchmark the GPAW density functional theory code for making such calculations.

Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.

BACKGROUND AND AIMS: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease. PATIENTS AND METHODS: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3. RESULTS: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families. CONCLUSIONS: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.

Maternal thrombocytopenia at term: a population-based study.

BACKGROUND: Thrombocytopenia is a common problem during pregnancy and often inappropriately managed. This study aimed to assess the prevalence and causes of maternal thrombocytopenia at term with special attention to immune mechanisms of thrombocytopenia and the need for assessing fetal risks. METHODS: We conducted a 1-year population-based surveillance study involving 4,382 fullterm (at least 37 weeks' gestation) women (83.8% of the study population) and their infants from the city of Helsinki. Maternal and cord platelet counts were performed at delivery. Immune studies were performed if maternal platelet counts were less than 100 x 10(9)/l; 95% confidence intervals (CIs) were calculated from the binomial distribution. RESULTS: A total of 317 women (7.3%; 95% CI 6.5, 8.1) had platelet counts of less than 150 x 10(9)/l. Most cases (81%) of maternal thrombocytopenia at term were due to gestational thrombocytopenia, which had no impact on either the mother or the fetus unless associated with some other medical or obstetric disorder. Other causes of thrombocytopenia were preeclampsia (16%) and idiopathic thrombocytopenic purpura (ITP) (3%). There was no association between maternal and fetal platelet counts: of the infants born to thrombocytopenic mothers, 2.1%, had thrombocytopenia in the cord blood, which did not differ significantly from the 2.0% of thrombocytopenic infants born to non-thrombocytopenic mothers. CONCLUSION: Women with gestational thrombocytopenia do not require alteration of their treatment. Fetal blood sampling is not considered necessary when thrombocytopenia is discovered unexpectedly at term.

Detection of reticulated platelets: estimating the degree of fluorescence of platelets stained with thiazole orange.

The primary problem in the measurement of reticulated platelets (RP) stained with thiazole orange (TO) by flow cytometry is the definition of a threshold limit for fluorescence positivity. We evaluated settings for the threshold gate for TO positivity based on two principles: a fluorescence histogram (median FL1, Relative FL1) or a plot of forward light scatter (FSC; reflecting the distribution of the platelet size) versus fluorescence intensity (% RP). These methods were applied prospectively in examination of 54 healthy blood donors (16 females) and a total of 50 blinded patient samples: pregnant women with thrombocytopenia (Group 1A, n = 11), thrombocytopenic women after delivery (Group 1B, n = 9) and healthy women with a thrombocytopenic newborn (Group 2, n = 30). Group 1A displayed higher median FL1 (mean 306, CI 279-332) as compared to that of Group 2 (mean 266, CI 255-277; p = 0.0038) or to that of the female controls (mean 249, CI 231-268; p < 0.001). Relative FL1 was also higher in the patients of Group 1A than those of Group 2 (p = 0.037). When analysing the % RP, the difference between these groups was not significant. In the patients (n = 50), the median FSC (mean 407, SD 40, CI 395-418) was also higher than that of the controls (n = 54; mean 383, SD 25, CI 376-390; Mann-Whitney U-test, p = 0.0015). In Group 1A, a significant correlation was observed between the Patient median FL1 and Patient median FSC (r = 0.62, p = 0.043). When developing methods for the measurement of RP, it seems to be useful to analyse the data with more than one principle to define the threshold limit for TO positivity.

Oral guar gum, a gel-forming dietary fiber relieves pruritus in intrahepatic cholestasis of pregnancy.

BACKGROUND: Guar gum is a gel-forming fiber, which increases fecal elimination of bile acids. It may therefore be beneficial in the treatment of intrahepatic cholestasis of pregnancy. METHODS: Forty-eight patients with intrahepatic cholestasis of pregnancy were randomized double-blind to receive either guar gum or placebo until delivery. Serum bile acid concentration was measured. Pruritus was assessed by both the investigator and the patient. RESULTS: At baseline, the intensity of pruritus and the serum bile acid concentration were significantly related. Guar gum diminished or prevented worsening of pruritus, while in the placebo group pruritus was enhanced (p<0.05). In the placebo group serum bile acid concentration increased significantly, whereas in the guar gum group it remained unchanged (p<0.05 between the groups). Guar gum treatment-induced changes of the pruritus score and serum bile acid concentrations were significantly related (p<0.01). CONCLUSIONS: Guar gum relieved the intensity of pruritus without any side effects and prevented the rise in serum bile acid concentration in this placebo-controlled and double-blind study of patients with intrahepatic cholestasis of pregnancy.

Thrombocytopenia in term infants: a population-based study.

OBJECTIVE: To assess the prevalence and causes of thrombocytopenia among full-term infants. METHODS: We conducted a 1-year, population-based surveillance study involving all full-term infants (at least 37 weeks' gestation) born to native Finnish women in Helsinki. In cases of thrombocytopenia (cord platelet count less than 150 x 10(9)/L) clinical risk factors were evaluated and immunologic studies were performed on both parents and on the infant; 95% confidence intervals (CIs) were calculated on the basis of binomial distribution. RESULTS: Platelet counts were done in cord blood from 4,489 infants, 84.9% of the study population. Eighty-nine infants had platelet counts below 150 x 10(9)/L (2.0%; 95% CI 1.5, 2.3) in cord blood and 11 were less than 50 x 10(9)/L (0.24%; 95% CI 0.10, 0.38). All causes of clinically important thrombocytopenia, those presenting with bleeding and requiring treatment, were related to fetomaternal alloimmune thrombocytopenia. The incidence of severe alloimmune thrombocytopenia was one in 1500 live births and one in 900 of all thrombocytopenia. An immunologic mechanism was involved in ten of 65 (15.4%; 95% CI 6.6, 24.2) infants studied and in four of 15 (26.7%; 95% CI 4.3, 49.1) cases of severe thrombocytopenia. CONCLUSION: Immunologic studies should be considered in all cases of severe neonatal thrombocytopenia for careful monitoring and prevention of potentially severe complications in subsequent pregnancies.

Oral guar gum treatment of intrahepatic cholestasis and pruritus in pregnant women: effects on serum cholestanol and other non-cholesterol sterols.

BACKGROUND: Our aim was to investigate whether intestinal binding of bile acids by guar gum, a dietary fibre, relieves cholestasis and pruritus in intrahepatic cholestasis of pregnancy. METHODS: Forty-eight pregnant women with cholestasis and pruritus were randomized double-blind to guar gum and placebo until the time of delivery, and 20 healthy pregnant women were used as control subjects. The pruritus score and serum bile acids, lipids and non-cholesterol sterols were measured at baseline, at least 2 weeks after treatment, just before delivery and up to 4 weeks after delivery. RESULTS: The increase in serum bile acids and worsening of pruritus were prevented by guar gum in relation to placebo (P < 0.05). Serum cholesterol was unchanged, but increased cholesterol precursor sterol values suggested that cholesterol synthesis was increased by guar gum. Serum cholestanol proportion, an indicator of cholestasis, was related to pruritus but was unaffected by guar gum. CONCLUSION: We conclude that in intrahepatic cholestasis of pregnancy and pruritus, guar gum treatment is beneficial in relieving pruritus, even although indicators of cholestasis are only partially reduced.

Idiopathic thrombocytopenic purpura in pregnancy.

OBJECTIVE: The aim of this study was to evaluate retrospectively our strategies in monitoring and treating pregnant women with idiopathic thrombocytopenic purpura (ITP). METHODS: Medical records were reviewed for diagnosis, clinical course, treatment, and neonatal outcome in 35 Finnish women with ITP giving birth to 55 neonates during 53 pregnancies. The outcome of the first (i.e. index) pregnancy was used in the statistical analyses. The platelet immunofluorescence test (PIFT) was used for detection of platelet autoantibodies. The correlation between neonatal platelet counts and results of PIFT was calculated with the Pearson's correlation coefficient and the Fisher's exact test. RESULTS: There were no serious bleeding complications although five of 35 women had platelet counts of less than 50 x 10(9)/l in the third trimester of the index pregnancy. Prophylactic platelet transfusions were given to six of 15 women delivered by cesarean section. Five of 35 (14.3%; 95% confidence interval, 2.6 to 25.8%) neonates had platelet counts of less than 50 x 10(9)/l median 3 days after delivery versus only one of 28 (3.6%; 95% confidence interval, 0.1 to 10.5%) at birth. No infant showed any clinical signs of intracranial hemorrhage. No significant correlation was encountered between neonatal thrombocytopenia and maternal platelet autoantibodies. The history of a previous infant with thrombocytopenia was the only important information in estimating the risk of fetal thrombocytopenia. CONCLUSIONS: To avoid unnecessary and possibly harmful monitoring and treatment, we need further tests for predicting the perinatal risks in pregnant women with ITP.

Serum squalene and noncholesterol sterols before and after delivery in normal and cholestatic pregnancy.

Mechanisms of hyperlipidemia were studied by measurement of serum lipid concentrations and the ratios of cholesterol precursors (squalene, delta 8-cholestenol, desmosterol, and lathosterol), plant sterols (campesterol and sitosterol), and cholestanol (a 5 alpha-derivative of cholesterol) to cholesterol in nonpregnant women, and normal and cholestatic pregnancies near term, and a few days and 6 weeks after delivery. The ratios of the precursors are known to reflect cholesterol synthesis, those of plant sterols and cholestanol the absorption efficiency and biliary sterol secretion of cholesterol. In normal pregnancy, increased serum cholesterol was associated with up to 2-fold increases in squalene, desmosterol, and lathosterol proportions, and the values remained elevated, especially for desmosterol, during the lactation period. These findings suggest that pregnancy and lactation are associated with increased cholesterol synthesis. The proportions of plant sterols were slightly lower, but that of cholestanol was 2-fold that of the nonpregnant women. In contrast to the latter group, the cholestanol proportions were not related to those of plant sterols or the campesterol/sitosterol ratio. The values, especially of cholestanol, became normal during lactation. In cholestatic pregnancy the changes were basically similar, but the serum values of delta 8-cholestenol increased more, and those of squalene, desmosterol and lathosterol less markedly, and the mean cholestanol proportion was 40% higher and the campesterol/sitosterol ratio 15% lower than in the normal pregnancy. Cholestanol was positively related to serum bilirubin and bile acids in cholestatic pregnancy, yet only one-third of the cholestatic pregnant women exhibited cholestanol values higher than in the healthy pregnant women.

Slow-release theophylline in pregnant asthmatics.

STUDY OBJECTIVE: Oral theophylline treatment may be helpful in controlling severe asthma during pregnancy. This treatment, however, has been suspected of causing both complications and malformations. The objective of this investigation was to study the influence of theophylline treatment on the course of pregnancy and delivery and on maternal and infant health. SETTING: Respiratory unit, antenatal outpatient departments, and labor and delivery rooms. DESIGN: Case-control study. PATIENTS: The data of 212 pregnant asthmatics with theophylline treatment (AT) were compared with findings in 292 pregnant asthmatics without theophylline (A) and 237 nonasthmatic pregnant control subjects (C). RESULTS: There were no significant differences among groups as to age, height, age of onset of asthma, lung function, parity, or smoking. In the AT group, 19% were treated for acute exacerbations of the asthma as compared with 6% in the A group (p < 0.001). The incidence of preeclampsia was higher in the AT (15.6%) than in the C (6.4%) group (p < 0.03). Theophylline treatment at term was not associated with premature contractions or premature rupture of membranes, hemorrhage, placenta previa, abruption of the placenta, abnormal fetus position, frequent induction or augmentation of labor, prolonged third phase of delivery, or increased hemorrhage post partum. No differences among groups were seen with regard to gestational age, birth weight, Apgar scores, or perinatal deaths. Jaundice in the newborn, necessitating treatment with blue light, was more common in the AT (15.0%) than in the C group (7.8%) (p < 0.05). Three infants of 121 patients treated with theophylline during the first trimester were born with malformations; in the 91 patients treated with theophylline only during the second and third trimester, and the asthmatic control group, the corresponding figures were 4 and 3. CONCLUSIONS: During the second and third trimesters until term, theophylline treatment using moderate doses can be considered safe. The safety of theophylline treatment during the first trimester with regard to teratogenicity remains to be determined.

Serum concentrations of erythropoietin in healthy and anaemic pregnant women.

We have found serum erythropoietin (EPO) concentration significantly (p < 0.01) increased during normal pregnancy. Erythropoietin concentration was significantly (p < 0.05) higher before the 24th gestational week than after it. In pregnant women with iron deficiency anaemia serum EPO concentration was significantly (p < 0.001) higher than in healthy pregnant women. In anaemic women significant (p < 0.001) linear correlation between haemoglobin (hgb) and log serum EPO concentrations was observed. In pregnant women including both healthy and anaemic women log serum EPO concentrations correlated inversely with hgb concentrations (p < 0.01). We conclude that erythropoietin secretion is raised in normal pregnancy and is at highest in the first and second trimesters, when hgb mass begins to grow. In pregnancy with concomitant anaemia a more extensive demand for erythropoietin secretion is obvious.