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The structural and dynamical properties of water are known to be affected by ion solvation. However, a consistent molecular picture that describes how and to what extent ions perturb the water structure is still missing. Here we apply 2D Raman-terahertz spectroscopy to investigate the impact of monatomic cations on the relaxation dynamics of the hydrogen-bond network in aqueous salt solutions. The inherent ability of multidimensional spectroscopy to deconvolute heterogeneous relaxation dynamics is used to reveal the correlation between the inhomogeneity of the collective intermolecular hydrogen-bond modes and the viscosity of a salt solution. Specifically, we demonstrate that the relaxation time along the echo direction t 1  = t 2 correlates with the capability of a given cation to 'structure' water. Moreover, we provide evidence that the echo originates from the water-water modes, and not the water-cation modes, which implies that cations can structure the hydrogen-bond network to a certain extent.

Objective: To evaluate cephalometric changes in posterior airway space (PAS) and in hyoid bone distance to mandibular plane (MP) 1-3 years after bilateral sagittal split osteotomy (BSSO)., Material and Methods: The sample consisted of 36 females and 16 males who underwent mandibular advancement by BSSO. To observe sagittal changes in PAS and in hyoid bone distance to MP both pre- and postoperative cephalograms were analyzed using WinCeph ® 8.0 software. For the statistical analyses paired T-test and multivariate logistic regression models were used., Results: By the surgical-orthognathic treatment the sagittal dimension of PAS showed variable changes but it mainly diminished when the mandibular advancement exceeded 6 mm. In most cases the hyoid bone moved superiorly by BSSO. Logistic regression models showed that males, patients with narrow PAS at the baseline, and those with counterclockwise rotation of the mandible by the treatment gained more increase in PAS. However, an increase in sagittal PAS dimension tended to relapse over time. Concerning the movement of the hyoid it was found that the more PAS increased the less hyoid moved superiorly. In males the change in hyoid position was more obvious than in females., Conclusion: Males, patients with narrow PAS at the baseline, and those whose mandible moved in the counterclockwise direction with moderate advancement gained more retrolingual airway patency by BSSO.

Background: The use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), has been questioned due to poor efficacy and safety. We examined whether young violent offenders were more likely antidepressant users prior to their first violent offence than other young persons., Methods: The study is a follow-up of children born in Finland in 1987 (n=59 120), linking national registers to each other using personal identity codes. Data on psychotropic drug use came from a register of reimbursed drugs and data on crimes from a register on court convictions (after the age of 14 years). Participants were followed until the age of 18 years, and for some analyses until the end of the follow-up (mean 21 years). To adjust for differences in background characteristics, regression analyses for antidepressant use were made, using the no-conviction group as the reference., Results: Proportions of young people convicted by the age of 18 years were: 5% of boys (1.7% for violent crimes) and 1% (0.5%) of girls. Antidepressant use (both overall and for SSRIs) prior to violent crime was more common among those convicted than among those without convictions. Among boys with repeated violent crimes, it was also more common than among boys with non-violent crimes. Adjustment for differences in background characteristics decreased the associations between antidepressant use and violent crime, but did not eliminate them., Conclusions: The results add further evidence for caution in prescribing antidepressants among young persons. It also calls for a reanalysis of violence measures in the original trial data., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Children and adolescents exposed to multiple contextual risks are more likely to have academic difficulties and externalizing behavior problems than those who experience fewer risks. This study used data from the Northern Finland Birth Cohort 1986 (a population-based study; N = 6961; 51 % female) to investigate (a) the impact of cumulative contextual risk at birth on adolescents' academic performance and misbehavior in school, (b) learning difficulties and/or externalizing behavior problems in childhood as intervening mechanisms in the association of cumulative contextual risk with functioning in adolescence, and (c) potential gender differences in the predictive associations of cumulative contextual risk at birth with functioning in childhood or adolescence. The results of the structural equation modeling analysis suggested that exposure to cumulative contextual risk at birth had negative associations with functioning 16 years later, and academic difficulties and externalizing behavior problems in childhood mediated some of the predictive relations. Gender, however, did not moderate any of the associations. Therefore, the findings of this study have implications for the prevention of learning and conduct problems in youth and future research on the impact of cumulative risk exposure., Competing Interests: The authors report no conflicts of interest.

Dispersion control is a key objective in the field of photonics and spectroscopy, since it enhances non-linear effects by both enabling phase matching and offering slow light generation. In addition, it is essential for frequency comb generation, which requires a phase-lock mechanism that is provided by broadband compensation of group velocity dispersion (GVD). At optical frequencies, there are several well-established concepts for dispersion control such as prism or grating pairs. However, terahertz dispersion control is still a challenge, thus hindering further progress in the field of terahertz science and technology. In this work, we present a hybrid waveguide with both broadband, tuneable positive and more than octave-spanning negative terahertz GVD on the order of 10 -22 s 2 /m, which is suitable for either intra- or extra cavity operation. This new terahertz device will enable ultra-short pulse compression, allow soliton propagation, improve frequency comb operation and foster the development of novel non-linear applications.

Background: Research indicates that risk factors cluster in the most vulnerable youth, increasing their susceptibility for adverse developmental outcomes. However, most studies of cumulative risk are cross-sectional or short-term longitudinal, and have been based on data from the United States or the United Kingdom. Using data from the Northern Finland Birth Cohort 1986 Study (NFBC1986), we examined cumulative contextual risk (CCR) at birth as a predictor of adolescent substance use and co-occurring conduct problems and risky sex to determine the degree to which CCR predicts specific outcomes over-and-above its effect on general problem behavior, while testing for moderation of associations by gender., Methods: Analyses of survey data from 6963 participants of the NFBC1986 followed from the prenatal/birth period into adolescence were conducted using structural equation modeling., Results: CCR had long-term positive associations with first-order substance use, conduct problems, and risky sex factors, and, in a separate analysis, with a second-order general problem behavior factor. Further analyses showed that there was a positive specific effect of CCR on risky sex, over-and-above general problem behavior, for girls only., Conclusions: This study, conducted within the Finnish context, showed that CCR at birth had long-term general and specific predictive associations with substance use and co-occurring problem behaviors in adolescence; effects on risky sex were stronger for girls. Results are consistent with the hypothesis that early exposure to CCR can have lasting adverse consequences, suggesting the need for early identification and intervention efforts for vulnerable children., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

People suffering from allergies can be treated with repeated injections of increasing amounts of a specific allergen. This type of specific immunotherapy is currently the only way to treat the underlying pathological immune response associated with an allergy. The approach can afford long-lasting protection, but the process takes 3-5 years, can produce allergic reactions, and in severe cases treatment is often aborted due to anaphylaxis. However, treatment can be optimized with the use of specific adjuvants that modify the immune response, its duration, and that increase the production of the correct type of antibodies. In the pursuit of such adjuvants, two new trivalent acetylated β-(1→2)-linked mannobioses based on a previously discovered lead molecule were prepared. The new molecules, along with the previously developed lead, were investigated by rigorous NMR and molecular modeling experiments in order to elucidate their behavior and preferred conformations in solution. Furthermore, the molecules were subjected to a biological investigation in which their immunostimulatory properties were evaluated by assessing their effect on the production of TH 2-type cytokine interleukin-4 (IL-4) and Treg pro-inflammatory cytokine tumor necrosis factor (TNF). Treatment of peripheral mononuclear blood cell cultures from patients suffering from birch allergy with birch allergen Bet v induced a strong IL-4 response, whereas the same treatment together with the trivalent acetylated mannobioses caused significant suppression of the induced IL-4., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Allergen-specific immunotherapy balances the Th2-biased immunity towards Th1 and Treg responses. Adjuvants are used in allergen preparations to intensify the immune responses. The increased prevalence of allergies in developed societies has been associated with decreased microbial load during childhood. This has initiated a search for microbial structures to be used as adjuvants. Our study has shown that a synthetic triacedimannose (TADM) may suppress the Th2-type allergic inflammatory response. The aim of this study was to compare the properties of TADM with capacities of other adjuvants, CpG ODN and MPL, to modulate cytokine production in PBMC and regulate sensitisation in an OVA-sensitised mouse asthma model., Methods: The effects of TADM were studied in vitro on birch stimulated PBMC cultures of birch allergic rhinitis patients with other known adjuvants. Cytokines in supernatants were measured by Luminex. Effects of TADM were analysed in vivo in a mouse model of OVA-induced allergic asthma by analysing BAL, cytokine mRNA and serum antibodies., Results: TADM was the only adjuvant that significantly suppressed the production of all birch induced Th2-type cytokines. In a murine model, TADM significantly suppressed the specific IgE production and enhanced IFN-γ production., Conclusions: TADM suppresses the birch allergen induced Th2-type cytokine responses in allergic subjects more efficiently than the two other adjuvants, MPL and CpG ODN. TADM is immunomodulatory also in vivo and decreases the IgE levels and increases the IFN-γ responses in a murine model. These results suggest that TADM may be a promising candidate for novel adjuvants in immunotherapy., (Copyright © 2014 SEICAP. Published by Elsevier Espana. All rights reserved.)

Background: Although a pathway from childhood behavioural disorders to criminal offending is well established, the aetiological processes remain poorly understood. Also, it is not clear if attention deficit hyperactivity disorder (ADHD) is predictive of crime in the absence of comorbid disruptive behaviour disorder (DBD)., Hypothesis: We examined two research questions: (1) Does ADHD have a unique effect on the risk of criminal offending, independently of DBD? (2) Is the effect of childhood behavioural disorders on criminal offending direct or mediated by adolescent processes related to school experience, substance misuse and peers?, Method: Structural equation modelling, with latent variables, was applied to longitudinally collected data on 4644 men from the 1986 Northern Finland Birth Cohort Study., Results: Both ADHD and DBD separately predicted felony conviction risk. Most of these effects were mediated by adolescent alcohol use and low academic performance. The effect of DBD was stronger and included a direct pathway to criminal offending., Conclusion: Findings were more consistent with the life course mediation hypothesis of pathways into crime than the behavioural continuity path, in that the effects of each disorder category were mediated by heavy drinking and educational failure. Preventing these adolescent risk outcomes may be an effective approach to closing pathways to criminal behaviour amongst behaviourally disordered children. However, as there was some evidence of a direct pathway from DBD, effective treatments targeting this disorder are also expected to reduce criminal offending., (Copyright © 2014 John Wiley & Sons, Ltd.)

Energy relaxation between two electronic states of a molecule is mediated by a set of relevant vibrational states. We describe this fundamental process in a fully quantum mechanical framework based on first principles. This approach explains population transfer rates as well as describes the entire transient absorption signal as vibronic transitions between electronic states. By applying this vibronic energy relaxation approach to carotenoids, we show that β-carotene's transient absorption signal can be understood without invoking the intensely debated S* electronic state. For a carotenoid with longer chain length, we find that vibronic energy relaxation does not suffice to explain all features in the transient absorption spectra, which we relate to an increased ground state structural inhomogeneity. Our modeling approach is generally applicable to photophysical deactivation processes in molecules. As such, it represents a well-founded alternative to data fitting techniques such as global target analysis.

The initial energy transfer steps in photosynthesis occur on ultrafast timescales. We analyze the carotenoid to bacteriochlorophyll energy transfer in LH2 Marichromatium purpuratum as well as in an artificial light-harvesting dyad system by using transient grating and two-dimensional electronic spectroscopy with 10 fs time resolution. We find that Förster-type models reproduce the experimentally observed 60 fs transfer times, but overestimate coupling constants, which lead to a disagreement with both linear absorption and electronic 2D-spectra. We show that a vibronic model, which treats carotenoid vibrations on both electronic ground and excited states as part of the system's Hamiltonian, reproduces all measured quantities. Importantly, the vibronic model presented here can explain the fast energy transfer rates with only moderate coupling constants, which are in agreement with structure based calculations. Counterintuitively, the vibrational levels on the carotenoid electronic ground state play the central role in the excited state population transfer to bacteriochlorophyll; resonance between the donor-acceptor energy gap and the vibrational ground state energies is the physical basis of the ultrafast energy transfer rates in these systems.

Background: The Lapinlahti 2005-2010 study was carried out to explore cardiovascular disease risk factors and changes in lifestyle in Lapinlahti residents in eastern Finland. Our aim was to analyse factors influencing the level of cholesterol in the community., Methods: In 2005, 480 subjects aged 30-65 years underwent a complete health survey (baseline study) that consisted of a structured questionnaire and a health examination. The follow-up was carried out five years later in 2010. The present study population included 326 individuals who did not use lipid-lowering medication at the baseline. A trained research nurse measured weight, height, waist circumference and blood pressure at the baseline and follow-up. Respectively, lifestyle factors (nutrition, exercise, smoking and alcohol use) were examined with a structured questionnaire. Each lifestyle item was valued as -1, 0 or 1, depending on how closely it fitted to the recommendations. Cholesterol level analyses at the baseline and follow-up were performed according to the protocol of the Kuopio University Hospital's medical laboratory. Based on their baseline cholesterol levels, the participants were divided into tertiles. The age- and sex-adjusted linear trend between the tertiles was tested., Results: The change in cholesterol level was associated with lipid-lowering medication (P < 0.001). Lifestyle improvement was associated with the cholesterol level change but did not reach statistical significance (P = 0.061), although the interaction of lipid-lowering medication and lifestyle change was associated with the change in cholesterol level (P = 0.018). In multivariate analysis, a favourable change in fat consumption (P = 0.007) and lipid-lowering medication (P < 0.001) were associated with decreasing cholesterol levels., Conclusions: At the population level, dyslipidaemia is one of the most easily modifiable risk factors of CHD. Lipid-lowering medication may have the most significant impact on cholesterol level in communities with primary health care with good coverage. On the other hand, the potential of health-promoting and population-based prevention strategies may be underused.

It is generally assumed that the hydrated electron occupies a quasi-spherical cavity surrounded by only a few water molecules in its equilibrated state. However, in the very moment of its generation, before water has had time to respond to the extra charge, it is expected to be significantly larger in size. According to a particle-in-a-box picture, the frequency of its absorption spectrum is a sensitive measure of the initial size of the electronic wavefunction. Here, using transient terahertz spectroscopy, we show that the excess electron initially absorbs in the far-infrared at a frequency for which accompanying ab initio molecular dynamics simulations estimate an initial delocalization length of ≈ 40 Å. The electron subsequently shrinks due to solvation and thereby leaves the terahertz observation window very quickly, within ≈ 200 fs.

Background: Emotional and behavioral problems are commonly associated with substance use in adolescence but it is unclear whether substance use precedes or follows mental health problems. The aim was to investigate longitudinal associations between externalizing and internalizing psychopathology and substance use in a prospective population study design., Method: The sample was the Northern Finland Birth Cohort 1986 Study (NFBC 1986; n = 6349; 3103 males). Externalizing and internalizing mental health problems were assessed at age 8 years (Rutter scales), substance use and externalizing and internalizing problems [Youth Self-Report (YSR)] at age 15-16 years, and hospital diagnoses for internalizing disorders (age 25) and criminal offences (age 20) from nationwide registers in adulthood., Results: Externalizing problems at age 8 were associated with later substance use. After adjustment for sociodemographic factors, parental alcohol use and psychiatric disorders, and earlier externalizing and internalizing problems, substance use predicted criminality, especially among males, with the highest odds ratio (OR) for cannabis use [adjusted OR 6.2, 95% confidence interval (CI) 3.1-12.7]. Early internalizing problems were not a risk for later substance use. Female adolescent cannabis (OR 3.2, 95% CI 1.4-7.3) and alcohol (OR 2.1, 95% CI 1.1-4.2) use predicted internalizing disorders in adulthood., Conclusions: Externalizing problems precede adolescent substance use in both genders, whereas, among boys, substance use also precedes criminal offences. Internalizing problems may follow substance use in females. These associations were robust even when taking into account previous mental health problems.

Background: The Lapinlahti 2005 study was carried out to explore cardiovascular disease risk factors, lifestyle and quality of life in Lapinlahti residents in eastern Finland. Our aim was to study the association between lifestyle and health-related quality of life (HRQoL) in the community., Subjects and Methods: The present study is based on the baseline data of the followed up (2005-2010) population-based cohort (N = 376, n of males = 184). A trained research nurse measured weight, height, waist circumference and blood pressure. Self-reported HRQoL was measured using a 15D questionnaire. A BDI-21 inventory was used to assess the presence of self-reported depressive symptoms. Lifestyle factors (nutrition, exercise, smoking and alcohol use) were examined with a structured questionnaire. Each lifestyle item was valued as -1, 0 or 1, depending on how well it corresponded to the recommendations. Based on the index the participants were divided into three lifestyle sum tertiles: I = unhealthy, II = neutral and III = healthy. The age- and sex-adjusted linear trend between the tertiles was tested., Results: The 15D score had a positive linear relationship with the lifestyle tertiles (P = .0048 for linearity, age- and sex-adjusted). Respectively, self-reported depressive symptoms were less frequent among subjects with a healthier lifestyle (P = .038)., Conclusions: People who are expected to strive most to change their lifestyle have the lowest quality of life and psychological welfare, which should be taken into account in both clinical work and health promotion.

Fabrication of precisely tailored layers of conductive polymers in thin film assemblies is an attractive extension of the layer-by-layer technique. This approach provides tools for fabricating thin films with customized optical and electrical properties. In this paper, we study inorganic layer-by-layer assembled films prepared using polyphosphate and cerium(IV). It is shown that these multilayers can oxidize certain monomers from the adjacent aqueous solution to produce conducting polymer layers. We studied the thermodynamic factors that allow the aforementioned autopolymerization. A five bilayer polyphosphate/cerium(IV) film was shown to possess high oxidative power in acidic solutions. It was found that the polymerization of pyrrole, aniline and 3,4-ethylenedioxythiophene in contact with the redox active multilayer is thermodynamically favored. The rate of polymer formation and the thickness of the conducting film could be controlled by the concentration of the monomer in solution and the number of cerium/polyphosphate bilayers in the oxidative film. The oxidative polymerization of pyrrole was unambiguously recognized on UV-vis spectra with characteristic reduction and oxidation bands. The film formation was not restricted by charge diffusion and the reaction formally followed first-order kinetics. The results suggest that the reaction takes place effectively within the whole pre-existing polypyrrole film and it continues until all oxidant in the film was used. The spectral changes that are characteristic for conducting polypyrrole are shown on spectroelectrochemical analysis of the films indicating that cationic (polaron) and dicationic (bipolaron) species are involved in the redox processes of the film. The functional polymer films formed are found to be electroactive and conducting. Therefore, they fully resemble of conducting polymer films prepared using traditional electropolymerization.

We show theoretically as well as experimentally that the Gouy-phase shift, which depends on the exact positioning of a sample in relation to the focus of a probe beam in a pump-probe experiment, may have a pronounced effect on the shape of the pump-probe signal. The effect occurs only when single-cycle probe pulses are used, i.e. when the slowly varying envelope approximation breaks down, while it disappears for multi-cycle pulses. The effect is thus most relevant in THz time-resolved spectroscopy, where such single cycle pulses are most commonly used, but it should not be overlooked also in other spectral regimes when correspondingly short pulses are involved.

We demonstrate and discuss a simple scheme that significantly enhances the detectivity of THz electro-optical sampling by introducing a sequence of Brewster windows that increases the ellipticity of the probe beam. By varying the window material or the number of Brewster windows, the enhancement factor can be adjusted; we demonstrate an enhancement factor of ≈20 with four ZnSe Brewster windows. The scheme is particularly useful when very small THz fields are to be measured in connection with low-repetition rate amplified Ti:S laser systems.

Two-dimensional Raman-terahertz (THz) spectroscopy is presented as a multidimensional spectroscopy directly in the far-IR regime. The method is used to explore the dynamics of the collective intermolecular modes of liquid water at ambient temperatures that emerge from the hydrogen-bond networks water forming. Two-dimensional Raman-THz spectroscopy interrogates these modes twice and as such can elucidate couplings and inhomogeneities of the various degrees of freedoms. An echo in the 2D Raman-THz response is indeed identified, indicating that a heterogeneous distribution of hydrogen-bond networks exists, albeit only on a very short 100-fs timescale. This timescale appears to be too short to be compatible with more extended, persistent structures assumed within a two-state model of water.

Research on social class and crime is dominated by perspectives that assume socioeconomic disadvantage to exert causal influence on offending. As an alternative approach, the present study examined hypotheses derived from a social selection perspective which treats intergenerational continuity in antisocial propensity as the primary source of socioeconomic differences in criminal activity. Under this theory, individual characteristics of the parents influence their personal socioeconomic attainment as well as the behavioral traits they pass on to their children. Consistent with both of these perspectives, longitudinal data tracking Finnish males born in 1987 (n=21,513) showed strong negative associations between family socioeconomic status (SES) and offspring rates of criminal offending. In critical support for the selection perspective: (1) these association were linear rather than discrete, (2) parents' educational attainment accounted for most of the association between the occupational measure of family SES and crime, and (3) measures of offspring criminal propensity mediated a substantial share of these effects. Adolescent educational marginalization emerged as the key factor linking childhood socioeconomic status to the risk of criminal offending in emerging adulthood. We discuss the implications of this finding for social influence and social selection models of explanation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The first year of infancy is crucial for the development of atopic immune response. Inadequate early Th1 and Treg responses and increased production of Th2 cytokines are associated with atopy. Breast milk contains several immunomodulatory cytokines and other factors that might influence the maturation of the infant's immune system. We assessed the cytokines in breast milk of mother of newborn infants and their associations with black currant seed oil (BCSO) supplementation during pregnancy, mother's atopic status and the development of infant's atopic dermatitis., Methods: Mothers and infants from an intervention study by black currant seed oil (n = 31) or olive oil as placebo (n = 30) were included in the study. Breast milk samples were collected during the first 3 months of breastfeeding. Breast milk levels of IL-4, IL-5, IL-10, IL-12, IFN-γ and TNF were measured by Luminex technology., Results: BCSO intervention group had decreased level of IL-4 (p = 0.044) and elevated level of IFN-γ (p = 0.014) in breast milk as compared to olive oil group. No significant differences were observed in IL-5, IL-10, IL-12 and TNF levels between the BCSO and olive oil groups. Mothers who had atopic dermatitis had significantly decreased levels of IL-10 (p = 0.044) in breast milk. Breast milk of the mothers of the children who developed atopic dermatitis had lower levels of IFN-γ (p = 0.039) as compared to the breast milk of the mothers of the children without dermatitis., Conclusion: Dietary intervention with BCSO had immunomodulatory effects on breast milk cytokine production towards Th2 to Th1 immunodeviation., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Disruptive behavioral disorders (DBD) and attention-deficit hyperactivity disorder (ADHD) are both characterized by certain patterns of misbehavior among adolescents., Aims: The aim of this study was to examine how the comorbidity of DBD and ADHD affects in misbehavior among adolescents., Methods: A total of 158 adolescents aged 16-18 years, from a subsample of the Northern Finland Birth Cohort 1986 (NFBC 1986), were interviewed with the Finnish translation of the semi-structured Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime (K-SADS-PL) in order to obtain DBD, including conduct disorder (CD) and oppositional defiant disorder (ODD), and ADHD diagnoses. The structure of the CD symptoms, obtained from the K-SADS-PL, was compared with the previously formed model about the development of the problematic behavior. The severity of the CD symptoms was compared with adolescents diagnosed with only DBD, only ADHD and with both DBD and ADHD. Also, the associations with other psychiatric disorders diagnosed at age 16 were evaluated., Results: The boys in the study sample were diagnosed with ADHD or with comorbid DBD and ADHD more often than girls. The severity of CD symptoms was statistically significantly associated with the comorbid DBD and ADHD group. The adolescents diagnosed with comorbid DBD and ADHD had an increased risk for anxiety disorders, depressive disorders and substance abuse disorders., Conclusions: The comorbidity of DBD and ADHD seems to indicate the severity of CD symptoms., Clinical Implications: The comorbidity between DBD and ADHD should be considered in clinical practice because it could indicate more serious problematic behavior than pure disorders alone.

Objective: Positive outcomes associated with opioid substitution treatment include reduced illicit opioid use and lower risk of HIV and other blood-borne infections. The effect on the reduction of criminal activity remains unclear. Our aim was to investigate the impact of treatment on criminal activity using conviction register data., Method: This observational retrospective study included all new patients (N=169) enrolled in an opioid substitution treatment program in the Helsinki University Central Hospital Clinic for Addiction Psychiatry between 2000 and 2005. Psychiatric and psychosocial services were provided as part of the program. Patient treatments were followed up for 18 months. Data on criminal convictions were collected for approximately 3 years before and after the start of treatment., Results: Mean rates of convictions decreased significantly during treatment. The effects were similar for total convictions, drug convictions, and property crime convictions. Although the numbers of violence and drunk driving convictions were too small to be analysed separately, on a bivariate level there was no indication of reduction in these crime types. Patients with amphetamine co-dependence fared best. Sex, age, other co-dependences or psychiatric diagnoses, negative urine analyses during the treatment, and dropping out from treatment had little impact on the outcomes., Conclusions: Opioid substitution treatment seems to reduce criminal activity effectively. However, more information is needed to determine how treatment influences different types of criminality and which types of patients benefit most., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of oligovalent carbohydrate assemblies (ranging from mono- to pentavalent), derived from three structurally different β-linked or β-(1→2)-linked mannosides, has been chemically synthesized, and the respective compounds have been biologically evaluated in order to investigate their immunostimulatory properties. The Crich methodology for β-mannosylation was successfully utilized to introduce the β-linkages, and a click chemistry protocol was utilized to generate the oligovalent derivatives. A convenient protecting group strategy involving the simultaneous use of both p-methoxybenzyl and benzylidene groups was employed, which allowed a simple and cost-effective global deprotection step. The immunomodulatory properties of the synthesized multivalent mannosides were evaluated by assessing cytokine production in human white blood cell cultures. The Th2-type cytokines interleukin-4 and interleukin-5 (IL-4 and IL-5), the Th1 cytokine interferon-γ (IFN-γ), the Treg cytokine IL-10, and the pro-inflammatory cytokine tumor necrosis factor (TNF) were included in the screening. A single trivalent acetylated mannobiose derivative was identified as a potent inducer of Treg and Th1 immune response, resulting in strong IL-10 and moderate IFN-γ productions dose-dependently, while inducing no Th2 cytokine response. The immunomodulatory properties of this trivalent mannoside were further studied in vitro in allergen (Bet v)-stimulated human peripheral blood mononuclear cell cultures of birch pollen allergic subjects. Stimulation with birch pollen induced strong IL-4 and IL-5 responses, which could be suppressed by the trivalent acetylated mannobiose derivative. The IL-10 response was also suppressed, whereas the production of IFN-γ was strongly enhanced. The results suggest that the identified lead compound has suppressive effects on the Th2-type allergic inflammatory response and shows potential as a possible lead adjuvant for the specific immunotherapy of allergies., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ganglion cysts are benign soft tissue tumours occurring in or near joints such as the wrist, foot or knee. They are rarely encountered in the region of the temporomandibular joint (TMJ). The authors report a ganglion cyst of the TMJ in a 56-year-old woman. The patient experienced pain and presented with a prominence in the right TMJ region, anterior to the tragus. She had some divergence in skin sensation in the right mental region of mandible. Magnetic-resonance imaging showed a rounded hypodense mass of soft tissue lateral to the right TMJ region. The surgical excision of the tumour was performed through a preauricular approach extending to the temporal region. During the 6-month postoperative follow-up there was no sign of recurrence. Surgical excision should be the treatment of choice for ganglion cysts in the region of TMJ., (Copyright © 2012 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Immunoglobulin E-mediated allergies have doubled in prevalence during recent decades in developed countries.This increase has been attributed, in part, to high hygiene standards, which have reduced exposure to microbes. The capacity of microbes to induce type 1 helper T cell (TH1) responses may imply suppression of TH2 responses. However, little research has been performed with fungal extracts., Objectives: To evaluate the TH1-inducing properties of fungal extracts., Methods: A total of 24 fungal extracts, including Cetavlon-precipitated polysaccharides from different yeasts, molds, and mushrooms were prepared.The extracts were screened for production of interferon (IFN)gamma in human peripheral blood mononuclear cells. The active compounds were further purified by mild acid hydrolysis and by column chromatography and studied in human peripheral blood mononuclear cells., Results: Expression of IFN-gamma was induced by several extracts. The strongest expression of IFN-gamma was induced by Candida albicans. The Cetavlon-precipitated mannans of fungi induced cytokine responses that were similar or superior to those induced by whole extracts, C albicans being the most potent inducer of IFN-gamma. Column chromatography-fractionated mild acid hydrolysis of Calbicans mannan was performed. Fractions containing oligosaccharides of 12-16 mannoses induced production of tumor necrosis factor., Conclusions: Several fungal extracts induce IFN-gamma. The most promising preparations were yeast-derived oligosaccharides. Further research should be focused on purification and eventual synthesis of the extracts.

In this work we report on the ultrafast photodynamics of the photosensitizer zinc phthalocyanine (ZnPc) and manipulation thereof. Two approaches are followed: active control via pulse shaping and passive control via strategic manipulation in the periphery of the molecular structure. The objective of both of these control experiments is the same: to enhance the yield of the functional pathway and to minimize loss channels. The aim of the active control experiments is to increase the intersystem crossing yield in ZnPc, which is important for application in photodynamic therapy (PDT). Pulse shaping allowed an improvement in triplet to singlet ratio of 15% as compared to a transform-limited pulse. This effect is ascribed to a control mechanism that utilizes multiphoton pathways to higher-lying states from where intersystem crossing is more likely to occur. The passive control experiments are performed on ZnPc derivatives deposited onto TiO2, serving as a model system of a dye-sensitized solar cell (DSSC). Modification of the anchoring ligand of the molecular structure resulted in an increased rate for electron injection into TiO2 and slower back electron transfer, improving the DSSC efficiency.

Immunostimulatory properties of synthetic structures mimicking the β-(1→2)-linked mannans of Candida albicans were evaluated in vitro. Contrary to earlier observations, tumor necrosis factor (TNF) production was not detected after stimulation with mannotetraose in mouse macrophages. Divalent disaccharide 1,4-bis(α-D-mannopyranosyloxy)butane induced TNF and some molecules induced low levels of gamma interferon (IFN-γ) in human peripheral blood mononuclear cells (PBMC).

Background: During infancy, a disturbed cytokine balance leads to an atopic immune response. Many risk factors have been associated with the development of atopy. These include parental smoking, elevated cord blood IgE, early exposure to pets and family history of atopy, but the knowledge of their impact on cytokine balance is limited., Objective: To assess the cytokines induced by mitogen in peripheral blood mononuclear cells (PBMC) of infants at 3 months and 12 months of age and their potential association with fatty acid (FA) intervention, parental atopy, atopic dermatitis and parental smoking., Methods: Infants from an intervention study using black currant seed oil (BCSO, n = 34) or placebo (n = 34) were included. PBMC samples were taken at the age of 3 and 12 months. Signs of atopic dermatitis and parental smoking were registered. PBMC were isolated from heparinized blood samples, stimulated with ConcanavalinA mitogen and the cytokine responses were detected at 72 h of stimulation by Luminex technology., Results: Children of smoking parents had elevated levels of IL-4 (P = 0.0004), IL-5 (P = 0.0002), IFN-γ (P = 0.039) and TNF (P = 0.0003) at 12 months of age. Children who had atopic dermatitis by the age of 3 months showed elevated levels of IL-5 at 3 months (P = 0.0027) and 12 months of age (P = 0.022). The production of TNF at the age of 3 months was higher (P = 0.010) and the production of IL-12 at the age of 12 months was lower (P = 0.025) in infants whose parents were atopic. BCSO intervention did not have any effect on any cytokine production or mRNA expression., Conclusion: Children of smoking parents had highly significantly elevated levels of Th2-type cytokines IL-4, IL-5 and pro-inflammatory cytokine TNF. The detrimental effects of parental smoking on the child's immune function should lead us to pay more attention to supporting parents to stop smoking., (© 2012 Blackwell Publishing Ltd.)

Sublingually administered midazolam is commonly used for premedication of pediatric patients. However, the irritating taste and low aqueous solubility of midazolam complicate its sublingual use. Cyclodextrin complexation can be used to improve both the taste and aqueous solubility of drugs, but based on earlier studies, the complexation efficiency of midazolam is relatively low. In the present study, the complexation of midazolam with hydroxypropyl-beta-cyclodextrin (HP-β-CD) was investigated in the presence of various excipients. The aqueous solubility of midazolam improved significantly when HP-β-CD was used together with sucrose. Sucrose alone did not increase the solubility of midazolam. In addition, sucrose increased the apparent stability constant of the midazolam/HP-β-CD complex. The pharmacokinetics of midazolam in different dosage forms was investigated in rabbits (dose 1mg/rabbit) after intravenous administration of midazolam solution and after sublingual administration of midazolam solution, midazolam/HP-β-CD/sucrose solution or midazolam/HP-β-CD/sucrose powder. Midazolam displayed rapid sublingual absorption (mean t(max) ≤30min from the liquid formulations and 60 min from the solid formulation) with high absolute bioavailability (>68%) from all evaluated formulations. Based on the results, HP-β-CD and sucrose can be utilized together to prepare more concentrated and palatable midazolam formulations for sublingual administration in pediatric patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We discuss the hybrid 2D-Raman-THz spectroscopy of liquid water. This two-dimensional spectroscopy is designed to directly work in the low-frequency range of the intermolecular degrees of freedom. The information content of 2D-Raman-THz spectroscopy is similar to 2D-Raman or 2D-THz spectroscopy, but its experimental implementation should be easier. That is, 2D-Raman-THz spectroscopy is a 3rd-order nonlinear spectroscopy and as such completely avoids cascading of consecutive 3rd-order signals, which turned out to be a major difficulty in 5th-order 2D-Raman spectroscopy. On the other hand, it does not require any intense THz pump-pulse, the lack of which limits 2D-THz spectroscopy to the study of semiconductor quantum wells as the currently available pulse energies are too low for molecular systems. In close analogy to 2D-Raman spectroscopy, the 2D-Raman-THz response of liquid water is simulated from an all-atom molecular dynamics simulation, and the expected spectral features are discussed., (© 2012 American Institute of Physics)

Immunotherapy involves the specific treatment of IgE-mediated allergic diseases, indicated for allergic rhinitis and conjunctivitis, allergic asthma, insect sting (bee and wasp) allergy, and food allergy (especially cow's milk, egg and wheat). Subcutaneous injection immunotherapy with pollens (both trees and grass), animal danders, insect venoms and house dust mite preparations for allergic rhinitis and asthma is effective for both adults and children. Sublingual immunotherapy indicated for allergic rhinitis caused by grass pollens (especially timothy), is effective and appears to be a safe route of administration. Specific oral tolerance induction is used in children over five years of age with severe food allergy.

A sensitive and selective gas chromatographic mass spectrometric method for the determination of midazolam and its biologically active metabolite, 1-hydroxymidazolam, in rabbit plasma has been developed and validated. Sample preparation includes mixed-mode solid-phase extraction and derivatization with silylating reagents. Midazolam-d4 was used as an internal standard for the determination of parent drug and its active metabolite. The instrumentation consisted of a capillary column gas chromatography and a single quadrupole mass spectrometer with a negative chemical ionization. The method was found to be valid in terms of selectivity, linearity, precision, accuracy, and recovery over the concentration range of 2-200 ng/ml and 1-100 ng/ml for midazolam and 1-hydroxymidazolam, respectively. For both analytes, the lower limit of quantification was 2 ng/ml. Midazolam was stable in stock solutions stored three months at -20°C and in human plasma stored for three months at -80°C. In addition, no degradation of midazolam was found after three freeze-thaw cycles, in short-term stability at room temperature for 24h, or in post-preparative stability in the autosampler. The validity of the method was further tested by performing a pharmacokinetic study of sublingual administration of midazolam in rabbits. The method will be used in studies related to a formulation development of novel midazolam formulations for use in paediatric anaesthesia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

According to established view, the underlying factor in allergic immune response is imbalance between the number and function of allergen-specific CD4+ lymphocytes. In atopic allergy, type 2 helper T lymphocytes (Th2 cells) are elevated in relation to regulatory T lymphocytes (Treg cells). In healthy subjects the ratio is vice versa. It seems that tolerance generated through allergen-specific Treg cells is the immunologic reaction mode towards allergens in healthy non-atopic subjects. It has been found that hyposensitization will correct the imbalance of Th2 and Treg cells and restore the normal immune response to allergens.

Background: The present increased incidence of atopic diseases has been associated with an altered intake of essential fatty acids (EFAs). The composition of blackcurrant seed oil (BCSO) corresponds to the recommended dietary intake of EFAs, and as a dietary supplement could, in small doses, modify the imbalance of EFAs in an efficient way., Objective: To assess the effect of dietary supplementation with BCSO on the prevalence of atopy at 12 months of age., Methods: Three hundred and thirteen pregnant mothers were randomly assigned to receive BCSO (151) or olive oil as placebo (162). The first doses were administered at 8th-16th weeks of pregnancy and were continued until the cessation of breastfeeding, followed by supplementation to the infants until the age of 2 years. Atopic dermatitis and its severity (SCORAD index) were evaluated, serum total IgE was measured and skin tests were performed at the age of 3, 12 and 24 months., Results: Parental atopy was common (81.7%) among study subjects, making them infants with increased atopy risk. There was a significantly lower prevalence of atopic dermatitis in the BCSO group than in the olive oil group at the age of 12 months (33.0% vs. 47.3%, P=0.035). SCORAD was also lower in the BCSO group than in the olive oil group at 12 months of age (P=0.035). No significant differences in the prevalence of atopic dermatitis were observed between the groups at the age of 24 months (P=0.18)., Conclusion: Dietary supplementation with BCSO was well tolerated and it transiently reduced the prevalence of atopic dermatitis. It could therefore be one potential tool in the prevention of atopic symptoms when used at an early stage of life. (Registration number SRCTN14869647, http://www.controlled-trials.com)

Compound 1 is an investigational, nanomolar inhibitor of catechol-O-methyltransferase (COMT) that suffers from poor oral bioavailability, most probably due to its low lipophilicity throughout most of the gastrointestinal tract and, to a lesser extent, its rapid systemic clearance. Several lipophilic esters were designed as prodrugs and synthesized in an attempt to optimize presystemic drug absorption. A modest twofold increase in 6-h exposure of 1 was observed with two prodrugs, compared to that of 1, after oral treatment in rats., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Induction of allergen-specific, tolerogenic, IL-10 and/or TGF-β-producing T-regulatory (Treg) cells that express transcription factor FOXP3 is considered as one of the key mechanisms of allergen-specific immunotherapy. However, little is known of the induction of FOXP3 expression in children during sublingual immunotherapy (SLIT). Recently, also, a novel subgroup of T-helper (Th) cells, the Th17 cells, secreting predominantly IL-17 (IL-17A), was identified. The expressions of IL-17 or the Th17-regulating cytokines IL-23 and IL-27 during SLIT are currently completely unexplored. This randomized, placebo-controlled dose-response study was performed to analyze the effects of SLIT on FOXP3, IL-17, IL-23, and IL-27 expressions in peripheral blood mononuclear cells (PBMC) of children with allergic rhinitis and their associations with clinical outcome. Thirty children were included: ten received SLIT with a glycerinated mixture of birch, hazel and alder with a cumulative weekly dose of 24,000 SQ-U, 10 with dose 200,000 SQ-U/wk, and ten received placebo. Cytokine and FOXP3 mRNA expressions in allergen-, purified protein derivative-stimulated and non-stimulated PBMC were determined at 0, 1 and 2 yr of SLIT by real-time RT-PCR (TaqMan). Symptoms and medications were recorded using diary cards. Allergen-induced IL-17 mRNA expression was significantly increased in the study subjects with elevated combined Symptom Medication Score (SMS) after 2 yr. There was also a significant positive correlation between the allergen-induced IL-17 and SMS in whole study group (r = 0.38, p = 0.039) and especially the 200,000 SQ-U dose-treated group (r = 0.74, p = 0.027) at 2 yr. Allergen-induced FOXP3 mRNA expression was significantly increased in the 200,000 SQ-U dose-treated children after two study years as compared with baseline (p = 0.016) and placebo-treated children (p = 0.028). The changes in FOXP3 mRNA expression positively correlated with IL-10 and TGF-β mRNAs during SLIT in whole study population. Increased allergen-induced IL-17 responses during SLIT are associated with elevated SMS. Increased tolerogenic, allergen-specific Treg responses are also observed in children during SLIT., (© 2009 John Wiley & Sons A/S.)

This study assessed the independent and interactive associations between sense of coherence (SOC) and socio-economic status (SES) with oral health-related behaviours. Data from 5,399 dentate adults regarding their demographic characteristics, years of education, SOC score, and oral health-related behaviours were analysed. Household income was obtained from tax authorities. Logistic regression was used to test the adjusted association of SOC with each behaviour and to test the statistical interaction between each SES indicator and the SOC score. Subjects were 1.20 [95% confidence interval (95% CI): 1.11-1.28] and 1.22 (95% CI: 1.12-1.32) times more likely to visit dentists regularly for check-ups and to brush their teeth twice daily or more often, respectively, and were 1.11 (95% CI: 1.03-1.20) and 1.21 (95% CI: 1.12-1.32) times less likely to be daily smokers and to consume sugar-added products on a daily basis, respectively, for every unit increase in SOC score. The findings provide strong support for an association between higher levels of SOC and more favourable oral health-related behaviours, independently of current SES and demographic characteristics of the participants and across the four behaviours assessed. By contrast, the findings give limited support for the moderating role of SOC on the relationship between SES and oral health-related behaviours.

Objectives: To assess the role of adulthood socioeconomic status (SES) and sense of coherence (SOC) in the relationship between childhood SES and adult oral health-related behaviours., Methods: This study analysed responses of 5318 dentate subjects aged 30 years and over who participated in the Finnish Health 2000 Survey. Participants provided information on their demographic characteristics (sex, age, marital status and urbanization), childhood SES (parental education), adulthood SES (years of education and household income), the SOC scale and four oral health-related behaviours (dental attendance, toothbrushing frequency, sugar intake frequency and daily smoking). Structural equation modelling was used to test a model including adult SES and SOC as mediating factors of the relationship between childhood SES and adult oral health-related behaviours. Multi-group comparison was conducted to test the model within each sex and age group., Results: Childhood SES was related to adult oral health-related behaviours (P < 0.001) but only indirectly, via adulthood SES (P < 0.001) and adult SOC (P = 0.001). However, the relationship via adulthood SES was much stronger than that via SOC (standardized path coefficients were 0.24 and 0.01 respectively). In the multi-group comparison, the model was invariant across sex and age groups., Conclusions: The relationship between childhood SES and adult oral health-related behaviours was mainly mediated by adulthood SES, and to a much less extent by SOC. A stronger SOC was significantly associated with better adult oral health-related behaviours, after controlling for the effect of adulthood SES and demographic characteristics of the participants.

Many spectroscopic applications of femtosecond laser pulses require properly-shaped spectral phase profiles. The optimal phase profile can be programmed on the pulse by adaptive pulse shaping. A promising optimization algorithm for such adaptive experiments is evolution strategy (ES). Here, we report a four fold increase in the rate of convergence and ten percent increase in the final yield of the optimization, compared to the direct parameterization approach, by using a new version of ES in combination with Legendre polynomials and frequency-resolved detection. Such a fast learning rate is of paramount importance in spectroscopy for reducing the artifacts of laser drift, optical degradation, and precipitation.

In similarity to many other western countries, the burden of allergic diseases in Finland is high. Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases. Along with urbanization, such exposure has dramatically reduced, both in terms of diversity and quantity. Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cell response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma. Restoration of impaired allergen-specific regulatory T-cell response and tolerance induction has furthermore been demonstrated during allergen-specific subcutaneous and sublingual immunotherapy and is crucial for good therapeutic outcome. However, tolerance can also be strengthened unspecifically by simple means, e.g. by consuming farm milk and spending time in nature. Results so far obtained from animal models indicate that it is possible to restore tolerance by administering the allergen in certain circumstances both locally and systemically. It has become increasingly clear that continuous exposure to microbial antigens as well as allergens in foodstuffs and the environment is decisive, and excessive antigen avoidance can be harmful and weaken or even prevent the development of regulatory mechanisms. Success in the Finnish Asthma Programme was an encouraging example of how it is possible to reduce both the costs and morbidity of asthma. The time, in the wake of the Asthma Programme, is now opportune for a national allergy programme, particularly as in the past few years, fundamentally more essential data on tolerance and its mechanisms have been published. In this review, the scientific rationale for the Finnish Allergy Programme 2008-2018 is outlined. The focus is on tolerance and how to endorse tolerance at the population level.

Background: Allergen-specific immunotherapy (SIT) is known to affect the allergen-specific T helper cell (Th2/Th1) balance and to induce T regulatory (Treg) cells. These observations have usually been made during the first treatment year and often without symptom monitoring. This study was performed to investigate allergen-induced Th2 (IL-4, IL-5)-, Th1 [IFN-gamma, IL-18, signalling lymphocytic activation molecule (SLAM)]- and Treg (IL-10)-type immune responses in peripheral blood mononuclear cells (PBMC) and their association with symptom improvement in allergic rhinitis patients after 3 years of SIT., Methods: Twenty patients were treated with SIT and 8 patients were studied as untreated controls. PBMC were collected before and after 1 and 3 years of SIT and stimulated with specific allergen. Cytokine and SLAM mRNA expression was determined by TaqMan(R) RT-PCR. Symptoms were recorded yearly using visual analogue scale (VAS) scoring., Results: IL-18, SLAM and IL-10 mRNA expression increased after 3 years of SIT, with a peak at 1 year, whereas IL-5 mRNA expression transiently decreased and IFN-gamma mRNA expression transiently increased after 1 year of SIT. The increases in IL-18 and SLAM expression were not associated with symptom improvement, whereas decreases in both IL-4 expression and the IL-4/IFN-gamma ratio after 1 year of SIT were found in patients with a good therapeutic outcome (>40 percentage unit reduction in VAS)., Conclusions: SIT has long-term effects on allergen-specific immune responses. The induced Treg- and Th1-type responses persist over 3 years of SIT, whereas Th2-type responses are transiently decreased only during early therapy., (Copyright 2009 S. Karger AG, Basel.)

The effects of novel quaternary chitosan derivatives on the paracellular transport of mannitol and cell viability were studied in the Caco-2 cell model. The N-betainate derivative with the degree of substitution of 0.05 was very effective at 1.0% (w/v) concentration. The activity decreased as the degree of substitution increased. The cytotoxicity of N-betainates was rather low. The N-piperazines were at least equally effective as the N-betainates with a similar degree of substitution (>0.15). Most of the N-piperazines did not exert toxic effects on the cell monolayers. Overall, the inverse proportionality between the degree of substitution and activity suggests that an intact chitosan backbone is essential for the bioactivity of chitosan derivatives. The quaternary group does not substitute for the activity of the free amine group. In particular, the N-betainate derivatives of chitosan should contain only the minimum number of substituents required for water solubility.

Adaptive femtosecond pulse shaping in an evolutionary learning loop is applied to a bioinspired dyad molecule that closely mimics the early-time photophysics of the light-harvesting complex 2 (LH2) photosynthetic antenna complex. Control over the branching ratio between the two competing pathways for energy flow, internal conversion (IC) and energy transfer (ET), is realized. We show that by pulse shaping it is possible to increase independently the relative yield of both channels, ET and IC. The optimization results are analyzed by using Fourier analysis, which gives direct insight to the mechanism featuring quantum interference of a low-frequency mode. The results from the closed-loop experiments are repeatable and robust and demonstrate the power of coherent control experiments as a spectroscopic tool (i.e., quantum-control spectroscopy) capable of revealing functionally relevant molecular properties that are hidden from conventional techniques.

What Is Already Known About This Subject: Diclofenac, a nonselective nonsteroidal anti-inflammatory drug,, exerts analgesic action both in the peripheral tissues and in the central nervous system by inhibiting cyclooxygenase enzymes COX-1/2, but central nervous system penetration of diclofenac has not been evaluated in humans., What This Study Adds: Diclofenac penetrates the cerebrospinal fluid rapidly, and after a single intravenous dose of 1 mg kg(-1), sufficient concentrations to inhibit COX-1/2 are sustained for up to 4 h., Aims: The primary aim was to study the cerebrospinal fluid (CSF) penetration of intravenous diclofenac in children. The secondary aim was to evaluate the plasma diclofenac concentration at the onset of wound pain after inguinal surgery in children., Methods: A total of 31 children (24 boys) aged 3 months to 12 years received a single intravenous injection of diclofenac 1 mg kg(-1). Paired CSF and blood samples were obtained 5 min to 22 h (median 69 min) later. In children having inguinal surgery a second blood sample was obtained at the time that the children felt wound pain for the first time after surgery. Diclofenac concentrations in CSF, plasma and protein free plasma were measured by gas chromatography with mass spectrometric detection., Results: In the 28 CSF samples obtained at 5 min to 3 h 43 min after injection, diclofenac concentrations ranged between 0.5 and 4.7 microg l(-1). At 5.5 h the CSF concentration was 0.1 microg l(-1), and no diclofenac was detected in the two CSF samples obtained at 22 h. The median of plasma diclofenac concentration at the time when pain returned after inguinal surgery was 104 microg l(-1) (range 70-272 microg l(-1)). No serious or unexpected adverse effects were reported., Conclusions: Diclofenac penetrates the CSF rapidly, and a sufficient concentration to inhibit cyclooxygenase enzymes is sustained for up to 4 h.

Ketorolac is a potent nonsteroidal anti-inflammatory analgesic used in postoperative pain management. Ketorolac elicits its analgesic action by inhibiting the cyclo-oxygenase enzyme in peripheral tissues and in the spinal cord. Central nervous system penetration of parenteral ketorolac has been evaluated in adults but not in children. In the present study we investigated ketorolac cerebrospinal fluid penetration via spinal anesthesia in 30 healthy children undergoing surgery in the lower part of the body. A single cerebrospinal fluid and blood sample was obtained between 11 minutes and 6 hours after receiving ketorolac 0.5 mg x kg(-1) IV. Ketorolac concentrations were determined by gas chromatography with mass spectrometric detection. Ketorolac was detected from 22 of the 30 cerebrospinal fluid samples, and the concentrations ranged between 0.2 and 7.6 microg x L(-1) (median, 0.6 microg x L(-1)). The cerebrospinal fluid to unbound plasma concentration-ratio ranged between 0.01 and 0.69 (median, 0.08). These low concentrations indicate that ketorolac does not readily penetrate cerebrospinal fluid in children.

A caroteno-purpurin dyad molecule was studied by steady-state and pump-probe spectroscopies to resolve the excited-state deactivation dynamics of the different energy levels as well as the connecting energy flow pathways and corresponding rate constants. The data were analyzed with a two-step multi-parameter global fitting procedure that makes use of an evolutionary algorithm. We found that following ultrafast excitation of the donor (carotenoid) chromophore to its S2 state, the energy flows via two channels: energy transfer (70%) and internal conversion (30%) with time constants of 54 and 110 fs, respectively. Additionally, some of the initial excitation is found to populate the hot ground state, revealing another limitation to the functional efficiency. At later times, a back transfer occurs from the purpurin to the carotenoid triplet state in nanosecond timescales. Details of the energy flow within the dyad as well as species associated spectra are disentangled for all excited-state and ground-state species for the first time. We also observe oscillations with the most pronounced peak on the Fourier transform spectrum having a frequency of 530 cm(-1). The dyad mimics the dynamics of the natural light-harvesting complex LH2 from Rhodopseudomonas acidophila and is hence a good model system to be used in studies aimed to further explain previous work in which the branching ratio between the competing pathways of energy loss and energy transfer could be manipulated by adaptive femtosecond pulse shaping.

Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.