Recognition, comorbidity, and outcome of DSM-IV bipolar I and II disorders in psychiatric care

This study is part of an ongoing collaborative bipolar research project, the Jorvi Bipolar Study (JoBS). The JoBS is run by the Department of Mental Health and Alcohol Research of the National Public Health Institute, Helsinki, and the Department of Psychiatry, Jorvi Hospital, Helsinki University Central Hospital (HUCH), Espoo, Finland. It is a prospective, naturalistic cohort study of secondary level care psychiatric in- and outpatients with a new episode of bipolar disorder (BD). The second report also included 269 major depressive disorder (MDD) patients from the Vantaa Depression Study (VDS). The VDS was carried out in collaboration with the Department of Psychiatry of the Peijas Medical Care District. Using the Mood Disorder Questionnaire (MDQ), all in- and outpatients at the Department of Psychiatry at Jorvi Hospital who currently had a possible new phase of DSM-IV BD were sought. Altogether, 1630 psychiatric patients were screened, and 490 were interviewed using a semistructured interview (SCID-I/P). The patients included in the cohort (n=191) had at intake a current phase of BD. The patients were evaluated at intake and at 6- and 18-month interviews. Based on this study, BD is poorly recognized even in psychiatric settings. Of the BD patients with acute worsening of illness, 39% had never been correctly diagnosed. The classic presentations of BD with hospitalizations, manic episodes, and psychotic symptoms lead clinicians to correct diagnosis of BD I in psychiatric care. Time of follow-up elapsed in psychiatric care, but none of the clinical features, seemed to explain correct diagnosis of BD II, suggesting reliance on cross- sectional presentation of illness. Even though BD II was clearly less often correctly diagnosed than BD I, few other differences between the two types of BD were detected. BD I and II patients appeared to differ little in terms of clinical picture or comorbidity, and the prevalence of psychiatric comorbidity was strongly related to the current illness phase in both types. At the same time, the difference in outcome was clear. BD II patients spent about 40% more time depressed than BD I patients. Patterns of psychiatric comorbidity of BD and MDD differed somewhat qualitatively. Overall, MDD patients were likely to have more anxiety disorders and cluster A personality disorders, and bipolar patients to have more cluster B personality disorders. The adverse consequences of missing or delayed diagnosis are potentially serious. Thus, these findings strongly support the value of screening for BD in psychiatric settings, especially among the major depressive patients. Nevertheless, the diagnosis must be based on a clinical interview and follow-up of mood. Comorbidity, present in 59% of bipolar patients in a current phase, needs concomitant evaluation, follow-up, and treatment. To improve outcome in BD, treatment of bipolar depression is a major challenge for clinicians.

Cow's milk allergy and the development of tolerance

Aims: To gain insight on the immunological processes behind cow’s milk allergy (CMA) and the development of oral tolerance. To furthermore investigate the associations of HLA II and filaggrin genotypes with humoral responses to early oral antigens. Methods: The study population was from a cohort of 6209 healthy, full-term infants who in a double-blind randomized trial received supplementary feeding at maternity hospitals (mean duration 4 days): cow’s milk (CM) formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed CM associated symptoms that subsided during elimination diet (n=223) underwent an open oral CM challenge (at mean age 7 months). The challenge was negative in 112, and in 111 it confirmed CMA, which was IgE-mediated in 83. Patients with CMA were followed until recovery, and 94 of them participated in a follow-up study at age 8-9 years. We investigated serum samples at diagnosis (mean age 7 months, n=111), one year later (19 months, n=101) and at follow-up (8.6 years, n=85). At follow-up, also 76 children randomly selected from the original cohort and without CM associated symptoms were included. We measured CM specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and β-lactoglobulin, α-casein and ovalbumin specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay in sera. We applied a microarray based immunoassay to measure the binding of IgE, IgG4 and IgA serum antibodies to sequential epitopes derived from five major CM proteins at the three time points in 11 patients with active IgE-mediated CMA at age 8-9 years and in 12 patients who had recovered from IgE-mediated CMA by age 3 years. We used bioinformatic methods to analyze the microarray data. We studied T cell expression profile in peripheral blood mononuclear cell (PBMC) samples from 57 children aged 5-12 years (median 8.3): 16 with active CMA, 20 who had recovered from CMA by age 3 years, 21 non-atopic control subjects. Following in vitro β-lactoglobulin stimulation, we measured the mRNA expression in PBMCs of 12 T-cell markers (T-bet, GATA-3, IFN-γ, CTLA4, IL-10, IL-16, TGF-β, FOXP3, Nfat-C2, TIM3, TIM4, STIM-1) with quantitative real time polymerase chain reaction, and the protein expression of CD4, CD25, CD127, FoxP3 with flow cytometry. To optimally distinguish the three study groups, we performed artificial neural networks with exhaustive search for all marker combinations. For genetic associations with specific humoral responses, we analyzed 14 HLA class II haplotypes, the PTPN22 1858 SNP (R620W allele) and 5 known filaggrin null mutations from blood samples of 87 patients with CMA and 76 control subjects (age 8.0-9.3 years). Results: High IgG and IgG4 levels to β-lactoglobulin and α-casein were associated with the HLA (DR15)-DQB1*0602 haplotype in patients with CMA, but not in control subjects. Conversely, (DR1/10)-DQB1*0501 was associated with lower IgG and IgG4 levels to these CM antigens, and to ovalbumin, most significantly among control subjects. Infants with IgE-mediated CMA had lower β -lactoglobulin and α-casein specific IgG1, IgG4 and IgG levels (p<0.05) at diagnosis than infants with non-IgE-mediated CMA or control subjects. When CMA persisted beyond age 8 years, CM specific IgE levels were higher at all three time points investigated and IgE epitope binding pattern remained stable (p<0.001) compared with recovery from CMA by age 3 years. Patients with persisting CMA at 8-9 years had lower serum IgA levels to β-lactoglobulin at diagnosis (p=0.01), and lower IgG4 levels to β-lactoglobulin (p=0.04) and α-casein (p=0.05) at follow-up compared with patients who recovered by age 3 years. In early recovery, signal of IgG4 epitope binding increased while that of IgE decreased over time, and binding patterns of IgE and IgG4 overlapped. In T cell expression profile in response to β –lactoglobulin, the combination of markers FoxP3, Nfat-C2, IL-16, GATA-3 distinguished patients with persisting CMA most accurately from patients who had become tolerant and from non-atopic subjects. FoxP3 expression at both RNA and protein level was higher in children with CMA compared with non-atopic children. Conclusions: Genetic factors (the HLA II genotype) are associated with humoral responses to early food allergens. High CM specific IgE levels predict persistence of CMA. Development of tolerance is associated with higher specific IgA and IgG4 levels and lower specific IgE levels, with decreased CM epitope binding by IgE and concurrent increase in corresponding epitope binding by IgG4. Both Th2 and Treg pathways are activated upon CM antigen stimulation in patients with CMA. In the clinical management of CMA, HLA II or filaggrin genotyping are not applicable, whereas the measurement of CM specific antibodies may assist in estimating the prognosis.

Search for the Higgs boson produced in association with Z→ℓ+ℓ- using the matrix element method at CDF II

We present a search for associated production of the standard model (SM) Higgs boson and a $Z$ boson where the $Z$ boson decays to two leptons and the Higgs decays to a pair of $b$ quarks in $p\bar{p}$ collisions at the Fermilab Tevatron. We use event probabilities based on SM matrix elements to construct a likelihood function of the Higgs content of the data sample. In a CDF data sample corresponding to an integrated luminosity of 2.7 fb$^{-1}$ we see no evidence of a Higgs boson with a mass between 100 GeV$/c^2$ and 150 GeV$/c^2$. We set 95% confidence level (C.L.) upper limits on the cross-section for $ZH$ production as a function of the Higgs boson mass $m_H$; the limit is 8.2 times the SM prediction at $m_H = 115$ GeV$/c^2$.

Inclusive Search for Standard Model Higgs Boson Production in the WW Decay Channel using the CDF II Detector

We present a search for standard model (SM) Higgs boson production using ppbar collision data at sqrt(s) = 1.96 TeV, collected with the CDF II detector and corresponding to an integrated luminosity of 4.8 fb-1. We search for Higgs bosons produced in all processes with a significant production rate and decaying to two W bosons. We find no evidence for SM Higgs boson production and place upper limits at the 95% confidence level on the SM production cross section (sigma(H)) for values of the Higgs boson mass (m_H) in the range from 110 to 200 GeV. These limits are the most stringent for m_H > 130 GeV and are 1.29 above the predicted value of sigma(H) for mH = 165 GeV.

Measurement of the WW+WZ Production Cross Section Using the lepton+jets Final State at CDF II

We report two complementary measurements of the WW+WZ cross section in the final state consisting of an electron or muon, missing transverse energy, and jets, performed using p\bar{p} collision data at sqrt{s} = 1.96 TeV collected by the CDF II detector. The first method uses the dijet invariant mass distribution while the second more sensitive method uses matrix-element calculations. The result from the second method has a signal significance of 5.4 sigma and is the first observation of WW+WZ production using this signature. Combining the results gives sigma_{WW+WZ} = 16.0 +/- 3.3 pb, in agreement with the standard model prediction.

Measurement of the top quark mass and pp̅ →tt̅ cross section in the all-hadronic mode with the CDF II detector

We present a measurement of the top quark mass and of the top-antitop pair production cross section using p-pbar data collected with the CDFII detector at the Tevatron Collider at the Fermi National Accelerator Laboratory and corresponding to an integrated luminosity of 2.9 fb-1. We select events with six or more jets satisfying a number of kinematical requirements imposed by means of a neural network algorithm. At least one of these jets must originate from a b quark, as identified by the reconstruction of a secondary vertex inside the jet. The mass measurement is based on a likelihood fit incorporating reconstructed mass distributions representative of signal and background, where the absolute jet energy scale (JES) is measured simultaneously with the top quark mass. The measurement yields a value of 174.8 +- 2.4(stat+JES) ^{+1.2}_{-1.0}(syst) GeV/c^2, where the uncertainty from the absolute jet energy scale is evaluated together with the statistical uncertainty. The procedure measures also the amount of signal from which we derive a cross section, sigma_{ttbar} = 7.2 +- 0.5(stat) +- 1.0 (syst) +- 0.4 (lum) pb, for the measured values of top quark mass and JES.

Search for Supersymmetry with Gauge-Mediated Breaking in Diphoton Events with Missing Transverse Energy at CDF II

We present the results of a search for supersymmetry with gauge-mediated breaking and $\NONE\to\gamma\Gravitino$ in the $\gamma\gamma$+missing transverse energy final state. In 2.6$\pm$0.2 \invfb of $p{\bar p}$ collisions at $\sqrt{s}$$=$1.96 TeV recorded by the CDF II detector we observe no candidate events, consistent with a standard model background expectation of 1.4$\pm$0.4 events. We set limits on the cross section at the 95% C.L. and place the world's best limit of 149\gevc on the \none mass at $\tau_{\tilde{\chi}_1^0}$$

Part I: Enzyme replacement versus neurotrophic factor viral vector-mediated gene therapy of Parkinson’s disease, Part II: The effects of orally dosed tolcapone and entacapone on dopamine metabolism in the dorsal striatum and nucleus accumbens in rats

Part I: Parkinson’s disease is a slowly progressive neurodegenerative disorder in which particularly the dopaminergic neurons of the substantia nigra pars compacta degenerate and die. Current conventional treatment is based on restraining symptoms but it has no effect on the progression of the disease. Gene therapy research has focused on the possibility of restoring the lost brain function by at least two means: substitution of critical enzymes needed for the synthesis of dopamine and slowing down the progression of the disease by supporting the functions of the remaining nigral dopaminergic neurons by neurotrophic factors. The striatal levels of enzymes such as tyrosine hydroxylase, dopadecarboxylase and GTP-CH1 are decreased as the disease progresses. By replacing one or all of the enzymes, dopamine levels in the striatum may be restored to normal and behavioral impairments caused by the disease may be ameliorated especially in the later stages of the disease. The neurotrophic factors glial cell derived neurotrophic factor (GDNF) and neurturin have shown to protect and restore functions of dopaminergic cell somas and terminals as well as improve behavior in animal lesion models. This therapy may be best suited at the early stages of the disease when there are more dopaminergic neurons for neurotrophic factors to reach. Viral vector-mediated gene transfer provides a tool to deliver proteins with complex structures into specific brain locations and provides long-term protein over-expression. Part II: The aim of our study was to investigate the effects of two orally dosed COMT inhibitors entacapone (10 and 30 mg/kg) and tolcapone (10 and 30 mg/kg) with a subsequent administration of a peripheral dopadecarboxylase inhibitor carbidopa (30 mg/kg) and L- dopa (30 mg/kg) on dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens of freely moving rats using dual-probe in vivo microdialysis. Earlier similarly designed studies have only been conducted in the dorsal striatum. We also confirmed the result of earlier ex vivo studies regarding the effects of intraperitoneally dosed tolcapone (30 mg/kg) and entacapone (30 mg/kg) on striatal and hepatic COMT activity. The results obtained from the dorsal striatum were generally in line with earlier studies, where tolcapone tended to increase dopamine and DOPAC levels and decrease HVA levels. Entacapone tended to keep striatal dopamine and HVA levels elevated longer than in controls and also tended to elevate the levels of DOPAC. Surprisingly in the nucleus accumbens, dopamine levels after either dose of entacapone or tolcapone were not elevated. Accumbal DOPAC levels, especially in the tolcapone 30 mg/kg group, were elevated nearly to the same extent as measured in the dorsal striatum. Entacapone 10 mg/kg elevated accumbal HVA levels more than the dose of 30 mg/kg and the effect was more pronounced in the nucleus accumbens than in the dorsal striatum. This suggests that entacapone 30 mg/kg has minor central effects. Also our ex vivo study results obtained from the dorsal striatum suggest that entacapone 30 mg/kg has minor and transient central effects, even though central HVA levels were not suppressed below those of the control group in either brain area in the microdialysis study. Both entacapone and tolcapone suppressed hepatic COMT activity more than striatal COMT activity. Tolcapone was more effective than entacapone in the dorsal striatum. The differences between dopamine and its metabolite levels in the dorsal striatum and nucleus accumbens may be due to different properties of the two brain areas.

Enzymatic cross-linking of β-casein and its impact on digestibility and allergenicity

Protein modification via enzymatic cross-linking is an attractive way for altering food structure so as to create products with increased quality and nutritional value. These modifications are expected to affect not only the structure and physico-chemical properties of proteins but also their physiological characteristics, such as digestibility in the GI-tract and allergenicity. Protein cross-linking enzymes such as transglutaminases are currently commercially available, but also other types of cross-linking enzymes are being explored intensively. In this study, enzymatic cross-linking of β-casein, the most abundant bovine milk protein, was studied. Enzymatic cross-linking reactions were performed by fungal Trichoderma reesei tyrosinase (TrTyr) and the performance of the enzyme was compared to that of transglutaminase from Streptoverticillium mobaraense (Tgase). Enzymatic cross-linking reactions were followed by different analytical techniques, such as size exclusion chromatography -Ultra violet/Visible multi angle light scattering (SEC-UV/Vis-MALLS), phosphorus nuclear magnetic resonance spectroscopy (31P-NMR), atomic force (AFM) and matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF MS). The research results showed that in both cases cross-linking of β-casein resulted in the formation of high molecular mass (MM ca. 1 350 kg mol-1), disk-shaped nanoparticles when the highest enzyme dosage and longest incubation times were used. According to SEC-UV/Vis-MALLS data, commercial β-casein was cross-linked almost completely when TrTyr and Tgase were used as cross-linking enzymes. In the case of TrTyr, high degree of cross-linking was confirmed by 31P-NMR where it was shown that 91 % of the tyrosine side-chains were involved in the cross-linking. The impact of enzymatic cross-linking of β-casein on in vitro digestibility by pepsin was followed by various analytical techniques. The research results demonstrated that enzymatically cross-linked β-casein was stable under the acidic conditions present in the stomach. Furthermore, it was found that cross-linked β-casein was more resistant to pepsin digestion when compared to that of non modified β-casein. The effects of enzymatic cross-linking of β-casein on allergenicity were also studied by different biochemical test methods. On the basis of the research results, enzymatic cross-linking decreased allergenicity of native β-casein by 14 % when cross-linked by TrTyr and by 6 % after treatment by Tgase. It can be concluded that in addition to the basic understanding of the reaction mechanism of TrTyr on protein matrix, the research results obtained in this study can have high impact on various applications like food, cosmetic, medical, textile and packing sectors.

Search for the Decays B(s)0→e+μ- and B(s)0→e+e- in CDF Run II

We report results from a search for the lepton flavor violating decays $B^0_{(s)}\to e^+\mu^-$, and the flavor-changing neutral-current decays $B^0_{(s)} \to e^+ e^-$. The analysis uses data corresponding to ${\rm 2 fb^{-1}}$ of integrated luminosity of $p \bar{p}$ collisions at $\sqrt{s}=1.96 {\rm TeV}$ collected with the upgraded Collider Detector (CDF II) at the Fermilab Tevatron. The observed number of $B^0_{(s)}$ candidates is consistent with background expectations. The resulting Bayesian upper limits on the branching ratios at 90% credibility level are $\mathcal{B}(B^0_s \to e^{+}\mu^{-}) e^{+}\mu^{-})e^{+}\mu^{-}) 47.8 {\rm TeV/c^2}$, and ${M_{LQ}}(B^0\to e^+ \mu^-) > 59.3 {\rm TeV/c^2}$, at 90% credibility level.

Päijänteen yhteenvetotutkimus II : Nykytila ja siihen johtanut kehitys ; biologiset selvitykset

English summary: Lake Päijänne research II