The role of the stress hormone prolactin and sex differences in early psychosis

In the last 20 years, a huge effort has been made to implement and apply the principles of early diagnosis and treatment, already well established in other branches of medicine, to the field of psychotic disorders. The goal of research on early detection was and still is to prospectively identify people at-risk of developing full-blown psychosis. However, until now it is still not possible to predict transition to psychosis with adequate accuracy. Therefore, the prospective Früherkennung von Psychosen (Fepsy) study aims at improving early detection of psychosis via a multilevel assessment containing a systematic assessment of psychopathological symptoms, a neuropsychological examination, blood sampling, electroencephalography (EEG) and magnetic resonance imaging (MRI). The present dissertation addresses the role of the hormone prolactin in emerging psychosis on one hand and on the other hand aims to elucidate whether there are any sex differences in emerging psychosis specifically regarding the hormone prolactin, cognitive functioning and the correlation of self- and observer-ratings of psychopathology. In the first publication, the role of the hormone prolactin in early psychosis is discussed whereas the topic of possible sex differences is covered by all of the publications included in this dissertation (1, 2 and 3). The first study validates literature by providing further evidence for frequent hyperprolactinemia in emerging psychosis and that it can even be observed in antipsychotic-naïve patients (>30%). Hence, prolactin is not necessarily elevated as a side effect of antipsychotics but can also be a pre-existing condition probably in relation with the function of prolactin as stress hormone. Furthermore, all three publications which are included in this dissertation consider the aspect of sex differences, which may help to elucidate pathogenic mechanisms underlying psychosis that are specific to women or men. The first study demonstrated higher prolactin levels in women even after correction for the normal biological variation in prolactin levels between the sexes, which potentially provides an indication for a sex dependant stress reaction regarding the hormone prolactin. The results of our second study suggest that sex differences in cognitive functioning in patients are not different from those seen in healthy controls (HC). Specifically, the female advantage in verbal learning and memory, which has frequently been found in HC seems to be equally present in patients with an at-risk mental state (ARMS) for psychosis as well as in patients with a first episode psychosis (FEP). The third study shows that the associations of self- and observer-ratings of psychopathology were rather low and generally not different for men and women. Therefore, the results imply that self-rating scales cannot be a substitute for the more time-consuming observer-rating scales neither for men nor for women. In summary, prolactin plays a possible role in emerging psychosis in relation with its function as stress hormone and stress reactivity seems to be enhanced in women. Overall, there were few sex differences which could have been shown in the second and third study. Regarding sex differences in cognitive functioning (publication 2), they resemble those of the general population and were not different between HC and patients (ARMS, FEP)

The Consumer Movement in the United States

What ever happened to the consumer movement in the United States? In stark contrast to the high visibility and widespread support enjoyed by the consumer movement during the last two decades, overt concern for consumer protection seems to have disappeared since the election of President Ronald Reagan. To answer this question it is necessary first to identify the market conditions that currently dominate the U. S. economy and second to review the history of the consumer movement as it has evolved in this country during the last eighty years

Position-dependent effects on stability in tricyclo-DNA modified oligonucleotide duplexes

A series of oligodeoxyribonucleotides and oligoribonucleotides containing single and multiple tricyclo(tc)-nucleosides in various arrangements were prepared and the thermal and thermodynamic transition profiles of duplexes with complementary DNA and RNA evaluated. Tc-residues aligned in a non-continuous fashion in an RNA strand significantly decrease affinity to complementary RNA and DNA, mostly as a consequence of a loss of pairing enthalpy ΔH. Arranging the tc-residues in a continuous fashion rescues Tm and leads to higher DNA and RNA affinity. Substitution of oligodeoxyribonucleotides in the same way causes much less differences in Tm when paired to complementary DNA and leads to substantial increases in Tm when paired to complementary RNA. CD-spectroscopic investigations in combination with molecular dynamics simulations of duplexes with single modifications show that tc-residues in the RNA backbone distinctly influence the conformation of the neighboring nucleotides forcing them into higher energy conformations, while tc-residues in the DNA backbone seem to have negligible influence on the nearest neighbor conformations. These results rationalize the observed affinity differences and are of relevance for the design of tc-DNA containing oligonucleotides for applications in antisense or RNAi therap

Nuclear antisense effects in cyclophilin A pre‐mRNA splicing by oligonucleotides: a comparison of tricyclo‐DNA with LNA

The nuclear antisense properties of a series of tricyclo (tc)‐DNA oligonucleotide 9-15mers, targeted against the 3′ and 5′ splice sites of exon 4 of cyclophilin A (CyPA) pre‐mRNA, were evaluated in HeLa cells and compared with those of corresponding LNA‐oligonucleotides. While the 9mers showed no significant antisense effect, the 11-15mers induced exon 4 skipping and exon 3+4 double skipping to about an equal extent upon lipofectamine mediated transfection in a sequence‐ and dose‐dependent manner, as revealed by a RT-PCR assay. The antisense efficacy of the tc‐oligonucleotides was found to be superior to that of the LNA‐oligonucleotides in all cases by a factor of at least 4-5. A tc‐oligonucleotide 15mer completely abolished CyPA mRNA production at 0.2 µM concentration. The antisense effect was confirmed by western blot analysis which revealed a reduction in CyPA protein to 13% of its normal level. Fluorescence microscopic investigations with a fluorescein labeled tc‐15mer revealed a strong propensity for homogeneous nuclear localization of this backbone type after lipofectamine mediated transfection, while the corresponding lna 15mer showed a less clear cellular distribution pattern. Transfection without lipid carrier showed no significant internalization of both tc‐ and LNA‐ oligonucleotides. The obtained results confirm the power of tc‐DNA for nuclear antisense applications. Moreover, CyPA may become an interesting therapeutic target due to its important role in the early steps of the viral replication of HIV‐

Aberrant Current Source-Density and Lagged Phase Synchronization of Neural Oscillations as Markers for Emerging Psychosis

Background: Converging evidence indicates that neural oscillations coordinate activity across brain areas, a process which is seemingly perturbed in schizophrenia. In particular, beta (13-30 Hz) and gamma (30-50 Hz) oscillations were repeatedly found to be disturbed in schizophrenia and linked to clinical symptoms. However, it remains unknown whether abnormalities in current source density (CSD) and lagged phase synchronization of oscillations across distributed regions of the brain already occur in patients with an at-risk mental state (ARMS) for psychosis. Methods: To further elucidate this issue, we assessed resting-state EEG data of 63 ARMS patients and 29 healthy controls (HC). Twenty-three ARMS patients later made a transition to psychosis (ARMS-T) and 40 did not (ARMS-NT). CSD and lagged phase synchronization of neural oscillations across brain areas were assessed using eLORETA and their relationships to neurocognitive deficits and clinical symptoms were analyzed using linear mixed-effects models. Results: ARMS-T patients showed higher gamma activity in the medial prefrontal cortex compared to HC, which was associated with abstract reasoning abilities in ARMS-T. Furthermore, in ARMS-T patients lagged phase synchronization of beta oscillations decreased more over Euclidian distance compared to ARMS-NT and HC. Finally, this steep spatial decrease of phase synchronicity was most pronounced in ARMS-T patients with high positive and negative symptoms scores. Conclusions: These results indicate that patients who will later make the transition to psychosis are characterized by impairments in localized and synchronized neural oscillations providing new insights into the pathophysiological mechanisms of schizophrenic psychoses and may be used to improve the prediction of psychosi

Constitutional Law—Exclusionary Rule Applied to State Liquor Authority Administrative Searches

Matter of Finn\u27s Liquor Shop, Inc. v. State Liquor Authority, 24 N.Y.2d 647 (1969)

TricycloDNA-modified oligo-2′-deoxyribonucleotides reduce scavenger receptor B1 mRNA in hepatic and extra-hepatic tissues—a comparative study of oligonucleotide length, design and chemistry

We report the evaluation of 20-, 18-, 16- and 14-mer phosphorothioate (PS)-modified tricycloDNA (tcDNA) gapmer antisense oligonucleotides (ASOs) in Tm, cell culture and animal experiments and compare them to their gap-matched 20-mer 2′-O-methoxyethyl (MOE) and 14-mer 2′,4′-constrained ethyl (cEt) counterparts. The sequence-matched 20-mer tcDNA and MOE ASOs showed similar Tm and activity in cell culture under free-uptake and cationic lipid-mediated transfection conditions, while the 18-, 16- and 14-mer tcDNA ASOs were moderate to significantly less active. These observations were recapitulated in the animal experiments where the 20-mer tcDNA ASO formulated in saline showed excellent activity (ED50 3.9 mg/kg) for reducing SR-B1 mRNA in liver. The tcDNA 20-mer ASO also showed better activity than the MOE 20-mer in several extra-hepatic tissues such as kidney, heart, diaphragm, lung, fat, gastrocnemius and quadriceps. Interestingly, the 14-mer cEt ASO showed the best activity in the animal experiments despite significantly lower Tm and 5-fold reduced activity in cell culture relative to the 20-mer tcDNA and MOE-modified ASOs. Our experiments establish tcDNA as a useful modification for antisense therapeutics and highlight the role of chemical modifications in influencing ASO pharmacology and pharmacokinetic properties in animal

Feature Comment: OMB Issues Final Build America, Buy America (BABA) Guidance Which May Trigger Compliance, Enforcement and Trade Issues—And Bid Protests

The Biden administration’s Office of Management and Budget (OMB) has issued final guidance implementing the “Build America, Buy America” (BABA) provisions in the Infrastructure Investment and Jobs Act (IIJA), which President Joseph Biden signed in November 2021. The final guidance is intended, as President Biden said in his 2023 State of the Union address, to ensure that when hundreds of billions of dollars of federally funded infrastructure projects are built with federal grant funding, “we’re going to Buy American.” But because of its extraordinary complexity and the conflicts it creates with other domestic-preference laws, in practice the new OMB guidance may impose heavy compliance burdens on contractors and suppliers, disrupt existing supply chains, and trigger disputes (through bid protests or otherwise) over states’ prior commitments to open their procurement markets under international trade agreements