Homo- and heterobimetallic transition metal cluster derived from [Cp*Fe(η5-E5)] (E = P, As) - unprecedented structural motifs of the resulting polypnictogen ligands.

A general synthetic procedure to neutral homo- and heterobimetallic cage compounds exhibiting various structural motifs of the polypnictogen ligands starting from [Cp*Fe(η5-E5)] (E = P (1), As (2); Cp* = C5Me5) is reported. The impact of the implemented transition metal precursors {Cp'''M} (M = Cr, Mn, Fe, Ni; Cp''' = 1,2,4-tBu3C5H2) emphasises the variability of the isolated complexes exhibiting a broad variety of structural motifs of the pnictogen ligands. Spectroscopic, crystallographic, and theoretical investigations provide insight into the structure of the partially unprecedented polypnictogen ligands.

Uranium versus Thorium: A Case Study on a Base-Free Terminal Uranium Imido Metallocene.

The structure of and bonding in two base-free terminal actinide imido metallocenes, [η5-1,2,4-(Me3C)3C5H2]2An═N(p-tolyl) (An = U (1), Th (1')) are compared and connected to their individual reactivity. While structurally rather similar, the U(IV) derivative 1 is slightly more sterically crowded. Furthermore, density functional theory (DFT) studies imply that the 5f orbital contribution to the bonding within the individual actinide imido An═N(p-tolyl) moieties is significantly larger for 1 than for 1', which makes the bonds between the [η5-1,2,4-(Me3C)3C5H2]2U2+ and [(p-tolyl)N]2- fragments more covalent. Therefore, steric and electronic factors impact the reactivity of these imido complexes. For example, complex 1 is inert toward internal alkynes, but it readily forms Lewis base adducts [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(L) (L = OPMe3 (6), dmap (9), PhCN (14), and 2,6-Me2PhNC (17)) with Me3PO, 4-dimethylaminopyridine (dmap), nitrile, PhCN, or isonitrile 2,6-Me2PhNC. It may also react as a nucleophile or undergo a [2 + 2] cycloaddition with CS2, isothiocyanates, thio-ketones, ketones, lactides, and acyl nitriles, forming the four- or five-membered metallaheteroacycles, terminal sulfido, or oxido complexes, and cyanide amidate complexes, respectively. In contrast, after the addition of aldehyde p-tolylCHO, the tetranuclear complex [η5-1,2,4-(Me3C)3C5H2]4[OCH(p-tolyl)CH(p-tolyl)O]2U4O4 (10) is isolated. However, while 1 is unreactive toward dicyclohexylcarbodiimide (DCC), an equilibrium exists in benzene solution between N,N'-diisopropylcarbodiimide (DIC), 1, and the four-membered metallaheterocycle [η5-1,2,4-(Me3C)3C5H2]2U[N(p-tolyl)C(═NiPr)N(iPr)] (12). Furthermore, 1 may also engage in single- and two-electron transfer processes. It is singly oxidized by Ph3CN3, CuI, Ph2S2, and Ph2Se2, yielding the uranium(V) imido complexes [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(X) (X = N3 (20), I (22), PhS (23), and PhSe (24)), or is doubly oxidized by organic azides (RN3) and 9-diazofluorene, forming the uranium(VI) bis-imido metallocenes [η5-1,2,4-(Me3C)3C5H2]2U═N(p-tolyl)(=NR) (R = p-tolyl (18), mesityl (19)) and [η5-1,2,4-(Me3C)3C5H2]2U=N(p-tolyl)[=NN=(9-C13H8)] (21), respectively.

Cannabis Consumers' View of Regulated Access to Recreational Cannabis: A Multisite Survey in Switzerland.

INTRODUCTION: There is considerable effort in legalizing recreational use of cannabis globally. The successful implementation of a program of regulated access to recreational cannabis (PRAC) depends on the consumers' engagement. The aim of this study was to examine the acceptability of twelve different regulatory aspects by cannabis users including those obtaining cannabis from the illicit market and vulnerable populations such as young adults and problematic users. METHODS: The current study is a multisite online survey conducted in Switzerland. A total of 3,132 adult Swiss residents who consumed cannabis within the previous 30 days represented the studied population. Mean age was 30.5 years, 80.5% were men, and 64.2% of the participants stated that they always or often obtain cannabis from the illicit market. We described consumers' acceptability of twelve regulatory aspects concerning THC content control, disclosure of sensitive personal data, security aspects, and follow-up procedures by applying descriptive statistics and multiple regression models. RESULTS: THC content regulation showed most discrepancy with 89.4% of the participants stating to engage in a PRAC if five different THC contents were available as compared to 54% if only 12% THC was available. The least accepted regulatory aspect was disposal of contact details with an acceptability rate of 18.1%. Consumers mainly obtaining cannabis from the illicit market, young adults, and problematic users showed similar acceptability patterns. Participants obtaining cannabis from the illicit market were more likely to engage in a PRAC if five different THC contents were available as compared to participants obtaining cannabis from other sources (OR 1.94, 95% CI: 1.53-2.46). CONCLUSION: A carefully designed PRAC that takes into account the consumers' perspective is likely to transfer them to the regulated market and to engage vulnerable populations. We cannot recommend the distribution of cannabis with only 12% THC content as this is unlikely to engage the target population.

Low-Coordinate Iron(II) Amido Half-Sandwich Complexes with Large Internal Magnetic Hyperfine Fields.

The half-sandwich complex [Cp'Fe{N(dipp)(SiMe3)}] (Fe-dipp; Cp' = 1,2,4-tri-tert-butylcyclopentadienyl and dipp = 2,6-diisopropylphenyl) and the mixed metallocene [Cp'Fe{(η5-C6H3iPr2)═N(SiMe3)}] (Fe-chd) formed in the reaction between [{Cp'Fe(µ-I)}2] and [Li{N(dipp)(SiMe3)}]2 were characterized by NMR spectroscopy and X-ray diffraction analysis. Fe-dipp complements the series of low-coordinate, quasi-linear iron amido half-sandwich complexes [Cp'Fe{N(tBu)(SiMe3)}] (Fe-tBu) and [Cp'Fe{N(SiMe3)2}] (Fe-tms) reported earlier, and all three compounds were characterized in the solid state by zero-field 57Fe Mössbauer spectroscopy and magnetic susceptibility measurements, confirming their S = 2 electronic ground state. Moreover, the Mössbauer absorption spectra reveal slow paramagnetic relaxation at low temperatures with large internal magnetic hyperfine fields of Bhf = 96.4 T (Fe-dipp, 20 K), Bhf = 101.3 T (Fe-tBu, 15 K), and Bhf = 96.9 T (Fe-tms, 20 K). The magnetic measurements further confirm that the presence of significant axial zero-field splitting and slow relaxation of magnetization is detected, which is revealed even in the absence of a static magnetic field in the case of Fe-tBu. Supplementary ab initio and density functional theory calculations were performed and support the experimental data.

TNF-α Increase in a Cohort of Depressive Patients.

Background: The model of neuroinflammation has been proposed as a possible explanation of depression. Investigations of serum levels of tumor necrosis factor-α (TNF-α) in depressed patients have previously shown contradictory results of increased and decreased levels of TNF-α during the treatment of depression. Methods: We compared the serum levels of TNF-α in two cohorts of patients suffering from depression (ICD-10 criteria): one cohort from a psychotherapeutic unit (n = 18), where patients were treated with Cognitive Behavioral Analysis System of Psychotherapy (CBASP), and the other cohort from a psychiatric day care unit (n = 16). Both cohorts were investigated at the beginning and at the end of treatment. The intensity of depression was measured by means of the Beck Depression Inventory, 2nd edition (BDI-II) at both time points. Results: We observed a statistically significant increase of TNF-α in the psychotherapeutic unit at time point 2 compared to time point 1 (T = -14.71, p < 0.001), but not in the psychiatric day care unit. In both cohorts, BDI-II scores at time point 2 were significantly decreased compared to time point 1 (psychiatric day care unit: T = 3.32, p = 0.005; psychotherapeutic unit: T = 6.22, p < 0.001). There was a significant correlation in the psychotherapeutic unit at time point 2 (r = -0.682, p = 0.02). Conclusion: As TNF-α was increased at time point 2 in the psychotherapeutic unit but not in patients of the psychiatric day care unit, we propose the different durations of pretreatments in both cohorts and the associated processes of neuroinflammation as a possible explanation for our results. The lack of information about the time course of TNF-α in depression could in general explain the huge variety of TNF-α levels in different cohorts of depressed patients reported in the literature.

Uranium versus Thorium: Synthesis and Reactivity of [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U[η2 -C2 Ph2 ].

The synthesis, electronic structure, and reactivity of a uranium metallacyclopropene were comprehensively studied. Addition of diphenylacetylene (PhC≡CPh) to the uranium phosphinidene metallocene [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U=P-2,4,6-tBu3 C6 H2 (1) yields the stable uranium metallacyclopropene, [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U[η2 -C2 Ph2 ] (2). Based on density functional theory (DFT) results the 5f orbital contributions to the bonding within the metallacyclopropene U-(η2 -C=C) moiety increases significantly compared to the related ThIV compound [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 Th[η2 -C2 Ph2 ], which also results in more covalent bonds between the [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 U2+ and [η2 -C2 Ph2 ]2- fragments. Although the thorium and uranium complexes are structurally closely related, different reaction patterns are therefore observed. For example, 2 reacts as a masked synthon for the low-valent uranium(II) metallocene [η5 -1,2,4-(Me3 C)3 C5 H2 ]2 UII when reacted with Ph2 E2 (E=S, Se), alkynes and a variety of hetero-unsaturated molecules such as imines, ketazine, bipy, nitriles, organic azides, and azo derivatives. In contrast, five-membered metallaheterocycles are accessible when 2 is treated with isothiocyanate, aldehydes, and ketones.

NH3 formation from N2 and H2 mediated by molecular tri-iron complexes.

Living systems carry out the reduction of N2 to ammonia (NH3) through a series of protonation and electron transfer steps under ambient conditions using the enzyme nitrogenase. In the chemical industry, the Haber-Bosch process hydrogenates N2 but requires high temperatures and pressures. Both processes rely on iron-based catalysts, but molecular iron complexes that promote the formation of NH3 on addition of H2 to N2 have remained difficult to devise. Here, we isolate the tri(iron)bis(nitrido) complex [(Cp'Fe)3(µ3-N)2] (in which Cp' = η5-1,2,4-(Me3C)3C5H2), which is prepared by reduction of [Cp'Fe(µ-I)]2 under an N2 atmosphere and comprises three iron centres bridged by two µ3-nitrido ligands. In solution, this complex reacts with H2 at ambient temperature (22 °C) and low pressure (1 or 4 bar) to form NH3. In the solid state, it is converted into the tri(iron)bis(imido) species, [(Cp'Fe)3(µ3-NH)2], by addition of H2 (10 bar) through an unusual solid-gas, single-crystal-to-single-crystal transformation. In solution, [(Cp'Fe)3(µ3-NH)2] further reacts with H2 or H+ to form NH3.

Non-oxidative Methane Coupling over Silica versus Silica-Supported Iron(II) Single Sites.

Non-oxidative CH4 coupling is promoted by silica with incorporated iron sites, but the role of these sites and their speciation under reaction conditions are poorly understood. Here, silica-supported iron(II) single sites, prepared via surface organometallic chemistry and stable at 1020 °C in vacuum, are shown to rapidly initiate CH4 coupling at 1000 °C, leading to 15-22 % hydrocarbons selectivity at 3-4 % conversion. During this process, iron reduces and forms carburized iron(0) nanoparticles. This reactivity contrasts with what is observed for (iron-free) partially dehydroxylated silica, that readily converts methane, albeit with low hydrocarbon selectivity and after an induction period. This study supports that iron sites facilitate faster initiation of radical reactions and tame the surface reactivity.

Trauma Severity in Early Childhood Correlates with Stress and Satiety Hormone Levels in a Pilot Cohort Receiving Diamorphine Maintenance Treatment.

AIMS: Childhood trauma is of importance for the manifestation of substance-related disorders and maintenance of hypothalamic-pituitary-adrenal (HPA)-axis disorders. Since stress plays a crucial role in opioid compliance and craving, we investigated the immediate effects of diacetylmorphine application on the HPA axis. In particular, adrenocorticotropic hormone (ACTH) and cortisol secretion, as well as satiety regulating proopiomelanocortin peptides α-melanocyte-stimulating hormone (MSH) and ß-endorphin (END) in a cohort of opioid-dependent patients in diamorphine maintenance treatment concerning the clinical severity of their childhood trauma. METHODS: We compared the serum levels of ACTH, cortisol, MSH, and END in 15 opioid-dependent patients. All participants received treatment with diamorphine and were observed at 5 timepoints before and after injection. We split the cohort into 2 subgroups concerning childhood trauma measured by the Childhood Trauma Questionnaire. RESULTS: Splitting in 2 subgroups for mild (5) and severe trauma (10), we found that while both groups show a significant reduction of ACTH and cortisol levels over time, slopes display different progressions over time for cortisol (F[1.6] = 9.38, p = 0.02), while remaining identical for ACTH (F[1.6] = 1.69, p = 0.24). Also, levels of both MSH and END were significantly lower in severely traumatized patients. CONCLUSIONS: For the first time, we present a detailed representation of stress- and addiction-related proteins for the first 5 h after diamorphine application, demonstrating the interrelationship between stress hormones and childhood trauma as well as its potential effects on the progression of addictions such as opioid dependence.

Neuro-Endocrine Recovery After Pituitary Apoplexy: Prolactin as a Predictive Factor.

OBJECTIVE: Pituitary apoplexy is a serious medical complication of a pre-existing pituitary adenoma characterized by a variety of clinical symptoms ranging from mild headache to neurologically impaired and finally comatose patients. Management options are surgery or conservative treatment (e. g., with dexamethasone). Surgery is commonly performed in case of severe acute neurological and visual symptoms. However, prospective studies demonstrating a benefit of surgery over conservative treatment in terms of visual, neurological and even endocrine outcomes are lacking. Decision making is still controversial, and recommendations for surgery are based on low evidence grades and focus on visual impairment. Endocrine function and especially markers identifying patients with potential for pituitary recovery after surgery are not well described in the literature. PATIENTS AND DESIGN: We analysed data from 24 patients (m:f/16:8) with a median age of 64 yrs (38 to 83yrs) that underwent surgery for pituitary apoplexy regardless of time from symptom onset. Apoplexies were necrotic in 14 cases and haemorrhagic in 10 cases. RESULTS: Preoperatively, 7 patients (29.2%) showed complete anterior pituitary insufficiency, 16 patients (66.6%) had partial anterior pituitary insufficiency and one patient (4.17%) had normal pituitary functions. Persistent panhypopituitarism was found in 7 patients (29.2%), whereas an overall improvement of pituitary function was noted in 13 (57.1%) patients. Preoperative prolactin (PRL) levels were significantly associated with recovery of endocrine functions, whereas specifically all patients with preoperative PRL levels of at least 8.8 ng/ml recovered partially or fully. Time to surgery (0-7 days vs. 1-4 weeks vs.>4 weeks) was not significantly associated with outcome. CONCLUSIONS: Our data emphasize that normal and high preoperative PRL levels are associated with better endocrine outcome after surgery. We conclude that patients benefit from surgical intervention even after delayed diagnosis with the serum PRL levels is being a valid biomarker for clinical decision making.

Pogo-Stick Iron and Cobalt Complexes: Synthesis, Structures, and Magnetic Properties.

The synthesis, structures, and magnetic properties of monomeric half-sandwich iron and cobalt imidazolin-2-iminato complexes have been comprehensively investigated. Salt metathesis reactions of [Cp'M(µ-I)]2 (1-M, M = Fe, Co; Cp' = η5-1,2,4-tri-tert-butylcyclopentadienyl) with [ImDippNLi]2 (ImDippN = 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-iminato) furnishes the terminal half-sandwich compounds [Cp'M(NImDipp)] (2-M, M = Fe, Co), which can be regarded as models for elusive half-sandwich iron and cobalt imido complexes. X-ray diffraction analysis confirmed the structure motif of a one-legged piano stool. Complex 2-Co can also be prepared by an acid-base reaction between [Cp'Co{N(SiMe3)2}] (3-Co) and ImDippNH. The electronic and magnetic properties of 2-M and 3-Co were probed by 57Fe Mössbauer spectroscopy (M = Fe), X-band EPR spectroscopy (M = Co), and solid-state magnetic susceptibility measurements. In particular, the central metal atom adopts a high-spin (S = 2) state in 2-Fe, while the cobalt complex 2-Co represents a rare example of a Co(II) species with a coordination number different from six displaying a low-spin to high-spin spin-crossover (SCO) behavior. The experimental observations are complemented by DFT calculations.

Experimental and computational studies on a three-membered diphosphido thorium metallaheterocycle [η5-1,3-(Me3C)2C5H3]2Th[η2-P2(2,4,6-iPr3C6H2)2].

A three-membered thorium metallaheterocycle [η5-1,3-(Me3C)2C5H3]2Th[η2-P2(2,4,6-iPr3C6H2)2] (4) is readily prepared besides H2 from [η5-1,3-(Me3C)2C5H3]2Th(PH-2,4,6-iPr3C6H2)2 (3) upon heating in toluene solution. Density functional theory (DFT) studies were performed to elucidate the 5f orbital contribution to the bonding within Th-(η2-P-P) revealing more covalent bonds between the [η5-1,3-(Me3C)2C5H3]2Th2+ and [η2-P2(2,4,6-iPr3C6H2)2]2- fragments than those in the related thorium metallacyclopropene. Consequently, distinctively different reactivity patterns emerge, e.g., while 4 reacts with pyridine derivatives such as 4-dimethyaminopyridnie (DMAP) and forms the DMAP adduct [η5-1,3-(Me3C)2C5H3]2Th[η2-P2(2,4,6-iPr3C6H2)2](DMAP) (5), it may also act as a [η5-1,3-(Me3C)2C5H3]2Th(ii) synthon when reacted with bipy, Ph2S2 or Ph2Se2. Nevertheless, no reaction of complex 4 with alkynes is observed, but it reacts as a nucleophile towards nitriles and aldehydes resulting in five- or seven-membered metallaheterocycles, respectively. DFT computations provide some additional insights into the experimental observations.

Cannabis use in Switzerland 2015-2045: A population survey based model.

BACKGROUND: Alternative cannabis regulation models are discussed and implemented worldwide. A baseline scenario under the assumption of no policy or market changes may prove useful to forecast cannabis use and treatment demand and evaluate changes in legislation. METHODS: Based on data of the Continuous Rolling Survey of Addictive Behaviours and Related Risks on cannabis use, age, gender and nationality from 2011 to 2015, we used general estimating equation analysis to model lifetime and 30-days prevalence from 2015 to 2045 in Switzerland accounting for demographic trends. RESULTS: Lifetime prevalence of cannabis use is projected to grow from 28.3% (CI 95% 27.8-28.8) in 2015 to 42.0% (CI 95% 41.0-43.0) in 2045. 30-days prevalence would increase slightly from 2.70% (CI 95% 2.53-2.88) to 3.39% (CI 95% 3.11-3.66). Due to population growth, absolute numbers with past 30-day cannabis use are estimated to increase from 202,784 (CI 95% 189,534-216,035) to 314,302 (CI 95% 288,504-340,100). Among those aged under 30 years no substantial change in lifetime and 30-days prevalence of cannabis use is projected. Larger changes are estimated to occur in the age group 30+. The mean age of past 30-day cannabis users would increase for men with Swiss nationality from 30.3 to 38.7 years. DISCUSSION: Population-based survey data and demographic projections can be used to develop baseline scenarios of future cannabis use. Assuming no changes in cannabis legislation, growing absolute numbers of users will likely increase treatment demand. Cannabis use is estimated to increase among the group aged >30 years, which is currently underrepresented in clinical treatment and research. Our findings highlight the need for prospective baseline scenarios to evaluate the impact of legislative changes on cannabis use. Moreover, in Switzerland effective prevention and treatment interventions for cannabis use disorders are required even if cannabis legislation remains unchanged.

A base-free terminal thorium phosphinidene metallocene and its reactivity toward selected organic molecules.

The stable base-free terminal phosphinidene thorium metallocene, [η5-1,2,4-(Me3C)3C5H2]2Th[double bond, length as m-dash]P-2,4,6-tBu3C6H2 (2), can be isolated from the reaction of the thorium dichloride complex [η5-1,2,4-(Me3C)3C5H2]2ThCl2 (1) with 2 equiv. of 2,4,6-(Me3C)3C6H2PHK in THF. The reactivity of 2 in the activation of various small organic molecules such as diselenides, phosphines, imines, ketones, phosphine oxides, thiazole, imidazole derivatives and amines was explored. For example, when complex 2 is treated with Ph2Se2, the phosphinidene is replaced, yielding diselenido compound [η5-1,2,4-(Me3C)3C5H2]2Th(SePh)2 (3). Moreover, E-H (E = P, N, C) bond activation occurs on exposure of 2 to 2,4,6-iPr3C6H2PH2, PhPH2, (p-tolyl)2C[double bond, length as m-dash]NH, 1-indanone, cyclohexanone, Me3PO, thiazole, 1-methylimidazole and p-toluidine, resulting in the phosphido complex [η5-1,2,4-(Me3C)3C5H2][η5,κ-C-1,2-(Me3C)2-4-(CH2CMe2)C5H2]Th(PH-2,4,6-iPr3C6H2) (4), the metallaheterocycle [η5-1,2,4-(Me3C)3C5H2]2Th(η2-P2Ph2) (5), the iminato phosphido complex [η5-1,2,4-(Me3C)3C5H2]2Th(PH-2,4,6-tBu3C6H2)[N[double bond, length as m-dash]C(p-tolyl)2] (6), the phosphido enolyl compound [η5-1,2,4-(Me3C)3C5H2]2Th(PH-2,4,6-tBu3C6H2)(κ-O-1-OC9H7) (7), the enolyl complex [η5-1,2,4-(Me3C)3C5H2][η5,κ-C-1,2-(Me3C)2-4-(CH2CMe2)C5H2]Th(κ-O-1-OC6H9) (8), the alkyl complex [η5-1,2,4-(Me3C)3C5H2][η5,κ-C-1,2-(Me3C)2-4-(CH2CMe2)C5H2]Th(κ-O,C-OPMe2CH2) (9), the phosphido thiazolyl complex [η5-1,2,4-(Me3C)3C5H2]2Th(PH-2,4,6-tBu3C6H2)(C3H2NS) (10), the bis-imidazolyl complex [η5-1,2,4-(Me3C)3C5H2]2Th[2-(1-MeC3H2N2)]2 (11), and the imido complex [η5-1,2,4-(Me3C)3C5H2]2Th[double bond, length as m-dash]N(p-tolyl) (12), respectively. Several spectroscopic techniques were employed for the characterisation of the new complexes 3-11, and in addition the solid-state molecular structures of compounds 3-6, 8-9 and 11 were further confirmed by X-ray diffraction analyses.

Polypyrenes as High-Performance Cathode Materials for Aluminum Batteries.

The pressing need for low-cost and large-scale stationary storage of electricity has led to a new wave of research on novel batteries made entirely of components that have high natural abundances and are easy to manufacture. One example of such an anode-electrolyte-cathode architecture comprises metallic aluminum, AlCl3 :[EMIm]Cl (1-ethyl-3-methylimidazolium chloride) ionic liquid and graphite. Various forms of synthetic and natural graphite cathodes have been tested in recent years in this context. Here, a new type of compelling cathode based on inexpensive pyrene polymers is demonstrated. During charging, the condensed aromatic rings of these polymers are oxidized, which is accompanied by the uptake of aluminum tetrachloride anions (AlCl4- ) from the chloroaluminate ionic liquid. Discharge is the fast inverse process of reduction and the release of AlCl4- . The electrochemical properties of the polypyrenes can be fine-tuned by the appropriate chemical derivatization. This process is showcased here by poly(nitropyrene-co-pyrene), which has a storage capacity of 100 mAh g-1 , higher than the neat polypyrene (70 mAh g-1 ) or crystalline pyrene (20 mAh g-1 ), at a high discharge voltage (≈1.7 V), energy efficiency (≈86%), and cyclic stability (at least 1000 cycles).

Depression in the Context of Medical Disorders: New Pharmacological Pathways Revisited.

The depressive state has been characterised as one of elevated inflammation, changed cardiovascular parameters and a deranged metabolic situation all of which holds promise for a better understanding and handling of treatment-resistance in affective disorders as well as for future developments in treatment algorithms. In this context several biomarkers are differentially regulated by antidepressant treatment and connected to metabolic, inflammatory, cardiovascular and apoptotic components of the pathophysiology, i.e. adiponectin, apolipoprotein-B, B-type natriuretic peptide, cortisol, CRP, cysteine, homocysteine, fibrinogen, adiponectin, BMI, glycated hemoglobin A1c, leptin, interferon-gamma, high-density lipoprotein, interleukin interleukin-1alpha, -1beta, -2, -4, -5, -6, -8, -10, -12, -13, -17, insulin-like growth factor-1, low-density lipoprotein, myeloperoxidase, osteoprotegerin, tumour necrosis factor alpha, troponins, triglycerides etc. In this context antidepressants exert different modulatory effects on the outcome, incidence and mortality concerning several severe disorders, i.e. cancer, diabetes, stroke, inflammation, stroke and cardiovascular risk. Vice versa different drugs used in the treatment of these disorders have a favourable effect in depressive states, e.g. statins, aspirine, NSAIDs, pioglitazone, celecoxib, peroxisome proliferator-activated receptor-gamma agonists and minocycline. In this review, actions of different antidepressant treatment strategies on cancer, stroke, diabetes and cardiovascular disorders are shown and the influence on the outcome of the disorders is differentially discussed. In conclusion a hypothetic model for the implication of actual findings in everyday clinical practice is proposed. In this context personalized treatment could be used to tailor treatment to specific individuals according to their clinical endophenotypes. Moreover a potential target for the development of novel intervention strategies might be used.

Synthesis and Electronic Ground-State Properties of Pyrrolyl-Based Iron Pincer Complexes: Revisited.

The pyrrolyl-based iron pincer compounds [(tBuPNP)FeCl] (1), [(tBuPNP)FeN2] (2), and [(tBuPNP)Fe(CO)2] (3) were prepared and structurally characterized. In addition, their electronic ground states were probed by various techniques including solid-state magnetic susceptibility and zero-field 57Fe Mössbauer and X-band electron paramagnetic resonance spectroscopy. While the iron(II) starting material 1 adopts an intermediate-spin (S = 1) state, the iron(I) reduction products 2 and 3 exhibit a low-spin (S = 1/2) ground state. Consistent with an intermediate-spin configuration for 1, the zero-field 57Fe Mössbauer spectrum shows a characteristically large quadrupole splitting (ΔEQ ≈ 3.7 mm s-1), and the solid-state magnetic susceptibility data show pronounced zero-field splitting (|D| ≈ 37 cm-1). The effective magnetic moments observed for the iron(I) species 2 and 3 are larger than expected from the spin-only value and indicate an incompletely quenched orbital angular momentum and the presence of spin-orbit coupling in the ground state. The experimental findings are complemented by density functional theory computations, which are in good agreement with the experimental data. Most notably, these calculations reveal a low-lying (S = 2) excited state for complex 1; furthermore, the computed Mössbauer parameters for all complexes studied herein are in excellent agreement with the experimental findings.

TNFα drives mitochondrial stress in POMC neurons in obesity.

Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity.

Patients with non-substance-related disorders report a similar profile of childhood trauma experiences compared to heroin-dependent patients.

BACKGROUND AND OBJECTIVES: Exposure to traumatic events is common among patients with substance use disorders (SUD). In patients with non-substance-related disorders, especially with gambling disorders (GD) and internet addiction (IA), traumatic childhood experiences have not been investigated extensively. The objective of this study was to compare trauma histories in patients with GD and IA to patients with heroin dependence. METHODS: Cross-sectional surveys including the childhood trauma questionnaire (CTQ) and clinical data among 107 participants; 59 patients with non-substance-related disorders (GD [n = 39]; IA [n = 20]) were compared to 28 patients prescribed injectable heroin for opioid dependence in heroin-assisted treatment (HAT) and to a healthy control group (HC) (n = 20). RESULTS: The findings revealed a high prevalence of trauma exposure in all three clinical groups, with 74.4% of patients with GD, 80.0% of patients with IA, and 93.0% of patients in HAT compared to 40% in HC. All three groups (GD, IA, HAT) reported significantly higher levels of "emotional neglect" compared to HC. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results provide clinically relevant information suggesting that the burden of childhood traumatic experiences may be as common in patients with GD and IA as in patients with heroin dependence. These findings could pose an important starting-point for treatment. (Am J Addict 2017;26:215-220).

Epigenetic Effects of Intravenous Diacetylmorphine on the Methylation of POMC and NR3C1.

The administration of diacetylmorphine (DAM) reduces the activation of the hypothalamic-pituitary-adrenal (HPA) axis in opioid-maintained patients. However, the epigenetic effects of DAM on addiction-related genes have not been investigated yet. In a randomized controlled study, we examined the immediate effects of intravenous DAM versus placebo on the promoter methylation of the POMC (pro- opiomelanocortin) and NR3C1 (glucocorticoid receptor 1) genes. Twenty-eight heroin-dependent patients on DAM-assisted treatment received either DAM or saline in a randomized crossover design and 17 healthy participants received saline only. EDTA blood samples were taken 25 min before and 10 min after the injection of DAM or saline. We found reciprocal regulation effects for DAM versus saline application regarding the methylation of POMC; while DAM injection significantly increased methylation, saline injection led to a significant decrease in methylation for patients as well as controls. NR3C1 data did not show significant changes in methylation. Injection of DAM blunted stress hormone levels and the POMC promoter methylation of heroin-dependent patients. These findings provide first preliminary insights into the epigenetic mechanisms underlying the emotional regulation effects of DAM-assisted treatment in severe heroin-dependent patients.