General medical conditions and mortality in women with postpartum psychiatric disorders.

BACKGROUND: Psychiatric patients have an increased risk of general medical conditions and mortality, but no study has systematically explored these outcomes among women with mental disorders following childbirth (postpartum psychiatric disorders: PPD). Therefore, we aimed to investigate the risk of subsequent general medical conditions and mortality in women with a broad spectrum of PPD. METHODS: This register-based cohort study followed all Danish women born after January 1, 1960, until January 1, 2016. The exposure of interest was (i) mild-moderate PPD: first-ever prescription of psychotropic medication (ATC codes: N03-N07) and (ii) severe PPD: first-ever in- or out-patient contact to a psychiatric facility, both within six months postpartum. Outcomes of interest were (i) hospital-registered chronic medical conditions and (ii) mortality from natural and unnatural causes. We included 1 841 949 women representing 22 615 310 person-years at risk. RESULTS: Among 15 852 women with mild-moderate PPD and 4266 women with severe PPD, we found a higher risk of any subsequent general medical condition (mild-moderate PPD: IRR 1.25; 95% CI 1.20-1.31 and severe PPD: IRR 1.35; 95% CI: 1.24-1.48) when compared to the female background population. Mortality from both natural and unnatural causes was higher in both groups: Mild-moderate PPD: natural causes MRR 1.37; 95% CI: 1.17-1.61; unnatural causes MRR 1.52; 95% CI: 1.10-2.11, and severe PPD: natural causes MRR 1.42; 95% CI 1.02-2.00, and unnatural causes MRR 5.05; 95% CI: 3.40-7.51. CONCLUSIONS: This first overview of general medical prognosis in PPD shows that women at either end of the spectrum are at increased risk of subsequent chronic medical conditions and overall mortality.

Perinatal psychiatric episodes: a population-based study on treatment incidence and prevalence.

Perinatal psychiatric episodes comprise various disorders and symptom severity, which are diagnosed and treated in multiple treatment settings. To date, no studies have quantified the incidence and prevalence of perinatal psychiatric episodes treated in primary and secondary care, which we aimed to do in the present study. We designed a descriptive prospective study and included information from Danish population registers to study first-time ever and recurrent psychiatric episodes during the perinatal period, including treatment at psychiatric facilities and general practitioners (GPs). This was done for all women who had records of one or more singleton births from 1998 until 2012. In total, we had information on 822 439 children born to 491 242 unique mothers. Results showed first-time psychiatric episodes treated at inpatient facilities were rare during pregnancy, but increased significantly shortly following childbirth (0.02 vs 0.25 per 1000 births). In comparison, first-time psychiatric episodes treated at outpatient facilities were more common, and showed little variation across pregnancy and postpartum. For every single birth resulting in postpartum episodes treated at inpatient psychiatric facilities, 2.5 births were followed by an episode treated at outpatient psychiatric facility and 12 births by GP-provided pharmacological treatment. We interpret our results the following way: treated severe and moderate psychiatric disorders have different risk patterns in relation to pregnancy and childbirth, which suggests differences in the underlying etiology. We further speculate varying treatment incidence and prevalence in pregnancy vs postpartum may indicate that the current Diagnostic and Statistical Manual of Mental Disorders-5 peripartum specifier not adequately describes at-risk periods across moderate and severe perinatal psychiatric episodes.

Pre-eclampsia and first-onset postpartum psychiatric episodes: a Danish population-based cohort study.

BACKGROUND: Recent evidence suggests that postpartum psychiatric episodes may share similar etiological mechanisms with immune-related disorders. Pre-eclampsia is one of the most prevalent immune-related disorders of pregnancy. Multiple clinical features are shared between pre-eclampsia and postpartum psychiatric disorders, most prominently a strong link to first pregnancies. Therefore, we aimed to study if pre-eclampsia is a risk factor for first-onset postpartum psychiatric episodes. METHOD: We conducted a cohort study using the Danish population registry, with a total of 400 717 primiparous women with a singleton delivery between 1995 and 2011. First-lifetime childbirth was the main exposure variable and the outcome of interest was first-onset postpartum psychiatric episodes. The main outcome measures were monthly incidence rate ratios (IRRs), with the period 11-12 months after birth as the reference category. Adjustments were made for age, calendar period, reproductive history, and perinatal maternal health including somatic and obstetric co-morbidity. RESULTS: Primiparous women were at particularly high risk of first-onset psychiatric episodes during the first month postpartum [IRR 2.93, 95% confidence interval (CI) 2.53-3.40] and pre-eclampsia added to that risk (IRR 4.21, 95% CI 2.89-6.13). Having both pre-eclampsia and a somatic co-morbidity resulted in the highest risk of psychiatric episodes during the 3-month period after childbirth (IRR 4.81, 95% CI 2.72-8.50). CONCLUSIONS: We confirmed an association between pre-eclampsia and postpartum psychiatric episodes. The possible explanations for this association, which are not mutually exclusive, include the psychological impact of a serious medical condition such as pre-eclampsia and the neurobiological impact of pre-eclampsia-related vascular pathology and inflammation.

Biodistribution and catabolism of 18F-labelled isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine.

Isopeptide bonds between the epsilon-amino group of lysine and the gamma-carboxamide group of glutamine are formed during strong heating of pure proteins or, more important, by enzymatic reaction mediated by transglutaminases. Despite the wide use of a microbial transglutaminase in food biotechnology, up to now little is known about the metabolic fate of the isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine. In the present study, N-succinimidyl-4-[(18)F]fluorobenzoate was used to modify N(epsilon)-(gamma-glutamyl)-L-lysine at each of its two alpha-amino groups, resulting in the 4-[(18)F]fluorobenzoylated derivatives, for which biodistribution, catabolism, and elimination were investigated in male Wistar rats. A significant different biochemical behavior of the two labelled isopeptides was observed in terms of in vitro stability, in vivo metabolism as well as biodistribution. The results suggest that the metabolic fate of isopeptides is likely to be dependent on how they are reabsorbed - free or peptide bound.

The usefulness of radiotracers to make the body biochemically transparent.

Radioactive isotopes are uniquely applicable to observe reactions or circuits of reactions at the molecular level without disturbing the system being studied. The advent of molecular imaging modalities, particularly positron emission tomography (PET), is a major breakthrough for the visualisation and quantitative assessment of cellular and molecular processes occurring in living tissues. The recent development of animal PET scanners that offers 2-mm resolution and is tailored to laboratory rodent models, has made a further great impact on in vivo biochemistry. With these live-imaging modalities at hand, radiotracer-based technologies allow to look directly at biochemical distribution and interaction processes. Tremendous progress made in radiotracer chemistry, primarily in carbon-11 and fluorine-18 radiochemistry, and in the design of imaging devices strengthens the usefulness of radiotracers in nuclear medicine and drug research and development and opens exciting opportunities for new applications, e.g., in food science.

Novel tumortropic ester derivatives of 99mTc(V) mesodimercapto succinic acid with low affinity for bone tissue.

Starting from our previous finding that 99mTc(V) dimercaptosuccinic acid (99mTc(V)-DMSA), a useful agent for the localization of osteosarcoma and bone metastases, loses its bone affinity when one ester group is introduced into the complex we studied the impact of esterification in more detail. This paper reports on the evaluation of various ester complexes of 99mTc(V)-DMSA in rats and tumour-bearing nude mice with regard to their tumour retention and improvement of the tumour to tissue ratios. The distribution patterns of the complexes [99mTcO(DMSA)2]- (A), [99mTcO(DMSA/DMSEt)]- (B) and [99mTcO(DMSEt)2]- (C) are gradually changed with the number of ester groups in the anionic complex. However, the asymmetric diester complex [99mTcO(DMSA/DMSEt2)]- (D) is very slowly cleared, especially from the blood of nude mice. Moreover, this complex differs significantly from the symmetrical complex C in its elimination behaviour from the liver and kidneys. The tumour uptake is maintained with complexes that contain one or two non-hydrolysable ester functions. Preliminary biodistribution studies of the monoethyl and diethyl ester complexes B, C and D in comparison with A in tumour-bearing nude mice showed similar uptake into the human squamous cell carcinoma (FaDu) as well as into the human colonic cell carcinoma (HT29) of nude mice. The low bone accumulation of B, C and D results in excellent tumour-to-bone ratios, e.g., approx. 3:1 for the ester complex B compared to approx. 1:2 for complex A. Differences were observed in the accumulation and elimination behaviour of the complexes A and B in various bone structures of rats. The age-dependent uptake of A and B was compared in long bone (femur) and in cranial bone of rats. The results suggest that 99mTc(V)-DMSA complexes that contain a functional ester, and their 188Re analogues, may be superior to 99mTc(V)/188Re(V)-DMSA in diagnostic and therapeutic nuclear medicine.

Radiolabelling of isopeptide N epsilon-(gamma-glutamyl)-L-lysine by conjugation with N-succinimidyl-4-[18F]fluorobenzoate.

The isopeptide N(epsilon)-(gamma-glutamyl)-L-lysine 4 was labelled with 18F via N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). A modified approach for the convenient synthesis of [18F]SFB was used, and [18F]SFB could be obtained in decay-corrected radiochemical yields of 44-53% (n = 20) and radiochemical purity >95% within 40 min after EOB. For labelling N(epsilon)-(gamma-glutamyl)-L-lysine with [18F]SFB the effects of isopeptide concentration, temperature, and pH were studied to determine the optimum reaction conditions. The coupling reaction was shown to be temperature and pH independent while being strongly affected by the isopeptide concentration. Using the optimized labelling conditions, in a typical experiment 1.3GBq of [18F]SFB could be converted into 447MBq (46%, decay-corrected) of [18F]fluorobenzoylated isopeptide within 45 min, including HPLC purification.

3-O-methyl-6-[18F]fluoro-L-DOPA and its evaluation in brain tumour imaging.

3-O-Methyl-6-[(18)F]fluoro-L-DOPA (OMFD) is a major metabolite of 6-[(18)F]fluoro-L-DOPA. Although synthesis of OFMD was primarily established to study the dopaminergic system, as it is an amino acid analogue, uptake in experimental tumours has been found. The aim of this study was to evaluate the applicability of OMFD for brain tumour imaging and to obtain initial estimates of whole-body biodistribution and radiation dosimetry in humans. Nineteen patients with suspected or confirmed brain tumours were investigated with OMFD and dynamic brain PET, complemented by whole-body PET in seven patients. Tracer kinetics were compared for normal brain and intracerebral lesions. Tissue accumulation was quantified with standardised uptake values (SUVs). Whole-body distribution in combination with tracer kinetics from animal experiments was used for the calculation of radiation dosimetry data. On the basis of OMFD PET, viable brain tumour was suspected in 16 patients with SUVs of 3.0+/-0.8 and a tumour to non-tumour ratio of 1.9+/-0.5. Highest tumour and normal brain uptake occurred between 15 and 30 min, with a subsequent slow decrease. Late whole-body tracer distribution was uniform without specific organ accumulation. Elimination occurred via urine. The mean radiation dose to the whole body was estimated at 0.016 mSv/MBq, with the kidneys as dose-critical organ (0.033 mGy/MBq). In conclusion, OMFD enables the visualisation of brain tumours with SUVs similar to other fluorinated amino acids. The whole-body radiation exposure from OMFD is comparable to that from FDG imaging.

Distribution of 16alpha-[18F]fluoro-estradiol-3,17beta-disulfamate in rats, tumour-bearing mice and piglets.

Based on a high affinity to the enzyme estrone sulfatase (ES), 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate ([18F]FESDS) has been suggested as a potential PET radiotracer for imaging steroid-dependent breast tumours. The distribution of [18F]FESDS was studied in rats, tumour-bearing nude mice and piglets. In all species evidence for binding to a second target, the enzyme carbonic anhydrase (CA), was obtained. ES and CA inhibitors significantly reduced the radiotracer uptake in various organs but not in tumours. It is concluded that [18F]FESDS binds to ES and CA in vivo but this binding is not strong enough to allow tumour imaging with positron emission tomography (PET).

Distribution of estrone sulfatase in rat brain determined by in vitro autoradiography with 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate.

16Alpha-fluoroestradiol-3,17beta-disulfamate (FESDS) strongly inhibits estrone sulfatase (ES), an enzyme which is also present in the brain. The enzyme is probably involved in important regulatory functions of neurosteroids which may be disturbed in certain brain diseases. In the present study, [18F]FESDS was used to measure the amount of ES in various rat brain regions using quantitative in vitro autoradiography. The obtained values vary between 0.29 pmol (mg protein)(-1) (pons) and 11.5 pmol (mg protein)(-1) (striatum). They are positively correlated with the enzyme activity measured in homogenates of the corresponding regions. Because this radiotracer binds also to carbonic anhydrase in the brain it is only of limited use for in vivo imaging studies.

Synthesis, biological and autoradiographic evaluation of a novel Tc-99m radioligand derived from WAY 100635 with high affinity for the 5-HT(1A) receptor and the alpha1-adrenergic receptor.

This paper reports the synthesis, biological evaluation, in vitro and ex vivo autoradiography of the first Tc-99m ligand with subnanomolar affinity for the 5-HT(1A) receptor and a remarkably high affinity for the alpha1-adrenergic receptor. The neutral "3+1" mixed-ligand complex combines 4-(6-mercaptohexyl)-1-(2-methoxyphenyl)piperazine as monodentate and 3-(N-methyl)azapentane-1,5-dithiol as tridentate unit with oxotechnetium(V). The analogous rhenium complex was synthesized for complete structural characterization and used in receptor binding assays. In competition experiments both complexes display subnanomolar affinity for the 5-HT(1A) receptor (IC(50)0.24 nM for Re, 0.13 nM for Tc) but also very high affinities for the alpha1-adrenergic receptor (IC(50) 0.05 nM for Re, 0.03 nM for Tc). Biodistribution studies show a brain uptake in rat of 0.22% ID five minutes post injection. In vitro autoradiographic studies in rat brain and postmortem human brain indicate accumulation of the Tc-99m complex in brain areas which are rich in 5-HT(1A) receptors or in alpha1-adrenergic receptors. This in vitro enrichment can be blocked respectively by the 5-HT(1A) receptor agonist 8-OH-DPAT or by prazosin hydrochloride, an alpha1-adrenergic receptor antagonist. Ex vivo autoradiographic studies in rats show a slight accumulation of the Tc-99m complex in 5-HT(1A) receptor-rich areas of the brain, which could not be blocked, as well as in regions rich in alpha1-adrenergic receptors, which could be blocked by prazosin hydrochloride.

Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT(1A) receptor and the alpha1-adrenergic receptor.

Tc(III) and Re(III) complexes [M(NS(3))(CNR)] (M = Re, 99mTc, NS(3) = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT(1A) as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT(1A) receptor-rich brain regions. However, addition of the specific 5-HT(1A) receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.

Synthesis of S-([18F]fluoromethyl)-(+)-McN5652 as a potential PET radioligand for the serotonin transporter.

The present study describes the synthesis of the [18F]fluoromethyl analogue of (+)-McN5652 ([18F]FMe-McN) as a new potential tracer for the serotonin transporter. In vitro binding studies have shown that FMe-McN displays only slightly lower affinity for the serotonin transporter (K(i) = 2.3 +/- 0.1 nM) than (+)-McN5652 (K(i) = 0.72 +/- 0.2 nM). The radiofluorinated tracer [18F]FMe-McN was prepared by reaction of normethyl (+)-McN5652 with the fluoromethylation agent [18F]bromofluoromethane in an overall radiochemical yield of 5 +/- 1% (decay-corrected, related to [18F]fluoride) and with high specific radioactivity (200-2,000 GBq/micromol at the end of synthesis).

[99mTc]oxotechnetium(V) complexes amine-amide-dithiol chelates with dialkylaminoalkyl substituents as potential diagnostic probes for malignant melanoma.

[99mTc]oxotechnetium(V) complexes of amine-amide-dithiol (AADT) chelates containing tertiary amine substituents were synthesized and shown to have affinity for melanoma. For complexation the AADT-CH2[CH2]nNR2 (n = 1, 2; R = Et, n-Bu) ligand was mixed with a [99mTc]oxotechnetium(V)-glucoheptonate precursor to make the AADT-[99mTc]oxotechnetium(V) complexes in nearly quantitative yield. Structurally analogous nonradioactive oxorhenium(V) complexes were also synthesized and characterized. In vitro sigma-receptor affinity measurements indicate these complexes to possess sigma-affinity in the low micromolar range with K(i) values in the 7.8-26.1 and 0.18-2.3 microM range for the sigma1- and sigma2-receptors, respectively. In vitro cell uptake of the 99mTc complexes in intact B16 murine melanoma cells at 37 degrees C after a 60-min incubation ranged from 12% for complex 2 (n = 1, R = n-Bu) to 68% for complex 4 (n = 2, R = n-Bu). In vivo evaluation of complexes 1-Tc-4-Tc in the C57Bl/B16 mouse melanoma model demonstrated significant tumor localization. Complex 1-Tc (n = 1, R = Et) displayed an in vivo tumor uptake of 7.6% ID/g at 1 h after administration with initial melanoma/blood (M/B), melanoma/spleen (M/S), and melanoma/lung (M/L) ratios >4; these ratios increased to 10.8, 10.1, and 7.3, respectively, at 6 h. While complex 3-Tc (n = 3, R = Et) had an initial tumor uptake of 3.7% ID/g 1 h after administration with M/B, M/S, and M/L ratios >2, a greater tumor retention and slightly faster clearance from nontumor-containing organs resulted in M/B, M/S, and M/L ratios of 19.1, 19.1, and 12.7, respectively, at 6 h. The high tumor uptake and significant tumor/nontumor ratios indicate that such small technetium-99m-based molecular probes can be developed as in vivo diagnostic agents for melanoma and its metastases.

Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression.

Various radiotracers based on uracil nucleosides (e.g. [124I]2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil, [124I]FIAU) and acycloguanosine derivatives (e.g. [18F]9-[(3-fluoro-1-hydroxy-2-propoxy) methyl] guanine, [18F]FHPG) have been proposed for the non-invasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, these radiotracers have been evaluated in different in vitro and in vivo models, precluding a direct comparison. Therefore, we directly compared [18F]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression. The uptake of [125I]FIAU, [18F]FHPG and [3H]acyclovir was determined in vitro using four different HSV1-tk expressing cell lines and their respective negative controls. The in vitro tracer uptake was generally low in non-transduced parental cell lines. In HSV1-tk expressing cells, [3H]acyclovir showed approximately a twofold higher tracer accumulation, the [18F]FHPG uptake increased by about sixfold and the [125I]FIAU accumulation increased by about 28-fold after 120-min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines. In addition, biodistribution and positron emission tomography (PET) studies with [18F]FHPG and [124/125I]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific accumulation of radioactivity was found for [125I]FIAU compared with [18F]FHPG. The ratio of specific tracer accumulation between [125I]FIAU and [18F]FHPG increased from 21 (30 min p.i.) to 119 (4 h p.i.). PET imaging, using [124I]FIAU, clearly visualised and delineated HSV1-tk expressing tumours, whereas only a negligible uptake of [18F]FHPG was observed. This study demonstrated that in vitro and in vivo, the radioiodinated uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [18F]FHPG. This suggests that [124I]FIAU should be the preferred reporter probe for PET imaging of HSV1-tk gene expression. Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tk gene expression should also focus on 18F-labelled uracil derivatives.

Radio fluorination and positron emission tomography (PET) as a new approach to study the in vivo distribution and elimination of the advanced glycation endproducts N epsilon-carboxymethyllysine (CML) and N epsilon-carboxyethyllysine (CEL).

After synthesis of fluorine-18 labelled analogues by [18F]fluorobenzoylation at the alpha-amino group, biodistribution and elimination of individual advanced glycation endproducts, namely N epsilon-carboxymethyllysine and N epsilon-carboxyethyllysine, were studied in comparison to lysine in rats after intravenous injection using positron emission tomography (PET). The [18F]radiofluorinated amino acids were fast distributed via the blood, followed by a rapid excretion through the kidneys. Elimination kinetics were similar for both AGEs and lysine. For CML and CEL, but not for lysine, a temporary liver accumulation could be observed, which was not connected with any metabolisation or enterohepatic circulation. No further accumulation in any tissues was observable, indicating that increased tissue levels of CML or CEL, which have been described for certain disorders, are exclusively derived from endogenous origin and should not depend on a dietary intake. However, under uremic conditions, an impaired kidney function might result in a significant increase of the AGE-load of blood and tissues. PET based on 18F-labelled AGEs proved to be a promising tool to elucidate the physiological fate of post-translationally modified amino acids and to clarify the role of AGEs as possible "glycotoxins".

Ligand-exchange reaction of labile "3 + 1"99mTc(V) complexes with SH group-containing proteins.

The reactivity of labile 3 + 1 mixed-ligand 99mTc complexes of the type [99mTcO(SES)(RS)] with SES being a tridentate dithiol ligand and glutathione or dimethylcysteamine as monodentate ligands RSH towards proteins was investigated in vitro and in vivo. It was found that the complexes undergo reversible transchelation reactions with SH group-containing components of blood such as albumin or haemoglobin. High labelling yields were obtained when 3 + 1 complexes with the tridentate SSS ligand were used. The biodistribution of blood proteins labelled by ligand-exchange reaction with the [99TcO(SSS)] or [99mTcO(SNMeS)] core was studied and compared with the in vivo distribution of the labile 3 + 1 complexes containing glutathione as monodentate ligand.

Stability studies on (99m)technetium(III) complexes with tridentate/monodentate thiol ligands and phosphine ('3 + 1 + 1' complexes).

The preparation and characterisation of 3 + 1 + 1 technetium complexes of the general formula [Tc(SES)(RS)(PMe2Ph)] (SES = tridentate dithiol ligand, E = S, O, NMe; RSH = monothiol ligand) at the n.c.a. level is described. The Tc(III) complexes are prepared in a one-step procedure starting from pertechnetate in yields of 85-95% of radiochemical purity. A comparison of their chromatographic data with the fully characterised 99Tc complexes indicate the identity of the investigated compounds. Stability studies show that the 99mTc complexes undergo some alteration in solution. They are oxidised to the 3 + 1 oxotechnetium (V) complexes and/or decompose in aqueous solution. In challenge experiments performed with glutathione, exchange of the monothiolato ligand occurs in the same manner as known for the 3 + 1 complexes.