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.

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.

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.

'3+1' mixed-ligand oxotechnetium(V) complexes with affinity for melanoma: synthesis and evaluation in vitro and in vivo.

'3+1' Mixed-ligand [(99m)Tc]oxotechnetium complexes with affinity for melanoma were synthesized in a one-pot reaction. Complexation of technetium-99m with a mixture of N-R(3-azapentane-1,5-dithiol) [R = Me, Pr, Bn, Et(2)N(CH(2))(2)] and N-(2-dialkylamino)ethanethiol [alkyl = X = Et, Bu, morpholinyl] using Sn(2+) as the reducing agent resulted in the formation of '3+1' mixed-ligand technetium-99m complexes [TcO(SN(R)S)(SNX(2))] in high radiochemical yield (60-98%). In vitro uptake studies in B16 murine melanoma cells indicated a moderate tumor-cell accumulation (40%) of compound 1 [R = Me, X = Et] and a higher accumulation (69%) of compound 2 [R = Me, X = Bu] after a 60-min incubation. In vivo evaluation of compounds 1-6 in the C57Bl6/B16 mouse melanoma model demonstrated tumor localization. Compound 2 displayed the highest accumulation with up to 5% ID/g at 60 min after injection. In vivo, 2 also showed a low blood-pool activity and high melanoma/spleen (4.3) and melanoma/lung (1.9) ratios at 1 h. These results suggest that small technetium-99m complexes could be useful as potential melanoma-imaging agents.

[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.

Radioactivity in gastric juice-a simple adjunct to the Yb-169 DTPA cisternographic diagnosis of CSF rhinorrhea: concise communication.

A new method is offered as an adjunct to radionuclide cisternography and the measuring of radioactivity in nasal pledgets. The activity in gastric juice following the intrathecal injection of Yb-169-DTPA is measured and the ratio of gastric juice to blood is calculated. In patients suffering from CSF rhinorrhea the ratios significantly exceed the normal range. This method can be used to detect CSF leakage at the back of the nasopharynx, and in patients with head injuries too severe to permit the use of nasal pledgets.

Chemical and biological characterization of different Tc complexes of cysteine and cysteine derivatives.

The labeling of cysteine and its derivatives (penicillamine, N-acetylcysteine, cysteine ethyl ester) with 99Tc (99mTc) was studied as a model for the radiopharmaceutical preparation of Tc-99m mercaptide complexes. After the use of TcO4-, TcOCl52-, and TcBr62- as labeling agents for the Tc oxidation states VII, V, and IV, respectively, complexes of Tc(V) and Tc(IV) were prepared and characterized. The biologic behavior of these complexes was studied in rats. The substitutions in cysteine are responsible for substantial changes of net charge and lipophilicity in the Tc complexes, and the consequences on the excretion patterns in Wistar rats are discussed.

Different response of cerebral and non-cerebral endothelial cells to cytotoxic hypoxia.

The present study investigated the effect of cytotoxic hypoxia on cerebral and non-cerebral endothelial cells. Hypoxia was induced by inhibiting the cellular respiratory chain with 1 mM sodium cyanide. Cerebral endothelial cells were damaged after 2 h of hypoxia as assessed by a decrease in cell viability by 25% and by a 2.7-fold higher lactate dehydrogenase release compared to controls. Additional glucose deprivation did not significantly exacerbate hypoxic injury. In addition, we found after 2 h of hypoxia an increase in the release of lactate of 1.02 and 0.42 mg/mg protein compared to 0.27 and 0.07 mg/mg protein in controls in the presence and absence of glucose, respectively. While the activity of ALP of cerebral endothelial cells was maintained at the control level, we found a significant decrease in the gamma-GT activity from 3.8 +/- 1.3 to 1.09 +/- 0.3 U/mg protein after 3 h of hypoxia in the presence as well as in the absence of glucose. The paracellular permeability of the cell monolayer decreased after 1 h and returned to control level after 3 h of hypoxia in the presence of glucose. Non-cerebral endothelial cells remained 98% viable with no change in the release of lactate dehydrogenase and lactate after 2 h of hypoxia in the presence and absence of glucose. The activities of ALP and gamma-GT in non-cerebral endothelial cells were 10 and 3 times lower and remained unchanged during hypoxia. We conclude from our experiments that sodium cyanide is useful to study hypoxic injury and that cerebral endothelial cells are more sensitive than non-cerebral endothelial cells to cytotoxic hypoxia.

pH-controlled inclusion and release of oxyanions by dendrimers bearing methyl orange moieties.

We report the synthesis of POPAM dendrimers, bearing up to 64 chromophores at their periphery. For these dendrimers, a radiotracer technique was used to study the liquid-liquid partition of pertechnetate and (14)C-labeled nucleotides in trichloromethane-aqueous systems. Inclusion and release of guest molecules can be controlled by changing the pH. The extraction efficacy increases with rising generation number.

High-affinity binding of [3H]paroxetine to caudate nucleus and microvessels from porcine brain.

Serotonin (5-HT) is an important signal molecule not only for neurones but also for a variety of other cell types. Targeting the brain endothelium, the constitutive element of the blood-brain barrier (BBB), it elicits permeability changes. Using the selective 5-HT uptake inhibitor [3H]paroxetine we demonstrated the presence of a 5-HT transporter-like protein at the BBB. The binding capacities (Bmax) at the BBB (382 fmol mg-1) and on caudate nucleus membranes (392 fmol mg-1) were similar. However, the binding affinities differed by a factor of 5 (membranes: Kd = 0.10 nM, BBB: 0.47 nM). The affinities of various specific uptake inhibitors were also 2- to 13-fold lower in the microvessel preparation. It is suggested that the 5-HT transporter(s) in the brain and microvessels are different or differently regulated proteins.

Simultaneous measurement of [18F]FDOPA metabolism and cerebral blood flow in newborn piglets.

Available information on the dopamine (DA) metabolism of the immature brain is rare. In order to establish a useful animal model we have performed PET experiments in anesthetized neonatal pigs using 6-[18F]-fluoro-L-DOPA (FDOPA) as tracer. In this study, we have simultaneously determined the cerebral blood flow and the rate constant of FDOPA conversion by the aromatic amino acid decarboxylase, the ultimate enzyme in the synthesis of dopamine. The estimated values of FDOPA decarboxylation in the basal ganglia were similar to values calculated in adult animals and humans. However, in contrast to those studies a significant decarboxylation was also found in the frontal cortex and the cerebellum. HPLC analysis of brain samples also revealed extensive and rapid metabolism of FDOPA in the five investigated brain regions. At 8 min after tracer injection about 80% of FDOPA was already converted to FDA and its metabolites. Surprisingly, a rather high fraction (16-21%) of [18F]-fluoro-3-methoxytyramine was found which may indicate a low storage capacity of vesicular DA at this perinatal stage. It is suggested that the findings are related to the ontogenetic development of the dopaminergic system. The knowledge of the regulation of the DA metabolism in the immature brain may have implications for the understanding of neurodevelopmental effects of perinatal oxygen deprivation.

Regional distribution of cerebral blood volume and cerebral blood flow in newborn piglets--effect of hypoxia/hypercapnia.

The relationship between regional parenchymal cerebral blood volume (CBV), regional cerebral blood flow (CBF) and the calculated mean transit time (MTT) was investigated in 14 newborn piglets. The effects of combined hypoxic hypoxia (PaO2 = 32 +/- 5 mm Hg) and hypercapnia (paCO2 = 68 +/- 5 mm Hg) were measured in seven animals. Remaining animals served as the control group. During baseline conditions the highest CBF and CVB values were found in the lower brainstem and cerebellum, whereas white matter exhibited the lowest values (p < 0.05). MTT was prolonged within the cerebral cortex (2.34 +/- 0.42 s-1) compared with the thalamic MTT (1.53 +/- 0.38 s-1) (p < 0.05). Under moderate hypoxia/hypercapnia, a CBF increase to the forebrain (p < 0.05) resulted in an elevated brain oxygen delivery (p < 0.05) and so CMRO2 remained unchanged. Moreover, a moderate increase of CBV and a marked shortening of MTT occurred (p < 0.05). The CBV increase was higher in structures with lowest baseline values, i.e., thalamus (66% increase) and white matter (62% increase) (p < 0.05). MTT was between 22% of baseline in the lower brainstem and 49% in white matter (p < 0.05). We conclude that under normoxic and normocapnic conditions the newborn piglets exhibit a comparatively enlarged intraparenchymal CBV. Moderate hypoxia and hypercapnia induced a marked increase in cerebral blood flow which appears to be caused by an increased perfusion velocity, expressed by a strongly reduced mean transit time and by a concomitant CBV increase.

Specific binding of [3H]imipramine indicates the presence of a specific serotonin transport system on endothelial cells of porcine brain.

The blood-brain barrier (BBB) represents a complex epithelial interface in vertebrates that separates the blood compartment from the extracellular fluid compartment of the brain. Isolated microvessels are a tool to study the function of this interface in vitro. Here we report on attempts to demonstrate the presence of the serotonin transporter on microvessels from the porcine brain. For comparison, membrane preparations of brain tissue were used. The enrichment of the microvessel fraction determined by measurement of alkaline phosphatase activity was about 30-fold. In saturation experiments high- and low-affinity binding of [3H]imipramine could be demonstrated on brain microvessels. Different concentrations of unlabelled imipramine were used to inhibit the binding of [3H]imipramine in brain tissue and microvessels. Comparison of both preparations revealed a two-fold higher density of the high-affinity binding site, while the density of the low-affinity binding site was 28-fold higher in brain microvessels. Imipramine binding could be inhibited by potent non-tricyclic inhibitors of the serotonin transporter such as paroxetine and fluoxetine but also by the tricyclic antidepressant drugs clomipramine and desipramine. Therefore, it is concluded that [3H]imipramine labels serotonin uptake sites localized on porcine brain microvessels.

Sources of radiochemical impurities in the 99mTc/S-unprotected MAG3 system.

With the aim of obtaining a general insight into the technetium/S-unprotected MAG3 system, the reactions of technetium with the unprotected MAG3 ligand, both at c.a.- and n.c.a.-level, were investigated. Based on a profound knowledge of the reaction route and the TcMAG3 complexes, sources of by-products were identified and eliminated as far as possible. Only a small percentage (< 5%) of intermediate Tc-MAG3 complexes occurs, but this may increase by improper handling of the kit, such as insufficient reaction time. In conclusion, two kinds of impurity may occur in the Tc/MAG3 kit: One is derived from impurities in the ligand (MAG3 disulphide), which can be excluded by careful preparation and storage. The other is caused by insufficient reaction time according to the scheme (Fig. 3) during the labelling procedure. Its content can be minimized by optimization of the reaction time. A reaction time of at least 10 minutes gives about 98% of the renal agent.

Uptake of 169Yb complexes in normal and tumour cells: influence of ligand and metabolic cell activity and stability of cellular association.

For better understanding of the accumulation of trivalent radiometal tracers in tumours, studies of uptake of different 169Yb complexes into cultured normal (V79/4) and tumour (KTCTL-2) cells were performed. Cellular uptake of 169Yb3+ is dependent on both the metabolic activity of the cells and the nature of the ligand used. Uptake of 169Yb3+ from the citrate complex is an active cellular transport process but not tumour-specific. The 169Yb-aminopolycarboxylic acid complexes are taken up via a different, unknown mechanism, and in higher amounts by the tumour cells than by the V79/4 cell line, but the general features of uptake were principally the same with the normal and the tumour cells. Uptake of the complexes studied leads to a stable association of cellular components, which is a good premise for the therapeutic use of trivalent radiometals.

Assessment of the in vitro and in vivo properties of a (99m)Tc-labeled inhibitor of the multidrug resistant gene product P-glycoprotein.

Overexpression of P-glycoprotein (Pgp), which is present in the plasma membrane of various tumor cells and in several normal cell types, contributes to the multidrug resistance (MDR) phenotype of many human cancers. As a prerequisite for therapy, the expression of Pgp must be studied. The available clinical radiopharmaceuticals for studying the expression of Pgp include the lipophilic (99m)Tc cations (sestamibi, tetrofosmin) as well as [(99m)Tc]Q57, [(99m)Tc]Q58, and [(99m)Tc]Q63. Here we describe the in vitro and in vivo properties of the structurally different complex (3-thiapentane-1, 5-dithiolato)[[N-(3-phenylpropyl)-N-2(3-quinazoline-2, 4-dionyl)-ethyl]amino-ethylthiolato¿ oxotechnetium(V) ((99/99m)Tc1) as a potential inhibitor of Pgp. (99)Tc1 enhances the net cell accumulation of Pgp substrates [(3)H]vinblastine, [(3)H]vincristine, [(3)H]colchicine, [(99m)Tc]sestamibi, and [(99m)Tc]tetrofosmin in rat brain endothelial cells (RBE4), an immortalized endothelial cell line that expresses Pgp. In addition, the cell accumulation of (99m)Tc1 could be increased by verapamil and reserpine, which are known Pgp inhibitors. A multitracer approach was used to study the side effects of (99)Tc1 on cell metabolism. The cells were simultaneously incubated with [(99m)Tc]sestamibi, 2-[(18)F]fluoro-2-deoxyglucose ([(18)F]FDG), and various (3)H-labeled tracers. Two-dimensional scatter plots of [(99m)Tc]sestamibi uptake/[(18)F]FDG uptake show typical changes of known Pgp inhibitors including (99)Tc1. The effects of (99)Tc1 on the in vivo distribution of [(99m)Tc]sestamibi and [(18)F]FDG in rats also are comparable with the effects of verapamil, an established Pgp inhibitor and calcium channel blocker. We conclude that (99/99m)Tc1 is a transport substrate and a potential inhibitor of Pgp. Our approach may be useful in the design of further radiotracers with specificity to Pgp.

Technetium(V) and rhenium(V) complexes for 5-HT2A serotonin receptor binding: structure-affinity considerations.

Starting from the lead structure of ketanserin, a prototypic serotonin (5-HT) antagonist, new oxotechnetium(V) and oxorhenium(V) complexes were synthesized that are able to compete with [3H]ketan-serin in receptor-binding assays. To imitate organic 5-HT2 receptor ligands, fragments of ketanserin were combined with chelate moieties. Neutral compounds of the general formula [MOL1L2] (M = Tc, Re; L1 = HS-CH2CH2-S-CH2CH2-SH, N-(2-mercaptophenyl)salicylideneimine, N-(2-mercaptoethyl)-salicylideneimine, 3-(2-([N,N-bis(2-mercapto-S-ethyl)]-amino)ethyl)-2,4-(1H, 3H)-quinazolinedione and L2 = HS-R with R = subst. alkyl) were prepared by common action of a Tc(V) or Re(V) precursor with a mixture of equimolar amounts of a tridentate ligand L1 and a monodentate thiolate L2 bearing fragments of the lead structure. Lipophilic complexes consisting of a small S4 thiolate/thioether chelate unit, protonable nitrogen-containing spacer, and simple benzyl moiety significantly inhibited the specific binding of [3H]ketan-serin with IC50 values between 10 and 50 nM.

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).

Synthesis and autoradiographic evaluation of a novel high-affinity Tc-99m ligand for the 5-HT2A receptor.

The synthesis and in vitro autoradiography of a novel Tc-99m ligand with subnanomolar affinity to the 5-HT2A receptor is reported. The complex combines the 4-(4-fluoro)-benzoyl piperidine portion derived from the 5-HT2A receptor antagonist ketanserin with a neutral oxotechnetium(V) chelate in form of a mixed ligand "3 + 1" unit containing the SNS/S donor set. The analogous rhenium compound has been synthesized as a surrogate for the Tc-99m complex for use in receptor binding assays and for complete structural characterization. In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity toward the 5-HT2A receptor (Ki 0.44 nM for Tc, 0.25 nM for Re). The subnanomolar 5-HT2A receptor binding of the Re complex was confirmed by functional in vitro antagonism of contractile effects evoked by 5-HT in rat arterial tissue. Re 1 inhibited 5-HT-induced, 5-HT2A receptor-mediated contractions of isolated rat tail artery in a competitive fashion and possessed nanomolar affinity (pA2 = 9.08, pA2 representing the negative decadic logarithm of the Re 1/5-HT2A-receptor dissociation constant [mol/L]). Like ketanserin, Re 1 displayed moderate affinity for adrenergic alpha1D (pA2 = 8.23) and histamine H1 receptors (pA2 = 8.00), and was >600-fold up to 10,700-fold less active at several neurotransmitter receptor subtypes. In vitro autoradiographic studies clearly indicate the accumulation of the Tc-99m compound in 5-HT2A-receptor-rich areas of the brain. This enrichment can be blocked by 5-HT2A receptor antagonists such as mianserin and ketanserin and is therefore specific.