The cost of mental disorders: a systematic review.

AIMS: To identify and synthesise the literature on the cost of mental disorders. METHODS: Systematic literature searches were conducted in the databases PubMed, EMBASE, Web of Science, EconLit, NHS York Database and PsychInfo using key terms for cost and mental disorders. Searches were restricted to January 1980-May 2019. The inclusion criteria were: (1) cost-of-illness studies or cost-analyses; (2) diagnosis of at least one mental disorder; (3) study population based on the general population; (4) outcome in monetary units. The systematic review was preregistered on PROSPERO (ID: CRD42019127783). RESULTS: In total, 13 579 potential titles and abstracts were screened and 439 full-text articles were evaluated by two independent reviewers. Of these, 112 articles were included from the systematic searches and 31 additional articles from snowball searching, resulting in 143 included articles. Data were available from 48 countries and categorised according to nine mental disorder groups. The quality of the studies varied widely and there was a lack of studies from low- and middle-income countries and for certain types of mental disorders (e.g. intellectual disabilities and eating disorders). Our study showed that certain groups of mental disorders are more costly than others and that these rankings are relatively stable between countries. An interactive data visualisation site can be found here: https://nbepi.com/econ. CONCLUSIONS: This is the first study to provide a comprehensive overview of the cost of mental disorders worldwide.

New risk markers may change the HeartScore risk classification significantly in one-fifth of the population.

The study aim was to determine whether urine albumin/creatinine ratio (UACR), high-sensitivity C-reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (Nt-proBNP) added to risk prediction based on HeartScore and history of diabetes or cardiovascular disease. A Danish population sample of 2460 individuals was divided in three groups: 472 subjects receiving cardiovascular medication or having history of diabetes, prior myocardial infarction or stroke, 559 high-risk subjects with a 10-year risk of cardiovascular death above 5% as estimated by HeartScore, and 1429 low-moderate risk subjects with estimated risk below 5%. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (CEP) occurred in 204 subjects. CEP was predicted in all three groups by UACR (HRs: 2.1, 2.1 and 2.3 per 10-fold increase, all P<0.001) or by hsCRP (HRs: 1.9, 1.9 and 1.7 per 10-fold increase, all P<0.05), but not by Nt-proBNP (HRs: 1.1, 2.6 and 3.7 per 10-fold increase, last two P<0.001) (P<0.05 for interaction). In the low-moderate risk group, pre-specified gender adjusted (men/women) cutoff values of UACR> or =0.73/1.06 mg mmol(-1) or hsCRP> or =6.0/7.3 mg l(-1) identified a subgroup of 16% who experienced one-third of the CEPs. In the patient group, combined absence of high UACR and high Nt-proBNP> or =110/164 pg ml(-1) (men/women) identified a subgroup of 52% who experienced only 15% of the CEPs. Additional use of UACR and hsCRP in subjects with low-moderate risk and UACR and Nt-proBNP in subjects with known diabetes of cardiovascular disease changed HeartScore risk classification significantly in 19% of the population.

Impact of the metabolic syndrome on the predictive values of new risk markers in the general population.

Although the metabolic syndrome (MetS) is positively associated with high-sensitivity C-reactive protein (hsCRP), negatively associated with N-terminal pro-brain natriuretic peptide (Nt-proBNP) and inconsequently related to urine albumin/creatinine ratio (UACR) they are all associated with cardiovascular events. Therefore, we wanted to determine the influence of MetS on the predictive values of UACR, hsCRP and Nt-proBNP. On the basis of the definition of MetS by the International Diabetes Federation, a Danish population sample of 1983 apparently healthy subjects was divided into three groups: 530 subjects without any elements of MetS, 1093 subjects with some elements of MetS and 360 subjects with MetS. During the following 9.5 years the composite end point of cardiovascular death, non-fatal myocardial infarction or stroke (composite cardiovascular end point, CEP) occurred in 204 subjects. In Cox-regression analyses adjusting for age, gender and smoking, all three cardiovascular risk markers predicted CEP independently of MetS. Despite no significant interaction with MetS, high log(hsCRP) was associated with CEP primarily in subjects without any elements of MetS (hazard ratio (HR)=4.5 (1.5-14.0), P<0.01), log(Nt-proBNP) primarily in subjects with some elements of MetS (HR=3.0 (1.6-5.6), P<0.01), and logUACR independently of elements of MetS. Pre-specified gender-adjusted (men/women) cutoff values of hsCRP > or = 6.0/7.3 mg l(-1) predicted CEP in subjects without elements of MetS with positive and predictive values of 11.5 and 98%, respectively. UACR > or = 0.73/1.06 mg mmol(-1) predicted CEP in subjects with MetS with positive and predictive values of 23.5 and 93%, respectively. In apparently healthy subjects, high hsCRP was associated with CEP primarily in subjects without MetS, high Nt-proBNP in subjects with elements of MetS and UACR independently of MetS.

Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy.

Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured sitting BP, serum collagen type I carboxy-terminal telopeptide (ICTP) reflecting degradation, procollagen type I carboxy-terminal propeptide (PICP) reflecting synthesis and LV mass by echocardiography after 2 weeks of placebo treatment and after 1 year of antihypertensive treatment with a losartan- or an atenolol-based regimen. Furthermore, we measured intima-media thickness of the common carotid arteries (IMT), minimal forearm vascular resistance (MFVR) by plethysmography and ambulatory 24-h BP in around half of the patients. At baseline, PICP/ICTP was positively related to IMT (r=0.24, P<0.05), MFVR(men) (r=0.35, P<0.01), 24-h systolic BP (r=0.24, P<0.05) and 24-h diastolic BP (r=0.22, P<0.05), but not to LV mass. After 1 year of treatment with reduction in systolic BP (175+/-15 vs 151+/-17 mmHg, P<0.001) and diastolic BP (99+/-8 vs 88+/-9 mmHg, P<0.001), ICTP was unchanged (3.7+/-1.4 vs 3.8+/-1.4 microg/l, NS) while PICP (121+/-39 vs 102+/-29 microg/l, P<0.001) decreased. The reduction in PICP/ICTP was related to the reduction in sitting diastolic BP (r=0.31, P<0.01) and regression of IMT (r=0.37, P<0.05) in patients receiving atenolol and to reduction in heart rate in patients receiving losartan (r=0.30, P<0.01). In conclusion, collagen markers reflecting net synthesis of type I collagen were positively related to vascular hypertrophy and BP load, suggesting that collagen synthesis in the vascular wall is increased in relation to high haemodynamic load in a reversible manner.

Zinc-containing afferent projections to the rat corticomedial amygdaloid complex: a retrograde tracing study.

The mammalian amygdaloid complex is densely innervated by zinc-containing neurons. The distribution of the terminals throughout the region has been described, but the origins of these zinc-containing fibers have not. The present work describes the origins of one major component of the zinc-containing innervation of the amygdaloid complex, namely, the component that innervates the corticomedial complex. Selective labeling of zinc-containing axons was accomplished by intracerebral microinfusion of selenium anions (SeO3(2-)), a procedure that produces a ZnSe precipitate in zinc-containing axonal boutons with subsequent retrograde transport to the neurons of origin. After infusions of SeO3(2-) into combinations of cortical, medial, or amygdalohippocampal regions, retrogradely labeled zinc-containing somata were found in all amygdaloid nuclei except for the medial and central nuclei, the bed nucleus of the accessory olfactory tract, the nucleus of the lateral olfactory tract, and the anterior amygdaloid area. Extrinsic zinc-containing projections to the same amygdaloid terminal fields were found to originate from the infralimbic, cingulate, piriform, perirhinal and entorhinal cortices, and from the prosubiculum and CA1. Commissural zinc-containing projections were found to originate from the posterolateral and posteromedial cortical nuclei and from the posterior part of the basomedial nucleus. Zinc-containing neurons have been implicated in the pathophysiology of epilepsy, in cell death after seizure or stroke, and in Alzheimer's disease, all clinical conditions that involve the amygdaloid complex. Identification of the zinc-containing pathways is a prerequisite to the elucidation of zinc's role in these disorders.

Retrograde tracing of zinc-containing neurons by selenide ions: a survey of seven selenium compounds.

The autometallographic retrograde tracing of zinc-containing neurons by intracerebral injection of sodium selenite (Na2SeO3), introduced by Danscher in 1982, has recently been described in more detail. Intracerebral injections of both sodium selenide (Na2Se) and sodium selenite (Na2SeO3) have been successfully used; however, sodium selenite had a rather toxic effect on the injected tissue. In the present study, we tested seven different selenium compounds to find the most suitable compound for retrograde tracing of zinc-positive pathways. Among the tested compounds, sodium selenide (Na2Se) caused insignificant necrosis within the injection site and was easily transported retrogradely when handled anaerobically. Sodium selenide is therefore recommended as the compound of choice.

Callosal neurones give rise to zinc-rich boutons in the rat visual cortex.

Sodium selenide was used as a retrograde tracer to assess the callosal origin of zinc-rich boutons in the neocortex of the rat. Selenide injections were placed in the lateral end of area Oc1 (area 17). Zinc present in synaptic boutons precipitated as zinc selenide and was transported retrogradely to the parent cell bodies. In addition to the ipsilateral labelling, contralateral retrogradely labelled somata were mainly observed along the border between areas Oc1 and Oc2L (area 18a). Labelled neurones were present in layer 2-3 and layer 6. In contrast to tracing studies with peroxidase, no labelled neurone was observed in layers 4 and 5 except at the inner border of layer 5. This study reveals the chemical heterogeneity of callosal projections, which may be divided into zinc-rich and zinc-poor systems.

Distribution of neurons of origin of zinc-containing projections in the amygdala of the rat.

The present study describes the distribution of neurons of origin of zinc-containing pathways in the amygdaloid complex of the rat, using the selenium method for simultaneous retrograde labeling of all zinc-containing neurons. With this method, vesicular ionic zinc is precipitated intravitally with selenium compounds and transported retrogradely to the parent neurons, where it can be visualized by silver amplification. Neurons labeled retrogradely with silver-amplified precipitate were observed in all amygdaloid nuclei except for the lateral olfactory tract nucleus, the accessory olfactory tract nucleus and the central nucleus. Very few labeled cell bodies were seen in the anterior amygdaloid area and the medial nucleus. The amygdalo-hippocampal area and the amygdalo-piriform transition area both showed a substantial number of labeled somata throughout their rostrocaudal extent. In the anterior cortical nucleus, very few labeled cell bodies were found in the rostral pole, whereas they were abundant in the caudal quarter of the nucleus. In the posterolateral cortical nucleus, the number of labeled cell bodies increased gradually; there were none in the rostral pole, but most of the neurons in the caudal part were labeled. The posteromedial cortical nucleus contained a great number of labeled somata, but with some variation in the rostrocaudal extent of the nucleus. Considerable numbers of labeled neurons were observed throughout the lateral nucleus. In the basolateral nucleus, a small number of labeled cell bodies was present in the rostral half, but a gradual increase was observed in the caudal direction. Finally, in the basomedial nucleus, very few labeled cell bodies were present in the rostral two-thirds, whilst a considerable number was encountered in the caudal one-third. Possible functional implications of neuronal zinc are considered. The distribution of neurons of origin of zinc-containing projections has been compared with previously described intrinsic connections of the rat amygdala, and tracts that may possibly be zinc-containing are outlined and discussed. It is concluded that in all probability a substantial proportion of the intrinsic connectivity of the rat amygdaloid complex is zinc-containing.

High mass resolution time of flight mass spectrometer for measuring products in heterogeneous catalysis in highly sensitive microreactors.

We demonstrate a combined microreactor and time of flight system for testing and characterization of heterogeneous catalysts with high resolution mass spectrometry and high sensitivity. Catalyst testing is performed in silicon-based microreactors which have high sensitivity and fast thermal response. Gas analysis is performed with a time of flight mass spectrometer with a modified nude Bayard-Alpert ionization gauge as gas ionization source. The mass resolution of the time of flight mass spectrometer using the ion gauge as ionization source is estimated to m/Δm > 2500. The system design is superior to conventional batch and flow reactors with accompanying product detection by quadrupole mass spectrometry or gas chromatography not only due to the high sensitivity, fast temperature response, high mass resolution, and fast acquisition time of mass spectra but it also allows wide mass range (0-5000 amu in the current configuration). As a demonstration of the system performance we present data from ammonia oxidation on a Pt thin film showing resolved spectra of OH and NH(3).

Antinociceptive effects of the stereoisomers of nicotine given intrathecally in spinal rats.

Spinalized rats received an intrathecal injection of either (-)-nicotine or (+)-nicotine in order to study the stereoselectivity of antinociception. Pain threshold was measured using the tail-flick test. Both stereoisomers had anti-nociceptive effects, but (-)-nicotine was up to 970 times more potent, depending on test conditions. The antinociceptive action of (-)-nicotine was antagonized by mecamylamine and yohimbine but not by naloxone and atropine. The findings show that spinal mechanisms are highly stereoselective toward nicotine, and suggest that primarily nicotinergic and alpha-adrenergic receptors are involved in its central antinociceptive effects.

Mercury in the rat hypothalamic arcuate nucleus and median eminence after mercury vapor exposure.

A histochemical technique has been used to reveal mercury deposits in the hypothalamic arcuate nucleus and median eminence of adult male rats. After exposure to long-term, low-level or short-term, high-level mercury vapor, silver-enhanced mercury grains were found in neurons of the arcuate nucleus. In addition mercury deposits were found in tanycytes, ciliated ependymal cells, and in the walls of capillaries. The mechanisms underlying uptake and possible induction of toxic effects are discussed.

Extradural anaesthesia for repeated surgical treatment in the presence of infection.

The use of extradural catheters in patients with systemic or localized infection is controversial. The catheter may act as a focus for secondary infection resulting in an extradural abscess. in this study we have examined the use of extradural catheters for anaesthesia over the past 7 yr in patients with localized infections. The records of 69 patients were reviewed and patients interviewed (letter/phone). These patients had a total of 120 extradural catheters placed and received, on average, four anaesthetics, with the extradural catheter remaining in place for a mean of 9 days. On 12 occasions (eight patients) the catheter was removed because of signs or symptoms of local infection. Specific antibiotic therapy was not initiated, but ongoing therapy was continued. A single case of spondylitis was the only serious complication found but was not related to the extradural technique. We conclude that extradural anaesthesia for patients who require repeated surgical treatments for abscesses or infected wound is a relatively safe procedure.

Constrained glycopeptide ligands for MPRs. Limitations of unprotected phosphorylated building blocks.

A new methodology for the synthesis of cyclic and phosphorylated glycopeptide templates was developed. First, fully protected building blocks containing mannose and mannose disaccharides with bis-trichloroethyl phosphate on Fmoc-Thr-OPfp were synthesized. These were used in solid-phase assembly through side chain anchoring of glycosylated hexa- and octa-peptides protected at the C-terminal carboxylate as the allyl ester. Selective allyl ester cleavage and head-to-tail cyclization under pseudodilution conditions gave a high yield of pure cyclic peptide templates. Unprotected phosphate in the building block was evaluated as an alternative to the problematic trichloroethyl group. It was found that one unprotected phosphate is readily incorporated, whereas the second unprotected phosphorylated building block react very slowly due to electrostatic repulsion in the solid-phase synthesis. For comparison with previous binding studies modified glycopeptide templates containing only phosphorylated mannose monosaccharides or templates modified in the peptide part were synthesized. All the structures were tested for their binding to the mannose 6-phosphate receptor, and it was found that although mannose disaccharides are required for optimal interaction, the detailed structure of the peptide template has a strong influence on binding to the receptor. The restricted conformations of the cyclic peptides decreased the binding considerably.