Trends in psychiatric diagnoses, medications and psychological therapies in a large Swedish region: a population-based study.

BACKGROUND: Health services utilization for mental health disorders is reported to increase sharply in many countries. The aim of this study was to report trends in all aspects of mental health care utilization in a total population sample. METHODS: Repeated cross-sectional register study of the Stockholm Region (VAL) including both primary and secondary care. Trends in the proportion of adults in the total population of Stockholm Region with a recorded ICD-10 psychiatric diagnosis or psychological therapy during 2007-2017 as well as claims of psychiatric medication from 2011 were calculated. RESULTS: The proportion of adults utilizing any mental health care increased from 13.2% in 2011 to 16.1% in 2017. In 2017, 49.3% were treated in primary care, 32.2% in secondary care and 18.5% were jointly managed. The increase was most pronounced in younger adults. Women were more likely to receive mental health care than men in all ages. Medication decreased from 71.0 to 67.7%, while psychological therapy increased from 33.1 to 37.6%. The use of psychiatric medication increased with age while psychological therapy decreased. All time trends were statistically significant (p < .0001). CONCLUSION: Care for mental health disorders has been increasing mainly in primary care and was delivered to one in seven adult individuals in 2017. Interventions are needed to address the growing burden of mental health disorders while avoiding overtreatment.

Comparing cohort incidence of schizophrenia with that of bipolar disorder and affective psychosis in individuals born in Stockholm County 1955-1967.

BACKGROUND: Perinatal factors are associated with increased risk for both schizophrenia and bipolar disorder. Improvements in obstetric and maternal healthcare and positive socioeconomic development in Sweden from the 1950s onwards could be expected to affect incidence estimates. However, commonly incidence rates are calculated during a specific year, i.e. time of diagnosis, which mirrors proximal precipitating risk factors. To examine whether incidence estimates are compatible with the hypothesis of an impact of perinatal exposures on the risk of the different disorders we here instead calculate incidence rates for consecutive birth cohorts born between 1955 and 1967. We hypothesized that schizophrenia incidence would be more affected compared to bipolar disorder and other affective psychoses since most perinatal risk factors are more pronounced in schizophrenia aetiology. METHOD: Birth cohorts of individuals born in Sweden and resident in Stockholm (N = 2,16,322), were followed in The National Patient Register regarding incident inpatient episodes Incident cases/10,000 person-years and birth cohort were calculated. Linear regression was used to estimate change in incidence rate. RESULTS: We found stable birth cohort-based incidence estimates for bipolar disorder and other affective psychoses, but a continuous reduction in incidence estimates for schizophrenia as well as other non-affective psychoses in subsequent birth cohorts from 1955 to 1967. CONCLUSIONS: The consecutive birth cohort-based incidence estimates unveiled patterns that are compatible with the hypothesis of an impact of early life exposures decreasing over time, in the aetiology of schizophrenia, whereas this pattern is less apparent in affective psychoses..

Testing Ødegaard's selective migration hypothesis: a longitudinal cohort study of risk factors for non-affective psychotic disorders among prospective emigrants.

BACKGROUND: The selection hypothesis posits that the increased rates of psychosis observed among migrants are due to selective migration of people who are predisposed to develop the disorder. To test this hypothesis, we examined whether risk factors for psychosis are more prevalent among future emigrants. METHOD: A cohort of 49,321 Swedish military conscripts was assessed at age 18 years on cannabis use, IQ, psychiatric diagnosis, social adjustment, history of trauma and urbanicity of place of upbringing. Through data linkage we examined whether these exposures predicted emigration out of Sweden. We also calculated the emigrants' hypothetical relative risk compared with non-emigrants for developing a non-affective psychotic disorder. RESULTS: Low IQ [odds ratio (OR) 0.5, 95% confidence interval (95% CI) 0.3-0.9] and 'poor social adjustment' (OR 0.4, 95% CI 0.2-0.8) were significantly less prevalent among prospective emigrants, whereas a history of urban upbringing (OR 2.3, 95% CI 1.4-3.7) was significantly more common. Apart from a non-significant increase in cannabis use among emigrants (OR 1.6, 95% CI 0.8-3.1), there were no major group differences in any other risk factors. Compared to non-emigrants, hypothetical relative risks for developing non-affective psychotic disorder were 0.7 (95% CI 0.4-1.2) and 0.8 (95% CI 0.7-1.0), respectively, for emigrants narrowly and broadly defined. CONCLUSIONS: This study adds to an increasing body of evidence opposing the selection hypothesis.

Potency determination of factor VIII and factor IX for new product labelling and postinfusion testing: challenges for caregivers and regulators.

A workshop organized by the European Medicines Agency and the European Directorate for the Quality of Medicines and HealthCare was held in London, UK on November 28-29, 2013, to provide an overview of the current knowledge of the characterization of new factor VIII (FVIII) and factor IX (FIX) concentrates with respect to potency assays and testing of postinfusion material. The objective was to set the basis for regulatory authorities' discussion on the most appropriate potency assay for the individual products, and European Pharmacopoeia (Ph. Eur.) discussion on whether to propose revision of the Ph. Eur. monographs with respect to potency assays in the light of information on new FVIII and FIX concentrates. The workshop showed that for all products valid assays vs. the international concentrate standards were obtained and potency could be expressed in International Units. The Ph. Eur. chromogenic potency assay gave valid assay results which correlate with in vivo functionality of rFVIII products. For some modified rFVIII products and all modified rFIX products, one-stage clotting assay methods result in different potencies depending on the activated partial thromboplastin time reagent. As a consequence, monitoring of patients' postinfusion levels is challenging but it was pointed out that manufacturers are responsible for providing the users with appropriate information for use and laboratory testing of their product. Strategies to avoid misleading determination of patents' plasma levels, e.g. information on suitable assays, laboratory standards or correction factors were discussed.

Inhibition of carnitine palymitoyltransferase1b induces cardiac hypertrophy and mortality in mice.

Recent reports suggest that short-term pharmacological carnitine palmitoyltransferase 1 (Cpt1) inhibition improves skeletal muscle glucose tolerance and insulin sensitivity. Although this appears promising for the treatment of diabetes, these Cpt1 inhibitors are not specific to skeletal muscle and target multiple Cpt1 isoforms. To assess the effects of inhibiting the Cpt1b isoform we generated mice with a heart- and skeletal muscle-specific deletion of the Cpt1b, Cpt1b(HM-/-). These mice seem to develop normally with similar bodyweights as control mice. However, premature mortality was observed by 15 weeks of age in the Cpt1b(HM-/-) mice. The hearts of Cpt1b(HM-/-) mice were four times the size of controls. Cpt1b(HM-/-) mice were also subject to stress-induced seizures that accompanied an increased risk for premature mortality. Our data suggests that prolonged Cpt1b inhibition poses severe cardiac risk and emphasizes that attempts to improve insulin sensitivity by targeting Cpt1 with current inhibitors is not viable.

Artemisia dracunculus L. extract ameliorates insulin sensitivity by attenuating inflammatory signalling in human skeletal muscle culture.

AIMS: Bioactives of Artemisia dracunculus L. (termed PMI 5011) have been shown to improve insulin action by increasing insulin signalling in skeletal muscle. However, it was not known if PMI 5011's effects are retained during an inflammatory condition. We examined the attenuation of insulin action and whether PMI 5011 enhances insulin signalling in the inflammatory environment with elevated cytokines. METHODS: Muscle cell cultures derived from lean, overweight and diabetic-obese subjects were used. Expression of pro-inflammatory genes and inflammatory response of human myotubes were evaluated by real-time polymerase chain reaction (RT-PCR). Insulin signalling and activation of inflammatory pathways in human myotubes were evaluated by multiplex protein assays. RESULTS: We found increased gene expression of monocyte chemoattractant protein 1 (MCP1) and TNFα (tumour necrosis factor alpha), and basal activity of the NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway in myotubes derived from diabetic-obese subjects as compared with myotubes derived from normal-lean subjects. In line with this, basal Akt phosphorylation (Ser473) was significantly higher, while insulin-stimulated phosphorylation of Akt (Ser473) was lower in myotubes from normal-overweight and diabetic-obese subjects compared with normal-lean subjects. PMI 5011 treatment reduced basal phosphorylation of Akt and enhanced insulin-stimulated phosphorylation of Akt in the presence of cytokines in human myotubes. PMI 5011 treatment led to an inhibition of cytokine-induced activation of inflammatory signalling pathways such as Erk1/2 and IkBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha)-NFkB and moreover, NFkB target gene expression, possibly by preventing further propagation of the inflammatory response within muscle tissue. CONCLUSIONS: PMI 5011 improved insulin sensitivity in diabetic-obese myotubes to the level of normal-lean myotubes despite the presence of pro-inflammatory cytokines.

Hearing and speech impairment at age 4 and risk of later non-affective psychosis.

BACKGROUND: Schizophrenia often becomes manifest in late adolescence and young adulthood but deviations in physical and behavioural development may already be present in childhood. We investigated the relationship between hearing impairment (measured with audiometry) and speech impairment (broadly defined) at age 4 years and adult risk of non-affective psychosis. METHOD: We performed a population-based, case­control study in Sweden with 105 cases of schizophrenia or other non-affective psychoses and 213 controls matched for sex, date and place of birth. Information on hearing and speech impairment at age 4, along with potential confounding factors, was retrieved from Well Baby Clinic (WBC) records. RESULTS: Hearing impairment [odds ratio (OR) 6.0, 95% confidence interval (CI) 1.6­23.2] and speech impairment (OR 2.6, 95% CI 1.4­4.9) at age 4 were associated with an increased risk of non-affective psychotic illness. These associations were mutually independent and not explained by parental psychiatric history, occupational class or obstetric complications. CONCLUSIONS: These results support the hypothesis that psychosis has a developmental aspect with presentation of antecedent markers early in childhood, long before the disease becomes manifest. Our findings add to the growing evidence that early hearing impairment and speech impairment are risk indicators for later non-affective psychosis and possibly represent aetiological clues and potentially modifiable risk factors. Notably, speech impairment and language impairment are both detectable with inexpensive, easily accessible screening.

Rapid gene mapping in Caenorhabditis elegans using a high density polymorphism map.

Single nucleotide polymorphisms (SNPs) are valuable genetic markers of human disease. They also comprise the highest potential density marker set available for mapping experimentally derived mutations in model organisms such as Caenorhabditis elegans. To facilitate the positional cloning of mutations we have identified polymorphisms in CB4856, an isolate from a Hawaiian island that shows a uniformly high density of polymorphisms compared with the reference Bristol N2 strain. Based on 5.4 Mbp of aligned sequences, we predicted 6,222 polymorphisms. Furthermore, 3,457 of these markers modify restriction enzyme recognition sites ('snip-SNPs') and are therefore easily detected as RFLPs. Of these, 493 were experimentally confirmed by restriction digest to produce a snip-SNP map of the worm genome. A mapping strategy using snip-SNPs and bulked segregant analysis (BSA) is outlined. CB4856 is crossed into a mutant strain, and exclusion of CB4856 alleles of a subset of snip-SNPs in mutant progeny is assessed with BSA. The proximity of a linked marker to the mutation is estimated by the relative proportion of each form of the biallelic marker in populations of wildtype and mutant genomes. The usefulness of this approach is illustrated by the rapid mapping of the dyf-5 gene.

Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II.

Members of the transforming growth factor beta (TGF-beta) family transduce signals through Smad proteins. Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin. Here we report that Smad-TGF-beta-dependent transcriptional responses are prevented by expression of a constitutively activated Ca(2+)-calmodulin-dependent protein kinase II (Cam kinase II). Smad2 is a target substrate for Cam kinase II in vitro at serine-110, -240, and -260. Cam kinase II induces in vivo phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3. A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed with Cam kinase II and by activation of the platelet-derived growth factor receptor, the epidermal growth factor receptor, HER2 (c-erbB2), and the TGF-beta receptor. Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation, while preventing TGF-beta-dependent Smad2-Smad3 interactions. These findings provide a novel cross-talk mechanism by which Ca(2+)-dependent kinases activated downstream of multiple growth factor receptors antagonize cell responses to TGF-beta.

Menopause in Latin America: Symptoms, attitudes, treatments and future directions in Costa Rica.

Similar to their US counterparts, Costa Rican women enter menopause at ∼50 years of age, have similar symptoms, including hot flashes and night sweats, as well as an overall negative attitude toward the menopausal transition. One study of rural women in Monteverde reported that women knew little about the menopausal transition, as the subject was not discussed. Similar to other Latin American women, the use of hormone therapy by Costa Rican women is low and instead they use alternative therapies, including massage, dietary changes and herbal medicines. A wide variety of herbal therapies are used, and some of these herbs have estrogenic activities in vitro. However, clinical data on the safety and efficacy of any of these treatments is lacking. Recently, a disturbing increase in the incidence of human papilloma virus infections in menopausal women has been reported, due in part to more sexual freedom after menopause. Fortunately, the strain of HPV infecting these women is not associated with cervical cancer. Overall, there is a significant lack of scientific and medical research on menopausal women in Costa Rica. Considering the aging population, the high use of herbal medicines by menopausal women and the lack of clinical studies on these treatments, future research should focus on gaining a better understanding of menopause in this population. Furthermore, new educational programs for these women and the health professionals who serve them are necessary, as well as investigations of the safety and efficacy of the herbal supplements women use to manage their menopausal symptoms.

Elaborating European Pharmacopoeia monographs for biotherapeutic proteins using substances from a single source.

For more than twenty years, the European Pharmacopoeia (Ph. Eur.) monographs for biotherapeutic proteins have been elaborated using the multisource approach (Procedure 1), which has led to robust quality standards for many of the first-generation biotherapeutics. In 2008, the Ph. Eur. opened up the way towards an alternative mechanism for the elaboration of monographs (Procedure 4-BIO pilot phase), which is applied to substances still under patent protection, based on a close collaboration with the Innovator company, to ensure a harmonised global standard and strengthen the quality of the upcoming products. This article describes the lessons learned during the P4-BIO pilot phase and addresses the current thinking on monograph elaboration in the field of biotherapeutics. Case studies are described to illustrate the standardisation challenges associated with the complexity of biotherapeutics and of analytical procedures, as well as the approaches that help ensure expectations are met when setting monograph specifications and allow for compatibility with the development of biosimilars. Emphasis is put on monograph flexibility, notably by including tests that measure process-dependent microheterogeneity (e.g. glycosylation) in the Production section of the monograph. The European Pharmacopoeia successfully concluded the pilot phase of the P4-BIO during its 156th session on 22-23 November 2016.

Mutations of the caenorhabditis elegans brain-specific inorganic phosphate transporter eat-4 affect habituation of the tap-withdrawal response without affecting the response itself.

The studies reported here were designed to investigate the role of the mutation eat-4 in the response to tap and in habituation in the nematode Caenorhabditis elegans. In C. elegans eat-4 has been found to affect a number of glutamatergic pathways. It has been hypothesized to positively regulate glutaminase activity and therefore glutamatergic neurotransmission. In the eat-4(ky5) loss-of-function worms, there is presumably insufficient glutamate available for sustained transmission. In the experiments reported here eat-4 worms showed no differences from wild-type in the magnitude of response to a single tap, indicating that the neural circuit underlying the response was intact and functional in the mutant worms. However, when eat-4 worms were given repeated taps the resulting habituation was different from that seen in wild-type worms: eat-4 worms habituate more rapidly and recover more slowly than wild-type worms at all interstimulus intervals tested. In addition, eat-4 worms do not show dishabituation. The same transgene rescues pharyngeal activity defects and both the habituation and dishabituation deficits seen in the eat-4 worms. Our results suggest that neurotransmitter regulation plays a role in habituation and may play a role in dishabituation.

Effects of tap withdrawal response habituation on other withdrawal behaviors: the localization of habituation in the nematode Caenorhabditis elegans.

Four experiments were conducted to identify the possible loci of habituation of the nematode tap withdrawal response (TWR) by characterizing the effects of TWR habituation on other nonmechanosensory withdrawal behaviors that are mediated by overlapping sets of neurons. Experiments 1-2 established behavioral and anatomical relationships between spontaneous and tap-induced backward locomotion in the worm. Experiment 3 demonstrated that habituation of the TWR affected neither the magnitude nor frequency of spontaneous reversal activity. Experiment 4 extended this result to an evoked response: Habituation of the TWR had no effect on reversals evoked by a thermal stimulus. These studies, which show that the loci of change associated with habituation of the TWR are presynaptic to the interneurons and motor neurons that control locomotion, probably distributed among the mechanosensory neurons, illustrate that a complete understanding of plasticity requires a knowledge of both the anatomical and molecular substrates of change.

Recovery from habituation in Caenorhabditis elegans is dependent on interstimulus interval and not habituation kinetics.

The habituation of the tap withdrawal reflex of Caenorhabditis elegans was assessed to determine whether the kinetics of recovery from habituation were dependent on the interstimulus interval (ISI) used during habituation training, or alternately, on the rate and asymptotic level of habituation produced at a given ISI. Two groups of intact animals were trained at either a 10-s (CON10) or a 60-s (CON60) ISI. Laser ablation was used to alter the habituation kinetics in one further group of animals (PLM10), independent of ISI. Although the PLM10 animals trained at a 10-s ISI habituated like CON60 worms, the recovery from habituation of the PLM10 animals very closely resembled the recovery of the CON10 worms. Thus recovery kinetics are dictated by consequences of a given ISI, which do not impact upon habituation rate and asymptote. This suggests the recruitment of multiple ISI-dependent processes during habituation in C. elegans.

Time trends in first admissions for schizophrenia and paranoid psychosis in Stockholm County, Sweden.

Several studies have reported decreasing time trends in first diagnosed schizophrenia patients. The aim of this study was to analyze time trends for first admissions with a diagnosis of schizophrenia or a diagnosis of either schizophrenia or paranoid psychosis during 1978-1994 in Stockholm County, Sweden, with a population of around 1.8million. Information about first psychiatric admission with the diagnosis schizophrenia or paranoid psychosis for residents of Stockholm County was obtained from the Swedish population-based psychiatric inpatient register. Age-adjusted average yearly changes in first hospitalization rates were estimated in a Poisson regression model. Time trends in first admission rates were calculated from 1978 to 1994, while admissions during 1971 to 1977 were observed only to eliminate later re-admissions. First admissions for schizophrenia declined by 1.9% annually for females and by 1.3% for males, while first admissions for schizophrenia and paranoid psychosis together were unchanged over the study period for both genders. Our results indicate that the incidence of schizophrenia and paranoid psychosis taken together was essentially the same over the studied time period in Stockholm County, and that the apparent decline in first admission rates for schizophrenia may be an effect of changes in clinical diagnosis over time.

Activation of the NMDA receptor: a correlate in the dentate gyrus field potential and its relationship to long-term potentiation and kindling.

Stimulation trains, but not stimulation pulses, are capable of inducing long-term potentiation (LTP). In this paper we report experiments designed to examine, in chronic preparations, the characteristics of a component unique to the train-evoked response. Stimulation trains applied to the perforant path evoked population EPSP's and population spikes in the dentate gyrus that were nearly identical to those evoked by single pulses of comparable intensity. The trains also triggered a prolonged potential, negative at the dendritic pole of our electrodes, which far outlasted the pulse-evoked response. We substracted pulse-evoked responses from these train-evoked responses which left us with a waveform that peaked at about 15 ms and lasted for about 50-70 ms. The GABA agonists, diazepam and sodium pentobarbital, had no significant effect on this component, but the NMDA antagonists, ketamine and MK-801, both depressed it by over 30%. The late component had a very low threshold, which might account for the frequent observation of LTP induction at very low thresholds. Also, the late component is reliably seen in all animals showing LTP, even in the occasional animals that show no population spikes. The late component did not appear to be affected by the induction of LTP, and was either not affected or was depressed following the completion of kindling. When the 'NMDA-component' of the train-evoked response was monitored, along with LTP, in an ascending intensity train series, it was found that both the NMDA-component and the LTP increased smoothly. There was no sudden appearance of the NMDA-component at the LTP threshold. The presence of an NMDA component in the field potential of the chronic preparation allows the monitoring of the levels of NMDA activation over prolonged periods.

Effect of formulation on the pharmacokinetics and efficacy of doramectin.

The pharmacokinetics of doramectin, a novel avermectin, were evaluated following parenteral administration in a range of oil-based formulations in an attempt to optimise the formulation. Therapeutic and persistent efficacies against Cooperia oncophora were also evaluated. This approach led to the identification of formulations based upon sesame oil and ethyl oleate which gave more prolonged doramectin plasma concentrations with no loss in therapeutic efficacy and improved persistent efficacy following subcutaneous administration to cattle at a dosage of 200 micrograms kg-1. The importance of using both pharmacokinetic and efficacy end points to distinguish between formulations is discussed. All formulations were well tolerated as evidenced by the absence of any reaction to injection either in the form of behavioural responses, injection site swelling or postmortem lesions. Sesame oil with ethyl oleate was the best parenteral vehicle tested for doramectin, allowing the expression of a high level of therapeutic and persistent efficacy and offering the benefit of excellent injection site toleration.

Doramectin--a potent novel endectocide.

Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.

Factors Affecting the Short-Term Prognosis of Alcohol Dependent Patients Undergoing Inpatient Detoxification.

Stable measures of psychological functioning require a considerable period of abstinence. However, the duration of inpatient detoxification programs has decreased dramatically in most health care systems, posing a novel challenge for clinical evaluation of patients. The present study was carried out to examine whether factors predicting short-term prognosis can be identified in alcohol dependent subjects during early stages of inpatient detoxification. Self-reports of mood states were obtained, and executive cognitive functioning was examined. Outcome was studied at 2-3 months. No correlation was found between self-reported symptoms of depression, hopelessness, and anxiety, and percentage of nondrinking days. A significant positive correlation was found between Wisconsin Card Sorting Test (WCST) performance and short-term prognosis measured by this parameter. Thus, in addition to transient withdrawal-related effects, impairments of WCST performance in early stages of alcohol detoxification may reflect more long standing deficits in problem-solving strategies, of possible relevance for matching patients to treatment services.

Stress in air traffic personnel: low-density towers and flight service stations.

Stress and anxiety levels were measured in 10 air traffic control specialists (ATCS) at two low traffic-density towers in Fayetteville (FYV), Ar, and Roswell (ROW), NM, and in 24 flight service (FS) specialists at those airports and at Okalhoma City (OKC), Ok. Physiological measurements consisted of heart rate and urine biochemical analysis for 17-ketogenic steroids, epinephrine, and norepinephrine. On-duty arousal in ATCSs and FS specialists was evident both physiologically and psychologically; such arousal was within psychologically normal limits and was generally low physiologically compared to other air traffic control (ATC) facilities studied in the past. Physiological stress levels at these low-density towers and flight service stations were also low compared to other ATC facilities studied previously. Therefore, it is inappropriate to describe all air traffic control work, as is commonly done in the popular press, as unusually stressful. Such accounts in the popular press tend to deal with the exceptional, rather than with the typical, controller or facility.