Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice.

BACKGROUND: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. METHODS: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. RESULTS: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. LIMITATIONS: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology. CONCLUSION: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.

Regional inequality and vaccine uptake: a multilevel analysis of the 2007 Welfare Monitoring Survey in Malawi.

BACKGROUND: A significant part of childhood mortality can be prevented given the existence of a well functioning health care system that can deliver vaccines to children during their first year of life. This study assesses immunization differentials between regions in Malawi, and attempts to relate regional disparities in immunization to factors on individual, household and village level. METHOD: We used data from the 2007 Welfare Monitoring Survey which includes 18 251 children ages 10-60 months. Multilevel logistic regression models were applied for data analysis. RESULTS: Major differences in full vaccine coverage (children receiving all of the 9 recommended vaccines) were documented between the 27 official regions, called districts, of Malawi. The vaccine coverage among regions varied from 2% to 74% when all children 10 - 60 months old were included. Vaccine coverage was significantly higher for women that had their delivery attended by a midwife/nurse, or gave birth at a hospital or maternity clinic. Regions with a high percentage of deliveries attended by health personnel were also characterized by a higher coverage. Characteristics of health care utilization on the individual level could in part account for the observed regional variations in coverage.Several factors related to socio-demographic characteristics of individuals and households were significantly correlated with coverage (child's age, illiteracy, income, water and sanitary conditions), implying a lower coverage among the most vulnerable parts of the population. However, these factors could only to a minor extent account for the regional variation in coverage. CONCLUSIONS: The persistent regional inequalities suggest that the low immunization coverage in Malawi is less likely to be a result of geographical clustering of social groups with difficult level-of living conditions. Although the mean vaccine coverage in Malawi is low, some regions have succeeded in reaching a relatively high proportion of their children. The relative success of some regions implies that there is a substantial potential for political intervention to improve vaccine coverage. One important negative implication of regional inequality is the presence of clusters with under-vaccinated children, leading to an increased vulnerability during outbreaks of vaccine-preventable diseases.

Accessing vulnerable undocumented migrants through a healthcare clinic including a community outreach programme: a 12-year retrospective cohort study in Denmark.

BACKGROUND: Little is known about the healthcare needs of the increasing number of undocumented migrants in Europe. We aimed to gain knowledge about undocumented migrants use of a free healthcare clinic including an outreach programme in Denmark. METHODS: We conducted a retrospective cohort study of all patients registered in the database at the AmiAmi healthcare clinic in Fredericia, Denmark, 1 January 2006-30 July 2019. RESULTS: In all, 579 patients from 47 different countries were included, of which 525 (90.7%) were cis-women (= assigned female sex at birth and identifies as female). They had a total of 3135 consultations (median 3, interquartile range 2-6), and 19% used the clinic over a period of >2 years. In all, 820 consultations (26%) were done as part of the outreach programme, and the number of outreach contacts increased significantly over the study period (P < 0.001). Of 738 tests for sexually transmitted infections (STIs), 76 (13.1%) patients were found positive for one or several STIs. Transgender women and cross-dressing men had significantly higher risk of STIs (25.8% vs 10.3%, P = 0.007) compared with cis-women. Of 94 patients referred to the public healthcare system, the majority (n = 64) was referred to the department of gynaecology during pregnancy or for induced abortion. A total of 52 patients (9.0%) reported being submitted to abuse or violence while in Denmark, and another 24 (4.1%) were registered as victims of human trafficking. CONCLUSIONS: Our results highlight the multifaceted healthcare needs of undocumented migrants, with an increasing use of healthcare services over the study period. It underlines the importance of outreach programmes to reach this patient group at their place of work or stay. Finally, it emphasizes that transgender female and cross-dressing male sex workers are an especially vulnerable group with higher risk of human immunodeficiency virus and other STIs compared with cis-women.

In vitro and in vivo characterization of Lu AA41178: A novel, brain penetrant, pan-selective Kv7 potassium channel opener with efficacy in preclinical models of epileptic seizures and psychiatric disorders.

Activation of the voltage-gated Kv7 channels holds therapeutic promise in several neurological and psychiatric disorders, including epilepsy, schizophrenia, and depression. Here, we present a pharmacological characterization of Lu AA41178, a novel, pan-selective Kv7.2-7.5 opener, using both in vitro assays and a broad range of in vivo assays with relevance to epilepsy, schizophrenia, and depression. Electrophysiological characterization in Xenopus oocytes expressing human Kv7.2-Kv7.5 confirmed Lu AA41178 as a pan-selective opener of Kv7 channels by significantly left-shifting the activation threshold. Additionally, Lu AA41178 was tested in vitro for off-target effects, demonstrating a clean Kv7-selective profile, with no impact on common cardiac ion channels, and no potentiating activity on GABAA channels. Lu AA41178 was evaluated across preclinical in vivo assays with relevance to neurological and psychiatric disorders. In the maximum electroshock seizure threshold test and PTZ seizure threshold test, Lu AA41178 significantly increased the seizure thresholds in mice, demonstrating anticonvulsant efficacy. Lu AA41178 demonstrated antipsychotic-like activity by reducing amphetamine-induced hyperlocomotion in mice as well as lowering conditioned avoidance responses in rats. In the mouse forced swim test, a model with antidepressant predictivity, Lu AA41178 significantly reduced immobility. Additionally, behavioral effects typically observed with Kv7 openers was also characterized. In vivo assays were accompanied by plasma and brain exposures, revealing minimum effective plasma levels <1000 ng/ml. Lu AA41178, a potent opener of neuronal Kv7 channels demonstrate efficacy in assays of epilepsy, schizophrenia and depression and might serve as a valuable tool for exploring the role of Kv7 channels in both neurological and psychiatric disorders.

Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine.

The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d'). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0-1.0 mg/kg, i.p.) dose-dependently improved d' in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d' impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.

A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission.

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission.

A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment.

RATIONALE: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. METHOD: Experiments 1-2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAA receptor antagonism. Experiments 4-6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7-12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. RESULTS: In experiments 1-3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAA receptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4-6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7-12. CONCLUSION: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.

[HIV screening in pregnancy--too many failures?]. / Hiv-screening af gravide--svigter det for tit?

Danish official guidelines recommend that women belonging to risk groups should be offered HIV testing during pregnancy. Universal HIV testing during antenatal care is not required. We describe three infants with vertically acquired HIV infection born to mothers, who, despite belonging to high-risk groups (one from Thailand, two from Sub-Saharan Africa), had not been offered an HIV test during pregnancy. The infants, born within a one-year period, presented with AIDS-defining symptoms during their first months of life. Two children had Pneumocystis carinii pneumonia and one had severe failure to thrive. These cases demonstrate that a significant number, perhaps up to 20% of women with known risk factors, are not HIV-tested during pregnancy. Thus, selective screening for HIV during pregnancy is ineffective and should be replaced by a universal offer of an HIV test.

[Lactic bacteria and other probiotics in infections and inflammatory diseases in children. What do we believe? - What do we know?]. / Maelkesyrebakterier og andre probiotika ved infektiøse og inflammatoriske sygdomme hos børn. Hvad tror vi?--hvad ved vi?

Probiotics are microorganisms which, when ingested, may have a positive effect in the prevention or treatment of a specific pathologic condition. Probiotics are used for a number of gastrointestinal and certain systemic infectious and inflammatory diseases. The efficacy of selected probiotics to promote recovery from acute viral gastroenteritis in young children is well-documented. However, the role of probiotics in systemic diseases, e.g. atopic dermatitis, need to be confirmed in larger randomised controlled trials. This paper describes the theoretical background for the use of probiotics and reviews results from randomised controlled trials describing the effect of probiotics, particularly in paediatric diseases.

[Uterine rupture caused by placenta percreta in the first half of the pregnancy]. / Uterusruptur forårsaget af placenta percreta i første halvdel af graviditeten.

A 32-year-old woman in her 18th week of gestation was admitted to hospital due to abdominal pain and hypotension. A CT scan showed bleeding from the uterus into the abdomen and an acute laparotomy revealed a uterine rupture due to placenta percreta. The placenta was removed and a Bakri balloon was installed in the uterus. However the next morning the bleeding continued and a total hysterectomy was unavoidable. This case report shows that uterine rupture due to placenta percreta is a differential diagnosis in pregnant woman with abdominal pain and hypotension, even in the first half of the pregnancy.

A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations.

BACKGROUND: Genome-wide scans have uncovered rare copy number variants conferring high risk of psychiatric disorders. The 15q13.3 microdeletion is associated with a considerably increased risk of idiopathic generalized epilepsy, intellectual disability, and schizophrenia. METHODS: A 15q13.3 microdeletion mouse model (Df[h15q13]/+) was generated by hemizygous deletion of the orthologous region and characterized with focus on schizophrenia- and epilepsy-relevant parameters. RESULTS: Df(h15q13)/+ mice showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures but decreased propensity for clonic and tonic seizures. Furthermore, they had impaired long-term spatial reference memory and a decreased theta frequency in hippocampus and prefrontal cortex. Electroencephalogram characterization revealed auditory processing deficits similar to those observed in schizophrenia. Gamma band power was increased during active state, but evoked gamma power following auditory stimulus (40 Hz) was dramatically reduced, mirroring observations in patients with schizophrenia. In addition, Df(h15q13)/+ mice showed schizophrenia-like decreases in amplitudes of auditory evoked potentials. Although displaying a grossly normal behavior, Df(h15q13)/+ mice are more aggressive following exposure to mild stressors, similar to what is described in human deletion carriers. Furthermore, Df(h15q13)/+ mice have increased body weight, and a similar increase in body weight was subsequently found in a sample of human subjects with 15q13.3 deletion. CONCLUSIONS: The Df(h15q13)/+ mouse shows similarities to several alterations related to the 15q13.3 microdeletion syndrome, epilepsy, and schizophrenia, offering a novel tool for addressing the underlying biology of these diseases.

[Imperforate hymen can cause abdominal pain and primary amenorrhoea]. / Hymen imperforatum kan forårsage abdominale smerter og primær amenoré.

Imperforate hymen (HI) is a rare condition caused by the hymen covering the entire opening of the vagina. This prevents the menstruation blood from being drained and the blood fills up the vagina and later the uterus and Fallopian tubes. The produced strain on these organs causes cyclic pain in the lower abdomen. We present two cases where two adolescent girls were diagnosed with HI. It is important to remember HI as a differential diagnosis in young girls with amenorrhoea and lower abdominal pain. In both cases a hymenectomy was performed and the patients recovered afterwards.

[Prevention of vertical transmission of HIV in Denmark]. / Forebyggelse af vertikal transmission af human immundefektvirus i Danmark.

INTRODUCTION: Human immunodeficiency virus (HIV) is a RNA virus that can be transmitted parenterally, sexually or vertically. An effective prevention strategy has been implemented in industrialised countries, thereby reducing vertical transmission from 15-25% to < 1%. The aim of this study was to describe vertical transmission of HIV in Denmark after the introduction of ART. MATERIALS AND METHODS: The study was a retrospective study of all HIV-infected women who gave birth in Denmark between 1 January 2000 and 31 May 2005 and their children. RESULTS: 83 HIV-infected women gave birth to 96 children during the study period. In 79% of the cases, the woman knew her HIV status at the beginning of her pregnancy. The median CD4 count before delivery was 447 x 10(6)/l, and in 76% of the cases the HIV-RNA was < 20 copies/ml. 88% of the women delivered by Caesarean section. None of the children were breastfed. None of the children were infected during pregnancy, delivery or after birth. During the same period of time, 8 children were diagnosed with HIV in Denmark; they were born to mothers whose HIV infection was not diagnosed during pregnancy or delivery and therefore preventive treatment was not initiated. CONCLUSION: As long as preventive treatment strategies are followed, there is no transmission of HIV from mother to child, neither during pregnancy nor during or after birth.

[Children hospitalised with fever following a stay abroad]. / Børn indlagt med feber efter udlandsophold.

INTRODUCTION: The aim of this study was to describe cases of illness in children admitted to hospital with a fever following a stay abroad. MATERIALS AND METHODS: We performed a retrospective study based on journals dating from June 2003 to September 2003. Patients with a temperature of > or = 37.5 degrees C and of whom it was recorded that they had travelled abroad within the previous three months were included, as were demographic data, travel destination, discharge diagnosis and the results of microbiological and serological tests performed, if any. RESULTS: A total of 48 children were included; 56% were immigrants. Fifteen (31%) suffered from diarrhea/gastroenteritis; eight of these cases were caused by Salmonella species. Ten (21%) had a serologically verified hepatitis A infection. There was one case of verified malaria. Nine patients (19%) were discharged with a diagnosis of unspecified viral infection, while nine had a commonly occurring infection with an unidentified focus. CONCLUSION: Immigrant children constituted the majority of the hospitalised children. This group contracts not only more infections but also more serious ones than do children with Danish parents. As for infectious hepatitis, it is remarkable that despite the recommendations of the National Board of Health to vaccinate immigrant children against hepatitis A before a visit to their native country, this seems to be far from the actual practice.

Demographics in HIV-infected children in Denmark: results from the Danish Paediatric HIV Cohort Study.

We present the demographic data on HIV-infected children from the Danish Paediatric HIV Cohort Study, an observational database on HIV in Denmark. Up to 1 July 2003 a total of 89 children had been diagnosed with HIV infection before the age of 16 y, of which 12 (13.5%) had died, 2 (2.2%) had emigrated from Denmark, and 13 had reached the age of 16 y. Estimates of prevalence and incidence of HIV infection in the area were 5.77/100,000 and 0.39/100,000 respectively, which are lower than in the adult population. After 1993 the number of newly diagnosed HIV infected children remained quite constant with an average of 4.2 diagnoses per y. Of the enrolled patients only 15.7% had both their parents of Danish origin, while 58.5% had at least 1 of the parents from an African country. Of the entire cohort, 20% were Caucasians, 51% were males and 76% were infected perinatally. There has been a shift in the HIV epidemic in children over recent y, with a higher proportion of newly diagnosed HIV patients having contracted the infection perinatally, a higher proportion being of non-Caucasian race, and the newly diagnosed individuals being younger. Even since 1995, a major part of the newly diagnosed children was born in Denmark by mothers from high-endemic areas and we therefore suggest that HIV-testing should actively be offered to all pregnant women coming from these high-risk areas.