Habituation deficits induced by metabotropic glutamate receptors 2/3 receptor blockade in mice: reversal by antipsychotic drugs

Cortical metabotropic glutamate receptors (mGluRs) seem to be involved in habituation of simple stimulus-bound behaviors (e.g., habituation to acoustic startle or odor-elicited orienting response). Habituation deficits may contribute to the cognitive symptoms of schizophrenia. In the present study, male NMRI mice were injected with mGluR2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495) 30 min before being placed into novel arenas for automatic motor activity recording (2-h sessions). Administration of LY-341495 (1-10 mg/kg s.c.) dose-dependently prevented the habituation of the locomotor activity. Effects of LY-341495 (10 mg/kg) were fully and dose-dependently reversed by i.p. administration of haloperidol (0.03-0.3 mg/kg), clozapine (1-10 mg/kg), risperidone (0.01-0.1 mg/kg), olanzapine (0.3-3 mg/kg), aripiprazole (1-10 mg/kg), and sulpiride (3-30 mg/kg), each of which was given 15 min before the test. Effects of antipsychotic drugs were observed at the dose levels that did not affect spontaneous motor activity. LY-341495-induced delayed hyperactivity was also partially attenuated by lithium (50-200 mg/kg), amisulpride (1-10 mg/kg), and the selective dopamine D3 antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011A; 3-30 mg/kg). Application of diazepam, imipramine, or several agonists and/or antagonists acting at various receptors that are thought to be relevant for antipsychotic treatment [e.g., 5-hydroxytryptamine (5-HT)(2A), 5-HT(3), and 5-HT(6) antagonists; 5-HT(1A) agonist; D4 antagonist; CB1 antagonist; ampakines; and glycine transporter inhibitor) had no appreciable effects. Thus, behavioral deficits induced by mGluR2/3 blockade (such as delayed motor hyperactivity) are selectively reversed by clinically used antipsychotic drugs.     

Different Evolutionary Histories of the Coagulation Factor VII Gene in Human Populations?

Immoderate blood clotting constitutes a risk factor for cardiovascular disease in modern industrialised societies, but is believed to have conferred a survival advantage, i.e. faster recovery from bleeding, on our ancestors. Here, we investigate the evolutionary history of the Coagulation Factor VII gene (F7) by analysing five cardiovascular-risk-associated mutations from the F7 promoter and nine neutral polymorphisms (six SNPs and three microsatellites) from the flanking region in 16 populations from the broader Mediterranean region, South Saharan Africa and Bolivia (687 individuals in total). Population differentiation and selection tests were performed and linkage disequilibrium patterns were investigated. In all samples, no linkage disequilibrium between adjacent F7 promoter mutations −402 and −401 was observed. No selection signals were detected in any of the samples from the broader Mediterranean region and South Saharan Africa, while some of the data suggested a potential signal of positive selection for the F7 promoter in the Native American samples from Bolivia. In conclusion, our data suggest, although do not prove, different evolutionary histories in the F7 promoter region between Mediterraneans and Amerindians.     

From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression

According to the present view, metastasis marks the end in a sequence of genomic changes underlying the progression of an epithelial cell to a lethal cancer. Here, we aimed to find out at what stage of tumor development transformed cells leave the primary tumor and whether a defined genotype corresponds to metastatic disease. To this end, we isolated single disseminated cancer cells from bone marrow of breast cancer patients and performed single-cell comparative genomic hybridization. We analyzed disseminated tumor cells from patients after curative resection of the primary tumor (stage M0), as presumptive progenitors of manifest metastasis, and from patients with manifest metastasis (stage M1). Their genomic data were compared with those from microdissected areas of matched primary tumors. Disseminated cells from M0-stage patients displayed significantly fewer chromosomal aberrations than primary tumors or cells from M1-stage patients (P < 0.008 and P < 0.0001, respectively), and their aberrations appeared to be randomly generated. In contrast, primary tumors and M1 cells harbored different and characteristic chromosomal imbalances. Moreover, applying machine-learning methods for the classification of the genotypes, we could correctly identify the presence or absence of metastatic disease in a patient on the basis of a single-cell genome. We suggest that in breast cancer, tumor cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metastatic cells thereafter. Thus, our data challenge the widely held view that the precursors of metastasis are derived from the most advanced clone within the primary tumor.     

Dermatoglyphic characterization of Berbers from Morocco: qualitative and quantitative digital and palm data

Background : The demographic impact of the Arabization in the Berber genetic background has been extensively studied by means of different classical and DNA genetic markers. Information from other biological traits as dermatoglyphics could be of interest in order to gain an insight into the relationship between these two North African groups. Aim : The Moroccan Berber population is characterized by means of digital and palm dermatoglyphics to determine the degree of genetic affinities among Berber and other Mediterraneans, especially the Moroccan Arab-speakers. Subjects and methods : Finger patterns, pattern intensity, finger total ridge counts, pattern frequencies in the five configuration areas of the palm, mainline D terminations, and a-b ridge count were analysed in a sample of 120 males and 103 females of Moyen Atlas (Morocco). Results : Bilateral asymmetry was more pronounced than sexual differences in the overall distribution of the analysed traits. Our two series (males and females) exhibit high values of total ridge count (TRC) and mainline D terminations in comparison with other Mediterranean series. Several pattern frequencies in fingers and palm areas also differentiate the Berbers of Moyen Atlas from North Africans. Conclusion : The picture obtained by principal components based on qualitative digital and palm data revealed that Berber males were within the variation range of North African groups while Berber females clustered with some Iberian samples. The population pattern obtained in a bivariate plot of quantitative finger data showed the Berbers (males and females) as the most differentiated population in the Mediterranean context. Dermatoglyphic data failed to indicate any particular proximity between Berbers and Arab-speakers from Morocco.     

Body mass index as independent predictor of overall survival in patients with advanced renal cell carcinoma at start of systemic treatment—Analyses from the German clinical RCC-Registry

Objectives

A high body mass index (BMI) is associated with an increased risk for developing renal cell carcinoma (RCC), a higher complication rate after surgery, and a postoperative decline in renal function after nephrectomy. In contrast, a high preoperative BMI has been associated with increased survival in patients with localized RCC. We examined the prognostic impact of the BMI in patients treated for metastatic RCC (mRCC) in daily routine practice in Germany.

Effects of repeated dizocilpine treatment on adult rat behavior after neonatal lesions of the entorhinal cortex

Disturbed cortical development is implicated in some psychiatric diseases, e.g. in schizophrenia. Additionally, N-methyl-d-aspartate (NMDA) receptor antagonists like ketamine or phencyclidine have been reported to exacerbate schizophrenic symptoms. We here investigated the effects of neonatal entorhinal cortex (EC) lesions on adult rat behavior before and after repeated high-dose treatment with the NMDA antagonist dizocilpine, in order to combine these etiopathogenetical factors in an animal model. Bilateral neonatal (postnatal day 7) lesions were induced by microinjection of ibotenic acid (1.3 microg/0.2 microl PBS) into the EC. Naive and sham-lesioned rats served as controls. Adult rats were tested for behavioral flexibility on a cross maze, for locomotor activity in the open field and for sensorimotor gating using prepulse inhibition (PPI) of startle. Rats were then treated with dizocilpine (0.5 mg/kg b.i.d. for 7 days) and retested 1 week after withdrawal using the same behavioral tests as before. PPI was additionally measured after acute low-dose challenge with dizocilpine (0.15 mg/kg). EC lesions reduced behavioral flexibility as shown by impaired switching between spatial (allocentric) and non-spatial (egocentric) maze strategies. High-dose dizocilpine treatment disturbed switching to the egocentric strategy in all groups, which added to the effect of EC lesions. Neonatal EC lesions did not alter locomotor activity or PPI, but high-dose dizocilpine treatment reduced motor activity of all groups without changing PPI. The combination of neonatal EC lesions and adult dizocilpine treatment does not lead to super-additive effects on behavior. However, both treatments may serve to model certain aspects of psychiatric symptoms.     

Palliative treatment of colorectal cancer in Germany: cost of care and quality of life

Introduction

To estimate the costs of palliative care for colorectal cancer (CRC) from the perspective of German statutory health insurance and to measure the patients’ quality of life (QoL) for a 2-year time period.

Methods

A prospective observational multicentre study was carried out to estimate the direct costs of care over a 2-year period. Case report forms, medical records, and claims data were all applied to document medical and resource usage data in real-world settings. QoL was measured by using the Short Form-12 Health Survey.

Results

In total 101 patients (mean age 67.09 ± 11.13 years, 68 % male) from 12 different settings were included. The mean costs per patient during the 1st and 2nd years were calculated to be 42,361€ and 32,023€, respectively. Highest mean costs were calculated for the second quarter, which reached an amount of 12,900€ (95 % CI: 11,127€–14,673€). Mean physical summary scores and mean mental summary scores were 41.8 and 49.7, respectively.

Discussion

This is the first study assessing the costs of palliative care and the quality of life of patients with CRC in real-world health-care delivery in Germany. It could be shown that CRC treatment represents an enormous economic burden to the German health-care system. Increased efforts in promoting effective and efficient treatment options, or performance-based medication reimbursement schemes, might be helpful in reducing the costs.