Survival of women with breast cancer in Europe: Variation with age,year of diagnosis and country

Breast cancer is the most frequent malignancy among women in developed countries. Prognosis is better than for other major cancers, and an improvement in survival has been reported for several populations in recent decades. Within the framework of EUROCARE, a population-based project concerned with the survival and care of cancer patients in Europe, we analysed data from 119,139 women diagnosed with breast cancer between 1978 and 1985 in 12 countries and followed for at least 6 years. Multiple regression models of relative survival, which take mortality from all other causes in each area into account, were used to estimate the effect of age, period of diagnosis and country on survival. For the comparison between countries, survival rates were age-standardised to the age structure of the entire study population. Women aged 40–49 years at diagnosis had the best prognosis in all countries and throughout the study period. Women younger than 30 years at diagnosis had a worse prognosis than those aged 30–39. The highest relative survival at 5 years was in Finland and Switzerland (about 74%), intermediate levels were found for Italy, France, The Netherlands, Denmark and Germany (about 70%) and the lowest rates were in Spain, the United Kingdom, Estonia and Poland (55–64%). During the 6 months following diagnosis, survival was highly dependent on age and was sharply lower in women older than 49 years. For women surviving more than 6 months after diagnosis, survival was similar for all ages, although women aged 40–49 still had the better prognosis. The average rate of death from breast cancer fell by about 2.5% for each year of diagnosis between 1978 and 1985. This improvement manifested mainly in younger and older women, for whom survival was initially less good. The largest improvement was seen in Poland (−15% death risk per year). We suggest that the better survival of women aged 40–49 at diagnosis is related to lower levels of circulating sex hormones, resulting in reduced stimulation of tumour cell growth. Early diagnosis may also be important in the peri-menopausal period due to increased diagnostic attention. Low survival in the United Kingdom may be due to inadequate adherence to consensus treatment guidelines and greater variation in treatment. Int. J. Cancer 77:679–683, 1998.© 1998 Wiley-Liss, Inc.     

GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABA_A and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [³H]-Ro15-4513 was used to quantify the density of α5GABA_A receptors (α5GABA_AR), [³H]-flumazenil to quantify α1-3;5GABA_AR, and [³H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABA_AR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABA_AR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [³H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABA_AR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.Subject terms: Psychosis, Schizophrenia, Experimental models of disease, Schizophrenia, Psychosis     

Complexes of Ghrelin GHS-R1a,GHS-R1b,and Dopamine D1 Receptors Localized in the Ventral Tegmental Area as Main Mediators of the Dopaminergic Effects of Ghrelin

Ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R1a), is coexpressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D₁ dopamine receptor (D1R) and D5R constitute the two D₁-like receptor subtypes. Previous studies showed that GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in the contribution of ghrelin to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R, but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells, and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with ex vivo experiments, on somatodendritic dopamine release with in vivo microdialysis and on the activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin.SIGNIFICANCE STATEMENT The activation of ghrelin receptors localized in the ventral tegmental area (VTA) plays a significant role in the contribution of ghrelin to motivated behavior. We present evidence that indicates these receptors form part of oligomeric complexes that include the functional ghrelin receptor GHS-R1a, its truncated nonsignaling isoform GHS-R1b, and the dopamine D₁ receptor (D1R). The binding of ghrelin to these complexes promotes activation of the dopaminergic neurons of the VTA by activation of adenylyl cyclase–protein kinase A signaling, which can be counteracted by both GHS-R1a and D1R antagonists. Our study provides evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in rodent VTA as main mediators of the dopaminergic effects of ghrelin.     

Dietetic Management of Adults with Phenylketonuria (PKU) in the UK: A Care Consensus Document

There is an increasing number of adults and elderly patients with phenylketonuria (PKU) who are either early, late treated, or untreated. The principal treatment is a phenylalanine-restricted diet. There is no established UK training for dietitians who work with adults within the specialty of Inherited Metabolic Disorders (IMDs), including PKU. To address this, a group of experienced dietitians specializing in IMDs created a standard operating procedure (SOP) on the dietetic management of adults with PKU to promote equity of care in IMD dietetic services and to support service provision across the UK. The group met virtually over a period of 12 months until they reached 100% consensus on the SOP content. Areas of limited evidence included optimal blood phenylalanine reporting times to patients, protein requirements in older adults, management of weight and obesity, and management of disordered eating and eating disorders. The SOP does not include guidance on maternal PKU management. The SOP can be used as a tool for training dietitians new to the specialty and to raise the standard of education and care for patients with PKU in the UK.     

Intracranial self-stimulation in the parafascicular nucleus of the rat

A behavioral analysis of intracranial self-stimulation was provided for parafascicular nucleus. To evaluate whether intracranial self-stimulation in this nucleus could be site-specific and to determine if the positive sites are the same parafascicular areas that facilitate learning when stimulated, rats were tested via monopolar electrodes situated throughout the parafascicular nucleus. Animals were trained to self-stimulate by pressing a lever in a conventional Skinner box (1-5 sessions). Twenty-two of the 42 animals included in the study, had the electrode at the parafascicular nucleus. Only two of them showed intracranial self-stimulation. Histological analyses indicated that the latter rats had the electrode implanted at the anterior area of the medial parafascicular. Other two animals also showed intracranial self-stimulation but they had the electrode in a more posterior brain region, between the Dark-schewitsch nucleus and the red nucleus. The animals implanted at the parafascicular showed higher response rates than the other two rats. These results confirm that: (a) the anterior region of the medial parafascicular is a positive site for stable and regular intracranial self-stimulation behavior, and (b) these positive sites do not coincide with the parafascicular regions related to learning improvement.     

Haploinsufficiency,Dominant Negative,and Gain-of-Function Mechanisms in Epilepsy: Matching Therapeutic Approach to the Pathophysiology

This review summarizes the pathogenic mechanisms that underpin the monogenic epilepsies and discusses the potential of novel precision therapeutics to treat these disorders. Pathogenic mechanisms of epilepsy include recessive (null alleles), haploinsufficiency, imprinting, gain-of-function, and dominant negative effects. Understanding which pathogenic mechanism(s) that underlie each genetic epilepsy is pivotal to design precision therapies that are most likely to be beneficial for the patient. Novel therapeutics discussed include gene therapy, gene editing, antisense oligonucleotides, and protein replacement. Discussions are illustrated and reinforced with examples from the literature.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01137-z.