A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor

Abstract We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK1R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK1R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N- or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK1R preference for distinct G protein-mediated signaling pathways. NK1R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells. The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK1R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK1R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor

Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?

Background: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. Methods: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N = 31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N = 788 twin pairs (affected with schizophrenia spectrum) and a subsample of N = 448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. Findings: We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. Discussion: Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating that age might be perceived as a clinical marker for genetic vulnerability for the illness

Гестационный транзиторный тиреотоксикоз

Приведены современные данные литературы о гестационном транзиторном тиреотоксикозе. Освещены особенности гормональной регуляции щитовидной железы.Modern literature data about gestation thyrotoxicosis are presented. The peculiarities of hormonal regulation of the thyroid gland are featured

Diagnostic stability among chronic patients with functional psychoses: an epidemiological and clinical study

<p>Abstract</p> <p>Background</p> <p>Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors.</p> <p>Method</p> <p>100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers. To study the stability of diagnoses (i.e. shifts per time), we used registry data to define four measures of diagnostic variation that were subsequently examined in relation to four possible measures of time (i.e. observation periods or hospitalisation events). Afterwards, we identified putative co-variables and predictors of the best measures of diagnostic stability.</p> <p>Results</p> <p>All four measures of diagnostic variation are very strongly associated with numbers-of-hospitalisations and less so with duration-of-illness, duration-of-hospitalisation and with year-of-first-admission. The four measures of diagnostic variation corrected for numbers-of-hospitalisations were therefore used to study the diagnostic stability. Conventional predictors of illness course – e.g. age-of-onset and premorbid-functioning – are not significantly associated with stability. Only somatic-comorbidity is significantly associated with two measures of stability, while family-history-of-psychiatric-illness and global-assessment-of-functioning (GAF) scale score show a trend. However, the traditional variables age-of-first-admission, civil-status, first-diagnosis-being-schizophrenia and somatic-comorbidity are able to explain two-fifth of the variation in numbers-of-hospitalisations.</p> <p>Conclusion</p> <p>Diagnostic stability is closely linked with the contact between patient and the healthcare system. This could very likely be due to fluctuation of disease manifestation over time or presence of co-morbid psychiatric illness in combination with rigid diagnostic criteria that are unable to capture the multiple psychopathologies of the functional psychoses that results in differential diagnoses and therefore diagnostic instability. Not surprisingly, somatic-comorbidity was found to be a predictor of diagnostic variation thereby being a non-psychiatric confounder.</p

Genetic stratification of depression in UK Biobank

Depression is a common and clinically heterogeneous mental health disorder that is frequently comorbid with other diseases and conditions. Stratification of depression may align sub-diagnoses more closely with their underling aetiology and provide more tractable targets for research and effective treatment. In the current study, we investigated whether genetic data could be used to identify subgroups within people with depression using the UK Biobank. Examination of cross-locus correlations were used to test for evidence of subgroups using genetic data from seven other complex traits and disorders that were genetically correlated with depression and had sufficient power (>0.6) for detection. We found no evidence for subgroups within depression for schizophrenia, bipolar disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, anorexia nervosa, inflammatory bowel disease or obesity. This suggests that for these traits, genetic correlations with depression were driven by pleiotropic genetic variants carried by everyone rather than by a specific subgroup