The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease.

Pathogenic changes in γ-secretase activity, along with its response to different drugs, can be affected by changes in the saturation of γ-secretase with its substrate. We analyze the saturation of γ-secretase with its substrate using multiscale molecular dynamics studies. We found that an increase in the saturation of γ-secretase with its substrate could result in the parallel binding of different substrate molecules at the docking site and the active site.

Regional Differences in Anxiolytic Prescribing in Light of Hofstede's Cultural Dimensions Theory.

Background: Anxiolytics such as benzodiazepines are widely used in the treatment of anxiety disorders, although they are no longer recommended as first-line therapy for these conditions due to increased risk of dependence, as well as cognitive adverse effects, especially among the elderly. High prescribing rates of anxiolytics may be indicative of higher prevalence of anxiety-related phenomena in a given society, either in a form of an anxiety disorder or as pressure on physicians to keep prescribing them, against current guidelines.

Subjects And Methods: We inspected prescribing rates of anxiolytics in 21 European countries and compared them with six dimensions of Hofstede's cross-cultural framework, namely uncertainty avoidance (UAI), power distance (PD), individualism (IDV), masculinity (MAS), long-term orientation (LTO) and indulgence (IND).

Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer's Disease: A Systematic Review.

Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression.

An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia.

The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group.

Association between PLA2G6 gene polymorphism for calcium-independent phospholipase A2 and nicotine dependence among males with schizophrenia.

We investigated the relationship between the rs10798059 (BanI) and rs4375 polymorphisms in the phospholipase A2 (PLA2)G4A and PLA2G6 genes and the risk of nicotine dependence in 263 Croatian patients with schizophrenia. We also examined whether interactions between these polymorphisms and smoking contributed to schizophrenia onset and Positive and Negative Syndrome Scale (PANSS) psychopathology. We found no significant differences in the distribution of PLA2G4A genotypes and alleles according to smoking status, and no effect of the PLA2G4A genotype-smoking interaction on disease onset or PANSS.

The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and nicotine dependence in schizophrenia patients.

We investigated the relationship between the functional insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene and the risk of nicotine dependence in Croatian schizophrenia patients. We also tested whether interactions between ACE-I/D polymorphism and smoking status affected the clinical psychopathology findings in patients as measured using Positive and Negative Symptom Scale (PANSS) scores. Polymerase chain reaction analysis was used to genotype 267 chronically ill schizophrenia patients (140 males/127 females).

An association between the PPARα-L162V polymorphism and nicotine dependency among patients with schizophrenia.

Objective: Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha (PPARα) in schizophrenia, together with nicotine dependency, to investigate whether the PPARα-L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARα-L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARα-L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale.

Mind in the Gap Between Neural and Social Networks - Cyberspace and Virtual Reality in Psychiatry and Healthcare.

In terms of health and healthcare cyberspace and virtual reality can be used differently and for different purposes and consequently create different outcomes. The three main areas which we shall discuss here are: 1) cyberspace as provider of health information and self-help resources, since the anonymity cyberspace provides is particularly important in the highly stigmatized field of psychiatry where a large number of people never seek professional help, which in turn negatively affects not only the person in question, but the family and ultimately the society (work efficiency, disability-adjusted life year - DALY, etc.), 2) cyberspace and virtual reality (VR) as cause of psychopathology, starting from violent behaviour, to addictive behaviour and other, 3) and finally cyberspace and VR as providers of efficient professional therapy in the field of psychiatry.

Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease.

Background: Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of Aβ peptides and decrease in maximal activity of a membrane-embedded protease γ-secretase.

Results: We compared activity of WT γ-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in Aβ-part of its APP substrate (Familial Alzheimer's disease). All 11 FAD mutations show linear correlation between the decrease in maximal activity and the clinically observed age-of-onset and age-of-death.

Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease.

Background: Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism.

Results: Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves.

Modulation of γ-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease.

Background: We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides.

Results: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product.

Reproductive rights of mentally retarded persons.

Mental retardation denotes sub-average intellectual functioning, based on IQ, i.e. the inability of normal learning, accompanied by behavioral and developmental disorders.

Psychiatric hospital--from asylums to centres for mind-body wellness.

Throughout history mental illness was mystified, feared and condemned, but over time perception and treatment of psychiatric patients changed. Systematic care for the mentally ill in specialised institutions began about six hundred years ago. However, it was of a repressive and restrictive character towards the patients until as late as 19th century, a time of significant progress and development for the science of psychiatry.

HFE mutations and transferrin C1/C2 polymorphism among Croatian patients with schizophrenia and schizoaffective disorder.

The aim of this study was to investigate the possible influence of hemochromatosis gene mutations (HFE-C282Y and H63D) and transferrin gene C2 variant (TF-C2) on susceptibility to schizophrenia and schizoaffective disorder and/or age at first hospital admission. Genotyping was performed in 176 Croatian patients and 171 non-psychiatric Croatian controls using PCR-RFLP analyses. Regarding the H63D mutation, allele and genotype frequencies reached boundary statistical significance.

Ethical approach to pharmacotherapy of comorbid states.

Ethics is an indispensable component of health care policy. Pharmacotherapy of comorbidity requires the use of a greater number of different drugs that have complex drug-drug interactions and drug-patient interactions which can cause various side-effects in the patient. The basic moral questions that justify the applied psychopharmacotherapy are the patient's welfare and preference, optimal relationship between risk and gain for the patient, and some include cost benefit as well.

The relationships between self-esteem, emotional reactions and quality of life in pediatric locomotory trauma patients.

The main aim of this study was to establish the relationships between several psychosocial characteristics in children and adolescents differently treated for isolated long tubular bones' fractures. Examined variables were: self-esteem, basic emotional reactions toward illness or injury including depression and anxiety, as well as perception of quality of life and social support during the treatment. Whole sample comprehends 135 patients, both gender, 10-18 years of age, treated for mentioned fractures in period 2003-2005 at the Departments of Pediatric Surgery of 3 hospitals: University Hospital Centre in Rijeka and Clinical Children's Hospital in Zagreb, both in Croatia and University Hospital in Mostar, BiH.

The influence of temperament and character of psychotic individuals on the possibility of committing criminal offences.

Cloninger's theoretical biosocial model of personality represents the personality as a hierarchical organisational system consisting of 4 temperament dimensions and 3 character dimensions as 3 aspects of self-concept. It attempts to define behavioural and bio-genetic aspects of temperament, and the neuroanatomical and biochemical brain network responsible for activation, maintenance and inhibition of behaviour. The basic objective of this research is to establish whether temperament and character act as measures of personalities in psychotic persons on the possibility of committing criminal offences.

The quality of life during the treatment of long bone fractures in children and adolescents.

This paper evaluates and compares basic emotional reactions towards the illness, as well as the quality of life in relation to the various types of treatment of isolated long tubular bone fractures of extremities in children and adolescents. This prospective clinical research comprehends 135 patients (94 males and 41 females), aged 10 to 18, treated for the mentioned bone fractures in the period from October 2003 till March 2005 at The Departments for Pediatric Surgery of three hospitals: the Clinical Hospital Centre in Rijeka (88.8% of the patients), the Clinical Children's Hospital in Zagreb (9.

Mental illness and ethnicity - being a stateless person (apatride).

The main aim of this study has been to perceive the state of mentally ill stateless person hospitalized in Psychiatric Hospital Rab, Croatia with forensic status. This is a case report of such a person, F.V.