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. The C-terminal domain of the substrate bound at the docking site can interact with the most dynamic presenilin sites at the cytosolic end of the active site tunnel. Such interactions can inhibit the ongoing catalytic activity and increase the production of the longer, more hydrophobic, and more toxic Aß proteins. Similar disruptions in dynamic presenilin structures can be observed with different drugs and disease-causing mutations. Both, C99-ßCTF-APP substrate and its different Aß products, can support the toxic aggregation. The aggregation depends on the substrate N-terminal domain. Thus, the C99-ßCTF-APP substrate and ß-secretase path can be more toxic than the C83-αCTF-APP substrate and α-secretase path. Nicastrin can control the toxic aggregation in the closed conformation. The binding of the C99-ßCTF-APP substrate to γ-secretase can be controlled by substrate channeling between the nicastrin and ß-secretase. We conclude that the presented two-substrate mechanism could explain the pathogenic changes in γ-secretase activity and Aß metabolism in different sporadic and familial cases of Alzheimer's disease. Future drug-development efforts should target different cellular mechanisms that regulate the optimal balance between γ-secretase activity and amyloid metabolism.

Ketamine - Undrawn Lines between Medical and Recreational Use - Implications for Clinical Practice.

Ketamine, synthesized in 1962, approved in 1970, is considered safe for use in controlled conditions, mainly as an anesthetic, especially in pediatric populations and in people suffering from pulmonary diseases, as well as in emergency departments and in war situations. Dissociative states (derealization and depersonalization) produced by ketamine made it a popular recreational drug, which led to increased regulation in most countries. Intravenous application of ketamine has shown rapid, although transitory antidepressant and antisuicidal effects in patients with unipolar and bipolar depression. Esketamine, the S(+) enantiomer of ketamine, with better pharmacodynamic selectivity, has just been approved for treatment-resistant major depressive disorder, in the form of a nasal spray. Presently, the high cost of the spray not only limits its widespread use, but also makes it less prone to abuse and diversion. Additional measures are needed to hinder it from becoming a new "street drug".

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). RESULTS: According to our findings, anxiolytic prescribing patterns in selected European countries correlate positively with Hofstede's dimensions of UAI and PD and negatively with IDV. CONCLUSION: Differences in prescribing rates of anxiolytics and trends in their use may be affected by cross-cultural factors. More research is needed to shed light on these regional differences in anxiolytic prescribing.

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. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.

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. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.

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 PLA2G6-TT homozygous genotype was significantly overrepresented in male smokers compared to nonsmokers (34.7% vs. 17.1%, p < 0.05). These patients had ∼2.6-fold higher risk of becoming smokers than males with heterozygous PLA2G6-CT and homozygous PLA2G6-CC genotypes. In addition, male smokers without the PLA2G6-C allele (PLA2G6-TT homozygous) experienced earlier onset than nonsmoking homozygous PLA2G6-TT males. Thus, the PLA2G6 polymorphism affected the risk of nicotine dependence in male patients and the PLA2G6 genotype-smoking interaction was linked to the age of disease onset.

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). There were no significant differences in the distribution of ACE genotypes and alleles in male or female schizophrenia patients who were stratified based on their smoking status. However, there was a trend toward a difference in the ACE genotype distribution in female smokers vs. nonsmokers (χ 2 = 5.13, p = 0.077) that was due mainly to the significant overrepresentation of ACE-ID heterozygous genotypes in female smokers compared to nonsmokers (62.3 vs. 42.0%, p = 0.025). ACE-ID heterozygous females had about a twofold higher smoking risk than ACE-II and ACE-DD homozygous carriers (OR = 2.29, 95% CI 1.1-4.7, p = 0.026). We observed no contribution of the ACE genotype-smoking interaction to PANSS psychopathology. This is the first study to investigate the possible association between ACE-I/D polymorphism and nicotine dependence in schizophrenia. Our results suggest that the ACE-I/D polymorphism may be relevant in determining the risk of nicotine dependence in female patients with schizophrenia while the ACE genotype-smoking interaction does not contribute to the clinical expression of schizophrenia.

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. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARα gene and nicotine dependency. PATIENTS AND METHODS: Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction. RESULTS: A significant excess of PPARα-L162V genotypes and PPARα-162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs. 2.0%, and 9.1% vs. 1.0%, p<0.01, respectively). We also revealed a significant PPARα genotype-smoking interaction that predicted positive symptom severity among male patients (F=4.43, p<0.05). These data indicated that the PPARα-L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARα-L162V polymorphism and smoking for the time of onset of schizophrenia was detected (p>0.05, respectively). CONCLUSION: We demonstrated two significant yet weak effects. The first showed an effect of the PPARα-L162V polymorphism on the risk of nicotine dependency. The second linked the PPARα genotype-smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.

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 Aß 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 Aß-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. Biphasic-inhibitors showed that a higher ratio between physiological Aß-production and the maximal activity of γ-secretase can be observed in cells that can facilitate pathogenic changes in Aß-products. For example, Aß production in cells with WT γ-secretase is at 11% of its maximal activity, with delta-exon-9 mutant at 26%, while with M139V mutant is at 28% of the maximal activity. In the same conditions, G384A mutant is fully saturated and at its maximal activity. Similarly, Aß production in cells with γ-secretase complex carrying Aph1AL component is 12% of its maximal activity, while in cells with Aph1B complex is 26% of its maximal activity. Similar to the cell-based studies, clinical studies of biphasic dose-response in plasma samples of 54 healthy individuals showed variable ratios between physiological Aß production and the maximal activity of γ-secretase. CONCLUSIONS: The increase in the ratio between physiological Aß production and maximal activity of γ-secretase can be an early sign of pathogenic processes in enzyme-based, cell-based, and clinical studies of sporadic and Familiar Alzheimer's disease.

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

BACKGROUND: Selective modulation of different Aß 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 Aß metabolism. RESULTS: Aß 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation. SIGNIFICANCE: Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aß-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aß metabolism.

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 Aß peptides. RESULTS: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aß42/Aß40 ratio is observed in pre-steady-state when Aß40 is the dominant product. Aß42 is produced after Aß40, and therefore Aß42 is not a precursor for Aß40. The longer more hydrophobic Aß products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aß40 with concomitant increase in the longer Aß products and Aß42/Aß40 ratio. To different degree the same changes in Aß products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aß catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aß-bundles. CONCLUSIONS: Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aß-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis.

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. Persons with impairments (cognitive, motor, sensory or psychiatric) have often been, both through human history and today victims of discrimination and deprived of their basic human rights, both in the public and the private life spheres. Since the end of the 20th century, throughout the developed world, many disabled persons can accomplish their dreams and rights. However, the issue of sexuality is still an obstacle in realizing oneself as a whole person, of course in accordance with personal psychophysical abilities. The greatest problem is present in persons with severe disablement, considered not apt enough for information on sexuality and for expressing themselves as persons with their own sexual needs. Thus it is desirable to observe each disabled person individually and flexibly enough in order to establish parameters for the functioning of an intimate affair on the level of understanding and assent. The legal system must protect the most vulnerable and ensure for them the right of choice and consent, as well as the possibility of fulfilling their sexual needs, so that they could love and be loved. Naturally, the system must be built on foundations that satisfy the needs of its users, but also of persons engaged in work with them. Sex education should contain information regarding biological, socio-cultural and spiritual dimensions of sexuality, including cognitive, affective and behavioral domains. Unfortunately, very few educational programs with such aims provide sex education, not only for the disabled young population but also for the healthy. This review article is based on international investigations and Croatian legislative postulates. Its aim is to focus the attention of both professionals and non-professionals on this delicate problem.

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. Other allele and genotype distributions were not significantly different between two groups. We also analyzed age at first hospital admission as a continuous variable using the non-parametric Mann-Whitney U-test and Kruskal-Wallis test, and multiple regression analysis. The results of these tests were negative. We concluded that investigated HFE mutations and TF-C2 variant are not high-risk genetic variants for schizophrenia/schizoaffective disorder in our population. Also our data do not support their impact on age at onset of the first psychotic symptoms.

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. It was then that the effect of one's immediate environment on human emotions, mood, and recovery became the subject of many scientific studies, and the role of architectural design in the care and treatment of psychiatric patients gained much attention. Over the years significant evidence has been accumulated of the effect of architectural design on humans. However, psychiatric hospitals very often occupy buildings not originally designed for that specific purpose. This is the case with the Rab Psychiatric Hospital, demonstrating a functional and efficient use of its premises, which have yet to be recognised as a historical, cultural and architectural landmark.

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.