Effects of salt and stress on blood pressure parameters and antioxidant enzyme function in the heart and aorta of borderline hypertensive rats.

NEW FINDINGS: What is the central question of this study? Although the involvement of reactive oxidative species in triggering hypertension has been documented, there are no data about the role of antioxidant enzymes in the heart and aorta of borderline hypertensive rats kept in baseline conditions or exposed to high salt with or without repeated stress. What is the main finding and its importance? In borderline hypertensive rats, high salt intake and stress contribute significantly to increase blood pressure and antioxidative defence in the aorta but decrease it in the heart. Elucidating the early changes that accompany elevated blood pressure could provide new therapeutical venues for prevention and treatment of the condition. ABSTRACT: Hypertension and its complications are a leading cause of death in the human population. Several factors can contribute to development of hypertension, such as genetic predisposition, high salt intake and environmental stressors, underlying oxidative stress as one of its key trademarks. We studied the effects of increased salt intake and chronic stress on blood pressure parameters and the activity and protein levels of antioxidant enzymes in the heart and aorta of borderline hypertensive rats (BHRs) with genetic susceptibility to hypertension. All animals were randomized into four groups: (1) Wistar rats kept in baseline conditions; (2) BHRs kept in baseline conditions; (3) BHRs drinking 0.9% saline solution; and (4) BHRs drinking 0.9% saline solution and exposed to repeated heterotypic stress. The BHRs exhibited significantly higher blood pressure, mitochondrial superoxide dismutase (SOD2) and catalase (CAT) protein levels and lower glutathione peroxidase (GPx) and glutathione reductase (GR) activities in the aorta, followed by lower CAT and GPx protein levels and higher CAT and GR activities in the heart, compared with normotensive Wistar rats. In the BHR aorta, high salt intake elevated CAT and GPx activities, and when combined with stress it increased GPx and GR activities. In BHR hearts, high salt intake provoked lower CAT activity. Adding repeated stress to salt treatment further decreased CAT activity, in addition to Cu2+ -Zn2+ superoxide dismutase (SOD1) and GR activities. The protein level of CAT was lower, whereas SOD2 and GPx increased. Overall, our results suggest that BHR hearts are better adapted to oxidative pressure, compared with the aorta, when exposed to salt and stress.

Perceived sustainability of psychosocial treatment in low- and middle-income countries in South-Eastern Europe.

BACKGROUND: DIALOG+ is an evidence-based, generic, cost-saving and easily deliverable psychosocial intervention, adaptable to clinicians' personal manner of interaction with patients. It was implemented in mental health services in five low- and middle-income countries in South-Eastern Europe during a 12-month randomised-controlled trial (IMPULSE) to improve the effectiveness of out-patient treatment for people with psychotic disorders. AIMS: To investigate barriers and facilitators to the perceived sustainability of DIALOG+ that has been successfully implemented as a part of the IMPULSE project. METHOD: Three months after the IMPULSE trial's end, perceived sustainability of the DIALOG+ intervention was assessed via a short survey of clinicians and patients who took part in the trial. Quantitative data collected from the survey were analysed using descriptive statistics; content analysis assessed qualitative survey data. The views and experiences of key informants (patients, clinicians and healthcare policy influencers) regarding the sustainability and scale-up of DIALOG+ were further explored through semi-structured interviews. These data were explored using framework analysis. RESULTS: Clinicians mostly appreciated the comprehensiveness of DIALOG+, and patients described DIALOG+ meetings as empowering and motivating. The barrier most commonly identified by key informants was availability of financial resources; the most important facilitators were the clinically relevant structure and comprehensiveness of the DIALOG+ intervention. CONCLUSIONS: Participants showed a willingness to sustain the implementation of DIALOG+. It is important to maintain collaboration with healthcare policy influencers to improve implementation of DIALOG+ across different levels of healthcare systems and ensure availability of resources for implementing psychosocial interventions such as DIALOG+.

Maintenance Therapy of Psychosis Spectrum Disorders in a Real-World Setting: Antipsychotics Prescription Patterns and Long-Term Benzodiazepine Use.

Background: Maintenance therapy of patients with primary psychosis spectrum disorders (PSD) in the Western Balkans has received limited interest so far. The present study aimed to investigate long-term prescription patterns among outpatients with PSD. Methods: Information about prescription of antipsychotics (AP), benzodiazepines (BZD) and other psychotropic medication over a 6-month period was collected from outpatients (n = 134; ICD-10 diagnosis F20-29) recruited by a larger multi-site study, to find mean daily number of psychotropic drugs, AP prescription patterns (including AP daily dose, route of administration, monotherapy vs. polypharmacy) and BZD utilization (long-term add-on BZD therapy). Additionally, sex-differences in the variables were explored. Results: Clinically stable outpatients (age 41.7 ± 11.0; male 62.7%; duration of untreated illness 12.7 ± 8.7 years; mean number of lifetime hospitalizations 2.6 ± 0.7) were prescribed 2.8 ± 1.1 psychotropic medications daily. The mean 6-month AP dose was 14.2 ± 7.8 mg olanzapine equivalents. Long-acting injectable AP was prescribed to 25.2% of the patients. Long-term AP monotherapy was found in 52.7% patients and most of them were prescribed second generation AP (65.2%). Long-term AP polypharmacy (42.7%) was more common in males (p = 0.015). The most frequent co-prescription patterns were first generation AP plus clozapine. The highest rate of long-term AP co-prescription was found for BZD (in 42.7% cases, average 6-months daily dose of 2.8 ± 2.7 mg lorazepam equivalents) and anticholinergics (33.6%). Conclusion: Existing appropriately designed interventions aiming to safely switch the inappropriate therapeutic regimens, i.e. very high prevalence of long-term AP polypharmacy and non-rational BZD co-prescription, should be implemented in the region of Western Balkans.

The Paraventricular Nucleus of the Hypothalamus in Control of Blood Pressure and Blood Pressure Variability.

The paraventricular nucleus (PVN) is a highly organized structure of the hypothalamus that has a key role in regulating cardiovascular and osmotic homeostasis. Functionally, the PVN is divided into autonomic and neuroendocrine (neurosecretory) compartments, both equally important for maintaining blood pressure (BP) and body fluids in the physiological range. Neurosecretory magnocellular neurons (MCNs) of the PVN are the main source of the hormones vasopressin (VP), responsible for water conservation and hydromineral balance, and oxytocin (OT), involved in parturition and milk ejection during lactation. Further, neurosecretory parvocellular neurons (PCNs) take part in modulation of the hypothalamic-pituitary-adrenal axis and stress responses. Additionally, the PVN takes central place in autonomic adjustment of BP to environmental challenges and contributes to its variability (BPV), underpinning the PVN as an autonomic master controller of cardiovascular function. Autonomic PCNs of the PVN modulate sympathetic outflow toward heart, blood vessels and kidneys. These pre-autonomic neurons send projections to the vasomotor nucleus of rostral ventrolateral medulla and to intermediolateral column of the spinal cord, where postganglionic fibers toward target organs arise. Also, PVN PCNs synapse with NTS neurons which are the end-point of baroreceptor primary afferents, thus, enabling the PVN to modify the function of baroreflex. Neuroendocrine and autonomic parts of the PVN are segregated morphologically but they work in concert when the organism is exposed to environmental challenges via somatodendritically released VP and OT by MCNs. The purpose of this overview is to address both neuroendocrine and autonomic PVN roles in BP and BPV regulation.

Paroxetine mitigates cardiac remodelling by doxorubicin and increases survival.

Doxorubicin (DOX) is an effective anticancer drug. However, its use is hampered by the development of very mortal cardiomyopathy. Here, we investigate whether the co-administration of the antidepressant paroxetine (P), known to exert beneficial cardiovascular effects, would provide effective cardioprotection. Experiments were performed in male Wistar rats randomly assigned to control group (0.5 mL/kg 0.9% NaCl, i.v., n = 7), DOX group (DOX 5 mg /kg i.v., n = 23) and DOX+P group (DOX 5 mg/kg, i.v. plus P 10 mg/kg p.o. daily, beginning five days before DOX administration and during the follow-up period, n = 11). Rats' body weight and echocardiography parameters were monitored before and after drug/vehicle administration. Cardiac histology was performed post-mortem, as well as beta1-adrenergic receptor (ß1-AR), beta2-adrenergic receptor (ß2-AR), G protein-coupled receptor kinases type 2 (GRK2), type 3 (GRK3), beta-arrestin 1, and beta-arrestin 2 gene expression using RT-qPCR. DOX-treated rats exhibited bad general condition, adynamia, loss of body weight, and low survival. Echocardiography revealed two phenotypes: cardiomyopathy with left ventricular (LV) hypertrophy (DOX-HCM) and cardiomyopathy with LV dilation (DOX-DCM). In DOX-HCM rats only, there was an increased GRK2 and GRK3 gene expression and synthesis. DOX+P co-treated rats exhibited good general condition, normal spontaneous behaviour, gained weight over time, had increased survival, and preserved LV morphology and contractility. In these rats, gene expression and synthesis of GRK2 and GRK3 were decreased, while ß1-AR and ß2-AR were increased. Present results show for the first time that P effectively reduces DOX-induced cardiotoxicity and enhances survival.

Long-Term Benzodiazepine Prescription During Maintenance Therapy of Individuals With Psychosis Spectrum Disorders-Associations With Cognition and Global Functioning.

BACKGROUND: Cognitive difficulties have a significant impact on life functioning and overall well-being in patients with psychosis spectrum disorders (PSDs). There are indications that continuous use of benzodiazepines (BZDs) in various patient groups has a detrimental effect on cognition. Our aim was to explore the association between long-term BZD prescription, global functioning, and cognitive functioning in persons with PSD. METHODS: This exploratory study included 55 PSD patients, recruited from 2 outpatient services in Serbia. Patients were grouped into BZD long-term prescription group and BZD-other group. Brief Psychiatric Rating Scale was used for symptom assessment, functioning was measured by Global Assessment and Functioning Scale, and cognition was assessed by the Global Assessment of Functioning-Cognition in Schizophrenia Scale. RESULTS: The sample comprised 52.7% patients who were prescribed with BZD for 6 months or more continually (29/55), with a mean daily dose of 3.16 ± 0.66 mg lorazepam equivalents. There were no differences between study groups in any of the sociodemographic characteristics, duration of illness, or antipsychotic daily dosages. The BZD long-term prescription group had lower global (P < 0.01) and cognitive functioning (P < 0.01), higher Brief Psychiatric Rating Scale scores (1.86 vs 1.58, respectively, P < 0.01), and more psychotropic drugs prescribed on a daily basis than the other group (median: 4 vs 2, respectively, P < 0.01). CONCLUSIONS: The study explored a topic that continues to be underresearched, especially in the Balkans. Prospective studies and comprehensive cognitive batteries are needed to further elucidate the associations between polypharmacy, long-term BZD use, cognitive functioning, and global functioning during maintenance therapy of individuals with PSD.

Factorial Structure of the Serbian Version of the Clinical Assessment Interview for Negative Symptoms - Evidence for Three Factors of Negative Symptoms.

Introduction: Negative symptoms are a common occurrence in patients with psychosis spectrum disorders. Previous analysis of the latent structure of the Clinical Assessment Interview for Negative Symptoms (CAINS) - which was developed to advance the assessment of negative symptomatology - showed two underlying sub-domains (Motivation and Pleasure; Expression). Recent findings indicate that a more complex structure might be more applicable. Aim: To evaluate the psychometric properties of the Serbian version of the CAINS in a sample of outpatients (N = 67) with psychosis spectrum disorders. Materials and Methods: Negative symptoms and general level of psychopathology were assessed with Serbian translations of the CAINS, the 53-item version of the Brief Symptom Inventory (BSI), and the 24-item version of the Brief Psychiatric Rating Scale (BPRS). Principal component analysis (PCA) was carried out on the CAINS items, and correlation analyses were done to assess its convergent and discriminant validity. Results: Our results showed an excellent internal consistency (Cronbach's alpha = 0.92). PCA revealed a three-component solution consisting of Expressiveness and Motivation for Social and Family Relationships (Factor 1), Motivation for Vocational Activities (Factor 2), and Motivation for Recreation (Factor 3). Convergent validity was supported by significant correlations with the Negative symptoms domain of the BPRS (Factor 1, 0.695, p < 0.01; Factor 2, 0.352, p < 0.05; Factor 3, 0.452, p < 0.01). When assessing discriminant validity, weak correlations were found with BPRS and BSI scores. Conclusion: The Serbian version of CAINS is a valid, reliable and useful tool for the assessment of negative symptomatology. Our findings support a three-factor structure of CAINS, which indicates that the construct is more complex than envisaged by the original conceptualization of two distinct factors.

Vasopressin and v1br gene expression is increased in the hypothalamic pvn of borderline hypertensive rats.

Vasopressin (VP) is a neurohypophyseal peptide best known for its role in maintaining osmotic and cardiovascular homeostasis. The main sources of VP are the supraoptic and paraventricular (PVN) nuclei of the hypothalamus, which coexpress the vasopressin V1a and V1b receptors (V1aR and V1bR). Here, we investigated the level of expression of VP and VP receptors in the PVN of borderline hypertensive rats (BHRs), a key integrative nucleus for neuroendocrine cardiovascular control. Experiments were performed in male BHRs and Wistar rats (WRs) equipped with a radiotelemetry device for continuous hemodynamic recording under baseline conditions and after saline load without or with stress. Autonomic control of the circulation was evaluated by spectral analysis of blood pressure (BP) and heart rate (HR) variability and baroreceptor reflex sensitivity (BRS) using the sequence method. Plasma VP was determined by radioimmunoassay, and VP, V1aR, and V1bR gene expression was determined by RT-qPCR. Under baseline conditions, BHRs had higher BP, lower HR, and stronger BRS than WRs. BP and HR variability was unchanged. In the PVN, overexpression of the VP and V1bR genes was found, and plasma VP was increased. Saline load downregulated V1bR mRNA expression without affecting VP mRNA expression or plasma VP and BP. Adding stress increased BP, HR, and low-frequency sympathetic spectral markers and decreased plasma VP without altering the level of expression of VP and VP receptors in the PVN. It follows that overexpression of VP and V1bR in the PVN is a characteristic trait of BHRs and that sympathetic hyperactivity underlies stress-induced hypertension.

Maintenance phase treatment of psychotic disorders in outpatients from Serbia - focus on long-term benzodiazepine use.

Introduction: Prescribing trends in maintenance therapy of patients with primary psychotic disorders (PSD) may vary worldwide. Present study aimed to investigate prescription patterns in a sample of outpatients with PSD from Serbia.Methods: In a sample of 73 PSD outpatients we analysed the rate of antipsychotic polypharmacy and psychotropic polypharmacy, concomitant continual benzodiazepine use, and associations between therapy, psychotic symptoms and quality of life.Results: Maintenance therapy (median daily dose 321 mg of chlorpromazine equivalents) predominantly consisted of monotherapy with second generation antipsychotics (45.2%), followed by antipsychotic polypharmacy based on first and second generation combination (25.0%). The median number of psychotropic drugs was 3. Benzodiazepines were continually prescribed to more than 60% of patients (mean daily dose 2.9 ± 2.0 mg lorazepam equivalents). Patients with benzodiazepine use had significantly more psychotropic medications and more antipsychotic polypharmacy, poorer quality of life and more severe psychopathology in comparison to another group.Conclusion: The present study demonstrated new information regarding the prescription patterns of psychotropic drugs in outpatients with PSD in Serbia, amplified with clinically relevant information. This study also revealed distinct prescription patterns concerning antipsychotic/benzodiazepine polypharmacy. Overall, such findings are likely to contribute to improving clinical practice and care for patients with PSD in general.KeypointsPresent exploratory research aimed to elucidate trends of antipsychotics polypharmacy and concomitant use of psychotropic medications including benzodiazepines in the maintenance treatment of outpatients with schizophrenia and other psychotic disorders, amplified with clinically relevant information (symptoms and quality of life).'Antipsychotic (AP) polypharmacy' was defined as concurrent use of more than one AP for at least 1 month; 'Psychotropic polypharmacy' was defined as the combination of AP and a different class of psychotropic drugs medication for at least one month.The median number of prescribed psychotropic drugs was 3 (mean 3.1 ± 1.1) and the average AP daily dose was moderate (median 321 mg of chlorpromazine equivalents). However, the rates of AP polypharmacy (45.2%) and benzodiazepine prescription on a continual basis (>60%) found in our sample could be considered relatively high.Outpatients with higher AP daily dose and higher BPRS symptom score were receiving more benzodiazepines.For improvement of the local, as well as general clinical practice and care for patients with psychotic disorders, and for education in psychiatry, such analyses need to be done on a regular basis and on larger samples.

Transcriptome Analysis Reveals Downregulation of Urocortin Expression in the Hypothalamo-Neurohypophysial System of Spontaneously Hypertensive Rats.

The chronically increased blood pressure characteristic of essential hypertension represents an insidious and cumulative risk for cardiovascular disease. Essential hypertension is a multifactorial condition, with no known specific aetiology but a strong genetic component. The Spontaneously Hypertensive rat (SHR) shares many characteristics of human essential hypertension, and as such is a commonly used experimental model. The mammalian hypothalamo-neurohypophyseal system (HNS) plays a pivotal role in the regulation of blood pressure, volume and osmolality. In order to better understand the possible role of the HNS in hypertension, we have used microarray analysis to reveal differential regulation of genes in the HNS of the SHR compared to a control normotensive strain, the Wistar Kyoto rat (WKY). These results were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One of the genes identified and validated as being downregulated in SHR compared to WKY was that encoding the neuropeptide urocortin (Ucn). Immunohistochemical analyses revealed Ucn to be highly expressed within magnocellular neurons of the PVN and SON, with pronounced localisation in dendritic projections containing oxytocin and vasopressin. When Ucn was overexpressed in the PVN of the SHR by in vivo lentiviral mediated gene transfer, blood pressure was unaffected but there were significant, transient reductions in the VLF spectra of systolic blood pressure consistent with an action on autonomic balance. We suggest that Ucn may act, possibly via dendritic release, to subtly regulate neurohumoral aspects of arterial pressure control.

The Penrod score: a prognostic instrument to balance an increasing geriatric fracture caseload with diminishing health care resources?

INTRODUCTION: Geriatric hip fracture patients are a highly heterogeneous collective, what distinctly aggravates the best possible treatment. Consequently, it is becoming more important to identify selection criteria that can distinguish those patients who can benefit the most from treatment in a geriatric fracture center. In our pilot study, we assessed the 2007 published Penrod score for its utility as a useful selection tool by prospectively comparing our own patient's outcome with the Penrod study. METHODS: 77 patients treated for geriatric hip fracture were preoperatively classified according to the Penrod score. Patients were divided into three clusters by age (1: <75 years, 2: 75-84 years, 3: ≥85 years). Clusters 2 and 3 were then classified according to their ability to perform activities of daily living (ADL's) and cognitive status (presence or absence of dementia). In 51 out of these 77 patients, the ability to perform ADLs could be assessed 6 months postoperatively and was compared with the Penrod scores. RESULTS: 58 % of cluster 1 patients were able to perform 4 ADLs independently 6 months postoperatively (52.9 % Penrod study). In clusters 2A and 3A, 48 and 50 %, respectively, were able to perform 4 ADLs independently, compared with 40.6 and 31.5 % (Penrod collective). 22 % of our patients in 2B performed all ADLs independently (3.6 % Penrod) and 25 % in cluster 3B (9.4 % Penrod). CONCLUSION: Our preliminary results support the prognostic value of the Penrod score in the treatment of geriatric hip fracture patients. With the help of the Penrod score, it may be possible to identify patients, who are expected to significantly profit from an intensified treatment in a geriatric fracture center (clusters 2B, 3A, and 3B). By utilizing this score, improved outcomes and simultaneously a more effective utilization of valuable health care resources could be achieved.

Auxin amidohydrolases from Brassica rapa cleave the alanine conjugate of indolepropionic acid as a preferable substrate: a biochemical and modeling approach.

Two auxin amidohydrolases, BrIAR3 and BrILL2, from Chinese cabbage [Brassica rapa L. ssp. pekinensis (Lour.) Hanelt] were produced by heterologous expression in Escherichia coli, purified, and screened for activity towards N-(indol-3-ylacetyl)-L-alanine (IAA-Ala) and the long-chain auxin-amino acid conjugates, N-[3-(indol-3-yl)propionyl]-L-alanine (IPA-Ala) and N-[4-(indol-3-yl)butyryl]-L-alanine (IBA-Ala). IPA-Ala was shown to be the favored substrate of both enzymes, but BrILL2 was approximately 15 times more active than BrIAR3. Both enzymes cleaved IBA-Ala and IAA-Ala to a lesser extent. The enzyme kinetics were measured for BrILL2 and the obtained parameters suggested similar binding affinities for the long-chain auxin-amino acid conjugates (IPA-Ala and IBA-Ala). The velocity of the hydrolyzing reaction decreased in the order IPA-Ala > IBA-Ala > IAA-Ala. In a root growth bioassay, higher growth inhibition was caused by IPA-Ala and IBA-Ala in comparison with IAA-Ala. Neither these conjugates nor the corresponding free auxins affected the expression of the BrILL2 gene. A modeling study revealed several possible modes of IPA-Ala binding to BrILL2. Based on these results, two possible scenarios for substrate hydrolysis are proposed. In one the metal binding water is activated by the carboxyl group of the substrate itself, and in the other by a glutamate residue from the active site of the enzyme.