Current Status of Repetitive Transcranial Magnetic Stimulation (rTMS) in Croatia and in University Psychiatric Hospital Sveti Ivan.

This article reviews the history, evolution, and current status of repetitive transcranial magnetic stimulation (rTMS) in Croatia. University Psychiatric Hospital Sveti Ivan experts performed the first rTMS in 2015 as a first treatment and research group in Croatia. In addition to being a leading center for rTMS in clinical trials and in treating depression, University Psychiatric Clinic Sveti Ivan TMS center continues to research rTMS for depression and other neuropsychiatric disorders and conditions, exploring novel stimulation parameters and individualized treatment protocols. Since 2017 rTMS treatment for MDD in Croatia has been reimbursed by the National Insurance Fund and has been available to hospital and ambulatory patients by indication, and now is widely used in other health centers in Croatia, to treat depression and other neuropsychiatric disorders and conditions, especially when drugs are ineffective or produce harmful side effects.

A pilot investigation of accelerated deep transcranial magnetic stimulation protocols in treatment-resistant depression.

Accelerated repetitive transcranial magnetic stimulation (rTMS) protocols are being increasingly studied because of their potential to provide quicker and enhanced treatment efficacy. However, there is a lack of accelerated deep TMS with H1-coil (adTMS) treatment research. This randomized pilot study investigated the efficacy and safety of adTMS protocols. Twenty-eight TRD patients received 20-min sessions twice daily for 10 or 15 days. Primary outcomes were changes in Hamilton Depression Rating Scale (HDRS) scores and discontinuation because of adverse events (AE). Secondary outcomes were response, remission, daily changes in Beck Depression Inventory-II (BDI-II) scores, and AE incidence. HDRS scores decreased by 13 (95% CI 11-17; 59%, 95% CI 45-73%) and 13 (95% CI 11-14; 62%, 95% CI 54-69%) points in the 10- and 15-day protocols, respectively. The adjusted difference between the two protocols was not significant or clinically relevant. Remission was achieved by 38% and 42% after 10-day and 15-day protocols, respectively. The intervention was discontinued because of AEs in 3/33 (9%) patients. The BDI-II decreases were significant and clinically relevant during the first 8 days. Twice-daily adTMS for 10 days seems to be safe and effective, with rapid clinical benefits during the first week of treatment. These promising results warrant further investigation in larger randomized clinical trials comparing adTMS with the standard dTMS protocol.

Hyperprolactinemia - side effect or part of the illness.

BACKGROUND: Hyperprolactinemia is associated with side effect of antipsychotics in people suffering from psychotic disorders. However, increased prolactin levels (mlU/L) were found in patients suffering from the first psychotic episode who were not receiving antipsychotic therapy. The assumption of this study is that the abnormality in the level of prolactin is associated with the effect and influence of the disease, not the therapy that is carried out. SUBJECTS AND METHODS: Study involved 54 female patients hospitalized in Psychiatric hospital "Sveti Ivan", whose average age was 33.9 years. All patients had been diagnosed with a psychotic disorder (according to MKB-10, F20-F29). 18 patients had their first psychotic episode, while 36 patients had relapses of psychotic disorder. The methods used were: PANSS scale and measurement of prolactin concentration (Immunoanalyzer ACCESS 2, CLIA method). Arithmetic mean, standard deviations, correlation coefficient, Mann Whitney U test and the chi-squared test were used. RESULTS: 75.5% of patients had prolactin values above the reference values (min 121, max 4192 ml/L). In a sample of patients with first psychotic episode, 77.8% had elevated prolactin levels, while among re-hospitalized patients, elevated levels had 74.2%. Statistically significant results were obtained: patients with higher pronounced symptoms had higher prolactin values, especially particles on PANSS: P1 (delusions), N4 (Apathy), G15 (preoccupation) and G16 (active avoidance). CONCLUSION: Elevated prolactin in patients has been demonstrated regardless of antipsychotic therapy, therefore the question of etiology of hyperprolactinemia in psychotic disorders is questionable. The association of hyperprolactinemia with the severity of the clinical picture has also been demonstrated, higher prolactin values indicating a stronger clinical picture, which calls into question the protective role of prolactin in psychotic disorders.

Clinical Challenges in Patients with First Episode Psychosis and Cannabis Use: Mini-Review and a Case Study.

The influence of cannabis use on the occurrence, clinical course and the treatment of the first psychotic episode (FEP) is well documented. However, the exact link is still not clearly established. The aim of this article is to review and report the noticed increase in the number of hospitalizations of young people with a clinical appearance of severe psychotic decompensation following cannabis consumption and to show the clinical challenges in treatment of the FEP. The case study describes the clinical course of a five selected patients with a diagnosis of the FEP and positive tetrahydrocannabinol (THC) urine test who were hospitalized in a similar pattern of events. They all have a history of cannabis consumption for at least 6 years in continuity and were presented with severe psychomotor agitation, disorganisation, confusion and aggression at admission. Although the chosen drug to treat all patients was atypical antipsychotic and benzodiazepines, the course of the disorder and the clinical response to therapy were noticeably different in each patient. The clinical presentation of FEP in cannabis users can be atypical and highly unpredictable from mild psychotic symptoms to severe substance intoxication delirium. In clinical practice clinicians treating new onset psychosis need to be watchful for cannabis and synthetic cannabinoids induced psychosis. Pharmacotherapeutic interventions include prompt and adequate use of the benzodiazepine, second-generation antipsychotic, and mood-stabilizers. Further research in the pharmacotherapy of cannabis-induced psychosis is required.

Efficacy of Center for Integrative Psychiatry Multimodal Early Intervention Services in Early-Phase Psychosis on Hospital Readmission.

BACKGROUND: Growing body of evidence has opened new opportunities to enhance treatment outcomes during early-phase psychosis (EPP). The objective of this study was to evaluate the effect of the Centre for integrative psychiatry (CIP) multimodal Early Intervention Services (EIS) on time to relapse in the patients with early-phase psychosis (EPP) during 12 and 24 month period. SUBJECTS AND METHODS: We performed a retrospective cohort study on the sample of 454 EPP patients (duration of the diagnosed disorder ≤5 years) admitted to Psychiatric Hospital "Sveti Ivan", Zagreb Croatia, from January 2, 2015, to December 5, 2018, for the acute treatment of EPP. The end of follow up was March 5, 2019. The primary outcome was the time to rehospitalization because of relapse during the 12 months from the hospital discharge. Independent variable was the EIS. RESULTS: We analyzed 454 EPP patients, 260 in EIS group and 194 in no EIS group. After the adjustment for twenty possible confounding factors using the Cox proportional hazard regression, patients who received EIS had significantly and clinically relevantly lower hazard for rehospitalization because of relapse during the first 12 months (HR=0.39; CI95% 0.21-0.61; p<0.001), and during the first 24 months from the hospital discharge (HR=0.56; CI95% 0.39-0.80; p=0.003; sequential Holm-Bonferroni corrected pcorr=0.004). CONCLUSIONS: Our study indicated efficacy of the CIP multimodal EIS in patients with EPP demonstrated through the time to the hospital readmission because of relapse during the 12 and 24 months from the hospital discharge. These results strongly support the need for implementation of multimodal EIS in all patients with EPP.

Early Intervention Services for Early-Phase Psychosis - Centre for integrative psychiatry in Psychiatric Hospital "Sveti Ivan", Croatia.

BACKGROUND: There is a growing body of evidence suggesting that early and effective management in the critical early years of schizophrenia can improve long-term outcomes. The objective of this study was to evaluate time to relapse of the patients with early-phase psychosis treated in the Centre for integrative psychiatry (CIP). SUBJECT AND METHODS: We performed a retrospective cohort study on the sample of 373 early-phase psychosis patients admitted to Psychiatric Hospital "Sveti Ivan", Zagreb Croatia: from January 1, 2015 to December 31, 2017. The primary outcome was time to relapse. RESULTS: Patients who were admitted to group psychotherapeutic program after the end of acute treatment had 70% lower hazard for relapse (HR=0.30; 95% CI 0.16-0.58). Patients who were included first in the psychotherapeutic program and then treated and controlled in the daily hospital had 74% lower hazard for relapse (HR=0.26; 95% CI 0.10-0.67). CONCLUSIONS: In early-phase psychosis, integrative early intervention service has relevant beneficial effects compare to treatment as usual. These results justified the implementation of multimodal early intervention services in treatment of patients with early-phase psychosis.

Day Hospital Treatment as a Missing Link for Single Patients with Posttraumatic Stress Disorder (PTSD): a Preliminary Study.

BACKGROUND: The aim of this study was to examine the day hospital treatment outcome on severity of clinical manifestations, general neuroticism and coping mechanisms in patients suffering from chronic combat-related PTSD. SUBJECTS AND METHODS: The sample consisted of 38 consecutive patients admitted to the Day Hospital treatment of PTSD during one year observation period. The average age of the sample was 46.03 years. The patients completed 3 self-report measures upon admission to the hospital and upon discharge: The Mississippi scale for combat-related PTSD (M-PTSD), The Crown-Crisp experiential index (CCEI), and The COPE inventory. RESULTS: There was no significant change in the severity of clinical manifestations of PTSD, general neuroticism and coping mechanisms among the whole sample. However, compared to married participants and participants with children, single participants and those without children reported higher levels of anxiety when admitted to the hospital, but lower levels at discharge. In addition, patients without children reduced their avoidance behavior during the treatment. CONCLUSION: This preliminary study showed that single patients and those without children may benefit more from the day hospital treatment program. Our findings emphasize the importance of social support in the recovery process of severely traumatized persons, and may assist with the development of more effective therapeutic approaches.

Somatic comorbidities are independently associated with the poor health-related quality of life in psychiatric patients.

BACKGROUND: Despite the increased risk, the quality of somatic healthcare is lower for patients with mental illnesses. Currently dominant approach separates physical and mental, primary and secondary healthcare. Objective of our study was to explore whether somatic comorbidities are associated with a poor HRQoL independently of some sociodemographic and clinical factors. Majority of studies have explored particular somatic and psychiatric illnesses. Therefore we decided to access the problem from the general perspective of the universe of somatic and mental illnesses in the large psychiatric institution. SUBJECTS AND METHODS: This nested cross-sectional study was done during May 2016 at Psychiatric hospital Sveti Ivan, Zagreb, Croatia on the sample of 506 patients diagnosed with psychiatric illnesses (ICD-10: F00-F99). Key outcome was the lowest 25% results on the SF-36 General health sub-scale, indicating the worst HRQoL. Predictors were all detected somatic illnesses. By multivariate logistic regression we controlled different sociodemographic, vital and clinical factors. RESULTS: After adjustment for different sociodemographic and clinical factors, three somatic comorbidities remained independently associated with the worst HRQoL: endocrine, nutritional and metabolic diseases (E00-E90), diseases of respiratory system (J00-J99) and diseases of musculoskeletal system and connective tissue (M00-M99) CONCLUSIONS: Somatic comorbidities in psychiatric patients are associated with the poor HRQoL independently of different sociodemographic, vital and clinical factors and they should be treated seriously and integrally with mental aspects of HRQoL. Early comorbidities detection and adequate pharmacological and psychotherapeutic treatment, as well as the prevention of risk factors, may improve the quality of life and reduce morbidity and mortality of psychiatric patients.

Deep coverage of the Escherichia coli proteome enables the assessment of false discovery rates in simple proteogenomic experiments.

Recent advances in mass spectrometry (MS) have led to increased applications of shotgun proteomics to the refinement of genome annotation. The typical "proteo-genomic" workflows rely on the mapping of peptide MS/MS spectra onto databases derived via six-frame translation of the genome sequence. These databases contain a large proportion of spurious protein sequences which make the statistical confidence of the resulting peptide spectrum matches difficult to assess. Here we performed a comprehensive analysis of the Escherichia coli proteome using LTQ-Orbitrap MS and mapped the corresponding MS/MS spectra onto a six-frame translation of the E. coli genome. We hypothesized that the protein-coding part of the E. coli genome approaches complete annotation and that the majority of six frame-specific (novel) peptide spectrum matches can be considered as false positive identifications. We confirm our hypothesis by showing that the posterior error probability distribution of novel hits is almost identical to that of reversed (decoy) hits; this enables us to estimate the sensitivity, specificity, accuracy, and false discovery rate in a typical bacterial proteo-genomic dataset. We use two complementary computational frameworks for processing and statistical assessment of MS/MS data: MaxQuant and Trans-Proteomic Pipeline. We show that MaxQuant achieves a more sensitive six-frame database search with an acceptable false discovery rate and is therefore well suited for global genome reannotation applications, whereas the Trans-Proteomic Pipeline achieves higher specificity and is well suited for high-confidence validation. The use of a small and well-annotated bacterial genome enables us to address genome coverage achieved in state-of-the-art bacterial proteomics: identified peptide sequences mapped to all expressed E. coli proteins but covered 31.7% of the protein-coding genome sequence. Our results show that false discovery rates can be substantially underestimated even in "simple" proteo-genomic experiments obtained by means of high-accuracy MS and point to the necessity of further improvements concerning the coverage of peptide sequences by MS-based methods.

Quantitative phosphoproteomics of murine Fmr1-KO cell lines provides new insights into FMRP-dependent signal transduction mechanisms.

Fragile X mental retardation protein (FMRP) is an RNA-binding protein that has a major effect on neuronal protein synthesis. Transcriptional silencing of the FMR1 gene leads to loss of FMRP and development of Fragile X syndrome (FXS), the most common known hereditary cause of intellectual impairment and autism. Here we utilize SILAC-based quantitative phosphoproteomics to analyze murine FMR1(-) and FMR1(+) fibroblastic cell lines derived from FMR1-KO embryos to identify proteins and phosphorylation sites dysregulated as a consequence of FMRP loss. We quantify FMRP-related changes in the levels of 5,023 proteins and 6,133 phosphorylation events and map them onto major signal transduction pathways. Our study confirms global downregulation of the MAPK/ERK pathway and decrease in phosphorylation level of ERK1/2 in the absence of FMRP, which is connected to attenuation of long-term potentiation. We detect differential expression of several key proteins from the p53 pathway, pointing to the involvement of p53 signaling in dysregulated cell cycle control in FXS. Finally, we detect differential expression and phosphorylation of proteins involved in pre-mRNA processing and nuclear transport, as well as Wnt and calcium signaling, such as PLC, PKC, NFAT, and cPLA2. We postulate that calcium homeostasis is likely affected in molecular pathogenesis of FXS.

High NF-κB and STAT3 activity in human urothelial carcinoma: a pilot study.

PURPOSE: Given that the tumor-promoting inflammation has been previously established in squamous cell carcinoma of the bladder but its contribution to development of urothelial carcinoma (UC) still remains elusive, our aim was to study changes in expression and activity of inflammation-mediating NF-κB and STAT3 transcription factors in human urothelial bladder carcinoma as well as expression of their target genes cyclin D1, VEGFA and TGFß1. METHODS: Gene expression of STAT3, NF-κB, TGFß1, cyclin D1 and VEGFA was measured by quantitative real-time polymerase chain reaction in both tumor and healthy bladder tissue from 36 patients with UC of the bladder. Activation of STAT3 and NF-κB was assessed with immunohistochemistry and immunoblot. RESULTS: Urothelial bladder carcinoma displayed elevated expression as well as activation of NF-κB (P = 5.38e-10) and STAT3 (P = 0.002) transcription factors. Furthermore, elevated level of expression was observed for cyclin D1, VEGFA and TGFß1 (P = 9.71e-09, P = 9.71e-09, P = 5.38e-10). Preliminary statistical analysis indicated that the level of upregulation of STAT3 or NF-κB was probably not dependent upon the grade (P = 0.984 and 0.803, respectively) and invasiveness of the tumor (0.399 and 0.949), nor to the gender (0.780 and 0.536) and age (0.660 and 0.816) of the patients. CONCLUSIONS: NF-κB and STAT3 signaling pathways, as main inflammatory mediators, are found to be activated in urothelial bladder carcinoma indicating that chronic inflammatory processes are accompanying development of this tumor type. Future studies will have to determine possible causative role of inflammatory processes in development of urothelial bladder carcinomas.

[The existence of geographical clusters of rheumatiod arhritis according to their origin in a tertiary care based register]. / Postojanje zemljopisnih klastera reumatoidnog artritisa na osnovu podrijetla prema podacima tercijarnog centra.

The objective was to analyse epidemiological tendencies of rheumatoid arthritis (RA) in Dalmatia County in order to identify possible spatial clusters of RA. Patient-interviewers were trained to administer telephone surveys. 197 RA patients controlled at Rheumatology and immunology department of Clinical hospital of Split were mapped to place of residence by telephone survey. Statistical evidence of clustering was determined by calculating Poisson probabilities in putative areas. Four clusters were identified; the largest one was in the region of Sinj. The female/male ratio was 5.79:1. Majority of RA patients were among age 50 to 59 (30.45 %). The results show inter-regional variations with the marked clusters in the north of Dalmatia suggesting that clusters with higher incidence of RA have specific genetic and environmental background. Prevalence of RA in female was higher than in current literature, while the age of onset 50-59 years is similar with data from recent studies.

The prevalence of diabetes mellitus and abnormal lipid status among Croatian hospitalized coronary heart disease patients.

The aim of this article was to investigate the prevalence of diabetes mellitus and abnormal lipid status with selected anthropometric variables in a sample of hospitalized coronary heart disease (CHD) patients in Croatia (N = 1,298). Prevalence of diabetes mellitus was 31.6% (statistically significantly more frequent in women, 35.7% vs. 30.0%), while prevalences of increased total cholesterol were 72.0%, decreased HDL-cholesterol 42.6% (statistically significantly more frequent in women, 50.2% vs. 39.6%), increased LDL-cholesterol 72.3% and increased triglycerides 51.5%. Reported data on prevalences of diabetes mellitus can be somewhat reassuring (a decrease in its prevalence compared to data from 2006, but they still signal a situation which is a lot worse than in 2002 and 2003); the trend of rising prevalences of dyslipidaemic cardiovascular risk factors must be a cause for an alarm, furthermore as today's preventive and treatment measures in cardiology, both primary and secondary, are strongly focused on dyslipidaemias.

Antipsychotics-induced hyperprolactinemia and screening for macroprolactin.

INTRODUCTION: High prolactin (PRL) concentrations are found in laboratory test results of patients on majority of antipsychotic drugs. Prevalence rates and degrees of severity of hyperprolactinemia (HPRL) based on PRL concentration may depend on the presence of macroprolactin in the serum. The aim of the study was to investigate the difference between PRL concentrations before and after precipitation of macroprolactin and to examine if there were any changes in the categorization of HPRL between samples prior and after precipitation. MATERIALS AND METHODS: Total of 98 female patients (median age 33; range 19-47 years) diagnosed with a psychotic disorder, proscribed antipsychotic drugs, and with HPRL were included. Total PRL concentration and PRL concentration after macroprolactin precipitation with polyethylene glycol (postPEG-PRL) were determined by the chemiluminometric method on the Beckman Coulter Access2 analyser. RESULTS: Total PRL concentrations (median 1471; IQC: 1064-2016 mlU/L) and postPEG-PRL concentrations (median 1453; IQC: 979-1955 mlU/L) were significantly correlated using intraclass correlation coefficient for single measurements (mean estimation 0.96; 95%CI 0.93-0.97) and average measurement (mean estimation 0.98; 95%CI 0.96-0.99), and all investigated female patient had HPRL according to PRL and postPEG-PRL concentration. The median PRL recovery following PEG precipitation was 95; IQC: 90-100%. There was substantial agreement (kappa test = 0.859, 95% CI: 0.764-0.953) between the categories of HPRL severity based on total PRL concentrations and postPEG-PRL concentrations. CONCLUSION: The study demonstrated that HPRL was present in all subjects using the reference interval for total PRL concentration and postPEG-PRL concentration with no significant impact of macroprolactin presence in the serum on the categorization of patients according to severity of HPRL.

Quantitative proteomics of the human skin secretome reveal a reduction in immune defense mediators in ectodermal dysplasia patients.

In healthy human skin host defense molecules such as antimicrobial peptides (AMPs) contribute to skin immune homeostasis. In patients with the congenital disease ectodermal dysplasia (ED) skin integrity is disturbed and as a result patients have recurrent skin infections. The disease is characterized by developmental abnormalities of ectodermal derivatives and absent or reduced sweating. We hypothesized that ED patients have a reduced skin immune defense because of the reduced ability to sweat. Therefore, we performed a label-free quantitative proteome analysis of wash solution of human skin from ED patients or healthy individuals. A clear-cut difference between both cohorts could be observed in cellular processes related to immunity and host defense. In line with the extensive underrepresentation of proteins of the immune system, dermcidin, a sweat-derived AMP, was reduced in its abundance in the skin secretome of ED patients. In contrast, proteins involved in metabolic/catabolic and biosynthetic processes were enriched in the skin secretome of ED patients. In summary, our proteome profiling provides insights into the actual situation of healthy versus diseased skin. The systematic reduction in immune system and defense-related proteins may contribute to the high susceptibility of ED patients to skin infections and altered skin colonization.

Carpal tunnel syndrome is associated with high fibrinogen and fibrinogen deposits.

BACKGROUND: Idiopathic carpal tunnel syndrome (ICTS) is a common entrapment neuropathy. Some cases of ICTS are linked to mutations of the transthyretin gene, whereas others are associated with systemic amyloidosis. The majority of ICTS cases are of unknown etiology. OBJECTIVE: To study molecular mechanisms of ICTS development. METHODS: A total of 71 ICTS patients and 68 control subjects were included in the study. The fibrinogen level was determined before surgery and its deposition in the transversal carpal ligament (TCL) was detected by immunohistochemistry, Western blot, and mass spectrometry. Fibrinogen interaction with other proteins was studied by immunoprecipitation assay. RESULTS: Plasma levels of the proinflammatory and hemostatic protein fibrinogen are elevated in ICTS patients. Other measured systemic inflammatory markers were not affected, and local inflammatory responses in TCL were absent. ICTS patients have shorter bleeding times, probably because of the elevated plasma levels of fibrinogen. Polymorphisms of the fibrinogen B promoter region were previously associated with increased plasma fibrinogen, but this association was not observed among patients with ICTS. Interestingly, we detected fibrinogen deposits in the TCL, whereas transcriptional activity of the fibrinogen genes was low. Amyloidogenic proteins, including transthyretin and α-synuclein, were also found in the TCL, whereas their local transcriptional activity was rather high. Finally, we demonstrated that fibrinogen interacts with transthyretin and α-synuclein in TCL lysates. CONCLUSION: Our data indicate that fibrinogen and other aggregation-prone proteins have potentially important roles in the pathogenesis of ICTS.