Impaired synaptic incorporation of AMPA receptors in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common monogenetic cause of inherited intellectual disability and autism in humans. One of the well-characterized molecular phenotypes of Fmr1 KO mice, a model of FXS, is increased translation of synaptic proteins. Although this upregulation stabilizes in adulthood, abnormalities during the critical period of plasticity have long-term effects on circuit formation and synaptic properties. Using high-resolution quantitative proteomics of synaptoneurosomes isolated from the adult, developed brains of Fmr1 KO mice, we show a differential abundance of proteins regulating the postsynaptic receptor activity of glutamatergic synapses. We investigated the AMPA receptor composition and shuttling in adult Fmr1 KO and WT mice using a variety of complementary experimental strategies such as surface protein crosslinking, immunostaining of surface receptors, and electrophysiology. We discovered that the activity-dependent synaptic delivery of AMPARs is impaired in adult Fmr1 KO mice. Furthermore, we show that Fmr1 KO synaptic AMPARs contain more GluA2 subunits that can be interpreted as a switch in the synaptic AMPAR subtype toward an increased number of Ca2+-impermeable receptors in adult Fmr1 KO synapses.

Prognostic value of coronary atherosclerosis and CAC score for the risk of chemotherapy-related cardiac dysfunction (CTRCD): The protocol of ANTEC study.

BACKGROUND: Cardiological complications of oncological treatment, including the most serious one, heart failure, constitute a significant and still unsolved clinical problem. A history of dyslipidemia and complications of atherosclerosis, including coronary artery disease, are established risk factors for cardiotoxicity in cancer patients. In recent years, a protective effect of statin treatment on the development of heart failure in cancer patients has been observed. This protocol describes a study aiming to assess the prognostic value of coronary atherosclerosis burden and the CAC score on the onset of cardiac dysfunction associated with cancer therapy. METHODS: ANTEC (Atherosclerosis iN chemoTherapy-rElated Cardiotoxicity) is a single-site, prospective, observational study to evaluate the influence of the coronary atherosclerosis and CAC score assessed by computed tomography on the development of left ventricular systolic dysfunction in cancer patients with at least moderate cardiotoxicity risk. A group of 80 patients diagnosed with cancer prior to high-dose anthracycline chemotherapy (doxorubicin ≥ 240 mg / m2 body weight or epirubicin ≥ 600 mg / m2 body weight), without a history of heart failure and coronary artery disease, will be included in the study. Patient follow-up is planned for 12 months. In all patients, coronary computed tomographic angiography (CCTA) will be performed once at the beginning of the study. The primary endpoint is the onset of cancer therapy-related cardiovascular toxicity, defined as mild, moderate, severe and very severe according to ESC 2022 Cardio-oncology guidelines. During follow up, echocardiography with GLS assessment will be performed every three months. Additionally, new biomarkers of atherosclerosis (IL-6, MPO, TNF-alpha) will be measured every 6 months. The study registration identifier on clinicaltrials.gov is NCT05118178. CLINICAL TRIALS REGISTRY: This study is listed on cinicaltrials.gov with identifier NCT05118178.

Smartphone as a monitoring tool for bipolar disorder: a systematic review including data analysis, machine learning algorithms and predictive modelling.

BACKGROUND: Bipolar disorder (BD) is a chronic illness with a high recurrence rate. Smartphones can be a useful tool for detecting prodromal symptoms of episode recurrence (through real-time monitoring) and providing options for early intervention between outpatient visits. AIMS: The aim of this systematic review is to overview and discuss the studies on the smartphone-based systems that monitor or detect the phase change in BD. We also discuss the challenges concerning predictive modelling. METHODS: Published studies were identified through searching the electronic databases. Predictive attributes reflecting illness activity were evaluated including data from patients' self-assessment ratings and objectively measured data collected via smartphone. Articles were reviewed according to PRISMA guidelines. RESULTS: Objective data automatically collected using smartphones (voice data from phone calls and smartphone-usage data reflecting social and physical activities) are valid markers of a mood state. The articles surveyed reported accuracies in the range of 67% to 97% in predicting mood status. Various machine learning approaches have been analyzed, however, there is no clear evidence about the superiority of any of the approach. CONCLUSIONS: The management of BD could be significantly improved by monitoring of illness activity via smartphone.

Preparation of polysomal fractions from mouse brain synaptoneurosomes and analysis of polysomal-bound mRNAs.

BACKGROUND: Here we describe a detailed, reliable protocol for isolation of polysomal fractions from mouse brain synaptoneurosomes. This method is an important tool to study local protein synthesis in neurons. NEW METHOD: We combined rapid preparation of synaptoneurosomes by filtration with polysome profiling. We provide a detailed protocol highlighting difficulties and critical steps of: i) preparation of synaptoneurosomes; ii) polyribosome fractionation from synaptoneurosomes; iii) extraction of proteins and RNA from sucrose gradient fractions. RESULTS: and Comparison with Existing Methods We fractionated polyribosomes from synaptoneurosomes and detected the association of Mmp9, Camk2a and Stx1B mRNA with polysomes in the unstimulated conditions. Synaptic stimulation led to increased levels of Mmp9 and Camk2a mRNA in the heavy polysomal fractions. We compared our protocol with existing methods CONCLUSIONS: We have developed a reliable, effective method to prepare polyribosomal fractions from synaptoneurosomes to study polyribosomal binding of mRNAs as an aspect of synaptic translation in vitro.

Structural and functional characterization of the triticale (x Triticosecale Wittm.) phytocystatin TrcC-8 and its dimerization-dependent inhibitory activity.

Phytocystatins are a group of proteins with significant potential to regulate activities of cysteine proteinases of native and pest/pathogen origins. The two-domain triticale (x Triticosecale Wittm.) phytocystatin TrcC-8 was characterized in this study. This protein belongs to the second group of phytocystatins and contains all the conserved sequences and motifs as well as both N-terminal (CY) and C-terminal (CY-L) domains that are characteristic of phytocystatins with the C-terminal extension. We demonstrated that TrcC-8 forms stable dimers with a significantly reduced inhibitory activity against papain compared to the activity of monomers, indicating the regulatory nature of the oligomerization. Moreover, according to our research, only the N-terminal domain possesses the ability to form dimers, indicating that this part of TrcC-8 is involved in the dimerization of the full-length protein. Homology modelling of TrcC-8 strongly suggests distinct specificities for the CY and CY-L domains, confirmed in experiments with inhibition of the papain. Our results suggest that the CY domain of TrcC-8 may, although markedly weakly and suboptimally, interact with papain in an analogous mode to tarocystatin, while the CY-L domain of TrcC-8 has distinct specificity than tarocystatin.

Psychotic symptoms as a complication of electroconvulsive therapy - a case report. / Objawy psychotyczne jako powiklanie przebiegu leczenia elektrowstrzasowego ­ opis przypadku.

We report a patient who experienced atypical symptoms in the course of electroconvulsive therapy (ECT). During ECT treatment patient experienced psychotic symptoms which should be differentiated with prolonged delirium and nonconvulsive status epilepticus. 46-year-old female was referred to hospital with a diagnosis of major depressive disorder with no psychotic features in the course of recurrent depression. Despite several changes of pharmacological treatment no improvement was achieved, therefore it was decided to initiate ECT. Physical and neurological examination revealed no deviations from the norm. The results of other tests (CT and EEG) were normal. 4 bilateral, bitemporal ECT procedures were performed. The course of each procedure was typical, the same doses of anesthetic medication and pulse dose was administered throughout all of the procedures. The duration of seizure was 32-40 s. Despite this mental symptoms observed during the course of the treatment differed from known to the authors from both their own experience and from literature. Delusions of reference, persecution, agitation, oneiric delusions and olfactory hallucinations which appeared after the 4th ECT session maintained for 14 days and resolved after treatment with olanzapine. To the best of our knowledge, this is the first report on delusions of reference and persecution, oneiric delusions and olfactory hallucinations associated with the course of ECT.

A sham-controlled randomized trial of adjunctive light therapy for non-seasonal depression.

BACKGROUND: The aim of the study was to examine the efficacy and safety of morning bright light therapy (BLT) in the treatment of patients with a current major depressive episode (MDE) in bipolar and unipolar disorder without a seasonal pattern. It was a randomized, sham-controlled trial. METHODS: Adults, ages 18-70 years were randomized to treatment either with BLT or a sham negative ion generator (as a placebo control). The subjects were required to be on a stable and therapeutic dose of psychotropic medication for at least 4 weeks prior to enrollment and their treatment had to be insufficiently effective. Their clinical state was monitored at the baseline and at the end of treatment. The Hamilton Depression Rating Scale-21 items (HDRS-21), Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI-II), Clinical Global Impression-Severity (CGI-S) and Patient Global Impression (PGI) were used. The results were analyzed with an intention-to-treat (ITT) analysis. RESULTS: Ninety-five patients were enrolled (50 diagnosed with bipolar disorder and 45 with unipolar depression). Fifty-two patients were randomized to treatment with BLT and forty-three were in the placebo group (ITT population). Eighty-three subjects completed the study. There were 12 dropouts (5 in the light group and 7 in the placebo group). After 14 days of treatment, a significant improvement was found in all groups (p<0.001). The subjects treated with BLT did not significantly differ in terms of improvement in HDRS-21 scores at the endpoint when compared to patients treated with placebo (p=0.2). However, further analysis demonstrated significantly higher response (50% v. 27.9%, p=0.02) and remission rates (28.8% v. 11.6%, p=0.04) among patients treated with morning BLT when compared to placebo group. It should be noted that in the population of drug-resistant patients, BLT was more efficacious than placebo. There were no statistically significant differences between unipolar and bipolar disorders (p=0.4). CONCLUSION: Although overall improvement in HDRS-21 scores were not superior in the BLT group, both response and remission rates were significantly higher among patients treated with BLT relative to those receiving the sham intervention. BLT was also more efficacious than placebo in the population of patients with drug-resistant depression. Further studies to define the subpopulation of patients with non-seasonal depression who may benefit the most from BLT are needed.

The presence of disulfide bonds reveals an evolutionarily conserved mechanism involved in mitochondrial protein translocase assembly.

Disulfide bond formation is crucial for the biogenesis and structure of many proteins that are localized in the intermembrane space of mitochondria. The importance of disulfide bond formation within mitochondrial proteins was extended beyond soluble intermembrane space proteins. Tim22, a membrane protein and core component of the mitochondrial translocase TIM22, forms an intramolecular disulfide bond in yeast. Tim22 belongs to the Tim17/Tim22/Tim23 family of protein translocases. Here, we present evidence of the high evolutionary conservation of disulfide bond formation in Tim17 and Tim22 among fungi and metazoa. Topological models are proposed that include the location of disulfide bonds relative to the predicted transmembrane regions. Yeast and human Tim22 variants that are not oxidized do not properly integrate into the membrane complex. Moreover, the lack of Tim17 oxidation disrupts the TIM23 translocase complex. This underlines the importance of disulfide bond formation for mature translocase assembly through membrane stabilization of weak transmembrane domains.

Cox17 Protein Is an Auxiliary Factor Involved in the Control of the Mitochondrial Contact Site and Cristae Organizing System.

The mitochondrial contact site and cristae organizing system (MICOS) is a recently discovered protein complex that is crucial for establishing and maintaining the proper inner membrane architecture and contacts with the outer membrane of mitochondria. The ways in which the MICOS complex is assembled and its integrity is regulated remain elusive. Here, we report a direct link between Cox17, a protein involved in the assembly of cytochrome c oxidase, and the MICOS complex. Cox17 interacts with Mic60, thereby modulating MICOS complex integrity. This interaction does not involve Sco1, a partner of Cox17 in transferring copper ions to cytochrome c oxidase. However, the Cox17-MICOS interaction is regulated by copper ions. We propose that Cox17 is a newly identified factor involved in maintaining the architecture of the MICOS complex.

A triticale water-deficit-inducible phytocystatin inhibits endogenous cysteine proteinases in vitro.

Water-deficit is accompanied by an increase in proteolysis. Phytocystatins are plant inhibitors of cysteine proteinases that belong to the papain and legumain family. A cDNA encoding the protein inhibitor TrcC-8 was identified in the vegetative organs of triticale. In response to water-deficit, increases in the mRNA levels of TrcC-8 were observed in leaf and root tissues. Immunoblot analysis indicated that accumulation of the TrcC-8 protein occurred after 72h of water-deficit in the seedlings. Using recombinant protein, inhibitory activity of TrcC-8 against cysteine proteases from triticale and wheat tissues was analyzed. Under water-deficit conditions, there are increases in cysteine proteinase activities in both plant tissues. The cysteine proteinase activities were inhibited by addition of the recombinant TrcC-8 protein. These results suggest a potential role for the triticale phytocystatin in modulating cysteine proteinase activities during water-deficit conditions.

[Effectiveness of ketamine in depressed patients resistant to ECT or rTMS therapy]. / Skutecznosc zastosowania ketaminy u pacjentów z depresja oporna na leczenie elektrowstrzasowe lub rTMS.

OBJECTIVES: In the last decade several authors described a robust and clinically relevant alleviation of depressive symptoms after infusions of the uncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist - ketamine. In the majority of published reports ketamine was administrated to patients with depression resistant to pharmacotherapy, but not to ECT. We present a series of 5 subjects suffering from multimodal treatment-resistant depression (including ECT or rTMS and various medications) treated with intravenous infusions of ketamine in a subanesthetic dose of 0.5 mg/kg in the naturalistic setting. To the best of our knowledge it is the first report on ketamine infusion in patient resistant to antidepressants and r TMS METHODS: Two subjects have been diagnosed with MDD, one with BD, two with severe depressive episode. The efficacy and possible adverse events were monitored using psychometric scales. Basic life parameters and ECG were observed. RESULTS: Ketamine's infusions showed transient antidepressant efficacy. Improvement rate in our group was significant lower than in previously reported. Ketamine was generally well tolerated. We noted transient BP variations and appearance of mild and transient dissociative symptoms. Low early response rate may be correlated with resistance to previous multimodal treatment, high rate of somatization and anxiety comorbidity or heterogeneity of our group. CONCLUSIONS: Our findings do not support the use of ketamine infusions as the monotherapy in the subgroup of patients with multimodal treatment resistant depression.

["Addiction" to phenelzine - case report]. / ,,Uzaleinienie" od fenelzyny - opis przypadku.

The use of non-selective monoamine oxidase inhibitors (IMAO) may be associated with the risk of addiction, which is confirmed by case studies published so far. Harmful use of antidepressants in patients with affective disorders and anxiety is not frequent, but due to the fact that in clinical practice can meet with this phenomenon, we present the case of a 30-year-old patient with a history of using phenelzine who presented a combination of symptoms that meet criteria for addiction. The current classification of ICD- 10 does not consist the diagnosis of dependence on antidepressants. In this case, the category F55.0: abuse of a substance which does not cause addiction, should be used. In the literature most often mentioned as a possible substances with addictive potential is a group of non-selective MAO, particularly tranylcypromine. The mechanism of non-selective MAO dependence may be associated with the similarity of their chemical structure to amphetamine (both amphetamine and IMAO are derivatives of phenylethylamine), although the mechanism of action is different. Furthermore, it was noted that there is a group of patients in whom treatment with IMAO is associated with greater risk of abuse of these substances. The study contains the characteristics of this group of patients.

[Antidepressant effect of ketamine, a N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, in the therapy of treatment-resistant depression]. / Zastosowanie antagonisty receptorów NMDA (N-metylo-D- -asparaginianu)--ketaminy w leczeniu depresji lekoopornej.

Clinical practice and data from literature indicate that up to 30% of the patients suffering from depression meet criteria for treatment-resistant depression. In the past decade, interest in the use of NMDA receptor modulators in the treatment of treatment-resistant depression is increasing. The use of ketamine--an noncompetitive antagonist of the NMDA receptors, allows some patients suffering from treatment resistant depression to achieve rapid and significant improvement. The authors reviewed results of clinical studies, series of cases and case reports on the use of ketamine. Most of the patient suffered from the treatment-resistant major depression. Neurobiological basis of the glutaminergic pathways and the postulated role of glutamate in mood modulation have been described, as well as possible adverse events associated with ketamine infusion. Concerns relate to the optimal dosage, frequency of administration, long-term safety and efficacy of the therapy. Interesting results of the published articles encourage further studies on therapeutic use of NMDA receptor modulators in the treatment of treatment-resistant depression.

[Syndrome of inappropriate antidiuretic hormone secretion in the course of treatment with venlafaxine--case report]. / Zespól nieadekwatnego wydzielania wazopresyny spowodowany przez wenlafaksyne--opis przypadku.

Treatment with some drugs may induce hyponatraemia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This is a report of a 52-year-old man who developed hyponatraemia after starting venlafaxine administration. Serum sodium level returned to the normal range following discontinuation of venlafaxine and application of SIADH--treatment within a few days. The study shows that routine assessment of blood electrolytes is needed in patients treated with drugs affecting vasopresin secretion.

[Cognitive-behavior therapy for late-life generalized anxiety disorder: literature overview]. / Przeglad badan efektywnosci terapii poznawczo-behawioralnej w zaburzeniach lekowych uogólnionych u osób w podeszlym wieku.

Of the pervasive anxiety disorders diagnosed in late life, generalized anxiety disorder (GAD) is the most prevalent. However GAD often goes unrecognised and untreated because of different clinical presentation in the elderly. Anxiety is also substantially less well studied than other forms of geriatric psychopathology. This dearth of research may result from methodological difficulties. In this paper, the clinical features of GAD among older adults are described. Psychotropic medication is the most common treatment for GAD but is not good enough and psychological treatments for GAD in older adults that are highly preferable and safer have been advocated. One of them is cognitive-behavioral therapy (CBT). In this article, literature investigating the potential usefulness of cognitive-behavioral treatments among older adults with well-diagnosed GAD is reviewed. Then, attention is given to enhancements to standard CBT, which take into account many factors and differences specific of the older cohort.