Multilevel Regulation of Membrane Proteins in Response to Metal and Metalloid Stress: A Lesson from Yeast.

In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The widespread presence of highly toxic compounds of arsenic, antimony, and cadmium in nature poses a particular threat to human health. Prolonged exposure to these toxins has been associated with severe human diseases, including cancer, diabetes, and neurodegenerative disorders. These toxins are known to induce analogous cellular stresses, such as DNA damage, disturbance of redox homeostasis, and proteotoxicity. To overcome these threats and improve or devise treatment methods, it is crucial to understand the mechanisms of cellular detoxification in metal and metalloid stress. Membrane proteins are key cellular components involved in the uptake, vacuolar/lysosomal sequestration, and efflux of these compounds; thus, deciphering the multilevel regulation of these proteins is of the utmost importance. In this review, we summarize data on the mechanisms of arsenic, antimony, and cadmium detoxification in the context of membrane proteome. We used yeast Saccharomyces cerevisiae as a eukaryotic model to elucidate the complex mechanisms of the production, regulation, and degradation of selected membrane transporters under metal(loid)-induced stress conditions. Additionally, we present data on orthologues membrane proteins involved in metal(loid)-associated diseases in humans.

UPF1-From mRNA Degradation to Human Disorders.

Up-frameshift protein 1 (UPF1) plays the role of a vital controller for transcripts, ready to react in the event of an incorrect translation mechanism. It is well known as one of the key elements involved in mRNA decay pathways and participates in transcript and protein quality control in several different aspects. Firstly, UPF1 specifically degrades premature termination codon (PTC)-containing products in a nonsense-mediated mRNA decay (NMD)-coupled manner. Additionally, UPF1 can potentially act as an E3 ligase and degrade target proteins independently from mRNA decay pathways. Thus, UPF1 protects cells against the accumulation of misfolded polypeptides. However, this multitasking protein may still hide many of its functions and abilities. In this article, we summarize important discoveries in the context of UPF1, its involvement in various cellular pathways, as well as its structural importance and mutational changes related to the emergence of various pathologies and disease states. Even though the state of knowledge about this protein has significantly increased over the years, there are still many intriguing aspects that remain unresolved.

Cerebrovascular accidents differ between patients with atrial flutter and patients with atrial fibrillation.

INTRODUCTION: Few studies have explored the potential impact of atrial flutter (AFl) on ischaemic stroke (IS) outcome. The aim of the present study was to compare the clinical course of IS in patients with AFl and patients with atrial fibrillation (AF). MATERIAL AND METHODS: A retrospective analysis of patients consecutively admitted to a tertiary care centre between 2013 and 2015 due to IS or transient ischaemic attack with permanent AFl or permanent or persistent AF was performed. RESULTS: The study groups consisted of 528 patients, including 490 (92.8%) patients with AF and 38 (7.2%) patients with AFl. The mean age and prestroke CHA2DS2-VASc scores were similar between the patients with AFl and those with AF. Most IS cases in the AF group were classified as cardioembolic strokes (74.9% vs. 39.5% in AFl, p < 0.01), and lacunar strokes were the most common in the AFl group (47.4% vs. 14.3% in AF, p < 0.01). The multivariable analysis revealed that the presence of AF (OR = 8.6, 95% CI: 1.2-57, p = 0.02), lacunar stroke (OR = 0.1, 95% CI: 0.03-0.31, p < 0.001), baseline Rankin scale score (OR = 16.6, 95% CI: 9.8-28), lack of prestroke therapeutic anticoagulation (OR = 6.1, 95% CI: 1.1-33), diabetes (OR = 2.9, 95% CI: 1.3-6.5, p < 0.01), chronic heart failure (OR = 14.2, 95% CI: 5.8-34, p < 0.001), and current smoking (OR = 0.92, 95% CI: 0.39-0.99, p < 0.01) were significantly associated with the stroke outcome. CONCLUSIONS: Disabling or fatal IS was observed less often in patients with AFl than in patients with AF. This finding can possibly be explained by the more frequent occurrence of lacunar strokes in the AFl group compared with that in the AF group.

IL-1α and IL-6 predict vascular events or death in patients with cerebral small vessel disease-Data from the SHEF-CSVD study.

PURPOSE: The natural clinical course of cerebral small vessel disease (CSVD) was not thoroughly described. The aim of this single center cohort study was to establish biochemical predictors of vascular events and death in CSVD patients during a 24-month follow-up. PATIENTS AND METHODS: A total of 130 functionally independent patients with marked MRI features of CSVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD) were prospectively recruited. Serum markers of endothelial dysfunction, inflammation and hemostasis were determined at baseline. The primary outcome was defined as occurrence of death or any vascular events during the observation. RESULTS: The mean age was 72 ± 8.1 years, and 37.6% of the patients were women. The mean follow-up time was 22.3 ± 4.3 months, and 84.6% of patients had extensive white matter lesions on baseline MRI. The overall mortality rate was 6.9%, and vascular events or death occurred in 27% of the patients. Kaplan-Meier survival curves revealed no significant differences between CSVD groups (log rank p = 0.49). Cox regression analysis revealed that IL-1α (HR 1.4; 95%CI 1.09-1.8), IL-6 (1.4;1.1-2.2), hs-CRP (1.1;1.06-1.9), homocysteine (1.4;1.1-1.8), fibrinogen (1.4;1.05-2), and d-dimer (2.7;1.6-4.5) were significantly associated with the primary outcome. IL-1α (1.3;1.07-1.8), IL-6 (1.4;1.02-2.2), d-dimer (2.8;1.6-5) and homocysteine (1.4;1.1-1.8) remained significant after adjusting for age, sex and CSVD radiological markers. CONCLUSIONS: Our study demonstrated the important prognostic role of various circulation markers of inflammation in individuals with different clinical signs and radiological markers of CSVD. The strongest association occurred between IL-1α, IL-6 and recurrent stroke, other vascular events and death.

IL-6, PF-4, sCD40 L, and homocysteine are associated with the radiological progression of cerebral small-vessel disease: a 2-year follow-up study.

BACKGROUND: Endothelial dysfunction (ED) is involved in the pathogenesis of cerebral small vessel disease (SVD), however, it is not clear if specific biomarkers related to ED are associated with radiological progression of SVD. METHODS: A single-center, prospective cohort study was conducted among consecutive, adult patients with SVD. Logistic regression was used to analyze the association of each baseline biomarker (highest vs lowest tertile) and the MRI radiological outcome after 2 years. The mean Z-score for vascular inflammation (VI) combined soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble platelet selectin (sP-selectin), CD40 ligand (sCD40 L), platelet factor-4 (PF-4) and homocysteine; Z-score for systemic inflammation (SI) combined high-sensitivity C-reactive protein (hsCRP), interleukin-1α and -6 (IL-1α and IL-6, respectively) and tumor necrosis factor-α (TNF-α). RESULTS: The study group comprised 123 patients (age, mean±SD: 72.2±8 years, 49% females), with lacunar stroke (n=49), vascular dementia (n=48), and vascular parkinsonism (n=26). Moreover, 34.9% patients experienced radiological progression, 43% had progression of isolated white matter lesions (WMLs), 23.2% had new lacunes, and 34.8% had both WMLs progression and new lacunes. After adjustment for confounders (age, sex, blood pressure, MRI lesions load), the PF-4 (OR; 95% CI 5.5; 1.5-21), sCD40L (4.6; 1.1-18.6), IL-6 (7.4; 1.48-37), Z-score for VI (4.5; 1.1-18.6), and, marginally, homocysteine (4.1; 0.99-17) were associated with the risk of any radiological progression; further, homocysteine (2.4; 1.4-14), Z-score for SI (2.1; 1.2-14) and, marginally, IL-6 (6.0; 0.95 -38) were related to the development of new lacunes; PF-4 (7.9; 1.6-38) and, marginally, the Z-score for VI (4.2; 0.9-19.5) were correlated with the risk of WMLs progression. Additional adjustment for clinical SVD manifestations did not significantly alter the results. CONCLUSION: The data supports the concept that ED modulates the radiological progression of SVD and WMLs and lacunes are associated with different inflammatory markers.

[Treatment of ischemic stroke with mechanical trombectomy systems]. / Leczenie udaru niedokrwiennego mózgu z zastosowaniem systemów do trombektomii mechanicznej.

The implementation of ischemic stroke therapy has created new opportunities for clinical improvement and the reversal of adverse prognosis in patients with ischemic stroke. Mechanical thrombectomy has become the recommended treatment for acute stroke in a select group of patients and in highly specialized centres with experience in endovascular therapy. AIM: The aim of the study was to evaluate of the efficacy and safety of mechanical thrombectomy in patients with acute ischemic stroke within the first six hours of illness was reported. MATERIALS AND METHODS: 34 patients previously hospitalized in the Department of Neurology due to ischemic stroke were included in the study during the first six hours of illness. Short-term efficacy and safety (1 month after surgery) and long-term (3 months) were evaluated based on the assessment of early mortality, functional status and neurological status. Factors that increase the risk of death were also analyzed. RESULTS: In the study group, the recanalization of the vessel was obtained in 52% of patients, which was associated with a significant improvement of functional status. Improvements in functional and neurological status were obtained in most of the patients (63%), including very good functional status (mRS 0-1) in 7 (20%) patients upon discharge from the hospital. CONCLUSIONS: In the study group, the recanalization of the vessel was obtained in 52% of patients, which was associated with a significant improvement of functional status. Improvements in functional and neurological status were obtained in most of the patients (63%), including very good functional status (mRS 0-1) in 7 (20%) patients upon discharge from the hospital.

[Stiff person syndrome--case report]. / Zespól sztywnosci uogólnionej--opis przypadku.

Stiff person syndrome (SPS) is the rare disease and cause great inefficient. It is characterized by progressive stiffness muscles of trunk and the limbs on which the cramps of muscles overlap. In the electrophysiological investigation of the patients the involuntary discharge of motor unit potentials find and also simultaneous contraction agonistic and antagonistic muscles. SPS is presented with insulin-dependent diabetes mellitus often or is the symptom of the paraneoplastic syndrome. It is commonly associated with high anti-glutamic acid decarboxylaze (GAD) antibody titters in the serum of the blood of patients. Establishing the diagnosis can cause difficulties. We observed the patient in the last period about the atypical course the disease. The diagnosis was confirmed occurrences of the high titters of antibodies anti-GAD, the discharge of motor unit potential in paraspinal muscles in the rest and good response the treatment with diazepamem.

[Fulminant adhesive arachnoiditis]. / Zlepne zapalenie pajeczynówki o piorunujacym przebiegu.

Adhesive arachnoiditis is a rare disease with insidious course. It causes damage of the spinal cord and nerve roots. The causes of adhesive arachnoiditis include earlier traumatic injury of the spinal cord, surgery, intrathecal administration of therapeutic substances (e.g. anaesthetics, chemotherapy) or contrast media, bleeding, and inflammation. It can also be idiopathic or iatrogenic. We present the case of a 42-year-old patient with fulminant adhesive arachnoiditis which was provoked by spinal surgery and caused severe neurological disability with profound, progressive, flaccid paraparesis and bladder dysfunction. The electromyography (EMG) showed serious damage of nerves of both lower limbs at the level of motor roots L2-S2 and damage of the motor neuron at the level of Th11-Th12 on the right side. Magnetic resonance imaging of the lumbosacral and thoracic part of the spinal cord demonstrated cystic liquid spaces in the lumen of the dural sac in the bottom part of the cervical spine and at the Th2-Th10 level, modelling the lateral and anterior surface of the cord. Because of the vast lesions, surgery could not be performed. Conservative treatment and rehabilitation brought only a small clinical improvement.

Degenerative pontine lesions in patients with familial narcolepsy.

BACKGROUND AND PURPOSE: Narcolepsy is characterized by chronic excessive daytime sleepiness with episodic sleep attacks. There are several associated symptoms of narcolepsy: cataplexy (bilateral muscle weakness without loss of consciousness provoked by an emotional trigger, e.g. laughter), sleep paralysis and hypnagogic-hypnopompic hallucinations. Most cases are sporadic; familial narcolepsy contributes to only 1-5% of all cases. While most cases of narcolepsy are idiopathic and are not associated with clinical or radiographic evidence of brain pathology, symptomatic or secondary narcolepsy may occur occasionally in association with lesions caused by tumours, demyelination or strokes of the diencephalon, midbrain, and pons. There are some examples of non-specific brainstem lesions found in magnetic resonance imaging (MRI) in patients with idiopathic narcolepsy. MATERIAL AND METHODS: The authors present eleven patients from a five-generation family with many members who suffer from episodic excessive daytime sleepiness. Narcolepsy was diagnosed in 9 patients. Sleepiness was frequently associated with cataplexy, hypnagogic-hypnopompic hallucinations and sleep paralysis. Improvement in their clinical state was observed during the treatment with modafinil. All probands had MRI of the brain, routine blood tests, EEG, polysomnography, examination of the level of hypocretin in cerebrospinal fluid and evaluation by means of Epworth and Stanford Sleepiness Scales. RESULTS: In 9 patients with narcolepsy, decreased thickness of the substantia nigra was found and in six of them degenerative lesions in the pontine substantia nigra were also noticed. CONCLUSIONS: The significance of these changes remains unclear. No data have been published until now concerning the presence of any brain lesions in patients with familial narcolepsy.

[Essential thrombocythemia as critical stroke risk factor--case report]. / Nadplytkowosc samoistna istotnym czynnikiem ryzyka udaru mózgowego--opis przypadku.

One of the haematological causes of stroke is essential thrombocythemia (ET). It is one of the proliferative syndromes of the haematopoietic system. Patients with ET have an increased risk of thrombosis and/or haemorrhage of veins and arteries. The patient aged 58 had a history of two stroke incidents within two month despite the treatment with acenocumarole for chronic atrial fibrillation. The clinical diagnostic procedure revealed an increased platelet count was 668 000/ml, and these cerebrovascular events were the first manifestation of ET Antithrombotic drugs were not effective in the secondary prevention of stroke while antiplatelets prevented this patient from further ischemic events for 12 months.

Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNFalpha, and INFgamma concentrations are elevated in patients with atypical and idiopathic parkinsonism.

We investigated serum levels of interleukin (IL)-2, IL-10, IL-6, IL-4, TNFalpha, INFgamma in 7 patients with atypical parkinsonism (AP), 31 idiopathic PD (iPD) patients, 17 idiopathic PD with cardiovascular risk factor (iPD-CVRF) patients, and 20 age-matched controls (healthy, non-parkinsonian patients). Cytokine concentrations were measured using the Becton Dickinson (BD) human Th1/Th2 Cytokine kit II with a flow cytometry system. The concentrations of IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma were detectable in the serum from all groups, including the control. Increased serum IL-2, IL-10, IL-4, IL-6, TNFalpha, and INFgamma concentrations were found in all groups of parkinsonian patients, as compared to the control group. The highest elevations of serum IL-2, IL-4, IL-6, TNFalpha, and INFgamma concentrations were observed in AP patients, as compared to the iPD and iPD-CVRF groups. However, the serum IL-6 concentration was higher in the iPD-CVRF group than in the iPD group. The IL-10 level was significantly higher in all groups of PD patients relative to the control group, but was the lowest in the serum from the AP patients. Moreover, the serum levels of lipid peroxidation products were enhanced 2.1- and 1.5-fold in AP and both iPD groups, respectively. These results argue in favor of the involvement of immunological events in the process of neurodegeneration in AP and PD.