The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognised in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine. Since this pathway – the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress it also stands in an unique position to mediate the effects of environmental factors on cognition and behaviour. Targetting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures

Traumatic bilateral dissection of cervical internal carotid artery in the wake of a car accident: A case report

Background Bilateral carotid artery dissection secondary to severe trauma is rare and can be potentially life -threatening if not diagnosed and treated properly. Case Presentation We report a 29-year-old female who was admitted to the emergency department after a car accident. The patient was conscious at the time of admission and presented with an initial Glasgow Coma Scale (GCS) of 15 presenting normal vital signs. The patient developed motor dysphasia with right upper limb paresis a few hours after the admission. Magnetic resonance imaging (MRI) revealed a bilateral cervical internal carotid artery (ICA) occlusion in addition to left frontal lobe infarct in a subacute phase. Medical management was successful and the patient was discharged from the hospital two weeks after the admission. Discussion Noninvasive vascular imagining modalities are merging as the gold standard in the early detection of carotid artery dissection (CAD). Typical pathognomonic findings on MRI include double lumen and intimal flap. The management with systemic anticoagulation or antiplatelet therapy is aimed to prevent the development of ischemic stroke. In case of medical therapy being ineffective or in case of complication or any disorders suffered by a patient, endovascular treatment is performed. Conclusion With early detection and proper management, traumatic dissection of cervical carotid artery can have a benign outcome. As for the current patient, medical treatment with anticoagulation was sufficient and surgical management was therefore not required. Improvement in the patients’ speech was observed; nevertheless the continuation of speech therapy was indicated

Endovascular stenting for extracranial internal carotid artery dissection : single-centre experience and literature overview

Purpose: Extracranial internal carotid artery dissections (EICAD) remain a relatively common cause of ischaemic events in young patients. Currently, there is no consensus on standardised use of endovascular therapy in the treatment of these patients, but available data suggest that conservative treatment is not sufficient in 15% of cases. The aim of our study was to evaluate if endovascular stent placement was safe and effective for the treatment of extracranial internal carotid artery dissection, and whether it should be considered in properly selected patients. Material and methods: This single-centre, retrospective study aimed to evaluate procedural and clinical outcomes of patients with EICAD who underwent endovascular stenting between 2015 and 2024. Procedural and clinical efficacy and safety, the rate of complications, and long-term outcomes were noted. Results: A total of 21 patients (10 females) with an average age of 53 years underwent stenting for EICAD. Technical success was achieved in all cases. Perioperative complications were noted in 2 cases. Neurological evaluation performed at 6-month follow-up showed very good clinical results in the majority of cases (mRS 0 and mRS 1 were 76% and 19%, respectively). Control imaging examinations confirmed stent patency in all cases. No long-term mortality was observed. Conclusions: This retrospective study demonstrated procedural and clinical safety and efficacy of endovascular stenting in patients with extracranial internal carotid artery dissection. That is why endovascular therapy should be proposed to individuals with unsatisfactory response to medical treatment and in cases of disease progression

Predictors of intracranial cerebral artery stenosis in patients before cardiac surgery and its impact on perioperative and long-term stroke risk

Background The aim of this prospective study was to determine the prevalence of stenosis within intracranial and extracranial arteries in patients before coronary artery bypass surgery (CABG), to evaluate the influence of intracranial artery stenosis on neurological outcome and to identify preoperative risk factors for these patients. Methods One hundred and seventy-five patients (71% males, mean age=66.1) scheduled for CABG were enrolled for extracranial Doppler duplex sonography, transcranial color-coded duplex sonography (TCCS) and transcranial Doppler (TCD) examination. Results Twenty-six patients (14.7%) had extracranial stenosis or occlusion and 13 patients (7.3%) intracranial vascular disease. Six patients (3.5%) had both extra- and intracranial artery disease. The presence of peripheral artery disease and diabetes mellitus was a strong risk factor for extracranial artery stenosis but not for intracranial artery stenosis, which occurred independently also of typical atherosclerotic risk factors like age >70, male sex, hypertension, hyperlipidemia, hyperhomocysteinemia, smoking habit, obesity (BMI>30) and waist to hip ratio >1. Functional neurological outcome of the patients with intracranial arterial disease evaluated 7 days after CABG was the same as the patients without extra- and intracranial stenosis. However, 12-months neurological follow-up revealed significantly more ischemic strokes in patients with intracranial artery stenosis compared to patients without intracranial stenosis (p=0.015). Conclusion The occurrence of intracranial artery stenosis in CABG patients cannot be predicted by well-known atherosclerotic risk factors and seems not to be associated with perioperative stroke

Choline supplementation sensitizes Legionella dumoffii to Galleria mellonella apolipophorin III

The growth of Legionella dumoffii can be inhibited by Galleria mellonella apolipophorin III (apoLp-III) which is an insect homologue of human apolipoprotein E., and choline-cultured L. dumoffii cells are considerably more susceptible to apoLp-III than bacteria grown without choline supplementation. In the present study, the interactions of apoLp-III with intact L. dumoffii cells cultured without and with exogenous choline were analyzed to explain the basis of this difference. Fluorescently labeled apoLp-III (FITC-apoLp-III) bound more efficiently to choline-grown L. dumoffii, as revealed by laser scanning confocal microscopy. The cell envelope of these bacteria was penetrated more deeply by FITC-apoLp-III, as demonstrated by fluorescence lifetime imaging microscopy analyses. The increased susceptibility of the choline-cultured L. dumoffii to apoLp-III was also accompanied by alterations in the cell surface topography and nanomechanical properties. A detailed analysis of the interaction of apoLp-III with components of the L. dumoffii cells was carried out using both purified lipopolysaccharide (LPS) and liposomes composed of L. dumoffii phospholipids and LPS. A single micelle of L. dumoffii LPS was formed from 12 to 29 monomeric LPS molecules and one L. dumoffii LPS micelle bound two molecules of apoLp-III. ApoLp-III exhibited the strongest interactions with liposomes with incorporated LPS formed of phospholipids isolated from bacteria cultured on exogenous choline. These results indicated that the differences in the phospholipid content in the cell membrane, especially PC, and LPS affected the interactions of apoLp-III with bacterial cells and suggested that these differences contributed to the increased susceptibility of the choline-cultured L. dumoffii to G. mellonella apoLp-III

How do xanthophylls protect lipid membranes from oxidative damage?

Here, we address the problem of the antioxidant activity of carotenoids in biomembranes. The activity of lutein and zeaxanthin in the quenching of singlet oxygen generated by photosensitization was monitored in lipid vesicles using a singlet oxygen-sensitive fluorescent probe and with the application of fluorescence lifetime imaging microscopy. The antioxidant activity of xanthophylls was interpreted on the basis of electron paramagnetic resonance oximetry results showing that xanthophylls constitute a barrier to the penetration of molecular oxygen into lipid membranes: to a greater extent in the 13-cis configuration than in all-trans. These results are discussed in relation to the trans-cis photoisomerization of xanthophylls observed in the human retina. It can be concluded that photoisomerization of xanthophylls is a regulatory mechanism that is important for both the modulation of light filtration through the macula and photoprotection by quenching singlet oxygen and creating a barrier to oxygen permeation to membranes

Quantitative characterization of fluorophores in multi-component nanoprobes by single-molecule fluorescence

Multi-modal nanoparticles incorporating fluorophores are increasingly being used for medical applications. The number of fluorophores incorporated into the nanoparticles during synthesis is stochastic, leaving some nanoparticles devoid of fluorophores. Determining the number, the brightness and the photostability of the fluorophores incorporated, and the percentage of labeled nanoparticles (labeling efficiency) remains challenging. We have determined the aforementioned quantities for two synthesized multi-modal nanoparticles by exploiting the photobleaching of fluorophores at the single-molecule level using a total internal reflection fluorescence microscope. Labeling efficiency was determined by fitting the distribution of incorporated fluorophores with a statistical model and verified by independent experiments

Single nucleotide polymorphisms as predictors of treatment efficacy and adverse effects of morphine in palliative medicine — a literature review

Introduction: Pain has a significant negative impact on the quality of life of cancer patients and implies numerous clinical consequences. Moderate to severe pain is common in patients receiving palliative care. A major issue is the individual variability resulting in different degrees of response to the analgesic effects of opioids, including morphine, and to the occurrence of their adverse effects. According to one of the theories of pharmacogenomics, single nucleotide polymorphisms (SNPs) are associated with opioid metabolism. Material and methods: A literature review of the PubMed database identified 18 scientific articles concerning SNPs that affect the analgesic effects and adverse effects of morphine or other opioids, per morphine equivalent, from which additional 22 scientific articles were retrieved. Results: The review identified SNPs in the genes OPRM1 A118G, COMT rs4680, ABCB1 C3435T, IL-6, IL-8, TNF-⍺, TAOK3, HTR3B, UGT1A1/UGT1A8 and OPRM1 Arg181Cys, which were found to affect both the occurrence of potential adverse effects and the different demand in palliative care patients for a dose of morphine that will effectively relieve pain. SNPs were found to significantly affect morphine metabolism; the determination of this effect is individual-based. Most studies were conducted in small groups of individuals from ethnically diverse populations, which, if mutations are present, may significantly affect the efficacy of opioid-related SNP assays and the response of patients to the analgesic treatment administered. Conclusions: Findings raise the prospect of the use of SNPs in clinical practice as part of personalised medicine in the future.Ból nowotworowy ma poważny wpływ na jakość życia chorych i implikuje liczne kliniczne konsekwencje. Ból w stopniu od umiarkowanego do ciężkiego doświadcza większość pacjentów medycyny paliatywnej. Problem stanowi zmienność osobnicza powodująca różny stopień odpowiedzi na działanie przeciwbólowe opioidów, w tym morfiny i na wystąpienie ich efektów ubocznych. Jedną z teorii farmakogenomicznych mających na celu wyjaśnienie zmienności są polimorfizmy pojedynczych nukleotydów (SNP – single nucleotide polymorphisms) związane z metabolizmem opioidów. Przegląd literatury przeprowadzony w bazie PubMed zidentyfikował 16 artykułów naukowych dotyczących SNP wpływających na działanie przeciwbólowe i działania niepożądane morfiny bądź innych opioidów z przeliczeniem na ekwiwalent morfiny, z których dodatkowo pozyskano 22 istotne dla przeglądu artykuły naukowe. W przeglądzie zidentyfikowano SNP w genach OPRM1 A118G, COMT rs4680, ABCB1 C3435T, IL-6, IL-8, TNF⍺, TAOK3, HTR3B, UGT1A1/UGT1A8, a także OPRM1 Arg181Cys, które wykazały wpływ na zróżnicowane zapotrzebowanie pacjentów paliatywnych na dawkę morfiny skutecznie kontrolującej ból oraz na wystąpienie potencjalnych działań niepożądanych. Wykazano, że SNP istotnie wpływa na metabolizm morfiny. Określenie tego wpływu jest zależne osobniczo. W przeprowadzonej analizie większość badań opierała się na niewielkich liczebnie grupach pacjentów z różnorodnych etnicznie populacji, co w przypadku występowania mutacji może mieć istotny wpływ na skuteczność oznaczania SNP związanych z opioidami i na odpowiedź pacjentów na zastosowane leczenie przeciwbólowe. Liczba dostępnych dowodów naukowych w literaturze daje nadzieję na wykorzystanie SNP w praktyce klinicznej w przyszłości jako element medycyny spersonalizowanej