Continuous monitoring of the intracranial pressure (ICP) is essential in neurocritical care. There are a variety of ICP monitoring systems currently available, with the intraventricular fluid filled catheter transducer currently representing the "gold standard". As the placement of catheters is associated with the attendant risk of infection, hematoma formation, and seizures, there is a need for a reliable, non-invasive alternative. In the present study we suggest a unique theoretical framework based on differential geometry invariants of cranial micro-motions with the potential for continuous non-invasive ICP monitoring in conservative traumatic brain injury (TBI) treatment. As a proof of this concept, we have developed a pillow with embedded mechanical sensors and collected an extensive dataset (> 550 h on 24 TBI coma patients) of cranial micro-motions and the reference intraparenchymal ICP. From the multidimensional pulsatile curve we calculated the first Cartan curvature and constructed a "fingerprint" image (Cartan map) associated with the cerebrospinal fluid (CSF) dynamics. The Cartan map features maxima bands corresponding to a pressure wave reflection corresponding to a detectable skull tremble. We give evidence for a statistically significant and patient-independent correlation between skull micro-motions and ICP time derivative. Our unique differential geometry-based method yields a broader and global perspective on intracranial CSF dynamics compared to rather local catheter-based measurement and has the potential for wider applications.
- MeSH
- Adult MeSH
- Intracranial Hypertension physiopathology MeSH
- Intracranial Pressure physiology MeSH
- Skull physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Monitoring, Physiologic MeSH
- Aged MeSH
- Brain Injuries, Traumatic physiopathology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a progressive disease characterized by disproportionate ventricular enlargement at brain imaging with gait disturbance and an increased risk of falling. Gait assessment is a key feature in the diagnosis of iNPH and characterization of post-surgical outcomes. RESEARCH QUESTION: How do gait parameters change 24 h after CSF tap test (CSFTT) and after ventriculoperitoneal shunt surgery? METHODS: The PRISMA guidelines were used to perform the systematic review. We conducted a search of the following electronic databases: PubMed, Medline, Web of Science and EBSCO. We included studies focusing on gait changes occurring 24 h after a CSFTT or after ventriculoperitoneal shunt surgery in patients with iNPH. All articles were assessed for methodological quality using an adapted version of The Standard Quality Assessment Criteria for Evaluating Primary Research Papers checklist. RESULTS: Twenty-seven studies were included in the systematic review. Studies were highly heterogeneous due to lack of standardization of CSFTT or shunt surgery methodology, with varying amounts of CSF removed during the tap test (20-50 ml) and varying time of outcome assessment after shunt surgery. Dynamic equilibrium measurements are generally used to assess preoperative levels of cardinal symptoms and postoperative outcomes in iNPH. The most sensitive spatio-temporal parameter assessed 24 h after CSFTT was self-selected walking speed followed by stride length, which increased significantly. Cadence is hence not suitable to consider in the evaluation of effect of CSFTT and shunt surgery. Changes in balance-related gait parameters after CSFTT and shunt surgery are still a controversial area of research. CONCLUSION: Gait assessment is a key feature in the diagnosis of iNPH and characterization of post-surgical outcomes. Dynamic equilibrium measurements are generally used to assess preoperative levels of cardinal symptoms and postoperative outcomes in iNPH, but quantitative and standardized gait analysis procedures are missing. Changes in balance-related gait parameters after CSFTT might be useful in deciding whether to perform shunt surgery in iNPH patients who hope for improvement in gait ability. The dual-task paradigm after CSFTT could improve the clinical evaluation of higher level frontal gait disturbances in patients with suspected iNPH before shunting.
- MeSH
- Gait * physiology MeSH
- Humans MeSH
- Hydrocephalus, Normal Pressure * surgery physiopathology cerebrospinal fluid diagnosis MeSH
- Cerebrospinal Fluid Shunts MeSH
- Spinal Puncture methods MeSH
- Ventriculoperitoneal Shunt MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Systematic Review MeSH
Článek porovnává možnosti měření likvorové dynamiky pomocí tří různých metod magnetické rezonance: metody fázového kontrastu (Phase contrast, PC), sekvence SPAMM (Spatial modulation of magnetization) a sekvence PSIF. Principy všech metod jsou zde stručně objasněny. Jedině PC umožňuje kvantifikovat okamžitou rychlost a průtok. Výhoda sekvence PSIF spočívá v jednoduchosti měření (bez potřeby EKG) a v možnosti zobrazit větší objem zájmu (3D). Jedinou výhodou sekvence SPAMM je možnost dynamického zobrazení toku i v případě turbulentního charakteru, kdy interpretace výsledku v pnpadě PC může být složitá. Mereni byla prováděna jak na skupině zdravých dobrovolníků (10 dospělých, 10 dětí), tak s pacienty (stenóza akveduktu, stav po ventrikulostomii, syringomyelic). V případě syringomyelic byl porov¬ L Časový charakter pulzace uvnitř míšní dutiny s extramedulárním prostorem. U malých dutin (zhruba do 2 cm délky) jsme nenaměřili výraznější pohyb likvoru. U rozměrnějších kavit (mezi 2 až 10 cm) byla délka pulzní likvorové vlny kratší v intramedulámí dutině než v extramedulárním prostoru. U rozsáhlých syringomyelií (více než 10 cm) jsme většinou naměřili shodnou pulzaci uvnitř a vně míchy.
The authors compare the possibilities of assessment of the dynamics of cerebrospinal fiuid (CSF) by three different methods of magnetic resonance: phase contrast (PC), SPAMM sequence (spatial modulation of magnetization) and the PSIF sequence. The principles of all methods are briefly explained. Only PC makes quantification of the rate and flow possible. The advantage of the PSIF sequence is in the simplicity of measurement (not requiring ECG) and the possibility to visualize a larger area of interest (3D). The only advantage of sequence SPAMM is the opportunity of dynamic imaging of the flow even when it is turbulent when the interpretation of results obtained by PC may be complicated. The assessments were made in a group of healthy volunteers (10 adults, 10 children) as well as in patients (stenosis of the aqueduct, condition after ventriculostomy, syringomyelia). In syringomye¬ lia the character of the pulsation in the spinal cavity was compared with the extramedullary space. In small cavities (under 2 cm long) no marked movement of CSF was found. In larger cavities (2 to 10 cm) the lenght of the pulse CSF wave was shorter in the intramedullary cavity than in the extramedullary space. In extensive syringomyelias (more than 10 cm) usually the same pulsation was recorded inside and outside the spinal cord.
Invasive meningococcal disease continues to be a life-threatening condition and rapid diagnosis is important for the administration of appropriate treatment. This study focused on the use of PCR for the diagnosis of meningococcal aetiology and the dynamics of PCR-based diagnosis over time in various biological samples. Sixty cerebrospinal fluid (CSF) and 144 serum samples collected during the first week of hospitalisation from 37 patients with laboratory-confirmed invasive meningococcal disease were investigated. Overall, 91.9% of CSF samples and 45.9% of serum samples were PCR-positive, while culture of CSF and blood was positive for only 35% and 39% samples, respectively. Positive PCR results were obtained until day 7 with CSF and until day 5 with serum. It is therefore recommended that samples for molecular diagnosis should be collected early in the course of suspected invasive meningococcal disease.
- MeSH
- Time Factors MeSH
- Child MeSH
- DNA, Bacterial analysis genetics MeSH
- Adult MeSH
- Infant MeSH
- Blood microbiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Meningitis, Meningococcal diagnosis MeSH
- Meningococcal Infections diagnosis MeSH
- Adolescent MeSH
- Cerebrospinal Fluid microbiology MeSH
- Neisseria meningitidis genetics isolation & purification growth & development MeSH
- Polymerase Chain Reaction methods MeSH
- Child, Preschool MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Comparative Study MeSH
BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe condition associated with high mortality. Early brain injury (EBI) plays an important role in the pathophysiology of SAH, and inflammation is a major contributor to EBI. Inflammation is a widely studied topic in both experimental and clinical conditions; however, just a few clinical studies have focused primarily on the early inflammatory response after SAH, and detailed information about the association between the dynamics of early inflammatory response with main clinical characteristics is lacking. This study analyzes the early dynamics of inflammatory response after SAH and evaluates the possible associations between the markers of early inflammatory response and main clinical characteristics. PATIENTS AND METHODS: A total of 47 patients with a diagnosis of aneurysmal SAH within the last 24 hours were enrolled in the study. All treatments, including treatment of aneurysm (surgery/coiling) and implantation of a drainage system (external ventricular drainage/lumbar catheter), were conducted in the same way as in other patients with this diagnosis. Blood and cerebrospinal fluid (CSF) samples were collected three times a day for 4 days. The dynamics of proinflammatory cytokines were assessed, and associations between levels of the proinflammatory cytokines interleukin (IL)-6, IL-1β, or tumor necrosis factor (TNF)α and main clinical characteristics were evaluated using linear mixed-effect models. RESULTS: The CSF levels of IL-6 were massively increased initially after SAH (up to 72 hours) with an additional increase in later phases (after 72 hours), but there was high variability in IL-6 levels. A significant association was noted between the Glasgow Outcome Scale score and both overall levels of IL-6 (p = 0.0095) and their dynamics (p = 0.0208); the effect of the Hunt and Hess scale was borderline (p = 0.0887). No association was found between IL-6 levels and Fisher grade, modality of treatment (surgery, coiling, no treatment), and later development of cerebral vasospasm. Plasmatic levels of IL-6 increased slightly, but no significant association was found. The levels of IL-1β and TNFα were within the physiologic range in both CSF and plasma. CONCLUSIONS: Early dynamics of IL-6 in CSF are associated with a patient́s outcome. But it is difficult to use IL-6 alone for outcome prediction due to its high variability. The question is whether the dynamics of IL-6 could be used in combination with other early markers associated with brain injury. More detailed research is required to answer this question.
- MeSH
- Biomarkers metabolism MeSH
- Cytokines blood MeSH
- Adult MeSH
- Drainage MeSH
- Glasgow Outcome Scale MeSH
- Interleukin-6 MeSH
- Intracranial Aneurysm blood complications MeSH
- Middle Aged MeSH
- Humans MeSH
- Predictive Value of Tests MeSH
- Prognosis MeSH
- Aged MeSH
- Subarachnoid Hemorrhage blood complications MeSH
- Tumor Necrosis Factor-alpha blood MeSH
- Inflammation MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cardiorespiratory signals have long been treated as "noise" in functional magnetic resonance imaging (fMRI) research, with the goal of minimizing their impact to isolate neural activity. However, there is a growing recognition that these signals, once seen as confounding variables, provide valuable insights into brain function and overall health. This shift reflects the dynamic interaction between the cardiovascular, respiratory, and neural systems, which together support brain activity. In this review, we explore the role of cardiorespiratory dynamics-such as heart rate variability (HRV), respiratory sinus arrhythmia (RSA), and changes in blood flow, oxygenation, and carbon dioxide levels-embedded within fMRI signals. These physiological signals reflect critical aspects of neurovascular coupling and are influenced by factors such as physiological stress, breathing patterns, and age-related changes. We also discuss the complexities of distinguishing these signals from neuronal activity in fMRI data, given their significant contribution to signal variability and interactions with cerebrospinal fluid (CSF). Recognizing the influence of these cardiorespiratory dynamics is crucial for improving the interpretation of fMRI data, shedding light on heart-brain and respiratory-brain connections, and enhancing our understanding of circulation, oxygen delivery, and waste elimination within the brain.
AIM: To determine cytotoxicity and effect of silica-coated magnetic nanoparticles (MNPs) on immune response, in particular lymphocyte proliferative activity, phagocytic activity, and leukocyte respiratory burst and in vitro production of interleukin-6 (IL-6) and 8 (IL-8), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and granulocyte macrophage colony stimulating factor (GM-CSF). METHODS: Maghemite was prepared by coprecipitation of iron salts with ammonia, oxidation with NaOCl and modified by tetramethyl orthosilicate and aminosilanes. Particles were characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier-transform infrared (FTIR), and X-ray photoelectron spectroscopy (XPS). Cytotoxicity and lymphocyte proliferative activity were assessed using [3H]-thymidine incorporation into DNA of proliferating human peripheral blood cells. Phagocytic activity and leukocyte respiratory burst were measured by flow cytometry; cytokine levels in cell supernatants were determined by ELISA. RESULTS: γ-Fe2O3&SiO2-NH2 MNPs were 13 nm in size. According to TEM, they were localized in the cell cytoplasm and extracellular space. Neither cytotoxic effect nor significant differences in T-lymphocyte and T-dependent B-cell proliferative response were found at particle concentrations 0.12-75 μg/cm2 after 24, 48, and 72 h incubation. Significantly increased production of IL-6 and 8, and GM-CSF cytokines was observed in the cells treated with 3, 15, and 75 µg of particles/cm2 for 48 h and stimulated with pokeweed mitogen (PHA). No significant changes in TNF-α and IFN-γ production were observed. MNPs did not affect phagocytic activity of monocytes and granulocytes when added to cells for 24 and 48 h. Phagocytic respiratory burst was significantly enhanced in the cultures exposed to 75 µg MNPs/cm2 for 48 h. CONCLUSIONS: The cytotoxicity and in vitro immunotoxicity were found to be minimal in the newly developed porous core-shell γ-Fe2O3&SiO2-NH2 magnetic nanoparticles.
- MeSH
- Phagocytes physiology MeSH
- Granulocyte-Macrophage Colony-Stimulating Factor metabolism MeSH
- Interleukin-6 metabolism MeSH
- Interleukin-8 metabolism MeSH
- Leukocytes physiology MeSH
- Humans MeSH
- Lymphocytes physiology MeSH
- Nanoshells chemistry ultrastructure MeSH
- Silicon Dioxide chemistry MeSH
- Flow Cytometry MeSH
- Respiratory Burst physiology MeSH
- Tumor Necrosis Factor-alpha metabolism MeSH
- Structure-Activity Relationship MeSH
- Ferric Compounds chemistry MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: ALZ-801 is an oral, small-molecule inhibitor of beta amyloid (Aβ) oligomer formation in clinical development for Alzheimer's disease (AD). ALZ-801 is a prodrug of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. During clinical studies, we discovered that the primary metabolite of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule in the human brain and present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases. OBJECTIVE: The objectives of this research were to (1) identify and confirm the presence of 3-SPA in CSF samples from elderly, drug-naïve patients with memory deficits; (2) quantify the levels of 3-SPA in the CSF of patients with AD from tramiprosate phase III North American (NA) trial; (3) evaluate the in vitro anti-Aβ42 oligomer activity of 3-SPA; and (4) characterize the pharmacokinetics and brain-penetration properties of 3-SPA. METHODS: Lumbar CSF samples from 64 drug-naïve patients with cognitive deficits (Mini-Mental State Examination [MMSE] score range 15-30) and six patients with AD treated with tramiprosate 150 mg twice daily in the phase III trial, at week 78, were analyzed. We used liquid chromatography-tandem mass spectrometry to confirm the structural molecular identity of endogenous 3-SPA with a 3-SPA reference standard and ion-mobility spectrometry-mass spectrometry with molecular dynamics to characterize interactions of 3-SPA with Aβ42 monomers, and the resultant conformational alterations. Rat studies using oral (30 mg/kg) and intravenous (10 mg/kg) doses were conducted to characterize the pharmacokinetic properties and brain penetration of 3-SPA. RESULTS: We confirmed the presence of 3-SPA in the CSF of drug-naïve patients with cognitive deficits (mean concentration 11.7 ± 4.3 nM). The mean concentration of 3-SPA in patients with AD treated with tramiprosate was 135 ± 51 nM. In vitro studies revealed a multi-ligand interaction of 3-SPA with monomeric Aβ42 that inhibits the aggregation of Aβ42 into small oligomers. Comparisons of the molecular interactions of tramiprosate and 3-SPA with Aβ42 are also presented. Furthermore, in rat preclinical studies, 3-SPA displayed 100% oral bioavailability and 25% brain penetration, indicating that the metabolite is well absorbed and crosses the blood-brain barrier. CONCLUSIONS: We confirmed the endogenous presence of 3-SPA, the major metabolite of tramiprosate, in the CSF of drug-naïve elderly patients with memory deficits due to AD and a variety of other neurodegenerative disorders. The levels of 3-SPA were up to 12.6-fold greater in patients with AD receiving tramiprosate than in drug-naïve patients. In addition, we showed that 3-SPA has potent anti-Aβ oligomer activity, inhibiting aggregation of Aβ42 into small oligomers with efficacy comparable to that of tramiprosate. 3-SPA displays excellent oral availability and brain penetration in rats, suggesting that the higher CSF concentrations of 3-SPA in the human brain after oral administration of ALZ-801 or tramiprosate (and subsequent conversion to 3-SPA) result from the penetration of the metabolite into the central nervous system. These data suggest that 3-SPA is an endogenous agent with potential activity stabilizing the conformational flexibility of Aβ monomers that, in turn, inhibit Aβ misfolding and formation of soluble toxic Aβ oligomers in humans, thereby preventing the initial pathogenic step in the progression of AD. Clinical improvements observed in patients with AD carrying the ε4 allele of the apolipoprotein E gene in tramiprosate phase III studies may in part be explained by the therapeutic effects of excess levels of the metabolite in the brains of these patients. The potential protective role of 3-SPA in AD pathogenesis, as well as its therapeutic role in AD and other neurodegenerative disorders, warrants further investigation.
- MeSH
- Alzheimer Disease complications drug therapy MeSH
- Amyloid beta-Peptides metabolism MeSH
- Models, Chemical MeSH
- Chromatography, Liquid MeSH
- Cognition Disorders etiology MeSH
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Brain drug effects metabolism MeSH
- Nonlinear Dynamics MeSH
- Peptide Fragments metabolism MeSH
- Computer Simulation MeSH
- Rats, Sprague-Dawley MeSH
- Prodrugs chemistry therapeutic use MeSH
- Propionates MeSH
- Aged MeSH
- Tandem Mass Spectrometry MeSH
- Taurine analogs & derivatives chemistry therapeutic use MeSH
- Valine analogs & derivatives chemistry therapeutic use MeSH
- Mental Status Schedule MeSH
- Drug Administration Routes MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Research Support, Non-U.S. Gov't MeSH
Skupina biosimilars je dynamicky se rozvíjející oblastí farmaceutického trhu. Biosimilars ale nelze považovat za biogenerika, protože každý biotechnologický produkt je biologicky unikátní a může mít také unikátní vlastnosti a rizika. Regulační agentury požadují ve srovnání s klasickými generiky mnohem rozsáhlejší preklinické a klinické doklady o účinnosti a bezpečnosti. Největším očekáváním z příchodu biosimilars je možnost úspory prostředků ve zdravotnictví.
The group of biosimilars is a dynamically developing area of the pharmaceutical market. But biosimilars could not be referred to as biogenerics because each biotech product is biologically unique, and may also have unique characteristics and risks. In comparison with traditional generics regulatory agencies require for biosimilars more extensive preclinical and clinical evidence of efficacy and safety. The greatest expectation of biosimilars' introduction is a possibility of saving resources in health care.
- Keywords
- biotechnologické léky,
- MeSH
- Biotechnology methods trends MeSH
- European Union MeSH
- Granulocyte Colony-Stimulating Factor pharmacology MeSH
- Drug Industry methods trends MeSH
- Pharmacology economics methods trends MeSH
- Filgrastim MeSH
- Drugs, Generic economics classification therapeutic use MeSH
- Pharmaceutical Preparations economics classification MeSH
- Humans MeSH
- Drug-Related Side Effects and Adverse Reactions MeSH
- Drug Discovery methods trends MeSH
- Drug Approval methods organization & administration legislation & jurisprudence MeSH
- Practice Guidelines as Topic MeSH
- Legislation, Drug MeSH
- Check Tag
- Humans MeSH
- Geographicals
- Czech Republic MeSH
- United States MeSH
