OBJECTIVE: Previous retrospective studies have reported vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM-related symptoms were reported in TSC infants. METHODS: The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty-nine age-matched non-TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid-attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated. RESULTS: Prevalence of VABAM in VGB-treated TSC patients was 35.5%. VABAM-like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43-6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB-treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM-like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68-8.77). SIGNIFICANCE: VABAM are common in VGB-treated TSC infants; however, VABAM-like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM-like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well-known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.
- MeSH
- Anticonvulsants * adverse effects therapeutic use MeSH
- Cohort Studies MeSH
- Infant MeSH
- Humans MeSH
- Magnetic Resonance Imaging * MeSH
- Brain * diagnostic imaging drug effects MeSH
- Child, Preschool MeSH
- Prospective Studies MeSH
- Registries MeSH
- Retrospective Studies MeSH
- Tuberous Sclerosis * diagnostic imaging complications MeSH
- Vigabatrin * therapeutic use adverse effects MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
TFE3 rearrangements characterize histogenetically, topographically, and biologically diverse neoplasms. Besides being a universal defining feature in alveolar soft part sarcoma (ASPS) and clear cell stromal tumor of the lung, TFE3 fusions have been reported in subsets of renal cell carcinoma, perivascular epithelioid cell tumor (PEComa), epithelioid hemangioendothelioma and ossifying fibromyxoid tumors. TFE3 -related neoplasms are rare in the head and neck and may pose diagnostic challenges. We herein describe 22 TFE3 fusion neoplasms affecting 11 males and 11 females aged 4 to 79 years (median, 25) and involving different head and neck sites: sinonasal cavities (n = 8), tongue (n = 4), oral cavity/oropharynx (n = 3), salivary glands (n = 2), orbit (n = 2), and soft tissue or unspecified sites (n = 3). Based on morphology and myomelanocytic immunophenotype, 10 tumors qualified as ASPS, 7 as PEComas (3 melanotic; all sinonasal), and 5 showed intermediate (indeterminate) histology overlapping with ASPS and PEComa. Immunohistochemistry for TFE3 was homogeneously strongly positive in all cases. Targeted RNA sequencing/FISH testing confirmed TFE3 fusions in 14 of 16 successfully tested cases (88%). ASPSCR1 was the most frequent fusion partner in ASPS (4 of 5 cases); one ASPS had a rare VCP::TFE3 fusion. The 6 successfully tested PEComas had known fusion partners as reported in renal cell carcinoma and PEComas ( NONO, PRCC, SFPQ , and PSPC1 ). The indeterminate tumors harbored ASPSCR1::TFE3 (n = 2) and U2AF2::TFE3 (n = 1) fusions, respectively. This large series devoted to TFE3-positive head and neck tumors illustrates the recently proposed morphologic overlap in the spectrum of TFE3 -associated mesenchymal neoplasms. While all PEComas were sinonasal, ASPS was never sinonasal and occurred in diverse head and neck sites with a predilection for the tongue. The indeterminate (PEComa-like) category is molecularly more akin to ASPS but shows different age, sex, and anatomic distribution compared with classic ASPS. We report VCP as a novel fusion partner in ASPS and PSPC1 as a novel TFE3 fusion partner in PEComa (detected in one PEComa). Future studies should shed light on the most appropriate terminological subtyping of these highly overlapping tumors.
- MeSH
- Sarcoma, Alveolar Soft Part * genetics pathology MeSH
- Child MeSH
- Adult MeSH
- Phenotype MeSH
- Genetic Predisposition to Disease MeSH
- Gene Rearrangement * MeSH
- In Situ Hybridization, Fluorescence MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Head and Neck Neoplasms * genetics pathology chemistry MeSH
- Perivascular Epithelioid Cell Neoplasms * genetics pathology chemistry MeSH
- Child, Preschool MeSH
- Aged MeSH
- Basic Helix-Loop-Helix Leucine Zipper Transcription Factors * genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Super-resolution (SR) microscopy is a cutting-edge method that can provide detailed structural information with high resolution. However, the thickness of the specimen has been a major limitation for SR methods, and large biological structures have posed a challenge. To overcome this, the key step is to optimise sample preparation to ensure optical homogeneity and clarity, which can enhance the capabilities of SR methods for the acquisition of thicker structures. Oocytes are the largest cells in the mammalian body and are crucial objects in reproductive biology. They are especially useful for studying membrane proteins. However, oocytes are extremely fragile and sensitive to mechanical manipulation and osmotic shocks, making sample preparation a critical and challenging step. We present an innovative, simple and sensitive approach to oocyte sample preparation for 3D STED acquisition. This involves alcohol dehydration and mounting into a high refractive index medium. This extended preparation procedure allowed us to successfully obtain a unique two-channel 3D STED SR image of an entire mouse oocyte. By optimising sample preparation, it is possible to overcome current limitations of SR methods and obtain high-resolution images of large biological structures, such as oocytes, in order to study fundamental biological processes. Lay Abstract: Super-resolution (SR) microscopy is a cutting-edge tool that allows scientists to view incredibly fine details in biological samples. However, it struggles with larger, thicker specimens, as they need to be optically clear and uniform for the best imaging results. In this study, we refined the sample preparation process to make it more suitable for SR microscopy. Our method includes carefully dehydrating biological samples with alcohol and then transferring them into a mounting medium that enhances optical clarity. This improved protocol enables high-resolution imaging of thick biological structures, which was previously challenging. By optimizing this preparation method, we hope to expand the use of SR microscopy for studying large biological samples, helping scientists better understand complex biological structures.
OBJECTIVES: Differentiating true progression or recurrence (TP/TR) from therapy-related changes (TRC) is complex in brain tumours. Amide proton transfer-weighted (APT) imaging is a chemical exchange saturation transfer (CEST) MRI technique that may improve diagnostic accuracy during radiological follow-up. This systematic review and meta-analysis elucidated the level of evidence and details of state-of-the-art imaging for APT-CEST in glioma and brain metastasis surveillance. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched for original articles about glioma and metastasis patients who received APT-CEST imaging for suspected TP/TR within 2 years after (chemo)radiotherapy completion. Modified Quality Assessment of Diagnostic Accuracy Studies-2 criteria were applied. A meta-analysis was performed to pool results and to compare subgroups. RESULTS: Fifteen studies were included for a narrative synthesis, twelve of which (500 patients) were deemed sufficiently homogeneous for a meta-analysis. Magnetisation transfer ratio asymmetry performed well in gliomas (sensitivity 0.88 [0.82-0.92], specificity 0.84 [0.72-0.91]) but not in metastases (sensitivity 0.64 [0.38-0.84], specificity 0.56 [0.33-0.77]). APT-CEST combined with conventional/advanced MRI rendered 0.92 [0.86-0.96] and 0.88 [0.72-0.95] in gliomas. Tumour type, TR prevalence, sex, and acquisition protocol were sources of significant inter-study heterogeneity in sensitivity (I2 = 62.25%; p < 0.01) and specificity (I2 = 66.31%; p < 0.001). CONCLUSION: A growing body of literature suggests that APT-CEST is a promising technique for improving the discrimination of TP/TR from TRC in gliomas, with limited data on metastases. CLINICAL RELEVANCE STATEMENT: This meta-analysis identified a utility for APT-CEST imaging regarding the non-invasive discrimination of brain tumour progression from therapy-related changes, providing a critical evaluation of sequence parameters and cut-off values, which can be used to improve response assessment and patient outcome. KEY POINTS: Therapy-related changes mimicking progression complicate brain tumour treatment. Amide proton imaging improves the non-invasive discrimination of glioma progression from therapy-related changes. Magnetisation transfer ratio asymmetry measurement seems not to have added value in brain metastases.
- MeSH
- Amides * MeSH
- Diagnosis, Differential MeSH
- Glioma * diagnostic imaging pathology MeSH
- Humans MeSH
- Neoplasm Recurrence, Local diagnostic imaging MeSH
- Magnetic Resonance Imaging * methods MeSH
- Brain Neoplasms * diagnostic imaging secondary MeSH
- Disease Progression * MeSH
- Protons MeSH
- Sensitivity and Specificity MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
Compounds in sand fly saliva elicit specific immune responses that may play a role in the establishment of canine Leishmania infection. Although canine antibodies to anti-sand fly saliva antigens have been extensively studied, little is known about cellular immune responses against Phlebotomus perniciosus salivary proteins. This study aimed to explore humoral and T-cell-mediated immunity against P. perniciosus salivary proteins in dogs (n = 85) from Mallorca (Spain), a leishmaniosis-endemic area, and find correlations with demographic (age, sex, and breed) and parasite-specific immunological parameters. Anti-sand fly saliva IgG was examined using a P. perniciosus whole salivary gland homogenate (SGH) ELISA and recombinant salivary protein rSP03B ELISA. Interferon gamma (IFN-γ) release whole blood assays with L. infantum soluble antigen (LSA), SGH, and rSP03B were also performed. Positive correlations were found between IgG levels in the SGH and rSP03B tests and between concentrations of SGH IFN-γ and rSP03B IFN-γ. While concentrations of SGH IFN-γ and rSP03B IFN-γ were low and produced only by a minority of dogs (less than 20%), high levels and frequencies of LSA IFN-γ as well as anti-saliva IgG for SGH and rSP03B were detected in a majority of dogs (61% and 75%, respectively). LSA IFN-γ levels were positively correlated with age and Leishmania-specific antibodies. In conclusion, dogs from a leishmaniosis-endemic area presented high humoral immunity against P. perniciosus salivary proteins, but their cellular immunity to these proteins was low and less frequent.
- MeSH
- Immunity, Cellular * MeSH
- Endemic Diseases MeSH
- Insect Proteins * immunology MeSH
- Immunity, Humoral * MeSH
- Immunoglobulin G blood immunology MeSH
- Interferon-gamma MeSH
- Leishmaniasis * immunology veterinary epidemiology MeSH
- Dog Diseases * immunology parasitology epidemiology MeSH
- Phlebotomus * immunology MeSH
- Dogs MeSH
- Salivary Proteins and Peptides * immunology MeSH
- T-Lymphocytes * immunology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Dogs MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Spain MeSH
BACKGROUND: A detailed understanding of alterations in olanzapine pharmacokinetics during acute inflammatory states, associated with infections, remains lacking. This study aimed to investigate the impact of endotoxemia on the pharmacokinetics of olanzapine and desmethylolanzapine (DMO) in mice. METHODS: C57BL/6N mice received an intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) or saline (controls), followed 24 hours later by single oral or intravenous doses of olanzapine or intravenous DMO. Concentrations and unbound fractions of olanzapine and DMO were measured in the plasma and brain homogenates. RESULTS: In LPS-injected mice, the area under the concentration-time curve (AUCs) for olanzapine increased 3.8-fold in the plasma and 5.2-fold in brain homogenates, in consequence of a higher absolute bioavailability of olanzapine (+200%), a lower plasma clearance (-34%), and a higher brain penetration ratio for the unbound drug relative to controls (Kp,uu,brain 6.2 vs. 4.1). LPS attenuated the hepatic mRNA expression of cytochrome P450 1A2 and the metabolism of olanzapine to DMO. However, the AUC of plasma DMO increased by 140% due to a 4.8-fold decrease in the plasma clearance of DMO. The brain penetration of DMO was minimal (Kp,uu,brain ≤ 0.051). The LPS-injected mice exhibited a downregulation of the hepatic and ileal mRNA expression of P-glycoprotein (Abcb1a), whereas the expression of Abcb1a and Abcb1b in the brain was upregulated. CONCLUSIONS: Endotoxemia notably increases olanzapine concentrations in the plasma and brain following oral administration in mice. Further studies should clarify whether altered pharmacokinetics results in adverse effects in acutely infected patients taking oral olanzapine.
- MeSH
- Antipsychotic Agents * pharmacokinetics blood administration & dosage MeSH
- Administration, Oral MeSH
- Benzodiazepines * pharmacokinetics blood administration & dosage MeSH
- Endotoxemia * metabolism chemically induced MeSH
- Lipopolysaccharides MeSH
- Brain * metabolism drug effects MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Olanzapine pharmacokinetics MeSH
- Inflammation * chemically induced metabolism MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA) are neurodegenerative disorders characterized by abnormal accumulation of α-synuclein. Plasmin is a serine protease with a role in various physiological processes, including tissue and synaptic remodeling, inflammation regulation, and modulation of neurotrophic factors. It has also been shown that plasmin is able to cleave extracellular α-synuclein in neuronal cell cultures. The plasminogen activator inhibitor-1 (PAI-1) and the tissue plasminogen activator (tPA) regulate the synthesis and activity of plasmin in the brain. We measured the serum levels of tPA and PAI-1 in 30 DLB, 10 PD, and 12 MSA patients and compared them to 10 adults (controls). tPA and PAI-1 serum protein concentrations were quantified by ELISA and compared across the groups. The findings demonstrated that PAI-1 serum levels were increased in DLB (p < 0.05), PD (p < 0.01), and MSA (p < 0.001) patients as compared to controls. In addition, MSA patients had higher PAI-1 serum levels (p < 0.01) as compared to DLB patients, showing the highest PAI-1 levels among all groups. No differences in tPA serum levels were found among groups. Our findings suggest an involvement of plasmin system in these synucleinopathies although there are some limitations due to the heterogeneity of our cohort of participants. Thus, these data must be seen as preliminary observations and further studies in larger and more homogenous cohorts are needed before drawing definitive conclusions.
- Publication type
- Journal Article MeSH
BACKGROUND: Processes shaping the formation of the present-day population structure in highly urbanized Northern Europe are still poorly understood. Gaps remain in our understanding of when and how currently observable regional differences emerged and what impact city growth, migration, and disease pandemics during and after the Middle Ages had on these processes. RESULTS: We perform low-coverage sequencing of the genomes of 338 individuals spanning the eighth to the eighteenth centuries in the city of Sint-Truiden in Flanders, in the northern part of Belgium. The early/high medieval Sint-Truiden population was more heterogeneous, having received migrants from Scotland or Ireland, and displayed less genetic relatedness than observed today between individuals in present-day Flanders. We find differences in gene variants associated with high vitamin D blood levels between individuals with Gaulish or Germanic ancestry. Although we find evidence of a Yersinia pestis infection in 5 of the 58 late medieval burials, we were unable to detect a major population-scale impact of the second plague pandemic on genetic diversity or on the elevated differentiation of immunity genes. CONCLUSIONS: This study reveals that the genetic homogenization process in a medieval city population in the Low Countries was protracted for centuries. Over time, the Sint-Truiden population became more similar to the current population of the surrounding Limburg province, likely as a result of reduced long-distance migration after the high medieval period, and the continuous process of local admixture of Germanic and Gaulish ancestries which formed the genetic cline observable today in the Low Countries.
- MeSH
- History, Medieval MeSH
- Genetic Variation MeSH
- Genome, Human MeSH
- Genomics MeSH
- Humans MeSH
- Plague epidemiology history genetics MeSH
- Genetics, Population MeSH
- Urbanization * history MeSH
- Check Tag
- History, Medieval MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Historical Article MeSH
- Geographicals
- Belgium MeSH
This study aimed to determine the paraoxonase activity and prooxidant-antioxidant balance in the brain tissue of Wistar rats following subacute treatment with selected K-oximes. Each K-oxime was administered intramuscularly (0.1 LD50/kg) twice per week for four weeks, and 7 days after the last treatment, the paraoxonase activity (PON1), the prooxidant-antioxidant balance (PAB), the levels of superoxide anion radical (O2•-), the concentration of nitrite (NO2-) and the content of free protein thiol groups in the brain homogenates were evaluated. The PON1 and PAB activity were significantly reduced in almost all oxime-treated groups (p < 0.01 and p < 0.001, respectively). The concentrations of O2•- were significantly increased in the obidoxime-, K048-, K074- and K075-treated groups (p < 0.001), while the levels of NO2- was significantly decreased in asoxime-, obidoxime-, K074 and K075-treated rats (p < 0.01, p < 0.001, respectively). The content of Thiol groups was significantly elevated in all oxime-treated groups (p < 0.001). Continuing our previously published data, these results confirmed that applied K-oximes improved the oxidative status and further harmful systemic effects of rats after subacute administration.
- MeSH
- Antioxidants * metabolism MeSH
- Aryldialkylphosphatase * metabolism MeSH
- Nitrites metabolism MeSH
- Rats MeSH
- Brain * drug effects metabolism enzymology MeSH
- Oximes * pharmacology administration & dosage MeSH
- Rats, Wistar MeSH
- Sulfhydryl Compounds metabolism MeSH
- Superoxides metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Radiotherapy can be both immunosuppressive and immunostimulatory. Radiation-induced lymphopenia (RIL) is an ongoing challenge in cancer treatment. We investigated weekly changes in the absolute lymphocyte count (ALC) during proton radiotherapy, evaluating the effects of different dosage, fractionation schedules, and pelvic node irradiation (PNI). Prostate cancer patients were prospectively chosen for this study, due to their relatively homogenous treatment plans. Treatment protocols were categorized into three groups: Group A (n=52) received 36.25 Gy/5-fractions, Group B (n=60) underwent 63 Gy/21-fractions and group C (n=69) received 63 Gy/21-fractions plus PNI. To account for individual characteristic differences, a new categorization method was made, according to the change in ALC relative to the baseline. Lymphopenia (ALC < 1000 K/μL) developed in 8%, 17% and 84% of patients in groups A, B, and C, respectively. An initial increase in ALC occurred in 44%, 47% and 28% of groups A, B and C, respectively, and declined with proceeding fractions. Patients with PNI had the most pronounced reduction in their ALC relative to the baseline. Increased dosage and fractionation led to a higher incidence of lymphopenia. Understanding which factors influence ALC in particle therapy is vital for leveraging the immune-enhancing effects of radiotherapy, while minimising its immunosuppressive impacts.
- Publication type
- Journal Article MeSH
