scholarly journals Joint ex vivo MRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies

2021 ◽  
Author(s):  
M. Dylan Tisdall ◽  
Daniel T Ohm ◽  
Rebecca Lobrovich ◽  
Sandhitsu R Das ◽  
Gabor Mizsei ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Ex Vivo ◽  
Cortical Layer ◽  
Heme Iron ◽  
Therapeutic Trials ◽  
Hyperintense Signal ◽  
Mri Features ◽  
Healthy Control ◽  
Hypointense Signal

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer's disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

scholarly journals Current Challenges in Volatile Organic Compounds Analysis as Potential Biomarkers of Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-16 ◽  
Author(s):  
Kamila Schmidt ◽  
Ian Podmore
Keyword(s):  
Volatile Organic Compounds ◽  
Organic Compounds ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Critical Evaluation ◽  
Detection Techniques ◽  
Volatile Organic ◽  
Potential Biomarkers

An early diagnosis and appropriate treatment are crucial in reducing mortality among people suffering from cancer. There is a lack of characteristic early clinical symptoms in most forms of cancer, which highlights the importance of investigating new methods for its early detection. One of the most promising methods is the analysis of volatile organic compounds (VOCs). VOCs are a diverse group of carbon-based chemicals that are present in exhaled breath and biofluids and may be collected from the headspace of these matrices. Different patterns of VOCs have been correlated with various diseases, cancer among them. Studies have also shown that cancer cells in vitro produce or consume specific VOCs that can serve as potential biomarkers that differentiate them from noncancerous cells. This review identifies the current challenges in the investigation of VOCs as potential cancer biomarkers, by the critical evaluation of available matrices for the in vivo and in vitro approaches in this field and by comparison of the main extraction and detection techniques that have been applied to date in this area of study. It also summarises complementary in vivo, ex vivo, and in vitro studies conducted to date in order to try to identify volatile biomarkers of cancer.

scholarly journals Effect of TGF-β1 on eosinophils to induce cysteinyl leukotriene E4 production in aspirin-exacerbated respiratory disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256237
Author(s):  
Youngwoo Choi ◽  
Soyoon Sim ◽  
Dong-Hyun Lee ◽  
Hee-Ra Lee ◽  
Ga-Young Ban ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cysteinyl Leukotriene ◽  
Aspirin Exacerbated Respiratory Disease ◽  
Healthy Control ◽  
Tgf Β1 ◽  
Eosinophil Degranulation

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E4 (LTE4) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE4. The function of TGF-β1 in LTE4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs (P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE4 had a positive correlation (r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C4 synthase (LTC4S) expression was enhanced in peripheral eosinophils to produce LTE4, which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE4 production via enhancing LTC4S expression which induces eosinophil degranulation, accelerating airway inflammation.

scholarly journals A Case of Mild Encephalopathy with a Reversible Splenial Lesion Associated with G5P[6]Rotavirus Infection

2013 ◽  
Vol 2013 ◽  
pp. 1-3 ◽  
Author(s):  
Tsuyoshi Matsuoka ◽  
Toshifumi Yodoshi ◽  
Misaki Sugai ◽  
Masato Hiyane ◽  
Takashi Matsuoka ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Acute Gastroenteritis ◽  
Clinical Symptoms ◽  
Good Condition ◽  
Splenial Lesion ◽  
Hyperintense Signal ◽  
Disturbance Of Consciousness ◽  
Adc Map ◽  
Hypointense Signal ◽  
The Relationship

We report a case of mild encephalopathy with a reversible splenial lesion (MERS) associated with acute gastroenteritis caused by rotavirus (RV) infection. The patient (male, 4 years and 3 months old) was admitted to our hospital for diarrhea and afebrile seizures. Head MRI revealed a hyperintense signal in the splenium of the corpus callosum on DWI and a hypointense signal on the ADC-map. After awakening from sedation, the patient's disturbance of consciousness improved. On day 5 after admission of the illness, the patient was discharged from the hospital in a good condition. Electroencephalography on day 2 after admission was normal. On day 8 of admission, head MRI revealed that the splenial lesion had disappeared. RV antigen-positive stools suggested that RV had caused MERS. This RV genotype was considered to be G5P[6]; it may have spread to humans as a strain reassortment through substitution of porcine RV into human RV gene segments. This extremely rare genotype was detected first in Japan and is not covered by existing vaccines; this is the first sample isolated from encephalopathy patients. Few reports have investigated RV genotypes in encephalopathy; we believe that this case is valuable for studying the relationship between genotypes and clinical symptoms.

PTH Immunoassay Interference Due to Human Anti-Mouse Antibodies in a Subject With Obesity With Normal Parathyroid Function

2019 ◽  
Vol 104 (12) ◽  
pp. 5840-5842
Author(s):  
Matthias Laudes ◽  
Janosch Frohnert ◽  
Kamelia Ivanova ◽  
Klaus-Peter Wandinger
Keyword(s):  
Clinical Symptoms ◽  
Ex Vivo ◽  
Detection System ◽  
Repeated Measurements ◽  
Diabetes Therapy ◽  
Parathyroid Function ◽  
Vitamin D Levels ◽  
Few Data

Abstract Context Immunoassay interference has been most often found with prolactin measurement. However, only few data exist on immunoassay interference for other hormones. Case Description A 36-year-old woman with obesity (body mass index, 31 kg/m2) had regularly attended our endocrine unit for type 2 diabetes therapy. When she was included as a control subject in a study for obesity management, detailed laboratory testing was performed, including PTH. In the absence of clinical symptoms, she presented with normal calcium, phosphate, and vitamin D levels. However, the PTH levels were >5000 ng/L. These results were obtained using the Roche Elecsys electrochemiluminescence assay. Repeated measurements with this assay (mouse antibody) led to the same findings. However, using an Euroimmun assay (goat antibody), the exact PTH values were measured at 18.0 ng/L. After pretreatment with a heterophilic antibody blocking reagent, the results of the Roche assay had decreased to a normal level. This phenomenon was explained by the detection of human anti-mouse antibodies in the proband’s serum. Conclusions In cases of prolactin immunoassay interference, endogenous antibodies will bind to the hormone in vivo, resulting in complexes of a high molecular weight that are less efficiently cleared by the kidneys and, thus, accumulate in the blood. In contrast, the PTH values >5000 ng/L detected in our subject most likely had resulted from the specific interference of the human anti-mouse antibodies present in the proband’s serum with the assay antibody, resulting in artificial stimulation of the Roche assay detection system ex vivo.

scholarly journals Preclinical and clinical study on [18F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer’s disease

2021 ◽  
Author(s):  
MiaoMiao Xu ◽  
Jun Guo ◽  
JiaCheng Gu ◽  
LinLin Zhang ◽  
ZiHao Liu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Ex Vivo ◽  
Small Animal ◽  
Small Animal Pet ◽  
Animal Pet ◽  
In Vitro Autoradiography ◽  
Healthy Control ◽  
The Brain

Abstract Background The deposition of β-amyloid (Aβ) in the brain is a biomarker of Alzheimer’s disease (AD). Highly sensitive Aβ positron emission tomography (PET) imaging plays an essential role in diagnosing and evaluating the therapeutic effects of AD. Aim To synthesize a new Aβ tracer [18F]DRKXH1 (5-(4-(6-(2-[18]fluoroethoxy)ethoxy)imidazo[1,2-alpha]pyridin-2-yl)phenyl) and evaluate the tracer performance by biodistribution analysis, in vivo small-animal PET-CT dynamic scan, ex vivo and in vitro autoradiography, and PET in human subjects. Methods [18F]DRKXH1 was synthesized automatically by the GE FN module. Log D (pH 7.4) and biodistribution of [18F]DRKXH1 were investigated. Small-animal-PET was used for [18F]DRKXH1 and [18F]AV45 imaging study in AD transgenic mice (APPswe/PSEN1dE9) and age-matched normal mice. The distribution volume ratios (DVR) and standardized uptake value ratios (SUVRs) were calculated with the cerebellum as the reference region. The deposition of Aβ plaques in the brain of AD transgenic mice was determined by ex vivo autoradiography and immunohistochemistry. In vitro autoradiography was performed in the postmortem brain sections of AD patients and healthy controls. Two healthy control subjects and one AD patient was subjected to in vivo PET study using [18F]DRKXH1. Results The yield of [18F]DRKXH1 was 40%, and the specific activity was 156.64 ± 11.55 GBq/μmol. [18F]DRKXH1 was mainly excreted through the liver and kidney. The small-animal PET study showed high initial brain uptake and rapid washout of [18F]DRKXH1. The concentration of [18F]DRKXH1 was detected in the cortex and hippocampus of AD transgenic mice brain. The cortex DVR of AD transgenic mice was higher than that of WT mice (P < 0.0001). Moreover, the SUVRs of AD transgenic mice were higher than those of WT mice based on the 0–60-min dynamic scanning. In vitro autoradiography showed a significant concentration of tracer in the Aβ plaque-rich areas in the brain of AD transgenic mice. The DVR value of [18F]-DRKXH1 is higher than that of [18F]-AV45 (1.29 ± 0.05 vs. 1.05 ± 0.08; t = 5.33, P = 0.0003). Autoradiography of postmortem human brain sections showed [18F]DRKXH1-labeled Aβ plaques in the AD brain. The AD patients had high retention in cortical regions, while healthy control subjects had uniformly low radioactivity uptake. Conclusions [18F]DRKXH1 is an Aβ tracer with high sensitivity in preclinical study and has the potential for in vivo detection of the human brain.

4H Leukodystrophy: Lessons from 3T Imaging

2017 ◽  
Vol 49 (02) ◽  
pp. 112-117 ◽  
Author(s):  
Ferdy Cayami ◽  
Marianna Bugiani ◽  
Petra Pouwels ◽  
Geneviève Bernard ◽  
Marjo van der Knaap ◽  
...  
Keyword(s):  
White Matter ◽  
Clinical Symptoms ◽  
Hypogonadotropic Hypogonadism ◽  
Medial Lemniscus ◽  
Imaging Data ◽  
Mri Findings ◽  
Mri Features ◽  
Mri Diagnosis ◽  
Magnetic Resonance Imaging Mri ◽  
Hypointense Signal

Abstract4H leukodystrophy is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With its variability in clinical symptoms, application of pattern recognition to identify specific magnetic resonance imaging (MRI) features proved useful for the diagnosis. We collected 3T MR imaging data of 12 patients with mutations in POLR3A (n = 8), POLR3B (n = 3), and POLR1C (n = 1), all obtained at the same scanner. We assessed these images and compared them with previously obtained 1.5T images in 8 patients. Novel MRI findings were myelin islets, closed eye sign, and a cyst-like lesion in the splenium. Myelin islets were variable numbers of small T1 hyperintense and T2 hypointense dots, mostly in the frontal and parietal white matter, and present in all patients. This interpretation was supported with perivascular staining of myelin protein in the hypomyelinated white matter of a deceased 4H patient. All patients had better myelination of the medial lemniscus with a relatively hypointense signal of this structure on axial T2-weighted (T2W) images (“closed eye sign”). Five patients had a small cyst-like lesion in the splenium. In 10 patients with sagittal T2W images, we also found spinal cord hypomyelination. In conclusion, imaging at 3T identified additional features in 4H leukodystrophy, aiding the MRI diagnosis of this entity.

Statins in Stable Angina Pectoris

2018 ◽  
Vol 23 (46) ◽  
pp. 7061-7068 ◽  
Author(s):  
Adam Ioannou ◽  
Nikolaos Papageorgiou ◽  
Vincent McCaughan ◽  
Marietta Charakida ◽  
Dimitris Bertsias ◽  
...  
Keyword(s):  
Angina Pectoris ◽  
Stable Angina ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Lipid Lowering ◽  
Stable Angina Pectoris ◽  
Excellent Safety Profile ◽  
Established Role

Background: Stable angina is a debilitating and progressive disease caused by narrowing of the coronary arteries, which in turn affects cardiac perfusion. Statins have a well-established role, modifying symptoms and progression of the disease not only through lipid lowering, but also through pleiotropic effects. </P><P> Objective: We sought to evaluate the effect of statins in stable angina pectoris </P><P> Method: We performed a systematic review of the literature searching MEDLINE via Pubmed for all studies which examine the possible effects of statins in stable angina pectoris. </P><P> Results: Statins have demonstrated favourable modification of both biochemical markers (oxidative stress, inflammatory and coagulation markers/factors) and clinical symptoms (anginal and ischemic) of the disease. These effects have been demonstrated in vitro, ex vivo and in vivo in animals and humans, independently of the lipid lowering effects. </P><P> Conclusion: With an excellent safety profile and evidence of efficacy in managing patients with stable angina, statins appear an essential part of the therapeutic armoury against atherosclerotic disease.

Coconut milk regulates the allergic response in Balb/c mice sensitized with whey proteins

2018 ◽  
Vol 8 (1) ◽  
pp. 19-25
Author(s):  
Yamina Benaissa ◽  
Samia Addou ◽  
Wafaa Dib ◽  
Hadria Grar ◽  
Omar Kheroua ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Ex Vivo ◽  
Short Circuit ◽  
Ussing Chamber ◽  
Whey Proteins ◽  
Milk Proteins ◽  
Short Circuit Current ◽  
Coconut Milk ◽  
Intestinal Damage

In this work the effect of coconut milk on mice sensitized to cow's milk proteins was evaluated. Balb/c mice treated orally for twenty eight days with coconut milk were sensitized intraperitoneally with β-lactoglobulin (β-Lg) or α-Lactoglobulin (α-Lac). We used Ussing chamber to analyze ex vivo electrical parameters characterizing the intestinal tissue of mice by measuring the variations of the short current circuit Isc (μA/cm2) as well as the epithelial conductance (G). Jejunal fragments of sensitized and treated mice were mounted in Ussing chamber and stimulated by the deposit of β-Lg or α-Lac. Symptom scores were determined after in vivo challenge to β-Lg or α-Lac. Intestinal damage was assessed by histological analysis. Coconut milk influ-enced the electrophysiological parameters by significantly decreasing the short-circuit current (Isc) (p < 0.001) and the epithelial conductance ((p< 0.01 and (p < 0.001, respectively). Moreover, in coconut milk-treated mice, no significant clinical symptoms were observed. Analysis of histological sections revealed that coconut milk reduced the microscopic lesions induced by β-Lg or α-Lac sensitization. We speculate that the administration of coconut milk could prevent the systemic and anaphylactic responses in sensitized mice.

Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

2019 ◽  
Vol 40 (06) ◽  
pp. 701-714 ◽  
Author(s):  
Carlo Castellani ◽  
Barry Linnane ◽  
Iwona Pranke ◽  
Federico Cresta ◽  
Isabelle Sermet-Gaudelus ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Sweat Test ◽  
Intestinal Epithelia ◽  
Sweat Testing ◽  
Cftr Protein ◽  
Cf Transmembrane Conductance Regulator

AbstractThe diagnosis of cystic fibrosis (CF) has traditionally relied on the presence of clinical features of the disease. Today, diagnosis through newborn screening (NBS) is becoming the standard of modern CF care. CF NBS programs can identify CF prior to clinical presentation, but for the advantages of an early diagnosis to accrue a scrupulous system must be in place to ensure all steps in the program are performing. As we move rapidly into the era of CF transmembrane conductance regulator (CFTR) protein modulators, the opportunity to start a presymptomatic infant, identified through CF NBS, on these agents offers the prospect of true disease-modifying interventions which could result in a paradigm shift in CF care.Conversely, the introduction of NBS has resulted in many children being asymptomatic at the time of diagnosis. Some screened newborns are classified as “CF Screening Positive, Inconclusive Diagnosis”, or “CFTR-related metabolic syndrome” when the diagnosis can neither be confirmed nor excluded. Appropriate assessment and follow-up should be arranged at specialist centers as a proportion of these infants and adults will eventually be diagnosed with CF.Symptoms and signs are particularly pertinent when considering a diagnosis of CF outside the context of NBS. In older patients with a late diagnosis, the spectrum of clinical presentation can be very variable with vigilant clinicians from multiple specialties suspecting the diagnosis in conditions such as recurrent pulmonary infections, male infertility, pancreatitis, nasal polyposis, and malabsorption.In addition to clinical symptoms or positive NBS results, sweat test and genetic analysis are cornerstones in the diagnosis of CF, but in some cases the diagnosis cannot be confirmed on genetic or sweat testing. Difficult diagnosis may be supported by in vivo or ex vivo electrophysiology measurements on respiratory or intestinal epithelia. This can be done by either measuring transepithelial nasal potential difference or intestinal current measurements.

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