Bacillus Calmette-Guérin (BCG) prostato-epididymitis in a patient treated for a non-invasive urothelial cancer: A case report.

Introduction: The Bacillus Calmette-Guérin (BCG) used as anti-tuberculous vaccine is also a well-known therapy for superficial urothelial cancer. Local or general side effects can occur, although it is generally well tolerated. Case: We present the case of a 65 year-old caucasian man consulting for gross hematuria and lower urinary tract symptoms. Magnetic resonance imaging (MRI) demonstrated a non-invasive urothelial carcinoma (NMIBC) and Prostate Imaging-Reporting and Data System (PIRADS) IV lesions. Transurethral resection of the bladder tumor revealed a non-invasive transitional cell carcinoma. Intravesical Bacillus Calmette Guerin (BCG) therapy was provided. After 6 intravesical instillations, the patient presented with prostato-epididymitis. Forthcoming BCG instillations were canceled, and cancer treatment was switched to epirubicine. Treatment with ethambutol, rifampicin and isoniazid was started with rapid resolution of the symptoms. Urinary and semen cultures grew Mycobacterium tuberculosis complex strain BCG. As prostate specific antigen (PSA) rose, prostate's biopsies were performed showing extensive necrosis boarded by granulomas without signs of malignancy. Discussion: BCGitis is a rare complication in patients treated for non-invasive urothelial cancer. Several risk factors, local and systemic, should be considered prior to this immunotherapy. BCGitis (local or disseminated) or hypersensitivity reactions to BCG must be included in the differential diagnosis even if therapy was administered several years before the symptoms. Adequate treatment must be started as fast as possible to avoid serious complications.

N-Formylation modifies membrane damage associated with PSMα3 interfacial fibrillation.

The virulence of Staphylococcus aureus, a multi-drug resistant pathogen, notably depends on the expression of the phenol soluble modulins α3 (PSMα3) peptides, able to self-assemble into amyloid-like cross-α fibrils. Despite remarkable advances evidencing the crucial, yet insufficient, role of fibrils in PSMα3 cytotoxic activities towards host cells, the relationship between its molecular structures, assembly propensities, and modes of action remains an open intriguing problem. In this study, combining atomic force microscopy (AFM) imaging and infrared spectroscopy, we first demonstrated in vitro that the charge provided by the N-terminal capping of PSMα3 alters its interactions with model membranes of controlled lipid composition without compromising its fibrillation kinetics or morphology. N-formylation eventually dictates PSMα3-membrane binding via electrostatic interactions with the lipid head groups. Furthermore, PSMα3 insertion within the lipid bilayer is favoured by hydrophobic interactions with the lipid acyl chains only in the fluid phase of membranes and not in the gel-like ordered domains. Strikingly, our real-time AFM imaging emphasizes how intermediate protofibrillar entities, formed along PSMα3 self-assembly and promoted at the membrane interface, likely disrupt membrane integrity via peptide accumulation and subsequent membrane thinning in a peptide concentration and lipid-dependent manner. Overall, our multiscale and multimodal approach sheds new light on the key roles of N-formylation and intermediate self-assembling entities, rather than mature fibrils, in dictating deleterious interactions of PSMα3 with membrane lipids, likely underscoring its ultimate cellular toxicity in vivo, and in turn S. aureus pathogenesis.

Postmortem imaging of fetuses at early gestations: A comparison of microfocus computed tomography with postmortem magnetic resonance at 9.4 T and postmortem ultrasound.

OBJECTIVE: To compare the diagnostic performance of postmortem ultrasound (PMUS), 9.4 T magnetic resonance imaging (MRI) and microfocus computed tomography (micro-CT) for the examination of early gestation fetuses. METHOD: Eight unselected fetuses (10-15 weeks gestational age) underwent at least 2 of the 3 listed imaging examinations. Six fetuses underwent 9.4 T MRI, four underwent micro-CT and six underwent PMUS. All operators were blinded to clinical history. All imaging was reported according to a prespecified template assessing 36 anatomical structures, later grouped into five regions: brain, thorax, heart, abdomen and genito-urinary. RESULTS: More anatomical structures were seen on 9.4 T MRI and micro-CT than with PMUS, with a combined frequency of identified structures of 91.9% and 69.7% versus 54.5% and 59.6 (p < 0.001; p < 0.05) respectively according to comparison groups. In comparison with 9.4 T MRI, more structures were seen on micro-CT (90.2% vs. 83.3%, p < 0.05). Anatomical structures were described as abnormal on PMUS in 2.7%, 9.4 T MRI in 6.1% and micro-CT 7.7% of all structures observed. However, the accuracy test could not be calculated because conventional autopsy was performed on 6 fetuses of that only one structure was abnormal. CONCLUSION: Micro-CT appears to offer the greatest potential as an imaging adjunct or non-invasive alternative for conventional autopsies in early gestation fetuses.

Assessment of whole-body MRI including diffusion-weighted sequences in the initial staging of breast cancer patients at high risk of metastases in comparison with PET-CT: a prospective cohort study.

OBJECTIVE: The aim of this study was to assess the diffusion-weighted whole-body-MRI (WBMRI) in the initial staging of breast cancer at high risk of metastases in comparison with positron emission tomography (PET)-CT. METHODS: Forty-five women were prospectively enrolled. The inclusion criteria were female gender, age >18, invasive breast cancer, an initial PET-CT, and a performance status of 0-2. The exclusion criteria were contraindication to WB-MRI and breast cancer recurrence. The primary outcome was the concordance of WB-MRI and PET-CT in the diagnosis of distant metastases, whereas secondary outcomes included their concordance for the primary tumor and regional lymph nodes (LN), as well as the agreement of WB-MRI interpretation between two radiologists. RESULTS: The mean age was 51.2 years with a median size of the primary tumor of 30 mm. Concordance between the two modalities was almost perfect for metastases staging, all sites included (k = 0.862), with excellent interobserver agreement. The accuracy of WB-MRI for detecting regional LN, distant LN, lung, liver, or bone metastases ranged from 91 to 96%. In 2 patients, WB-MRI detected bone metastases that were overlooked by PET-CT. WB-MRI showed a substantial agreement with PET-CT for staging the primary tumor, regional LN status, and stage (k = 0.766, k = 0.756, and k = 0.785, respectively) with a high interobserver agreement. CONCLUSION: WB-MRI including DWI could be a reliable and reproducible examination in the initial staging of breast cancer patients at high risk of metastases, especially for bone metastases and therefore could be used as a surrogate to PET-CT. CLINICAL RELEVANCE STATEMENT: Whole-body-MRI including DWI is a promising technique for detecting metastases in the initial staging of breast cancer at high risk of metastases. KEY POINTS: Whole-body-MRI (WB-MRI) was effective for detecting metastases in the initial staging of 45 breast cancer patients at high risk of metastases in comparison with PET-CT. Concordance between WB-MRI and PET-CT was almost perfect for metastases staging, all sites included, with excellent interobserver agreement. The accuracy of WB-MRI for detecting bone metastases was 92%.

Learning curve for fetal postmortem ultrasound.

OBJECTIVE: To determine the learning curve of fetal postmortem ultrasound (PMUS) and evaluate the evolution of its diagnostic performance over the past 8 years. METHODS: PMUS was performed by two fetal medicine specialists and two experts on 100 unselected fetuses of 12-38 weeks of gestation in a prospective, double-blind manner. 21 pre-defined internal structures were analyzed consecutively by the trainee alone and the expert, with a comparison of diagnosis and immediate feedback. The learning curves for examination duration, non-recognition of structures and final diagnoses were computed using cumulative summation analysis. Secondly, the expert PMUS diagnostic accuracy using autopsy as the gold standard was compared to the previously published data. RESULTS: The trainees reached expert level of PMUS at 28-36 cases for examination duration (12.1 ± 5.2 min), non-diagnostic rate (6.5%, 137/2100), and abnormality diagnosis. In a group of 33 fetuses ≥20 weeks who had an autopsy, the experts PMUS performance was improved after 8 years with a reduction of all organs non-diagnostic rate (6.5 %VS 11.4%, p < 0.01) and higher sensitivity for the heart (100% VS 40.9%, p < 0.01) and the abdomen (100%VS 56.5%, p < 0.05). CONCLUSION: PMUS offers a short learning curve for fetal medicine specialists and on-going improvement of diagnostic accuracy over time.

Pediatric Rheumatic Fever With Acute Fulminant Carditis: A Case Report.

Acute rheumatic fever (ARF) is a multi-system inflammatory autoimmune disease. It is a significant cause of heart disease and early death worldwide, especially in children in developing countries. We present a case of acute fulminant rheumatic carditis in a child with no obvious predisposing factors, who resided in a developed country where this disease is not endemic. After pathological examination, a diagnosis of ARF with pancarditis was confirmed. This disease was not suspected before the pathological examination because of its low prevalence in Belgium.

Chemical Imaging of RNA-Tau Amyloid Fibrils at the Nanoscale Using Tip-Enhanced Raman Spectroscopy.

In the presence of cofactors, tau protein can form amyloid deposits in the brain which are implicated in many neurodegenerative disorders. Heparin, lipids, and RNA are used to recreate tau aggregates in vitro from recombinant protein. However, the mechanism of interaction of these cofactors and the interactions between cofactors and tau are poorly understood. Herein, we use tip-enhanced Raman spectroscopy (TERS) to visualize the spatial distribution of adenine, protein secondary structure, and amino acids (arginine, lysine and histidine) in single polyadenosine (polyA)-induced tau fibrils with nanoscale spatial resolution (<10-20 nm). Based on reference unenhanced and surface-enhanced Raman spectra, we show that the polyA anionic cofactor is incorporated in the fibril structure and seems to be superficial to the ß-sheet core, but nonetheless enveloped within the random-coiled fuzzy coat. TERS images also prove the colocalization of positively charged arginine, lysine, and histidine amino acids and negatively charged polyA, which constitutes an important step forward to better comprehend the action of RNA cofactors in the mechanism of formation of toxic tau fibrils. TERS appears as a powerful technique for the identification of cofactors in individual tau fibrils and their mode of interaction.

A case of anti-HMGCR myopathy in a patient with breast cancer and anti-Th/To antibodies.

Statins competitively inhibit the activity of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), which is a key enzyme in cholesterol synthesis. These are effective drugs for the management of cardiovascular disease and are generally well tolerated but several side effects have been reported. Muscular adverse symptoms are various and, rarely, statin exposure may lead to authentic immune-mediated necrotizing myopathy (IMNM), namely anti-HMGCR myopathy. However, cases of IMNM associated with cancer have been described. We discuss herein a case of IMNM in a patient with breast cancer previously exposed to statins and with the presence of anti-Th/To antibodies without clinical correlation.

Interactions of REF1 and SRPP1 rubber particle proteins from Hevea brasiliensis with synthetic phospholipids: Effect of charge and size of lipid headgroup.

According to the fatty acid and headgroup compositions of the phospholipids (PL) from Hevea brasiliensis latex, three synthetic PL were selected (i.e. POPA: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate POPC: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and POPG: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol) to investigate the effect of PL headgroup on the interactions with two major proteins of Hevea latex, i.e. Rubber Elongation Factor (REF1) and Small Rubber Particle Protein (SRPP1). Protein/lipid interactions were screened using two models (lipid vesicles in solution or lipid monolayers at air/liquid interface). Calcein leakage, surface pressure, ellipsometry, microscopy and spectroscopy revealed that both REF1 and SRPP1 displayed stronger interactions with anionic POPA and POPG, as compared to zwitterionic POPC. A particular behavior of REF1 was observed when interacting with POPA monolayers (i.e. aggregation + modification of secondary structure from α-helices to ß-sheets, characteristic of its amyloid aggregated form), which might be involved in the irreversible coagulation mechanism of Hevea rubber particles.

Prediction of the penetration depth of multi-lamellar liposomes in artificial skin. Application to the vectorization of corticosteroid in human skin.

Our previous work showed that the size, elasticity and charge of multi-lamellar liposomes (MLLs) could not be considered separately to predict the fate of MLLs in the skin [1]. Based on this study, we developed several MLLs formulations containing a corticosteroid, betamethasone 17-valerate (B17) to transport the drug into the stratum corneum, living epidermis, dermis or through the skin. MLLs encapsulation efficiency was found to exceed 74 ± 3 % in all cases. In addition, we showed that MLLs protected the corticosteroid from thermal degradation. Comparing the penetration depth of all MLLs within artificial skin measured by Raman imaging, we established an equation for its determination, given the MLLs elasticity and size. This equation was verified experimentally on human explants: quantification of B17 in each skin layer, as well as its transdermal passage by ultra-high performance liquid chromatography, confirmed that B17 was predominantly and significantly transported in the desired layer. Eventually, we showed the benefits in using B17-loaded MLLs instead of a B17-containing pharmaceutical cream in terms of B17 penetration and thermal degradation.

Spatial distribution of anthropogenic particles and microplastics in a meso-tidal lagoon (Arcachon Bay, France): A multi-compartment approach.

Assessment of microplastic (MP) contamination is still needed to evaluate this threat correctly and tackle this issue. Here, MP contamination was assessed for a meso-tidal lagoon of the Atlantic coast (Arcachon Bay, France). Sea surface, water column, intertidal sediments and wild oysters were sampled. Five different stations were studied to assess the spatial distribution of the contamination. Two were outside of the bay and three were inside the bay (from the inlet to the back). A distinction was made between all anthropogenic particles (AP, i.e. visually sorted) and MP (i.e. plastic polymer confirmed by ATR-FTIR spectroscopy). The length of particles recovered in this study ranged between 17 µm and 5 mm. Concentration and composition in sea surface and water column samples showed spatial variations while sediment and oyster samples did not. At outside stations, the sea surface and the water column presented a blended composition regarding shapes and polymers and low to high concentrations (e.g. 0.16 ± 0.08 MP.m-3 and 561.7 ± 68.5 MP.m-3, respectively for sea surface and water column), which can be due to coastal processes and nearby input sources. The inlet station displayed a well-marked pattern only at the sea surface. High AP and MP concentrations were recorded, and fragments along with polyethylene overwhelmed (respectively 76.0 % and 73.2 %). Higher surface currents could explain this pattern. At the bay back, AP and MP concentrations were lower and fibers were mainly recorded. Weaker hydrodynamics in this area was suspected to drive this contamination profile. Overall, fragments and buoyant particles were mainly detected at the sea surface while fibers and negatively buoyant particles prevailed in other compartments. Most of the studied samples presented an important contribution of fiber-shaped particles (from 31.5 % to 94.2 %). Finally, contamination was ubiquitous as AP and MP were found at all stations in all sample types.

Structural polymorphism of the low-complexity C-terminal domain of TDP-43 amyloid aggregates revealed by solid-state NMR.

Aberrant aggregation of the transactive response DNA-binding protein (TDP-43) is associated with several lethal neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. Cytoplasmic neuronal inclusions of TDP-43 are enriched in various fragments of the low-complexity C-terminal domain and are associated with different neurotoxicity. Here we dissect the structural basis of TDP-43 polymorphism using magic-angle spinning solid-state NMR spectroscopy in combination with electron microscopy and Fourier-transform infrared spectroscopy. We demonstrate that various low-complexity C-terminal fragments, namely TDP-13 (TDP-43300-414), TDP-11 (TDP-43300-399), and TDP-10 (TDP-43314-414), adopt distinct polymorphic structures in their amyloid fibrillar state. Our work demonstrates that the removal of less than 10% of the low-complexity sequence at N- and C-termini generates amyloid fibrils with comparable macroscopic features but different local structural arrangement. It highlights that the assembly mechanism of TDP-43, in addition to the aggregation of the hydrophobic region, is also driven by complex interactions involving low-complexity aggregation-prone segments that are a potential source of structural polymorphism.

Transport of hydrocortisone in targeted layers of the skin by multi-lamellar liposomes.

Hydrocortisone (HyC), a hydrophobic pharmaceutical active, was encapsulated in multi-lamellar liposomes (MLLs) composed of P100, a mixture of phospholipids, and Tween®80. Three different HyC-loaded formulations were designed to target the stratum corneum, the living epidermis and the hypodermis. The impact of encapsulation on their size, elasticity and zeta potential, the three key factors controlling MLLs skin penetration, was studied. Raman mapping of phospholipids and HyC allowed the localisation of both components inside an artificial skin, Strat-M®, demonstrating the efficiency of the targeting. Percutaneous permeation profiles through excised human skin were performed over 48 h, supporting results on artificial skin. Their modelling revealed that HyC encapsulated in MLLs, designed to target the stratum corneum and living epidermis, exhibited a non-Fickian diffusion process. In contrast, a Fickian diffusion was found for HyC administered in solution, in a pharmaceutical cream and in transdermal MLLs. These results allowed us to propose a mechanism of interaction between HyC-containing MLLs and the skin.

Diffusion-Weighted MRI in the Evaluation of Early-Stage Breast Cancer Treated with a Short Preoperative Radiotherapy: Preliminary Results.

Objective: To assess tumor response with diffusion-weighted MRI (DW-MRI) after a short preoperative radiotherapy in early-stage breast cancer (BCa). Materials and Methods: This was a prospective, single-center pilot study. 3T-MRI were performed before and after radiotherapy. The longest diameter (LD) and the apparent diffusion coefficient (ADC) value of a region of interest (ROI) of the tumors were recorded. Histopathology and immunohistochemistry, including the Ki-67 index of the core biopsy and of the surgical specimen, were the reference standards. Results: Nineteen patients with 22 early-stage BCa were included. The mean ROI ADC value was 1.093 ± 0.278 × 10-3 mm2/s before radiotherapy and 1.490 ± 0.429 × 10-3 mm2/s (p-value < 0.001) after radiotherapy. The Ki-67 index was 9.2 ± 9.1% at the percutaneous biopsy before radiotherapy and 4.9 ± 7.5% (p-value = 0.005) after radiotherapy at the surgical specimen. After neoadjuvant radiotherapy, a 4.7% decrease in LD and a 36.3% increase in ROI-ADC of the tumors were measured at MRI and a 46.7% decrease in Ki-67 index was observed at histology of the surgical specimen in comparison with the percutaneous core biopsy. Conclusion: In early-stage BCa, a significant increase in ROI-ADC at DWI and a significant decrease in Ki-67 index were observed after a short preoperative radiotherapy, suggesting early tumor response.

Assessment of diffusion-weighted MRI in predicting response to neoadjuvant chemotherapy in breast cancer patients.

To compare region of interest (ROI)-apparent diffusion coefficient (ADC) on diffusion-weighted imaging (DWI) measurements and Ki-67 proliferation index before and after neoadjuvant chemotherapy (NACT) for breast cancer. 55 women were enrolled in this prospective single-center study, with a final population of 47 women (49 cases of invasive breast cancer). ROI-ADC measurements were obtained on MRI before and after NACT and were compared to histological findings, including the Ki-67 index in the whole study population and in subgroups of "pathologic complete response" (pCR) and non-pCR. Nineteen percent of women experienced pCR. There was a significant inverse correlation between Ki-67 index and ROI-ADC before NACT (r = - 0.443, p = 0.001) and after NACT (r = - 0.614, p < 0.001). The mean Ki-67 index decreased from 45.8% before NACT to 18.0% after NACT (p < 0.001), whereas the mean ROI-ADC increased from 0.883 × 10-3 mm2/s before NACT to 1.533 × 10-3 mm2/s after NACT (p < 0.001). The model for the prediction of Ki67 index variations included patient age, hormonal receptor status, human epidermal growth factor receptor 2 status, Scarff-Bloom-Richardson grade 2, and ROI-ADC variations (p = 0.006). After NACT, a significant increase in breast cancer ROI-ADC on diffusion-weighted imaging was observed and a significant decrease in the Ki-67 index was predicted. Clinical trial registration number: clinicaltrial.gov NCT02798484, date: 14/06/2016.

The impact of lipid polyunsaturation on the physical and mechanical properties of lipid membranes.

The lipid composition of cellular membranes and the balance between the different lipid components can be impacted by aging, certain pathologies, specific diets and other factors. This is the case in a subgroup of individuals with psychiatric disorders, such as schizophrenia, where cell membranes of patients have been shown to be deprived in polyunsaturated fatty acids (PUFAs), not only in brain areas where the target receptors are expressed but also in peripheral tissues. This PUFA deprivation thus represents a biomarker of such disorders that might impact not only the interaction of antipsychotic medications with these membranes but also the activation and signaling of the targeted receptors embedded in the lipid membrane. Therefore, it is crucial to understand how PUFAs levels alterations modulate the different physical properties of membranes. In this paper, several biophysical approaches were combined (Laurdan fluorescence spectroscopy, atomic force microscopy, differential scanning calorimetry, molecular modeling) to characterize membrane properties such as fluidity, elasticity and thickness in PUFA-enriched cell membranes and lipid model systems reflecting the PUFA imbalance observed in some diseases. The impact of both the number of unsaturations and their position along the chain on the above properties was investigated. Briefly, data revealed that PUFA presence in membranes increases membrane fluidity, elasticity and flexibility and decreases its thickness and order parameter. Both the level of unsaturation and their position affect these membrane properties.

A case of left foot drop as initial symptom of granulomatosis with polyangiitis: Triggered by COVID-19 disease?

In Granulomatosis with polyangiitis (GPA), involvement of the peripheral nervous system is frequent but its occurrence as an initial presentation is unusual. This case highlights the importance of this occurrence to permit an early diagnosis. Moreover, GPA started after a coronavirus disease 2019 infection and could have been induced by this.

Total Internal Reflection Tip-Enhanced Raman Spectroscopy of Tau Fibrils.

Total internal reflection tip-enhanced Raman spectroscopy (TIR-TERS) has recently emerged as a promising technique for noninvasive nanoscale chemical characterization of biomolecules. We demonstrate that the TERS enhancement achieved in this experimental configuration is nearly 30 times higher than that in linear polarization and 8 times higher than that in radial polarization using traditional bottom-illumination geometry. TIR-TERS is applied to the study of Tau amyloid fibrils formed with the human full-length Tau protein mixed with heparin. This technique reveals the possibility to perform TERS imaging with 1-4 nm axial and 5-10 nm lateral spatial optical resolution. In these Tau/heparin fibrils, spectral signatures assigned to aromatic amino acid residues (phenylalanine, histidine, and tyrosine) and nonaromatic ones (e.g., cysteine, lysine, arginine, asparagine, and glutamine) are distinctly observed. Amide I and amide III bands can also be detected. In a fibril portion, it is shown that antiparallel ß-sheets and fibril core ß-sheets are abundant and are often localized in amino acid-rich regions where parallel ß-sheets and random coils are present in lower proportions. This first TIR-TERS study on a nonresonant biological sample paves the way for future nanoscale chemical and structural characterization of biomolecules using this performant and original technique.

Structural Dissection of the First Events Following Membrane Binding of the Islet Amyloid Polypeptide.

The islet amyloid polypeptide (IAPP) is the main constituent of the amyloid fibrils found in the pancreas of type 2 diabetes patients. The aggregation of IAPP is known to cause cell death, where the cell membrane plays a dual role: being a catalyst of IAPP aggregation and being the target of IAPP toxicity. Using ATR-FTIR spectroscopy, transmission electron microscopy, and molecular dynamics simulations we investigate the very first molecular steps following IAPP binding to a lipid membrane. In particular, we assess the combined effects of the charge state of amino-acid residue 18 and the IAPP-membrane interactions on the structures of monomeric and aggregated IAPP. Distinct IAPP-membrane interaction modes for the various IAPP variants are revealed. Membrane binding causes IAPP to fold into an amphipathic α-helix, which in the case of H18K-, and H18R-IAPP readily moves beyond the headgroup region. For all IAPP variants but H18E-IAPP, the membrane-bound helix is an intermediate on the way to amyloid aggregation, while H18E-IAPP remains in a stable helical conformation. The fibrillar aggregates of wild-type IAPP and H18K-IAPP are dominated by an antiparallel ß-sheet conformation, while H18R- and H18A-IAPP exhibit both antiparallel and parallel ß-sheets as well as amorphous aggregates. Our results emphasize the decisive role of residue 18 for the structure and membrane interaction of IAPP. This residue is thus a good therapeutic target for destabilizing membrane-bound IAPP fibrils to inhibit their toxic actions.