Temporal evolution of quality of life in patients endoscopically treated for sinonasal malignant tumors.

BACKGROUND: The aim of our study is to assess which factors may affect the quality of life (QoL) and its fluctuation over time in adult patients who received endonasal endoscopic oncologic sinus surgery (EOSS) for sinonasal malignancies (SNM) in our center. METHODOLOGY: We analyzed EOSS cases for primary SNM from January 2015 to June 2020. For each patient, we have recorded the age at treatment, gender, smoking habits, use of psychotropic drugs for mood disorders, stage, histotype, type of surgical resection, need for skull-base reconstruction, development of postoperative major complications, and the use of adjuvant intensity-modulated radiotherapy (IMRT). We evaluated the patient's performance status pre-treatment using the ECOG scale. Quality of life was measured using three questionnaires (SNOT-22; ASK-9; EORTC QLQ-C30 version 3). RESULTS: Fifty-five patients were enrolled in our study, of whom thirty-two (58.18%) received adjuvant IMRT. Overall, a significant improvement in all QoL outcomes was observed at eighteen months, while, female sex, higher ECOG scores, advanced stage of disease, and adjuvant IMRT were associated with worse QoL. After 18 months the delta in QoL between women and men worsened (in SNOT-22 and EORTC QLQ-GLOBAL) while if only the most fragile patients according to ECOG are considered, this difference was reduced for both tools. CONCLUSION: Our analysis revealed that IMRT is the element that has the greatest impact on patient's quality of life, in association with the female sex, ECOG >2, and advanced stage of the disease.

Inflammatory Biomarker and Response to Antidepressant in Major Depressive Disorder: a Systematic Review and Meta-Analysis.

Inadequate response to antidepressant treatment, in a significant proportion of patients diagnosed with Major Depressive Disorder, contributes to the large burden of disability associated with the disease; thus, predicting treatment response is one of the most important challenge for clinicians who deal with depressed patients. The cytokine hypothesis of depression suggests that altered pheripheral cytokine levels are involved in the pathophysiology of depressive disorder and in modulating response to treatment. Present meta-analysis aimed to investigate the association between cytokine levels at baseline and response to antidepressant therapies. Authors performed a systematic search of PubMed and Embase databases for studies published between 2010 and January 2021: of 3345 identified records, 31 studies met the inclusion criteria for the qualitative synthesis, whereas 19 studies were eligible for quantitative analysis. Patients who failed to respond to antidepressant had aberrant inflammatory process, namely higher baseline levels of C-Reactive Protein and Interleukine-8, which is associated with treatment outcome in Major Depressive Disorder. Despite these promising results, further investigations are needed in order to replicate the data and to examine the potential role of inflammatory marker as a novel predictive tool for pharmacological treatment of depressive disorder.

The 6-D Model of National Culture as a Tool to Examine Cultural Interpretation of Migration Trauma-Related Dissociative Disorder: A Case Series.

Dissociative experiences are common in traumatized individuals who can use dissociation as a psychological escape from emotional and physical distress associated with overwhelming traumatic events. Traumatic experiences and the cultural interpretation of trauma-related symptoms often serve to explain the wide range of dissociative phenomenology; in fact, dissociation is a complex and ubiquitous construct present in a variety of mental disorders. The Six-Dimensions Model of National Culture has been used as a tool to compare patients' different cultural background that could have accounted for the different clinical manifestations. This paper reports three clinical cases in which the focus of interest is represented by the dissociative alterations of consciousness, as a response to trauma, specifically related to migration, and their correlation with cultural environment. The study shows as Hofstede's model has been used for the first time as a tool to explain how different cultural background could shape clinical manifestations.

Micro cone beam computed tomography for sensitive assessment of radiation-induced late lung toxicity in preclinical models.

BACKGROUND AND PURPOSE: Preclinical models are much needed to assess the effect of novel radio-sensitizers or mitigators on radiation dose limiting lung toxicity. Albeit showing radiation-induced lung pathologies, current mouse models lack the sensitivity to do so. Using micro image-guided radiotherapy (µIGRT) techniques, we aimed to establish murine models which enable the sensitive detection of lung damage aggravation and characterized functional, radiological and histological responses. MATERIALS AND METHODS: Right lungs of C57Bl/6J mice were irradiated using µIGRT with doses from 15 to 27 Gy and with 21 Gy and cisplatin as a radio-sensitizer in a second study. Mice were sacrificed for histological and pathological assessment at different time-points post-IR. Lung density was determined using the integrated micro cone-beam CT (µCBCT). Lung function was measured by double-chamber-plethysmography. RESULTS: µIGRT resulted in accurate deposition of the radiation dose in the right lung only as determined by É£H2AX staining. Lung fibrosis was confirmed by pathological assessments and increased significantly at 21 Gy as determined by automated quantification of histochemical analyses. Lung function was affected in a dose-dependent manner. µCBCT-determined lung densities increased significantly over time in the irradiated lungs and showed a strong radiation dose-dependence. Importantly, the µCBCT analyses allowed the detection of additional lung damage caused by 3 Gy dose increments or by the combination with cisplatin. CONCLUSION: µCBCT after right lung µIGRT enables the sensitive detection of effects inflicted by relative small dose increments or radio-sensitizers. Our preclinical model therefore facilitates the determination of lung damage exacerbation for the safety assessment of novel RT-drug combinations.

Twenty years of Lithium pharmacogenetics: A systematic review.

Lithium is among the best proven treatments for patients diagnosed with Bipolar Disorder, however response to Lithium appears to be considerably variable among individuals and it has been suggested that this inconstancy in Lithium response could be genetically determined. Starting from this perspective, in the last few decades, a number of pharmacogenetic studies have attempted to identify genetic variants, which might be associated with response to Lithium in bipolar patients, in order to develop a pharmacogenetics test to tailor treatment on patients, identifying who will benefit the most from therapy with Lithium. Within this context, authors have critically reviewed pharmacogenetic studies of Lithium response in bipolar disorder, suggesting strategies for future work in this field. Computerized searches of PubMed and Embase databases, for studies published between 1998 and January 2018, was performed: 1162 studies were identified but only 37 relevant papers were selected for detailed review. Despite some interesting preliminary findings, the pharmacogenetics of Lithium and the development of a specific pharmacogenetics test in bipolar disorder appears to be a field still in its infancy, even though the advent of genome-wide association studies holds particular promise for future studies, which should include larger samples.

Multi-institutional dosimetric and geometric commissioning of image-guided small animal irradiators.

PURPOSE: To compare the dosimetric and geometric properties of a commercial x-ray based image-guided small animal irradiation system, installed at three institutions and to establish a complete and broadly accessible commissioning procedure. METHODS: The system consists of a 225 kVp x-ray tube with fixed field size collimators ranging from 1 to 44 mm equivalent diameter. The x-ray tube is mounted opposite a flat-panel imaging detector, on a C-arm gantry with 360° coplanar rotation. Each institution performed a full commissioning of their system, including half-value layer, absolute dosimetry, relative dosimetry (profiles, percent depth dose, and relative output factors), and characterization of the system geometry and mechanical flex of the x-ray tube and detector. Dosimetric measurements were made using Farmer-type ionization chambers, small volume air and liquid ionization chambers, and radiochromic film. The results between the three institutions were compared. RESULTS: At 225 kVp, with 0.3 mm Cu added filtration, the first half value layer ranged from 0.9 to 1.0 mm Cu. The dose-rate in-air for a 40 × 40 mm(2) field size, at a source-to-axis distance of 30 cm, ranged from 3.5 to 3.9 Gy/min between the three institutions. For field sizes between 2.5 mm diameter and 40 × 40 mm(2), the differences between percent depth dose curves up to depths of 3.5 cm were between 1% and 4% on average, with the maximum difference being 7%. The profiles agreed very well for fields >5 mm diameter. The relative output factors differed by up to 6% for fields larger than 10 mm diameter, but differed by up to 49% for fields ≤5 mm diameter. The mechanical characteristics of the system (source-to-axis and source-to-detector distances) were consistent between all three institutions. There were substantial differences in the flex of each system. CONCLUSIONS: With the exception of the half-value layer, and mechanical properties, there were significant differences between the dosimetric and geometric properties of the three systems. This underscores the need for careful commissioning of each individual system for use in radiobiological experiments.

Diffusion-weighted magnetic resonance imaging in focal breast lesions: analysis of 78 cases with pathological correlation.

PURPOSE: This study assessed the usefulness of magnetic resonance diffusion-weighted imaging (DWI) in distinguishing between benign and malignant breast lesions. MATERIALS AND METHODS: Gadolinium-enhanced magnetic resonance imaging (MRI) and DWI with determination of the apparent diffusion coefficient (ADC) were performed on 78 women, each with a focal breast lesion at least 7 mm in diameter, which was studied by cytology or histology. RESULTS: Final diagnoses were obtained by cytology in 29 cases and histology in 49 (11 percutaneous biopsies and 38 surgical specimens). There were 43 benign lesions (13 fibrocystic disease, eight fibroadenoma, seven adenosis, five normal breast tissue, four inflammatory lesions, three intramammary lymph nodes, two scleroelastosis and one fat necrosis) and 35 malignant lesions (30 invasive ductal carcinoma, two invasive lobular carcinoma, one ductal carcinoma in situ, one carcinomatous mastitis and one metastasis from neuroendocrine carcinoma). The mean ADC values were 1.677±0.151 for benign lesions and 1.298±0.129 for malignant lesions (p<0.001). With an ADC cutoff value of 1.48, DWI had 88.6% sensitivity [confidence interval (CI) 78.1%-99.1%] and 95.3% specificity (CI 88.9%-100%), with 31 true positives, four false negatives (three invasive ductal carcinoma and one carcinomatous mastitis), 41 true negatives and two false positives (one fat necrosis and one fibroadenoma). With the cutoff value set at 1.52, DWI sensitivity (35 true positive, no false negative) was 100% and specificity was 86% (CI 75.7%-96.3%) due to 37 true negatives and six false positives (an additional two fibroadenoma and two fibrocystic disease compared with those recorded with the cutoff set at 1.48). The overall accuracy of DWI considering both cutoff values (72 correct evaluations out of 78 cases) was 92.3% (CI 86.4%-98.2%). CONCLUSIONS: DWI is a reliable tool for characterising focal breast lesions.

Altered microstructure integrity of the amygdala in schizophrenia: a bimodal MRI and DWI study.

BACKGROUND: The amygdala plays a central role in the fronto-limbic network involved in the processing of emotions. Structural and functional abnormalities of the amygdala have recently been found in schizophrenia, although there are still contradictory results about its reduced or preserved volumes. METHOD: In order to address these contradictory findings and to further elucidate the possibly underlying pathophysiological process of the amygdala, we employed structural magnetic resonance imaging (MRI) and diffusion weighted imaging (DWI), exploring amygdalar volume and microstructural changes in 69 patients with schizophrenia and 72 matched healthy subjects, relating these indices to psychopathological measures. RESULTS: Measuring water diffusivity, the apparent diffusion coefficients (ADCs) for the right amygdala were found to be significantly greater in patients with schizophrenia compared with healthy controls, with a trend for abnormally reduced volumes. Also, significant correlations between mood symptoms and amygdalar volumes were found in schizophrenia. CONCLUSIONS: We therefore provide evidence that schizophrenia is associated with disrupted tissue organization of the right amygdala, despite partially preserved size, which may ultimately lead to abnormal emotional processing in schizophrenia. This result confirms the major role of the amygdala in the pathophysiology of schizophrenia and is discussed with respect to amygdalar structural and functional abnormalities found in patients suffering from this illness.

Sublingual immunotherapy in polysensitized patients: effect on quality of life.

BACKGROUND: Quality of life (QOL) is an important issue in allergic rhinitis and has been evaluated in a number of studies that have shown how it is impaired in untreated patients and improved by effective treatment. However, there are no data concerning QOL after sublingual immunotherapy (SLIT) in polysensitized patients. OBJECTIVE: To evaluate the effect, in real-life clinical practice, of SLIT on QOL in a population of polysensitized patients with allergic rhinitis. METHODS: We prospectively evaluated 167 consecutively enrolled polysensitized patients with allergic rhinitis. QOL was measured in all cases with the Rhinoconjunctivitis Quality of Life Questionnaire at baseline and after 1 year of SLIT (performed in approximately 70% of cases using single allergen extracts provided by the same manufacturer). RESULTS: The most frequent causes of sensitization were grass pollen, Parietaria, and house dust mites. The mean number of sensitizations per patient was 3.65. SLIT was performed with 1 extract in 123 patients (73.6%), with 2 extracts in 31 patients (18.6%), and with more than 2 extracts in 13 patients (7.8%). The mean values of all the QOL items improved significantly (P < .01 in all cases), with the following reductions noted: activities, 3.96 to 2.89; sleep, 2.07 to 1.56; general problems, 2.16 to 1.5; practical problems, 3.69 to 2.58; nasal symptoms, 3.57 to 2.50; eye symptoms, 2.92 to 1.83; and emotional aspects, 2.2 to 1.44. CONCLUSIONS: This study provides evidence that QOL can be improved in polysensitized patients treated with SLIT, and that the use of just 1 or 2 allergen extracts seems to be sufficient and effective in terms of improving QOL.

Enhancement of superconductivity near the ferromagnetic quantum critical point in UCoGe.

We report a high-pressure single crystal study of the superconducting ferromagnet UCoGe. Measurements of the ac susceptibility and resistivity under pressures up to 2.2 GPa show ferromagnetism is smoothly depressed and vanishes at a critical pressure p(c) = 1.4 GPa. Near the ferromagnetic critical point superconductivity is enhanced. Upper-critical field measurements under pressure show B(c2)(0) attains remarkably large values, which provides solid evidence for spin-triplet superconductivity over the whole pressure range. The obtained p-T phase diagram reveals superconductivity is closely connected to a ferromagnetic quantum-critical point hidden under the superconducting "dome."

Muon spin rotation and relaxation in the superconducting ferromagnet UCoGe.

We report zero-field muon-spin rotation and relaxation measurements on the superconducting ferromagnet UCoGe. Weak itinerant ferromagnetic order is detected by a spontaneous muon-spin precession frequency below the Curie temperature TC=3 K. The micro+ precession frequency persists below the bulk superconducting transition temperature Tsc=0.5 K, where it measures a local magnetic field Bloc=0.015 T. The amplitude of the microSR signal provides unambiguous proof for ferromagnetism present in the whole sample volume. We conclude ferromagnetism coexists with superconductivity on the microscopic scale.

Characteristics of patients with allergic polysensitization: the POLISMAIL study.

BACKGROUND: The natural history of respiratory allergy is commonly characterized by a worsening of symptom severity, frequent comorbidity of rhinitis and asthma, and polysensitization to aeroallergens. The polysensitization phenomenon starts since childhood and is rare to find monosensitized adult patients. However, there are few studies investigating the characteristics of polysensitized patients. METHODS: This study was performed on a large cohort of patients with allergic rhinitis (assessed by ARIA criteria) and/or mild to moderate asthma (assessed by GINA). The kind and the number of sensitizations, their patterns, and the relation with quality of life (QoL) measured by the Juniper's RQLQ guestionnaire, were evaluated. RESULTS: Globally 418 patients (50.2% males, 49.8% females, mean age 26.4 years, range 3.5-65 years, 64 smokers, 371 non-smokers) were enrolled: 220 had allergic rhinitis alone, and 198 allergic rhinitis and asthma. The mean number ofsensitizations was 2.6. Three hundred-five patients (73%) had persistent rhinitis (PER), 220 of them with moderate-severe form. There was no significant derence in rate of rhinitis and asthma in monosensitized or polysensitized patients. Most patients were sensitized to pollens, whereas only 24.2% of them were sensitized to perennial allergens. Polysensitization was significantly associated with some issues of QoL, confirming previous findings, but not with number ofsensitizations. CONCLUSIONS: This study provides data confirming for poly-sensitized patients the relevance of ARIA classification of AR. PER is the most common form of AR in this cohort, symptoms are frequently moderate-severe, and asthma is present in about the half of patients with AR.

Continuous EEG-fMRI in Pre-Surgical Evaluation of a Patient with Symptomatic Seizures: Bold Activation Linked to Interictal Epileptic Discharges Caused by Cavernoma.

We used continuous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) to identify the linkage between the "epileptogenic" and the "irritative" area in a patient with symptomatic epilepsy (cavernoma, previously diagnosed and surgically treated), i.e. a patient with a well known "epileptogenic area", and to increase the possibility of a non invasive pre-surgical evaluation of drug-resistant epilepsies. A compatible MRI system was used (EEG with 29 scalp electrodes and two electrodes for ECG and EMG) and signals were recorded with a 1.5 Tesla MRI scanner. After the recording session and MRI artifact removal, EEG data were analyzed offline and used as paradigms in fMRI study. Activation (EEG sequences with interictal slow-spiked-wave activity) and rest (sequences of normal EEG) conditions were compared to identify the potential resulting focal increase in BOLD signal and to consider if this is spatially linked to the interictal focus used as a paradigm and to the lesion. We noted an increase in the BOLD signal in the left neocortical temporal region, laterally and posteriorly to the poro-encephalic cavity (residual of cavernoma previously removed), that is around the "epileptogenic area". In our study "epileptogenic" and "irritative" areas were connected with each other. Combined EEG-fMRI may become routine in clinical practice for a better identification of an irritative and lesional focus in patients with symptomatic drug-resistant epilepsy.

Effect of a Static Magnetic Field (1.5T) on Brain Oscillatory Activities in Resting State Condition.

The aim of the present study was to compare the EEG signal recorded outside and inside a 1.5T magnetic resonance (MR) scanner. The EEG was recorded in eyes open and eyes closed conditions using a digital recording MR-compatible system. To characterize how a static magnetic field induces changes in EEG signal, EEG data were analyzed using FFT frequency analysis. No significant difference between the alpha powers recorded outside and inside the magnetic field was observed in eyes closed conditions. However, in eyes open condition there was a significant increase in alpha power inside the magnet in comparison to the outside position. The changes in alpha power according to the eyes open/closed conditions could be inversely correlated to a subject's state of wakefulness and due to some physiological changes, rather than an effect of the magnetic field. This experiment suggests that subjects' state of wakefulness is of prime concern when performing functional MRI.

Superconductivity on the border of weak itinerant ferromagnetism in UCoGe.

We report the coexistence of ferromagnetic order and superconductivity in UCoGe at ambient pressure. Magnetization measurements show that UCoGe is a weak ferromagnet with a Curie temperature T(C)=3 K and a small ordered moment m(0)=0.03 micro(B). Superconductivity is observed with a resistive transition temperature T(s)=0.8 K for the best sample. Thermal-expansion and specific-heat measurements provide solid evidence for bulk magnetism and superconductivity. The proximity to a ferromagnetic instability, the defect sensitivity of T(s), and the absence of Pauli limiting, suggest triplet superconductivity mediated by critical ferromagnetic fluctuations.

Cortical white-matter microstructure in schizophrenia. Diffusion imaging study.

BACKGROUND: Several, although not all, of the previous small diffusion-weighted imaging (DWI) studies have shown cortical white-matter disruption in schizophrenia. AIMS: To investigate cortical white-matter microstructure with DWI in a large community-based sample of people with schizophrenia. METHOD: Sixty-eight people with schizophrenia and 64 healthy controls underwent a session of DWI to obtain the apparent diffusion coefficient (ADC) of white-matter water molecules. Regions of interest were placed in cortical lobes. RESULTS: Compared with controls, the schizophrenia group had significantly greater ADCs in frontal, temporal and occipital white matter (analysis of covariance, P < 0.05). CONCLUSIONS: Our findings confirm the presence of cortical white-matter microstructure disruption in frontal and temporo-occipital lobes in the largest sample of people with schizophrenia thus for studied with this technique. Future brain imaging studies, together with genetic investigations, should further explore white-matter integrity and genes encoding myelin-related protein expression in people with first-episode schizophrenia and those at high risk of developing the disorder.

Modified peptide nucleic acids are internalized in mouse macrophages RAW 264.7 and inhibit inducible nitric oxide synthase.

Overexpression of inducible nitric oxide synthase causes the production of high levels of nitric oxide, which, under pathological conditions, leads to immunosuppression and tissue damage. The results recently obtained using peptide nucleic acids, rather than traditional oligonucleotides as antigen and antisense molecules, prompted us to test their efficacy in the regulation of nitric oxide production, thereby overcoming the obstacle of cellular internalization. The cellular permeability of four inducible nitric oxide synthase antisense peptide nucleic acids of different lengths was evaluated. These peptide nucleic acids were covalently linked to a hydrophobic peptide moiety to increase internalization and to a tyrosine to allow selective 125I radiolabelling. Internalization experiments showed a 3-25-fold increase in the membrane permeability of the modified peptide nucleic acids with respect to controls. Inducible nitric oxide synthase inhibition experiments on intact stimulated macrophages RAW 264.7 after passive permeation of the two antisense peptide nucleic acids 3 and 4 demonstrated a significant decrease (43-44%) in protein enzymatic activity with respect to the controls. These data offer a basis for developing a good alternative to conventional drugs directed against inducible nitric oxide synthase overexpression.

Synthesis and characterization of a specific peptide nucleic acid that inhibits expression of inducible NO synthase.

Inducible nitric oxide synthase (iNOS) is modulated at the transcriptional level. Overexpression of this protein may result in high levels of nitric oxide leading to tissue damage and immunosuppression. In order to reduce the pathological effects of NO overproduction many efforts have been devoted to the identification of specific inhibitors of iNOS. The discovery of peptide nucleic acids (PNA), a novel class of molecules able to selectively interact with nucleic acids, prompted us to attempt a new way for the regulation of NO production. Here we describe the synthesis, characterization and in vitro effects of a PNA molecule bearing a homopyrimidine sequence complementary to the 5' coding region of murine iNOS mRNA. This PNA shows specific interactions with iNOS mRNA in RNase protection assays and is able to block the synthesis of iNOS protein selectively in a rabbit reticulocyte lysate system. These results strengthen the view of a possible pharmacological application of PNA as a compound able to interfere with a specific enzymatic activity even at low concentrations.

Macrophage protection against human immunodeficiency virus or herpes simplex virus by red blood cell-mediated delivery of a heterodinucleotide of azidothymidine and acyclovir.

Human herpesvirus (HSVs) are distributed worldwide and are among the most frequent causes of viral infection in HIV-1-immunocompromised patients. Hence, therapeutic strategies able to inhibit HSV-1 and HIV-1 replication are sorely needed. Until now, the most common therapies against HSV-1 and HIV-1 infectivity have been based on the administration of nucleoside analogs; however, to be active, these antiviral drugs must be converted to their triphosphorylated derivatives by viral and/or cellular kinases. At the cellular level, the main problems involved in the use of such drugs are their limited phosphorylation in some cells (e.g., antiretroviral drugs in macrophages) and the cytotoxic side effects of nucleoside analog triphosphates. To overcome these limitations, a new heterodinucleotide (AZTp2ACV) consisting of both an antiretroviral and an antiherpetic drug, bound by a pyrophosphate bridge, was designed and synthesized. The impermeant AZTp2ACV was encapsulated into autologous erythrocytes modified to increase their recognition and phagocytosis by human macrophages. Once inside macrophages, metabolic activation of the drug occurred. The addition of AZTp2ACV-loaded erythrocytes to human macrophages provided effective and almost complete in vitro protection from HIV-1 and HSV-1 replications, respectively. Therefore, AZTp2ACV acts as an efficient antiviral prodrug following selective targeting to macrophages by means of loaded erythrocytes.

Synthesis, uptake, and intracellular metabolism of a hydrophobic tetrapeptide-peptide nucleic acid (PNA)-biotin molecule.

Peptide nucleic acid (PNA) molecules are very promising tools for antigene and antisense therapies because of their remarkable refractoriness to degradation in biological fluids. However, very limited information is available on their uptake by potentially target cells and on their intracellular fate. A membrane-diffusable and fluorescence detectable PNA chimera, Phe-Leu-Phe-Leu-(Adenine)3-biotin, was obtained by solid phase peptide synthesis and characterized by combined HPLC and mass spectrometry (MS). This PNA chimera was found to permeate across the membrane of both human erythrocytes and B Namalwa cells much more extensively and rapidly than a control Gly-(Adenine)3-biotin PNA molecule. Fluorescence patterns of internalization were consistent for a diffusion process resulting in the appearance of uniform cytoplasmic distribution of the hydrophobic peptide-PNA chimera in the Namalwa cells. Degradation of the synthesized PNA chimera by cell lysates and to a much slower extent by the intact Namalwa cells was investigated by HPLC-MS analyses of the corresponding methanol extracts . It involved the progressive removal of each of the hydrophobic amino acid residues, while the linkage with the biotin label was completely resistant to cleavage. These results hold promise for the design and synthesis of membrane-permeable PNA sequences suitable for antigene therapies.