Development of hard X-ray photoelectron spectroscopy in liquid cells using optimized microfabricated silicon nitride membranes.

We present first hard X-ray photoelectron spectroscopy (HAXPES) results of aqueous salt solutions and dispersions of gold nanoparticles in liquid cells equipped with specially designed microfabricated thin silicon nitride membranes, with thickness in the 15-25 nm range, mounted in a high-vacuum-compatible environment. The experiments have been performed at the HAXPES endstation of the GALAXIES beamline at the SOLEIL synchrotron radiation facility. The low-stress membranes are fabricated from 100 mm silicon wafers using standard lithography techniques. Platinum alignment marks are added to the chips hosting the membranes to facilitate the positioning of the X-ray beam on the membrane by detecting the corresponding photoemission lines. Two types of liquid cells have been used, a static one built on an Omicron-type sample holder with the liquid confined in the cell container, and a circulating liquid cell, in which the liquid can flow in order to mitigate the effects due to beam damage. We demonstrate that the membranes are mechanically robust and able to withstand 1 bar pressure difference between the liquid inside the cell and vacuum, and the intense synchrotron radiation beam during data acquisition. This opens up new opportunities for spectroscopic studies of liquids.

Quantitative measures of the resting EEG in stroke: a systematic review on clinical correlation and prognostic value.

OBJECT: Quantitative electroencephalography (qEEG) has shown promising results as a predictor of clinical impairment in stroke. We systematically reviewed published papers that focus on qEEG metrics in the resting EEG of patients with mono-hemispheric stroke, to summarize current knowledge and pave the way for future research. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched the literature for papers that fitted our inclusion criteria. Rayyan QCRR was used to allow deduplication and collaborative blinded paper review. Due to multiple outcomes and non-homogeneous literature, a scoping review approach was used to address the topic. RESULTS: Or initial search (PubMed, Embase, Google scholar) yielded 3200 papers. After proper screening, we selected 71 papers that fitted our inclusion criteria and we developed a scoping review thar describes the current state of the art of qEEG in stroke. Notably, among selected papers 53 (74.3%) focused on spectral power; 11 (15.7%) focused on symmetry indexes, 17 (24.3%) on connectivity metrics, while 5 (7.1%) were about other metrics (e.g. detrended fluctuation analysis). Moreover, 42 (58.6%) studies were performed with standard 19 electrodes EEG caps and only a minority used high-definition EEG. CONCLUSIONS: We systematically assessed major findings on qEEG and stroke, evidencing strengths and potential pitfalls of this promising branch of research.

The Local Structure and Metal-Insulator Transition in a Ba3Nb5-xTixO15 System.

The local structure of the filled tetragonal tungsten bronze (TTB) niobate Ba3Nb5-xTixO15 (x = 0, 0.1, 0.7, 1.0), showing a metal-insulator transition with Ti substitution, has been studied by Nb K-edge extended X-ray absorption fine structure (EXAFS) measurements as a function of temperature. The Ti substitution has been found to have a substantial effect on the local structure, that remains largely temperature independent in the studied temperature range of 80-400 K. The Nb-O bonds distribution shows an increased octahedral distortion induced by Ti substitution, while Nb-Ba distances are marginally affected. The Nb-O bonds are stiffer in the Ti substituted samples, which is revealed by the temperature dependent mean square relative displacements (MSRDs). Furthermore, there is an overall increase in the configurational disorder while the system with Nb 4d electrons turns insulating. The results underline a clear relationship between the local structure and the electronic transport properties suggesting that the metal-insulator transition and possible thermoelectric properties of TTB structured niobates can be tuned by disorder.

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

The local structure of self-doped BiS2-based layered systems as a function of temperature.

We have studied the local structure of layered Eu(La,Ce)FBiS2 compounds by Bi L3-edge extended X-ray absorption fine structure (EXAFS) measurements as a function of temperature. We find that the BiS2 sub-lattice is largely distorted in EuFBiS2, characterized by two different in-plane Bi-S1 distances. The distortion is marginally affected by partial substitutions of Ce (Eu0.5Ce0.5FBiS2) and La (Eu0.5La0.5FBiS2). The temperature dependence of the local structure distortion reveals an indication of possible charge density wave like instability in the pristine self-doped EuFBiS2 and Ce substituted Eu0.5Ce0.5FBiS2 while it is suppressed in La substituted Eu0.5La0.5FBiS2. In compounds with higher superconducting transition temperature, the axial Bi-S2 bond distance is elongated and the related bond stiffness decreased, suggesting some important role of this in the charge transfer mechanism for self-doping in the active BiS2-layer. In-plane Bi-S1 distances are generally softer than the axial Bi-S2 distance and they suffer further softening by the substitutions. The results are discussed in relation to an important role of the Bi defect chemistry driven asymmetric local environment in the physical properties of these materials.

Neurobiological after-effects of non-invasive brain stimulation.

BACKGROUND: In recent years, many studies have evaluated the effects of noninvasive brain stimulation (NIBS) techniques for the treatment of several neurological and psychiatric disorders. Positive results led to approval of NIBS for some of these conditions by the Food and Drug Administration in the USA. The therapeutic effects of NIBS have been related to bi-directional changes in cortical excitability with the direction of change depending on the choice of stimulation protocol. Although after-effects are mostly short lived, complex neurobiological mechanisms related to changes in synaptic excitability bear the potential to further induce therapy-relevant lasting changes. OBJECTIVE: To review recent neurobiological findings obtained from in vitro and in vivo studies that highlight molecular and cellular mechanisms of short- and long-term changes of synaptic plasticity after NIBS. FINDINGS: Long-term potentiation (LTP) and depression (LTD) phenomena by itself are insufficient in explaining the early and long term changes taking place after short episodes of NIBS. Preliminary experimental studies indicate a complex scenario potentially relevant to the therapeutic effects of NIBS, including gene activation/regulation, de novo protein expression, morphological changes, changes in intrinsic firing properties and modified network properties resulting from changed inhibition, homeostatic processes and glial function. CONCLUSIONS: This review brings into focus the neurobiological mechanisms underlying long-term after-effects of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) recently obtained from in vitro and in vivo studies, both in animals and humans.

Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients.

The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improved in vivo and in vitro cytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients.

GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is still one of the most fatal cancers. Hence, it needs to identify always new putative markers to improve its diagnosis and prognosis. The selenium is an essential trace mineral implicated as a key factor in the early stage of cancer and exerts its biological function through the selenoproteins. In the last years our group has been studying the involvement of some selenoproteins in HCC. However, no many data are reported in literature about the correlation between HCC and the glutathione peroxidases (GPXs), both selenium and non selenium-containing GPXs. In this paper we have evaluated the GPX4 and GPX7 expression in some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC by immunohistochemistry and RT-qPCR analysis. Our results evidenced that i) GPX4 and GPX7 had a statistically significant over-expression in HCC tissues compared to cirrhotic counterparts used as non tumor tissues, and ii) their expression was higher in grade III HCC tissues with respect to grade I-II samples. Therefore, we propose to use GPX4 and GPX7 as possible markers for improving HCC diagnosis/prognosis.

Paroxysmal ataxia and dysarthria in multiple sclerosis.

Paroxysmal ataxia and dysarthria are part of the spectrum of transient neurological disturbances that can be frequently encountered in multiple sclerosis (MS). Prompt recognition of these symptoms is important because they can be the only manifestation of a MS relapse and symptomatic therapy is often beneficial. We report a patient who developed paroxysmal ataxia and dysarthria, documented by video imaging, while he was recovering from a MS relapse. Treatment with carbamazepine resulted in the complete reversal of the paroxysmal ataxia and dysarthria.

Assessment of the Selenoprotein M (SELM) over-expression on human hepatocellular carcinoma tissues by immunohistochemistry.

Selenium is an essential trace mineral of fundamental importance to human healthy and exerts its biological function through selenoproteins. In particular, Selenoprotein M (SELM) is located in the endoplasmic reticulum and contains the common redox motif of cysteine-X-X-selenocysteine type. It attracts great attention due to its high expression in brain and its potential roles as antioxidant, neuroprotective, and cytosolic calcium regulator. Recently, our group found SELM over-expression  in human hepatocellular carcinoma (HCC) cell lines. In this report some paraffin-embedded tissues from liver biopsy of patients with hepatitis C virus (HCV)-related cirrhosis and HCC were immunohistochemically stained and SELM expression scoring was evaluated. Our results evidence for the first time an increase of SELM expression in HCC liver tissues, and its gradual expression raise associated with an increased malignancy grade. Therefore, we propose to use i) SELM as putative marker for HCC as well as ii) simple immunohistochemistry technique to distinguish between the different grades of malignancy. 

Acquired resistance to zoledronic acid and the parallel acquisition of an aggressive phenotype are mediated by p38-MAP kinase activation in prostate cancer cells.

The nitrogen-containing bisphosphonates (N-BP) zoledronic acid (ZOL) inhibits osteoclast-mediated bone resorption, and it is used to prevent skeletal complications from bone metastases. ZOL has also demonstrated anticancer activities in preclinical models and, recently, in cancer patients, highlighting the interest in determining eventual mechanisms of resistance against this agent. In our study, we selected and characterised a resistant subline of prostate cancer (PCa) cells to better understand the mechanisms, by which tumour cells can escape the antitumour effect of ZOL. DU145R80-resistant cells were selected in about 5 months using stepwise increasing concentrations of ZOL from DU145 parental cells. DU145R80 cells showed a resistance index value of 5.5 and cross-resistance to another N-BP, pamidronate, but not to the non-nitrogen containing BP clodronate. Notably, compared with DU145 parental cells, DU145R80 developed resistance to apoptosis and anoikis, as well as overexpressed the anti-apoptotic protein Bcl-2 and oncoprotein c-Myc. Moreover, DU145R80 cells underwent epithelial to mesenchymal transition (EMT) and showed increased expression of the metalloproteases MMP-2/9, as well as increased invading capability. Interestingly, compared with DU145, DU145R80 cells also increased the gene expression and protein secretion of VEGF and the cytokines Eotaxin-1 and IL-12. At the molecular level, DU145R80 cells showed strong activation of the p38-MAPK-dependent survival pathway compared with parental sensitive cells. Moreover, using the p38-inhibitor SB203580, we completely reversed the resistance to ZOL, as well as EMT marker expression and invasion. Furthermore, SB203580 treatment reduced the expression of VEGF, Eotaxin-1, IL-12, MMP-9, Bcl-2 and c-Myc. Thus, for the first time, we demonstrate that the p38-MAPK pathway can be activated under continuous extensive exposure to ZOL in PCa cells and that the p38-MAPK pathway has a critical role in the induction of resistance, as well as in the acquisition of a more aggressive and invasive phenotype.

Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques.

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.

Dystonia in Costello syndrome.

BACKGROUND: Costello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear. METHODS: We evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation. RESULTS: All the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia. CONCLUSIONS: These findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients.

Characterization of metalloproteinases, oxidative status and inflammation levels in the different stages of fibrosis in HCV patients.

OBJECTIVES: This study was aimed at searching noninvasive markers of the transition from mild to severe fibrosis stage in HCV patients undergoing hepatic fibrosis. DESIGN AND METHODS: Thirty-three patients affected by chronic HCV vs. twenty healthy donors were evaluated for the serum levels of several circulating matrix metalloproteinases (MMPs), TRAIL and ß-NGF by multiplex biometric ELISA based immunoassay and anti- and pro-oxidant status (d-ROMs, BAP and NO) using a Diacron automated method. RESULTS: HCV patients displayed increased expression levels of MMP-8, MMP-9, TRAIL and ß-NGF, and an imbalance between pro- and antioxidant status, that contribute to liver fibrosis. CONCLUSIONS: Since the determination of these parameters represents a reliable and easily applicable method, these parameters are suggested as serum surrogate markers for HCV patients in the routine clinical practice.

When a pregnancy required a neurological consultation: a case report.

Posterior reversible encephalopathy syndrome (PRES) is a transient clinical and neuroradiological syndrome characterized by clinical signs and symptoms including hypertension, seizures, altered mental status, headache, and vision changes and characteristic features on head computed tomography (CT) or magnetic resonance imaging (MRI) scan. PRES is most commonly reported in the literature in association with obstetric patients suffering from pre-eclampsia or eclampsia. In the acute setting, it is important to recognize the characteristics of PRES and immediately treat patients' emerging conditions that are hypertension and seizures. The following case report describes a pregnant patient who presented clinical characteristics of eclampsia with recurrent episodes of seizure and hypertension complicated by PRES. This case highlights the importance of early recognition and treatment of this condition that is usually transient and completely reversible, but can lead to ischemic injury and irreversible brain damage.

I-wave origin and modulation.

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.

Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of human motor cortex can produce long-lasting changes in the excitability of excitatory and inhibitory neuronal networks. The effects of rTMS depend critically on stimulus frequency. The aim of our present study was to compare the effects of different rTMS protocols. We compared the aftereffects of 6 different rTMS protocols [paired associative stimulation at interstimulus intervals of 25 (PAS(25)) and 10 ms (PAS(10)); theta burst stimulation delivered as continuous (cTBS) or intermittent delivery pattern (iTBS); 1- and 5-Hz rTMS] on the excitability of stimulated and contralateral motor cortex in 10 healthy subjects. A pronounced increase of cortical excitability, evaluated by measuring the amplitude of motor evoked potentials (MEPs), was produced by iTBS (+56%) and PAS(25) (+45%). Five-hertz rTMS did not produce a significant increase of MEPs. A pronounced decrease of cortical excitability was produced by PAS(10) (-31%), cTBS (-29%), and 1-Hz rTMS (-20%). Short-interval intracortical inhibition was suppressed by PAS(10). Cortical silent period duration was increased by 1-Hz stimulation. No significant effect was observed in the contralateral hemisphere. Head-to-head comparison of the different protocols enabled us to identify the most effective paradigms for modulating the excitatory and inhibitory circuits activated by TMS.

Ultrasoundelastography: Can it provide valid information for differentiation of benign and malignant thyroid nodules?

Ultrasoundelastography (USE) is a new imaging technique that is performed with a normal ultrasound transducer. It provides improved characterization of a tissue or nodule based on the latter's elasticity and stiffness. The aim of the present, prospective study was to assess the validity of USE in characterizing thyroid nodules. USE patterns were analyzed in light of nodule cytology (British Thyroid Association classification) to determine whether these patterns can be used to decide whether or not fine-needle aspiration cytology (FNAC) is indicated. We examined a consecutive series of 617 thyroid nodules in patients referred for the first time to the Endocrinology Unit of Atri Hospital (Atri, [TE]). Patients underwent ultrasonographic and USE examinations of their thyroid nodules, which were then subjected to FNAC. All nodules with Thy 1 cytology were excluded, leaving 567 nodules for analysis. USE findings were classified on the basis of the degree and distribution of elasticity within the lesion: four patterns were identified (1, 2, 3a, 3b, or 4).None of the nodules with Thy 4 cytology (malignant) had USE pattern 1 or 2; patterns 3 and 4 were associated with higher cytologic grades. In conclusion, USE provides additional information on thyroid nodules, which can be used with ultrasound features of the nodules, to decide whether FNAC is indicated. In fact, patterns 1 and 2 do not seem to be associated with Thy 4 cytology.

Transient synovitis of the hip: Ultrasound appearance. Mini-pictorial essay.

We describe the ultrasound (US) appearance of transient synovitis. Transient synovitis of the hip typically occurs in 3 to 8-year-old children. The onset is clinically characterized by acute hip pain and limp with limited joint mobility, and the leg is usually held in a position of flexion and external rotation to avoid pain. US image is characterized by joint effusion in the hip joint anterior recess, as described in the literature. Our experience confirms the importance of the technique with which the US examination is performed. In order to obtain the best diagnostic information the hip must be examined with the patient in the supine position and the hip joint in a neutral position (abduction of the hip with extension and slight external rotation) by means of an anterior approach along the long axis of the femoral neck in the parasagittal plane.