What Electrophysiology Tells Us About Alzheimer’s Disease::A Window into the Synchronization and Connectivity of Brain Neurons

Electrophysiology provides a real-time readout of neural functions and network capability in different brain states, on temporal (fractions of milliseconds) and spatial (micro, meso, and macro) scales unmet by other methodologies. However, current international guidelines do not endorse the use of electroencephalographic (EEG)/magnetoencephalographic (MEG) biomarkers in clinical trials performed in patients with Alzheimer’s disease (AD), despite a surge in recent validated evidence. This Position Paper of the ISTAART Electrophysiology Professional Interest Area endorses consolidated and translational electrophysiological techniques applied to both experimental animal models of AD and patients, to probe the effects of AD neuropathology (i.e., brain amyloidosis, tauopathy, and neurodegeneration) on neurophysiological mechanisms underpinning neural excitation/inhibition and neurotransmission as well as brain network dynamics, synchronization, and functional connectivity reflecting thalamocortical and cortico-cortical residual capacity. Converging evidence shows relationships between abnormalities in EEG/MEG markers and cognitive deficits in groups of AD patients at different disease stages. The supporting evidence for the application of electrophysiology in AD clinical research as well as drug discovery pathways warrants an international initiative to include the use of EEG/MEG biomarkers in the main multicentric projects planned in AD patients, to produce conclusive findings challenging the present regulatory requirements and guidelines for AD studies

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Geophysical Investigations of Celestial Bodies through the Combination of Radio Science and Altimetric Crossover Data

The challenging science objectives of future planetary missions will require highly accurate trajectory reconstruction of deep space probes. Novel techniques that improve the navigation capabilities are developed with the purpose to expand the scientific return of geophysical investigations across the Solar System. Science instruments that provide geodetic data from the spacecraft orbit may support the orbit determination process in combination with deep space radio tracking measurements. Altimetric data that measure the relative distance of the spacecraft with respect to the celestial body’s surface yield key constraints on the orbit evolution. Differential measurements, from observations that are repeated over the same location (crossover), are less prone to errors associated with surface mismodeling, leading to significant improvements in the estimation of the spacecraft position. In this work, we present a method based on the combination of ground-based radio science and altimetric crossover measurements to enhance the estimation of the spacecraft orbit and geodetic parameters. The methodology is developed to carry out thorough numerical simulations of mission scenarios, including the generation of synthetic observables. We show the results of our covariance analysis of the NASA mission Europa Clipper by simulating and processing measurements of the Radar for Europa Assessment and Sounding: Ocean to Near-surface (REASON) and the Gravity and Radio science (G/RS) investigations

Non-urothelial bladder neoplasms: small-cell neuroendocrine cancer

BACKGROUND: Neuroendocrine tumors (NET) are uncommon neoplasms. Small cell carcinoma of the bladder (SCCB) is a rare, poorly differentiated neuroendocrine tumor. It takes origin from cells of nervous and endocrine systems whitin the bladder. Data in literature are limited and still remains under discussion the best therapeutic approach. Treatment may be multimodal. Prognosis remains poor. Here we report the case of old male affected by SCCB. While opportunely describing it, we also reviewed the literature. CASE REPORT: A 85 years old male presented to us for asymtomatic gross hematuria recently occurred. Bladder ultrasound (US) revealed a 4 cm mass on left wall highly suspicious for neoplasm. Total body contrast-enhanced CT confirmed the lesion; no signs of local infiltration, hydronephrosis or visceral-lyph nodes secundarisms were described. A trans urethral resection of the bladder (TURB) was offered. RESULTS: Pathology report revealed a high-grade T1G3 urothelial carcinoma (30% of specimen) associated to small-cell neuroendocrine variant (70% of specimen): microscopic muscle involvement was excuded. In order to better characterize the neuroendocrine differentiation, immunohistochemistry was mandatory: cytokeratin AE1-3, synaptophysin and Ki-67 were used as molecular markers (Fig. 1). Urothelial histotype resulted positive for cytokeratine but negative for synaptophysin while the neuroendocrine variant was positive for both of them. Ki-67, a molecular marker adopted as expression of proliferation rate, was 90% totally suggesting an aggressive mixed bladder neoplasm. The patient was classed as a highest-risk. Radical cystectomy with extended lymp nodes dissection was offered. DISCUSSION AND CONCLUSIONS: Non-urothelial bladder cancers are uncommon neoplasms: they include neuroendocrine tumor (NET), squamous cell carcinoma (SCC), adenocarcinoma, micropapillary (MCP), plasmocitoid (PUC) and sarcoma. Two forms of bladder NET have been described in literature: small- and a large-cell. Small-cell carcinoma of the bladder (SCCB) is a very rare, poorly differentiated neuroendocrine tumor accounting for 0,5-1,0% of all bladder neoplasms3 and characterized by a highly aggressive course. Patients affected are considered at highest-risk of metastatic spreading and poor prognosis. Risk factors are not completely known. SCCB commonly arises from cells of the endocrine and nervous systems differently expressed whitin the human bladder. Neuroendocrine lesions are histologically graded according to markers of cellular proliferation (Ki-67 index) rather than cellular polymorphism2: whenever urothelial hystotipe coexists, the WHO 2004 grading system is used to classify the urothelial variant. On immunoistochemistry, SCCB is reactive for neuroendocrine markers such as synaptophysin, chromogranin and periodically for CK7 and CK20. TNM system is currently used to staging these neoplasms. Clinical presentation is variable depending from location, staging and visceral-lymph nodes involvement. Radical cistectomy represents the gold standard. A multimodal treatment may be also offered differently combining surgery with chemoterapic regimens. The prognosis remains poor

Antinociceptive effect of stimulating the occipital or retrosplenial cortex in rats

A role for the occipital or retrosplenial cortex in nociceptive processing has not been demonstrated yet, but connections from these cortices to brain structures involved in descending pain-inhibitory mechanisms were already demonstrated. This study demonstrated that the electrical stimulation of the occipital or retrosplenial cortex produces antinociception in the rat tail-flick and formalin tests. Bilateral lesions of the dorsolateral funiculus abolished the effect of cortical stimulation in the tail-flick test. Injection of glutamate into the same targets was also antinociceptive in the tail-flick test. No rats stimulated in the occipital or retrosplenial cortex showed any change in motor performance on the Rota-rod test, or had epileptiform changes in the EEG recording during or up to 3 hours after stimulation. The antinociception induced by occipital cortex stimulation persisted after neural block of the retrosplenial cortex. The effect of retrosplenial cortex stimulation also persisted after neural block of the occipital cortex. We conclude that stimulation of the occipital or retrosplenial cortex in rats leads to antinociception activating distinct descending pain-inhibitory mechanisms, and this is unlikely to result from a reduced motor performance or a postictal phenomenon. Perspective: This study presents evidence that stimulation of the retrosplenial or occipital cortex produces antinociception in rat models of acute pain. These findings enhance our understanding of the role of the cerebral cortex in control of pain. (C) 2010 by the American Pain SocietyFAPESPFAPESP-CinapseCAPESCNPq-Brazi

Prepubertal intratesticular keratocyst. Case report and literature review

BACKGROUND: Testicular epidermoid cysts (TEC), also known as keratocysts, are rare lesions accounting for 1% of all testicular masses4,9,11. Most of them are incidentally discovered and radically treated5,8,9. Clinically they present as firm palpable mass highly undistinguishable from other testicular cancers. Scrotal sonography (US), contrast enhanced ultrasound (CEUS) or magnetic resonance (MR) describe the lesion1,2,8 but diagnosis depends on histology. Although no cases of metastases have been reported to date in literature7 ,the real understanding of biological behaviour and clinical management is unresolved2,3. We report the case of a young patient affected by testicular keratocyst who underwent to surgical enucleation. By describing this case we also reviewed literature about histologic features of pre-pubertal form and the feasibility and safety of this procedure. CASE REPORT: A 16 y.o. caucasian male presented for a firm mass recently discovered on self examination. Anamnesis was uneventfull for genital infections or trauma: no familiarity for testicular cancer was reported. The right testis presented with a palpable painless mass in the middle portion of the testis, entirely covered by normal parenchima. Inguinal and supraclavicular lymph nodes were negative and serum markers (AFP, bHCG, PLAP and LDH) too. Scrotal sonography (US) reported a well circumscribed 2 centimetres mass within the right testis with intervening septa and coexisting solid areas: intralesional calcifications were not described. Intralesional vascularity was ruled out on ecodoppler. MR was negative for secundarisms; furthermore the exam did not reveal any intralesional contrast enhancement, totally suggesting a bening lesion. Testicular biopsy was offered. RESULTS: Frozen section was suggestive for mature keratocyst and surgical enucleation was offered. The lesion presented macroscopically as a 20 x 22 x 25 millimetres mass highly indishinguable from any malignant neoplasms. And totally covered by normal testicular parenchima. On microscopic evaluation the lesion was composed by horny material well delimited by a cystic wall (Fig.1) of squamous epithelium. No association with Intratubular Germ Cell Neoplasms (IGCN) was found nor cellular atypia or mitotic activity. Definely it was classed as pre-pubertal mature intratesticular epidermoid cyst. DISCUSSION: TEC are benign tumors which arise from ectoderm, endoderm or mesoderm tissues4,9,11. They account for around 1-2% of all testicular masses4,9,11 and tipically present in mid-adulthood. Caucasian males are more involved. The etiology is still debated2,3 (Cakiroglu B.; Cook). Two main form of TEC have been described in literature: pre-and post-pubertal. Pre-pubertal TEC have been historically considered as benign lesions since no association with germ cell neoplasm in situ (GCNIS) have been reported nor cases of metastasic spread. Histology often rules out unfavorable prognostic features such coexisting lesions or association with germ cell neoplasms. Due to this reason, they have been names “simple testicular epidermoid cyst”. Clinically, they are as highly indistinguishable to all testicular cancers and often presenting as a firm, painless palpable mass within the testis: the right testis seems to be more involved than left (Kenan). Serum markers are always negative too7 (Kenan). US may guide diagnosis since these lesion show typical radiographic features: a well marginated intratesticular masses with a lamellar ‘onion skin’ or ‘bull-eye’ pattern and avascular centre1,2,8 might always suggest testicular keratocyst (Cakiroglu; Muoka; Anheuser). CEUS also provides with more informations ruling out intralesional vascularity. MR imaging better describes the tumor, rules out secundarism or local infiltration and evaluates the absence of contrast enhancement which further suggest a benign nature. Although these features can guide clinical orientation, diagnosis only depends on histology: differentiation from coexisting enthities such as pure teratomas, germ cell tumors (GCT) or granulomatous disease is mandatory also in pre-pubertal forms. Uncommon features such as cellular atypia, mitotic activity, necrosis, hemorrhage and epythelial hyperplasia need to be missing also in these forms5,6,11 (Umar; Dockerty; Ewen). Partial orchiectomy or testis-sparing excision with frozen section is becoming day by day the standard treatment2 (Carikoglu et al); however, as the final pathology report describes a teratomatous lesion or malignant features, further radical orchiectomy is required. In our case the patient underwent contrast enhanced MR at 6 and 12 month which ruled out any visceral or lymph nodes metastases. Ultrasound of the testis excluded local recurrence. CONCLUSION: Testicular keratocysts are rare lesions commonly presenting in young male and clinically indistinguishable from other testicular lesion. Pre- and post-pubertal form represent the two main variants. Biologic behaviour and clinical management is still unresolved. Pre-pubertal variants are not related to IGCNIS or unfavorable histologic features; no cases of spreading have been reported to date and they are considered benign tumors. Serum markers, CEUS and MR may be helpful in making diagnosis and surgical planning. Only histology confirms the nature of the lesion ruling out coexisting histotypes. The importance of accurate diagnosis is crucial for preventing unncessary orchiectomy: testicular sparing surgery should be offered