Stress-induced brain activity, brain atrophy, and clinical disability in multiple sclerosis

While psychological stress is considered to contribute to disease severity and progression in multiple sclerosis (MS)1, 2, the precise mechanism behind this association remains unknown. Earlier studies have shown that the peripheral stress regulation in MS patients is not entirely intact and their immune system less responsive to stress hormones3, 4, 5. To investigate the link between stress-induced brain activity and symptom severity on a functional-neural level, we measured brain activity in 36 MS patients and 21 healthy controls (HC) while they performed a mathematic task. The task was designed based on the Trier Social Stress Test (TSST), which is often used to evoke psychological stress in experimental setups6. The pace of the mental arithmetic task was adapted to each participant’s performance, on which they later received feedback. For the measurement of neural activity we used a functional Magnetic Resonance Imaging (fMRI) paradigm, more specifically a technique called Arterial Spin Labeling7. This method allows perfusion measurement of brain structures without the necessity of contrast agents. We detected physiological stress responses by measuring heart rate and salivary cortisol concentration8; the psychological stress level was assessed by self-reporting. Following our search for stress-induced increased neural activity across all participants, we tested for associations between activity in these stress sensitive areas and disease markers such as EDSS score, brain atrophy markers and T2 lesion load9. Our paradigm caused a significant change in heart rate, self-reporting and increased neural activity in the visual, cerebellar and insular cortex compared to resting condition across participants. Despite a lower cognitive workload in patients due to the performance-adapted paradigm, stress responses did not differ between groups. Consequently, we could exclude that these responses were caused by an increased cognitive workload and thus performance. No significant elevation of salivary cortisol was reported, which could be attributed to delayed cortisol secretion in acute stress. We found a negative link between increased insular cortex activity detected during the stress task and pyramidal and cognitive functional impairment in patients. Furthermore, increased cerebellar activity was negatively associated with grey matter (GM) atrophy in this group. This link also existed in congruent cerebellar regions in HC. Our study shows that stress induced brain activity reflects disease severity in MS patients. We found a similar link between stress induced brain activity and GM volume in HC as in patients, which suggests that this association does not exist solely due to the disease.Obwohl davon ausgegangen wird, dass Stress Auswirkungen auf die Krankheitsschwere und den Verlauf von Multipler Sklerose hat, ist der zugrundeliegende Mechanismus bisher weitestgehend unverstanden. In früheren Studien wurden Hinweise darauf gefunden, dass die periphere Stressregulation bei diesen Patienten nicht vollkommen intakt ist und ihr Immunsystem in geringerem Maße auf Stresshormone reagiert. Zur Untersuchung des Zusammenhangs zwischen Stress und funktioneller neuronaler Aktivität in MS-Patienten haben wir die Gehirnaktivität von 36 MS-Patienten und 21 gesunden Kontrollprobanden mittels funktioneller Magnetresonanztomographie (fMRT) bestimmt, während diese dazu aufgefordert waren, Kopfrechenaufgaben zu lösen. Unser fMRT-Paradigma stellt eine Abwandlung des Trier Social Stress Tests (TSST) dar, der häufig genutzt wird, um bei Probanden unter experimentellen Bedingungen Stress zu erzeugen. Die zur Lösung der Aufgaben verfügbare Zeit wurde an die Performanz der Teilnehmer angepasst; sie erhielten zudem Feedback bezüglich ihrer Leistung. Die fMRT-Technik, mit Hilfe derer eine Perfusionsmessung im Gehirn ohne die Nutzung von Kontrastmittel möglich ist, nennt sich Arterial Spin Labeling (ASL). Die physiologische Stressreaktion der Probanden haben wir anhand der Pulsrate und von Kortisolspeichelproben, die psychologische Reaktion anhand von Selbsteinschätzungen der Probanden erfasst. Wir haben die fMRT-Messungen zunächst topographisch hinsichtlich Stressinduzierter neuronaler Aktivitätssteigerungen ausgewertet und anschließend nach Zusammenhängen zwischen Aktivitätssteigerung in diesen Stress-assoziierten Arealen und Krankheitsschweremarkern (z.B. EDSS-Score, T2-Läsionslast und Hirnatrophie-Markern) gesucht. Bei allen Probanden verursachte das Stressparadigma eine signifikante Änderung der Pulsgeschwindigkeit, des subjektiven Stressempfindens und eine gesteigerte neuronale Aktivität im visuellen, zerebellären und Inselkortex im Vergleich zur Ruhephase. Die genannten Stressantworten unterschieden sich nicht zwischen Patienten und der Kontrollgruppe, obwohl die Leistungsfähigkeit und die kognitive Belastung der Patienten aufgrund des Leistungs-adaptierten Aufgabendesigns geringer ausfielen. Daraus konnten wir schließen, dass keine dieser Reizantworten auf die kognitive Belastung oder die Performanz als Kovariaten zurückzuführen war. Ein signifikanter Anstieg der Kortisolkonzentrationen im Speichel wurde nicht festgestellt, was sich durch die verzögerte Sekretion von Kortisol bei akutem Stress erklären lässt. Die Aktivität des Inselkortex war während des Stressparadigmas stark erhöht und korrelierte negativ mit der Beeinträchtigung der pyramidalen und kognitiven Funktionen der Patienten. Die zerebelläre Aktivität korrelierte negativ mit der Atrophie ihrer grauen Substanz. Diese Korrelation konnte ebenso in deckungsgleichen zerebellären Regionen der gesunden Kontrollkohorte beobachtet werden. Unsere Ergebnisse zeigen, dass Stress-bedingte Hirnaktivität die Krankheitsschwere von MS-Patienten wiederspiegelt. Auch bei gesunden Kontrollprobanden wurde ein Zusammenhang zwischen Stress-bedingter Hirnaktivität und Volumen der grauen Substanz in deckungsgleichen Regionen gefunden. Dies legt nahe, dass dieser Zusammenhang nicht ausschließlich auf Grund einer MS-Erkrankung besteht

Cluster Formation and The Virial Equation of State of Low-Density Nuclear Matter

We present the virial equation of state of low-density nuclear matter composed of neutrons, protons and alpha particles. The virial equation of state is model-independent, and therefore sets a benchmark for all nuclear equations of state at low densities. We calculate the second virial coefficients for nucleon-nucleon, nucleon-alpha and alpha-alpha interactions directly from the relevant binding energies and scattering phase shifts. The virial approach systematically takes into account contributions from bound nuclei and the resonant continuum, and consequently provides a framework to include strong-interaction corrections to nuclear statistical equilibrium models. The virial coefficients are used to make model-independent predictions for a variety of properties of nuclear matter over a range of densities, temperatures and compositions. Our results provide constraints on the physics of the neutrinosphere in supernovae. The resulting alpha particle concentration differs from all equations of state currently used in supernova simulations. Finally, the virial equation of state greatly improves our conceptual understanding of low-density nuclear matter.Comment: 15 pages, 17 figures, minor revisions, to appear in Nucl. Phys.

Development of an Array of Compound Refractive Lenses for Sub-Pixel Resolution, Large Field of View, and Time-Saving in Scanning Hard X-ray Microscopy

A two-dimensional array of compound refractive lenses (2D array of CRLs) designed for hard X-ray imaging with a 3.5 mm$^{2}$ large field of view is presented. The array of CRLs consists of 2D polymer biconcave parabolic 34 × 34 multi-lenses fabricated via deep X-ray lithography. The developed refractive multi-lens array was applied for sub-pixel resolution scanning transmission X–ray microscopy; a raster scan with only 55 × 55 steps provides a 3.5 megapixel image. The optical element was experimentally characterized at the Diamond Light Source at 34 keV. An array of point foci with a 55 µm period and an average size of ca. 2.1 µm × 3.6 µm was achieved. In comparison with the conventional scanning transmission microscopy using one CRL, sub-pixel resolution scanning transmission hard X-ray microscopy enables a large field of view and short scanning time while keeping the high spatial resolution

Cell Microbiol.

Helicobacter pylori is one of the most common bacterial pathogens, infecting about 50% of the world population. The presence of a pathogenicity island (PAl) in H. pylori has been associated with gastric disease. We present evidence that the H. pylori protein encoded by the cytotoxin- associated gene A (cagA) is translocated and phosphorylated in infected epithelial cells. Two-dimensional gel electrophoresis (2-DE) of proteins isolated from infected AGS cells revealed H. pylori strain-specific and time- dependent tyrosine phosphorylation and dephosphorylation of several 125-135 kDa and 75-80 kDa proteins. Immunoblotting studies, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), cell fractionation and confocal microscopy demonstrated that one of the 125-135 kDa proteins represents the H. pylori CagA protein, which is translocated into the host cell membrane and the cytoplasm. Translocation of CagA was dependent on functional cagA gene and virulence (vir) genes of a type IV secretion apparatus composed of virB4, virB7, virB10, virB11 and virD4 encoded in the cag PAl of H. pylori. Our findings support the view that H. pylori actively translocates virulence determinants, including CagA, which could be involved in the development of a variety of gastric disease.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Predictive and prognostic potential of liver function assessment in patients with advanced hepatocellular carcinoma: a systematic literature review

INTRODUCTION: We conducted a systematic literature review to assess the utility of liver function assessments for predicting disease prognosis and response to systemic anticancer therapy in patients with advanced hepatocellular carcinoma (aHCC). METHODS: This was a PRISMA-standard review and was registered with PROSPERO (CRD42021244588). MEDLINE and Embase were systematically searched (March 24, 2021) to identify publications reporting the efficacy and/or safety of systemic anticancer therapy (vs any/no comparator) in liver-function-defined subgroups in phase 2 or 3 aHCC trials. Screening was completed by a single reviewer, with uncertainties resolved by a second reviewer and/or the authors. English-language full-text articles and congress abstracts were eligible for inclusion. Included publications were described and assessed for risk of bias using the GRADE methodology. RESULTS: Twenty (of 2579) screened publications were eligible; seven categorised liver function using the albumin–bilirubin system, nine using the Child–Pugh system, four using both. GRADE assessment classified ten, nine, and one publication(s) as reporting moderate-quality, low-quality, and very-low-quality evidence, respectively. Analyses of cross-trial trends of within-exposure arm analyses (active and control) reported a positive relationship between baseline liver function and overall survival and progression-free survival, supporting liver function as a prognostic marker in aHCC. There were also signals for a modest relationship between more preserved baseline liver function and extent of systemic treatment benefit, and with more preserved liver function and lower incidence of safety events. CONCLUSION: This review supports liver function as a prognostic variable in aHCC, and highlights the value of a priori stratification of patients by baseline liver function in aHCC trials. The predictive value of liver function warrants further study. Findings were limited by the quality of available data

Cross section and analyzing power of pol{p}p -> pn pi+ near threshold

The cross section and analyzing power of the pol{p}p -> pn pi+ reaction near threshold are estimated in terms of data obtained from the pol{p}p -> d pi+ and pp -> pp pi0 reactions. A simple final state interaction theory is developed which depends weakly upon the form of the pion-production operator and includes some Coulomb corrections. Within the uncertainties of the model and the input data, the approach reproduces well the measured energy dependence of the total cross section and the proton analyzing power at a fixed pion c.m. angle of 90deg, from threshold to T_p = 330 MeV. The variation of the differential cross section with pion angle is also very encouraging.Comment: 20 pages, Latex including 4 eps figure

Parabolic gratings enhance the X-ray sensitivity of Talbot interferograms

In grating-based X-ray Talbot interferometry, the wave nature of X-ray radiation is exploited to generate phase contrast images of objects that do not generate sufficient contrast in conventional X-ray imaging relying on X-ray absorption. The phase sensitivity of this interferometric technique is proportional to the interferometer length and inversely proportional to the period of gratings. However, the limited spatial coherency of X-rays limits the maximum interferometer length, and the ability to obtain smaller-period gratings is limited by the manufacturing process. Here, we propose a new optical configuration that employs a combination of a converging parabolic micro-lens array and a diverging micro-lens array, instead of a binary phase grating. Without changing the grating period or the interferometer length, the phase signal is enhanced because the beam deflection by a sample is amplified through the array of converging-diverging micro-lens pairs. We demonstrate that the differential phase signal detected by our proposed set-up is twice that of a Talbot interferometer, using the same binary absorption grating, and with the same overall inter-grating distance

S-wave π0\pi^0 Production in pp Collision in a Covariant OBE Model

The total cross section for the pp -> pp pi^0 reaction at energies close to threshold is calculated using a covariant one-boson-exchange model, where a boson B created on one of the incoming protons is converted into a neutral pion on the second. The amplitudes for the conversion processes, B N -> N pi^0, are taken to be the sum of s, u and t-channel pole terms. The main contributions to the primary production amplitude is due to an effective isoscalar sigma meson pole in a t-channel, which is enhanced strongly due to offshellness. With this contribution included the model reproduces, both the scale and energy dependence of the cross section.Comment: REVTeX, graphicx, 22 pages (icluding 10 figures