The azimuthal anisotropy Fourier coefficients (v_{n}) in 8.16 TeV p+Pb data are extracted via long-range two-particle correlations as a function of the event multiplicity and compared to ...corresponding results in pp and PbPb collisions. Using a four-particle cumulant technique, v_{n} correlations are measured for the first time in pp and p+Pb collisions. The v_{2} and v_{4} coefficients are found to be positively correlated in all collision systems. For high-multiplicity p+Pb collisions, an anticorrelation of v_{2} and v_{3} is observed, with a similar correlation strength as in PbPb data at the same multiplicity. The new correlation results strengthen the case for a common origin of the collectivity seen in p+Pb and PbPb collisions in the measured multiplicity range.
In this work, we consider the case of a strongly coupled dark/hidden sector, which extends the Standard Model (SM) by adding an additional non-Abelian gauge group. These extensions generally contain ...matter fields, much like the SM quarks, and gauge fields similar to the SM gluons. We focus on the exploration of such sectors where the dark particles are produced at the LHC through a portal and undergo rapid hadronization within the dark sector before decaying back, at least in part and potentially with sizeable lifetimes, to SM particles, giving a range of possibly spectacular signatures such as emerging or semi-visible jets. Other, non-QCD-like scenarios leading to soft unclustered energy patterns or glueballs are also discussed. After a review of the theory, existing benchmarks and constraints, this work addresses how to build consistent benchmarks from the underlying physical parameters and present new developments for the PYTHIA Hidden Valley module, along with jet substructure studies. Finally, a series of improved search strategies is presented in order to pave the way for a better exploration of the dark showers at the LHC.
The blood-brain-barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. ...The brain endothelial cells, lining the brain’s vasculature, maintain close interactions with surrounding brain cells, e.g. astrocytes, pericytes and perivascular macrophages. This function facilitates critical intercellular crosstalk, giving rise to the concept of the neurovascular unit (NVU). The steady and appropriate communication between all components of the NVU is essential for normal CNS homeostasis and function, and dysregulation of one of its constituents can result in disease. Among the different brain regions, and along the vascular tree, the cellular composition of the NVU varies. Therefore, differential cues from the immediate vascular environment can affect BBB phenotype. To support the fluctuating metabolic and functional needs of the underlying neuropil, a specialized vascular heterogeneity is required. This is achieved by variances in barrier function, expression of transporters, receptors, and adhesion molecules. This mini-review will take you on a journey through evolving concepts surrounding the BBB, the NVU and beyond. Exploring classical experiments leading to new approaches will allow us to understand that the BBB is not merely a static separation between the brain and periphery but a closely regulated and interactive entity. We will discuss shifting paradigms, and ultimately aim to address the importance of BBB endothelial heterogeneity with regard to the function of the BBB within the NVU, and touch on its implications for different neuro-pathologies.
Tuberculous meningitis (TB meningitis) is the most severe form of tuberculosis (TB), requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. ...High-dose rifampin (35 mg/kg/d) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/d) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. We conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with postmortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.
Biomarkers in Alzheimer’s disease Janeiro, Manuel H.; Ardanaz, Carlos G.; Sola-Sevilla, Noemí ...
Advances in Laboratory Medicine / Avances en Medicina de Laboratorio,
03/2021, Letnik:
2, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Alzheimer's disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic ...criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed.
The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging.
Nowadays, there are three classical biomarkers for the diagnosis of AD: Aβ42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aβ and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography.
As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.
Preeclampsia is a syndrome characterized by hypertension during pregnancy, which is a leading cause of morbidity and mortality in both mother and newborn in developing countries. Some advances have ...increased the understanding of pathophysiology of this disease. For example, reduced utero-placental blood flow associated with impaired trophoblast invasion may lead to a hypoxic placenta that releases harmful materials into the maternal and feto-placental circulation and impairs endothelial function. Identification of these harmful materials is one of the hot topics in the literature, since these provide potential biomarkers. Certainty, such knowledge will help us to understand the miscommunication between mother and fetus. In this review we highlight how placental extracellular vesicles and their cargo, such as small RNAs (i.e., microRNAs), might be involved in endothelial dysfunction, and then in the angiogenesis process, during preeclampsia. Currently only a few reports have addressed the potential role of endothelial regulatory miRNA in the impaired angiogenesis in preeclampsia. One of the main limitations in this area is the variability of the analyses performed in the current literature. This includes variability in the size of the particles analyzed, and broad variation in the exosomes considered. The quantity of microRNA targets genes suggest that practically all endothelial cell metabolic functions might be impaired. More studies are required to investigate mechanisms underlying miRNA released from placenta upon endothelial function involved in the angiogenenic process.
Background & Aims Patients with cirrhosis and small hepatocellular carcinoma with normal bilirubin and hepatic venous pressure gradient (HVPG) <10 mm Hg have >70% 5-year survival after hepatic ...resection. On the contrary, patients with HVPG ⩾10 mm Hg (clinically significant portal hypertension, CSPH) frequently develop decompensation following surgery, with around 50% 5-year survival. Liver stiffness (LS) evaluation by transient elastography might non-invasively identify CSPH. We investigated the usefulness of LS predicting CSPH in patients with compensated cirrhosis and potentially resectable liver tumors. Methods Ninety-seven consecutive Child-Pugh A patients with potentially resectable liver tumors referred for HVPG measurement were prospectively evaluated. In fasting conditions LS was measured before the hemodynamic study. Results HVPG could be measured in all patients, whereas LS could not be measured in 18 (18.5%) obese patients. In the 79 patients with valid LS, 32 (40.5%) had CSPH; mean HVPG was 8.8 ± 4.7 mm Hg. Mean LS was 18.4 ± 12.3 kPa. LS showed a moderate correlation with HVPG (r = 0.552; p <0.001). LS <13.6 kPa had high sensitivity (91%) but low specificity (57%) excluding CSPH. Conversely, LS >21 kPa had low sensitivity (53%) and high specificity (91%) predicting CSPH. 35% of patients had LS between 13.6 and 21 kPa (“grey zone”). Conclusions These data suggest that in real-life scenarios half of patients with potentially resectable liver nodules can be non-invasively classified as having or not CSPH by LS. However, in the remaining half, LS is either not applicable or inaccurate. In this last population HVPG is still a non replaceable method to detect CSPH.
Background & Aims Both transient elastography (TE) and left lobe liver surface (LLS) ultrasound may non-invasively detect cirrhosis (LC). We aimed to examine the diagnostic value of these methods in ...patients with a suspicion but not a definite diagnosis of cirrhosis. Methods We enrolled 90 patients with clinical suspicion of cirrhosis and a strong co-existing differential diagnosis requiring further invasive evaluation. They underwent hepatic venous pressure gradient (HVPG) measurement ± transjugular liver biopsy, LLS and TE. Images of LLS were digitally post-processed to obtain a numerical value (quantitative LLS, qLLS). TE <12 kPa was considered to exclude LC, ⩾18 kPa diagnosed LC, and 12–18 kPa indeterminate. Technical failures were considered ‘indeterminate’. Diagnosis of cirrhosis was confirmed by histology (84%) or by clinical data and HVPG ⩾10 mm Hg. Diagnostic accuracy was evaluated by positive and negative likelihood ratios (+LR and −LR). Results Cirrhosis was diagnosed in 44 patients. There were 14 technical failures with TE and 1 with LLS ( p = 0.001). TE and LLS had similar diagnostic accuracy but gave complementary information: TE was mildly more accurate than LLS to rule out LC (−LR: 0.08 vs. 0.10), while it was less accurate to rule it in (+LR 5.05 vs. 11.15). Their combination offered the best diagnostic performance (+LR 9.15; −LR 0.06). Conclusions LLS is more technically applicable than TE. In patients with clinical suspicion of cirrhosis, LLS is the best non-invasive method to diagnose cirrhosis, while TE is preferable to rule it out. The combination of both holds the best diagnostic accuracy.
In Spain, data based on large population-based cohorts adequate to provide an accurate prediction of cardiovascular risk have been scarce. Thus, calibration of the EuroSCORE and Framingham scores has ...been proposed and done for our population. The aim was to develop a native risk prediction score to accurately estimate the individual cardiovascular risk in the Spanish population.
Seven Spanish population-based cohorts including middle-aged and elderly participants were assembled. There were 11800 people (6387 women) representing 107915 person-years of follow-up. A total of 1214 cardiovascular events were identified, of which 633 were fatal. Cox regression analyses were conducted to examine the contributions of the different variables to the 10-year total cardiovascular risk.
Age was the strongest cardiovascular risk factor. High systolic blood pressure, diabetes mellitus and smoking were strong predictive factors. The contribution of serum total cholesterol was small. Antihypertensive treatment also had a significant impact on cardiovascular risk, greater in men than in women. The model showed a good discriminative power (C-statistic=0.789 in men and C=0.816 in women). Ten-year risk estimations are displayed graphically in risk charts separately for men and women.
The ERICE is a new native cardiovascular risk score for the Spanish population derived from the background and contemporaneous risk of several Spanish cohorts. The ERICE score offers the direct and reliable estimation of total cardiovascular risk, taking in consideration the effect of diabetes mellitus and cardiovascular risk factor management. The ERICE score is a practical and useful tool for clinicians to estimate the total individual cardiovascular risk in Spain.
En España no existen unas cohortes poblacionales suficientemente grandes para hacer predicciones precisas del riesgo cardiovascular. Las ecuaciones de Framingham y EuroSCORE calibradas son las más utilizadas en España. El objetivo es desarrollar la primera ecuación de predicción autóctona para estimar con precisión el riesgo cardiovascular individual en España.
Análisis conjunto de siete cohortes españolas de población de mediana edad y anciana. La población del estudio —11.800 personas (6.387 mujeres)— aportó un total de 107.915 personas-año de seguimiento y 1.214 eventos cardiovasculares (633 de ellos, mortales). Se efectuó un análisis de regresión de Cox para examinar la contribución de los diferentes factores al riesgo de cualquier evento cardiovascular (mortal y no mortal).
La edad fue el principal factor de riesgo de eventos cardiovasculares. La presión arterial sistólica, la diabetes mellitus, el tabaquismo y el tratamiento antihipertensivo fueron factores predictivos fuertemente asociados con el riesgo cardiovascular. En cambio, la contribución del colesterol total sérico fue pequeña, especialmente en los mayores de 70 años. El modelo final de riesgo mostró un buen poder discriminatorio (estadístico C=0,789 en varones y C=0,816 en mujeres).
ERICE es una nueva ecuación de riesgo cardiovascular genuinamente española obtenida a partir del riesgo concurrente individual de los participantes en varias cohortes. La ecuación ERICE ofrece una estimación directa y fiable del riesgo cardiovascular total teniendo en cuenta factores como la diabetes mellitus y el tratamiento farmacológico de los factores de riesgo cardiovascular, habitualmente no incluidos en otras ecuaciones.
Hepatic venous pressure gradient (HVPG), the difference between wedge and free hepatic venous pressure, is the preferred method for estimating portal pressure. However, it has been suggested that ...hepatic atrial pressure gradient (HAPG)—the gradient between wedge hepatic venous pressure and right atrial pressure (RAP)—might better reflect variceal hemodynamics. The aim of this study was to (1) investigate whether HAPG with nonselective beta‐blockers correlates with prognosis in cirrhotic patients with portal hypertension at baseline and during treatment; (2) compare the prognostic value of HAPG with that of HVPG; and (3) investigate the agreement between portoatrial gradient (PAG) and portocaval gradient (PCG) in patients with transjugular intrahepatic portosystemic shunt (TIPS). We included 154 cirrhotic patients with varices with a complete hemodynamic study at baseline and on chronic treatment for primary (n = 71) or secondary (n = 83) prophylaxis for bleeding and 99 patients with TIPS. All patients were followed for up to 2 years; portal hypertensive‐related bleeding and bleeding‐free survival were analyzed. HVPG was equal or lower than HAPG in all patients (−3.2 mm Hg; P < 0.001). Agreement between HAPG and HVPG was modest, especially in patients with increased intra‐abdominal pressure. One hundred two patients were HVPG nonresponders and 52 patients were HVPG responders to nonselective beta‐blockers, whereas 101 patients were HAPG nonresponders and 53 patients were HAPG responders (k = 0.610). HVPG response revealed an excellent predictive value for bleeding risk and bleeding‐free survival; HAPG did not. In our TIPS patients, 20% had a PCG ≤12 mm Hg and a PAG >12 mm Hg, which may have induced unnecessary overdilation of the TIPS. Conclusion: The excellent prognostic information provided by HVPG response to drug therapy is lost if HAPG response is considered. RAP should not be used for the calculation of portal pressure gradient in patients with cirrhosis. Hepatology 2010;51:2108–2116
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