TGF-ß Signaling Prevents MHC Class II-Expressing Lymphatic Endothelial Cells from Reactivating Human Allogenic Memory CD4+ T Cells.

Lymphatic endothelial cells (LECs) express MHC class II (MHC-II) upon IFN-γ stimulation, yet recent evidence suggests that LECs cannot activate naive or memory CD4+ T cells. In this article, we show that IFN-γ-activated human dermal LECs can robustly reactivate allogeneic human memory CD4+ T cells (hCD4+ TMs), but only when TGF-ß signaling is inhibited. We found that in addition to upregulating MHC-II, IFN-γ also induces LECs to upregulate glycoprotein A repetitions predominant, which anchors latent TGF-ß to the membrane and potentially inhibits T cell activation. Indeed, hCD4+ TM proliferation was substantially increased when LEC-CD4+ TM cultures were treated with a TGF-ß receptor type 1 inhibitor or when glycoprotein A repetitions predominant expression was silenced in LECs. Reactivated hCD4+ TMs were characterized by their proliferation, CD25 expression, and cytokine secretion. CD4+ TM reactivation was dependent on LEC expression of MHC-II, confirming direct TCR engagement. Although CD80 and CD86 were not detected on LECs, the costimulatory molecules OX40L and ICOSL were upregulated upon cytokine stimulation; however, blocking these did not affect CD4+ TM reactivation by LECs. Finally, we found that human dermal LECs also supported the maintenance of Foxp3-expressing hCD4+ TMs independently of IFN-γ-induced MHC-II. Together, these results demonstrate a role for LECs in directly modulating CD4+ TM reactivation under inflammatory conditions and point to LEC-expressed TGF-ß as a negative regulator of this activation.

Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents.

Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses.

Variable Inter-assay Estimation of Sperm DNA Fragmentation In Stallions Classified as Good and Bad Semen Freezers.

BACKGROUND: Semen cryopreservation causes DNA damage, thus requiring continuous monitoring. OBJECTIVE: To compare two assays for sperm DNA fragmentation (SDF) from stallions with contrasting semen freezability. MATERIALS AND METHODS: Thirteen stallions were classified as good semen freezers (GSF) or bad semen freezers (BSF). Ejaculates were cryopreserved with three diluents. Semen was subject to SDF evaluation using the sperm chromatin structure assay (SCSA) and Halomax after thawing (0 h) and after a 4 h thermoresistance test. RESULTS: On semen of BSF, analysis by SCSA was similar between evaluations, but Halomax showed increased SDF at 4 h. The GSF group was similar between time points in both assays. Diluents did not affect SDF, irrespective of the assay. Halomax showed differences for BSF between time points, differently from SCSA. Linear regression did not show any correlation between assays. CONCLUSION: The use of Halomax should be encouraged for sperm DNA fragmentation analysis in horse frozen-thawed semen, particularly under field conditions.

Functioning and Disability in Leprosy.

This study has been carried out to investigate the frequency of musculoskeletal symptoms in people affected by leprosy and correlate this to their functional capacity to perform daily living and working activities and to their degree of disability. This cross-sectional study was performed on 100 clients who answered a questionnaire on personal and clinical data, the Nordic Musculoskeletal (QNSO), and the shoulder, arm and hand dysfunction (DASH) questionnaires. The mean age was 53.63 years and there was a predominance of men (67%), low education (53%), and multibacillary disease (84%). Physical impairment affected 95% of respondents and 92% indicated pain and/or paresthesia in the arms that interfered in functional capacity.Respondents with musculoskeletal symptoms have more difficulty to perform daily living and working activities compared to those without musculoskeletal symptoms (p-value<0.05). The presence of physical disabilities was not associated with difficulties to perform daily living (p-value=0.29) and labor activities (p-value=0.87). The majority of patients experienced pain and/or paresthesia of the arms, and this was associated with difficulties to perform daily living and working activities. However, the presence of physical disability does not seem to cause major impediments or limitations to perform these activities.

Functioning and disability in leprosy

This study has been carried out to investigate the frequency of musculoskeletal symptoms in people affected by leprosy and correlate this to their functional capacity to perform daily living and working activities and to their degree of disability. This cross-sectional study was performed on 100 clients who answered a questionnaire on personal and clinical data, the Nordic Musculoskeletal (QNSO), and the shoulder, arm and hand dysfunction (DASH) questionnaires. The mean age was 53.63 years and there was a predominance of men (67%), low education (53%), and multibacillary disease (84%). Physical impairment affected 95% of respondents and 92% indicated pain and/or paresthesia in the arms that interfered in functional capacity.Respondents with musculoskeletal symptoms have more difficulty to perform daily living and working activities compared to those without musculoskeletal symptoms (p-value<0.05). The presence of physical disabilities was not associated with difficulties to perform daily living (p-value=0.29) and labor activities (p-value=0.87). The majority of patients experienced pain and/or paresthesia of the arms, and this was associated with difficulties to perform daily living and working activities. However, the presence of physical disability does not seem to cause major impediments or limitations to perform these activities.

Uncertainty relations and topological-band insulator transitions in 2D gapped Dirac materials.

Uncertainty relations are studied for a characterization of topological-band insulator transitions in 2D gapped Dirac materials isostructural with graphene. We show that the relative or Kullback-Leibler entropy in position and momentum spaces, and the standard variance-based uncertainty relation give sharp signatures of topological phase transitions in these systems.

Interlayer coherence and entanglement in bilayer quantum Hall states at filling factor ν=2/λ.

We study coherence and entanglement properties of the state space of a composite bi-fermion (two electrons pierced by λ magnetic flux lines) at one Landau site of a bilayer quantum Hall system. In particular, interlayer imbalance and entanglement (and its fluctuations) are analyzed for a set of U(4) coherent (quasiclassical) states generalizing the standard pseudospin U(2) coherent states for the spin-frozen case. The interplay between spin and pseudospin degrees of freedom opens new possibilities with regard to the spin-frozen case. Actually, spin degrees of freedom make interlayer entanglement more effective and robust under perturbations than in the spin-frozen situation, mainly for a large number of flux quanta λ. Interlayer entanglement of an equilibrium thermal state and its dependence with temperature and bias voltage is also studied for a pseudo-Zeeman interaction.

A Density Functional Theory View of Quantum Phase Transitions.

It is shown that there is a one-to-one map between the ground state wave function and the control parameter. Wu et al. [Phys. Rev. A2006, 74, 052335] introduced an analogue of the Density Functional Theory (DFT) density and showed that the "density" determines the "control parameter" (corresponding to the DFT "external potential"). We prove that any strictly monotonous function can be used to obtain a new density with a different control parameter (or DFT "external potential"), and the new density determines the new control parameter. Moreover, there is also a one-to-one map between the Rényi entropy of a given order and the control parameter. Therefore, the Rényi entropy can be used as a control parameter.

Are somatosensory evoked potentials of the tibial nerve the most sensitive test in diagnosing multiple sclerosis?

BACKGROUND: Multiple sclerosis (MS) is mostly diagnosed clinically, but the diagnosis has significantly improved through the use of brain magnetic resonance imaging (MRI), testing of cerebrospinal fluid, and multimodal evoked potentials (MEPs). Even though MRI is the superior method in diagnosing this illness, MEPs remain important because they can detect clinically silent lesions in the sensory and motor pathways of the central nervous system (CNS). AIM: The aim of the study is to test the diagnostic sensitivity of MEPs and MRI and the ratio of their sensitivity in patients with MS. MATERIALS AND METHODS: The study subjects included 293 patients with MS with disease duration of two to six years: 249 patients with relapsing-remitting (RR) MS and 44 with primary-progressive (PP) MS. All patients were subjected to an MRI brain scan, visual evoked potentials (VEPs), median somatosensory evoked potentials (SEPs), tibial somatosensory evoked potentials (SEPs), and auditory evoked potentials (AEPs). Abnormal Findings Included : changed wave morphology, interside difference in wave amplitude, absolute and interwave latency increased by 2.5 SD as compared with the control group. The control group comprised of 35 healthy subjects. Results : In this study the most abnormal findings were tibial SEPs, median SEPs, and VEPs. Our results suggest different sensitivity of MEPs in patients suffering from different forms of MS. In RR-MS the sensitivity of tibial SEPs was statically significant (Fischer's exact probability test) as compared to other evoked potential modalities. Similarly VEPs were more sensitive as compared to AEPs. In the PP-MS, median SEPs have been found to be more sensitive than VEPs, while tibial SEPs have been found to be more sensitive than AEPs. There was no significant difference in the sensitivity of MRI and MEPs both the forms of MS. CONCLUSION: Tibial SEPs produce the most abnormal results and the highest sensitivity in the RR-MS. We propose that this test as useful criterion for the diagnosis of MS.

Obesity enhances eosinophilic inflammation in a murine model of allergic asthma.

BACKGROUND AND PURPOSE: Obesity is associated with deterioration in asthma outcomes. Although airways eosinophil accumulation is characteristic of lung allergic diseases, little is known about the influence of obesity on the allergic eosinophil trafficking from bone marrow to lung tissues, and recruitment to airways lumen. Here, we have assessed the effects of diet-induced obesity on allergic eosinophilic inflammation in mice, examining eosinophil trafficking from bone marrow to airways, and production of T(H)1/T(H)2 cytokines. EXPERIMENTAL APPROACH: C57BL/6 mice fed for 10 weeks with standard chow or high-fat diet were sensitized and challenged with ovalbumin. At 24-96 h post-ovalbumin challenge, bronchoalveolar lavage (BAL) fluid, lung tissue and bone marrow were examined. KEY RESULTS: The high-fat-fed mice exhibited increased body weight and epididymal fat, glucose intolerance and alterations in lipid profile compared with the lean mice. Obesity markedly elevated serum leptin and lowered adiponectin levels. Ovalbumin challenge in obese mice promoted a markedly higher eosinophil accumulation in bone marrow and connective tissue surrounding the bronchial and bronchiolar segments. Eosinophil number in BAL fluid of obese mice was lower at 24 and 48 h. Levels of interleukin (IL)-5, eotaxin, tumour necrosis factor-alpha and IL-10 in BAL fluid of obese mice were significantly higher than in lean mice. CONCLUSIONS AND IMPLICATIONS: Diet-induced obesity enhanced eosinophil trafficking from bone marrow to lung tissues, and delayed their transit through the airway epithelium into the airway lumen. Consequently, eosinophils remain longer in lung peribronchiolar segments due to overproduction of T(H)1/T(H)2 cytokines and chemokines.

Analysis of the inflammatory response in the rat paw caused by the venom of Apis melifera bee.

OBJECTIVE: This study examines the pro-inflammatory action caused by subcutaneous (s.c.) injection of the bee venom (BV) Apis melifera in the rat paw. METHODS: Male Wistar rats were used. The venom of Apis melifera was injected s.c. into the rat paw and the oedema formation and the activity of myeleperoxidase (MPO) were measured. RESULTS: Subcutaneous injection of BV caused dose-and time-dependent paw oedema (ED50 of 1.5 microg/paw) with peak at 30 min. The MPO activity increased about 1.6, 4.2 and 8.9 folds at 0.5, 4 and 6 h after s.c. injection of BV. The mast cell degranulating drug 48/80, pyrilamine or metysergide, inhibited BV-mediated oedema formation (88, 62 and 96%, respectively). Likewise, L-NAME, the NK1 antagonist FK 888, the B1 des-Arg9-[Leu8]-BK or B2 kinin antagonist Hoe 140 also antagonised the paw oedema induced by BV (60, 59, 49, and 49%, respectively). SR48968 and SR14280, respectively NK2 and NK3 antagonists and also indomethacin, inhibited by 31, 29 and 22%, respectively BV-induced oedema formation. In contrast, the PAF antagonist WEB 2086 or valeryl salycilate, did not affect the BV-induced paw oedema. The levels of MPO were inhibited by compound 48/80, cyproheptadine, Hoe 140, or by des-Arg9[Leu8]-BK (85, 61, 59, and 53%, respectively) measured 6 h after. CONCLUSION: These results indicate that the BV from Apis melifera causes a marked dose-and time-dependent oedema formation in the rat paw, an effect that is accompanied by intense leukocyte migration. The pro-inflammatory response induced by BV is mediated by several mechanisms, namely the release of histamine and/or serotonin from mast cells, activation of H1 histamine receptor, production of nitric oxide, the involvement of kinins through the activation of B1 and B2 receptors, and also tachykinins acting at NK1 receptor or and to a lesser extent at NK2 and NK3 receptors.

Chagas' disease: carcinogenic activity of the antitrypanosomal nitroarenes in mice.

The carcinogenic activity of antitrypanosomal 2-nitroimidazole, 5-nitroimidazole and 5-nitrofuran derivatives was assessed in female Swiss mice of the same age group. A statistically significantly higher incidence of growths was seen in mice into which 2-nitro had been injected than in mice receiving 5-nitro derivatives intraperitoneally. A histologic type of lymphoblastic lymphoma that invades lymph nodes, spleen, liver, lungs and lymphatic tissue elsewhere was frequently found in nitroarene-treated mice. Further, it is shown that the potency of the drug, rather than the duration of its administration, was usually associated with the growth of lymphomas. The 2-nitro derivative which induced the highest incidence of lymphomas significantly decreased the survival of treated mice; this probably occurred because it undergoes enzymatic reduction of the nitro group more efficiently than the 5-nitro compounds used. The differences of incidence of lymphomas in mice receiving any of these nitroarenes and in control mice that received daily injections of 0.15 M saline were statistically significant (alpha = 0.05). The indiscriminate use of these nitroarenes to treat Trypanosoma cruzi infections in man could therefore induce a significant number of lymphomas.

La desrotación dentaria / Dental disrotation

Se efectuó una investigación en 41 dientes correspondientes a distintos grupos dentarios (incisivos, caninos y bicúspides), que presentaron rotación y se clasificaron de acuerdo con su grado de rotación en 2 grupos; EL DE -45o y más. Al realizar la desrotación de los dientes , se obtuvo el tiempo que éstos terdaron en ocupar su posición normal en las arcadas

La desrotación dentaria / Dental disrotation

Se efectuó una investigación en 41 dientes correspondientes a distintos grupos dentarios (incisivos, caninos y bicúspides), que presentaron rotación y se clasificaron de acuerdo con su grado de rotación en 2 grupos; EL DE -45o y más. Al realizar la desrotación de los dientes , se obtuvo el tiempo que éstos terdaron en ocupar su posición normal en las arcadas

[Hypereosinophilic syndrome. Clinical case]. / Síndrome hipereosinofilico. Caso clínico.

We report the case of a 16 years old girl with hypereosinophilic syndrome, presenting with fever, abdominal pain, skin lesions and peripheral neuropathy, which responded successfully to treatment with prednisone.