Rapid leukocyte integrin activation by chemokines

Summary: Chemokines control selective targeting of circulating leukocytes to the microvasculature by triggering inside-out signal transduction pathways leading to integrin-dependent adhesion. Integrin activation by chemokines is very rapid, is downmodulated within minutes and appears to involve both enhanced heterodimer lateral mobility on the plasma membrane, facilitating encounters with dispersed ligand, as well as induction of a high-affinity state. These two modalities of integrin activation by chemokines involve distinct signaling pathways in the cell, yet complement each other functionally, allowing binding of rolling cells under conditions of low as well as high ligand density. Recent data show that chemokines generate both pro- and anti-adhesive intracellular signaling events, whose equilibrium is likely to be relevant to the kinetics of adhesion and de-adhesion, and to cell movement during diapedesis and chemotaxis. Importantly, chemokines utilize different signaling mechanisms to modulate the activity of distinct integrin subtypes. These recent advances suggest that chemokines may regulate adhesive responses of immune cells based not only on patterns of chemokine receptor expression, but also on variable signaling pathways that can modulate the pro-adhesive responses of leukocytes as a function of their differentiated state, and of the local microenvironment.     

Stereologic characterization and spatial distribution patterns of Betz cells in the human primary motor cortex

Betz cells are giant motoneurons located in layer Vb of the primate primary motor cortex. We conducted stereological analyses of Betz cells and neighboring pyramidal cells from the brains of six neurologically normal elderly humans to determine their volume, total number, and spatial distribution, and to relate these data to functional localization. The distribution of cellular volumes exhibits a bimodal pattern, delineating two different subpopulations. Betz cell volumes follow a mediolateral gradient, the largest Betz cells being located on the most medial part of the motor cortex. Additionally, the shape of Betz cells varies between the rostral and caudal parts of the primary motor cortex, supporting the notion that there are anatomically distinct zones in primary motor cortex. The total number of Betz cells per hemisphere accounts for about one-tenth of the total number of pyramidal cells in layer Vb. Analysis of spatial distribution using Voronoi tessellation revealed maximal clustering of Betz cells in a zone situated two-thirds from the midline along the mediolateral axis of the primary motor cortex. These data suggest that Betz cells have a discrete subregional distribution that may correspond to certain aspects of the functional parcellation of area 4. These results may offer a histological correlate of functional imaging studies and are relevant in the context of neurodegenerative diseases such as amyotrophic lateral sclerosis, progressive supranuclear palsy, and Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia, and in studies of normal brain aging.     

Axillary lymph node cellular immune response to HER-2/neu peptides in patients with carcinoma of the breast.

HER-2/neu peptides have recently been shown to induce a proliferative response by peripheral CD4(+) T cells in breast cancer patients. To investigate potential differences in the local cellular immune response between breast cancer patients with and without nodal metastases, lymphocytes were isolated from axillary lymph nodes from patients with breast cancer, and proliferative and cytokine responses to HER-2/neu peptides were determined. Freshly isolated lymphocytes from lymph nodes of 7 women undergoing surgery for invasive breast cancer were plated at 20 x 10(5) cells per well in triplicate. Cells were stimulated with HER-2/neu peptides at 50 microg/ml and with control antigens. Incorporation of tritium-labeled thymidine was determined 4 days later. The levels of the cytokines interferon-gamma (IFN-gamma), interleukin-4 (IL-4), and IL-10 were determined at priming and at restimulation with HER-2/neu peptides using a cytokine-specific, double-sandwich, enzyme-linked immunosorbent assay (ELISA). Lymphocytes isolated from the axillary lymph nodes of the patients mounted significant cellular immune response to HER-2/neu peptides, manifested by proliferation and specific cytokine elaboration. Proliferative responses to HER-2/neu peptides were seen in lymphocytes of patients with and without overexpression of HER-2/neu in the primary tumor. In some patients, the proliferative response to HER-2/neu peptides in lymphocytes from lymph nodes with metastases was absent or blunted compared with the response in lymphocytes from lymph nodes without metastases from the same patient (p < 0.05). HER-2/neu peptides induced a predominantly T helper type 1 (Th1) pattern of cytokine response in nodal lymphocytes isolated from breast cancer patients. A Th1-specific cytokine production pattern was maintained at priming and restimulation with HER-2/neu peptides and was amplified with IL-12 costimulation. These results indicate that HER-2/neu peptides can activate T cells in draining lymph nodes from women with invasive breast cancer. This activation is associated with a predominantly Th1 cytokine response, which suggests that conditioning with HER-2/neu peptides may be of value in the development of breast cancer vaccines.     

Prediction of AVM obliteration after stereotactic radiotherapy using radiobiological modelling

This study was carried out in order to derive the radiobiological parameters of the dose-response relation for the obliteration of arteriovenous malformation (AVM) following single fraction stereotactic radiotherapy. Furthermore, the accuracy by which the linear Poisson model predicts the probability of obliteration and how the haemorrhage history, location and volume of the AVM influence its radiosensitivity are investigated. The study patient material consists of 85 patients who received radiation for AVM therapy. Radiation-induced AVM obliterations were assessed on the basis of post-irradiation angiographies and other radiological findings. For each patient the dose delivered to the clinical target volume and the clinical treatment outcome were available. These data were used in a maximum likelihood analysis to calculate the best estimates of the parameters of the linear Poisson model. The uncertainties of these parameters were also calculated and their individual influence on the dose-response curve was studied. AVM radiosensitivity was assumed to be the same for all the patients. The radiobiological model used was proved suitable for predicting the treatment outcome pattern of the studied patient material. The radiobiological parameters of the model were calculated for different AVM locations, bleeding histories and AVM sizes. The range of parameter variability had considerable effect on the dose-response curve of AVM. The correlation between the dosimetric data and their corresponding clinical effect could be accurately modelled using the linear Poisson model. The derived response parameters can be introduced into the clinical routine with the calculated accuracy assuming the same methodology in target definition and delineation. The known volume dependence of AVM radiosensitivity was confirmed. Moreover, a trend relating AVM location with its radiosensitivity was observed.     

Histologic and immunohistochemical findings in the differential diagnosis of chronic lymphocytic leukemia of B-Cell type and lymphoplasmacytic/lymphoplasmacytoid lymphoma

Summary 114 cases of malignant lymphoma consisting chiefly of lymphocytes were classified by histology as chronic lymphocytic leukemia of the B-cell type (B-CLL) or lymphoplasmacytic/lymphoplasmacytoid lymphoma (LP immunocytoma) and investigated with the immunoperoxidase-bridge (PAP) method for the presence of heavy and light immunoglobulin chains. Fifteen cases were excluded because they showed a completely negative reaction, which might have been an artifact. Of the remaining 99 cases, 46 revealed polyclonal immunoglobulin-positive plasma cells only and could be clearly classified as B-CLL. In 33 cases there were a moderate or large number of plasma cells or plasmacytoid cells with monoclonal intracytoplasmic positivity. Two heavy chain classes were demonstrated in three other cases, and both light chain types were detected in one case. These 37 cases were finally classified as LP immunocytoma. Ten cases contained only a few monoclonal plasmacytoid cells and were interpreted as borderline cases between B-CLL and LP immunocytoma. Six cases have not yet been clarified — there was an inexplicable discrepancy between their histology and immunostaining.In LP immunocytoma, the heavy chain class demonstrated most often was the chain (27 cases). Light chains of the type were about 2.5 times as common as chains.The differential diagnostic criteria for distinguishing B-CLL from LP immunocytoma are discussed and compared. PAS-positive tumor cells are an almost definite criterion of LP immunocytoma. At present, a critical evaluation of the results of PAP immunostaining is the most reliable way to clearly distinguish B-CLL from LP immunocytoma.Supported by the Kind-Philipp-Stiftung     

Tumor control and trigeminal dysfunction improvement after stereotactic radiosurgery for trigeminal schwannomas: a systematic review and meta-analysis

Neurosurgical Review - Trigeminal nerve schwannomas (TS) are uncommon intracranial tumors, frequently presenting with debilitating trigeminal and/or oculomotor nerve dysfunction. While surgical...     

Clinical features and outcome of maintenance hemodialysis patients with COVID-19 from a tertiary nephrology care center in Romania

Background There is limited information about the clinical characteristics, treatment and outcome of maintenance hemodialysis patients with COVID-19. Moreover, regional differences are also conceivable since the extend and severity of outbreaks varied among countries.Methods In this retrospective, observational, single-center study, we analyzed the clinical course and outcomes of 37 maintenance hemodialysis patients (median age 64 years, 51% men) hospitalized with COVID-19 from 24 March to 22 May 2020 as confirmed by real-time PCR.Results The most common symptoms at admission were fatigue (51%), fever (43%), dyspnea (38%) and cough (35%). There were 59% mild/moderate patients and 41% severe/critical patients. Patients in the severe/critical group had a significantly higher atherosclerotic burden since diabetic kidney disease and vascular nephropathies were the most common primary kidney diseases and eighty percent of them had coronary heart disease. Also, Charlson comorbidity score was higher in this group. At admission chest X-ray, 46% had ground-glass abnormalities. Overall, 60% patients received hydroxychloroquine, 22% lopinavir–ritonavir, 11% tocilizumab, 24% systemic glucocorticoids, and 54% received prophylactic anticoagulation. Seven (19%) patients died during hospitalization and 30 were discharged. The main causes of death were cardiovascular (5 patients) and respiratory distress syndrome (2 patients). In Cox regression analysis, lower oxygen saturation, anemia and hypoalbuminemia at admission were associated with increased mortality.Conclusions In conclusion, we observed a high mortality rate among maintenance hemodialysis patients hospitalized for COVID-19. Anemia, lower serum albumin and lower basal oxygen saturation at admission were factors associated with poor prognosis.     

Early bone growth in chickens genetically selected for a high and low growth rate

Male chickens from lines divergently selected for fast (FGL) and slow (SGL) growth were compared for the growth of cortical bone. Morphology, histomorphometric, compositional and biomechanical properties of the tibiotarsi were analysed in both lines at 1, 8, 15 and 22 d of age. Tibial morphology (length, volume, cross-section and diameters) was similar in FGL and SGL chickens when compared at an equal body weight. Cortical area was also similar in both lines at an equal body weight but cortex porosity was higher in FGL. Tibial mineral density (ash:volume) was higher in FGL than in SGL at hatching and at 8 d of age. Biomechanical properties were lower in SGL than in FGL at 8 d of age, but then became higher in this line when compared at equal body weight. The very slow growth rate in SGL did not modify bone size when chickens were compared at equal body weight. Bone quality was modified in various ways: in SGL bone structure was strengthened by a lower porosity of the cortex while bone tissue was less mineralized up to 22 d of age. In both lines, cortical growth was slower than in commercial cross-breeds and bone quality (structure and composition) was improved compared to broilers.     

Synovial activation of chondrocytes: Evidence for complex cytokine interactions

Synoviocytes secrete factors which induce the synthesis of neutral metalloproteinases (NMP) and prostaglandin E₂ (PGE₂) by chondrocytes in a response called chondrocyte activation. We analyzed synovial chondrocyte activating factors (CAF) for the presence of cytokines which modulated the NMP production by articular chondrocytes. These studies suggested the presence of several other cytokines in addition to interleukin-1 (IL-1). Both resting and activated synoviocytes contained mRNA for basic fibroblast growth factor (bFGF) which is a synergist for IL-1 induced NMP production, and secreted bFGF into their culture media. They also expressed mRNA for transforming growth factor (TGF) which inhibits IL-1 induced NMP production. These cells also produce tumor necrosis factor (TNF) and trace amounts of interleukin-6 (IL-6). In addition to these there is evidence for a synovial activator of chondrocytes which is distinct from IL-1. Since a number of recombinant cytokines including TNF, IL-6 and bFGF failed to activate chondrocytes, this could be a novel cytokine.