Microarray reveals differences in both tumors and vascular specific gene expression in de novo CD5+ and CD5- diffuse large B-cell lymphomas

Malignant lymphoma is a heterogeneous disease with different clinical features. Among diffuse large B-cell lymphomas (DLBCLs), a unique subtype has been identified recently based on cell surface marker CD5 and clinicopathological features. These de novo CD5(+) DLBCLs account for approximately 10% of all of the DLBCLs and have poorer prognosis. To additionally understand this subtype of DLBCLs at the molecular level and to find genes that are differentially expressed in de novo CD5(+) DLBCLs, CD5(-) DLBCLs, and mantle cell lymphomas, which also have poor prognosis, we performed gene expression profiling using cDNA microarray technology. Data from a total of 9 samples of CD5(-) DLBCLs, 11 samples of de novo CD5(+) DLBCLs, and 10 samples of mantle cell lymphomas were acquired. A series of genes were identified that distinguish these three types of lymphomas. Among DLBCL cases, integrin beta1 and/or CD36 adhesion molecules were overexpressed in most cases of CD5(+) DLBCL. An immunohistochemical confirmation study revealed that integrin beta1 was expressed on lymphoma cells, which may account for the high extranodal involvement and poor prognosis of CD5(+) DLBCLs. In contrast, CD36 was overexpressed on vascular endothelia in CD5(+) DLBCLs, although there was no difference in vascularity detected by von Wilbrand factor antibody between CD5(+) and CD5(-) DLBCLs. Those results suggest that CD5(+) and CD5(-) DLBCLs have different gene expression signatures in both tumor cells and their vascular systems.     

Metastatic choriocarcinoma in a middle-aged man presenting as a right thigh mass with venous thrombosis: a case report

Choriocarcinoma is a highly aggressive beta-subunit of human chorionic gonadotropin (betaHCG)-producing germ cell tumor. In men, it is a rare neoplasm and can arise in the testes or in various extragonadal locations such as the retroperitoneum, mediastinum, and pineal body. We present a highly unusual case of a middle-aged man with primary metastatic betaHCG-producing choriocarcinoma of the right thigh along with right lower-extremity venous thrombosis. We comment on prognostic variables as well as discuss several theories to account for the unusual location of his choriocarcinoma.     

Production of the novel mesangial autocrine growth factors GDNF and IL-10 is regulated by the immunomodulator AS101

Mesangial cell (MC) proliferation is essential for the pathogenesis and progression of various glomerular diseases. This study shows that glial cell line-derived neurotrophic factor (GDNF) and IL-10 are mesangial autocrine growth factors that play a pivotal role in rat MC proliferation in vitro. Downstream targets of GDNF signaling and their role in MC hyperplasia are identified. The phosphatidylinositol 3-kinase (PI3K) pathway and its downstream target NF-kappaB were found to mediate GDNF-induced MC mitogenesis. This pathway also mediates GDNF-induced decrease in the cyclin-dependent kinase inhibitor p27(kip1) expression, resulting in the increased formation of cyclin D1/cdk4 and cyclin E/cdk2 complexes, followed by hyperphosphorylation of retinoblastoma, a key event for G1 to S phase progression. IL-10 appears to be a more potent MC growth factor that negatively regulates GDNF expression. Indeed, its inhibition by the nontoxic tellurium anti-IL-10 compound, ammonium trichloro(dioxoethylene-o,o') tellurate (AS101), extensively decreased MC clonogenicity despite GDNF upregulation. Identification of the mesangial GDNF and IL-10 pathways as critical mediators of mesangial cell proliferation may provide another target for therapeutic intervention in certain glomerular diseases. In vivo animal studies using AS101, currently undergoing phase II clinical trials on cancer patients, are warranted to determine its potential in the management of glomerular diseases associated with mesangial cell proliferation.     

Visualization of Connexin 43-positive cells of glioma and the periglioma zone by means of intravenously injected monoclonal antibodies

The selectivity of monoclonal antibodies against the E2 extracellular fragment of connexin 43 (Cx43) for a glioma focus was studied in in vivo experiments on animals with intracranial C6 glioma. Antibodies labeled with two alternative labels, the radioisotope (125)I and the fluorophore Alexa 660, were intravenously injected to rats with 18-day gliomas. Seventy-two hours after injection, (125)I-labeled antibodies accumulated in the hemisphere where the glioma was located to a concentration of 0.27?±?0.01% of the injected dose per gram of wet weight, which exceeded their accumulation in the liver, spleen, and other organs. Fluorescent-labeled antibodies against the Cx43 fragment E2 specifically visualized cells in the peritumoral astroglial bank (a zone of active invasion of glioma cells). Double immunofluorescent visualization using antibodies against the Cx43 fragment E2 and glial fibrillar acidic protein (GFAP) showed that only a small proportion of the cells that bound the antibodies injected into the blood circulation were reactive astrocytes, whereas most of these cells were GFAP-negative and morphologically corresponded to astroblasts. These results suggest that antibodies against the extracellular Cx43 fragment E2 can be used for targeted transport of diagnostic and therapeutic drugs to the peritumoral invasion zone of high-grade gliomas.     

TREC/KREC Levels and T and B Lymphocyte Subpopulations in COVID-19 Patients at Different Stages of the Disease

Background: T and B cell-mediated immunity can be assessed using T cell receptor excision circle (TREC) and Kappa-deleting recombination excision circle (KREC) analysis, respectively, and successful implementation of this method requires evaluation of the correlation between the TREC frequencies and T cell subsets as well as KREC levels and B lymphocyte subsets. The aim of the present study was to evaluate the correlation between the TREC/KREC concentrations and T/B lymphocyte subsets at different stages of COVID-19. Methods: We examined 33 patients in the acute stage of COVID-19 (including 8 patients with poor outcomes) and 33 COVID-19 survivors. TREC/KREC concentrations were measured using quantitative real-time PCR. T/B lymphocyte subsets were determined using flow cytometry. Results: Blood TREC and KREC levels were found to be significantly lower in the acute stage of COVID-19 compared to control values. Moreover, a zero blood TREC level was a predictor of a poor disease outcome. Reductions in CD3⁺CD4⁺CD45RO⁻CD62L⁻ and CD3⁺CD8⁺CD45RO⁻CD62L⁻ T cell counts (as well as in the main fractions of B1 and B2 B cells) indicated a favorable outcome in COVID-19 patients in the acute stage of the disease. Decreased CD3⁺CD4⁺CD45RO⁻CD62L⁺ and CD3⁺CD8⁺CD45RO⁻CD62L⁺ T cell frequencies and increased CD3⁺CD8⁺CD45RO⁻CD62L⁻ cell counts were found to indicate a poor outcome in patients with acute COVID-19. These patients were also found to have increased B1 cell counts while demonstrating no changes in B2 cell counts. The levels of effector T cell subsets an naïve B cells were normal in COVID-19 survivors. The most pronounced correlations between TREC/KREC levels and T/B cell subsets counts were observed in COVID-19 survivors: there were positive correlations with naïve T and B lymphocytes and negative correlations with central and effector memory T cell subsets. Conclusions: The assessment of correlations between TREC and T cell subsets as well as KREC levels and B cell subset counts in patients with acute COVID-19 and COVID-19 survivors has shown that blood concentrations of TREC and KREC are sensitive indicators of the stage of antigen-independent differentiation of adaptive immunity cells. The results of the TREC and KREC analysis correlated with the stages of COVID-19 and differed depending on the outcome of COVID-19.     

Acetazolamide: A New Treatment for Visual Vertigo

Visual vertigo is a disorder characterised by symptoms of dizziness, vertigo, unsteadiness, disorientation, and general discomfort induced by visual triggers. It is currently treated with vestibular rehabilitation therapy, with no effective pharmacotherapy available for treatment-resistant cases. The objective of this study was to evaluate the efficacy of oral acetazolamide in improving symptoms of visual vertigo. A comparative case series of adult patients clinically diagnosed with visual vertigo was conducted from January 1992 to May 2015. Patients without a full neurologic or otorhinolaryngologic work-up, negative magnetic resonance imaging (MRI), and an organic cause for their symptoms were excluded. The identified patients were then contacted by phone to complete a voluntary symptom survey. Main outcome was the subjective reported percentage in symptom improvement. Secondary outcomes were subjective improvement by symptom triggers. The participants were retrospectively divided into three groups based on their treatment with acetazolamide: currently on acetazolamide, terminated acetazolamide, or never initiated acetazolamide. Fifty-seven patients met the inclusion criteria and were willing to complete the phone survey (19 currently on acetazolamide, 27 terminated acetazolamide, and 11 never initiated therapy). Overall symptomatic improvement was reported by 18 (94.7%) patients currently on acetazolamide, 18 (66.7 %) who terminated acetazolamide, and 5 (45.5%) who never initiated therapy, varying significantly by group (p = 0.0061). Greatest improvement was reported in symptoms triggered by being a passenger in a car. These results show that acetazolamide has a positive association with improvement of symptoms of visual vertigo.     

Migraine is comorbid with multiple sclerosis and associated with a more symptomatic MS course

The objectives of this study were: (1) to assess relative frequency of migraine in multiple sclerosis (MS) patients using the validated self-administered diagnostic questionnaire, and to compare the migraine rates in MS outpatients to age- and gender-matched historical population controls; (2) to compare clinical and radiographic characteristics in MS patients with migraine and headache-free MS patients. We conducted a cross-sectional study to assess the demographic profiles, headache features and clinical characteristics of MS patients attending a MS clinic using a questionnaire based on the American Migraine Prevalence and Prevention (AMPP) study. We compared the relative frequency of migraine in MS clinic patients and AMPP cohort. We also compared clinical and radiographic features in MS patients with migraine to an MS control group without headache. Among 204 MS patients, the relative frequency of migraine was threefold higher than in population controls both for women [55.7 vs. 17.1%; prevalence ratio (PR) = 3.26, p < 0.001] and men (18.4 vs. 5.6%; PR = 3.29, p < 0.001). In a series of logistic regression models that controlled for age, gender, disease duration, β-interferon use, and depression, migraine in MS patients was significantly associated (p < 0.01) with trigeminal and occipital neuralgia, facial pain, Lhermitte’s sign, temporomandibular joint pain, non-headache pain and a past history of depression. Migraine status was not significantly associated with disability on patient-derived disability steps scale or T2 lesion burden on brain MRI. Migraine is three-times more common in MS clinic patients than in general population. MS–migraine group was more symptomatic than the MS–no headache group.     

Toxicological evaluation of a chicory root extract.

An Ames test and a 28-day sub-chronic toxicity study in male and female Sprague-Dawley rats were conducted to evaluate the safety of a chicory root extract being investigated as a therapeutic for inflammation. Chicory extract had no mutagenic activity in the Ames test although it was cytotoxic to certain strains of Salmonella at higher doses with and without metabolic activation. For the 28-day rat study, measurements included clinical observations, body weights, food consumption, clinical pathology, gross necropsy and histology. There were no treatment-related toxic effects from chicory extract administered orally at 70, 350, or 1000 mg/kg/day. Since there were no observed adverse effects of chicory extract in these studies, the NOAEL for the extract is 1000 mg/kg/g administered orally for 28 days.