Vascular Endothelial Growth Factor/Vascular Permeability Factor Is Temporally and Spatially Correlated with Ocular Angiogenesis in a Primate Model

Ischemia often precedes neovascularization. Inocular neovascularization, such as occurs in diabetic retinopathy, a diffusible angiogenic factor has been postulated to be produced by ischemicretina and to lead to neovascularization of theretina, optic nerve, or iris. However, no angiogenic factor has been conclusively identified that satisfies this hypothesis. Vascular endothelial growth factor/vascular permeability factor, hereafter referred to as VEGF, is a likely candidate for an ocular angiogenic factor because it is a secreted mitogen, specific for endothelial cells, and is upregulated by hypoxia. We investigated the association of VEGF with the development of experimental iris neovascularization in the cynomolgus monkey. Following theproduction of retinal ischemia by laser occlusion of all branch retinal veins, VEGF was increased in the aqueous fluid, and the aqueous VEGF levels changed synchronously and proportionally with the severity of iris neovascularization. Northern analysis and in situ hybridization revealed that VEGF messenger RNA is upregulated in the ischemic retina. These observations support the hypothesis that ocular neovascularization is regulated by a diffusible factor and identify VEGF as a likely candidate for a retina-derived vascular permeability and angiogenesis factor in vivo.     

Nineteen-year single-center experience in 76 patients with penile cancer treated with high-dose-rate brachytherapy

PURPOSETo report the outcomes for 76 patients with penile cancer treated with high-dose-rate brachytherapy (HDR-BT) at a single institution.METHODSSeventy-six patients with penile cancer treated with HDR-BT in our department between October 1998 and September 2018 were analyzed. Seventy underwent interstitial HDR-BT (fractionation dose range of 3–3.5 Gy given twice a day with an interval of at least six hours between the fractions), and six underwent superficial treatment with mold applicators (fractionation dose range of 4–7 Gy given once or twice a week).RESULTSMedian follow-up was 76 months (7–204 months). In the whole group, 22/76 local failures (28.9%) were observed: 14/76 (18.4%) local recurrences and 8/76 (10.5%) cases of persistent disease. Median time to recurrence was 24 months (9–54 months). Inguinal lymph node metastases were observed in 18/76 cases (23.7%). Distant metastases occurred in 12/76 (15.8%) cases. Patients with local recurrence and persistent disease underwent salvage penectomies, except four who refused surgery and underwent a second course of interstitial HDR-BT. Five- and 10-year cause-specific survival were 85.0% and 77.8%, respectively. Local control at 5 and 10 years was 65.6%. Five- and 10-year penile preservation were 69.5% and 66.9%, respectively. There was no G3 or G4 acute toxicity. One urethral stenosis (1.3%) occurred in a patient with a T3 tumor and was treated successfully with dilatation.CONCLUSIONSHDR-BT provides good local control of penile cancer and is a good option for penis preservation therapy and in our experience achieves a penile preservation rate at 10 years of 66.9%.     

The role of therapeutic use of interleukin-2 in HIV infection

Interleukin-2 (IL-2) is a cytokine produced by lymphocytes T CD4+, T CD8+ and NK cells. IL-2 increases the number of lymphocytes T and prolongs their survival and has extensive immunomodulatory effect. High levels of IL-2 are observed during asymptomatic phase of HIV infection (TH-1 dependent cytokine) and low levels are observed during progression of immunodeficiency. IL-2 inhibits apoptosis of CD4+ T cells, improves NK cells activity, has influence on production of soluble antiviral factor (CAF) which inhibits viral activity etc. That is why IL-2 has been introduced to the treatment of HIV infection along with highly active antiretroviral therapy (HAART). High T CD4+ cells count predicts long survival of HIV infected individual. Phase III clinical trials concerning IL-2 are now performed and the preliminary results are promising. Polish centers also take part in the ESPRIT study. Adverse events of various severity are seen in patients under treatment (anti inflammatory drugs are required). The symptoms usually resolve within a few days after IL-2 therapy is stopped.     

A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes

Despite advances in understanding autoimmune diabetes in animal models, there has been little progress in altering the natural course of the human disease, which involves progression to insulin deficiency. Studies with immunosuppressive agents have shown short-term effectiveness, but they have not induced tolerance, and continuous treatment is needed. We studied the effects of hOKT3gamma1(Ala-Ala), a humanized Fc mutated anti-CD3 monoclonal antibody, on the progression of type 1 diabetes in patients with recent-onset disease in a randomized controlled trial. In general, the drug was well tolerated. A single course of treatment, within the first 6 weeks after diagnosis, preserved C-peptide responses to a mixed meal for 1 year after diagnosis (97 +/- 9.6% of response at study entry in drug-treated patients vs. 53 +/- 7.6% in control subjects, P < 0.01), with significant improvement in C-peptide responses to a mixed meal even 2 years after treatment (P < 0.02). The improved C-peptide responses were accompanied by reduced HbA(1c) and insulin requirements. Clinical responses to drug treatment were predicted by an increase in the relative number of CD8(+) T-cells in the peripheral blood after the lymphocyte count recovered 2 weeks after the last dose of drug. We conclude that treatment with the anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improved C-peptide responses and clinical parameters in type 1 diabetes for at least 2 years in the absence of continued immunosuppressive medications.     

The Cholinergic Neuronal Phenotype in Alzheimer's Disease

The synthesis, storage and release of acetylcholine (ACh) requires the expression of several specialized proteins, including choline acetyltransferase (ChAT) and the vesicular ACh transporter (VAChT). The VAChT gene is located within the first intron of the ChAT gene. This unique genomic organization permits coordinated activation of expression of the two genes by extracellular factors. Much less is known about factors that reduce the expression of the cholinergic phenotype. A cholinergic deficit is one of the primary features of Alzheimer’s disease (AD), and AD brains are characterized by amyloid deposits composed primarily of Aβ peptides. Although Aβ peptides are neurotoxic, part of the cholinergic deficit in AD could be attributed to the suppression of cholinergic markers in the absence of cell death. Indeed, we and others demonstrated that synthetic Aβ peptides, at submicromolar concentrations that cause no cytotoxicity, reduce the expression of cholinergic markers in neuronal cells. Another feature of AD is abnormal phospholipid turnover, which might be related to the progressive accumulation of apolipoprotein E (apoE) within amyloid plaques, leading perhaps to the reduction of apoE content in the CSF of AD patients. ApoE is a component of very low density lipoproteins (VLDL). As a first step in investigating a potential neuroprotective function of apoE, we determined the effects of VLDL on ACh content in neuronal cells. We found that VLDL increases ACh levels, and that it can partially offset the anticholinergic actions of Aβ peptides.     

Cardiogenic shock in myocardial infarction-results of in-hospital follow-up

The purpose of this study was to present the outcomes of treatment of cardiogenic shock (CS) complicating acute myocardial infarction (AMI) among patients hospitalized from 1999 through 2006. The study enrolled 1003 patients. Group 1 comprised 87 patients presenting with AMI complicated with CS, whereas Group 2 comprised 916 patients presenting with AMI without CS symptoms. Determination of invasive treatment was according to standard guidelines. The endpoint comprised death, stroke, and reocclusion/reinfarction. Follow-up was confined to the intra-hospital period. CS was observed more frequently in cases of ST-elevation MI (STEMI) and right ventricular MI. The transportation and door-to-needle time were shorter in Group 1. CS patients were characterized by a more severe coronary artery disease, higher maximal creatinine kinase levels, lower global ejection fractions, and increased incidence of atrioventricular conduction disorders. The efficacy of percutaneous coronary intervention (PCI) was 82.26% in Group 1 and 95.03% in Group 2. Death occurred in 33.3% of CS patients and in 3.6% of AMI patients (p<0.0001). Our study proved that in a short-term follow-up, PCI is a procedure of high efficacy in CS patients. The short-term follow-up precluded a conclusion of statistically significant benefits from the shortening of the transportation and door-to-needle time.     

Usefulness of rheumatoid factor as an immunological and prognostic marker in PSS patients

Clinical Rheumatology - The rheumatoid factor (RF) is present in numerous autoimmune disorders, although its role in many of them remains a subject of research. The study assesses the role of RF as...