The Complex Network of Cytokines and Chemokines in Pediatric Patients with Long-Standing Type 1 Diabetes.

Type 1 diabetes (T1D) is a progressive disorder leading to the development of microangiopathies and macroangiopathies. Numerous cytokines and chemokines are involved in the pathogenesis of T1D complications. The study aimed to assess the presence of complications in patients with long-standing T1D and its relationship with serum biomarker concentrations. We examined 52 T1D subjects, with a disease duration ≥4 years and 39 healthy controls. The group of T1D patients was further divided into subgroups based on the duration of the disease (<7 years and ≥7 years) and the metabolic control assessed by the HbAlc level (<8% and ≥8%). We used Luminex Technology to assess a wide range of biomarker concentrations. A 24 h urine test was done to evaluate the rate of albuminuria. Optical coherence tomography (OCT) was conducted to detect early retinopathic changes. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (IMT). T1D patients showed remarkably higher concentrations of EGF, eotaxin/CCL11, MDC/CCL22, sCD40L, TGF-α, and TNF-α. Moreover, we reported statistically significant correlations between cytokines and IMT. Biomarker concentrations depend on numerous factors such as disease duration, metabolic control, and the presence of complications. Although the majority of pediatric T1D patients do not present signs of overt complications, it is indispensable to conduct the screening for angiopathies already in childhood, as its early recognition may attenuate the further progression of complications.

Local T cell infiltrates are predominantly associated with corneal allograft rejection.

BACKGROUND: Corneal transplantations (CTXs) are a vision-saving procedure. Routinely, while CTXs' survival rates remain high, the risk of graft failure increases significantly for repeated CTXs. The reason is an alloimmunization following previous CTXs and development of memory T (Tm) and B (Bm) cells. METHODS: We characterized populations of cells present in explanted human corneas from patients receiving the first CTX and marked as a primary CTX (PCTX) or the second or more CTXs and marked as a repeated CTX (RCTX). Cells extracted from resected corneas and from peripheral blood mononuclear cells (PBMCs) were analyzed by the flow cytometry method using multiple surface and intracellular markers. RESULTS: Overall, the number of cells was similar in PCTX and RCTX patients. Extracted infiltrates from PCTXs and RCTXs contained similar numbers of T cell subsets, namely CD4+, CD8+, CD4+ Tm, CD8+ Tm, CD4+Foxp3+ T regulatory (Tregs), CD8+ Treg cells, while very few B cells (all p = NS). However, when compared to peripheral blood, PCTX and RCTX corneas contained significantly higher percentages of effector memory CD4+ and CD8+ T cells (both p < 0,05). In comparison to PCTX, RCTX group had the highest levels of Foxp3 in T CD4+ Tregs (p = 0,04) but decreased percentage of Helios-positive CD4+ Tregs. CONCLUSION: PCTXs and especially RCTXs are rejected mainly by local T cells. The accumulation of effector CD4+ and CD8+ T cells, as well as CD4+ and CD8+ Tm cells is associated with the final rejection. Furthermore, local CD4+ and CD8+ Tregs expressing Foxp3 and Helios are probably insufficient to impose the acceptance of CTX.

Cytomegaloviral Retinitis in a Heart Transplant Patient: Case Report and Review of the Literature.

Cytomegalovirus (CMV) poses a significant threat to solid organ transplant recipients (SOTR). The incidence of CMV disease in SOTR varies according to immunosuppressive therapy, antiviral prophylaxis, donor and recipient serologic compatibility, and the transplanted organ: 9% to 23%, 22% to 29% and 8% to 32% after heart, liver and kidney transplant, respectively. CMV retinitis (CMVR) is a rare manifestation of CMV with a high risk of blindness. Infection may vary in severity, from initially clinically silent cases to full-blown advanced changes involving the eye. The most characteristic effects are changes in the retina, which usually begin at the retina's periphery and are asymptomatic, then these changes spread toward the center as the disease progresses and impairs vision. We describe CMV vitritis and retinitis in a 74-year-old patient after heart transplantation conducted in 1992. The first symptom of the disease was low vision in the left eye. Initially no blood viremia was observed; then the CMV viral load in the blood and vitreous body of the right eye was 2454 and 26 million IU/mL.Despite the initiation of treatment (intravitreal and then intravenous ganciclovir), the inflammatory process progressed rapidly and vision in the left eye was lost, although functional visual acuity in the right eye was maintained. Systemic antiviral therapy with intravenous ganciclovir lasted 6 weeks until the eradication of CMV viremia. The patient was on prophylactic therapy with oral valganciclovir for 12 months. A clinically silent course of CMVR delays diagnosis and therapy. Therefore, it is recommended that all SOTR undergo periodic ophthalmologic control to avoid delayed diagnosis.

Retinal nerve fiber and ganglion cell complex layer thicknesses mirror brain atrophy in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is associated with progressive brain atrophy, which in turn correlates with disability, depression, and cognitive impairment. Relapsing-remitting multiple sclerosis (RRMS) is a type of MS in which relapses of the disease are followed by remission periods. This is the most common type of the disease. There is a significant need for easy and low-cost methods to these cerebral changes. Changes in retinal layer thickness may reflect alterations in brain white and gray matter volumes. Therefore, this paper aims to determine whether retinal layer thickness, measured using optical coherence tomography (OCT), correlates with volumetric brain assessments obtained by magnetic resonance imaging (MRI). METHODS: This retrospective cohort study recruited 53 patients with relapsing-remitting MS who underwent MRI and OCT examinations for evaluation of brain compartment volumes and thickness of retinal layers, respectively. OCT parameters, including central retinal thickness; retinal nerve fiber layer thickness (RNFL, peripapillary thickness); ganglion cell complex thickness (GCC, macular thickness); and Expanded Disability Status Scale (EDSS) results were compared with MRI parameters (cerebral cortex; cerebral cortex and basal ganglia combined; brain hemispheres without the ventricular system; and white matter plaques). We also checked whether there is a correlation between the number of RRMS and OCT parameters. OBJECTIVE: Our primary objective was to identify whether these patients had retinal thickness changes, and our secondary objective was to check if those changes correlated with the MRI brain anatomical changes. RESULTS: RNFL and GCC thicknesses were strongly (p-value < 0.05) associated with (i) cerebral cortex volume, (ii) combination of brain cortex and basal ganglia volumes, and (iii) the hemispheres but without the ventricular system. White matter plaques (combined) showed only weak or no correlation with RNFL and GCC. There was no correlation between central retinal thickness and brain compartment volumes, and there were weak or no correlations between the summary EDSS scores and OCT results. CONCLUSIONS: Retinal layer thickness measured by OCT correlates with select volumetric brain assessments on MRI. During the course of RRMS, the anatomo-pathological structure of the retina might serve as a surrogate marker of brain atrophy and clinical progression within selected domains.

Corneal Allografts: Factors for and against Acceptance.

Cornea is one of the most commonly transplanted tissues worldwide. However, it is usually omitted in the field of transplantology. Transplantation of the cornea is performed to treat many ocular diseases. It restores eyesight significantly improving the quality of life. Advancements in banking of explanted corneas and progressive surgical techniques increased availability and outcomes of transplantation. Despite the vast growth in the field of transplantation laboratory testing, standards for corneal transplantation still do not include HLA typing or alloantibody detection. This standard practice is based on immune privilege dogma that accounts for high success rates of corneal transplantation. However, the increasing need for retransplantation in high-risk patients with markedly higher risk of rejection causes ophthalmology transplantation centers to reevaluate their standard algorithms. In this review we discuss immune privilege mechanisms influencing the allograft acceptance and factors disrupting the natural immunosuppressive environment of the eye. Current developments in testing and immunosuppressive treatments (including cell therapies), when applied in corneal transplantation, may give very good results, decrease the possibility of rejection, and reduce the need for retransplantation, which is fairly frequent nowadays.

Administration of CD4+CD25highCD127-FoxP3+ Regulatory T Cells for Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (Tconv) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4+CD25highCD127-FoxP3+ T regulatory (Treg) cells may inhibit this destruction through suppressive activity exerted on Tconv cells. METHODS: We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous Treg cells for relapsing-remitting MS. The patients received either expanded ex vivo Treg cells intravenously (intravenous [IV] group, n = 11; dose 40 × 106 Treg cells/kg of body weight) or freshly isolated Treg cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 106 Treg cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up. RESULTS: No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of Treg cells or Tconv cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, Treg cells in all patients consisted of two different phenotypes: peripheral Treg cells Helios(-) (≈ 20%) and thymic Treg cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group. CONCLUSIONS: No serious adverse events were reported in the 14 patients with MS treated with Treg cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety. TRIAL REGISTRATION: EudraCT: 2014-004320-22; registered 18 November 2014.

Haemodynamic parameters in postmenopausal women - beneficial effect of moderate continuous exercise training.

INTRODUCTION AND OBJECTIVE: Physical effort plays a positive role in reducing the risk of cardiovascular diseases. The aim of this study was to assess the cardiovascular status in postmenopausal women after several years of regular amateur training. MATERIAL AND METHODS: A total of 55 generally healthy females aged 50-70 years, of whom 38 were members of a senior exercise group and 17 comprised a control group, were enrolled in the study. Parameters of blood flow, vascular resistance, myocardial contractility and thoracic fluid content were measured in a 10-minute supine resting test by impedance cardiography. Thereafter, central blood pressure, augmentation index and pulse wave velocity were measured by applanation tonometry. RESULTS: Exercising women have a better outcome than the control group, when evaluated both with impedance cardiography and with applanation tonometry. They have a lower heart rate - HR (65.1 vs 71.5; p = 0.033), higher blood flow (stroke index - SI, 58.6 vs 50.3; p = 0.040), better myocardial contractility (acceleration index - ACI, 108.8 vs 88.1; p = 0.027), higher preload (thoracic fluid content index - TFCI, 20.5 vs 18.1; p = 0.002), lower afterload (systemic vascular resistance index - SVRI, 1972.9 vs 2110.5; p = 0.026), lower central systolic blood pressure - cBPsys (119.0 vs 129.5; p = 0.037), lower augmentation pressure - AP (10.3 vs 15.0; p = 0.044) and lower pulse wave velocity - PWV (7.4 vs 8.4; p = 0.001). CONCLUSIONS: Regular moderate continuous aerobic exercise training has a beneficial impact on the cardiovascular system in postmenopausal women.

Tubulointerstitial nephritis: diagnosis, treatment, and monitoring.

Tubulointerstitial nephritis (TIN) is a frequent cause of acute kidney injury (AKI) that can lead to chronic kidney disease (CKD). TIN is associated with an immune-mediated infiltration of the kidney interstitium by inflammatory cells, which may progress to fibrosis. Patients often present with nonspecific symptoms, which can lead to delayed diagnosis and treatment of the disease. Etiology can be drug-induced, infectious, idiopathic, genetic, or related to a systemic inflammatory condition such as tubulointerstitial nephritis and uveitis (TINU) syndrome, inflammatory bowel disease, or immunoglobulin G4 (IgG4)-associated immune complex multiorgan autoimmune disease (MAD). It is imperative to have a high clinical suspicion for TIN in order to remove potential offending agents and treat any associated systemic diseases. Treatment is ultimately dependent on underlying etiology. While there are no randomized controlled clinical trials to assess treatment choice and efficacy in TIN, corticosteroids have been a mainstay of therapy, and recent studies have suggested a possible role for mycophenolate mofetil. Urinary biomarkers such as alpha1- and beta2-microglobulin may help diagnose and monitor disease activity in TIN. Screening for TIN should be implemented in children with inflammatory bowel disease, uveitis, or IgG4-associated MAD.

Enzymatic vitreolysis with recombinant tissue plasminogen activator for vitreomacular traction.

AIMS: The aim of our research was to gain data about the efficacy of intravitreal injections of a recombinant tissue plasminogen activator (rTPA) in dissolving vitreoretinal tractions (VRTs). MATERIALS AND METHODS: The study group consisted of patients of our Ophthalmology Clinic who had received an injection of rTPA (TPA Group) for an existent vitreomacular traction confirmed by optical coherence tomography and stereoscopic examinations. The control group consisted of patients who had declined treatment despite the existence of a vitreomacular traction confirmed by the same diagnostic methods. Each group consisted of 30 people (30 eyes). The observation period was 6 months. CONCLUSION: In both groups some of the VRTs had dissolved. In the TPA group the traction dissolved in 10 patients (33.33%) and in the control group only in 5 (16.67%). It is also important to point out that the mean baseline membrane thickness was higher in the TPA group than in the control group. Observing patients in both groups we noticed that the dissolution of vitreoretinal membrane occurred most frequently in those cases where the membrane was thin. In the TPA group, the mean membrane thickness after 6 months decreased considerably. At the same time, no significant change in the membrane thickness could be observed in the control group. Observation of the retinal thickness allows us to draw the following conclusion: in the TPA group, the retinal thickness in the macular area (edema) had decreased over the study period, whereas in the control group it had increased. In those cases where the traction had dissolved, the edema of the retina decreased by the end of the 6-month period in both groups. In the TPA group, the dissolution of the membrane occurred most often within 3 months from the primary injection. Based on statistics, we can confirm that in the control group there was a decrease in visual acuity during the 6 months of the study period. At the same time, visual acuity in the TPA group underwent a small improvement. A 6-month observation had shown that in patients with strong VRTs, and in particular with VRTs accompanied by epiretinal membranes, a single intraocular injection is not enough to achieve posterior vitreous detachment. We have also shown that rTPA is a safe drug, with no adverse effects observed during the study period.

[The use of aflibercept (Eylea) in the treatment of polypoidal choroidal vasculopathy--case report]. / Zastosowanie afliberceptu (leku Eylea) w leczeniu polipoidainej waskulopatii naczyniówkowej--opis przypadku.

The paper presents a case of a 25-year-old woman referred to the Outpatient Clinic at the Department of Ophthalmology, University Clinical Centre in Gdansk, with sudden vision impairment in her right eye. Clinical manifestation and diagnostic tests gave a basis for the preliminary diagnosis of polypoidal choroidal vasculopathy. Polypoidal choroidal vasculopathy is a type of choroidal neovascularisation, frequently confused with age-related macular degeneration. Standard treatment includes photodynamic therapy and intravitreal injections of anti-vascular endothelial growth factor agents. 2.0 miligrams of aflibercept was administered as an intravitreal injection, causing a rapid, significant improvement of visual function and proper anatomical relationships within the retina.