Combined therapy with CD4+ CD25highCD127- T regulatory cells and anti-CD20 antibody in recent-onset type 1 diabetes is superior to monotherapy: Randomized phase I/II trial.

AIMS: Monotherapy with autologous expanded CD4+ CD25high CD127- T regulatory cells (Tregs) or rituximab has been documented to slow disease progression in patients with recent-onset type 1 diabetes mellitus (T1DM). Whether a combined therapy including both drugs would further benefit this patient population is unknown. MATERIALS AND METHODS: We conducted a three-arms clinical trial to explore the efficacy and safety of the combined treatment with Tregs and rituximab in paediatric patients with T1DM. The patients were allocated to three groups: Tregs only (n = 13), Tregs + rituximab (n = 12) and control (n = 11). The key primary efficacy analyses were C-peptide levels (mixed meal tolerance test) and the proportion of patients in remission at 12 and 24 months. RESULTS: At month 24, as compared with the control, both treatment groups remained superior in the area under the curve of C-peptide mixed meal tolerance test, whereas in the analysis of all visits only the combined therapy improved area under the curve at 12 and 24 months. The proportion of patients in remission was significantly higher in the combined group than in the control group at 3, 6, 9 and 21 months but not at 18 and 24 months. There was no significant difference between the Tregs only group and control group. Adverse events occurred in 80% patients, mostly in the combined group and Tregs only group. No adverse events led to the withdrawal of the intervention or death. All comparisons were performed with alpha level of 5%. CONCLUSIONS: Over 2 years, combined therapy with Tregs and rituximab was consistently superior to monotherapy in delaying T1DM progression in terms of C-peptide levels and the maintenance of remission.

Influence of stimulus presentation rate on intraoperative ECAP thresholds in cochlear implant users.

OBJECTIVE: The objective is to evaluate the influence of the presentation rate on intraoperative ECAP thresholds in cochlear implant users. DESIGN: The design was data on the ECAP thresholds (t-NRT) as well as the behavioural T- and C-levels have been collected in CI patients of a quaternary otologic referral centre. Measurements of the tNRT thresholds were performed intraoperatively for 250 Hz and 80 Hz presentation rates and correlated to the stabilised T- and C-levels measured at the 5th fitting session, 4-6 months after surgery. STUDY SAMPLE: There was a study sample of 35 consecutive CI patients. All patients were users of the Nucleus 24RECA (Freedom) or Nucleus CI512 cochlear implants with the Contour Advance-of-Stylet electrode. RESULTS: The result showed that the t-NRT thresholds were higher for the 250 Hz pulse rate typically used during the intraoperative stimulation under general anaesthesia than for the 80 Hz rate used typically during the postoperative fitting sessions. This difference was more pronounced for the basal electrodes where it exceeded 10 current levels (CL). Pearson's correlation coefficients between the t-NRT-measurements and the stabilised T- and C-levels r ranged between 0.34 and 0.47. CONCLUSION: In conclusion, the magnitude of the ECAP thresholds (t-NRT) recorded intraoperatively depends significantly on the stimulus presentation rate.

Circulating CD34+ and CD34+VEGFR2+ progenitor cells are associated with KLOTHO KL-VS polymorphism.

BACKGROUND: KLOTHO is a regulator of endothelial cells activity and integrity. It has been described for the first time because of its anti-aging properties. KLOTHO encoding gene is present in many functional variants in humans, including "KL-VS" variant that has been connected with longevity and cardiovascular disease development. Few mechanisms have been proposed to explain these associations, but none of them focused on cells from CD34+ population. The aim of our study was to investigate influence of KLOTHO KL-VS polymorphism on populations of CD34+ and CD34+VEGFR2+ cells. METHODS AND RESULTS: We examined 167 Polish subjects from Pomeranian region. The analysis concerned KL-VS polymorphism, flow cytometry evaluation of whole blood cells and determination of endothelium-associated serum/plasma factors. Our results indicate that individuals possessing at least one KL-VS allele are characterized by greater number of CD34+ and CD34+VEGFR2+ and their various subpopulations (CD34+CD133+, CD34+c-Kit+, CD34+CXCR4+ and CD34+VEGFR2+c-Kit+) than wild-type volunteers. This group also exhibited more favorable lipid profile and statistically insignificant decrease of vWF and angiotensin II in their blood, whereas VEGF levels were elevated. CONCLUSION: One of the mechanisms that are responsible for previously described KL-VS heterozygote advantage may be connected with maintaining greater size of hematopoietic and endothelial progenitor cells population.

Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes.

BACKGROUND: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. METHODS: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 106/kg b.w. of autologous expanded CD3+CD4+CD25highCD127- Tregs. RESULTS: The disease progressed and all patients were insulin-dependent 2 years after inclusion. The ß-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L+CD45RA+ to memory CD62L+CD45RA- Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes. CONCLUSIONS: The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462 ; registered retrospectively.

The GA genotype of the -1154 G/A (rs1570360) vascular endothelial growth factor (VEGF) is protective against hypertension-related chronic kidney disease incidence.

Vascular endothelial growth factor (VEGF) is a highly specific mitogen with angiogenic and vascular permeability activities for endothelial cells. VEGF participates in maintaining the renal vasculature integrity. There is no doubt that hypertension accelerates progression to renal dysfunction, resulting in chronic kidney disease (CKD). The purpose of our study was to examine the VEGF -1154 G/A (rs1570360) polymorphism among hypertensive patients with CKD. Additionally markers of endothelial damage have been related to the advancement of CKD. There were 96 consecutively admitted hypertensive patients referred to our Institution by their general practitioner. The patients were treated with an anti-hypertensive polytherapy. Ninety-nine healthy volunteers were enrolled as the control group. Our study revealed that both healthy and hypertensive groups frequencies of the genotypes varied significantly (p = 0.030, χ (2) test). The GA genotype frequency was significantly lower among patients in comparison with healthy. The presence of GA genotype was connected with a decreased risk of hypertension disease (OR = 0.48, p = 0.01). The VEGF -1154 GA carriers have been associated with the lowest values of Endostatin (p = 0.020), Angiogenin (p = 0.040) as well as vWf (p = 0.005). The GA genotype has been characterized by the highest values of eGFR (p = 0.024) and the lowest values of creatinine (p = 0.028) and BUN (p = 0.012). It is evident that the GA genotype of VEGF polymorphism localized at -1154 position is a genetic protective factor for development arterial hypertension and is associated with less progressed CKD.

The GG genotype of the -152 G/A vascular endothelial growth factor (VEGF) polymorphism predisposes to hypertension-related chronic kidney disease.

Our purpose was to determine whether the VEGF -152 G/A polymorphism could be associated with chronic kidney disease and endothelial dysfunction in hypertensive patients. There were 100 healthy volunteers enrolled into the control group. The group of patients was constituted by 99 consecutively admitted hypertensive patients referred to our Institution by their general practitioner. All patients were treated with anti-hypertensive polytherapy. Presented study revealed that the hypertensive patients bearing the GG genotype were characterized by the highest values of diastolic blood pressure and markers of endothelial damage such as Angiogenin, Endostatin, CRP as well as von Willebrandt factor. In addition, higher number of immature endothelial progenitor cells with CD34(+)CD133(+), CD34(+)CD133(-) markers was observed in GG hypertensive carriers while in normotensive individuals no differences were found. Such phenomenon may indicate an increased mobilization of bone-marrow derived endothelial progenitors. It may testify to the preserved compensatory mechanism in chronic kidney disease (CKD) patients until the G3a stage of the disease. Moreover, patients with higher estimated glomerular filtration rate (eGFR) level had lower of vWf and Endostatin values, and higher level of VEGF. Taken together our findings clearly indicate the -152 GG hypertensive carriers as more prone to develop CKD. We can suspect that the VEGF -152 GG genotype is strongly associated with hypertension-dependent CKD.

Vascular endothelial growth factor polymorphism (-460 T/C) is related to hypertension-associated chronic kidney disease.

Our aim was to characterize the endothelial progenitor cells (EPCs) in normotensive controls and treated hypertensive individuals within the vascular endothelial growth factor (VEGF) -460 C/T polymorphism as well as to investigate whether this polymorphism predisposes to hypertension-related chronic kidney disease. The hypertensive patients bearing the TT genotype had the highest levels of immature EPC with the following phenotypes: CD34(+), CD34(+)CD45(dim), CD34(+)CD133(+)CD45(dim). The study showed the estimated glomerular filtration rate values significantly lower and creatinine and BUN parameters higher among the TT hypertensive patients. We presume that the highest mobilization of EPCs from bone marrow may signalize more severe renal hypertension-related complications in the VEGF -460 TT genotype.

[Difference in efficacy of dyslipidaemia treatment in obese and not obese women. Analysis of date from 3ST-POL study].

Introduction: Cardiovascular diseases remain the first cause of premature death in polish society. In Poland mortality concerned with cardiovascular diseases is higher in women than in men. Dyslipidemia is one of the most important and one of the most common risk factor of cardiovascular diseases. The efficacy of treatment of dyslipidaemia in Poland remains poor however there is lack of date as far as influence of sex and coexistence obesity on efficacy of treatment of dyslipidaemia is concerned. Aim: Evaluation of difference in efficacy of treatment of dyslipidaemia in obese women and women with body mass index less than 30 kg/m2. Date from 3ST-POL Study. Methods: Post hoc analysis of date of 3ST-POL Study, conducted in 2007- 2008. The Study refers to efficacy of treatment of dyslipidaemia in ambulatory polish patients which remain under supervision of general practitioners, cardiologist or dialectologist. Results: Women comprise 53% (n=26099) of population of 3ST-POL Study. In 21769 of those it was possible to calculate body mass index (BMI). 16% of women ware obese. 70% of those in comparison of with 67.6% of women with BMI<30 kg/m2 were at high cardiovascular risk. (p<0.01). There was no difference in mean doses of statins between all groups (mean daily dose was 20 mg and 24 mg for atorvastatin and simvastatin respectively). LDL goal was reached in 9.67% vs, 15.8% of obese high risk and not at high risk women respectively (p<0.01). Total cholesterol goal was reached in 9.01% vs. 12.39% obese high risk and not at high risk women respectively (p<0.01). In group with BMI<30 kg/m2 LDL and total cholesterol goals in high risk and not at high risk women were reached in 10.02% vs. 14.46% and in 8.86% vs. 13.05% respectively (p<0.01 for both). Mean concentration of all lipids, except for triglycerides, was higher in non-obese women. Conclusions: The efficacy of treatment of dyslipidaemia in women from 3ST-POL study was higher in patients with lower global cardiovascular risk. Obesity or lack of it has no influence of that difference. Nevertheless global efficacy was very poor as far as both ­ LDL and total cholesterol goals were concerned. Moreover there were now difference in mean statins doses between groups. This may be due to therapeutic inertia of physicians.

Heat shock proteins (HSPs) in the homeostasis of regulatory T cells (Tregs).

Heat shock proteins (HSPs) belong to the family of conservative polypeptides with a high homology of the primary structure. The uniqueness of this family lies in their ability to interact with a large number of different proteins and provide protection from cellular and environmental stress factors as molecular chaperones to keep protein homeostasis. While intracellular HSPs play a mainly protective role, extracellular or membrane-bound HSPs mediate immunological functions and immunomodulatory activity. In immune system are subsets of cells including regulatory T cells (Tregs) with suppressive functions. HSPs are implicated in the function of innate and adaptive immune systems, stimulate T lymphocyte proliferation and immunomodulatory functions, increase the effectiveness of cross-presentation of antigens, and induce the secretion of cytokines. HSPs are also important in the induction, proliferation, suppressive function, and cytokine production of Tregs, which are a subset of CD4+ T cells maintaining peripheral tolerance. Together HSPs and Tregs are potential tools for future clinical interventions in autoimmune disease.

Postimplantation changes of electrophysiological parameters in patients with cochlear implants.

OBJECTIVE: To evaluate the postoperative changes of the basic electrophysiological and psychophysical parameters in cochlear implant (CI) patients: the impedance of the electrode contacts, the electrically-evoked compound action potential (ECAP) thresholds and the T/C levels. STUDY DESIGN AND SETTING: Retrospective case review in a quaternary otologic referral centre. MATERIALS AND METHODS: Data on the impedance of the electrode contacts, the ECAP thresholds and the T/C levels were collected in 20 consecutive CI patients divided into 2 groups. Group 1 comprised 10 prelingually deaf children implanted before the age of 18 months, and group 2 comprised 10 postlingually deaf adults (average age of 58 years). All patients were users of the Nucleus 24RECA (Freedom, Contour advance off-stylet electrode) CI. RESULTS AND CONCLUSIONS: (1) The mid-portion and the apical electrodes showed a decrease in the impedance values between the 1st and the 6th postoperative months and stabilization in the later course. Impedance of the most basal electrodes grew during the first postoperative months and stabilized later on, but remained higher than the impedance of the mid-portion and the apical electrodes. (2) The neural response telemetry threshold values tended to decrease within the first 3 months after surgery to reach a plateau afterwards. (3) The behavioural threshold levels remained generally stable, except for the basal electrodes where a decrease could be observed. The hearing comfort levels showed an increase during the first 6 months of the implant use and remained stable afterwards.

The prognostic value of positive T-wave in lead aVR in hemodialysis patients.

BACKGROUND: Given that cardiac disease is the leading cause of mortality in hemodialysis (HD) patients, identification of patients at risk for cardiac mortality is crucial. The aim of this study was to determine if positive T-wave amplitude in lead aVR (TaVR) was predictive of cardiovascular (CV) mortality and sudden cardiac death (SCD) in a group of HD patients. METHODS AND RESULTS: After exclusion, 223 HD patients were prospectively followed-up for 25.43 ± 3.56 months. Patients were divided into TaVR negative (n = 186) and TaVR positive (n = 37) groups. Myocardial infarction, diabetes and beta-blocker therapy were more frequent in positive TaVR patients. Patients with upright TaVR were older, had higher left ventricular mass index, lower ejection fraction, higher calcium × phosphate product, higher troponin T level, higher prevalence of ST-T abnormalities, and increased width of QRS complex and QT interval, compared with patients with negative TaVR. A Kaplan-Meier analysis showed that the cumulative incidences of CV mortality as well as SCD were higher in patients with positive TaVR compared with those with negative TaVR (log-rank, p < 0.001 in both cases). A multivariate analysis selected age [hazard ratio (HR) 1.71, p < 0.001], heart rate (HR 1.42, p = 0.016), and positive TaVR (HR 2.21, p = 0.001) as well as age (HR 1.88, p < 0.001), and positive TaVR (HR 1.53, p = 0.014) as independent predictors of CV mortality and SCD, respectively. CONCLUSION: In HD patients, positive TaVR is an independent and powerful predictor of CV mortality as well as SCD. This simple ECG parameter provides additional information beyond what is available with other known traditional risk factors and allows the identification of patients most at risk of CV events.

Elevated Serum Tryptase and Endothelin in Patients with ST Segment Elevation Myocardial Infarction: Preliminary Report.

UNLABELLED: An inflammatory response plays a crucial role in myocardial damage after an acute myocardial infarction. OBJECTIVES: To measure serum concentrations of several mediators in patients with an acute myocardial infarction (STEMI) and to assess their potential relationship with a risk of coronary instability. PATIENTS AND METHODS: The 33 patients with STEMI and 19 healthy volunteers were analyzed. The clinical data were obtained; as well serum concentrations of tryptase, endothelin (ET-1), angiogenin, soluble c-kit, and PDGF were measured. RESULTS: Patients with STEMI had higher serum tryptase and ET-1 than healthy volunteers (2,5 ± 0,4 ng/mL versus 1,1 ± 0,4 ng/mL and 0,7 ± 0,1 ng/mL versus 0,3 ± 0,1 ng/mL, resp.). Subjects with significant lesion in left anterior descending artery (LAD) had lower serum ET-1 compared to those with normal LAD (0,6 ± 0,2 pg/mL versus 0,9 ± 0,4 pg/mL). Patients with three-vessel coronary artery disease (CAD) had higher level of soluble c-kit compared to those with one- or two-vessel CAD: 19,9 ± 24,1 ng/mL versus 5,6 ± 1,9 ng/mL. CONCLUSIONS: Elevated serum tryptase and ET-1 may be markers of increased coronary instability; some cytokines may be related to the extension of CAD.

Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up.

It is hypothesized that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) can prevent destruction of pancreatic islets protecting from type 1 diabetes (DM1). Here we present results of one year follow-up of 12 DM1 children treated with autologous expanded ex vivo Tregs. Patients received either a single or double Tregs infusion up to the total dose of 30×10(6)/kg. No severe adverse effects were observed. The treatment did not impair post-immunization antibody responses. Tregs infusion was followed by increase in Tregs number in peripheral blood. Most of the patients responded to the therapy with increase in C-peptide levels (8/12 and 4/6 after the first and the second dose, respectively). Tregs administration resulted also in lower requirement for exogenous insulin (8/12 treated patients versus 2/10 untreated controls in remission) with two children completely insulin independent at one year. Repetitive administration of Tregs is safe and can prolong survival of ß-cells in DM1 (registration: ISRCTN06128462).

Enhanced apoptosis of monocytes from complication-free juvenile-onset diabetes mellitus type 1 may be ameliorated by TNF-α inhibitors.

Diabetes mellitus type 1 is associated with an enhanced apoptosis of different cells and tissues, accelerating occurrence of diabetic microvascular complications. The aim of our study was to determine spontaneous apoptotic potential of the monocyte subsets in juvenile-onset complication-free diabetes mellitus type 1 and to compare them with the corresponding values of the healthy. Moreover, we wanted to assess effects of TNF-R1 blocking agents and those of general TNF-α blocker (Infliximab) on spontaneous apoptosis of monocytes. Sixty randomly selected DM1 patients (14.5 ± 3.2 years) and 30 healthy (13.5 ± 2.8 years) volunteers were enrolled in the study. Our results indicate that three monocyte subsets are distinguishable in the groups of young diabetic patients and the healthy, similarly to in the blood of adults. DM1 patients were characterized by higher values of apoptotic monocytes than the healthy. The manipulation with drugs inhibiting TNF-R1 expression diminished the pool of CD16(+) apoptotic monocytes. Infliximab reduced the apoptotic CD16(-) cells. In conclusion, diabetes mellitus type 1 is associated with greater apoptosis of three monocyte subsets which may contribute to the development of microvascular complications. TNF-α modifiers appear to ameliorate monocyte apoptosis. They may be useful for controlling excessive monocyte apoptosis in diabetic patients.

[Are sleep disorders an underestimated symptom? Preliminary report from the screening study]. / Czy zaburzenia snu sa objawem niedocenianym? Raport wstepny z badan przesiewowych.

UNLABELLED: introduction: Sleep disorders are burdensome health problem coexisting with mental disorders and somatic diseases. The study aim was to assess prevalence of sleep disorders and analyses of comorbidity. MATERIAL AND METHODS: Study included 76 participants (50 women and 26 men; mean age: 48.5) who attended prophylactic examinations. We used Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ) created for preliminary diagnosis of mental disorders. Among items assessing depression there is a question concerning sleep disorders. Data from medical review were used. RESULTS: Sleep disorders were declared by 50% of participants, 54% of them were women. In age group between 60-76 disorders were declared by 68.2%, from group 16-39 years--45% and 41.2% aged 40-59 years. Among those with sleep disorders 42.1% had preliminary diagnosis of mental disorders. In this group significantly higher was the percentage of patients with diagnosed somatic disease as well as the number of somatic complaints and stress factors. CONCLUSIONS: 1. Sleep disorders are common symptoms, especially in older adults and women. 2. Mental disorders, somatic diseases and complaints as well as stress factors are significantly more common among patients with sleep disorders. 3. Sleep disorders consist important premise for diagnosing mental disorders. 4. Screening for sleep disorders may be vital element of diagnostic and therapeutic process in primary care.

An improvement of body surface area formulas using the 3D scanning technique.

OBJECTIVES: Body surface area (BSA) is one of the major parameters used in several medical fields. However, there are concerns raised about its usefulness, mostly due to the ambiguity of its estimation. MATERIAL AND METHODS: Authors have conducted a voluntary study to investigate BSA distribution and estimation in a group of 179 adult people of various sex, age, and physique. Here, there is provided an extended analysis of the majority of known BSA formulas. Furthermore, it was supplement with a comparison with the authors' propositions of enhanced formulas coefficients for known formulas models as well as with new power models based on an increased number of anthropometric data. RESULTS: Introduction of the enhanced formulas coefficients cause a reduction of at least 30.5% in mean absolute error and 21.1% in maximum error in comparison with their known counterparts. CONCLUSIONS: In the context of the analysis presented it can be stated that the development of a single universal body surface area formula, based on a small number of state variables, is not possible. Therefore, it is necessary and justified to search for new estimation models that allow for quick and accurate calculation of body surface area for the entire population, regardless of individual body variations. The new formulas presented are such an alternative, which achieves better results than the previously known methods. Int J Occup Med Environ Health. 2024;37(2):205-19.

Intradialytic Tolerance and Recovery Time in Different High-Efficiency Hemodialysis Modalities.

There are several forms of maintenance high-efficiency hemodialysis (HD), including hemodiafiltrations (HDF) in different technical modes and expanded HD, using dialyzers with medium cut-off membranes. The aim of the study was to assess the intradialytic tolerance and length of dialysis recovery time (DRT) in these modalities. This is an exploratory, crossover study in maintenance HD patients with low comorbidity and no clinical indications for the use of high-efficiency HD, who were exposed to five intermittent dialyses in random order: high-flux hemodialysis (S-HD), expanded HD (HDx), pre-dilution HDF (PRE-HDF), mix-dilution HDF (MIX-HDF) and post-dilution HDF (POST-HDF). Twenty-four dialysis sessions of each method were included in the analysis. Dialysis parameters, including blood flow rate, dialysis fluid flow rate and temperature, and pharmacological treatment were constant. Average total convection volume for post-HDF, pre-HDF and mix-HDF were 25.6 (3.8), 61.5 (7.2) and 47.1 (11.4) L, respectively. During all therapies, patients were monitored for the similarity of their hydration statuses using bioimpedance spectroscopy, and for similar variability over time in systemic blood pressure and cardiac output, while peripheral resistance was monitored using impedance cardiography. The lowest frequency of all intradialytic adverse events were observed during HDx. Delayed DRT was the shortest during PRE-HDF. Patients were also more likely to report immediate recovery while receiving PRE-HDF. These differences did not reach statistical significance; however, the study results suggest that intradialytic tolerance and DRT may depend on the dialysis method used. This supports the need of taking into account patient preferences and quality of life while individualizing high-efficiency therapy in HD patients.

PD-1 Receptor (+) T cells are associated with the efficacy of the combined treatment with regulatory t cells and rituximab in type 1 diabetes children via regulatory t cells suppressive activity amelioration.

An imbalance between exaggerated autoaggressive T cell responses, primarily CD8 + T cells, and impaired tolerogenic mechanisms underlie the development of type 1 diabetes mellitus. Disease-modifying strategies, particularly immunotherapy focusing on FoxP3 + T regulatory cells (Treg), and B cells facilitating antigen presentation for T cells, show promise. Selective depletion of B cells may be achieved with an anti-CD20 monoclonal antibody (mAb). In a 2-year-long flow cytometry follow-up, involving 32 peripheral blood T and B cell markers across three trial arms (Treg + rituximab N = 12, Treg + placebo N = 13, control N = 11), we observed significant changes. PD-1 receptor (+) CD4 + Treg, CD4 + effector T cells (Teffs), and CD8 + T cell percentages increased in the combined regimen group by the end of follow-up. Conversely, the control group exhibited a notable reduction in PD-1 receptor (+) CD4 + Teff percentages. Considering clinical endpoints, higher PD-1 receptor (+) expression on T cells correlated with positive responses, including a higher mixed meal tolerance test AUC, and reduced daily insulin dosage. PD-1 receptor (+) T cells emerged as a potential therapy outcome biomarker. In vitro validation confirmed that successful Teff suppression was associated with elevated PD-1 receptor (+) Treg levels. These findings support PD-1 receptor (+) T cells as a reliable indicator of treatment with combined immunotherapy consisting of Tregs and anti-CD20 mAb efficacy in type 1 diabetes mellitus.

Clinical application of regulatory T cells in type 1 diabetes.

Regulatory T cells (Tregs) are responsible for the maintenance of peripheral tolerance. Animal studies have shown that administration of Tregs can prevent type 1 diabetes (DM1). Several clinical trials attempted to induce Tregs with various agents, and thus provide long-term tolerance of ß cells in DM1. Nevertheless, most of these studies have focused on clinical parameters (e.g. C-peptide) and not Treg numbers nor their function after treatment. Therefore, it is not possible to conclude if the majority of these therapies failed because the drugs did not induce Tregs, or if they failed despite Treg expansion. The current knowledge regarding Tregs, along with our experience in Treg therapy of patients with graft versus host disease, prompted us to use ex vivo expanded Tregs in 10 children with recent-onset DM1. No adverse effects in the treated individuals were observed. There was a significant increase in Treg number in peripheral blood immediately after the treatment administration, while the first clinical differences between treated and control patients were observed 4 months after Treg injection. Treated individuals had higher C-peptide levels and lower insulin requirements than non-treated children. Eleven months after diagnosis of DM1, there are still 2 individuals who are independent of exogenous insulin. These results indicate that autologous Tregs are a safe and well-tolerated therapy in children with DM1, which can inhibit or delay the destruction of pancreatic ß cells. Additionally, Tregs can be a useful tool for local protection of transplanted pancreatic islets. Isolation and expansion of antigen-specific Tregs is one of the directions for future studies on cellular therapy of DM1.

Cardiovascular risk factors among Polish employees of uniformed services.

OBJECTIVES: Employees of uniformed services (EoUS) were screened for cardiovascular risk factors. MATERIAL AND METHODS: A total of 1138 EoUS (age M±SD 49.9±6.0 years) and 263 controls (age M±SD 54.4±9.7 years) under the care of the cardiology clinic in Gdansk, Poland, were included in the study. Medical history and blood samples were collected, and a physical examination was performed. Ten-year cardiovascular risk of death was calculated using the systematic coronary risk evaluation (SCORE) risk algorithm for high-risk countries. RESULTS: Significantly higher values of mean systolic and mean diastolic blood pressure, mean total cholesterol level and mean BMI were recorded among the EoUS compared to controls (M±SD 141.7±11.6 mm Hg vs. 135.5±11.0 mm Hg, p < 0.001; 90.1±5.9 mm Hg vs. 84.5±6.8 mm Hg, p < 0.001; 6.01±0.76 mmol vs. 5.44±0.87 mmol, p < 0.001; 29.3±4.7 vs. 29.0±4.1, p < 0.001, respectively). Smoking cigarettes was most frequently reported by the youngest group (20-39 years old) - 47.7% and it was significantly higher in the entire EoUS group compared to control group (35.5% vs. 16.7%, p = 0.001). The occurrence of observed risk factors (blood pressure ≥140/90 mm Hg, total cholesterol concentration >5 mmol, smoking,) was significantly higher among EoUS compared to controls (92.1% vs. 57.8%, p < 0.001; 89.0% vs. 66.9%, p < 0.001; 35.5% vs. 16.7%, p < 0.001, respectively). In the male group, the mean calculated ten-year risk of fatal cardiovascular events, the percentage of high calculated risk, and very high risk were higher in the EoUS group compared to controls (M±SD 4.44±3.49 vs. 4.23±3.86, p = 0.001; 23.7% vs. 20.2%, p = 0.007; 7.4% vs. 6.5%, p = 0.03, respectively). CONCLUSIONS: The prevalence of all identified risk factors was found to be higher among employees of uniformed services when compared to the control group. The presence of these risk factors within the population of uniformed service employees results in a greater risk of mortality from cardiovascular diseases. Int J Occup Med Environ Health. 2023;36(5):656-71.