High average daily temperature in summer and the incidence of thrombolytic treatment for acute ischemic stroke.

INTRODUCTION: Meteorological factors can increase stroke risk; however, their impact is not precisely understood. Heat waves during summer increase total mortality. Therefore, we hypothesized that the average daily temperature in summer may correlate with the incidence of thrombolytic treatment for acute ischemic stroke in Budapest and Pest County, Hungary. METHODS: We analyzed the relationship between the average daily temperature in summer months and the daily number of thrombolytic treatments (TT) performed with the indication of acute ischemic stroke between 1st June and 31st August each year from 2007 to 2016. The analysis was also performed after the omission of the data of the last day of the months due to possible psychosocial impact reported in our previous study. Spearman's correlation was used for statistical analysis. RESULTS: No significant correlation was found between the average summer daily temperature and the number of TT in the entire sample of the 10-year period. When omitting the data of the last day of each month, positive correlations were suspected in 2014 (r=0.225, P=0.034) and 2015 (r=0.276, P=0.009). CONCLUSION: Our findings did not confirm an association between the average daily temperature in summer and the daily number of TT throughout the examined 10-year period. However, importantly, in 2014 and 2015, the years with the highest average daily temperatures in this period, a positive correlation was found. The level of correlation is modest, indicating that risk factors, both meteorological and non-meteorological, other than the average temperature, play equally important roles in determining the incidence of thrombolytic treatment for acute ischemic stroke on the population level.

The Proportion of Recent Thymic Emigrant Lymphocytes in Breastfed and Formula Fed Term Neonates.

Recent thymic emigrants (RTEs) represent a distinct T cell subset characterized by a tolerance-prone status. We have recently demonstrated that the proportion of regulatory T cells (Tregs) is nearly two-fold higher in exclusively breastfed compared with exclusively formula-fed neonates. However, it has been unknown whether the type of milk is also associated with the proportion of the RTE cell compartment. Cord blood (CB) and, at three weeks of age, peripheral venous blood samples were collected from 19 healthy-term neonates. A maternal blood sample was also taken. The proportion of RTEs, naïve CD4 cells, naïve RTEs, and Tregs was analyzed by flow cytometry in blood samples. RTE cell proportions were comparable between CB and 3 weeks. At both time points, there was no difference in the proportion of naïve CD4 cells, RTE CD4 cells, and naïve RTE CD4 cells between the feeding groups. The fold change of RTE cells between birth and three weeks of life was highest in mixed-fed babies. Since RTE counts were comparable across the feeding groups at birth, this most likely reflects a postnatal upregulation, to which the dual antigenic exposure to both non-inherited maternal antigens via breastmilk, as well as to other environmental antigens in formula milk, may contribute.

Comparison of Homologous and Heterologous Booster SARS-CoV-2 Vaccination in Autoimmune Rheumatic and Musculoskeletal Patients.

Vaccination against SARS-CoV-2 to prevent COVID-19 is highly recommended for immunocompromised patients with autoimmune rheumatic and musculoskeletal diseases (aiRMDs). Little is known about the effect of booster vaccination or infection followed by previously completed two-dose vaccination in aiRMDs. We determined neutralizing anti-SARS-CoV-2 antibody levels and applied flow cytometric immunophenotyping to quantify the SARS-CoV-2 reactive B- and T-cell mediated immunity in aiRMDs receiving homologous or heterologous boosters or acquired infection following vaccination. Patients receiving a heterologous booster had a higher proportion of IgM+ SARS-CoV-2 S+ CD19+CD27+ peripheral memory B-cells in comparison to those who acquired infection. Biologic therapy decreased the number of S+CD19+; S+CD19+CD27+IgG+; and S+CD19+CD27+IgM+ B-cells. The response rate to a booster event in cellular immunity was the highest in the S-, M-, and N-reactive CD4+CD40L+ T-cell subset. Patients with a disease duration of more than 10 years had higher proportions of CD8+TNF-α+ and CD8+IFN-γ+ T-cells in comparison to patients who were diagnosed less than 10 years ago. We detected neutralizing antibodies, S+ reactive peripheral memory B-cells, and five S-, M-, and N-reactive T-cells subsets in our patient cohort showing the importance of booster events. Biologic therapy and <10 years disease duration may confound anti-SARS-CoV-2 specific immunity in aiRMDs.

Successful thrombolytic therapy is associated with increased granulocyte CD15 expression and reduced stroke-induced immunosuppression.

OBJECTIVES: Stroke-induced immunosuppression (SIIS) increases the risk of poststroke infections. We aimed to determine whether failed versus successful thrombolytic therapy (TT) resulted in SIIS-associated changes in peripheral granulocyte markers at 1 week following the insult. METHODS: We collected peripheral blood samples from 19 patients with acute ischemic stroke undergoing TT within 6 h after the onset of their first symptoms and 7 days after the insult. Age-matched controls were sampled on one occasion. We compared the expression of CD15 and CD64 on monocytes, granulocytes, and lymphocytes using flow cytometry. RESULTS: The proportion of granulocytes and CD15+ granulocytes was comparable between controls and stroke patients at both time points. While the proportion of CD15bright granulocytes was also comparable, the mean fluorescence intensity (MFI) of CD15 on this subset was reduced in stroke patients by day 7 but was overall higher at both time points compared to controls. The MFI of CD15 on granulocytes was lower in stroke patients with failed TT than in those with successful TT 1 week after the insult. CONCLUSIONS: Our current results indicate that TT may not only acutely reduce the systemic inflammatory response following stroke but may also play a role in reversing SIIS at a later stage following the insult, as reflected by the higher expression of the CD15 marker on granulocytes following successful TT.

The Impact of Short-Chain Fatty Acids on Neonatal Regulatory T Cells.

Over the first weeks of life, the neonatal gastrointestinal tract is rapidly colonised by a diverse range of microbial species that come to form the 'gut microbiota'. Microbial colonisation of the neonatal gut is a well-established regulator of several physiological processes that contribute to immunological protection in postnatal life, including the development of the intestinal mucosa and adaptive immunity. However, the specific microbiota-derived signals that mediate these processes have not yet been fully characterised. Accumulating evidence suggests short-chain fatty acids (SCFAs), end-products of intestinal bacterial metabolism, as one of the key mediators of immune development in early life. Critical to neonatal health is the development of regulatory T (Treg) cells that promote and maintain immunological tolerance against self and innocuous antigens. Several studies have shown that SCFAs can induce the differentiation and expansion of Tregs but also mediate pathological effects in abnormal amounts. However, the exact mechanisms through which SCFAs regulate Treg development and pathologies in early life remain poorly defined. In this review, we summarise the current knowledge surrounding SCFAs and their potential impact on the neonatal immune system with a particular focus on Tregs, and the possible mechanisms through which SCFAs achieve their immune modulatory effect.

Neonatal BCG: a time for change.

The BCG vaccination programme in the UK is risk based and has usually been given to eligible babies soon after birth. On advice from the Joint Committee on Vaccination and Immunisation, NHS England and Improvement recently revised the timing of this vaccination to 28 days after birth or soon thereafter. In this article, we highlight the change in timing of vaccination, the rationale and barriers to BCG uptake that this change may pose.

Humoral and Cellular Immunogenicity and Safety of Five Different SARS-CoV-2 Vaccines in Patients With Autoimmune Rheumatic and Musculoskeletal Diseases in Remission or With Low Disease Activity and in Healthy Controls: A Single Center Study.

Background: Vaccine-induced immunity is essential for controlling the COVID-19 pandemic. Data on humoral and cellular immunogenicity and safety of different SARS-CoV-2 vaccines in patients with autoimmune rheumatic and musculoskeletal diseases (RMDs) are limited. Methods: A single center observational study evaluated the immunogenicity and safety of the two-dose regimen of the BBIBP-CorV inactivated, Gam-COVID-Vac and AZD1222 adenovirus-based, and BNT162b2 and mRNA-1273 mRNA-based vaccines in patients with RMDs (n = 89) compared with healthy controls (n = 74). Neutralizing anti-RBD (receptor binding domain) specific antibodies and SARS-CoV-2 specific T-cell response were measured one and four months after the second vaccine dose in parallel with vaccination efficacy and safety. Results: Disease-specific comparison showed that antibody response at four months was higher in spondylarthropathies compared to rheumatoid arthritis and autoimmune RMDs. Risk factors for reduced immunogenicity included longer disease duration, positive immunoserological profile and anti-CD20 therapy of patients. The rate of positive anti-RBD antibody response for healthy controls versus patients after 4 months post vaccination was 69% vs. 55% for the inactivated viral vaccine BBIBP-CorV, 97% vs. 53% for the pooled data of adenovirus vector-based vaccines Gam-COVID-Vac and AZD1222, or 100% vs. 81% for the pooled data of mRNA vaccines BNT162b2 and mRNA-1273, respectively. Patients who received the Gam-COVID-Vac or mRNA-1273 vaccines had a higher proportion of TNF-α producing CD4+ T-cells upon SARS-CoV-2 antigen stimulation compared to the inactivated viral vaccine. Conclusion: All five investigated vaccines were immunogenic in the majority of patients and healthy controls with variable antibody and T-cell response and an acceptable safety profile.

The association between parental and neonatal BCG vaccination and neonatal T helper 17 cell expansion.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination reduces the severity of neonatal infections; this effect appears enhanced if the mother has received BCG. We performed immunophenotyping of the T-cell subset and characterized T-cell proliferation responses to assess possible immune response pathways. METHODS: Healthy BCG-vaccinated (n = 8) and unvaccinated (n = 9) neonates born by elective caesarean section were sampled 3 weeks after birth. We compared a wide panel of intracellular cytokine and cell surface expression markers as well as proliferation response in T-cells between BCG-vaccinated and unvaccinated neonates, stratified by parental BCG status. RESULTS: For all BCG-vaccinated neonates and 3 of 9 unvaccinated neonates that served as controls, both parents had a BCG scar. Th17 (CD4 + IL-17+) prevalence as percentage of total CD4 + T-cells was expanded 4-fold in BCG-vaccinated compared to unvaccinated, being 11.6% [3.6-19.6%] vs 2.8% [1.0-6.6%]. Th17 counts for 3 unvaccinated neonates born to BCG-vaccinated parents was comparable to vaccinated neonates, and higher than remaining controls, parental BCG = 8.5% [4.4-8.9%] vs 1.8% [0.8-3.3%] for no parental BCG (median [interquartile range] for all data). CONCLUSION: Among neonates born to BCG-vaccinated parents, the prevalence of Th17 cells, important in the response against bacterial infections, was substantially elevated. The interaction between neonatal and parental BCG for Th17 responses and the importance remains to be further investigated.

Recommendations for diagnosis and treatment of methemoglobinemia.

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions.

Fetal ultrasound diagnosis allows effective early postnatal treatment of hematometrocolpos.

Fetal hematometrocolpos is a rare finding with an incidence of 1 in 16 000 female births. We present a case of fetal hematometrocolpos managed exclusively by prenatal and postnatal ultrasound scans allowing for effective immediate postnatal surgical treatment.

T Lymphocytes, Multi-Omic Interactions and Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) remains a significant clinical challenge in neonatal medicine. BPD is clearly a multifactorial disease with numerous antenatal and postnatal components influencing lung development. Extremely immature infants are born in the late canalicular or early saccular stage and usually receive intensive care until the early alveolar stage of lung development, resulting in varying magnitudes of impairment of alveolar septation, lung fibrosis, and abnormal vascular development. The interactions between T lymphocytes, the genome and the epigenome, the microbiome and the metabolome, as well as nutrition and therapeutic interventions such as the exposure to oxygen, volutrauma, antibiotics, corticosteroids, caffeine and omeprazole, play an important role in pathogenesis and disease progression. While our general understanding of these interactions thanks to basic research is improving, this knowledge is yet to be translated into comprehensive prevention and clinical management strategies for the benefit of preterm infants developing BPD and later during infancy and childhood suffering from the disease itself and its sequelae. In this review, we summarise existing evidence on the interplay between T lymphocytes, lung multi-omics and currently used therapeutic interventions in BPD, and highlight avenues for potential future immunology related research in the field.

Fatal outcome of cervical myelopathy caused by fibrocartilaginous embolism. Rare cause of spinal vascular damage.

BACKGROUND AND PURPOSE: Fibrocartilaginous embolism is a rare cause of ischemic myelopathy. Authors report a case of a 39-year-old woman with progressive tetraparesis and severe autonomic dysfunction. Despite of the detailed examinations, the definite diagnosis was verified by autopsy. METHODS: The patient was admitted because of progressive pain and numbness of the upper extremities and tetraparesis. Hypotonic muscles of the lower extremities with mild tetraparesis were observed. Magnetic resonance imaging showed an intramedullary lesion at the level of the cervical V-VII vertebral. Patient's tetraparesis worsened gradually to plegia with urinary retention. Expansive, rapidly progressing multiple decubiti developed, which were resistant to therapy. In spite of the complex therapy, the patient died. RESULTS: No internal disease was found to explain the death by autopsy. Multiple subacute infarctions of the cervical myelon (involving the lateral columns as well) in the territory of the anterior spinal artery were verified by neuropathological examination. The occluded vessels were filled by a material containing cartilaginous cells, while signs of atherosclerosis or thrombosis were not present. CONCLUSION: Cartilaginous embolism of spinal arteries was diagnosed.

Kynurenic Acid Analog Attenuates the Production of Tumor Necrosis Factor-α, Calgranulins (S100A 8/9 and S100A 12), and the Secretion of HNP1-3 and Stimulates the Production of Tumor Necrosis Factor-Stimulated Gene-6 in Whole Blood Cultures of Patients With Rheumatoid Arthritis.

Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease with complex pathogenesis involving a variety of immunological events. Recently, it has been suggested that kynurenic acid (KYNA) might be a potential regulator of inflammatory processes in arthritis. KYNA has a definitive anti-inflammatory and immunosuppressive function. The aim of the present study is to investigate the complex effects of a newly synthesized KYNA analog-SZR72 on the in vitro production of tumor necrosis factor-α (TNF-α), tumor necrosis factor-stimulated gene-6 (TSG-6), calprotectin (SA1008/9), SA100 12 (EN-RAGE), and HNP1-3 (defensin-α) in the peripheral blood of patients with RA and the various effects of the disease. Methods: Patients with RA (n = 93) were selected based on the DAS28 score, medication, and their rheumatoid factor (RF) status, respectively. Peripheral blood samples from 93 patients with RA and 50 controls were obtained, and activated by heat-inactivated S. aureus. Parallel samples were pretreated before the activation with the KYNA analog N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride. Following the incubation period (18 h), the supernatants were tested for TNF-α, TSG-6, calprotectin, S100A12, and HNP1-3 content by ELISA. Results: SZR72 inhibited the production of the following inflammatory mediators: TNF-α, calprotectin, S100A12, and HNP1-3 in whole blood cultures. This effect was observed in each group of patients in various phases of the disease. The basic (control) levels of these mediators were higher in the blood of patients than in healthy donors. In contrast, lower TSG-6 levels were detected in patients with RA compared to healthy controls. In addition, the KYNA analog exerted a stimulatory effect on the TSG-6 production ex vivo in human whole blood cultures of patients with RA in various phases of the disease. Conclusion: These data further support the immunomodulatory role of KYNA in RA resulting in anti-inflammatory effects and draw the attention to the importance of the synthesis of the KYNA analog, which might have a future therapeutic potential.

Urine soluble urokinase plasminogen activator receptor as a potential biomarker of lupus nephritis activity.

There is a lack of non-invasive biomarkers to identify lupus nephritis (LN). Soluble urokinase plasminogen activator receptor (suPAR) is a sensitive biomarker of ongoing inflammation and a potential marker of podocyte dysfunction. The aim of this study was to assess urine and plasma suPAR in LN. 14 systemic lupus erythematosus (SLE) patients with newly diagnosed LN, 8 active SLE patients (SLEDAI >8) without LN and 31 healthy individuals were enrolled. Urine and plasma samples were taken before the initiation of LN induction therapy, and monthly thereafter. Global and renal disease activity were defined using the SLEDAI-2K and the SLEDAI-2K renal domain score, respectively. suPAR concentrations were measured with the suPARnostic Flex ELISA assay. Urine and plasma suPAR levels were elevated in SLE patients with active LN compared with resolved LN and healthy controls. Urine suPAR levels were comparable to healthy controls in active SLE without LN. Urine and plasma suPAR levels were higher before than after the initiation of LN induction therapy. Prospective follow-up measurements also suggested that urine suPAR levels raised again in patients with a relapse of LN according to SLEDAI-2K renal domain score, whereas plasma suPAR levels did not correlate with renal disease activity. Urine suPAR is a promising LN activity biomarker, given its isolated elevation in urine in active LN and pronounced decrease with LN improvement.

Non-specific effects of BCG vaccination on neutrophil and lymphocyte counts of healthy neonates from a developed country.

BCG vaccination is known to reduce neonatal mortality from infections in a pathogen-agnostic manner. In this observational study we report on whether an emergency granulopoietic response is elicited in term babies from a developed country following BCG vaccination. We studied a cohort of neonates re-admitted to the hospital from home for feeding support separated into 2 groups dependent on whether they had received BCG vaccination. Clinical data including gender, weight, gestational age, method of feeding and full blood count results were retrieved retrospectively. While lymphocyte counts increase following BCG vaccination irrespective of gender and in proportion with the time elapsed after vaccination, the increase in neutrophil counts, is only observed in boys. This increase appears to be temporary. Our results confirm the presence of emergency granulopoiesis following BCG vaccination in a neonatal cohort from a developed country. However, this effect appears to be gender-specific and is present only in boys.

Christmas, acute ischemic stroke and stroke-related mortality in Hungary.

OBJECTIVES: Risk factors for stroke include psychological effects, such as depression. Festive occasions (such as Christmas in Hungary) may carry a significant emotional impact and may therefore contribute to increased cardiovascular risk. Thrombolytic treatment of acute ischemic stroke has a narrow time window and allows for the precise assessment of stroke incidence. MATERIALS & METHODS: We analyzed anonymized national data of the number of thrombolytic treatments for acute ischemic stroke and the number of stroke-related deaths between 1 January 2007 and 31 December 2016 in Hungary within 2-day, 5-day, and 1-month periods preceding and following 24 December each year. Analysis of subgroups based on age (below and over 65 years) and sex was also performed. RESULTS: The number of thrombolytic treatments was higher in all three periods preceding Christmas compared to the corresponding period that follows the feast. This increase was particularly prominent in men below 65 years of age. While overall stroke-associated mortality was increased 1 month after Christmas, the death rate was higher a month before rather than after Christmas in men below 65 years of age and in women both below and over 65 years of age 5 days before Christmas. CONCLUSIONS: These findings may predominantly relate to emotional and psychological factors. In case of women, the anxiety secondary to festive preparations, while in men below 65 years, the increased psychological stress of providing financial security for the celebration may play an important role.

Breastfeeding promotes early neonatal regulatory T-cell expansion and immune tolerance of non-inherited maternal antigens.

BACKGROUND: Breastfeeding is associated with long-term health benefits, such as a lower incidence of childhood infections, asthma, obesity and autoimmune disorders. However, little is known regarding how the maternal and neonatal immune systems interact after parturition when the neonate receives nutrition from maternal breast milk. METHODS: We undertook a comparative analysis of immune repertoire and function at birth and 3 weeks of age in a cohort of 38 term neonates born by caesarean section grouped according to feeding method (breast milk versus formula). We used flow cytometry to study the immune phenotype in neonatal and maternal blood samples and mixed lymphocyte reactions to establish the proliferation response of neonatal versus maternal lymphocytes and vice versa. The microbiome of neonatal stool samples was also investigated using 16S rRNA sequencing. RESULTS: We show that the proportion of regulatory T cells (Tregs) increases in this period and is nearly twofold higher in exclusively breastfed neonates compared with those who received formula milk only. Moreover, breastfed neonates show a specific and Treg-dependent reduction in proliferative T-cell responses to non-inherited maternal antigens (NIMA), associated with a reduction in inflammatory cytokine production. We also observed the enrichment of short chain fatty acid producing taxa (Veillonella and Gemella) in stool samples of exclusively breastfed neonates. CONCLUSIONS: These data indicate that exposure of the neonate to maternal cells through breastfeeding acts to drive the maturation of Tregs and 'tolerizes' the neonate towards NIMA.

Epileptic Seizure Provoked by Bone Metastasis of Chronic Lymphoid Leukemia and Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare primary neuroendocrine cutaneous tumor, rarely metastasizing to the brain. Chronic lymphoid leukemia (CLL) is a disease predisposing to MCC. According to previous reports, headache and focal neurological deficits suggest disease progression to the brain. We present a patient with MCC whose seizure was not elicited by a cerebral metastasis, but by bone metastases compressing the brain. Case Presentation. A 62-year-old female patient had a history of CLL. A lesion with the appearance of an atheroma was removed from the right upper arm. Histology confirmed the diagnosis of MCC. She was admitted to the neurology department with her first GM seizure. The cranial MRI/MRA showed bone metastases in the right parietal and both frontal areas, compressing the brain. Flow cytometry of CSF did not reveal metastasis of MCC. CONCLUSIONS: The case history of the patient was unique even among the rare cases of MCC with neurological involvement. The seizure was not elicited by a cerebral metastasis, but by bone metastases compressing the brain. In addition to patient history, clinical presentation and radiological findings enabled a suspected diagnosis of skull metastasis of MCC compressing the brain, causing symptomatic epileptic seizures.