Long-term outcomes and immune profiling in children with multisystem inflammatory syndrome (MIS-C).

BACKGROUND AND AIM: Existing follow-up data after MIS-C is limited. PURPOSE OF THE STUDY: to investigate the long-term consequences in children who have undergone MIS-C. METHODS: The retrospective study included 93 children. The identified changes were divided into the following periods: occurred within first 6 months, 1 year, 2 years, and more than 2 years after MIS-C. Besides, 31 children underwent prospective immunophenotyping of peripheral blood and the determination of cytokines during the acute period of the disease and after discharge. RESULTS: Outpatient monitoring events included pneumonia (9.6%), somatic disorder syndrome (11.8%), visual impairment (7.5%), joint damage (6.6%), weight changes (2.2%), and MIS-C recurrence (2.2%). A study of the cardiovascular system showed a statistically significant decrease in the frequency of the right and left heart dilatation, left ventricular dysfunction, pericarditis, pulmonary arterial hypertension, coronaritis, mitral regurgitation. But at the same time an increase in pulmonary and tricuspid valve regurgitation and arrhythmias compared with the acute period was detected. Most of the changes took place within first year of observation. Immune profiling showed reconstitution of CD3, CD4 T-lymphocytes, NK-cells, maintenance of a high relative value of CD8, reduction of CD19+ B-cells, expression of CD3-HLA-DR+, CD25, CD279, CD95. CONCLUSIONS: After the history of MIS-C, children in the long-term follow-up had various somatic disorders and disease recurrence. Most patients (64.1%) showed subclinical signs of myocardial involvement within first year of observation. Low expression of CD95 may justify an certain role in the pathogenesis of the disease.

Distribution and density of CD1a+ and CD83+ dendritic cells in HPV-associated laryngeal papillomas.

BACKGROUND: Respiratory papillomatosis associated with human papilloma virus (HPV) infection is the most common benign laryngeal neoplasm. The age of patients at disease onset, HPV type, number of surgeries are well known prognostic factors of the disease course. The correlation between dendritic cell (DC) density in tumor tissue and clinical prognosis was established. AIM: The aim of our study was to estimate the density of DC in laryngeal papillomas associated with HPV types 6/11 infection and to evaluate the relationship between the number of DC and the disease severity. MATERIALS AND METHODS: Our study included 40 randomly selected biopsy specimens from patients with HPV-positive laryngeal papillomatosis aged from 1.7 to 20 year. DC were immunohistochemically labelled with anti-CD1a antibodies and anti-CD83 antibodies. The density of DC was analysed in epithelial layer and lamina propria. RESULTS: In the epithelial layer of papillomas the number of CD1a+ and CD83+ DC was 86.2 (47.5-119.9) cells/mm(2) and 2.6 (0.6-7.9) cells/mm(2), respectively. In lamina propria - 15.3 (5.1-27.9) and 16.0 (6.7-33.2) cells/mm(2). For subgroups of patients with high number of operations (more than 3), early disease onset (children under 3 years of age) and lingering duration of disease (more than 1 year) we detected an increase of CD83+ DC in the epithelial layer. However, our data did not demonstrate a statistically significant difference in CD1a+ DC count neither in the epithelium nor in the lamina propria. Probably, the increase of CD83+ DC density in epithelial layer of patients with severe course of disease can be an evidence of impaired migration of matured DC.

Human papilloma virus (HPV)-associated gynecological alteration in mothers of children with recurrent respiratory papillomatosis during long-term observation.

BACKGROUND: Human papilloma virus (HPV) is one of the most frequently observed sexually transmitted infections. The study' purpose was to investigate the relation between a mother's gynecological history and the local status of her child with recurrent respiratory papillomatosis (RRP). METHODS: Forty-two patients enrolled in a prospective multicenter study between 1983 and 1990. The study included patients with juvenile-onset and adult-onset RRP. All patients underwent surgery and treatment with alpha-interferon. Thirty-eight patients were followed up until 31.01.2006. Twenty-five mothers of these patients participated in a parallel prospective study of genital HPV infection. In 1989-1990, all received a routine gynecological examination, an expanded colposcopy, a Pap smear, and a cervical biopsy. The mothers were followed up until February 2006. RESULTS: 74% of patients with RRP were the first-born children. Five (20%) mothers had condylomata acuminata, newly diagnosed during pregnancy. Indicators of HPV infection such as koilocytes, koilocytotic dysplasia and condyloma acuminatum were revealed cytologically in 17% of cases and histologically in 71.4% of cases. Six (24%) of mothers had had a hysterectomy. HPV type 11 was prevalent in the children of mothers who had had a hysterectomy. Among the patients with juvenile-onset RRP, the death rate from squamous cell carcinoma of the lung was significantly higher in those patients whose mothers had a hysterectomy (p=0.028). CONCLUSIONS: Mothers of patients with RRP demonstrated cytological and histological indicators of HPV infection in the genital tract. An adverse outcome of the disease in the child was associated with adverse gynecological history in the mother.

Differences in dendritic cell activation and distribution after intravenous, intraperitoneal, and subcutaneous injection of lymphoma cells in mice.

Dendritic cells (DCs) are key antigen-presenting cells (APCs) for initiating immune responses. However, in recent years, several groups have shown the defective function of DCs in tumor-bearing mice and in cancer patients. Our aim was to study the effects of lymphoma on DC differentiation and maturation and to assess the input of the tumor microenvironment and intravasation of tumor cells on DC precursors. EL-4 lymphoma cells were administrated via different routes (intraperitoneal, subcutaneous, and intravenous) and DC phenotype was investigated. Bone marrow-derived DCs and APCs obtained from the spleen were examined by flow cytometry, and immunohistochemical analysis of lymphoma, lungs, livers, and spleens was also performed. Intravenous administration of lymphoma cells induced suppression of DC differentiation and maturation assessed as a significant decrease of the IAb, CD80, CD86, CD11b, and CD11c expression on DCs and IAb on splenic APCs. Upregulation of APC differentiation was observed in animals after subcutaneous and intraperitoneal administration of lymphoma cells determined as increased expression of CD40 and CD86 in spleen APCs. These data suggest that the development of antitumor immune response might differ in the host receiving tumor vaccines via different injection routes.

Activation of redox-systems of monocytes by hydrogen peroxide.

In this work the influence of H2O2 on the ability of human blood monocytes to generate ROS upon stimulation of cells by adhesion to glass surface and fMLP was studied using the luminol-dependent chemiluminescence (LDCL) method. Pretreatment of cells with H2O2 increased the adhesiveness of monocytes and ROS generation. Superoxide generation by cells in response to fMLP depended on the duration of pretreatment and the concentration of H2O2. The stimulatory effect on fMLP-induced LDCL of cells further depended on the Ca2+ concentration in the medium and on the activities of phospholipase A2, cyclooxygenases, and Mek1/2.

Children and partners of patients with recurrent respiratory papillomatosis have no evidence of the disease during long-term observation.

OBJECTIVE: Recurrent respiratory papillomatosis (RRP) is the most common benign neoplasm affecting the larynx and upper respiratory tract. The aim of our study was to investigate whether children and partners of patients with RRP develop the same disease and to determine whether there is an impact of pregnancy on the course of RRP. PATIENTS AND METHODS: Thirty-eight of 42 patients with RRP were accepted for a multicenter prospective study in Germany in 21.06.83-12.03.90. Mean follow-up duration was 15.3+/-1.8 years. The data of partners of patients with RRP was collected during the period of observation and then updated via interviews in January 2006. Twenty-nine children and four grandchildren were born to 14 patients with RRP. Fifteen of 448 cases of patients with RRP were treated in Saint Vladimir Moscow Children's Hospital in Russia in 1988-2003 and analyzed retrospectively. Sixteen children and one grandchild were born to 15 patients with RRP from Russia. In both studies, the virus type of patients with RRP was identified by nested PCR or Southern blot hybridization. Statistical analysis was performed using Fisher's exact test (probability value set at p<0.05). RESULTS: All children born to patients with RRP were healthy. RRP was not diagnosed in any of them on the basis of clinical or histological examination. Four of 45 children developed dysphonia, two of them had vocal cord nodules. None of the sexual partners of patients has developed RRP during the follow-up period. Pregnancy was accompanied by excessive growth of papillomas in all women (100%) with RRP associated with HPV type 11, and only in 16.7% of women with RRP associated with HPV type 6 (p=0.001). CONCLUSIONS: Patients with RRP are able to have healthy children regardless of the stage of the disease. Partners of RRP patients do not develop RRP during an observation period of 15 years. Pregnancy has a negative impact on the course of RRP and local laryngeal status in patients; it is more significant in HPV type 11 associated cases as it is manifested by more rapid papillomas growth and more frequent recurrence.

Retrospective cohort study of cancer mortality at the Minsk Leather Tannery.

The cohort of 768 workers who were actively employed for a minimum of 6 months and died was retrospectively followed from 1 January 1953 to 31 December 2000. There were 328 women and 440 men observed. Proportionate mortality ratios (PMRs) were calculated using the Minsk-city population mortality proportions to generate expected numbers. The significant excess of pancreatic cancer (PMR=366%; 95%CI=134-800) and melanoma and skin cancer (PMR=455%; 95% CI=123-1,164) in women-workers of Dyeing and stuffing workshops was shown. The significantly high mortality from pancreatic cancer among Dyeing and stuffing workshops' female workers hired and discharged between 1958 and 1984 (PMR=1,024%; 95% CI=11-2,109), melanoma and skin cancer (PMR=440%; 95% CI=240-2,327) among Dyeing and stuffing workshops female workers who started before 1970, lip and buccal cavity among men who began working within 1974-1978 (PMR=1,071%; 95% CI=220-3,128), cervix and corpus uteri cancer among workers employed before l960 was found. It should be noted that the significantly high mortality from above noted cancers was indicated for Dyeing and stuffing workshops female workers with seniority more than 10 yr. Thus it was shown for pancreatic cancer (PMR=418%; 95% CI=136-975), for melanoma and skin cancers (PMR=497%; 95% CI=102-1,450), for uterus cancers (PMR=269%; 95% CI=130-496).

Use of interferon-alpha in recurrent respiratory papillomatosis: 20-year follow-up.

OBJECTIVES: The aim of this study was analysis of the results of use of interferon-alpha (IFN-alpha) in patients with recurrent respiratory papillomatosis (RRP) and correlation of the results with human papillomavirus (HPV) type. METHODS: A multicenter prospective series (42 patients from 22 hospitals) yielded 20 years of follow-up of patients with RRP and HPV typing who were treated with IFN-alpha in doses of 3 MU/m2 3 times per week. RESULTS: During long-term follow-up (mean +/- SD, 172 +/- 36.8 months), the rate of event-free survival evaluated by Kaplan-Meier analysis was 42.8%, and the overall survival rate was 82.6%. The HPV typing revealed an association of HPV 11 with a more aggressive disease course (64% of HPV 11 patients versus 24% of HPV 6 patients), a lower incidence of long-term response to IFN-alpha therapy (14% of HPV 11 patients versus 64% of HPV 6 patients), and a higher incidence of malignant transformation and mortality during follow-up (36% and 24%, respectively, of HPV 11 patients versus 0% of HPV 6 patients). CONCLUSIONS: The obtained results revealed maximal effectiveness of IFN-alpha therapy in RRP patients with HPV 6 as compared with HPV 11. The association of HPV 11 with a worse long-term response to IFN-alpha therapy and a higher incidence of malignant transformation and mortality is clinically important and indicates the necessity of HPV typing in RRP patients after the first biopsy.

Incidence, age at onset, and potential reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years experience.

Forty-two patients with recurrent respiratory papillomatosis (RRP) were accepted into a multicenter prospective study in 1983 to 1990, treated with alfa-IFN 3 MU/m 2 3 times a week and then followed-up until August 1, 2003. All the patients who had disease progression with pulmonary spread were characterized by insufficient response to IFN-therapy and detection of HPV type 11. Five patients (4/5 smokers) presented malignant transformation in lungs or nasopharynx (mean RRP duration was 27.2 +/- 8 years from RRP onset and 14.6 +/- 6.3 years from pulmonary spread until malignant transformation) with persistent RRP in larynx. The results of long-term follow-up in RRP patients with HPV 11 underline the necessity of reanalyzing the current therapy.

Effects of S-acetylglutathione in cell and animal model of herpes simplex virus type 1 infection.

Intracellular glutathione (GSH) plays an important regulatory role in the host response to viral infections. Replenishment of intracellular GSH is a desirable yet challenging goal, since systemic GSH supplementation is rather inefficient due to a short half-life of GSH in blood plasma. Further, GSH is not taken up by cells directly, but needs to be broken down into amino acids and resynthesized to GSH intracellularly, this process often being impaired during viral infections. These obstacles may be overcome by a novel glutathione derivative S-acetylglutathione (S-GSH), which is more stable in plasma and taken up directly by cells with subsequent conversion to GSH. In the present study, in vitro effects of supplementation with S-GSH or GSH on intracellular GSH levels, cell survival and replication of human herpes simplex virus type 1 (HSV-1) were studied in human foreskin fibroblasts. In addition, in vivo effects of supplementation with S-GSH or GSH on HSV-1-induced mortality were studied in hr/hr mice. In cell culture, viral infection resulted in a significant decrease of intracellular GSH levels. S-GSH efficiently and dose-dependently (5 and 10 mM tested) restored intracellular GSH, and this replenishment was more efficient than with GSH supplementation. In mice, S-GSH, but not GSH, significantly decreased HSV-1-induced mortality ( P<0.05). The data suggest that S-GSH is a suitable antiviral agent against HSV-1 both in vitro and in vivo, indicating that this drug may be of benefit in the adjunctive therapy of HSV-1 infections.

Quantitative morphometric analysis of the submucous plexus in age-related control groups.

An increased number and density of the so-called "giant ganglia" (seven or greater ganglion cells per ganglion) serve as histopathological criteria for a bowel motility disorder called intestinal neuronal dysplasia of the submucous plexus (IND B). However, because these morphological criteria have been defined based upon observations in constipated patients, the diagnostic value of previous studies is open to controversy. Moreover, no age-related reference data from unaffected controls are available. This study reports on data from unaffected controls on the variability of size and distribution of ganglia in the submucous plexus during development. Therefore, for the first time, the normal status has been defined. Four age groups have been defined: (a) premature births, gestational age less than 35 weeks; (b) 1-365 days; (c) 1-14 years and (d) 15 years to greater than 70 years). All of these groups revealed giant ganglia in the submucous plexus. With advancing age, there was a decrease in the number of giant ganglia (from 32.7% in group a to 11.2% in group d) accompanied by an inverse increase in the mean distance between all ganglia (from 0.52 mm in group a to 1.17 mm in group d). The data presented permit the conclusion that the criteria mentioned above are not apt to define IND B as an entity, since they do not allow a sufficient demarcation from the age-correlated normal values presented here.

Granulocyte macrophage colony-stimulating factor regulates activity of the nervous system.

OBJECTIVES: The peripheral administration of granulocyte macrophage colony-stimulating factor (GM-CSF), widely used for the treatment of cytopenias, is often associated with neurological effects [Lieschke et al., N Engl J Med 1992;327:28-34]. This cytokine has recently been reported to affect neurotransmitter metabolism in the nervous system [Bianchi, Neuroreport 1997;8:3587-3590]. To further investigate the neuromodulatory effect of GM-CSF we studied the influence of GM-CSF on the efferent electric activity in the splenic nerve and the integral neuronal activity in medullary gigantocellular reticular formation (MGRF) in rats. METHODS: Anaesthetized (sodium thiopental 70 mg/kg, i.p.) Wistar rats were injected subcutaneously with 1 microg/kg of hr GM-CSF. Efferent electric activity in the splenic nerve and integral electric activity in MGRF were analyzed. The effectiveness of the applied dose of GM-CSF was verified by determining the elevation of the white blood cell count in peripheral blood 60 min after injection. RESULTS: We found that GM-CSF increases efferent electric activity in the splenic nerve and decreases that of MGRF as is evident by the frequency of electric discharges. The latency of both effects was 5-15 min. CONCLUSIONS: This data support the view that GM-CSF exerts a neuromodulatory effect and may provide a new link of neuroimmune communication.

Lung cancer-derived bombesin-like peptides down-regulate the generation and function of human dendritic cells.

Development of tumors is regulated by tumor-derived neuroendocrine factors, including bombesin-like peptides (BLP). We have evaluated neuroendocrine regulation of dendritic cell (DC) maturation and function by both tumor-derived and purified bombesin (BOM), neuromedin B (NMB), gastrin-releasing peptide (GRP), and a BOM antagonist D-Phe-bombesin (DPB). BOM, NMB and GRP dose-dependently inhibited maturation of DC assessed as down-regulation of CD40, CD80 and CD86 expression on DC. BOM and GRP also inhibited interleukin-12 (IL-12) production by DC and their ability to activate T cells. DPB partly abrogated immunosuppressive effect of tumor cells on DC. These data are a first evidence for the role of BLP in the regulation of DC maturation and function, demonstrating that BLP inhibit DC maturation and longevity in the lung cancer microenvironment. This suggests a new mechanism of tumor escape and provides new targets for the immunopharmacological correction of immune effectors in cancer.