Severe Inflammatory Complications Research Articles

Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome

Mutations in proteasome β-subunits or their chaperone and regulatory proteins are associated with proteasome-associated autoinflammatory disorders (PRAAS). We studied six unrelated infants with three de novo heterozygous missense variants in PSMB10, encoding the proteasome β2i-subunit. Individuals presented with T-B-NK± severe combined immunodeficiency (SCID) and clinical features suggestive of Omenn syndrome, including diarrhea, alopecia, and desquamating erythematous rash. Remaining Tcells had limited Tcell receptor repertoires, a skewed memory phenotype, and an elevated CD4/CD8 ratio. Bone marrow examination indicated severely impaired B cell maturation with limited V(D)J recombination. All infants received an allogeneic stem cell transplant and exhibited a variety of severe inflammatory complications thereafter, with 2 peri-transplant and 2 delayed deaths. The single long-term transplant survivor showed evidence for genetic rescue through revertant mosaicism overlapping the affected PSMB10 locus. The identified variants (c.166G>C [p.Asp56His] and c.601G>A/c.601G>C [p.Gly201Arg]) were predicted in silico to profoundly disrupt 20S immunoproteasome structure through impaired β-ring/β-ring interaction. Our identification of PSMB10 mutations as a cause of SCID-Omenn syndrome reinforces the connection between PRAAS-related diseases and SCID.

A232 TEMPORAL TRENDS IN RE-HOSPITALIZATION RATES AMONG PATIENTS WITH INFLAMMATORY BOWEL DISEASE IN THE POST-BIOLOGIC ERA

Abstract Background Hospitalization for severe inflammatory bowel disease (IBD) flares or complications are a major source of morbidity and healthcare expenditure. Aims To assess temporal trends in 30-day and 90-day re-hospitalization rates among persons with Crohn’s disease (CD) and ulcerative colitis (UC) in the post-biologic era. Methods We conducted a population-based study of all non-elective IBD-related hospitalizations among patients with CD and UC in Ontario, Canada between April 1, 2002 and March 31, 2020. We identified individuals, admissions, and variables of interest from Ontario population health administrative datasets housed at IC/ES. We performed multivariable logistic regression analysis to evaluate the association between time period of hospitalization (2002-2007 vs. 2002-2007 vs. 2007-2012 for CD; 2004-2008 vs. 2008-2012 vs. 2012-2016 vs. 2016-2020 for UC) and rates of 30-day and 90-day re-hospitalization, adjusting for patient age, sex, co-morbidities, residential setting, income quintile, hospital type of initial admission, and clustering of hospital admissions within patients. We excluded patients with elective admissions or length of stay ampersand:003C24 hours, and those without continuous valid Ontario health care registration during the 90-day period following hospital discharge. Results There were 18,625 hospitalizations among 14,868 patients with CD, and 10,830 hospitalizations among 9,264 patients with UC. The 30-day re-hospitalization rate was 8.5% for patients with CD and 9.7% for patients with UC, while the respective 90-day re-hospitalization rates were 15.0% and 13.8%. For CD, re-admission rates differed across the 3 time periods (pampersand:003C0.0001 for 30-day and p=0.012 for 90-day). For UC, re-hospitalization rates differed across the 4 time periods for 30-day re-hospitalization (p=0.048), but not 90-day (p=0.080). There was a higher relative odds of CD-related re-hospitalization in 2002-2007 as compared to 2012-2017 (adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.16-1.50 for 30-day; aOR 1.14, 95% CI [1.03-1.26] for 90-day). For UC, there was a higher relative odds of re-hospitalization in 2012-2016 as compared to 2016-2020 (aOR 1.26, 95% CI [1.05-1.52] for 30-day; aOR 1.22, 95% CI [1.04-1.43] for 90-day). Conclusions Up to 15% of patients with IBD in Ontario are re-admitted to hospital within 90 days of hospital discharge. The risk of re-hospitalization may have decreased over time in the post-biologic era. Our findings could be explained by changing access to inpatient and/or outpatient resources, improvements to medical and/or surgical care, shifting patient behaviour with respect to healthcare resource utilization, or residual confounding. These results require validation in other jurisdictions. Funding Agencies None

Dysimmunity in common variable immunodeficiency is associated with alterations in oral, respiratory, and intestinal microbiota

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by decreased immunoglobulins and recurrent infections. Its aetiology remains unknown, and some patients present with severe non-infectious autoimmune or inflammatory complications with elevated associated morbimortality. Recently, intestinal dysbiosis has been proposed as a driver of immune dysregulation. In this study, we assessed the oral, respiratory, and gastrointestinal microbiota of 41 CVID patients (24 with dysimmune and 17 with infection complications) and 15 healthy volunteers using 16S rRNA gene sequencing to explore associations between microbiome profiles and CVID phenotypes. Profound differences in the composition of the microbiota in saliva, sputum, and stool were detected between dysimmune CVID patients and healthy individuals. Globally, respiratory species diversity and faecal bacterial richness were lower in CVID individuals with immune complications. Although a single species could not be identified as a robust predictor of dysimmunity, a combination of around 5–7 bacterial species in each type of sample could predict this severe phenotype with an accuracy of around 90% in the study population. Our study provides new insights into these previously unexplored but highly interrelated ecological niches among themselves and with patient profiles. Our data suggest that this disease-related systemic dysbiosis could be implicated in the immune dysregulation associated with severe cases of CVID.

Review of Anti-inflammatory and Immunosuppressive Drugs Used in COVID-19 Epidemic

Introduction Immunosuppressive drugs are classified into different groups depending on the mechanism of action and are used in the control of acute and chronic inflammatory disorders. Considering the possibility of severe inflammatory complications such as acute respiratory failure and cytokine storm in the patients with COVID-19, there is a need to review the updated data on the effectiveness and side effects of administering these drugs in patients. In the present article, along with the brief introduction of different categories of immunosuppressive medications, positive and negative effects of using these drugs in corona patients have been discussed.
 Conclusion: Taken together, it seems that the administration of immunosuppressive drugs has positive effects on COVID-19 patients. Reduced need for mechanical ventilation, decreased admission to the intensive care unit, promotion of acute symptoms, and decreased mortality rate, especially in critically ill patients are some of these advantages. However, the possibility of treatment prolongation and increased risk of bacterial and fungal infections should be kept in mind. Maintaining a balance in the doses and duration of immunosuppressant drugs might diminish their adverse effects.

Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease.

Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.

Contribution of Helicobacter pylori to the Inflammatory Complications of Common Variable Immunodeficiency.

Common Variable Immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, is frequently associated with severe inflammatory complications that determine its morbidity and mortality. We hypothesize that Helicobacter pylori (HP), a very common worldwide infection, may contribute to the clinical and immune phenotype of CVID. We stratified 41 CVID patients into HP+ (n=26) and HPneg (n=15) groups, according to previous urease breath test and/or gastric biopsies, and compared their clinical manifestations and immune profile evaluated by flow cytometry. No genetic variants with known potential impact in HP infection were found upon WES/WGS. Gastric complications were significantly more frequent in HP+ patients. Importantly, the six CVID patients with gastric cancer were infected with HP. In contrast, a significantly higher frequency of cytopenias was observed in the HPneg. Moreover, HP+ did not feature higher prevalence of organ auto-immunity, as well as of lung, liver or intestinal inflammatory manifestations. We observed the same B-cell profiles in HP+ and HPneg groups, accompanied by marked CD4 and CD8 T-cell activation, increased IFNγ production, and contraction of naïve compartments. Notably, HP+ patients featured low CD25 despite preserved Foxp3 levels in CD4 T cells. Overall, HP impact in CVID inflammatory complications was mainly restricted to the gastric mucosa, contributing to increased incidence of early onset gastric cancer. Thus, early HP screening and eradication should be performed in all CVID patients irrespective of symptoms.

Индекс отношения нейтрофилов к лимфоцитам как показатель тяжести воспалительных осложнений

Determination of the ONL index (the ratio of neutrophils to lymphocytes) is a simple, inexpensive, very popular method abroad that allows to predict the course and outcomes of a wide range of diseases. The possibility of application of ONL in the diagnosis, course prognosis and differential diagnosis of diverticular disease of the colon represents significant clinical interest. Aim — to determine the diagnostic significance of the ONL index in complicated diverticulitis. Material and methods. In retrospective analysis, the ONL index was evaluated in 58 patients with diverticular disease, 42 patients with colon cancer, 31 patients with inflammatory bowel diseases and 46 patients with hemorrhoidal disease, who were hospitalized in the coloproctology department of the Republican Clinical Hospital of Tatarstan for the period from 2015 to 2021. Results. Average of ONL in patients with DD (diverticular disease) were 7,96±5,43, minimal value — 1,16, maximal — 27,42. ONL increased according to aggravation of inflammatory changes in the walls of diverticulum, its spreading beyond the bowel wall. On the contrary, decrease of ONL was marked as a result of relief of inflammation by conservative or surgical treatment, which allowed to state the tendency of decrease of the index at discharge from hospital to 2,75±1,3 (p<0,05). There was also a correlation in the prolongation of patients’ hospital treatment with high ONL indexes as a result of severe inflammatory complications. The correlation coefficient was rxy = 0,468 (p <0,05). There was a statistically significant difference in the ONL index in patients with diverticular disease and patients with cancer of the colon (p <0,05), as well as a significant difference in the ONL index between patients with diverticular disease and patients with hemorrhoidal disease (p <0,001), while the ONL index in patients with diverticular disease and patients with inflammatory bowel diseases did not demonstrate such differences (p >0,05). Conclusion. Thus, the determination of the ONL index can be used in clinical practice not only for the diagnosis and control of the disease, but also for differential diagnosis with other diseases of the colon.

Continent ileostomy: short- and long-term outcomes of a forgotten procedure.

BackgroundContinent ileostomy (CI) aims to provide control of gas and faecal evacuation; however, it is rarely performed. This paper reports on outcomes of CI in a large single-surgeon series.MethodsAll consecutive patients who underwent CI between 1986 and 2015 were reviewed. Patients were classified according to the CI procedure (single stage versus two stage) and according to the underlying disease conditions (inflammatory bowel disease (IBD) versus no IBD). Primary outcome measures were early mortality and complications requiring surgical revision within 30 days (group Ia), those requiring surgical revision within 1–12 months (group Ib), and long-term complications after more than 12 months (group II). Secondary outcome measures were pouch survival and quality of life (QoL) assessed using questionnaires for occupational, sports, sexual, and travel activities; patients undergoing CI after conversion from ileostomy. Analyses were performed using descriptive statistics and Kaplan–Meier curves for the long-term outcomes.ResultsSixty-two consecutive patients (28 men, 34 women) who underwent CI were reviewed, including 48 with IBD, and 14 without inflammatory conditions. Mean(s.d.) follow-up was 14.4 (9.5) (range 1–30) years. Twenty-seven patients (44 per cent) developed group I complications, of which 25 were corrected successfully. Two patients dropped out of the analysis: one who died from sepsis and the other owing to pouch loss attributed to unsolvable nipple complications. Of the remaining 60 patients, 23 (38 per cent) developed between one and five group II complications. The cumulative probability of reoperation was 54. per cent at 25 years. Overall, pouch survival was achieved in 90 per cent. The two-stage approach led to significantly fewer complications in group Ia (single stage versus two stage: 8 of 25 versus 2 of 37; P = 0.005), whereas complication rates in group Ib (5 of 23 versus 14 of 37) and group II (9 of 23 versus 14 of 37) were similar. Four CIs failed because of IBD complications. CI pouch and function were preserved in all patients without IBD, whereas in the group with IBD 2 of 31 with ulcerative colitis and 2 of 17 with Crohn’s colitis lost the CI owing to severe intractable inflammatory complications. In 16 patients who had conversion from ileostomy to CI, QoL improved significantly above precolectomy levels in all domainsConclusionsCI remains an alternative to conventional ileostomy. Although affected by high reoperation rates, it has the benefit of a high rate of pouch survival.

Transcriptomics of type 2 diabetic and healthy human neutrophils

ObjectivesChronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils.MethodsCell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction.ResultsWe observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05).ConclusionsThe neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution.

Reduced phagocytosis, ROS production and enhanced apoptosis of leukocytes upon alcohol drinking in healthy volunteers

BackgroundAlcohol drinking is associated with a serious risk of developing health problems as well as with a large number of traumatic injuries. Although chronic alcohol misuse is known to contribute to severe inflammatory complications, the effects of an acute alcohol misuse are still unclear. Here, the impact of acute alcohol drinking on leukocyte counts and their cellular functions were studied.MethodsTwenty-two healthy volunteers (12 female, 10 male) received a predefined amount of a whiskey-cola mixed drink (40% v/v), at intervals of 20 min, over 4 h to achieve a blood alcohol concentration of 1‰. Blood samples were taken before drinking T0, 2 h (T2), 4 h (T4), 6 h (T6), 24 h (T24) and 48 h (T48) after starting drinking alcohol. Leukocytes, monocytes and granulocyte counts and their functions regarding the production of reactive oxidative species (ROS), phagocytosis and apoptosis were analyzed by flow cytometry.ResultsTotal leukocyte counts significantly increased at T2 and T4, while granulocyte and monocyte counts decreased at T4 and T6 vs. T0. Monocytes increased significantly at T24 and T48 vs. T0. While the total number of ROS-producing leukocytes and notably granulocytes significantly increased, in parallel, the intracellular ROS intensity decreased at T2 and T6. The numbers of ROS-positive monocytes have shown a delayed modulation of ROS, with a significant reduction in the total number of ROS-producing cells at T48 and a significantly reduced intracellular ROS-intensity at T24. Phagocyting capacity of leukocytes significantly decreased at T4 and T6. In general leukocytes, and notably granulocytes demonstrated significantly increased early (T2), while monocyte exerted significantly increased late apoptosis (T24 and T48).ConclusionsAlcohol drinking immediately impacts leukocyte functions, while the impact on monocytes occurs at even later time points. Thus, even in young healthy subjects, alcohol drinking induces immunological changes that are associated with diminished functions of innate immune cells that persist for days.

Innate and Adaptive Gene Single Nucleotide Polymorphisms Associated With Susceptibility of Severe Inflammatory Complications in Acanthamoeba Keratitis.

PurposeOver a third of patients with Acanthamoeba keratitis (AK) experience severe inflammatory complications (SICs). This study aimed to determine if some contact lens (CL) wearers with AK were predisposed to SICs due to variations in key immune genes.MethodsCL wearers with AK who attended Moorfields Eye Hospital were recruited prospectively between April 2013 and October 2014. SICs were defined as scleritis and/or stromal ring infiltrate. Genomic DNA was processed with an Illumina Low Input Custom Amplicon assay of 58 single nucleotide polymorphism (SNP) targets across 18 genes and tested for association in PLINK.ResultsGenomic DNA was obtained and analyzed for 105 cases of AK, 40 (38%) of whom experienced SICs. SNPs in the CXCL8 gene encoding IL-8 was significantly associated with protection from SICs (chr4: rs1126647, odds ratio [OR] = 0.3, P = 0.005, rs2227543, OR = 0.4, P = 0.007, and rs2227307, OR = 0.4, P = 0.02) after adjusting for age, sex, steroids prediagnosis, and herpes simplex keratitis (HSK) misdiagnosis. Two TLR-4 SNPs were associated with increased risk of SICs (chr9: rs4986791 and rs4986790, both OR = 6.9, P = 0.01). Th-17 associated SNPs (chr1: IL-23R rs11209026, chr2: IL-1β rs16944, and chr12: IL-22 rs1179251) were also associated with SICs.ConclusionsThe current study identifies biologically relevant genetic variants in patients with AK with SICs; IL-8 is associated with a strong neutrophil response in the cornea in AK, TLR-4 is important in early AK disease, and Th-17 genes are associated with adaptive immune responses to AK in animal models. Genetic screening of patients with AK to predict severity is viable and this would be expected to assist disease management.

At the Crossroads: COVID-19 and Immune-Checkpoint Blockade for Cancer.

The immunomodulatory effects of immune-checkpoint blockade (ICB) therapy for cancer may act at the crossroads between the need to increase antiviral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to decrease the inflammatory responses in severe cases of coronavirus disease 2019 (COVID-19). There is evidence from preclinical models that blocking programmed death receptor 1 (PD1) protects against RNA virus infections, which suggests that patients with cancer receiving ICB may have lower rates of viral infection. However, given the heterogeneity of patient characteristics, this would be difficult to demonstrate using population-based registries or in clinical trials. Most studies of the impact of ICB therapy on the course of COVID-19 have centered on studying its potential detrimental impact on the course of the COVID-19 infection, in particular on the development of the most severe inflammatory complications. This is a logical concern as it is becoming clear that complications of COVID-19 such as severe respiratory distress syndrome are related to interferon signaling, which is the pathway that leads to expression of the PD1 ligand PD-L1. Therefore, PD1/PD-L1 ICB could potentially increase inflammatory processes, worsening the disease course for patients. However, review of the current evidence does not support the notion that ICB therapy worsens complications from COVID-19, and we conclude that it supports the continued use of ICB therapy during the COVID-19 pandemic provided that we now collect data on the effects of such therapy on COVID-19 vaccination.

Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications.

Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients. A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH). Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa-related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up. Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.

Late diagnosis of chronic granulomatous disease.

Modern era advancements in medical care, with improved treatment of infections, can result in delayed diagnosis of congenital immunodeficiencies. In this study we present a retrospective cohort of 16patients diagnosed with Chronic Granulomatous Disease (CGD) at adulthood. Some of the patients had a milder clinical phenotype, but others had a classic phenotype with severe infectious and inflammatory complications reflecting a profoundly impaired neutrophil function. It is therefore of great importance to investigate the individual journey of each patient through different misdiagnoses and the threads which led to the correct diagnosis. Currently the recommended definitive treatment for CGD is hematopoietic stem cell transplantation (HSCT). Although survival of our patients to adulthood might argue against the need for early HSCT during infancy, we claim that the opposite is correct, as most of them grew to be severely ill and diagnosed at a stage when HSCT is debatable with potentially an unfavorable outcome. This cohort stresses the need to increase awareness of this severe congenital immunodeficiency among clinicians of different specialties who might be treating undiagnosed adult patients with CGD.

Особенности послеоперационного заживления после остеопластики альвеолярных отростков у пациентов с гальванической патологией

Purpose. The features of healing of postoperative wounds after osteoplasty of alveolar processes of jaws with the use of titanium and bioresorbable membranes in patients with galvanic pathology were studied. Methods. There were examined 120 patients, aged 19 to 35 years, with or without metal dentures. In the course of surgical preparation of alveolar processes of jaws for further dental implantation (osteoplasty of alveolar processes), bioresorbable membranes based on polylactic acid and membranes made of titanium were used. Depending on the presence or absence of galvanic pathology, all patients were divided into 4 groups. Results. It was found that in patients without galvanic pathology, postoperative healing occurs without inflammatory complications. In patients with galvanic (compensated and/or decompensated form) in the early postoperative period, 51.6 % of the examined patients appeared complications in the form of severe pain and other inflammatory complications. In patients with galvanosis (atypical and typical forms) both early (82.8 %) and late (10.4 %) postoperative complications occurred in the postoperative period. All postoperative complications were equally common in the subjects who were using titanium membranes and in patients with bioresorbable membranes. Conclusions. It was established that in the presence of non-removable metal dentures in the oral cavity made of base of ignoble metal alloys, leading to the development of galvanism or galvanosis, there are early and late inflammatory complications in the preparation of alveolar processes for dental implantation, which significantly prolongs the time of healing of postoperative wounds.

Theoretical substantiation of the efficiency of biopolymers application in experimental TBI (literature review and own results)

Objective: based on the analysis of literary sources, to justify the feasibility of using collagen-based biopolymer films for dura mater, to analyze experimentally the ability of this material to biodegrade and form a new dura mater using light optical microscopy and IR spectroscopy, and to investigate the possibility of application of biopolymer collagen-based films as a substitute for the dura mater. Materials and methods. Thirteen rats weighing 200–250 g under general anesthesia were operated. Craniotomies were performed. The dura mater was incised crosswise from the middle to its corners. The surface of the cerebral cortex was exposed and was penetrated with a G18 needle to a depth of 2 mm. Dura mater flaps were not sutured with diastasis between the edges. A small piece of collagen film was placed over dissected dura and the bone flap was removed. The basic group consisted of 10 animals and the control group without collagen film included 3 animals. Three weeks after the intervention, all animals were euthanized and operating sites, including skull and cortical tissue, were explanted for histological, macroscopic examination and molecular analysis by infrared spectroscopy. Results. According to the results of macroscopic and histological examination, collagen substitute for the dura mater does not lead to severe inflammatory complications and excessive scar adhesions, prevents cerebrospinal fluid outflow, is capable of biodegradation with the replacement of connective tissue resembling a newly formed dura mater. Conclusions. 1. The experiment confirmed the ability of collagen-based films to biodegrade in 3 weeks after penetration trauma in rats. 2. The data of both infrared spectroscopy and morphological study indicate that at the border of the collagen implant and the native dura mater the regeneration processes prevail over the formation of scar tissue. 3. The data obtained confirm the collagen-based substitute to be used for dura mater plastics.

The Evidence for Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Neutrophil Disorders: A Comprehensive Review by the Inborn Errors Working Party Group of the EBMT.

Congenital disorders of the immune system affecting maturation and/or function of phagocytic leucocytes can result in severe infectious and inflammatory complications with high mortality and morbidity. Further complications include progression to MDS/AML in some cases. Allogeneic stem cell transplantation is the only curative treatment for most patients with these diseases. In this review, we provide a detailed update on indications and outcomes of alloHSCT for congenital neutrophil disorders, based on data from the available literature.

Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD.

Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P<0.05). According to the results of the present study, TJ-100 has an effect on the change in serum cytokine levels from POD1 to POD3 following PD. However, the role of different transition pattern of cytokines in postoperative recovery following PD has to be investigated by further mechanical studies focusing on these extracted cytokines (ClinicalTrials.gov; no. NCT01607307; May 30, 2012).

The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity

BackgroundCommon variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. MethodsThe study population comprised patients with CVID, LRBA deficiency and age–sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. ResultsThe main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. ConclusionsOur findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients.

NEW ALGORITHMS OF DIAGNOSTICS OF HEAVY COMPLICATIONS OF ACUTE ODONTOGENIC INFECTION

Introduction. At present, objective difficulties remain in the timely diagnosis and treatment of severe complications of acute odontogenic infection, including progressive odontogenic phlegmon, contact odontogenic mediastinitis, odontogenic sepsis. Goal. Develop an algorithm for diagnosis and treatment of severe inflammatory complications of acute odontogenic infection, taking into account the criteria of “Sepsis-3” and evaluate its effectiveness. Material and methods. To conduct a comparative evaluation of the results of the study, patients (311 people) were divided into 2 groups: a control group (247 people), in which diagnosis and treatment were performed using the criteria “Sepsis-1”, and the main group (64 people), diagnosis and treatment were performed with using the developed algorithm for diagnosis and treatment, which includes a number of additions to the criteria of “Sepsis-3” of the European Society of Critical States Medicine and the Society of Critical States Medicine (SCCM / ESICM). Results. Using the developed algorithm for diagnosis and treatment of patients with odontogenic inflammatory diseases of the maxillofacial area allows to significantly increase the efficiency of early diagnosis of purulent-inflammatory processes in the maxillofacial region (by 5.7%), to reduce the number of severe septic complications (by 6.6%). Discussion. The application of the criteria “Sepsis-3” is not an effective method of early diagnosis of odontogenic sepsis. The conclusion. The conducted study confirmed the effectiveness of the developed algorithm for diagnosis and treatment of severe inflammatory complications of acute odontogenic infection, taking into account the criteria of “Sepsis-3”.