Biomarkers of Inflammation among Patients with COVID-19: A Single-Centre Prospective Study from Prishtina, Kosovo.

SARS-CoV-2 infection involves the phase of viral replication and inflammatory response predicting the severity of COVID-19. The aim of the study was to analyze the association between IL-6 and hematological and inflammatory parameters and outcomes of patients with COVID-19. Plasma interleukin 6 (IL-6) levels and other inflammatory and hematological parameters were analyzed in 86 adult patients diagnosed with SARS-CoV-2 infection in Kosovo. The median age of patients was 61.50 (49.75-67.25) years. Over half of patients were categorised as severe (58%) and had comorbidities (69%) with hypertension being the most common. The overall mortality rate was 4.7%. The distribution of biochemical parameters across disease severity groups was significantly different for C-reactive protein (CRP), lactate dehydrogenase (LDH), erythrocyte sedimentation rate (ESR), white blood cells (WBC), and granulocytes with higher median values in more severe and critically ill patients whereas lower percentage of lymphocytes, monocytes, and platelet count in severe and critically ill patients. IL-6 levels were increased in 63% of patients with significant differences in the distribution across the following groups; age, disease severity, hospitalisation status, pulmonary infiltrates, oxygen therapy, and hypertension status. IL-6 significantly correlated with CRP, LDH, CK, ESR, and percentages of granulocytes. IL-6 and other inflammatory and hematological parameters were strongly associated with disease severity and may predict the outcome of the SARS-CoV-2 infection.

Molecular mechanisms involved in pathogenicity of SARS-CoV-2: Immune evasion and implications for therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of unusual viral pneumonia that emerged in late 2019 in the city of Wuhan, China. Since then, because of its high transmission and pathogenic potential it spread almost all over the world causing the pandemic, as an extraordinary threat to the world public health. Rapid activation of a well-orchestrated and functional immune system with its both arms innate and adaptive immune response is pivotal to eradication of the disease caused by this coronavirus (COVID-19). Therefore, in this review are summarized the most recent data on complex molecular mechanisms involved in the innate and adaptive immune response to combat COVID-19. In addition to widely used vaccines against SARS-CoV-2, because of the induction of short-lived immunity and appearance of variants of concern (VOCs), there will be also discussed newly developed strategies to target different viral proteins, which are not prone to frequent mutations. Obviously, SARS-CoV-2 cannot evade the effect of these novel drugs and therefore they show a great promise as an antiviral therapy not only in COVID-19 but also in future viral outbreaks.

Relationship of anti-SARS-CoV-2 IgG antibodies with Vitamin D and inflammatory markers in COVID-19 patients.

Several studies have found an association of COVID-19 disease severity with Vitamin D deficiency and higher levels of anti-SARS-CoV-2 IgGs. The aim of this study was to determine whether levels of Vitamin D and "inflammatory state" influence the magnitude of anti-SARS-CoV-2 IgGs levels in COVID-19 patients. For this purpose, in 67 patients levels of anti-SARS-CoV-2 IgG were measured in week 4 whereas in 52 patients levels of Vitamin D were measured in week 1 after symptom onset. We found that low Vitamin D levels were significantly associated with age and disease severity whereas there was a trend without significance, towards negative correlation of Vitamin D with anti-SARS-CoV-2 IgG. Anti-SARS-CoV-2 IgG were significantly higher in older ages, patients with severe disease, diabetes and those who received corticosteroid and antibiotic therapy. There was a positive correlation of anti-SARS-CoV-2 IgG with IL-6, CRP, LDH, ESR and with percentages of granulocytes. In conclusion, Vitamin D and anti-SARS-CoV-2 IgG share common parameters associated with inflammatory state. However, even though Vitamin D protects against severe forms of COVID-19 it could not directly affect anti-SARS-CoV-2 IgG production.

Corrigendum to "There Is No Elevation of Immunoglobulin E Levels in Albanian Patients with Autoimmune Thyroid Diseases".

[This corrects the article DOI: 10.1155/2014/283709.].

Incidence of haematological malignancies in Kosovo-A post "uranium war" concern.

BACKGROUND: During the Kosovo War (1998-99) approximately 31,000 rounds with Depleted Uranium (DU) were fired on 85 targets in Kosovo. The number of haematological malignancies (HM) increased after the war and the concern was the use of DU during the war. The aim of this study was to analyse the incidence rates of HM in Kosovo throughout a 20-year that includes pre- and post- war period (1995-2015); and to examine if there is any association between the use of DU rounds and incidence rates of HM in different regions of Kosovo. METHODS: In this retrospective register-based study, 1,798 new patients diagnosed with leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma and Multiple myeloma were analysed over a 20 year period. Incidence rates were calculated focusing on specific time periods, regions and age-groups. In addition, the correlation between the use of DU in different regions and their incidence of HM was analysed. RESULTS: The average annual crude rate of all HM in Kosovo was 5.02 cases per 100,000 persons. Incidence rates of HM in first post-war period (2000-2003) increased by 0.37 cases/100,000 persons (9.51%) compared to the pre-war period (1995-1998) whereas in the last post-war period (2012-2015), incidence of HM increased by 3.19/100,000 persons (82%). Gjakova and Peja, the first and third most exposed regions to DU ordnance ranked first and second in difference in HM. Prishtina, Gjilan and Ferizaj, regions with the least number of rounds/km2, were characterized by a decline of incidence rates. CONCLUSIONS: After the war, the increase in incidence rate of HM was higher in two regions with most DU rounds/km2 expended Despite these findings, this study warrants further investigation and does not lead us to a conclusive finding on the existence of a causal relationship between the use of DU during the war and the rise in incidence of HM in Kosovo.

Relationship of Cord Blood Immunoglobulin E and Maternal Immunoglobulin E with Birth Order and Maternal History of Allergy in Albanian Mother/Neonate Pairs.

BACKGROUND: Previous studies reported that familial factors such as birth order and mothers atopy might influence cord blood levels and development of allergies. AIM: The aim of the study was to evaluate the relationship of cord blood IgE and maternal IgE with birth order and mothers history of allergy in Albanian mother/neonate pairs. MATERIAL AND METHODS: Study population represented 291 mother-infant pairs. Mothers were interviewed with a questionnaire for personal history of allergy and pregnancy history whereas serum IgE levels were determined using sandwich IRMA assay. RESULTS: The mean level of cIgE in neonates with detectable levels was 1.59 (n = 78). No significant difference in means of cIgE was found between first born and later born neonates (p = 0.232) and between neonates of mothers with a negative and positive history of allergy (p = 0.125). Also, no significant difference was found between means of mIgE by birth order, whereas there was a significant difference of mIgE between mothers with and without a history of allergy (p = 0.01). In a group of neonates with detectable cIgE levels, maternal IgE levels were moderately correlated with cIgE levels. CONCLUSION: Cord blood IgE is not affected by birth order and mothers history of allergy, whereas mothers IgE are affected by the history of allergy but not by birth order.

In vitro migration and proliferation ("wound healing") potential of mesenchymal stromal cells generated from human CD271(+) bone marrow mononuclear cells.

BACKGROUND: Emerging evidence indicates that mesenchymal stromal cells (MSCs) isolated from different tissue sources may be used in vivo as tissue restorative agents. To date, there is no evidence, however, on migration and proliferation ("wound healing") potential of different subsets of MSCs. The main goal of this study was therefore to compare the in vitro "wound healing" capacity of MSCs generated from positively selected CD271(+) bone marrow mononuclear cells (CD271-MSCs) and MSCs generated by plastic adherence (PA-MSCs). METHODS: The in vitro model of wound healing (CytoSelect™ 24-Well Wound Healing Assay) was used in order to compare the migration and proliferation potential of CD271-MSCs and PA-MSCs of passage 2 and 4 cultured in presence or absence of growth factors or cytokines. RESULTS: CD271-MSCs of both passages when compared to PA-MSCs demonstrated a significantly higher potential to close the wound 12 and 24 h after initiation of the wound healing assay (P < 0.003 and P < 0.002, respectively). Noteworthy, the migration capacity of PA-MSCs of second passage was significantly improved after stimulation with FGF-2 (P < 0.02), PDGF-BB (P < 0.006), MCP-1 (P < 0.002) and IL-6 (P < 0.03), whereas only TGF-ß enhanced significantly migration process of PA-MSCs of P4 12 h after the treatment (P < 0.02). Interestingly, treatment of CD271-MSCs of both passages with growth factors or cytokines did not affect their migratory potential. CONCLUSIONS: Our in vitro data provide the first evidence that CD271-MSCs are significantly more potent in "wound healing" than their counterparts PA-MSCs.

Gender Associated High Body Mass Index in Allergic Diseases.

BACKGROUND: The increasing prevalence of allergic diseases and atopy is affected by sex, age and lifestyle factors. Obesity and excess weight are reported to be potential risk factors for atopy and specifically for asthma symptoms in children and adults. OBJECTIVE: To assess the relation between body mass index (BMI) and allergic diseases in patients of both genders, as well as association of BMI with atopy in healthy subjects. METHODS: BMI (kg/m(2)), skin-prick test and total serum immunoglobulin E levels were assessed in 139 subjects: 109 were patients with allergic diseases (M to F ratio was 51:58) and 30 were healthy controls (M to F ratio was 6:24). RESULTS: The study population was grouped into asthma, asthmarhinitis, rhinitis, Urticaria oreczema and controls by BMI and sex. Females with the highest BMI were in asthma and urticaria/eczema group. Males with the highest BMI were in asthmarhinitis and urticariaeczema group. High BMI was associated with atopy in both genders of healthy controls. High levels of total IgE were in male allergic patients. CONCLUSION: High BMI was associated with asthma in females, urticaria/eczema in both genders and atopy in both genders of healthy controls. Higher levels of total IgE were concluded in male patients.

There is no elevation of immunoglobulin e levels in Albanian patients with autoimmune thyroid diseases.

Background. Studies in several ethnic groups reported high incidence of elevated levels of immunoglobulin E (IgE) in patients with autoimmune thyroid diseases (ATD), especially in patients with Graves' disease. Objective. To study association between serum levels of IgE and thyroid stimulating hormone receptor antibodies (TRAb) in Albanian patients with ATD. Material and Methods. Study was performed in 40 patients with Graves' disease, 15 patients with Hashimoto's thyroiditis, and 14 subjects in the control group. The IgE levels were measured by immunoradiometric assay, whereas the TRAb levels were measured by radioreceptor assay. Results. In all groups of subjects the IgE levels were within reference values (<200 kIU/L). Significant difference in mean concentration of IgE was found between two groups of Graves' disease patients, and those with normal and elevated TRAb levels (22.57 versus 45.03, P < 0.05). Positive correlation was found between TRAb and IgE only in Graves' disease patients (r = 0.43, P = 0.006). Conclusion. In Albanian patients with ATD there is no elevation of IgE levels. This could be the result of low prevalence of allergic diseases in Albanian population determined by genetic and environmental factors.

Association Between Autoantibodies Against Thyroid Stimulating Hormone Receptor and Thyroid Diseases.

AIM: The aim of this study is to determine the relationship between TRAb and different diseases. The highest percentage of increased TRAb levels can be found at patients with Graves'™ diseases. MATERIAL AND METHODS: Study was performed in 70 patients, grouped in three gr oups, and 14 persons who based on the clinical status and the levels of thyroid hormones do not ha ve any thyroid disease. The TRAb levels has been determined in patients with Graves'™ disease (N=40) , Hashimoto'™s disease (N=15), Plummer'™s disease (N=15) and the control group (N=14). RESULTS: The highest mean TRAb levels exist in patients with Graves'™ disease. There exists a positive correlation between TRAb levels and T3, and T4, while there is no correlat ion between TSH and TRAb levels in patients with Graves'™ disease,. On the other hand, the correlati on between TRAb and T3 and T4 in patients with Hashimoto'™s diseases and Plummers disease was shown to be positive, but of a low levels.

Clonal analysis of multipotent stromal cells derived from CD271+ bone marrow mononuclear cells: functional heterogeneity and different mechanisms of allosuppression.

Previous reports demonstrated a relationship between proliferation potential and trilineage differentiation in mesenchymal stromal cell-derived clones generated using plastic adherence (PA-MSCs). However, there are no reports presenting a clonal analysis of the proliferative potential, differentiation potential and allosuppressive effects of human mesenchymal stromal cell subsets. In this study, we performed a clonal analysis of mesenchymal stromal cells generated from human CD271(+) bone marrow mononuclear cells (CD271-MSCs). After transfection with the gene encoding green fluorescent protein, the cells were single-cell sorted and cultured for 2-4 weeks. A population doubling analysis demonstrated that 25% of CD271-MSC clones are fast-proliferating clones compared to only 10% of PA-MSC clones. Evaluation of the allosuppressive potential demonstrated that 81.8% of CD271-MSC clones were highly allosuppressive compared to only 58% of PA-MSC clones. However, no consistent correlation was observed between allosuppression and proliferative potential. Prostaglandin E2 levels were positively correlated with the allosuppressive activity of individual clones, suggesting that this molecule may be a useful predictive biomarker for the allosuppressive potential of mesenchymal stromal cells. In contrast, inhibitory studies of indoleamine 2,3 dioxygenase indicated that none of the clones used this enzyme to mediate their allosuppressive effect. Differentiation studies revealed the presence of tripotent, bipotent and unipotent CD271-MSC and PA-MSC clones which suppressed the allogeneic reaction to differing extents in vitro. In conclusion, our findings demonstrate differences between CD271-MSCs and PA-MSCs and indicate that neither proliferation potential nor differentiation potential represents a consistent predictive parameter for the immunomodulatory effects of either type of mesenchymal stromal cells.

CD271 antigen defines a subset of multipotent stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties.

UNLABELLED: Background In vitro proliferative and differentiation potential of mesenchymal stromal cells generated from CD271(+) bone marrow mononuclear cells (CD271-mesenchymal stromal cells) has been demonstrated in several earlier and recent reports. In the present study we focused, in addition to proliferative and differentiation potential, on in vitro and in vivo immunosuppressive and lymphohematopoietic engraftment-promoting potential of these mesenchymal stromal cells compared to bone marrow-derived mesenchymal stromal cells generated by plastic adherence (plastic adherence-mesenchymal stromal cells). DESIGN AND METHODS: We set up a series of experimental protocols in order to determine the phenotype of CD271-mesenchymal stromal cells, and their clonogenic, proliferative, differentiation and immunosuppressive potential. The potential of CD271-mesenchymal stromal cells to improve the engraftment of CD133(+) hematopoietic stem cells at co-transplantation was evaluated in immunodeficient NOD/SCID-IL2Rgamma(null) mice. RESULTS: In vitro studies demonstrated that CD271-mesenchymal stromal cells differentiate along adipogenic, osteogenic and chondrogenic lineages (trilineage potential), produce significantly higher levels of cytokines than plastic adherence-mesenchymal stromal cells, and significantly inhibit the proliferation of allogeneic T-lymphocytes in mixed lymphocyte reaction assays. Elevated levels of prostaglandin E(2), but not nitric monoxide, mediated the majority of this immunosuppressive effect. In vivo studies showed that CD271-mesenchymal stromal cells promoted significantly greater lymphoid engraftment than did plastic adherence-mesenchymal stromal cells when co-transplanted with CD133(+) hematopoietic stem cells at a ratio of 8:1 in immunodeficient NOD/SCID-IL2Rgamma(null) mice. They induced a 10.4-fold increase in the number of T cells, a 2.5-fold increase in the number of NK cells, and a 3.6-fold increase in the number of B cells, indicating a major qualitative difference between these two mesenchymal stromal cell populations. Conclusions Our results indicate that CD271 antigen provides a versatile marker for prospective isolation and expansion of multipotent mesenchymal stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties. The co-transplantation of such cells together with hematopoietic stem cells in patients with hematologic malignancies may prove valuable in the prevention of impaired/delayed T-cell recovery and graft-versus-host disease.

Adult stem cells as an alternative source of multipotential (pluripotential) cells in regenerative medicine.

Embryonic stem cells are by definition the master cells capable of differentiating into every type of cells either in vitro or in vivo. Several lines of evidence suggest, however, that adult stem cells and even terminally differentiated somatic cells under appropriate microenvironmental cues are able to be reprogrammed and contribute to a much wider spectrum of differentiated progeny than previously anticipated. This has been demonstrated by using tissue- specific stem cells, which like embryonic stem cells do not express CD45 as an exclusive hematopoietic marker (skin, adipose, cord blood and bone marrow- derived stem cells). On the other side, there is a great number of reports which demonstrate that hematopoietic cells (CD45+) from different sources (peripheral blood, cord blood, bone marrow) are also able to cross the tissue boundaries and give rise to the cells of the other germ layers. Herein we discuss the differentiation and reprogramming potential of both hematopoietic and non- hematopoietic stem cells along endodermal, mesodermal and neuroectodermal lineage and their importance for regenerative medicine.