The Interaction of Complement and Intrinsic Coagulation System: A Comparative Study between COVID-19 and Bacterial Sepsis Patients.

Background/Objectives: Through the past several years, a constant interaction has been implicated between complement and coagulation cascades. SARS-CoV-2 infection and bacterial sepsis are potent activators of both cascades. This study aims to compare the extent of complement and intrinsic coagulation pathway activation (and the interplay between them) among patients with COVID-19 and bacterial sepsis. Methods: Serum and plasma samples were collected from 25 ICU patients (11 patients with COVID-19 and 14 patients with bacterial sepsis) at two time points (on admission and either on improvement or deterioration). The activities of coagulation factors XI and XII and complement factors C3a and C5a were measured at both time points. Results: The activities of factors XI and XII were increased in both groups of patients and at both time points. However, there were no statistically significant differences between SARS-CoV-2 and bacterial sepsis patients. On the other hand, both C3a and C5a were significantly higher in the COVID-19 group on admission. This correlation was preserved on reassessment. Conclusions: Complement activation seems to be more enhanced in COVID-19 than bacterial sepsis. However, the lack of statistical significance in factors XI and XII indicates t the presence of additional pathways for complement activation in SARS-CoV-2 infection.

Erythropoietin Effect on Complement Activation in Chronic Kidney Disease.

The complement system is an important part of innate immunity. Despite its known protective role, the complement system may contribute to increased inflammation and tissue injury in cases where its balanced activation is disrupted. The kidneys have been shown to be largely affected by complement dysregulation. The aim of the present study was to investigate the effect of erythropoietin administration, on the complement system, in chronic kidney disease patients. The study involved 20 patients with CKD who received erythropoietin and measurements of levels of complement factors C3a and C5a and complement regulatory proteins (CregPs) CD55, CD46, and CD59. An increase in serum C3a and C5a levels was observed in response to EPO therapy. The increase in C3a was statistically significant (p < 0.05) and concurrent with a statistically significant decrease in CD55 in CD4+ T cells (p < 0.05) and B cells (p < 0.05) and CD59 levels in CD4+ and CD8+ T cells (p < 0.05) at completion of EPO therapy compared with healthy controls. The above observations demonstrate that EPO induces complement activation in patients undergoing EPO therapy with a simultaneous restriction of CRegPs expression, thus possibly allowing the uncontrolled complement activation, which may contribute to tissue injury and disease progression.

Prevalence and Causes of Vitamin D Deficiency in a Cohort of Greek HIV-Infected Individuals: A Prospective, Single Center, Observational Study.

BACKGROUND: Vitamin D deficiency and/or insufficiency (hypovitaminosis D) has been associated with several disorders including autoimmune diseases, like type 1 diabetes mellitus; cardiovascular diseases; neoplasms; obesity; insulin resistance, and type 2 diabetes mellitus. This problem is common in southern European countries, especially in elderly and institutionalized persons. In HIV-infected individuals, hypovitaminosis D has been correlated with various complications like tuberculosis, hyperparathyroidism, bone mass loss, premature atherosclerosis, and systemic arterial hypertension, deterioration of immune function, progression of the disease and overall mortality. OBJECTIVE: The objective of this study was to examine the prevalence and causes of hypovitaminosis D in a cohort of Greek HIV-infected patients, as well as possible complications associated with it. METHODS: All patients attending our HIV unit for a period of 5 months were included in this study. Vitamin D status, medical anamnes, and laboratory tests were obtained at baseline; patients were followed for 3 years and HIV-related complications were noted. No patient received vitamin D supplementation during the follow-up period. RESULTS: Hypovitaminosis D was common, with 83.7% of the patients showing levels below 30 ng/dl and 55.4% below 20 ng/dl. After multivariable analysis, age and duration of treatment were the only significant factors for low vitamin D levels. During follow-up, 26 patients exhibited a total of 34 HIV-related complications, the most common being pneumonocystis jiroveci pneumonia (PCP). Hypovitaminosis D showed a positive correlation with overall complications, PCP as well as wasting syndrome. CONCLUSION: Overall, our study shows that hypovitaminosis D is common in HIV-infected individuals and should probably be treated as soon as possible to protect these patients from serious HIVrelated complications like PCP or wasting syndrome.

Precision Oncology: Circulating Microvesicles as New Biomarkers in a Very Early Stage of Colorectal Cancer.

BACKGROUND: The release of microvesicles (MVs) is an essential phenomenon for inter-cellular signaling in health and disease. The role of MVs in cancer is multidimensional and includes cancer cell survival, proliferation, and invasion. In this prospective study, we analyzed MV levels in colorectal cancer patients and assessed the importance of MV release in early-stage colorectal cancer and survival. METHODS: This study included 98 patients and 15 controls. The characterization of MVs from human plasma was performed by flow cytometry using monoclonal antibodies. RESULTS: The levels of total MVs and MUC-1-positive, tissue factor (TF)-positive, and endothelial cell-derived MVs (EMVs) were statistically significantly higher in the colon cancer patients than in the controls (p < 0.001). Furthermore, the subgroup of patients with very early-stage colorectal cancer also had statistically significant differences in the levels of the abovementioned MVs compared to the controls (p < 0.01). Highly differentiated tumors had lower levels of MUC-1-positive MVs (p < 0.02), EMVs (p < 0.002), and EMV/TF combinations (p < 0.001) versus those with tumors with low/intermediate differentiation. CONCLUSIONS: Our data demonstrate that the analysis of circulating MV levels in plasma could possibly become a tool for the early diagnosis of colon cancer at a very early stage of the disease.

A Cardiac Rehabilitation Program Increases the Acute Response of Endothelial Progenitor Cells to Maximal Exercise in Heart Failure Patients.

Purpose: The purpose of this study was to investigate the effect of a cardiac rehabilitation program on the acute response on endothelial progenitor cells and circulating endothelial cells after maximal exercise in patients with chronic heart failure of different severity. Methods: Forty-four chronic heart failure patients were enrolled in a 36-session cardiac rehabilitation program. All patients underwent an initial maximal cardiopulmonary exercise test before and a final maximal cardiopulmonary exercise test after the cardiac rehabilitation program. The patients were divided in two groups of severity according to the median value of peak VO2. Blood was collected at 4 time points; 2 time points at rest, and 2 time points after each cardiopulmonary exercise test. Five endothelial cellular populations were quantified by flow cytometry. Results: Although there was a higher increase in the mobilization of subgroups of endothelial progenitor cells and circulating endothelial cells after the final cardiopulmonary exercise test compared to the initial test within each severity group (p < 0.05), no significant differences between severity groups were observed (p > 0.05). Conclusions: A 36-session cardiac rehabilitation program had similar beneficial effects on the acute response of endothelial progenitor cells and circulating endothelial cells after maximal exercise in patients with chronic heart failure of different severity.

Herbals and Plants in the Treatment of Pancreatic Cancer: A Systematic Review of Experimental and Clinical Studies.

BACKGROUND: Pancreatic cancer represents the most lethal malignancy among all digestive cancers. Despite the therapeutic advances achieved during recent years, the prognosis of this neoplasm remains disappointing. An enormous amount of experimental (mainly) and clinical research has recently emerged referring to the effectiveness of various plants administered either alone or in combination with chemotherapeutic agents. Apart from Asian countries, the use of these plants and herbals in the treatment of digestive cancer is also increasing in a number of Western countries as well. The aim of this study is to review the available literature regarding the efficacy of plants and herbals in pancreatic cancer. METHODS: The authors have reviewed all the experimental and clinical studies published in Medline and Embase, up to June 2021. RESULTS: More than 100 plants and herbals were thoroughly investigated. Favorable effects concerning the inhibition of cancer cell lines in the experimental studies and a favorable clinical outcome after combining various plants with established chemotherapeutic agents were observed. These herbals and plants exerted their activity against pancreatic cancer via a number of mechanisms. The number and severity of side-effects are generally of a mild degree. CONCLUSION: A quite high number of clinical and experimental studies confirmed the beneficial effect of many plants and herbals in pancreatic cancer. More large, double-blind clinical studies assessing these natural products, either alone or in combination with chemotherapeutic agents should be conducted.

Successful Pregnancy and Persistent Polyclonal B Cell Lymphocytosis (PPBL): A Case Study of a Rare Co-Existence.

BACKGROUND Persistent polyclonal B cell lymphocytosis (PPBL) is a benign clinical condition, which is characterized by persistent absolute polyclonal B lymphocytosis (>4.0 K/µL), with the presence of circulating binucleated lymphocytes on the peripheral blood smear and an extra 3 chromosome long arm i(3q) in most cases. Immunophenotype reveals the polyclonal population of B cell lymphocytes with expression of CD19, CD20, and CD22 antigens, and kappa and lambda immunoglobulin light chains. Patients are mostly asymptomatic. Although PPBL has a benign clinical course and does not affect the survival expectancy of most patients, pregnancy seems to be extremely rare in these patients, as only 1 case reported so far. Although the real role of immunologic disorders, possibly PPBL, in recurrent pregnancy losses remains unclear, the rarity of successful pregnancy in PPBL patients could be attributed to the possible association of PPBL with infertility or recurrent miscarriages. CASE REPORT In the present study we present the second published case of a woman with a typical PPBL and recurrent pregnancy loss with a successful pregnancy outcome. Close clinical and laboratory monitoring in combination with the administration of thromboprophylaxis and the induction of mild immunosuppression with low-dose prednisolone may have contributed to the successful outcome of the pregnancy. CONCLUSIONS In conclusion and taking all these findings into consideration, pregnancy in patients with PPBL seems to be extremely rare and the contribution of PPBL to the 2 previous miscarriages in our case could not be excluded.

The acute and long-term effects of a cardiac rehabilitation program on endothelial progenitor cells in chronic heart failure patients: Comparing two different exercise training protocols.

BACKGROUND: Vascular endothelial dysfunction is an underlying pathophysiological feature of chronic heart failure (CHF). Endothelial progenitor cells (EPCs) are also impaired. The purpose of the study was to assess the effect of a cardiac rehabilitation (CR) program on the increase of EPCs at rest and on the acute response after maximal exercise in patients with CHF and investigate whether there were differences between two exercise training protocols and patients of NYHA II and III classes. METHODS: Forty-four patients with stable CHF enrolled in a 36-session CR program and were randomized in one training protocol; either high-intensity interval training (HIIT) or HIIT combined with muscle strength (COM). All patients underwent maximum cardiopulmonary exercise testing (CPET) before and after the CR program and venous blood was drawn before and after each CPET. Five endothelial cellular populations, expressed as cells/106 enucleated cells, were quantified by flow cytometry. RESULTS: An increase in all endothelial cellular populations at rest was observed after the CR program (p < 0.01). The acute response after maximum exercise increased in 4 out of 5 endothelial cellular populations after rehabilitation. Although there was increase in EPCs at rest and the acute response after rehabilitation in each exercise training group and each NYHA class, there were no differences between HIIT and COM groups or NYHA II and NYHA III classes (p > 0.05). CONCLUSIONS: A 36-session CR program increases the acute response after maximum CPET and stimulates the long-term mobilization of EPCs at rest in patients with CHF. These benefits seem to be similar between HIIT and COM exercise training protocols and between patients of different functional classes.

The Effects of Ascorbic Acid and U-74389G on Renal Ischemia-Reperfusion Injury in a Rat Model.

BACKGROUND/AIM: U-74389G and ascorbic acid protect the cells from oxidation. This study aimed to depict their role in ischemia-reperfusion injury in a renal rat model. MATERIALS AND METHODS: Sixty Wistars rats were randomized into six groups of 10 animals each. Group A Ischemia 30 min, reperfusion 60 min; Group B Ischemia 30 min, reperfusion 120 min; Group C Ischemia 30 min, ascorbic acid administration, reperfusion 60 min; Group D Ischemia 30 min, ascorbic acid administration, reperfusion 120 min; Group E Ischemia 30 min, U-74389G administration, reperfusion 60 min; Group F Ischemia 30 min, U-74389G administration, reperfusion 120 min. We then collected tissue and blood samples. RESULTS: Histology and the significantly decreased malondialdehyde and tumor necrosis factor-α levels indicated that ascorbic acid was superior to U-74389G, at pre-defined time intervals. CONCLUSION: Ascorbic acid and U-74389G ameliorated renal damage induced by ischemia-reperfusion injury, suggesting a therapeutic effect.

Student Views on a Novel Holistic Surgical Education Curriculum (iG4): A Multi-national Survey in a Changing Landscape.

AIM: Essential Skills in the Management of Surgical Cases (ESMSC Marathon Course™) Integrated Generation 4 (iG4) is the first reported multifaceted undergraduate surgical course aiming to provide holistic surgical teaching. In this prospective observational study, we explored students' views on the iG4 curriculum, and identified how it can potentially address modern challenges in surgical training. MATERIAL AND METHODS: Medical students were invited to apply to the course online and were screened against pre-defined criteria. A multi-national structured questionnaire incorporating five domains related to the course curriculum and our dedicated research network, was designed and distributed to participants after successful completion of the course. RESULTS: Forty-one students from European and Asian medical schools completed the course and filled in the survey. The median overall evaluation score of the course was 4.73 out of 5 (interquartile range=4.21-4.72) and all students found that iG4 served the vision of holistic surgical education. ESMSC had a positive motivational effect towards following a career in surgery (p=0.012) and 92.7% of students declared that it should be an essential part of a future medical school curriculum. There was no statistically significant difference (p>0.05) in results between participants of different countries of study, year of studies or age group. CONCLUSION: The ESMSC Marathon Course™ is perceived as a unique course model, with an established educational value and a positive motivational effect towards surgery. It might potentially be implemented in future medical school curricula as an essential element of undergraduate surgical education. The iG4 curriculum has opened a new exciting horizon of opportunities for advancing undergraduate holistic surgical education.

Beneficial Effect of U-74389 G and Sildenafil in An Experimental Model of Flap Ischemia/Reperfusion Injury in Swine. Histological and Biochemical Evaluation of the Model.

Purpose of the study: Tissue reconstruction after burns, tumor excisions, infections or injuries is a frequent surgical challenge to avoid Ischemia-reperfusion injury. Lazaroids and sildenafil, through their mechanisms of action, have been studied for their protective effects on various organs subjected to IRI. In this study, we aimed to evaluate the therapeutic potential of U-74389G and sildenafil in a swine model of ischemia and reperfusion injury of latissimus dorsi flap. Materials and methods: Forty-two Landrace male pigs, weighing 28-35 kg, were equally (n = 6) randomized into the following groups: (a) Group I: control, (b) Group II: administration of U-74389G after ischemia, (c) Group III: administration of sildenafil after ischemia, (d) Group IV: administration of U-74389G and sildenafil after ischemia, (e) Group V: administration of U-74389G prior to ischemia, (f) Group VI: administration of sildenafil prior to ischemia, and (g) Group VII: administration of U-74389G and sildenafil prior to ischemia. Blood and tissue sampling was conducted before ischemia, 15 and 30 min after occlusion, 30, 60, 90, and 120 min after reperfusion. Results: Statistically significant reduction (p < 0.05) was detected in lymphocytes and polymorphonuclear leukocytes concentrations as well as in the appearance of edema after histopathologic evaluation of the ischemic tissue, especially in the groups of combined treatment. Measurements of malondialdeyde and tumour necrosis factor alpha in tissues revealed a significant decrease (p < 0.001) of these markers in the treatment groups when compared to the control, particularly in the latest estimated timepoints. Conclusions: The synergistic action of U-74389G and sildenafil seems protective and promising in cases of flap IRI during tissue reconstruction surgery.

Treatment with Molgramostim (Recombinant Human Granulocyte-Macrophage Colony Stimulating Factor, Rhugm-Csf, Mielogen) and Lenograstim (Granulocyte-Colony Stimulating Factor) Improves Experimental Colitis in Rats.

BACKGROUND/AIM: Treatment with growth factors could be beneficial in both inflammatory bowel disease and experimental colitis. The aim of this study was to investigate the effect of Colony Stimulating Factor (CSF), and Recombinant Human (rHu) Granulocyte Stimulating Factor (GSF) in experimental colitis in rats. METHODS: Experimental colitis was induced in 62 male Wistar rats, divided into 9 groups, using 2,4,6-trinitrobenzensulfonic acid (TNBS). Group 1: Ten rats with colitis without treatment (control group). Euthanasia after 15 days. Group 2: Ten animals with colitis without treatment (control group). Euthanasia after 30 days. Group 3: Six animals with colitis. Immediate treatment with CSF. Euthanasia after 19 days. Group 4: Six animals with colitis. Treatment started 7 days after the induction of colitis. Animals were kept for 19 days. Group 5: Six animals with colitis. Treatment started 2 weeks after the induction of colitis. Group 6: Six animals with colitis, the same as in group 3. Treatment with GSF. Group 7: Six animals with colitis, the same as in group 4. Treatment with GSF. GROUP 8: Six animals with colitis, the same as in group 5. Treatment with GSF. Group 9: Six animals with colitis. Immediate treatment with prednisolone. Euthanasia after 15 days. RESULTS: CSF and GSF administration significantly improved the histological score (P < 0.05) and reduced malondialdehyde contents (P < 0.05), compared to control groups in all animals. CSF was superior to GSF and to prednisolone. CONCLUSION: Administration of both CSF and GSF could significantly improve the histological score and oxidative stress in experimental colitis in rats.

Emerging patterns of resistance in a cohort of Greek patients with recurrent UTIs: a pilot study.

Bacterial urogenital infections caused by multi-drug resistant organisms (MDROs), are increasingly becoming a severe public health issue. The purpose of the present study was to examine the epidemiology of recurrent UTIs along with antimicrobial resistance patterns in a cohort of patients followed as outpatients at an Infectious Disease clinic of a tertiary care center in Greece. One hundred, sequential patients suffering from recurrent UTIs and coming for clinical evaluation, follow-up and treatment were examined; microbiological urine culture results were analyzed. Patients were separated into Group A: patients with ≥3 urogenital infections during the last study year, and Group B: patients with ≤2 urogenital infections. Furthermore, antimicrobial resistance patterns and presence of MDROs in relation to the number of urogenital infections during a three years period was evaluated. Group A had a mean of 4.3 ± 1.7 urogenital infections during the last year of the study, while patients in Group B 1.9 ± 0.3 infections over a three years period. An age cut-off of 30 years was critical for higher UTI rates. Escherichia Coli was the predominant isolated pathogen in 96.2% of the patients. Patients with diabetes mellitus had a 3 fold-higher risk for ≥3 UTIs. Resistance to colistin and imipenem was associated with a history of more than 2 episodes of UTIs but observed in a small number of patients with comorbidities. In this pilot study MDRO detection in patients suffering from recurrent UTIs emphasizes the need for continuous epidemiological surveillance in order to improve our understanding of the evolution of resistance in a common community infection as well as to implement successful prevention strategies.

Oral Contraceptives and HRT Risk of Thrombosis.

Estrogen-containing medication, prescribed either for contraception in women of reproductive age or for prevention of cardiovascular events and osteoporosis as well as for alleviation of symptoms related to menopause, is associated with changes in the hemostatic balance and contributes to increased risk of development of venous thromboembolic complications. This risk is dose and medication dependent, increases with age, congenital and/or acquired predisposition to thrombosis, and mode of administration. This review attempts to summarize the current knowledge regarding the pathophysiology of oral contraceptive (OC) and hormone replacement therapy (HRT) -induced prothrombotic state in women, the risk of thrombosis associated with administration of various commercially available OCs and HRT, the additional risk in women with hereditary or acquired thrombophilia, and the currently available recommendations regarding massive screening of women for thrombophilia prior to initial prescription or continuation of treatment with OCs and HRT preparations.

Seroprevalence of hepatitis E in HIV infected patients in Greece.

HEV infection is an emerging public health problem worldwide Data concerning HEV infection in HIV+ patients in Greece is scare. The aim of the study was to determine HEV seroprevalence in patients with HIV infection in Greece. We studied 243 HIV(+) patients 214 men (88%) and 29 women (12%) with a median age of 45 years (range 19-83) who attended the HIV unit of Pathophysiology Department of Laikon General Hospital in Athens for the presence of anti-HEV IgG antibodies with (EIA) (EIA HEV IgG, Adaltis, Rome, Italy Eighteen/243 patients (7.3%) were positive for HEV IgG antibodies, a seroprevalence that was not different from that described for the blood donors group from Greece There was no difference of the presence of HbsAg, hepatitis C and hepatitis A between the HEV(+) and HEV(-) patients. There was no statistically significant difference between the HEV(+) and HEV(-) group in terms of HIV acquisition, sexual orientation, median duration of HIV infection, ART treatment, or duration of ART. Only the median age of HEV(+) was 52 years (35-78) while that of HEV(-) was 44 years (19-83)(P = 0.03). Only 2/18(11.1%) HEV(+) HIV(+) patients had abnormal ALT and AST values. The seroprevalence of hepatitis E in HIV(+) patients in Greece seems to be the same with that of the general population thus implying that HIV infection is not a risk factor for HEV infection and only age shows a positive correlation with seropositivity.

Seroprevalence of HHV-6 and HHV-8 among blood donors in Greece.

BACKGROUND: Herpes viruses infection transmitted through healthy but infected blood donors pose a danger to herpes-naive immunocompromised recipients. The risk of transfusion-related HHV-8 transmission is different in endemic and not endemic areas. HHV-6 and HHV-8 seroprevalence and viral load among blood donors have been reported from different countries. The aim of our study was to assess the seroprevalence of HHV-8 and HHV-6 in volunteer blood donors from Greece which is unknown. FINDINGS: Serum samples from 179 healthy blood donors were tested for the presence of IgG antibodies against HHV-6 and HHV-8 with ELISA. None of the 179 donors of Greek origin tested was positive for HHV-8. HHV-6 seropositivity was assessed in 160 blood donors' samples and was found to be 78.75% (126/160). The HHV-6 seroprevalence did not differ either between males and females or among different decade age groups. CONCLUSIONS: The fact, that no blood donor was positive for HHV-8 IgG antibodies indicates that the risk for transfusion related HHV-8 transmission in Greece, if any, is negligible and does not warrant broad testing for HHV-8. Definitely further studies are needed, in order to clarify the potential risk of HHV-6 transmission.

Modified CLSI extended-spectrum ß-lactamase (ESBL) confirmatory test for phenotypic detection of ESBLs among Enterobacteriaceae producing various ß-lactamases.

The worldwide dissemination of Enterobacteriaceae producing AmpC ß-lactamases and carbapenemases makes difficult the phenotypic detection of extended-spectrum ß-lactamases (ESBLs), as they may be masked by these additional enzymes. A modification of the CLSI ESBL confirmatory test was developed and evaluated in a comparative study for its ability to successfully detect ESBLs among Enterobacteriaceae producing various carbapenemases (Klebsiella pneumoniae carbapenemase [KPC], VIM, NDM, and OXA-48) and plasmidic or derepressed AmpCs. The modified CLSI ESBL confirmatory test was performed with cefotaxime and ceftazidime disks with and without clavulanate, on which both boronic acid (BA) and EDTA were dispensed. A total of 162 genotypically confirmed ESBL-positive Enterobacteriaceae isolates (83 carbapenemase/ESBL producers, 25 AmpC/ESBL producers, and 54 ESBL-only producers) were examined. For comparison, 139 genotypically confirmed ESBL-negative Enterobacteriaceae isolates (94 of them possessed carbapenemases and 20 possessed AmpCs) were also tested. The standard CLSI ESBL confirmatory test was positive for 106 of the 162 ESBL producers (sensitivity, 65.4%) and showed false-positive results for 4 of the 139 non-ESBL producers (specificity, 97.1%). The modified CLSI ESBL confirmatory test detected 158 of 162 ESBL producers (sensitivity, 97.5%) and showed no false-positive results for non-ESBL producers (specificity, 100%). The findings of the study demonstrate that the modified CLSI ESBL confirmatory test using antibiotic disks containing both BA and EDTA accurately detects ESBLs in Enterobacteriaceae regardless of the coexistence of additional ß-lactam resistance mechanisms.