Oxidative Stress in Military Missions-Impact and Management Strategies: A Narrative Analysis.

This narrative review comprehensively examines the impact of oxidative stress on military personnel, highlighting the crucial role of physical exercise and tailored diets, particularly the ketogenic diet, in minimizing this stress. Through a meticulous analysis of the recent literature, the study emphasizes how regular physical exercise not only enhances cardiovascular, cognitive, and musculoskeletal health but is also essential in neutralizing the effects of oxidative stress, thereby improving endurance and performance during long-term missions. Furthermore, the implementation of the ketogenic diet provides an efficient and consistent energy source through ketone bodies, tailored to the specific energy requirements of military activities, and significantly contributes to the reduction in reactive oxygen species production, thus protecting against cellular deterioration under extreme stress. The study also underlines the importance of integrating advanced technologies, such as wearable devices and smart sensors that allow for the precise and real-time monitoring of oxidative stress and physiological responses, thus facilitating the customization of training and nutritional regimes. Observations from this review emphasize significant variability among individuals in responses to oxidative stress, highlighting the need for a personalized approach in formulating intervention strategies. It is crucial to develop and implement well-monitored, personalized supplementation protocols to ensure that each member of the military personnel receives a regimen tailored to their specific needs, thereby maximizing the effectiveness of measures to combat oxidative stress. This analysis makes a valuable contribution to the specialized literature, proposing a detailed framework for addressing oxidative stress in the armed forces and opening new directions for future research with the aim of optimizing clinical practices and improving the health and performance of military personnel under stress and specific challenges of the military field.

The Interference between SARS-CoV-2 and Tyrosine Kinase Receptor Signaling in Cancer.

Cancer and viruses have a long history that has evolved over many decades. Much information about the interplay between viruses and cell proliferation and metabolism has come from the history of clinical cases of patients infected with virus-induced cancer. In addition, information from viruses used to treat some types of cancer is valuable. Now, since the global coronavirus pandemic erupted almost a year ago, the scientific community has invested countless time and resources to slow down the infection rate and diminish the number of casualties produced by this highly infectious pathogen. A large percentage of cancer cases diagnosed are strongly related to dysregulations of the tyrosine kinase receptor (TKR) family and its downstream signaling pathways. As such, many therapeutic agents have been developed to strategically target these structures in order to hinder certain mechanisms pertaining to the phenotypic characteristics of cancer cells such as division, invasion or metastatic potential. Interestingly, several authors have pointed out that a correlation between coronaviruses such as the SARS-CoV-1 and -2 or MERS viruses and dysregulations of signaling pathways activated by TKRs can be established. This information may help to accelerate the repurposing of clinically developed anti-TKR cancer drugs in COVID-19 management. Because the need for treatment is critical, drug repurposing may be an advantageous choice in the search for new and efficient therapeutic compounds. This approach would be advantageous from a financial point of view as well, given that the resources used for research and development would no longer be required and can be potentially redirected towards other key projects. This review aims to provide an overview of how SARS-CoV-2 interacts with different TKRs and their respective downstream signaling pathway and how several therapeutic agents targeted against these receptors can interfere with the viral infection. Additionally, this review aims to identify if SARS-CoV-2 can be repurposed to be a potential viral vector against different cancer types.

Host immune response in chronic hepatitis C infection: involvement of cytokines and inflammasomes.

Chronic liver disease is a major health issue worldwide and chronic hepatitis C (CHC) is associated with an increased risk of cirrhosis and hepatocellular carcinoma (HCC). There is evidence that the hepatitis C virus (HCV) infection is correlated with immune senescence by way of immune activation and chronic inflammation, which lead to increased metabolic and cardiovascular risk, as well as progressive liver damage. Both the innate and adaptive immunity are firmly tied to the prognosis of an infection with HCV and its response to antiviral therapy. HCV is therefore associated with increased pro-inflammatory status, heightened production of cytokines, prolonged systemic inflammation, as well as increased morbidity and mortality, mainly due to the progression of hepatic fibrosis and HCC, but also secondary to cardiovascular diseases. Viral hepatic pathology is increasingly considered a disease that is no longer merely limited to the liver, but one with multiple metabolic consequences. Numerous in vitro studies, using experimental models of acute or chronic inflammation of the liver, has brought new information on immunopathological mechanisms resulting from viral infections and have highlighted the importance of involving complex structures, inflammasomes complex, in these mechanisms, in addition to the involvement of numerous proinflammatory cytokines. Beyond obtaining a sustained viral response and halting the aforementioned hepatic fibrosis, the current therapeutic "treat-to-target" strategies are presently focused on immune-mediated and metabolic disorders, to improve the quality of life and long-term prognosis of CHC patients.

The role of mediating factors involved in angiogenesis during implantation.

Angiogenesis is a critical component of normal implantation and placentation and underlines the importance of vascularization in early pregnancy. Differentiated expression of angiogenesis factors in different decision tissues during different stages of implantation, indicates their involvement in the regulation of vascular remodeling and angiogenesis. Disorders in vascular development may play a role in the pathogenesis of recurrent abortions. The success of implantation, placentation and subsequent pregnancy evolution requires coordination of vascular development and adaptations at both sides of the maternal-fetal interface. The human implantation process is a continuous process, which begins with the apposition and attachment of the blastocyst to the apical surface of the luminal endometrial epithelium and continues throughout the first trimester of pregnancy until the extravillous trophoblast invades and remodels maternal vascularization. Numerous regulatory molecules play functional roles in many processes, including preparation of the endometrial stroma (decidualization), epithelium for implantation, control of trophoblastic adhesion and invasion. These regulatory molecules include cytokines, chemokines, and proteases, many of which are expressed by different cell types, having slightly different functions as the implant progresses.

Evaluation of iNOS -2087A>G polymorphism in recurrent pregnancy loss.

BACKGROUND: Due to its role in angiogenesis, the inducible nitric oxide synthase (iNOS) gene promoter polymorphism may have a presumed role in recurrent spontaneous abortions (RSA). It is an intensely studied protein, a biological mediator, a modulator and an effector molecule by implication in numerous physiological processes: vasodilatation, angiogenesis, immunity, tissue remodeling, smooth muscle activity. AIM: Our study aims to investigate a possible association between iNOS -2087A>G (rs2297518) polymorphism and the occurrence of idiopathic recurrent pregnancy loss (RPL). PATIENTS, MATERIALS AND METHODS: In this study, as in the previously published one, 169 women, diagnosed with RPL, in the Clinics of Obstetrics and Gynecology, "Filantropia" Municipal Hospital, Craiova, Romania, were subjected to the analysis, from October 2009 to October 2016. As a control group, we used 145 women. Subjects from both groups were genotyped using specific probes for TaqMan polymerase chain reaction (PCR), allelic discrimination technique. RESULTS: We evaluated in this study a possible association between iNOS -2087A>G (rs2297518) polymorphism and the occurrence of idiopathic RPL. The chi-square test showed no significant association between the presence of this polymorphism and the increased risk to develop RPL. When we performed a comparative analysis of the frequency of genotypes and our statistical data, it was observed that this polymorphism, iNOS -2087A>G (rs2297518), has not been associated with an increased risk of developing RPL. Also, when one genotype was compared with another, we did not obtain any association that would have statistical significance, between the presence of this polymorphism and the increased risk for patients to develop RPL [in dominant - A allele carriers, iNOS 2087 AG+AA vs. GG: odds ratio (OR) 1.31, 95% confidence interval (CI) 0.83-2.07, p=0.24]. Analyzing the overall risk of developing RPL by iNOS 2087 single-nucleotide polymorphism (SNP) genotype frequencies, between controls and RPL patients (which were stratified by number of consecutive PLs), taking into account the number of consecutive pregnancies, the chi-square test showed no association between the presence of this polymorphism and the increased risk for developing RPL in all three subgroups we analyzed (in a dominant model - A allele carriers, iNOS 2087 AG+AA vs. GG: the first subgroup, OR 1.31, 95% CI 0.83-2.07, p=0.24; the second subgroup, OR 1.26, 95% CI 0.76-2.11, p=0.37; the three subgroup, OR 1.4, 95% CI 0.77-2.53, p=0.272). CONCLUSIONS: The iNOS -2087A>G (rs2297518) gene polymorphism does not influence RPL in the study area of Dolj County, Romania.

Serological and immunohistochemical biomarkers for discrimination between benign and malignant ovarian tumors.

BACKGROUND: Ovarian tumors are difficult to diagnose because symptoms are nonspecific, occurring in late stages when the tumor mass reaches large proportions, when complications arise or when dissemination occurs in neighboring organs. Research over the past decades has been aimed at clarifying the mechanisms of ovarian oncogenesis, to identify ways of transforming normal cells into a neoplastic cell, as well as discovering of tumor markers used in the detection of neoplastic processes, along with the synthesis of therapeutic substances, which would influence its development. AIMS: In our study, we aimed to determine the serum concentrations of cancer antigen 125 (CA125), human epididymis protein 4 (HE4) and the risk of ovarian malignancy algorithm (ROMA) in patients with ovarian tumors, as well as assessing their diagnostic performance. Furthermore, another objective of the study was to identify a concordant relation between serological and immunohistochemical (IHC) biomarkers in supporting and aiding the differentiation between benign and malignant tumors, here including the group of borderline tumors. PATIENTS, MATERIALS AND METHODS: We accomplished a study that included a group of 92 patients diagnosed with ovarian tumors (benign and malignant), who were examined and treated between January 2015 and July 2018. The study was conducted at the Clinics of Obstetrics and Gynecology, "Filantropia" Municipal Hospital of Craiova, Romania. The patients were divided into two groups: the group of patients with benign tumors, subdivided into pre-menopausal (51 cases, 55.43%) and post-menopausal (30 cases, 32.6%) patients, and a group of patients who presented with malignant formation (seven cases with malignant tumors, 7.61% and four cases with borderline tumors, 4.34%, respectively). In parallel, we investigated 35 women as control subjects, who did not have a personal history of ovarian tumors. RESULTS: In our study, we have observed that for the analyzed parameters, CA125, HE4, and the ROMA index, significantly higher serum concentrations were detected in the malignant tumor group, when these have been compared to the values obtained for the pre-menopausal and for the post-menopausal subgroup, respectively. The IHC results also showed different expression patterns for the different markers studied. Corroboration of the results of the serological biomarkers with the IHC data is necessary and useful for differentiating borderline tumors and for their final integration as benign or malignant ovarian tumors. This can only be done for the cases with surgical resections, thus having tissue available. CONCLUSIONS: The serum levels of CA125 and HE4, ROMA index and IHC markers for surgical tissue fragments play a very important role in discriminating and reporting borderline ovarian tumors, as well as benign or malignant ovarian forms. Due to the superior sensitivity and specificity of CA125 and HE4, we can consider these markers as an alternative or additional diagnostic criterion to the ROMA index.

Sepsis and identification of reliable biomarkers for postoperative period prognosis.

Sepsis is currently defined as the presence of organ dysfunction occurring as the result of a disturbed host response to a serious infection. Sepsis is one of the most common diseases, which cause mortality and a considerable absorber of healthcare resources. Despite progress in technology and improving knowledge of pathophysiology, the disease mechanism is still poorly understood. At present, diagnosis is based on non-specific physiological criteria and on the late identification of the pathogen. For these reasons, the diagnosis may be uncertain, treatment delayed or an immunomodulatory therapy cannot be established. An early and reliable diagnosis is essential to achieve better outcomes on disease progression. The host response to infection involves hundreds of many mediators of which have been proposed as biomarkers. There is a need for new diagnostic approaches for sepsis, new sepsis biomarkers that can aid in diagnosis, therapeutic decision and monitoring of the response to therapy. The differentiation of sepsis from non-infectious systemic inflammatory response syndrome is difficult, and the search for a highly accurate biomarker of sepsis has become one important objective of the medicine. The goal of our review is to summarize the recent advances on the most commonly studied serum biomarkers, evaluated in clinical and experimental studies, for early diagnosis of sepsis and their informative value in diagnosis, prognosis, or response to therapy. In this context, we have tracked the clinical utility of measuring serum biomarkers, such as procalcitonin, pro- and anti-inflammatory cytokines, C-reactive protein, leptin and their combinations. Currently, has not been identified an ideal biomarker to aid in the diagnosis of sepsis. It is hoped that the discovery of new serum markers, as well as their combinations, will serve for the diagnosis and prognosis of sepsis.

Current and emerging EGFR therapies for glioblastoma.

Glioblastomas (GBMs) are the most lethal and hard to treat malignancies in clinical practice. The standard of care for treating GBM involving surgery and adjuvant radiotherapy and concomitant temozolomide (TMZ) has remained virtually unchanged in the past decade. Molecular targeted therapies against cancer-specific structures have reported mediocre results in the treatment of GBM, due to multiple factors such as the presence of the blood brain barrier or a vast array of molecular alterations which greatly hinder the action of the most therapeutic agents. One such therapy is directed against the epidermal growth factor (EGF) and its' receptor (EGFR) using either monoclonal antibodies or tyrosine kinase inhibitors. Even though anti-EGF/EGFR treatment produced encouraging results in other forms of cancer it failed to present any clinical benefit for patients with GBM. Lately, immunotherapies that focus on using the host's own immune system against cancer cells have gained popularity, with approaches like peptide vaccination being successfully used in clinical trials for different types of malignancies. These immune-based therapies could hold the key to improving both the prognosis and quality of life for patients suffering for cancers previously considered incurable, such as GBM.

Determination of VEGFR-2 (KDR) -604A>G polymorphism in recurrent pregnancy loss.

BACKGROUND: Placental angiogenesis and vascular adaptation during pregnancy, along with diminished placental trophoblastic vascular endothelial growth factor immunoreactivity, play an important role in the early stages of human pregnancy, being possible causes of recurrent pregnancy loss (RPL). AIMS: Our focus was directed towards investigating a possible association between vascular endothelial growth factor receptor-2 (kinase insert domain receptor) VEGFR-2 (KDR) -604A>G (rs 2071559) gene polymorphism and RPL in the study area of Dolj County, Romania. PATIENTS, MATERIALS AND METHODS: In this study, 169 women, diagnosed with RPL, were included. They were hospitalized in the Clinics of Obstetrics and Gynecology, "Filantropia" Municipal Hospital, Craiova, during the following period: October 2009-October 2016. The control group consisted of 145 women. All subjects were genotyped by means of allelic discrimination TaqMan polymerase chain reaction assay with specific probes. RESULTS: No statistically significant difference was observed between the RPL patients and the control group, when one genotype was compared to another [in a dominant model, -604 AG+GG vs. AA: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.99-2.96, p=0.051]. While studying the overall risk of RPL by the genotype frequencies of KDR polymorphism between controls and RPL patients, which were stratified according to the number of consecutive pregnancy losses (PLs), the chi-square test showed a significant association between the presence of this polymorphism and the increased risk observed in patients with four or more consecutive PLs, to develop RPL (in a dominant model - G allele carriers, KDR -604 AG+GG vs. AA: OR 1.91, 95% CI 1.03-3.52, p=0.037). These results prove that G allele carriers have an increased risk of RPL about 1.91-fold higher than those with the AA genotype do. Although our results bear limited statistical significance, the study nonetheless represents a step forward in the evaluation of recurrent abortion, which has not yet been explored sufficiently. CONCLUSIONS: VEGFR-2 (KDR) polymorphism does not influence RPL susceptibility in the study area of Dolj County, Romania. Therefore, further studies, which include a larger sample size, are required in order to clarify the role of KDR polymorphism in RPL.

Serum Biomarkers for Discrimination between Hepatitis C-Related Arthropathy and Early Rheumatoid Arthritis.

In the present study, we aimed to estimate the concentrations of cytokines (interleukin 6, IL-6, tumor necrosis factor-α, TNF-α) and auto-antibodies (rheumatoid factor IgM isotype, IgM-RF, antinuclear auto-antibodies, ANA, anti-cyclic citrullinated peptide antibodies IgG isotype, IgG anti-CCP3.1, anti-cardiolipin IgG isotype, IgG anti-aCL) in serum of patients with eRA (early rheumatoid arthritis) and HCVrA (hepatitis C virus-related arthropathy) and to assess the utility of IL-6, TNF-α together with IgG anti-CCP and IgM-RF in distinguishing between patients with true eRA and HCVrA, in the idea of using them as differential immunomarkers. Serum samples were collected from 54 patients (30 diagnosed with eRA-subgroup 1 and 24 with HCVrA-subgroup 2) and from 28 healthy control persons. For the evaluation of serum concentrations of studied cytokines and auto-antibodies, we used immunoenzimatique techniques. The serum concentrations of both proinflammatory cytokines were statistically significantly higher in patients of subgroup 1 and subgroup 2, compared to the control group (p < 0.0001). Our study showed statistically significant differences of the mean concentrations only for ANA and IgG anti-CCP between subgroup 1 and subgroup 2. We also observed that IL-6 and TNF-α better correlated with auto-antibodies in subgroup 1 than in subgroup 2. In both subgroups of patients, ROC curves indicated that IL-6 and TNF-α have a higher diagnostic utility as markers of disease. In conclusion, we can say that, due to high sensitivity for diagnostic accuracy, determination of serum concentrations of IL-6 and TNF-α, possibly in combination with auto-antibodies, could be useful in the diagnosis and distinguishing between patients with true eRA and HCV patients with articular manifestation and may prove useful in the monitoring of the disease course.

The role of autoantibodies in health and disease.

Serum of healthy individuals contains antibodies that react with self and non-self antigens, generated in absence of external antigen stimulation. These antibodies, called natural antibodies, are particularly IgM isotype, are considered natural autoantibodies (NAA), displaying a moderate affinity for self-antigens. Although incidence of NAA in healthy individuals is not reported, it is established that autoreactive antibodies and B-cells, as well as autoreactive T-cells, are present in healthy persons. The functional abilities of NAA are not clear but is well accepted that they may participate in a variety of activities, such as maintenance of immune homeostasis, regulation of the immune response, resistance to infections, transport and functional modulation of biologically active molecules. On the other hand, specific adaptive immune responses through high-affinity, class-switched IgG autoantibodies, which bind self-proteins, can cause tissue damage or malfunctions, inducing autoimmune diseases. The new technology that allows for more autoantibody screening may further enhance the clinical utility of autoantibody tests, making it possible to diagnose autoimmune disease in its early stages and to intervene before installing injuries. The aim of this review paper is to succinctly analyze the progress in the physiological role and regulatory significance of natural autoantibodies in health and disease.

Histological factors that predict the liver fibrosis in patients with chronic hepatitis C.

In chronic hepatitis, pathologies reveal a prominent inflammatory infiltrate portal consisting mostly of lymphocytes and plasma cells invading the portal spaces, although one can also identify macrophages, neutrophils or eosinophils. In all the forms of chronic hepatitis, fibrosis starts in the portal area, namely periportally, subsequently extends towards the lobules to the central veins, causing septa, followed by fibrosis. We studied 52 patients with chronic hepatitis C, who underwent a hematological, biochemical, virological and histopathological investigation. We found that the severity degree of the portal inflammation was in direct relation to the hepatitis activity index (HAI) and to the degree of fibrosis. The portal inflammation is dependent to the degree of fibrosis. The degree of inflammation significantly changes the distribution of cases with different degrees of fibrosis (chi-square p=0.00011 <0.001). Periportal inflammation, periportal necrosis and focal necrosis are the morphological aspects of the necroinflammatory process best correlated to the occurrence and development of fibrosis.

Matrix metalloproteinases (MMP-3 and MMP-9) implication in the pathogenesis of inflammatory bowel disease (IBD).

Inflammatory bowel disease is a chronic disease, with unknown etiology, characterized by a sustained inflammatory cascade that gives rise to the release of mediators, capable of degrading and modifying bowel wall structure. The present study investigated changes of circulating metalloproteinases (MMP-3, MMP-9) and CRP levels in patients with ulcerative colitis and Crohn's disease, in order to contribute to the elucidation of pathogenesis. We have studied serum samples of 67 patients, of which 46 with ulcerative colitis (mean age 44.8 years) and 21 affected by Crohn's diseases (mean age 39.52 years), who were hospitalized in the Clinic of Gastroenterology of the Emergency County Hospital of Craiova, Romania. For the quantitative determination of MMP-3, MMP-9 and CRP, the ELISA technique was used. Both patients, with Crohn's disease and ulcerative colitis, showed increased production of studied immunomarkers, which were correlated with some clinical stages, indicating their involvement in the disease activity.

Investigation of inflammatory activity in ulcerative colitis.

Inflammatory bowel diseases (IBDs), ulcerative colitis and Crohn's disease are lifelong disorders, characterized by the chronic inflammation of all or part of our digestive tract. Cytokines have an essential role in the pathogenesis of IBDs, because they control the inflammatory response, and the disequilibrium of pro-inflammatory/anti-inflammatory cytokines may lead directly to tissue destruction. Histopathologically, these diseases are characterized by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the present cell types, but these features frequently overlap. We performed a prospective study, which included 46 patients diagnosed with ulcerative colitis (UC) (gender ratio 25 males/21 females, mean age 44.8 years) and 30 subjects, with similar demographic characteristics, which were selected from the patients investigated for other digestive disorders, unaffected by UC. Serological investigations were performed by quantitative determination of IL-17, IL-13, and CRP using ELISA sandwich technique. We have achieved significantly higher concentrations of IL-13, IL-17 and CRP in the serum of patients with UC, compared to the control group. We have found in our study correlations between ulcerative colitis activity and serum levels of interleukins, IL-13 and IL-17. Because IL-17 serum levels were significantly correlated with the disease severity and only cytokine had a significantly statistic correlation with high serum levels of CRP in UC patients, IL-17 can be considered an important progress inflammation marker of this disease.