The Modulation of Euglycemic Endocrine and Exocrine Pancreatic Secretions in Iron Deficiency.

OBJECTIVES: The contribution of pancreatic secretions in iron metabolism is elucidated. Still, the clinical outcomes of iron deficiency on pancreatic function are debatable. This study aimed to investigate the modulation of euglycemic endocrine and exocrine pancreatic excretions in response to variations in iron availability. SUBJECTS AND METHODS: A total of one hundred and seventy (N=170) adult subjects with variable extents of serum iron levels were included. Serum levels of insulin, glucagon, insulin-to-glucagon ratio (IGR), and amylase were determined. RESULTS: Control (n=46) and iron-deficient (n=124) subjects had significant differences (p <0.001) in their average levels of insulin (68.7 ± 0.5 vs. 100.0 ± 2.0 pmol/dL), glucagon (17.9 ± 0.6 vs. 10.8 ± 0.8 pmol/dL), IGR (4.0 ± 0.1 vs. 19.5 ± 2.1) and amylase (29.7 ± 0.9 vs. 17.5 ± 0.2), respectively. The upregulation of serum insulin level exacerbates proportionally and gradually to the extent of iron deficiency as compared to an abrupt downregulation of serum glucagon and amylase levels. A significant association between serum iron and IGR (r = -0.645, p<0.001) and amylase levels (r = 0.653, p <0.001). The receiver operating characteristic (ROC) curve analysis defines an excellent predictivity of the reduced serum iron level to discriminate subjects with upregulated IGR and amylase levels with area under curves of 0.938 and 0.905, respectively. CONCLUSION: Iron deficiency confronts an adaptive modulation of euglycemic endocrine and exocrine secretions that is consistent with a status of insulin resistance.

Investigation of the diagnostic importance and accuracy of CT in the chest compared to the RT-PCR test for suspected COVID-19 patients in Jordan.

This article aims to synthesize the existing literature on the implementation of public policies to incentivize the development of treatments for rare diseases, (diseases with very low prevalence and therefore with low commercial interest) otherwise known as orphan drugs. The implementation of these incentives in the United States (US), Japan, and in the European Union (EU) seems to be related to a substantial increase in treatments for these diseases, and has influenced the way the pharmaceutical research & development (R&D) system operates beyond this policy area. Despite the success of the Orphan Drug model, the academic literature also highlights the negative implications that these public policies have on affordability and access to orphan drugs, as well as on the prioritization of certain disease rare areas over others. The synthesis focuses mostly on the United States' Orphan Drug Act (ODA) as a model for subsequent policies in other regions and countries. It starts with a historical overview of the creation of the term "rare diseases", continues with a summary of the evidence available on the US ODA's positive and negative impacts, and provides a summary of the different proposals to reform these incentives in light of the negative outcomes described. Finally, it describes some key aspects of the Japanese and European policies, as well as some of the challenges captured in the literature related to their impact in Low- and Middle-Income Countries (LMICs).

The modulation of Plasma Levels of Dopamine, Serotonin, and Brain-derived neurotrophic factor in response to variation in iron availability.

BACKGROUND AND AIM: In the context of iron deficiency anemia, central dopamine, serotonin, and brain-derived neurotrophic factor (BDNF) are intensively investigated. However, peripheral isoforms are poorly investigated. This study aimed to investigate the modulation of plasma levels of dopamine, serotonin, and BDNF among children with iron deficiency anemia. METHODS: A total of seventy-three iron-deficient (n=38) and iron-sufficient (n=35) children were included in the study.  Twenty-nine subjects were showing clinical presentations and were diagnosed with iron deficiency anemia and forty-four were asymptomatic normal children. Plasma levels of dopamine, serotonin, and brain-derived neurotrophic factor were determined by enzyme-linked immunosorbent assay. RESULTS: As compared to corresponding levels among control subjects, Anemic subjects were having significantly higher plasma dopamine and lower plasma brain-derived neurotrophic factor levels. A significant linear and monotonic association of plasma dopamine and brain-derived neurotrophic factor with hemoglobin concentration (r=-0.520, P < 0.001 and ρ = 0.411, P = 0.001), respectively. Furthermore, there were significantly higher plasma serotonin levels among iron-deficient subjects with a significant inverse linear association with serum ferritin levels (r = -0.337, P = 0.005). CONCLUSIONS: Iron deficiency anemia is associated with the modulation of peripheral dopamine, serotonin, and brain-derived neurotrophic factor. Upregulation of dopamine and downregulation of brain-derived neurotrophic factor are correlated to the anemic status. The upregulation of plasma serotonin levels is iron-dependent and, probably, is attributed to the impairment of its metabolic fate. Further investigation is required to explore the pathophysiological and clinical association of these peripheral biomolecules in the context of iron deficiency anemia. (www.actabiomedica.it).

Evidence on the Heroin-Mediated Impairment of the Oxidative Status of Erythrocytes.

Away from hemorheological properties, the effect of heroin addiction on erythrocytes is poorly investigated. This study aimed to investigate the oxidative impacts of heroin administration on erythrocytes. Study subjects included chronic intravenous heroin addicts and control subjects. Hematological analysis and redox parameters were measured, including serum concentration of methemoglobin ([MethHb]), serum glutathione peroxidase-1 ([GPX-1]), serum glutathione peroxidase (GPX) activity, erythrocytic protein carbonyl content, and oxidized to reduced glutathione (GSSG/GSH) ratio. Hematological analysis revealed that addicts had a significantly higher red cell distribution width, consistent with the mild anisocytosis and poikilocytosis of erythrocytes. As compared to control subjects, significantly higher levels of serum [Met-Hb], [GPX-1], and GPX activity (p < 0.001) were reported among addicted subjects. A significant association between [MetHb] and GPX activity was observed with r = 0.764 (p < 0.001). Furthermore, significantly higher erythrocytic protein carbonyl contents and GSSG/GSH ratio were evident among heroin addicts (p < 0.005) that were significantly associated with r = 0.429 (p=0.01). Results demonstrate preliminary evidence that heroin addiction is implicated in impaired redox status of erythrocytes. Considering the pharmacokinetics of heroin, erythrocytic antioxidant mechanisms, and turnover rate, further investigation is required to evaluate the extent and clinical outcomes, especially upon over-dose administration.

A Proposed Kinetic Model for the Diagnostic and Prognostic Value of WT1 and p53 in Acute Myeloid Leukemia.

BACKGROUND: Wilms tumor (WT1) and p53 proteins were identified in the pathogenesis of several malignancies, including hematological malignancies. As a result of their interaction and diverse context-specific functions, this study aimed to emphasize the diagnostic and prognostic impacts of WT1 and p53 expression in acute myeloid leukemia (AML). METHODS: Twelve bone marrow (BM) biopsies were obtained from AML patients who were diagnosed in accordance with the French-American-British diagnostic criteria. For comparative purposes, nine normal BM biopsies were included. The expression rate of WT1 and p53 were determined by an immunohistochemistry assay. RESULTS: A significantly higher (p < 0.005) and strongly correlated ( = 0.855, p = 0.001) expression rates of WT1 and p53 were observed in the BM of AML patients in comparison to control BM. Furthermore, relapsed AML patients had significantly higher expression of WT1, but not p53, when compared to newly diagnosed patients. In regard of patient's responsiveness to chemotherapy, no significant difference was reported between good and poor responders. However, the relative ratio of p53 to WT1 expression was evidently correlated to the responsiveness groups (p < 0.05), where the ratio was observed to be significantly higher among poor responders. Poor responders were characterized by a statistically significant and dominant p53 expression (p53/WT1 > 1.0) while both good responding patients and control subjects had a dominant WT1 expression (p53/WT1 < 1.0). CONCLUSIONS: The enhanced expression levels of WT1 and p53 proteins in the BM of AML patients is supportive of their intermediate role in the pathogenesis of the disease. WT1 expression rate may encompass a negative prognostic value of the disease. Furthermore, the ratio of p53/WT expression may serve as a hallmark of the patient's responsiveness to chemotherapy, where a dominant WT1 expression may reveal good responsiveness to chemotherapy. Herein, we are proposing a kinetic model where the p53/WT1 ratio might be useful as a laboratory approach to evaluate the prognostic value of AML including the patient's responsiveness to chemotherapeutic regimen.

Changes of serum growth factors profiles in patients with venous thromboembolism.

BACKGROUND AND RATIONALE: Venous thromboembolism (VTE) is a multifactorial disorder. Multiple hits to the tightly regulated blood hemostasis systems are required to trigger VTE. Growth factors, such as angiopoietins 1 and 2 (Ang-1 and Ang-2), and the epidermal growth factor (EGF) are critically involved in the maintenance of endothelial activity and vascular stability. The aim of this study was to evaluate the changes of these serum growth factors in patients with VTE. METHODS: This is a multi-institutional retrospective case-control study. The first arm included 50 patients diagnosed with deep vein thrombosis (DVT), pulmonary embolism (PE) or both. The control arm included 25 healthy subjects with no current or previous VTE. Both arms were investigated for changes in their serum levels of Ang-1, Ang-2 and EGF. RESULTS: Compared to healthy controls, Ang-2 was significantly higher (p = .001) while Ang-1 and EGF were significantly lower (p = .001 and p = .004; respectively) in VTE patients compared to healthy subjects. The type of VTE (DVT vs. PE) did not affect the observed changes in serum growth factors profiles. These changes were not time- or frequency-dependent, as there were no significant differences between acute versus chronic, or between the first-time versus recurrent cases of VTE. CONCLUSIONS: Serum profiles of Ang-1, Ang-2 and EGF change dramatically during VTE. This hints the significant role that these growth factors played in the pathogenesis of VTE. Thus, serum levels of growth factors may help in the first-time diagnosis of VTE, but not in diagnosing a recurrent episode of VTE. Larger studies are required to determine 'threshold levels' or 'likelihood ranges' of each biomarker for accurate diagnosis.

Tempol protects blood proteins and lipids against peroxynitrite-mediated oxidative damage.

Oxidative stress is characterized by excessive production of various free radicals and reactive species among which, peroxynitrite is most frequently produced in several pathological conditions. Peroxynitrite is the product of the superoxide anion reaction with nitric oxide, which is reported to take place in the intravascular compartment. Several studies have reported that peroxynitrite targets red blood cells, platelets and plasma proteins, and induces various forms of oxidative damage. This in vitro study was designed to further characterize the types of oxidative damage induced in platelets and plasma proteins by peroxynitrite. This study also determined the ability of tempol to protect blood plasma and platelets against peroxynitrite-induced oxidative damage. The ability of various concentrations of tempol (25, 50, 75, and 100 µM) to antagonize peroxynitrite-induced oxidation was evaluated by measuring the levels of protein carbonyl groups and thiobarbituric-acid-reactive substances in experimental groups. Exposure of platelets and plasma to 100 µM peroxynitrite resulted in an increased levels of carbonyl groups and lipid peroxidation (P < 0.05). Tempol significantly inhibited carbonyl group formation in plasma and platelet proteins (P < 0.05). In addition, tempol significantly reduced the levels of lipid peroxidation in both plasma and platelet samples (P < 0.05). Thus, tempol has antioxidative properties against peroxynitrite-induced oxidative damage in blood plasma and platelets.

Inhibition of allogeneic inflammatory responses by the Ribonucleotide Reductase Inhibitors, Didox and Trimidox.

BACKGROUND: Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle. METHODS: The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, synonymous to the initial stages of tissue and organ destruction by T-cell responses in organ rejection and Graft-versus-host disease. Using this approach, we examined the effectiveness of two ribonucleotide reductase inhibitors (RRI), Didox and Trimidox, to inhibit T-cell activation and proliferation. RESULTS: The compounds caused a marked reduction in the proliferative responses of T-cells, which is also accompanied by decreased secretion of cytokines IL-6, IFN-gamma, TNF-alpha, IL-2, IL-13, IL-10 and IL-4. CONCLUSIONS: In conclusion, these data provide critical information to justify further investigation into the potential use of these compounds post allogeneic bone marrow transplantation to alleviate graft-versus-host disease thereby achieving better outcomes.

Periovulatory leukocyte infiltration in the rat ovary.

Ovulation is preceded by intraovarian inflammatory reactions that occur in response to the preovulatory gonadotropin surge. As a main inflammatory event, leukocytes infiltrate the ovary and release proteolytic enzymes that degrade the extracellular matrix weakening the follicular wall, a required step for follicle rupture. This study aimed to quantitatively measure the infiltrating leukocytes, determine their cell types, and localize infiltration sites in the periovulatory rat ovary. Cycling adult and gonadotropin-stimulated immature rats were used as animal models. Ovaries were collected at five different stages of estrous cycle in the adult rats (diestrus, 1700 h; proestrus, 1500 h; proestrus, 2400 h; estrus, 0600 h; and metestrus, 1700 h) and at five different time points after superovulation induction in the immature rats (pregnant mare's serum gonadotrophin, 0 h; pregnant mare's serum gonadotrophin, 48 h; human chorionic gonadotropin, 6 h; human chorionic gonadotropin, 12 h; and human chorionic gonadotropin, 24 h). The ovaries were either dissociated into a single cell suspension for flow cytometric analysis or fixed for immunohistochemical localization of the leukocytes. Similar numbers of leukocytes were seen throughout the estrous cycle (approximately 500,000/ovary), except proestrus 2400 when 2-fold higher numbers of leukocytes were found (approximately 1.1 million/ovary). A similar trend of periovulatory rise of leukocyte numbers was seen in the superovulation-induced immature rat model, recapitulating a dramatic increase in leukocyte numbers upon gonadotropin stimulation. Both macrophage/granulocytes and lymphocytes were among the infiltrating leukocytes and were localized in the theca and interstitial tissues, where platelet-endothelial cell adhesion molecule-1 and intercellular adhesion molecule-1 may play roles in the transmigration of leukocytes, because their expressions correlates spatiotemporally with the infiltrating leukocytes. In addition, a strong inverse relationship between leukocyte numbers in the ovary and spleen, as well as significant reduction of leukocyte infiltration in the splenectomized rats, were seen, indicating that the spleen may serve as an immediate supplier of leukocytes to the periovulatory ovary.