Dietary Iron

Iron metabolism differs from the metabolism of other metals in that there is no physiologic mechanism for iron excretion, it is unusual; approximately 90% of daily iron needs are obtained from an endogenous source, the breakdown of circulating RBCs. Additionally humans derive iron from their everyday diet, predominantly from plant foods and the rest from foods of animal origin. Iron is found in food as either haem or non-haem iron. Iron bioavailability has been estimated to be in the range of 14–18% for mixed diets and 5–12% for vegetarian diets in subjects with no iron stores. Iron absorption in humans is dependent on physiological requirements, but may be restricted by the quantity and availability of iron in the diet. Bioavailability of food iron is strongly influenced by enhancers and inhibitors in the diet. Iron absorption can vary from 1 to 40%. A range of iron bioavailability factors that depend on the consumption of meat, fruit, vegetables, processed foods, iron-fortified foods, and the prevalence of obesity. The methods of food preparation and processing influence the bioavailability of iron. Cooking, fermentation, or germination can, by thermal or enzymatic action, reduce the phytic acid and the hexa- and penta-inositol phosphate content. Thus improving bioavailability of non-haem iron. This chapter will elaborate the dietary iron sources and means of enhancing bioavailability.

Physiological and Clinical Impact of Repeated Inhaled Oxygen Variation on Erythropoietin Levels in Patients After Surgery

The “Normobaric Oxygen Paradox” (NOP) is a physiologic mechanism that induces an increase of endogenous erythropoietin (EPO) production by creating a state of relative hypoxia in subjects previously exposed to hyperoxia, followed by a rapid return to normoxia. Oxygen exposure duration and inspired oxygen fraction required to observe a significant increase in EPO or hemoglobin are not clearly defined. Consequently, we here study the effect of one model of relative hypoxia on EPO, reticulocytes and hemoglobin stimulation in patients after surgery. Patients were prospectively randomized in two groups. The O2 group (n = 10) received 100% oxygen for 1 h per day for eight consecutive days, via a non-rebreathing mask. The control group (n = 12) received no oxygen variation. Serum EPO, hemoglobin and reticulocyte count were measured on admission and postoperatively on days seven and nine. Percentage EPO at day nine with respect to the baseline value was significantly elevated within the groups [O2 group: 323.7 (SD ± 139.0); control group: 365.6 (SD± 162.0)] but not between them. No significant difference was found between the groups in terms of reticulocytes count and hemoglobin. Our NOP model showed no difference on EPO increase between the two groups. However, both groups expressed separately significant EPO elevation.

Physiologic Regulation of Systemic Klotho Levels by Renal CaSR Signaling in Response to CaSR Ligands and pHo

Background: The kidney is the source of sKlotho and kidney-specific loss of Klotho leads to a phenotype resembling the premature multi-organ failure phenotype in Klothohypomorphic mice (kl/kl mice). Klotho and the Ca-sensing receptor (CaSR) are highly expressed in the distal convoluted tubule (DCT). The physiologic mechanisms that regulate sKlotho levels are unknown. Methods: We measured sKlotho in WT and tubule-specific CaSR-/- (TS-CaSR-/-) mice treated with calcimimetics, alkali, or acid, and Klotho shed from minced mouse kidneys, as well as from HEK-293 cells expressing the CaSR and Klotho, in response to calcimimetics, calcilytics, alkalotic and acidic pH, and ADAM protease inhibitors. The CaSR, Klotho, and ADAM10 were imaged in mouse kidneys and cell expression systems using confocal microscopy. Results: The CaSR, Klotho, and ADAM10 co-localize on the baso-lateral membrane of the DCT. Calcimimetics and HCO3 increase serum sKlotho levels in WT but not in CaSR-/- mice and acid pH suppresses sKlotho levels in WT mice. In minced kidneys and cultured cells, CaSR activation with high Ca, calcimimetics, or alkali increase shed Klotho levels via ADAM10, as demonstrated using the ADAM10 inhibitor GI254023X and siRNA. In cultured cells the CaSR, Klotho, and ADAM10 form cell surface aggregates that disperse following CaSR activation. Conclusions: We identify a novel physiologic mechanism for regulation of sKlotho levels by the renal CaSR-ADAM10-Klotho pathway. We show that CaSR activators, including alkali, increase renal CaSR-stimulated Klotho shedding and predict that this mechanism is relevant to the effects of acidosis and alkali therapy on CKD progression.

Core binding factor leukemia hijacks T-cell prone PU.1 antisense promoter

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we demonstrate that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving non-coding antisense transcription. Core binding factor (CBF) fusions, RUNX1-ETO and CBFβ-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense towards antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared to normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus utilize a physiologic mechanism employed by T-cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

O24: THE PANCREATIC EPSILON-CELLS RECOVER THE EMBRYONIC GHRELIN SECRETION IN RESPONSE TO BARIATRIC SURGERY

Introduction Many surgical techniques are employed in the treatment of obesity. A main consequence of these techniques is the severe improvement of Type 2 Diabetes mellitus. Many hypotheses had been exposed to know the intrinsic mechanism developed in this relationship. The enterohormones seems to be a definitive effector. The ghrelin is an enterohormone released for the gastric fundus and it has been related to the mentioned improvement. We hypothesized about the role of pancreatic epsilon cells, which have the capacity to release ghrelin during the embryonic stages. We studied the changes in the ghrelin immunostaining in endocrine pancreas of rats which underwent bariatric surgery. MATERIAL AND Method We employed 16 non obese euglycemic male Wistar rats, randomised in the surgical groups. These groups were the surgical techniques (Sleeve gastric –SG- and Roux en Y Gastric Bypass –RYGB-), and two controls (fasting and surgical). After three months, rats were sacrificed; the pancreas were obtained and processed for the immuno-cytochemical technique. Result We reported a significant increase of epsilon cells (ghrelin positive/mm2 pancreatic area) in the pancreas of SG versus the control groups (vs FC, P<0.01 and vs sham, P<0.05). CONCLUSION. SG and RYGB are surgical techniques broadly employed in humans and both reduce severely the fundus. Paradoxically, the serum level of ghrelin in patients are preserved. We reported that the total suppression of the fundus gastric produced the recovery of an embryonic pancreatic function. This mechanism could be related with the complex physiologic mechanism that improve T2DM after bariatric surgery. Take-home message After bariatric surgery, the pancreas release of ghrelin increased as the response to gastric reduction.

P31: INTESTINAL GIP RELEASE MODIFICATIONS WOULD BE RELATED TO DUODENAL EXCLUSION: BARIATRIC SURGERY CONSEQUENCES

Introduction The surgical techniques employed in the treatment of obesity discovered consequences on the global enterohomonal equilibrium. Many hypotheses focused on these enterohormonal system to explain the improvement of Type 2 Diabetes mellitus; as many other functional improvements. GIP is a hormone released for the duodenal and jejunal K cells, which had been implied in the glucose homeostasis. Our purpose was studied the changes in K cells populations, that could be related to the GIP serum level. Method We employed 16 non obese euglycemic male Wistar rats, randomised in the surgical groups. These groups were the surgical techniques (Sleeve gastric –SG-, Roux en Y Gastric Bypass –RYGB- and massive intestinal resection –IR50-), and two controls (fasting and Sham). After three months, rats were sacrificed. The intestinal portions (duodenum, jejunum and ileum) were resected and processed for the immunocytochemical technique. Result analysis showed several aspects. We found a significant increase of GIP K-cells (number GIP+/mm2 intestinal portion) in the duodenum of RYGB and RI50 versus both control groups. Other data showed a significant decrease of GIP K-cells in SG jejunum versus both control groups. Ileum did not significances. Conclusion GIP hormone was related to the nutrient flow through the intestine. Our data showed that GIP expression was inverse to the exclusion to this flow, as in RYGB technique. The increase was severe in IR50 too, which the duodenum was not affected. This mechanism revealed a complex physiologic mechanism, probably established by the feed-back with other hormones, as PPY. Take-home message The metabolic consequences after bariatric surgeries are related in enterohormones changes. The GIP release cellularity suffer changes according to the flow of nutrients.

The Role of Mediobasal Hypothalamic PACAP in the Control of Body Weight and Metabolism

Body energy homeostasis results from balancing energy intake and energy expenditure. Central nervous system administration of pituitary adenylate cyclase activating polypeptide (PACAP) dramatically alters metabolic function, but the physiologic mechanism of this neuropeptide remains poorly defined. PACAP is expressed in the mediobasal hypothalamus (MBH), a brain area essential for energy balance. Ventromedial hypothalamic nucleus (VMN) neurons contain, by far, the largest and most dense population of PACAP in the medial hypothalamus. This region is involved in coordinating the sympathetic nervous system in response to metabolic cues in order to re-establish energy homeostasis. Additionally, the metabolic cue of leptin signaling in the VMN regulates PACAP expression. We hypothesized that PACAP may play a role in the various effector systems of energy homeostasis, and tested its role by using VMN-directed, but MBH encompassing, adeno-associated virus (AAVCre) injections to ablate Adcyap1 (gene coding for PACAP) in mice (Adcyap1MBHKO mice). Adcyap1MBHKO mice rapidly gained body weight and adiposity, becoming hyperinsulinemic and hyperglycemic. Adcyap1MBHKO mice exhibited decreased oxygen consumption (VO2), without changes in activity. These effects appear to be due at least in part to brown adipose tissue (BAT) dysfunction, and we show that PACAP-expressing cells in the MBH can stimulate BAT thermogenesis. While we observed disruption of glucose clearance during hyperinsulinemic/euglycemic clamp studies in obese Adcyap1MBHKO mice, these parameters were normal prior to the onset of obesity. Thus, MBH PACAP plays important roles in the regulation of metabolic rate and energy balance through multiple effector systems on multiple time scales, which highlight the diverse set of functions for PACAP in overall energy homeostasis.

Non-surgical skin tightening

Skin laxity is an unavoidable consequence of aging and chronic sun exposure. Patients are increasingly turning to non-surgical skin tightening measures for a more youthful look. Non-surgical methods can be effective in treating mild to moderate skin laxity, while offering decreased downtimes and fewer serious complications than surgical interventions. This article reviews the major non-surgical interventions for skin laxity: ablative and non-ablative lasers, radiofrequency, and microfocused ultrasound, noting their physiologic mechanism of actions, clinical benefits, and side effects. Regardless of the procedure, patient selection and expectation setting are crucial to achieving desired results and ensuring patient satisfaction.

From SARS-CoV-2 infection to COVID-19 disease: a proposed mechanism for viral spread to the lower airway based on in silico estimation of virion flow rates

ABSTRACTWhile the nasopharynx in the upper respiratory airway is the dominant initial infection site for SARS-CoV-2, the physiologic mechanism that launches the infection in the lower airway is still not well-understood. Based on the rapidity with which SARS-CoV-2 infection progresses to the lungs, it has been conjectured that the nasopharynx acts as the seeding zone for subsequent contamination of the lower airway via aspiration of virus-laden boluses of nasopharyngeal fluids. In this study, we examine the plausibility of this proposed mechanism. To this end, we have developed computational fluid mechanics models of the inhalation process in two medical imaging based airway reconstructions and have quantified the nasopharyngeal liquid volume ingested into the lower airspace during each aspiration. The numerical predictions are validated by comparing the number of projected aspirations (approximately 2 – 4) during an eight-hour sleep cycle with prior observational findings of 3 aspirations in human subjects. Extending the numerical trends on aspiration volume to earlier records on aspiration frequency for the entire day indicates a total aspirated nasopharyngeal liquid volume of 0.3 – 0.76 ml per day. We then used sputum assessment data from hospitalized COVID-19 patients to estimate the number of virions that are transmitted daily to the lungs via nasopharyngeal liquid boluses. For mean sputum viral load, our modeling projects that the number of virions penetrating to the lower airway per day will range over 2.1 × 106 – 5.3 × 106; for peak viral load, the corresponding number of penetrating virions hovers between 7.1 × 108 – 17.9 × 108. These findings fill in a key piece of the mechanistic puzzle of the progression from SARS-CoV-2 infection of the nasopharynx to the development of COVID-19 disease within a patient, and point to dysphagia as a potential underlying risk factor for COVID-19. The findings also have significant practical implications in the design of COVID-19 prophylactics and therapeutics that aim to constrain the pathogenic progress of the disease within the limits of the upper airway.

Detrimental and Beneficial Effect of Autophagy and a Potential Therapeutic Target after Ischemic Stroke

Autophagy, a physiologic mechanism that promotes energy recycling and orderly degradation through self-regulated disassembly of cellular components, helps maintain homeostasis. A series of evidences suggest that autophagy is activated as a response to ischemia and has been well-characterized as a therapeutic target. However, the role of autophagy after ischemia remains controversial. Activated-autophagy can remove necrotic substances against ischemic injury to promote cell survival. On the contrary, activation of autophagy may further aggravate ischemic injury, causing cell death. Therefore, the present review will examine the current understanding of the precise mechanism and role of autophagy in ischemia and recent neuroprotective therapies on autophagy, drug therapies, and nondrug therapies, including electroacupuncture (EA).