Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis.
Abstract
Patients with diabetic ketoacidosis (DKA) are uniquely predisposed to mucormycosis, an angioinvasive fungal infection with high mortality. Previously, we demonstrated that Rhizopus invades the endothelium via binding of fungal CotH proteins to the host receptor GRP78. Here, we report that surface expression of GRP78 is increased in endothelial cells exposed to physiological concentrations of β-hydroxy butyrate (BHB), glucose, and iron that are similar to those found in DKA patients. Additionally, expression of R. oryzae CotH was increased within hours of incubation with DKA-associated concentrations of BHB, glucose, and iron, augmenting the ability of R. oryzae to invade and subsequently damage endothelial cells in vitro. BHB exposure also increased fungal growth and attenuated R. oryzae neutrophil-mediated damage. Further, mice given BHB developed clinical acidosis and became extremely susceptible to mucormycosis, but not aspergillosis, while sodium bicarbonate reversed this susceptibility. BHB-related acidosis exerted a direct effect on both GRP78 and CotH expression, an effect not seen with lactic acidosis. However, BHB also indirectly compromised the ability of transferrin to chelate iron, as iron chelation combined with sodium bicarbonate completely protected endothelial cells from Rhizopus-mediated invasion and damage. Our results dissect the pathogenesis of mucormycosis during ketoacidosis and reinforce the importance of careful metabolic control of the acidosis to prevent and manage this infection.
- PMID:
- 27159390
- PMCID:
- PMC4887168
- DOI:
- 10.1172/JCI82744
Disrupting Hypoxia-Induced Bicarbonate Transport Acidifies Tumor Cells and Suppresses Tumor Growth.
Abstract
Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extracellularly by CA9 could exacerbate the intracellular acidity produced by hypoxic conditions, perhaps compromising cell growth and viability as a result. In 8 of 10 cancer cell lines, we found that hypoxia induced the expression of at least one bicarbonate transporter. The most robust and frequent inductions were of the sodium-driven bicarbonate transporters SLC4A4 and SLC4A9, which rely upon both HIF1α and HIF2α activity for their expression. In cancer cell spheroids, SLC4A4 or SLC4A9 disruption by either genetic or pharmaceutical approaches acidified intracellular pH and reduced cell growth. Furthermore, treatment of spheroids with S0859, a small-molecule inhibitor of sodium-driven bicarbonate transporters, increased apoptosis in the cell lines tested. Finally, RNAi-mediated attenuation of SLC4A9 increased apoptosis in MDA-MB-231 breast cancer spheroids and dramatically reduced growth of MDA-MB-231 breast tumors or U87 gliomas in murine xenografts. Our findings suggest that disrupting pH homeostasis by blocking bicarbonateimport might broadly relieve the common resistance of hypoxic tumors to anticancer therapy. Cancer Res; 76(13); 3744-55. ©2016 AACR.
©2016 American Association for Cancer Research.
- PMID:
- 27197160
- DOI:
- 10.1158/0008-5472.CAN-15-1862
Sodium Bicarbonate Prevents Contrast-Induced Nephropathy in Addition to Theophylline: A Randomized Controlled Trial.
Abstract
In this study, we investigated whether hydration with sodium bicarbonate is superior to hydration with saline in addition to theophylline (both groups) in the prophylaxis of contrast-induced nephropathy (CIN). It was a prospective, randomized, double-blinded study in a university hospital on 2 general intensive care units (63% of investigations) and normal wards.After approval of the local ethics committee and informed consent 152 patients with screening serum creatinine ≥1.1 mg/dL and/or at least 1 additional risk factor for CIN undergoing intravascular contrast media (CM) exposure were randomized to receive a total of 9 mL/kg bicarbonate 154 mmol/L (group B; n = 74) or saline 0.9% (group S; n = 78) hydration within 7 h in addition to intravenous application of 200 mg theophylline. Serum creatinine was determined immediately before, 24 and 48 h after CM exposure. As primary endpoint we investigated the incidence of CIN (increase of serum creatinine ≥0.5 mg/dL and/or ≥25% within 48 h of CM).Both groups were comparable regarding baseline characteristics. Incidence of CIN was significantly less frequent with bicarbonate compared to sodium hydration (1/74 [1.4%] vs 7/78 [9.0%]; P = 0.035). Time course of serum creatinine was more favorable in group B with decreases in serum creatinine after 24 h (-0.084 mg/dL [95% confidence interval: -0.035 to -0.133 mg/dL]; P = 0.008) and 48 h (-0.093 mg/dL (-0.025 to -0.161 mg/dL); P = 0.007) compared to baseline which were not observed in group S.In patients at increased risk of CIN receiving prophylactic theophylline, hydration with sodium bicarbonate reduces contrast-induced renal impairment compared to hydration with saline.
- PMID:
- 27227933
- PMCID:
- PMC4902357
- DOI:
- 10.1097/MD.0000000000003720
A randomized controlled trial evaluating the efficacy of a 67% sodium bicarbonate toothpaste on gingivitis.
Abstract
INTRODUCTION:
In previous studies, toothpastes with high levels of sodium bicarbonate (>50%) have reduced gingival inflammation and oral malodour. This study compared the effects of brushing for 6 weeks with 67% (test group) or 0% (control group) sodium bicarbonate toothpaste on gingival health.
METHODS:
This was a single-centre, single examiner-blind, randomized, controlled, two-treatment, parallel-group study. Eligible subjects (≥18 years) had ≥20 gradable teeth, mild-to-moderate gingivitis, a positive response to bleeding on brushing and ≥20 bleeding sites. The primary objective was to compare the number of bleeding sites following twice-daily use of 67% sodium bicarbonatetoothpaste or 0% sodium bicarbonate toothpaste after 6 weeks. Secondary endpoints included Modified Gingival Index (MGI), Bleeding Index (BI) and volatile sulphur compounds (VSC), assessed after 6 weeks. Safety was assessed by treatment-emergent oral soft tissue abnormalities and adverse events.
RESULTS:
Of 148 patients randomized (74 to each treatment), 66 (89.2%) completed the study in the test group, compared with 69 (93.2%) in the control group. Compared with the control group, the test group had a significant reduction in the number of bleeding sites at Week 6 (absolute difference – 11.0 [-14.0, -8.0], P < 0.0001; relative difference – 25.4%), together with significant reductions in MGI and BI (both P < 0.0001). Although the median reductions from baseline for VSC were numerically greater in the test group, the difference did not reach statistical significance (P = 0.9701).
CONCLUSIONS:
This 67% sodium bicarbonate toothpaste provided statistically significant improvements in gingival health and bleeding after 6 weeks of use.
© 2016 The Authors. International Journal of Dental Hygiene Published by John Wiley & Sons Ltd.
KEYWORDS:
dentifrice; gingivitis; sodium bicarbonate; toothpaste; volatile sulphur compounds
Serum alkalinisation is the cornerstone of treatment for amitriptyline poisoning.
Abstract
A 28-year-old woman was admitted in a comatose state following ingestion of 5 g of amitriptyline. On arrival, there was intermittent seizure activity and a broad complex tachycardia on the ECG. Immediate resuscitation included 8 mg lorazepam, 2 L crystalloid fluid, 100 mL 8.4% sodium bicarbonate, 2 g of magnesium sulphate and lipid emulsion infusion. Despite this, the broad complex tachycardia persisted with haemodynamic instability. The case was discussed with the National Poisons Information Service, which advised further 8.4% sodium bicarbonate to achieve serum alkalinisation. Following this, the QRS duration reduced and haemodynamic stability was achieved. Serum alkalinisation continued in the intensive treatment unit before the patient was successfully extubated on day 5 and discharged on day 7 with no neurological sequelae. To our knowledge, this case is the largest recorded overdose of amitriptyline to have survived to discharge. The importance of serum alkalinisation in the management of tricyclic antidepressant poisoning is highlighted.
2016 BMJ Publishing Group Ltd.
- PMID:
- 27068728
- DOI:
- 10.1136/bcr-2016-214685
[The influence of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning].
Abstract
OBJECTIVE:
To observe the effect of sodium bicarbonate combined with ulinastatin on cholinesterase activity for patients with acute phoxim pesticide poisoning.
METHODS:
A total of 67 eligible patients with acute phoxim pesticide poisoning, Who were admitted to the emeryency department of hospital from March 2011 to February 2014, Acording to different treatments au patients were randomly divided into the conventional treatment group (n=34) and the sodium bicarbonate+ulinastatin group (n=35) . The conventional treatment group were given thorough gastric lavage with water, the sodium bicarbonate + ulinastatin group were given gastric lavage with 2% sodium bicarbonate solution. Both groups were given such treatments as catharsis, administration of oxygen, fluid infusion, diuresis, and antidotes such as atropine and pralidoxime methylchloride. On the basis of comprehensive treatment, people in the sodium bicarbonate+ulinastatin group were given 5% sodium bicarbonate injection and ulinastatin. The clinical effect of the two groups were compared.
RESULTS:
The serum cholinesterase activity of the sodium bicarbonate+ulinastatin group was significantly higher than the conventional treatment group from the 5th day, and the difference was statistically significant (P<0.05) . The total atropine dosage, total pralidoxime methylchloride dosage and hospitalization days were better than the conventional treatment group, and the differences were statistically significant (P<0.05) . The difference in the time of atropinization between the two groups was not statistically significant (P>0.05) . The results of arterial blood pH, HCO3- of the sodium bicarbonate + ulinastatin group were higher than the conventional treatment group, and the difference of HCO3- at the 10th day was statistically significant (P<0.05) .
CONCLUSIONS:
Sodium bicarbonate combined with ulinastatin can improve the therapeutic effect and reduce complications in the treatment of acute phoxim pesticide poisoning, and have beneficial effects on the recovery of cholinesterase activity.
- PMID:
- 27014821
- [PubMed – indexed for MEDLINE]
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