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PloS One 2024The infant gut microbiome is a crucial factor in health and development. In preterm infants, altered gut microbiome composition and function have been linked to serious...
The infant gut microbiome is a crucial factor in health and development. In preterm infants, altered gut microbiome composition and function have been linked to serious neonatal complications such as necrotizing enterocolitis and sepsis, which can lead to long-term disability. Although many studies have described links between microbiome composition and disease risk, there is a need for biomarkers to identify infants at risk of these complications in practice. In this pilot study, we obtained stool samples from preterm infant participants longitudinally during the first postnatal months, and measured pH and redox, as well as SCFA content and microbiome composition by 16S rRNA gene amplicon sequencing. These outcomes were compared to clinical data to better understand the role of pH and redox in infant gut microbiome development and overall health, and to assess the potential utility of pH and redox as biomarkers. We found that infants born earlier or exposed to antibiotics exhibited increased fecal pH, and that redox potential increased with postnatal age. These differences may be linked to changes in SCFA content, which was correlated with pH and increased with age. Microbiome composition was also related to birth weight, age, pH, and redox. Our findings suggest that pH and redox may serve as biomarkers of metabolic state in the preterm infant gut.
Topics: Infant; Infant, Newborn; Humans; Infant, Premature; Gastrointestinal Microbiome; Pilot Projects; RNA, Ribosomal, 16S; Oxidation-Reduction; Alkalosis; Biomarkers; Hydrogen-Ion Concentration
PubMed: 38261587
DOI: 10.1371/journal.pone.0290598 -
Veterinary Sciences Jan 2024This study aimed to investigate the association of respiratory rate (RR), oxygen saturation (SpO), and blood findings with respiratory disease in dogs and to compare the...
This study aimed to investigate the association of respiratory rate (RR), oxygen saturation (SpO), and blood findings with respiratory disease in dogs and to compare the examination findings in the chronic and acute phases. Dogs that visited a veterinary referral hospital with respiratory symptoms were classified into the chronic disease group (GC), and those that visited the emergency veterinary hospital were classified into the acute disease group (GA). In total, 704 and 682 dogs were included in GC and GA, respectively. The RR and SpO were significantly higher and lower, respectively, in patients with lung disease compared to other disease sites in both groups. White blood cell counts were significantly increased in patients with lung and pleural diseases in both groups. Respiratory alkalosis and respiratory acidosis were most common in GC and GA, respectively. The C-reactive protein levels were elevated in both groups, primarily in patients with lung disease. Associations between the results of several tests for understanding and diagnosing respiratory conditions and diseases were recognized, and differences in the trends of the chronic and acute phases were clarified. These tools may be used as adjuncts to other tests for the diagnosis and monitoring of treatment responses.
PubMed: 38250933
DOI: 10.3390/vetsci11010027 -
Cancer Medicine Feb 2024It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth....
BACKGROUND
It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects.
METHODS
We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using F-NaF for HAP and F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods.
RESULTS
Within 24 h of adding the small concentration of 1X of NSPS (~7 μM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in F-Na Fuptake post NSPS treatment as expected; F uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone.
CONCLUSION
Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.
Topics: Humans; Male; Animals; Mice; Pharmaceutical Preparations; Fluorodeoxyglucose F18; Immunotherapy; Drug-Related Side Effects and Adverse Reactions; Lung Neoplasms; Alkanesulfonates; Glucose; Hydroxyapatites; Tumor Microenvironment
PubMed: 38239047
DOI: 10.1002/cam4.6812 -
Cureus Dec 2023Bartter syndrome is a genetic condition characterized by autosomal recessive inheritance, resulting in impaired salt reabsorption and clinical manifestations such as...
Bartter syndrome is a genetic condition characterized by autosomal recessive inheritance, resulting in impaired salt reabsorption and clinical manifestations such as low/normal blood pressure and extracellular fluid volume depletion. Multiple abnormalities of the electrolytes, including decreased potassium as well as chloride levels and, in some instances, hypomagnesemia, are its defining features. Metabolic alkalosis, hypokalaemia, hypocalcemia, and hypomagnesemia, together with adequate renal function, are all components of the Bartter-like syndrome. It is associated with certain antibiotics and antineoplastic drugs. We report a case of traumatic brain injury with pneumothorax who was on treatment on colistin and presented with metabolic disturbance.
PubMed: 38229782
DOI: 10.7759/cureus.50672 -
The International Journal of Artificial... Feb 2024To investigate the effectiveness and safety of regional citrate-anticoagulated (RCA) plasma exchange (PE) and whether citrate-related metabolic disorders can be improved... (Observational Study)
Observational Study
OBJECTIVE
To investigate the effectiveness and safety of regional citrate-anticoagulated (RCA) plasma exchange (PE) and whether citrate-related metabolic disorders can be improved by sequential RCA continuous renal replacement therapy (CRRT).
METHODS
This retrospective, single-center observational study included 79 critically ill children requiring PE followed by CRRT (June 2018 to June 2021) at the Pediatric Intensive Care Unit of Hunan Children's Hospital, China. Patients were divided into the RCA-PE ( = 30) and systemic heparin anticoagulation (SHA-PE) ( = 49) groups. Filter level comparison post-PE assessed RCA-PE efficacy, and metabolic changes occurring pre- and post-PE and CRRT were used to evaluate the effect of CRRT on RCA-based anticoagulation safety.
RESULTS
The RCA-PE group had a better overall filter performance than the SHA-PE group. Two hours after PE, pH and HCO₃ levels increased more significantly for the RCA-PE than the SHA-PE group. The RCA-PE incidence of metabolic alkalosis was 48.3%, higher by 4.2% ( < 0.001) compared to the SHA-PE group. In the RCA-PE group, pH and HCO₃ decreased significantly 4 h after CRRT; the metabolic alkalosis caused by RCA-PE decreased to 13.8% ( = 0.005). No significant difference in pH, HCO₃, and metabolic alkalosis incidence was observed between the two groups 4 h after CRRT.
CONCLUSIONS
The overall filtration performance of RCA-PE is superior to that of SHA-PE followed by CRRT. The metabolic complications associated with RCA-PE are mainly metabolic alkalosis that can be improved by using CRRT after RCA-PE and this is a better alternative for anticoagulation during PE in critically ill children.
Topics: Child; Humans; Alkalosis; Anticoagulants; Citrates; Citric Acid; Continuous Renal Replacement Therapy; Critical Illness; Plasma Exchange; Retrospective Studies
PubMed: 38229209
DOI: 10.1177/03913988231223375 -
American Journal of Physiology. Cell... Mar 2024Loss of function mutations in the gene cause chloride-losing diarrhea in mice and humans. Although systemic adaptive changes have been documented in these patients and...
Loss of function mutations in the gene cause chloride-losing diarrhea in mice and humans. Although systemic adaptive changes have been documented in these patients and in the corresponding knockout mice, how colonic enterocytes adapt to loss of this highly expressed and highly regulated luminal membrane anion exchanger remains unclear. To address this question, was deleted in the self-differentiating Caco2BBe colonic cell line by the CRISPR/Cas9 technique. We selected a clone with loss of SLC26A3 protein expression and morphological features indistinguishable from those of the native cell line. Neither growth curves nor development of transepithelial electrical resistance (TEER) differed between wild-type (WT) and SLC26A3 knockout (KO) cells. Real-time qPCR and Western analysis in SLC26A3-KO cells revealed an increase in AE2 expression without significant change in NHE3 expression or localization. Steady-state pH and apical and basolateral Cl/HCO exchange activities were assessed fluorometrically in a dual perfusion chamber with independent perfusion of luminal and serosal baths. Apical Cl/HCO exchange rates were strongly reduced in SLC26A3-KO cells, accompanied by a surface pH more acidic than that of WT cells. Steady-state pH was not significantly different from that of WT cells, but basolateral Cl/HCO exchange rates were higher in SLC26A3-KO than in WT cells. The data show that CRISPR/Cas9-mediated deletion strongly reduced apical Cl/HCO exchange rate and apical surface pH, but sustained a normal steady-state pH due to increased expression and function of basolateral AE2. The low apical surface pH resulted in functional inhibition of NHE-mediated fluid absorption despite normal expression of NHE3 polypeptide. SLC26A3 gene mutations cause chloride-losing diarrhea. To understand how colonic enterocytes adapt, SLC26A3 was deleted in Caco2BBe cells using CRISPR/Cas9. In comparison to the wild-type cells, SLC26A3 knockout cells showed similar growth and transepithelial resistance but substantially reduced apical Cl/HCO exchange rates, and an acidic surface pH. Steady-state intracellular pH was comparable between the WT and KO cells due to increased basolateral AE2 expression and function.
Topics: Humans; Animals; Mice; Chlorides; Sodium-Hydrogen Exchanger 3; Anions; Diarrhea; Enterocytes; Hydrogen-Ion Concentration; Sulfate Transporters; Chloride-Bicarbonate Antiporters
PubMed: 38223928
DOI: 10.1152/ajpcell.00590.2023 -
Pflugers Archiv : European Journal of... Apr 2024Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor... (Review)
Review
Secretin is a key hormone of the intestinal phase of digestion which activates pancreatic, bile duct and Brunner gland HCO secretion. Recently, the secretin receptor (SCTR) was also found in the basolateral membrane of the beta-intercalated cell (B-IC) of the collecting duct. Experimental addition of secretin triggers a pronounced activation of urinary HCO excretion, which is fully dependent on key functional proteins of the B-IC, namely apical pendrin and CFTR and the basolateral SCTR. Recent studies demonstrated that the SCTR knock-out mouse is unable to respond to an acute base load. Here, SCTR KO mice could not rapidly increase urine base excretion, developed prolonged metabolic alkalosis and exhibited marked compensatory hypoventilation. Here, we review the physiological effects of secretin with distinct focus on how secretin activates renal HCO excretion. We describe its new function as a hormone for HCO homeostasis.
Topics: Mice; Animals; Secretin; Cell Membrane; Sulfate Transporters; Biological Transport; Homeostasis; Bicarbonates
PubMed: 38221598
DOI: 10.1007/s00424-024-02906-3 -
Pflugers Archiv : European Journal of... Apr 2024The kidney plays a crucial role in acid-base homeostasis. In the distal nephron, α-intercalated cells contribute to urinary acid (H) secretion and β-intercalated cells... (Review)
Review
The kidney plays a crucial role in acid-base homeostasis. In the distal nephron, α-intercalated cells contribute to urinary acid (H) secretion and β-intercalated cells accomplish urinary base (HCO) secretion. β-intercalated cells regulate the acid base status through modulation of the apical Cl/HCO exchanger pendrin (SLC26A4) activity. In this review, we summarize and discuss our current knowledge of the physiological role of the renal transporter AE4 (SLC4A9). The AE4, as cation-dependent Cl/HCO exchanger, is exclusively expressed in the basolateral membrane of β-intercalated cells and is essential for the sensing of metabolic acid-base disturbances in mice, but not for renal sodium reabsorption and plasma volume control. Potential intracellular signaling pathways are discussed that might link basolateral acid-base sensing through the AE4 to apical pendrin activity.
Topics: Animals; Mice; Chloride-Bicarbonate Antiporters; Kidney; Kidney Tubules, Collecting
PubMed: 38195948
DOI: 10.1007/s00424-023-02899-5 -
Biology of Sport Jan 2024It was reported that metabolic acidosis inhibits the activity of warm-sensitive hypothalamic neurons. The present study was designed to test the hypothesis that...
It was reported that metabolic acidosis inhibits the activity of warm-sensitive hypothalamic neurons. The present study was designed to test the hypothesis that metabolic alkalosis may improve heat loss during intensive exercise in men. Fifteen male subjects aged 22-24 years were submitted to incremental exercise on two randomized occasions one week apart. During the bicarbonate trial exercise was preceded by ingestion of NaHCO at a dose 250 mg/kg whilst during the placebo trial lactose was administered. Exercise load was increased every 3 min by 30 W until volitional exhaustion. Ambient temperature was kept at 23-24°C and humidity 50-60%. Tympanic and skin temperatures were recorded and the rate of sweating was assayed by humidity measurement of nitrogen flowing through a capsule attached to the mid posterior chest. Total sweat loss was determined by the changes in body mass. Venous blood samples were taken before exercise and at the end of each workload for determination of acid-base parameters. The subjects attained similar maximal workload in the two tests (260 ± 6 W) with heart rate 185 ± 6 beats/min. Blood concentration of hydrogen ions was lower (p < 0.001) in the bicarbonate than in the placebo trial throughout the whole exercise period. There were no significant differences between these tests in tympanic and mean skin temperatures, sweating rate and total sweat loss. The present data showed that in men attenuation of metabolic acidosis by bicarbonate ingestion did not influence thermoregulation during incremental exercise performed until volitional exhaustion, possibly due to too short duration of exertional uncompensated metabolic acidosis.
PubMed: 38188109
DOI: 10.5114/biolsport.2024.129475 -
Pediatric Nephrology (Berlin, Germany) Apr 2024A 3-year-old female patient with no significant medical history presented to her pediatrician with foamy urine. Initial testing revealed moderate proteinuria on...
A 3-year-old female patient with no significant medical history presented to her pediatrician with foamy urine. Initial testing revealed moderate proteinuria on qualitative testing, although she was incidentally noted to have severe hypertension (240/200 mmHg). Physical examination of the carotid and femoral areas revealed significant systolic vascular murmurs. Labs showed elevated serum creatinine, hypokalemia, metabolic alkalosis, elevated renin and aldosterone and hypercalciuria. Echocardiography identified ventricular hypertrophy. Computed tomography (CT) of the abdomen and magnetic resonance angiography of the head showed multiple tortuous or interrupted arteries and multiple calcifications in the renal sinus area. B-mode ultrasonography suggested thickening of the carotid and femoral artery walls, with numerous spotted calcifications. Genetic testing revealed that ABCC6 had a complex heterozygous mutation (exon 24: c.3340C > T and intron 30: c.4404-1G > A). Our panel of experts reviewed the evaluation of this patient with hypertension, proteinuria, hypercalciuria, and vascular abnormalities as well as the diagnosis and appropriate management of a rare disease.
Topics: Female; Humans; Child, Preschool; Hypercalciuria; Hypertension; Hypokalemia; Genetic Testing; Proteinuria
PubMed: 38165475
DOI: 10.1007/s00467-023-06230-3