Therapeutic Actions Oxygen Therapy

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Metal-Organic-Framework-Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy.

Related Articles Metal-Organic-Framework-Derived Carbon Nanostructure Augmented Sonodynamic Cancer Therapy. Adv Mater. 2018 Apr 19;:e1800180 Authors: Pan X, Bai L, Wang H, Wu Q, Wang H, Liu S, Xu B, Shi X, Liu H Abstract Sonodynamic therapy (SDT) can overcome the critical issue of depth-penetration barrier of photo-triggered therapeutic modalities. However, the discovery of sonosensitizers with high sonosensitization efficacy and good stability is still a significant challenge. In this study, the great potential of metal-organic-framework (MOF)-derived carbon nanostructure (PMCS) to act as an excellent sonosensitizer is identified. Excitingly, the superior sonosensitization effect of PMCS is believed to be closely linked to the porphyrin-like macrocycle in MOF-derived nanostructure in comparison to amorphous carbon nanospheres, due to their large highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) gap for high reactive oxygen species (ROS) production. The nanoparticle-assisted cavitation process, including the visualized formation of the cavitation bubbles and microjets, is also first captured by high-speed camera. High ROS production in PMCS under ultrasound is validated by electron spin resonance and dye measurement, followed by cellular destruction and high tumor inhibition efficiency (85%). This knowledge is important from the perspective of understanding the structure-dependent SDT enhancement of a MOF-derived carbon nanostructure. PMID: 29672956 [PubMed - as supplied by publisher]

Postoperative Monitoring of Free DIEP Flap in Breast Reconstruction with Near-Infrared Spectroscopy: Variables Affecting the Regional Oxygen Saturation.

Related Articles Postoperative Monitoring of Free DIEP Flap in Breast Reconstruction with Near-Infrared Spectroscopy: Variables Affecting the Regional Oxygen Saturation. J Reconstr Microsurg. 2018 Apr 19;: Authors: Salgarello M, Pagliara D, Rossi M, Visconti G, Barone-Adesi L Abstract BACKGROUND:  The timing of surgical reexploration in microanastomotic thrombosis is directly related to the salvage rate of free flap. Near-infrared spectroscopy (NIRS) is a noninvasive technique, which allows a continuous bedside monitoring of flap oxygenation. The current literature is lacking in the assessment of variables able to modify the NIRS monitoring. The aim of this study is to identify patient and flap-related variables that can affect regional oxygen saturation (rSO2). METHODS:  We retrospectively analyzed the data obtained from 45 consecutive patients undergoing breast reconstruction with deep inferior epigastric perforator (DIEP) flap. The monitoring device used is the Somanetics INVOS 5100C Cerebral/Somatic Oximeter (Covidien). Baseline measures of demographic-anthropometric variables (age, weight, height, body mass index [BMI]) and flap factors (flap size in grams, skin flap area in square centimeters, perforator number, and perforator size in millimeters) were collected from preoperative and intraoperative assessment. We investigated the linear correlation between mean rSO2 and BMI, flap size, skin flap area, perforator number, and perforator size. RESULTS:  A positive linear correlation between rSO2 values and skin flap area, perforator number, and perforator size was found. A negative linear correlation between rSO2 values and BMI and flap size was found. All correlations are statistically significant. Despite the overall negative linear correlation between rSO2 values and flap size, we observed a bimodal trend: a positive relation up to 800 g, which is inverted above 800 g. CONCLUSION:  The NIRS is a reliable additional tool in free flap monitoring. A careful evaluation should be given to patient and surgery factors that can change the oximetry data. PMID: 29672776 [PubMed - as supplied by publisher]

Scintillation Yield Estimates of Colloidal Cerium-Doped LaF3 Nanoparticles and Potential for "Deep PDT".

Related Articles Scintillation Yield Estimates of Colloidal Cerium-Doped LaF3 Nanoparticles and Potential for "Deep PDT". Radiat Res. 2018 Apr 19;: Authors: Kudinov KA, Cooper DR, Ha JK, Hill CK, Nadeau JL, Seuntjens JP, Bradforth SE Abstract A hybrid of radiotherapy and photodynamic therapy (PDT) has been proposed in previously reported studies. This approach utilizes scintillating nanoparticles to transfer energy to attached photosensitizers, thus generating singlet oxygen for local killing of malignant cells. Its effectiveness strongly depends upon the scintillation yield of the nanoparticles. Using a liquid scintillator as a reference standard, we estimated the scintillation yield of Ce0.1La0.9F3/LaF3 core/shell nanoparticles at 28.9 mg/ml in water to be 350 photons/MeV under orthovoltage X-ray irradiation. The subsequent singlet oxygen production for a 60 Gy cumulative dose to cells was estimated to be four orders of magnitude lower than the "Niedre killing dose," used as a target value for effective cell killing. Without significant improvements in the radioluminescence properties of the nanoparticles, this approach to "deep PDT" is likely to be ineffective. Additional considerations and alternatives to singlet oxygen are discussed. PMID: 29672241 [PubMed - as supplied by publisher]

No Effect on Mortality with Oxygen Therapy in Nonhypoxemic Patients with Suspected MI.

Related Articles No Effect on Mortality with Oxygen Therapy in Nonhypoxemic Patients with Suspected MI. Am Fam Physician. 2018 Feb 15;97(4):Online Authors: Shrikant Kulkarni N PMID: 29671525 [PubMed - in process]

Hyperbaric oxygen therapy reduces astrogliosis and helps to recovery brain damage in hydrocephalic young rats.

Related Articles Hyperbaric oxygen therapy reduces astrogliosis and helps to recovery brain damage in hydrocephalic young rats. Childs Nerv Syst. 2018 Apr 18;: Authors: da Silva SC, Feres O, da Silva Beggiora P, Machado HR, Menezes-Reis R, Araújo JE, Brandão RA, da Silva Lopes L Abstract PURPOSE: We investigated the possible beneficial effects that hyperbaric oxygen therapy could offer in different brain structures affected by ventriculomegaly in pup rats submitted to experimental hydrocephalus. METHODS: Seven-day-old Wistar rats were submitted to hydrocephalus by intracisternal injection of 10% kaolin into the cisterna magna. The animals were divided into four groups: control (n = 5); control with HBOT (3ATA/2 h/day) (n = 5); untreated hydrocephalic (n = 10); hydrocephalic treated with HBOT (3ATA/2 h/day) (n = 10). The treatment with HBOT was performed daily for 14 days post-induction of hydrocephalus. To evaluate the response to treatment, behavioral tests (open field, Morris water maze, and activity monitor) were performed. After 14 days, the animals were euthanized, and the brain was removed for histological (hematoxylin-eosin and solochrome-cyanine) and immunohistochemical (GFAP and Ki-67) studies. RESULTS: The hyperbaric treatment, although not causing changes in ventricular enlargement, resulted in a significant improvement in the behavioral performance (p = 0.0001), with greater agility and exploration of the environment, preservation of spatial memory, and greater learning capacity (p = 0.0001). Through the immunohistochemical study, the astrocytic activity (glial fibrillary acidic protein) in the corpus callosum (p = 0.0001) and in the germinative matrix (p = 0.0033) was significantly reduced as compared to that in the H group. CONCLUSION: The results suggest that hyperbaric treatment bettered the behavioral performance and offered benefits to the structures affected by the ventricular increase helping to recover the brain damages. In this way, the HBOT it can be considered an adjuvant therapy for the treatment of hydrocephalus. PMID: 29671042 [PubMed - as supplied by publisher]

[Prognostic relevance of tissue oxygen saturation in patients in the early stage of multiple organ dysfunction syndrome].

Related Articles [Prognostic relevance of tissue oxygen saturation in patients in the early stage of multiple organ dysfunction syndrome]. Med Klin Intensivmed Notfmed. 2018 Apr 18;: Authors: Huster D, Härtel F, Nuding S, Schroeder J, Zhang Y, Werdan K, Ebelt H Abstract BACKGROUND: Patients in circulatory shock exhibit insufficient peripheral perfusion to ensure adequate oxygenation of vital organs such as the heart and brain. Early detection of reduced tissue oxygen saturation (StO2) could be used for rapid therapeutic intervention and thus improve the prognosis of patients in the early stage of multiple organ dysfunction syndrome (MODS). MATERIALS AND METHODS: A total of 60 patients in the early stage of MODS (APACHE [Acute Physiology and Chronic Health Evaluation] II score ≥20) were investigated in a monocentric, prospective, randomized phase II study. StO2 was measured using the InSpectraTM StO2 system and compared with known indicators of hypoxia (peripheral oxygen saturation [SpO2], arterial oxygen saturation [SaO2], central venous oxygen saturation [ScvO2], pH, serum lactate). Clinical endpoints of the study were 28-day and 6‑month mortality as well as the need for invasive mechanical ventilation and renal replacement therapy during the hospital stay, respectively. RESULTS: An increased 28-day and 6‑month mortality is found for patients with StO2 <75% in contrast to patients with StO2 ≥75%. Correlations of StO2 with SpO2, ScvO2, and serum lactate are confirmed. Patients with reduced StO2 tend to show a higher disease severity as measured by APACHE II score. CONCLUSION: StO2 shows prognostic relevance in patients at the early stage of MODS. Thus, the rapid and noninvasive assessment of StO2 could be useful in risk stratification of these patients. PMID: 29671035 [PubMed - as supplied by publisher]

Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy.

Related Articles Pancreatic Beta Cell Death: Novel Potential Mechanisms in Diabetes Therapy. J Diabetes Res. 2018;2018:9601801 Authors: Rojas J, Bermudez V, Palmar J, Martínez MS, Olivar LC, Nava M, Tomey D, Rojas M, Salazar J, Garicano C, Velasco M Abstract Purpose of Review: Describing the diverse molecular mechanisms (particularly immunological) involved in the death of the pancreatic beta cell in type 1 and type 2 diabetes mellitus. Recent Findings: Beta cell death is the final event in a series of mechanisms that, up to date, have not been entirely clarified; it represents the pathophysiological mechanism in the natural history of diabetes mellitus. These mechanisms are not limited to an apoptotic process only, which is characteristic of the immune-mediated insulitis in type 1 diabetes mellitus. They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. Summary: Necroptosis, autophagy, and pyroptosis are molecular mechanisms that modulate the survival of the pancreatic beta cell, demonstrating the importance of the immune system in glucolipotoxicity processes and the potential role for immunometabolism as another component of what once known as the "ominous octet." PMID: 29670917 [PubMed - in process]

Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine.

Related Articles Diaphragm Muscle Weakness Following Acute Sustained Hypoxic Stress in the Mouse Is Prevented by Pretreatment with N-Acetyl Cysteine. Oxid Med Cell Longev. 2018;2018:4805493 Authors: O'Leary AJ, Drummond SE, Edge D, O'Halloran KD Abstract Oxygen deficit (hypoxia) is a major feature of cardiorespiratory diseases characterized by diaphragm dysfunction, yet the putative role of hypoxic stress as a driver of diaphragm dysfunction is understudied. We explored the cellular and functional consequences of sustained hypoxic stress in a mouse model. Adult male mice were exposed to 8 hours of normoxia, or hypoxia (FiO2 = 0.10) with or without antioxidant pretreatment (N-acetyl cysteine, 200 mg/kg i.p.). Ventilation and metabolism were measured. Diaphragm muscle contractile function, myofibre size and distribution, gene expression, protein signalling cascades, and oxidative stress (TBARS) were determined. Hypoxia caused pronounced diaphragm muscle weakness, unrelated to increased respiratory muscle work. Hypoxia increased diaphragm HIF-1α protein content and activated MAPK, mTOR, Akt, and FoxO3a signalling pathways, largely favouring protein synthesis. Hypoxia increased diaphragm lipid peroxidation, indicative of oxidative stress. FoxO3 and MuRF-1 gene expression were increased. Diaphragm 20S proteasome activity and muscle fibre size and distribution were unaffected by acute hypoxia. Pretreatment with N-acetyl cysteine substantially enhanced cell survival signalling, prevented hypoxia-induced diaphragm oxidative stress, and prevented hypoxia-induced diaphragm dysfunction. Hypoxia is a potent driver of diaphragm weakness, causing myofibre dysfunction without attendant atrophy. N-acetyl cysteine protects the hypoxic diaphragm and may have application as a potential adjunctive therapy. PMID: 29670681 [PubMed - in process]

Colloidal plasmonic gold nanoparticles and gold nanorings: shape-dependent generation of singlet oxygen and their performance in enhanced photodynamic cancer therapy.

Related Articles Colloidal plasmonic gold nanoparticles and gold nanorings: shape-dependent generation of singlet oxygen and their performance in enhanced photodynamic cancer therapy. Int J Nanomedicine. 2018;13:2065-2078 Authors: Yang Y, Hu Y, Du H, Ren L, Wang H Abstract Introduction: In recognition of the potentials of gold nanoparticles (Au NPs) in enhanced photodynamic therapy (PDT) for cancer, it is desirable to further understand the shape-dependent surface plasmonic resonance (SPR) properties of various gold nanostructures and evaluate their performances in PDT. Materials and methods: Monodispersed colloidal spherical solid Au NPs were synthesized by UV-assisted reduction using chloroauric acid and sodium citrate, and hollow gold nanorings (Au NRs) with similar outer diameter were synthesized based on sacrificial galvanic replacement method. The enhanced electromagnetic (EM) field distribution and their corresponding efficiency in enhancing singlet oxygen (1O2) generation of both gold nanostructures were investigated based on theoretical simulation and experimental measurements. Their shape-dependent SPR response and resulted cell destruction during cellular PDT in combination with 5-aminolevulinic acid (5-ALA) were further studied under different irradiation conditions. Results: With comparable cellular uptake, more elevated formation of 1O2 in 5-ALA-enabled PDT was detected with the presence of Au NRs than that with Au NPs under broadband light irradiation in both cell-free and intracellular conditions. As a result of the unique morphological attributes, exhibiting plasmonic effect of Au NRs was still achievable in the near infrared (NIR) region, which led to an enhanced therapeutic efficacy of PDT under NIR light irradiation. Conclusion: Shape-dependent SPR response of colloidal Au NPs and Au NRs and their respective effects in promoting PDT efficiency were demonstrated in present study. Our innovative colloidal Au NRs with interior region accessible to surrounding photosensitizers would serve as efficient enhancers of PDT potentially for deep tumor treatment. PMID: 29670350 [PubMed - in process]

AlPcS4-PDT for gastric cancer therapy using gold nanorod, cationic liposome, and Pluronic® F127 nanomicellar drug carriers.

Related Articles AlPcS4-PDT for gastric cancer therapy using gold nanorod, cationic liposome, and Pluronic® F127 nanomicellar drug carriers. Int J Nanomedicine. 2018;13:2017-2036 Authors: Xin J, Wang S, Wang B, Wang J, Wang J, Zhang L, Xin B, Shen L, Zhang Z, Yao C Abstract Purpose: As a promising photodynamic therapy (PDT) agent, Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) provides deep penetration into tissue, high quantum yields, good photostability, and low photobleaching. However, its low delivery efficiency and high binding affinity to serum albumin cause its low penetration into cancer cells, further limiting its PDT effect on gastric cancer. In order to improve AlPcS4/PDT effect, the AlPcS4 delivery sys tems with different drug carriers were synthesized and investigated. Materials and methods: Gold nanorods, cationic liposomes, and Pluronic® F127 nanomicellars were used to formulate the AlPcS4 delivery systems. The anticancer effect was evaluated by CCK-8 assay and colony formation assay. The delivery efficiency of AlPcS4 and the binding affinity to serum proteins were determined by fluorescence intensity assay. The apoptosis and necrosis ability, reactive oxygen species and singlet oxygen generation, mitochondrial transmembrane potential and ([Ca2+]i) concentration were further measured to evaluate the mechanism of cell death. Results: The series of synthesized AlPcS4 delivery systems with different drug carriers improve the limited PDT effect in varying degrees. In contrast, AlPcS4 complex with gold nanorods has significant anticancer effects because gold nanorods are not only suitable for AlPcS4 delivery, but also exhibit enhanced singlet oxygen generation effect and photothermal effect to induce cell death directly. Moreover, AlPcS4 complex with cationic liposomes shows the potent inhibition effect because of its optimal AlPcS4 delivery efficiency and ability to block serum albumin. In addition, AlPcS4 complex with Pluronic F127 exhibits inferior PDT effect but presents lower cytotoxicity, slower dissociation rate, and longer retention time of incorporated drugs; thus, F127-AlPcS4 is used for prolonged gastric cancer therapy. Conclusion: The described AlPcS4 drug delivery systems provide promising agents for gastric cancer therapy. PMID: 29670347 [PubMed - in process]

Cell-penetrating peptide conjugates of gambogic acid enhance the antitumor effect on human bladder cancer EJ cells through ROS-mediated apoptosis.

Related Articles Cell-penetrating peptide conjugates of gambogic acid enhance the antitumor effect on human bladder cancer EJ cells through ROS-mediated apoptosis. Drug Des Devel Ther. 2018;12:743-756 Authors: Lyu L, Huang LQ, Huang T, Xiang W, Yuan JD, Zhang CH Abstract Background: Gambogic acid (GA) is the main active ingredient of resin gamboges and possesses anti-cancer activity toward various human cancer cells. However, clinical application of GA has been limited by its poor aqueous solubility and dose-limiting toxicities. Cell-penetrating peptides (CPPs) are widely used to deliver anti-cancer drugs into cancer cells and to enhance the water solubility of drugs. Purpose: The object of this study was to synthesize peptide-drug conjugates in which the cell-penetrating peptide TAT (trans-activator of transcription) was conjugated to GA and evaluated the anti-cancer activity of this GA-CPP conjugate (GA-TAT) in EJ bladder cancer cells. Methods: GA is built onto the TAT, and the GA-TAT conjugates are cleaved from the solid support and purified via HPLC. The equilibrium solubility of GA-TAT was measured using the shake-flask method. The effects of GA-TAT on EJ cell viability and proliferation were determined by MTT assay, Edu assay and colony formation assay, respectively. After treated with 1.0 μM GA-TAT for 24 h, the apoptosis rate of EJ cells were detected by Acridine orange/ethidium bromide (AO/EB) assay and flow cytometry assay. The proteins of caspase-3 (processing), caspase-9 (processing), Bcl-2 and Bax were analyzed by Western blotting, and the intracellular reactive oxygen species (ROS) production was evaluated by a reactive oxygen species assay. Results: In contrast to free GA, the solubility of GA-TAT in water was significantly improved. Meanwhile, GA-TAT significantly increased EJ cellular uptake, toxicity and apoptosis. Mechanistic analysis revealed that GA-TAT enhanced the anti-cancer effect of GA against EJ cells through ROS-mediated apoptosis. The results were demonstrated that GA-TAT increased the ROS level in EJ cells, and N-acetyl-L-cysteine (NAC; a well-known ROS scavenger) inhibited GA-TAT-induced ROS generation and apoptosis. Additionally, GA-TAT activated caspase-3 and caspase-9 and down-regulated the Bcl-2/Bax ratio, but these effects were largely rescued by NAC. Conclusion: GA-TAT has outstanding potential for promoting tumor apoptosis and exhibits promise for use in bladder cancer therapy. PMID: 29670331 [PubMed - in process]

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.

Related Articles Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease. J Neuroinflammation. 2017 Jul 21;14(1):142 Authors: Yamamoto S, Yamashina K, Ishikawa M, Gotoh M, Yagishita S, Iwasa K, Maruyama K, Murakami-Murofushi K, Yoshikawa K Abstract BACKGROUND: Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. METHODS: To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. RESULTS: We demonstrated that 2ccPA suppressed the CoCl2-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. CONCLUSIONS: We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis. PMID: 28732510 [PubMed - indexed for MEDLINE]

Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations.

Related Articles Hemoglobin Is a Vital Determinant of Arterial Oxygen Content in Hypoxemic Patients with Pulmonary Arteriovenous Malformations. Ann Am Thorac Soc. 2017 Jun;14(6):903-911 Authors: Rizvi A, Macedo P, Babawale L, Tighe HC, Hughes JMB, Jackson JE, Shovlin CL Abstract RATIONALE: PaO2 and SaO2 are commonly measured in respiratory practice, but arterial oxygen content (CaO2) refers to the volume of oxygen delivered to the tissues per unit blood volume. CaO2 is calculated from SaO2 and the hemoglobin concentration in blood, recognizing that each gram of hemoglobin can transport approximately 1.34 ml of oxygen when fully saturated. OBJECTIVES: To prospectively evaluate serial changes in CaO2 in humans, incorporating and excluding dynamic changes to oxygenation and hemoglobin parameters that may occur during life. METHODS: A cohort of 497 consecutive patients at risk of both hypoxemia and anemia were recruited. The patients had radiologically proven pulmonary arteriovenous malformations (PAVMs), which result in hypoxemia due to right-to-left shunting, and concurrent hereditary hemorrhagic telangiectasia, which placed them at risk of iron deficiency anemia due to recurrent hemorrhagic iron losses. Presentation SaO2 (breathing room air, by pulse oximetry), hemoglobin, red cell and iron indices were measured, and CaO2 calculated as SaO2 × hemoglobin × 1.34 ml/g. Serial measurements were evaluated in 100 cases spanning up to 32.1 (median, 10.5) years. RESULTS: Presentation CaO2 ranged from 7.6 to 27.5 (median, 17.6) ml/dl. CaO2 did not change appreciably across the SaO2 quartiles. In contrast, hemoglobin ranged from 5.9 to 21.8 g/dl (median, 14.1 g/dl), with a linear increase in CaO2 across hemoglobin quartiles. After PAVM embolization and an immediate increase in SaO2, hemoglobin fell and CaO2 was unchanged 1.6-12 (median, 4) months later. When hemoglobin fell because of iron deficiency, there was no change in SaO2. Similarly, when hemoglobin rose after iron treatment, there was no change in SaO2, and the expected CaO2 increment was observed. These relationships were not evident during pregnancy when hemoglobin fell, and PAVMs usually deteriorated: in pregnancy SaO2 commonly increased, and serial CaO2 values (incorporating hemodilution/anemia) more accurately reflected deteriorating PAVM status. An apparent fall in CaO2 with age in females was attributable to the development of iron deficiency. There was an unexplained increase in CaO2 with age in follow-up of males after embolization. CONCLUSIONS: Hemoglobin/CaO2 should be further incorporated into oxygenation considerations. More attention should be given to modest changes in hemoglobin that substantially modify CaO2. PMID: 28267932 [PubMed - indexed for MEDLINE]

Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy.

Related Articles Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy. J Physiol. 2017 Aug 01;595(15):5095-5102 Authors: Cottrell E, Tropea T, Ormesher L, Greenwood S, Wareing M, Johnstone E, Myers J, Sibley C Abstract Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth. PMID: 28090634 [PubMed - indexed for MEDLINE]

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation.

Related Articles Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation. Sci Rep. 2016 11 08;6:35533 Authors: Wang LX, Wang JD, Chen JJ, Long B, Liu LL, Tu XX, Luo Y, Hu Y, Lin DJ, Lu G, Long ZJ, Liu Q Abstract The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells. AKI603 inhibited cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation. Surprisingly, inhibition of AurA by AKI603 induced leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells. Furthermore, the induction of senescence was associated with enhancing reactive oxygen species (ROS) level. Moreover, the anti-tumor effect of AKI603 was proved in the BALB/c nude mice KBM5-T315I xenograft model. Taken together, our data demonstrate that the small molecule AurA inhibitor AKI603 may be used to overcome drug resistance induced by BCR-ABL-T315I mutation in CML. PMID: 27824120 [PubMed - indexed for MEDLINE]

Gait speed response to aerobic versus resistance exercise training in older adults.

Related Articles Gait speed response to aerobic versus resistance exercise training in older adults. Aging Clin Exp Res. 2017 Oct;29(5):969-976 Authors: Henderson RM, Leng XI, Chmelo EA, Brinkley TE, Lyles MF, Marsh AP, Nicklas BJ Abstract BACKGROUND: Little is known about the comparative effect of aerobic training (AT) versus resistance training (RT) on gait speed, a strong predictor of disability. AIMS: To compare the effect of AT versus RT on gait speed and other functional measures. METHODS: Overweight and obese [body mass index (BMI) ≥27.0 kg/m2] sedentary men and women aged 65-79 years engaged in 5 months of either 4 days/weeks moderate-intensity treadmill walking, AT, (n = 44) or 3 days/weeks moderate-intensity RT (n = 56). Usual-pace gait speed, fast-pace gait speed and short physical performance battery (SPPB) were evaluated in all participants before and after training. Peak oxygen consumption (VO2peak) was assessed in AT participants only, and knee extensor strength was assessed in RT participants. RESULTS: Both AT and RT resulted in clinically significant improvements in usual-pace gait speed (0.08 ± 0.14 and 0.08 ± 0.17 m/s, respectively, both p < 0.05) and SPPB (0.53 ± 1.40 and 0.53 ± 1.20 points, both p < 0.05) and chair rise time (-1.2 ± 3.2 and -1.7 ± 3.0 s, p < 0.05). Only AT improved fast-pace gait speed (0.11 ± 0.10 m/s, p < 0.05). In the RT participants, lower baseline knee strength was associated with less improvement in usual-pace gait speed. In AT participants, lower baseline VO2peak was associated with less improvement in chair rise time and self-reported disability. DISCUSSION: While both AT and RT improved usual-pace gait speed, only AT improved fast-pace gait speed. Lower baseline fitness was associated with less improvement with training. CONCLUSION: Research to directly compare which mode of training elicits the maximum improvement in older individuals with specific functional deficits could lead to better intervention targeting. PMID: 27682435 [PubMed - indexed for MEDLINE]

Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial.

Related Articles Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial. Eur J Nutr. 2017 Jun;56(4):1577-1587 Authors: Todd JJ, McSorley EM, Pourshahidi LK, Madigan SM, Laird E, Healy M, Magee PJ Abstract PURPOSE: Vitamin D inadequacy is a global health concern in athletes as well as the general population. Whilst the role of vitamin D in skeletal health is well defined, there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health. METHODS: This randomised placebo-controlled trial in healthy male and female Gaelic footballers (n = 42) investigated the effect of vitamin D3 supplementation [3000 IU (75 µg) daily for 12 weeks, via an oral spray solution] on VO2 max which was the primary outcome measure. Secondary outcomes included skeletal muscle and lung function. RESULTS: Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group (mean ± SD change from baseline, 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L, respectively; P = 0.006). At baseline, 50 and 22 % of footballers presented with vitamin D insufficiency (31-49 nmol/L) and deficiency (<30 nmol/L), respectively. Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance. Analysis of covariance (ANCOVA) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO2 max (P = 0.375), vertical jump height (P = 0.797), left and right handgrip strength (P = 0.146 and P = 0.266, respectively), forced vital capacity (P = 0.573) or forced expiratory volume at 1 s (P = 0.665), after adjusting for confounders. The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health. CONCLUSIONS: Twelve-week daily supplementation with 3000 IU (75 µg) vitamin D3 successfully resolved deficiency but did not have any significant effect on VO2 max, skeletal muscle or lung function. PMID: 27015912 [PubMed - indexed for MEDLINE]