Avnesh Thakor

All Publications

• Percutaneous autologous pancreatic islet cell transplantation for traumatic pancreatic injury. journal of clinical endocrinology & metabolism Thakor, A. S., Sangha, B. S., Ho, S. G., Warnock, G. L., Meloche, M., Liu, D. M. 2015; 100 (4): 1230-1233

  Abstract

  Traumatic pancreatic injury with pancreatic duct disruption is surgically managed with at least a partial pancreatectomy, often leading to poor blood glucose control and the subsequent development of diabetes mellitus. Autologous ?-islet cell transplantation may therefore help to preserve pancreatic endocrine function.We describe 3 patients with pancreatic duct disruption from traumatic pancreatic injury who were treated with a partial pancreatectomy followed by autologous ?-islet cell transplantation via a percutaneous transhepatic approach. Immediately after trauma, 2 of the 3 patients had difficulty with glucose control that resolved after autologous ?-islet cell transplantation. At follow-up, all patients remained normoglycemic.In patients requiring partial pancreatectomy after pancreatic trauma, percutaneous transhepatic autologous ?-islet cell transplantation should be considered to minimize the risk of development of diabetes mellitus.

  View details for DOI 10.1210/jc.2014-4165

  View details for PubMedID 25590216

• Nanooncology: The Future of Cancer Diagnosis and Therapy CA-A CANCER JOURNAL FOR CLINICIANS Thakor, A. S., Gambhir, S. S. 2013; 63 (6): 395-418

  Abstract

  In recent years, there has been an unprecedented expansion in the field of nanomedicine with the development of new nanoparticles for the diagnosis and treatment of cancer. Nanoparticles have unique biological properties given their small size and large surface area-to-volume ratio, which allows them to bind, absorb, and carry compounds such as small molecule drugs, DNA, RNA, proteins, and probes with high efficiency. Their tunable size, shape, and surface characteristics also enable them to have high stability, high carrier capacity, the ability to incorporate both hydrophilic and hydrophobic substances and compatibility with different administration routes, thereby making them highly attractive in many aspects of oncology. This review article will discuss how nanoparticles are able to function as carriers for chemotherapeutic drugs to increase their therapeutic index; how they can function as therapeutic agents in photodynamic, gene, and thermal therapy; and how nanoparticles can be used as molecular imaging agents to detect and monitor cancer progression.

  View details for DOI 10.3322/caac.21199

  View details for PubMedID 24114523

• Gold Nanoparticles: A Revival in Precious Metal Administration to Patients NANO LETTERS Thakor, A. S., Jokerst, J., Zavaleta, C., Massoud, T. F., Gambhir, S. S. 2011; 11 (10): 4029-4036

  Abstract

  Gold has been used as a therapeutic agent to treat a wide variety of rheumatic diseases including psoriatic arthritis, juvenile arthritis, and discoid lupus erythematosus. Although the use of gold has been largely superseded by newer drugs, gold nanoparticles are being used effectively in laboratory based clinical diagnostic methods while concurrently showing great promise in vivo either as a diagnostic imaging agent or a therapeutic agent. For these reasons, gold nanoparticles are therefore well placed to enter mainstream clinical practice in the near future. Hence, the present review summarizes the chemistry, pharmacokinetics, biodistribution, metabolism, and toxicity of bulk gold in humans based on decades of clinical observation and experiments in which gold was used to treat patients with rheumatoid arthritis. The beneficial attributes of gold nanoparticles, such as their ease of synthesis, functionalization, and shape control are also highlighted demonstrating why gold nanoparticles are an attractive target for further development and optimization. The importance of controlling the size and shape of gold nanoparticles to minimize any potential toxic side effects is also discussed.

  View details for DOI 10.1021/nl202559p

  View details for PubMedID 21846107

• The Fate and Toxicity of Raman-Active Silica-Gold Nanoparticles in Mice SCIENCE TRANSLATIONAL MEDICINE Thakor, A. S., Luong, R., Paulmurugan, R., Lin, F. I., Kempen, P., Zavaleta, C., Chu, P., Massoud, T. F., Sinclair, R., Gambhir, S. S. 2011; 3 (79)

  Abstract

  Raman spectroscopy is an optical imaging method that is based on the Raman effect, the inelastic scattering of a photon when energy is absorbed from light by a surface. Although Raman spectroscopy is widely used for chemical and molecular analysis, its clinical application has been hindered by the inherently weak nature of the Raman effect. Raman-silica-gold-nanoparticles (R-Si-Au-NPs) overcome this limitation by producing larger Raman signals through surface-enhanced Raman scattering. Because we are developing these particles for use as targeted molecular imaging agents, we examined the acute toxicity and biodistribution of core polyethylene glycol (PEG)-ylated R-Si-Au-NPs after different routes of administration in mice. After intravenous administration, PEG-R-Si-Au-NPs were removed from the circulation by macrophages in the liver and spleen (that is, the reticuloendothelial system). At 24 hours, PEG-R-Si-Au-NPs elicited a mild inflammatory response and an increase in oxidative stress in the liver, which subsided by 2 weeks after administration. No evidence of significant toxicity was observed by measuring clinical, histological, biochemical, or cardiovascular parameters for 2 weeks. Because we are designing targeted PEG-R-Si-Au-NPs (for example, PEG-R-Si-Au-NPs labeled with an affibody that binds specifically to the epidermal growth factor receptor) to detect colorectal cancer after administration into the bowel lumen, we tested the toxicity of the core nanoparticle after administration per rectum. We observed no significant bowel or systemic toxicity, and no PEG-R-Si-Au-NPs were detected systemically. Although additional studies are required to investigate the long-term effects of PEG-R-Si-Au-NPs and their toxicity when carrying the targeting moiety, the results presented here support the idea that PEG-R-Si-Au-NPs can be safely used in living subjects, especially when administered rectally.

  View details for DOI 10.1126/scitranslmed.3001963

  View details for PubMedID 21508310

• Oxidative Stress Mediates the Effects of Raman-Active Gold Nanoparticles in Human Cells SMALL Thakor, A. S., Paulmurugan, R., Kempen, P., Zavaleta, C., Sinclair, R., Massoud, T. F., Gambhir, S. S. 2011; 7 (1): 126-136

  Abstract

  Polyethylene glycol (PEG)ylated Raman-active gold nanoparticles (PEG-R-AuNPs) consist of an interchangeable Raman organic molecule layer held onto a gold nanocore by a silica shell. PEG-R-AuNPs have been shown preclinically to increase the sensitivity and specificity of Raman spectroscopy, with picomolar sensitivity and multiplexing capabilities. Although clinical trials are being designed to use functionalized PEG-R-AuNPs in various applications (e.g., to target dysplastic bowel lesions during colonoscopy), the effects of these nanoparticles on human cells remain unknown. The occurrence and mechanisms underlying any potential cytotoxicity induced by these nanoparticles (0-1000 PEG-R-AuNPs/cell) are investigated in immortalized human HeLa and HepG2 cell lines at several time points (0-48 h) after exposure. Using fluorometric assays, cell viability (MTT), reactive oxygen species (ROS) generation (dichlorofluorescein diacetate), protein oxidation (protein carbonyl content), and total cellular antioxidant concentrations the concentrations (metmyoblobin-induced oxidation of ABTS) are assessed. Analysis of lipid oxidation using an enzyme immunoassay (8-isoprostane concentrations), gene expression of antioxidant enzymes using quantitative reverse transcription polymerase chain reactions, and the intracellular location of PEG-R-AuNPs using transmission electron microscopy is also undertaken. PEG-R-AuNPs cause no cytotoxicity in either HeLa or HepG2 cells in the acute setting as ROS generation is balanced by antioxidant enzyme upregulation. Following prolonged exposures (48 h) at relatively high concentrations (1000 PEG-R-AuNPs/cell), nanoparticles are found within vesicles inside cells. Under these conditions, a minimal amount of cytotoxicity is seen in both cell lines owing to increases in cellular oxidative stress, most likely due to ROS overwhelming the antioxidant defenses. Evidence of oxidative stress-induced damage includes increased lipid and protein oxidation. Although further in vivo toxicity studies are necessary, these initial encouraging results show that PEG-R-AuNPs cause minimal toxicity in human cells in the acute setting, which bodes well for potential future applications of these nanoparticles in living subjects.

  View details for DOI 10.1002/smll.201001466

  View details for PubMedID 21104804

• Melatonin and vitamin C increase umbilical blood flow via nitric oxide-dependent mechanisms JOURNAL OF PINEAL RESEARCH Thakor, A. S., Herrera, E. A., Seron-Ferre, M., Giussani, D. A. 2010; 49 (4): 399-406

  Abstract

  Inadequate umbilical blood flow leads to intrauterine growth restriction, a major killer in perinatal medicine today. Nitric oxide (NO) is important in the maintenance of umbilical blood flow, and antioxidants increase NO bioavailability. What remains unknown is whether antioxidants can increase umbilical blood flow. Melatonin participates in circadian, seasonal, and reproductive physiology, but has also been reported to act as a potent endogenous antioxidant. We tested the hypothesis that treatment during pregnancy with melatonin increases umbilical blood flow via NO-dependent mechanisms. This was tested in pregnant sheep by investigating in vivo the effects on continuous measurement of umbilical blood flow of melatonin before and after NO blockade with a NO clamp. These effects of melatonin were compared with those of the traditional antioxidant, vitamin C. Under anesthesia, 12 pregnant sheep and their fetuses (0.8 of gestation) were fitted with catheters and a Transonic probe around an umbilical artery, inside the fetal abdomen. Following 5 days of recovery, cardiovascular variables were recorded during fetal i.v. treatment with either melatonin (n=6, 0.5±0.1 ?g/kg/min) or vitamin C (n=6, 8.9±0.4 mg/kg/min) before and after fetal NO blockade with the NO clamp. Fetal treatment with melatonin or vitamin C increased umbilical blood flow, independent of changes in fetal arterial blood pressure. Fetal NO blockade prevented the increase in umbilical blood flow induced by melatonin or vitamin C. Antioxidant treatment could be a useful clinical tool to increase or maintain umbilical blood flow in complicated pregnancy.

  View details for DOI 10.1111/j.1600-079X.2010.00813.x

  View details for Web of Science ID 000283169300010

  View details for PubMedID 20958954

• Redox modulation of the fetal cardiovascular defence to hypoxaemia JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Richter, H. G., Kane, A. D., Dunster, C., Kelly, F. J., Poston, L., Giussani, D. A. 2010; 588 (21): 4235-4247

  Abstract

  Episodes of hypoxia in utero present a potentially serious challenge to the fetus, but are counteracted by defence responses including marked redistribution of blood flow from peripheral circulations to the brain. Here, we report the novel observation that the oxidant tone is an important modulator of this cardiovascular defence. Using pregnant Welsh Mountain sheep surgically prepared for long-term recording, we investigated in vivo the effects on the fetal cardiovascular defence to acute hypoxaemia of fetal treatment with the antioxidant vitamin C. The mechanisms via which vitamin C may affect the vascular oxidant tone were investigated by monitoring fetal plasma concentrations of nitrates and nitrites, by determining changes in the activity of superoxide dismutase (SOD) in fetal plasma, and by investigating the effect of vitamin C treatment on the fetal cardiovascular defence to hypoxaemia following nitric oxide (NO) synthase blockade. Fetal treatment with vitamin C markedly depressed the normal femoral constrictor response to acute hypoxaemia in the fetus (5.2 ± 1.0 vs. 1.1 ± 0.3 mmHg (ml min(-1))(-1), mean ± s.e.m.; P < 0.05) an effect which was completely restored following NO synthase blockade (6.2 ± 1.3 mmHg (ml min(-1))(-1)). Compared to saline infusion, fetal treatment with vitamin C during acute hypoxaemia also significantly increased fetal plasma SOD activity from normoxic baseline (-8.9 ± 6.5 vs. 15.0 ± 6.6% inhibition, P < 0.05) and decreased the plasma concentration ratio of nitrate:nitrite from normoxic baseline (?NO3(-):NO2(-); 0.15 ± 0.30 vs. -0.29 ± 0.11, P < 0.05). The data provide in vivo evidence of redox modulation of redistribution of blood flow in the fetus, part of the fetal brain sparing during acute hypoxaemic stress.

  View details for DOI 10.1113/jphysiol.2010.196402

  View details for Web of Science ID 000283718800021

  View details for PubMedID 20807788

• Role of nitric oxide in mediating in vivo vascular responses to calcitonin gene-related peptide in essential and peripheral circulations in the fetus CIRCULATION Thakor, A. S., Giussani, D. A. 2005; 112 (16): 2510-2516

  Abstract

  The role of calcitonin gene-related peptide (CGRP) in cardiovascular regulation is gaining clinical and scientific interest. In the adult, in vivo studies have shown that CGRP-stimulated vasodilation in several vascular beds depends, at least in part, on nitric oxide (NO). However, whether CGRP acts as a vasodilator in the fetus in vivo and whether this effect is mediated via NO have been addressed only minimally. This study tested the hypothesis that CGRP has potent NO-dependent vasodilator actions in essential and peripheral vascular beds in the fetus in late gestation.Under anesthesia, 5 fetal sheep at 0.8 gestation were instrumented with vascular catheters and Transonic flow probes around an umbilical artery and a femoral artery. Five days later, fetuses received 2- and 5-microg doses of exogenous CGRP intra-arterially in randomized order. Doses were repeated during NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for tonic production of the gas, thereby maintaining basal cardiovascular function. CGRP resulted in potent and long-lasting NO-dependent dilation in the umbilical and femoral circulations, hypotension, and a positive cardiac chronotropic effect. During NO blockade, the femoral vasodilator response to CGRP was diminished. In contrast, in the umbilical vascular bed, the dilator response was not only prevented but reversed to vasoconstriction.CGRP has potent NO-dependent vasodilator actions in fetal essential and peripheral vascular beds. CGRP-induced NO-dependent effects in the umbilical vascular bed may provide an important mechanism in the control and maintenance of umbilical blood flow during pregnancy.

  View details for DOI 10.1161/CIRCULATIONAHA.105.562546

  View details for Web of Science ID 000232607000019

  View details for PubMedID 16216959

• Emerging role of stem cell-derived extravesicular microRNAs in age-associated human diseases and in different therapies of longevity. Ageing Research Reviews Ullah, M., Ng, N. N., Concepcion, W., Thakor, A. S. 2020

  View details for DOI 10.1016/j.arr.2019.100979

• Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism Oncotarget Ullah, M., Akbar, A., Ng, N. N., Concepcion, W., Thakor, A. S. 2019; 10 (37): 3435-3450

  View details for DOI 10.18632/oncotarget.26952

• Use of Blood Pool Agents With Steady-State MRI to Assess the Vascular System JOURNAL OF MAGNETIC RESONANCE IMAGING Thakor, A. S., Chung, J., Patel, P., Chan, A., Ahmed, A., McNeil, G., Liu, D. M., Forster, B., Klass, D. 2017; 45 (6): 1559-1572

  Abstract

  Over the past two decades there have been significant advances in the use of magnetic resonance imaging (MRI) to assess the vascular system. New imaging sequences and improvements in magnet design have enabled the creation of higher spatial resolution images. MRI is now a viable alternative imaging modality when compared to both invasive angiography and computed tomographic angiography. The use of blood pool agents has further facilitated the use of MR angiography (MRA); their high molecular weight allows for lower doses of contrast medium administration while their prolonged presence in the blood stream allows for repeated high-quality volumetric imaging of both the arterial and venous circulation. As such, MRA is now no longer constrained by the tight windows for first-pass arterial and venous enhancement, which has resulted in the ability to assess and diagnose a large range of vascular pathologies in both arterial and venous systems. The intent of this review is to highlight MRI findings in common vascular pathologies including peripheral arterial disease (PAD), abnormalities of the abdominal aortic branches, postendovascular aortic aneurysm repair (EVAR) endoleak assessment, popliteal artery entrapment syndrome (PAES), deep venous thrombosis (DVT), vascular thoracic outlet syndrome (TOS), and vascular malformations. In addition, the latest MRI techniques currently used to optimally assess each of these pathologies will be discussed.5 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;45:1559-1572.

  View details for DOI 10.1002/jmri.25636

  View details for PubMedID 28422344

• Stereotactic body radiotherapy for pediatric hepatocellular carcinoma with central biliary obstruction PEDIATRIC BLOOD & CANCER Hiniker, S. M., Rangaswami, A., Lungren, M. P., Thakor, A. S., Concepcion, W., Balazy, K. E., Kovalchuk, N., Donaldson, S. S. 2017; 64 (6)

  Abstract

  Here, we present the case of a pediatric patient with newly diagnosed hepatocellular carcinoma causing central biliary obstruction and persistently elevated bilirubin of 3.0-4.3 mg/dl despite placement of bilateral internal-external biliary drains. The tumor was not resectable, and the patient was not a candidate for liver transplant due to nodal disease, for chemotherapy due to hyperbilirubinemia, or for local therapies aside from stereotactic body radiotherapy (SBRT). In this report, we discuss the successful use of SBRT in the management of this patient, and its role in allowing the patient to become a candidate for additional therapies.

  View details for DOI 10.1002/pbc.26330

  View details for PubMedID 28436210

• Transradial Access for Interventional Radiology: Single-Centre Procedural and Clinical Outcome Analysis. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Alshammari, M. T., Liu, D. M., Chung, J., Ho, S. G., Legiehn, G. M., Machan, L., Fischman, A. M., Patel, R. S., Klass, D. 2017

  Abstract

  The study sought to describe a single centre's technical approach to transradial intervention and report on clinical outcomes and safety.A total of 749 transradial access (TRA) procedures were performed at a single hospital in 562 patients (174 women and 388 men). Procedures included 445 bland embolizations or chemoembolizations of the liver, 88 uterine artery embolizations, and 148 procedures for Selective Internal Radiation Therapy (Y90), which included mapping and administration. The mean age of the patients was 62 years (range 27-96 years).Four cases (0.5%) required crossover to transfemoral (tortuous anatomy, inability to secure a stable position for embolization, vessel spasm and base catheter not being of a sufficient length). A single asymptomatic, short-segment radial artery occlusion occurred (0.3%), 3 patients (0.4%) developed small hematomas postprocedurally, and 2 patients (0.7%) had transient neurological pain, which was resolved within a week without treatment. It was found that 98% of patients who had a previous femoral access procedure would choose radial access for subsequent procedures.Transradial access is a safe, effective technique, with a learning curve; however, this procedure has the potential to significantly improve departmental workflow and cost savings for the department and patient experience.

  View details for DOI 10.1016/j.carj.2016.09.003

  View details for PubMedID 28396005

• Clinically Approved Nanoparticle Imaging Agents. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Thakor, A. S., Jokerst, J. V., Ghanouni, P., Campbell, J., Mittra, E., Gambhir, S. S. 2016

  Abstract

  Nanoparticles are a new class of imaging agent used for both anatomic and molecular imaging. Nanoparticle-based imaging exploits the signal intensity, stability, and biodistribution behavior of submicron-diameter molecular imaging agents. This review focuses on nanoparticles used in human medical imaging, with an emphasis on radionuclide imaging and MRI. Newer nanoparticle platforms are also discussed in relation to theranostic and multimodal uses.

  View details for PubMedID 27738007

• MR cone-beam CT fusion image overlay for fluoroscopically guided percutaneous biopsies in pediatric patients PEDIATRIC RADIOLOGY Thakor, A. S., Patel, P. A., Gu, R., Rea, V., Amaral, J., Connolly, B. L. 2016; 46 (3): 407-412

  Abstract

  Lesions only visible on magnetic resonance (MR) imaging cannot easily be targeted for image-guided biopsy using ultrasound or X-rays but instead require MR guidance with MR-compatible needles and long procedure times (acquisition of multiple MR sequences). We developed an alternative method for performing these difficult biopsies in a standard interventional suite, by fusing MR with cone-beam CT images. The MR cone-beam CT fusion image is then used as an overlay to guide a biopsy needle to the target area under live fluoroscopic guidance. Advantages of this technique include (i) the ability for it to be performed in a conventional interventional suite, (ii) three-dimensional planning of the needle trajectory using cross-sectional imaging, (iii) real-time fluoroscopic guidance for needle trajectory correction and (iv) targeting within heterogeneous lesions based on MR signal characteristics to maximize the potential biopsy yield.

  View details for DOI 10.1007/s00247-015-3479-5

  View details for PubMedID 26563298

• Fetal in vivo continuous cardiovascular function during chronic hypoxia. journal of physiology Allison, B. J., Brain, K. L., Niu, Y., Kane, A. D., Herrera, E. A., Thakor, A. S., Botting, K. J., Cross, C. M., Itani, N., Skeffington, K. L., Beck, C., Giussani, D. A. 2016; 594 (5): 1247-1264

  Abstract

  The in vivo fetal cardiovascular defence to chronic hypoxia has remained by and large an enigma because no technology has been available to induce significant and prolonged fetal hypoxia whilst recording longitudinal changes in fetal regional blood flow as the hypoxic pregnancy is developing. We introduce a new technique able to maintain chronically instrumented maternal and fetal sheep preparations under isobaric chronic hypoxia for most of gestation, beyond levels that can be achieved by high altitude and of relevance in magnitude to the human intrauterine growth-restricted fetus. This technology permits wireless recording in free-moving animals of longitudinal maternal and fetal cardiovascular function, including beat-to-beat alterations in pressure and blood flow signals in regional circulations. The relevance and utility of the technique is presented by testing the hypotheses that the fetal circulatory brain sparing response persists during chronic fetal hypoxia and that an increase in reactive oxygen species in the fetal circulation is an involved mechanism.Although the fetal cardiovascular defence to acute hypoxia and the physiology underlying it have been established for decades, how the fetal cardiovascular system responds to chronic hypoxia has been comparatively understudied. We designed and created isobaric hypoxic chambers able to maintain pregnant sheep for prolonged periods of gestation under controlled significant (10% O2 ) hypoxia, yielding fetal mean PaO2 levels (11.5 ± 0.6 mmHg) similar to those measured in human fetuses of hypoxic pregnancy. We also created a wireless data acquisition system able to record fetal blood flow signals in addition to fetal blood pressure and heart rate from free moving ewes as the hypoxic pregnancy is developing. We determined in vivo longitudinal changes in fetal cardiovascular function including parallel measurement of fetal carotid and femoral blood flow and oxygen and glucose delivery during the last third of gestation. The ratio of oxygen (from 2.7 ± 0.2 to 3.8 ± 0.8; P < 0.05) and of glucose (from 2.3 ± 0.1 to 3.3 ± 0.6; P < 0.05) delivery to the fetal carotid, relative to the fetal femoral circulation, increased during and shortly after the period of chronic hypoxia. In contrast, oxygen and glucose delivery remained unchanged from baseline in normoxic fetuses. Fetal plasma urate concentration increased significantly during chronic hypoxia but not during normoxia (?: 4.8 ± 1.6 vs. 0.5 ± 1.4 ?mol l(-1) , P<0.05). The data support the hypotheses tested and show persisting redistribution of substrate delivery away from peripheral and towards essential circulations in the chronically hypoxic fetus, associated with increases in xanthine oxidase-derived reactive oxygen species.

  View details for DOI 10.1113/JP271091

  View details for PubMedID 26926316

  View details for PubMedCentralID PMC4771786

• Melatonin modulates the fetal cardiovascular defense response to acute hypoxia JOURNAL OF PINEAL RESEARCH Thakor, A. S., Allison, B. J., Niu, Y., Botting, K. J., Seron-Ferre, M., Herrera, E. A., Giussani, D. A. 2015; 59 (1): 80-90

  Abstract

  Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.

  View details for DOI 10.1111/jpi.12242

  View details for PubMedID 25908097

• Radiological Evaluation of Abdominal Endovascular Aortic Aneurysm Repair. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Tanner, J., Ong, S. J., Hughes-Roberts, Y., Ilyas, S., Cousins, C., See, T. C., Klass, D., Winterbottom, A. P. 2015; 66 (3): 277-290

  Abstract

  Endovascular aortic aneurysm repair (EVAR) is an alternative to open surgical repair of aortic aneurysms offering lower perioperative mortality and morbidity. As experience increases, clinicians are undertaking complex repairs with hostile aortic anatomy using branched or fenestrated devices or extra components such as chimneys to ensure perfusion to visceral branch vessels whilst excluding the aneurysm. Defining the success of EVAR depends on both clinical and radiographic criteria, but ultimately depends on complete exclusion of the aneurysm from the circulation. Aortic stent grafts are monitored using a combination of imaging modalities including computed tomography angiography (CTA), ultrasonography, magnetic resonance imaging, plain films, and nuclear medicine studies. This article describes when and how to evaluate aortic stent grafts using each of these modalities along with the characteristic features of several of the main stent grafts currently used in clinical practice. The commonly encountered complications from EVAR are also discussed and how they can be detected using each imaging modality. As the radiation burden from serial follow up CTA imaging is now becoming a concern, different follow-up imaging strategies are proposed depending on the complexity of the repair and based on the relative merits and disadvantages of each imaging modality.

  View details for DOI 10.1016/j.carj.2014.12.003

  View details for PubMedID 25978867

• The Other Path-Think Radial. Canadian Association of Radiologists journal = Journal l'Association canadienne des radiologistes Thakor, A. S., Munk, P. L., Klass, D. 2015; 66 (3): 191-?

  View details for DOI 10.1016/j.carj.2015.06.001

  View details for PubMedID 26209289

• Endovascular aneurysm repair (EVAR) follow-up imaging: the assessment and treatment of common postoperative complications. Clinical radiology Ilyas, S., Shaida, N., Thakor, A. S., Winterbottom, A., Cousins, C. 2015; 70 (2): 183-196

  Abstract

  Endovascular abdominal aortic aneurysm repair (EVAR) is a well-established procedure, which has long-term mortality rates similar to that of open repair. It has the additional benefit of being less invasive, making it the favoured method of treating abdominal aortic aneurysms in elderly and high-risk patients with multiple co-morbidities. The main disadvantage of EVAR is the higher rate of re-intervention, due to device-related complications, including endoleaks, limb occlusion, stent migration, kinking, and infection. As a result lifelong surveillance is required. In order to avoid missing these complications, intricate knowledge of stent graft design, good-quality diagnostic ultrasound skills, multiplanar reformatting of CT images, and reproducible investigations are important. Most of these complications can be treated via an endovascular approach using cuff extensions, uncovered stents, coils, and liquid embolic agents. Open surgery is reserved for complex complications, where an endovascular approach is not feasible.

  View details for DOI 10.1016/j.crad.2014.09.010

  View details for PubMedID 25443774

• The use of cone-beam CT in assisting percutaneous translumbar catheter placement into the inferior vena cava. Clinical radiology Thakor, A. S., Chung, J., Patel, R., Cormack, R., Legiehn, G., Klass, D. 2015; 70 (1): 21-24

  View details for DOI 10.1016/j.crad.2014.09.009

  View details for PubMedID 25443775

• Y90 selective internal radiation therapy. Surgical oncology clinics of North America Lee, E. W., Thakor, A. S., Tafti, B. A., Liu, D. M. 2015; 24 (1): 167-185

  Abstract

  Primary liver malignancies and liver metastases are affecting millions of individuals worldwide. Because of their late and advanced stage presentation, only 10% of patients can receive curative surgical treatment, including transplant or resection. Alternative treatments, such as systemic chemotherapy, ablative therapy, and chemoembolization, have been used with marginal survival benefits. Selective internal radiation therapy (SIRT), also known as radioembolization, is a compelling alternative treatment option for primary and metastatic liver malignancies with a growing body of evidence. In this article, an introduction to SIRT including background, techniques, clinical outcomes, and complications is reviewed.

  View details for DOI 10.1016/j.soc.2014.09.011

  View details for PubMedID 25444474

• A review of conventional and drug-eluting chemoembolization in the treatment of colorectal liver metastases: principles and proof. Future oncology Liu, D. M., Thakor, A. S., Baerlocher, M., Alshammari, M. T., Lim, H., Kos, S., Kennedy, A. S., Wasan, H. 2015; 11 (9): 1421-1428

  Abstract

  The management of colorectal liver metastasis has undergone a significant change since the development of novel ablation and embolization. Drug-eluting microsphere platforms, designed to deliver targeted concentrations of systemic therapy directly into the tumor via its arterial vasculature, have garnered interest and gained in popularity in recent years. Based on in vitro and in vivo data, multiple factors contribute to locoregional exposure including carrier base, smaller particle size (larger surface area), chemotherapeutic and chemotherapeutic intensity. Based on the current published clinical data, therapy appears well tolerated but the questions remain as to the ideal technique, patient population and overall efficacy. The purpose of this article is to provide a perspective on the scientific basis, and clinical review of the current data supporting the use of this platform in the setting of metastatic colorectal carcinoma.

  View details for DOI 10.2217/fon.15.3

  View details for PubMedID 25602287

• Heart disease link to fetal hypoxia and oxidative stress. Advances in experimental medicine and biology Giussani, D. A., Niu, Y., Herrera, E. A., Richter, H. G., Camm, E. J., Thakor, A. S., Kane, A. D., Hansell, J. A., Brain, K. L., Skeffington, K. L., Itani, N., Wooding, F. B., Cross, C. M., Allison, B. J. 2014; 814: 77-87

  Abstract

  The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

  View details for DOI 10.1007/978-1-4939-1031-1_7

  View details for PubMedID 25015802

• A scanning transmission electron microscopy approach to analyzing large volumes of tissue to detect nanoparticles. Microscopy and microanalysis Kempen, P. J., Thakor, A. S., Zavaleta, C., Gambhir, S. S., Sinclair, R. 2013; 19 (5): 1290-1297

  Abstract

  The use of nanoparticles for the diagnosis and treatment of cancer requires the complete characterization of their toxicity, including accurately locating them within biological tissues. Owing to their size, traditional light microscopy techniques are unable to resolve them. Transmission electron microscopy provides the necessary spatial resolution to image individual nanoparticles in tissue, but is severely limited by the very small analysis volume, usually on the order of tens of cubic microns. In this work, we developed a scanning transmission electron microscopy (STEM) approach to analyze large volumes of tissue for the presence of polyethylene glycol-coated Raman-active-silica-gold-nanoparticles (PEG-R-Si-Au-NPs). This approach utilizes the simultaneous bright and dark field imaging capabilities of STEM along with careful control of the image contrast settings to readily identify PEG-R-Si-Au-NPs in mouse liver tissue without the need for additional time-consuming analytical characterization. We utilized this technique to analyze 243,000 ?m3 of mouse liver tissue for the presence of PEG-R-Si-Au-NPs. Nanoparticles injected into the mice intravenously via the tail vein accumulated in the liver, whereas those injected intrarectally did not, indicating that they remain in the colon and do not pass through the colon wall into the systemic circulation.

  View details for DOI 10.1017/S143192761300192X

  View details for PubMedID 23803218

• A role for xanthine oxidase in the control of fetal cardiovascular function in late gestation sheep JOURNAL OF PHYSIOLOGY-LONDON Herrera, E. A., Kane, A. D., Hansell, J. A., Thakor, A. S., Allison, B. J., Niu, Y., Giussani, D. A. 2012; 590 (8): 1825-1837

  Abstract

  Virtually nothing is known about the effects on fetal physiology of xanthine oxidase inhibition. This is despite maternal treatment with the xanthine oxidase inhibitor allopurinol being considered in human complicated pregnancy to protect the infant?s brain from excessive generation of ROS.We investigated the in vivo effects of maternal treatment with allopurinol on fetal cardiovascular function in ovine pregnancy in late gestation. Under anaesthesia, pregnant ewes and their singleton fetus were instrumented with vascular catheters and flow probes around an umbilical and a fetal femoral artery at 118±1 dGA (days of gestational age; termca. 145 days). Five days later, mothers were infused I.V. with either vehicle (n =11) or allopurinol (n =10). Fetal cardiovascular function was stimulated with increasing bolus doses of phenylephrine (PE) following maternal vehicle or allopurinol. The effects of maternal allopurinol on maternal and fetal cardiovascular function were also investigated following fetal NO blockade (n =6) or fetal ?1-adrenergic antagonism (n =7). Maternal allopurinol led to significant increases in fetal heart rate, umbilical blood flow and umbilical vascular conductance, effects abolished by fetal ?1-adrenergic antagonism but not by fetal NO blockade. Maternal allopurinol impaired fetal ?1-adrenergic pressor and femoral vasopressor responses and enhanced the gain of the fetal cardiac baroreflex. These effects of maternal allopurinol were restored to control levels during fetal NO blockade. Maternal treatment with allopurinol induced maternal hypotension, tachycardia and acid?base disturbance. We conclude that maternal treatment with allopurinol alters in vivo maternal, umbilical and fetal vascular function via mechanisms involving NO and ?1-adrenergic stimulation. The evidence suggests that the use of allopurinol in clinical practice should be approached with caution.

  View details for DOI 10.1113/jphysiol.2011.224576

  View details for Web of Science ID 000302799300012

  View details for PubMedID 22331413

• Developmental Programming of Cardiovascular Dysfunction by Prenatal Hypoxia and Oxidative Stress PLOS ONE Giussani, D. A., Camm, E. J., Niu, Y., Richter, H. G., Blanco, C. E., Gottschalk, R., Blake, E. Z., Horder, K. A., Thakor, A. S., Hansell, J. A., Kane, A. D., Wooding, F. B., Cross, C. M., Herrera, E. A. 2012; 7 (2)

  Abstract

  Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O(2)) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.

  View details for DOI 10.1371/journal.pone.0031017

  View details for Web of Science ID 000302733900020

  View details for PubMedID 22348036

• Preclinical Evaluation of Raman Nanoparticle Biodistribution for their Potential Use in Clinical Endoscopy Imaging SMALL Zavaleta, C. L., Hartman, K. B., Miao, Z., James, M. L., Kempen, P., Thakor, A. S., Nielsen, C. H., Sinclair, R., Cheng, Z., Gambhir, S. S. 2011; 7 (15): 2232-2240

  Abstract

  Raman imaging offers unsurpassed sensitivity and multiplexing capabilities. However, its limited depth of light penetration makes direct clinical translation challenging. Therefore, a more suitable way to harness its attributes in a clinical setting would be to couple Raman spectroscopy with endoscopy. The use of an accessory Raman endoscope in conjunction with topically administered tumor-targeting Raman nanoparticles during a routine colonoscopy could offer a new way to sensitively detect dysplastic lesions while circumventing Raman's limited depth of penetration and avoiding systemic toxicity. In this study, the natural biodistribution of gold surface-enhanced Raman scattering (SERS) nanoparticles is evaluated by radiolabeling them with (64) Cu and imaging their localization over time using micropositron emission tomography (PET). Mice are injected either intravenously (IV) or intrarectally (IR) with approximately 100 microcuries (?Ci) (3.7 megabecquerel (MBq)) of (64) Cu-SERS nanoparticles and imaged with microPET at various time points post injection. Quantitative biodistribution data are obtained as % injected dose per gram (%ID g(-1)) from each organ, and the results correlate well with the corresponding microPET images, revealing that IV-injected mice have significantly higher uptake (p < 0.05) in the liver (5 h = 8.96% ID g(-1); 24 h = 8.27% ID g(-1)) than IR-injected mice (5 h = 0.09% ID g(-1); 24 h = 0.08% ID g(-1)). IR-injected mice show localized uptake in the large intestine (5 h = 10.37% ID g(-1); 24 h = 0.42% ID g(-1)) with minimal uptake in other organs. Raman imaging of excised tissues correlate well with biodistribution data. These results suggest that the topical application of SERS nanoparticles in the mouse colon appears to minimize their systemic distribution, thus avoiding potential toxicity and supporting the clinical translation of Raman spectroscopy as an endoscopic imaging tool.

  View details for DOI 10.1002/smll.201002317

  View details for Web of Science ID 000294361200015

  View details for PubMedID 21608124

• The radiation burden from increasingly complex endovascular aortic aneurysm repair. Insights into imaging Thakor, A. S., Winterbottom, A., Mercuri, M., Cousins, C., Gaunt, M. E. 2011; 2 (6): 699?704

  Abstract

  OBJECTIVES: With increasing experience, endovascular aortic aneurysm repair (EVAR) has been extended to patients with less suitable aorto-iliac anatomy in an attempt to reduce peri-operative mortality. However, more complex EVAR procedures may take longer and can result in higher rates of complications, additional interventional procedures and more frequent radiological imaging, which may offset some of the benefit. This study determined the radiation burden for standard EVAR, as determined by the EVAR-1 trial criteria, and more complex EVAR. METHODS: A total of 123 elective patients aged >60, with aneurysms >5.5 cm who received a bifurcated stent-graft were allocated into a group based on whether or not they fulfilled strict EVAR-1 trial criteria. The mean radiation dose was calculated for each group, together with the additional radiation burden from routine pre- and post-EVAR CT examinations and pre-EVAR iliac artery embolisation. RESULTS: Patients not meeting the EVAR-1 trial criteria had significantly longer fluoroscopic screening times and higher radiation doses. The radiation burden in all patients was higher following exposure from routine CT examinations and following pre-EVAR iliac artery embolisation. CONCLUSION: Whilst the radiation from standard EVAR is acceptable, more complicated and challenging EVARs, accompanied with additional radiological investigations and procedures, can significantly increase the radiation burden.

  View details for DOI 10.1007/s13244-011-0120-5

  View details for PubMedID 22347987

  View details for PubMedCentralID PMC3259354

• Allopurinol Reduces Oxidative Stress in the Ovine Fetal Cardiovascular System After Repeated Episodes of Ischemia-Reperfusion PEDIATRIC RESEARCH Derks, J. B., Oudijk, M. A., Torrance, H. L., Rademaker, C. M., Benders, M. J., Rosen, K. G., Cindrova-Davies, T., Thakor, A. S., Visser, G. H., Burton, G. J., van Bel, F., Giussani, D. A. 2010; 68 (5): 374-380

  Abstract

  In complicated labor, neonatal outcome may depend not only on the extent of fetal asphyxia and acidosis but also on the effects on the fetal cardiovascular system of reactive oxygen species (ROS) generated during the ischemia-reperfusion (I/R) associated with repeated compressions of the umbilical cord. This study tested the hypothesis that maternal treatment with clinical doses of the antioxidant allopurinol in the setting of fetal asphyxia would reduce oxidative stress in the fetal cardiovascular system. The hypothesis was tested in chronically instrumented fetal sheep in late gestation by investigating the effects of maternal treatment with therapeutic doses of allopurinol or vehicle on the fetal cardiovascular system during and after episodes of I/R. The latter were produced by repeated, measured compressions of the umbilical cord. The data show that maternal treatment with allopurinol helped maintain umbilical blood flow and it reduced fetal cardiac oxidative stress after I/R of the type associated with clinically relevant acidemia and repetitive fetal heart rate decelerations. The data support the hypothesis tested and suggest that maternal treatment with allopurinol may offer plausible clinical intervention in the management of perinatal asphyxia in complicated labor.

  View details for Web of Science ID 000283409700002

  View details for PubMedID 20613682

• The relation of S100beta and metabolic and endocrine responses to acute fetal hypoxemia. Frontiers in bioscience (Elite edition) Thakor, A. S., Gazzolo, D., Frulio, R., Giussani, D. A. 2010; 2: 59-67

  Abstract

  Elevations in S100beta protein in umbilical cord blood have been proposed as a reproducible marker of fetal stress, leading to cell damage within the central nervous system. However, it remains unknown whether fetal S100beta concentrations correlate with established endocrine and metabolic indices of fetal distress. Hence, in the late gestation ovine fetus, plasma concentrations of S100beta, adrenocorticotropic hormone (ACTH), cortisol, neuropeptide Y (NPY), and catecholamines and blood concentrations of glucose and lactate were measured during acute hypoxemia. Under general anesthesia, 5 sheep fetuses were chronically instrumented with catheters and subjected 5 days later to 1h normoxia, 0.5h hypoxemia and 1h recovery. Plasma samples were taken during each experimental period. Hypoxemia induced significant falls in PaO2 with increases in fetal plasma concentrations of ACTH, cortisol, catecholamines and NPY, and elevations in blood glucose and lactate, all of which showed significant positive relationships with fetal plasma S100beta concentrations. Hence, evaluation of S100beta may provide a valuable clinical tool in the assessment of fetal well-being in suspected complicated pregnancies.

  View details for PubMedID 20036854

• Factor V Leiden Mutation and Antiphospholipid Syndrome: Risk Factors for Atherosclerotic and Arterial Thromboembolic Disease JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Thakor, A. S., Shah, D., Miller, F., Gaunt, M. E. 2009; 20 (8): 1097-1098

  View details for DOI 10.1016/j.jvir.2009.04.073

  View details for Web of Science ID 000269337200016

  View details for PubMedID 19574060

• Toxic epidermal necrolysis and neutropaenia: Complications of omeprazole AUSTRALASIAN JOURNAL OF DERMATOLOGY Thakor, A. S., Burke, A., Handfield-Jones, S., Sinha, A., Palmer, M., Burns, A. 2009; 50 (3): 207-210

  Abstract

  Worldwide, proton pump inhibitors (PPI) are one of the most frequently prescribed drugs; however, up to 70% of patients taking these drugs have no appropriate indication. Although PPI are relatively well tolerated, they are not free from side-effects and several life-threatening complications are associated with them. In the present report, a 43-year-old woman presented to her general practitioner with an erythematous rash over her face and chest, having been started on omeprazole for chronic abdominal bloating. Over the next 24 h she became increasingly unwell and was admitted to hospital with shortness of breath, pyrexia and the rash spreading over her back, arms and legs. Vesicles had now started to appear within the erythematous regions over her upper body and within 24 h the rash became confluent and desquamative, spreading to involve her entire body. A diagnosis of toxic epidermal necrolysis (TEN) was made. Despite supportive treatment within a critical care setting, she became neutropaenic and her skin loss became more extensive, resulting in 95% epidermal detachment. This case highlights that TEN is a life-threatening condition associated with a high incidence of morbidity and mortality. Optimal management requires early diagnosis and transfer to a specialized unit. Clinicians need to be aware that PPI are not free from side-effects and that their routine prescription should be strongly discouraged.

  View details for DOI 10.1111/j.1440-0960.2009.00540.x

  View details for Web of Science ID 000268260500010

  View details for PubMedID 19659985

• Nitric Oxide Reduces Vagal Baroreflex Sensitivity in the Late Gestation Fetus PEDIATRIC RESEARCH Thakor, A. S., Giussani, D. A. 2009; 65 (3): 269-273

  Abstract

  Goals to understand the etiology of essential hypertension have proposed that this problem arises, in part, because of changes within brainstem circuits involved in arterial blood pressure (ABP) control. It has been suggested that nitric oxide (NO) exerts inhibitory influences on the integration of afferent discharge from the arterial baroreceptors. This study tested the hypothesis that the inhibitory influence of NO on the arterial baroreflex is present in fetal life. Fetal baroreflex sensitivity was calculated in fetal sheep, before and during the NO-clamp; a technique that permits NO synthase (NOS) blockade with l-NAME while maintaining basal cardiovascular function with sodium nitroprusside. Under halothane anesthesia, five fetal sheep at 0.8 gestation were instrumented with vascular catheters. Five days later, fetuses received a range of bolus doses of phenylephrine (5-75 microg I.A.) in randomized order either during saline or treatment with the NO clamp. Basal fetal ABP and heart rate before (50 +/- 4 mm Hg, 170 +/- 3 bpm) or during (51 +/- 4 mm Hg, 173 +/- 3 bpm) the NO-clamp were similar. The gradient of the pulse interval-ABP relationship was nearly doubled during NOS blockade (14.2 =/- 2.5 versus 7.8 +/- 1.6 ms/mm Hg). The data provide in vivo evidence that NO attenuates the sensitivity of the cardiac baroreflex during fetal life.

  View details for Web of Science ID 000263543000003

  View details for PubMedID 19391249

• Infective endocarditis from injecting heroin into a leg ulcer. BMJ case reports Thakor, A. S., Wijenaike, N. 2009; 2009

  View details for DOI 10.1136/bcr.07.2008.0493

  View details for PubMedID 21686779

• Postpartum rupture of a splenic artery aneurysm presenting as disseminated intravascular coagulation INTERNATIONAL JOURNAL OF OBSTETRIC ANESTHESIA Sinha, A., Meldrum, D., Sinha, B., Thakor, A. S. 2009; 18 (1): 95-96

  View details for DOI 10.1016/j.ijoa.2008.08.002

  View details for Web of Science ID 000262736700027

  View details for PubMedID 19046872

• Multiple inflammatory aneurysms: A rare complication of idiopathic inflammatory aortitis European Journal of Radiology Thakor, A. S., Hiemstra, T. F., Cousins, C., See, T. C. 2009; 70: e141-e144
• Effects of acute acidemia on the fetal cardiovascular defense to acute hypoxemia AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Thakor, A. S., Giussani, D. A. 2009; 296 (1): R90-R99

  Abstract

  In complicated pregnancy, fetal hypoxemia rarely occurs in isolation but is often accompanied by fetal acidemia. There is growing clinical concern about the combined effects of fetal hypoxemia and fetal acidemia on neonatal outcome. However, the effects on the fetal defense responses to acute hypoxemia during fetal acidemia are not well understood. This study tested the hypothesis that fetal acidemia affects the fetal defense responses to acute hypoxemia. The hypothesis was tested by investigating, in the late-gestation sheep fetus surgically prepared for long-term recording, the in vivo effects of acute fetal acidemia on 1) the fetal cardiovascular responses to acute hypoxemia and 2) the neural and endocrine mechanisms mediating these responses. Under general anesthesia, five sheep fetuses at 0.8 gestation were instrumented with catheters and Transonic flow probes around the femoral and umbilical arteries. After 5 days, animals were subjected to an acute hypoxemia protocol during intravenous infusion of saline or treatment with acidified saline. Treatment with acidified saline reduced fetal basal pH from 7.35 +/- 0.01 to 7.29 +/- 0.01 but did not alter basal cardiovascular variables, blood glucose, or plasma concentrations of catecholamines, ACTH, and cortisol. During hypoxemia, treatment with acidified saline increased the magnitude of the fetal bradycardia and femoral vasoconstriction and concomitantly increased chemoreflex function and enhanced the increments in plasma concentrations of catecholamines, ACTH, and cortisol. Acidemia also reversed the increase in umbilical vascular conductance during hypoxemia to vasoconstriction. In conclusion, the data support our hypothesis and show that acute acidemia markedly alters fetal hemodynamic, metabolic, and endocrine responses to acute hypoxemia.

  View details for DOI 10.1152/ajpregu.90689.2008

  View details for Web of Science ID 000262056300013

  View details for PubMedID 18922958

• Double superior vena cavae. BMJ case reports Thakor, A. S., Massoud, T. 2009; 2009

  View details for DOI 10.1136/bcr.10.2008.1098

  View details for PubMedID 21686460

• A new effective non-invasive method of cooling patients with malignant hyperthermia ANAESTHESIA Thakor, A. S., Levy, N. 2008; 63 (11): 1266-1267

  View details for Web of Science ID 000259937300038

  View details for PubMedID 19032278

• Anaemia, weight loss, and round shadows in the lungs LANCET Thakor, A. S., Hiemstra, T. F., Jayne, D. R. 2008; 371 (9606): 88-88

  View details for Web of Science ID 000252192600035

  View details for PubMedID 18177780

• A rare life-threatening complication of an indwelling hemodialysis catheter KIDNEY INTERNATIONAL Thakor, A. S., Hiemstra, T. F., Bradley, J. R. 2008; 73 (2): 244-244

  View details for DOI 10.1038/sj.ki.5002582

  View details for Web of Science ID 000252115200020

  View details for PubMedID 18165817

• Acute small bowel obstruction as a result of a Meckel's diverticulum encircling the terminal ileum: A case report. Journal of medical case reports Thakor, A. S., Liau, S. S., O'riordan, D. C. 2007; 1: 8-?

  Abstract

  In the developed world, small bowel obstruction accounts for 20% of all acute surgical admissions. The aetiology for majority of these cases includes postoperative adhesions and herniae. However, a relatively uncommon cause is a Meckel's diverticulum. Although this diagnosis is primarily reported in the adolescent population, it should also be considered in adults.In the present report, we present a rare case where a fit and healthy 74-year-old gentleman, with no previous history of abdominal surgery, presented with the cardinal symptoms and signs of small bowel obstruction as the result of a Meckel's diverticulum encircling his terminal ileum. Initial investigations included a supine abdominal x-ray showing dilated loops of small bowel and computerised tomographic imaging of the abdomen, which revealed a stricture in the terminal ileum of unknown aetiology. At laparotomy, multiple loops of distended small bowel were seen from the duodeno-jeujenal junction to the terminal ileum, which was encircled by a Meckel's diverticulum. The Meckel's diverticulum was then divided to release the obstruction, mobilised and subsequently removed. Finally, the small bowel contents were decompressed into the stomach and the nasogastric tube aspirated, before returning the loops of bowel into the abdomen in sequence. The patient made a good postoperative recovery and was discharged home 5 days later.This report highlights the importance of considering a Meckel's diverticulum as a cause of small bowel obstruction in individuals from all age groups and especially in a person with no previous abdominal pathology or surgery.

  View details for PubMedID 17411459

• Comments on Point-Counterpoint "Positive effects of intermittent hypoxia (live high:train low) on exercise performance are/are not mediated primarily by augmented red cell volume". Journal of applied physiology Giussani, D. A., Thakor, A. S. 2006; 100 (1): 363-364

  View details for PubMedID 16402423

• The role of calcitonin gene-related peptide in the in vivo pituitary-adrenocortical response to acute hypoxemia in the late-gestation sheep fetus ENDOCRINOLOGY Thakor, A. S., Giussani, D. A. 2005; 146 (11): 4871-4877

  Abstract

  This study tested the hypothesis that calcitonin gene-related peptide (CGRP) has a role in mediating the in vivo fetal adrenal glucocorticoid response to acute stress. The hypothesis was tested by investigating the effects of fetal treatment with a selective CGRP antagonist on plasma ACTH and cortisol responses to acute hypoxemia in the late-gestation sheep fetus. Under anesthesia, six fetuses at 0.8 of gestation were surgically instrumented with vascular catheters. Five days later, fetuses were subjected to 0.5-h hypoxemia during treatment with either iv saline or a CGRP antagonist, in randomized order, on different days. Treatment started 30 min before hypoxemia and ran continuously until the end of the challenge. Arterial blood samples were collected for plasma ACTH and cortisol measurements (RIA) and blood gas monitoring. CGRP antagonism did not alter basal arterial blood gas or endocrine status. During hypoxemia, similar falls in arterial partial pressure of oxygen occurred in all fetuses. During saline infusion, acute hypoxemia induced significant increases in fetal ACTH and cortisol concentrations. During CGRP antagonism, the pituitary-adrenal responses were markedly attenuated. Correlation of paired plasma ACTH and cortisol values from all individual fetuses during normoxia and hypoxemia showed positive linear relationships; however, neither the slope nor the intercept of the peptide-steroid relationship was affected by CGRP antagonism. These data support the hypothesis that CGRP is involved in the in vivo regulation of fetal adrenocortical steroidogenesis during acute hypoxemia. In addition, the data reveal that CGRP may have a role in the control of other components of the hypothalamo-pituitary-adrenal axis during stimulated conditions in fetal life.

  View details for DOI 10.1210/en.2005-0444

  View details for Web of Science ID 000232585200034

  View details for PubMedID 16055428

• Acute hypoxia increases S100 beta protein in association with blood flow redistribution away from peripheral circulations in fetal sheep PEDIATRIC RESEARCH Giussani, D. A., Thakor, A. S., Frulio, R., Gazzolo, D. 2005; 58 (2): 179-184

  Abstract

  We investigated in fetal sheep during late gestation the effects of acute hypoxemia on fetal plasma S100beta protein concentrations and how these relate to fetal redistribution of blood flow and acid-base status. Under general anesthesia, five Welsh Mountain sheep fetuses were instrumented with vascular catheters, and transit-time flow transducers were implanted around a femoral artery and an umbilical artery. At least 5 d after surgery, fetuses were subjected to 1 h of normoxia, 0.5 h of hypoxemia, and 1 h of recovery. Hypoxemia induced significant falls in fetal pH(a), arterial oxygen pressure, acid-base excess, and [HCO(3)(-)], without alteration to arterial partial pressure of carbon dioxide. An increase in arterial blood pressure, a fall in heart rate, an increase in femoral vascular resistance, and a decrease in umbilical vascular resistance occurred in all fetuses. During hypoxemia, plasma S100beta increased significantly and remained elevated until the end of the protocol. Within individual fetuses, plasma S100beta correlated with femoral vascular resistance and pH. In contrast, no relationship was found between S100beta and umbilical vascular resistance. This study reports for the first time that a controlled period of fetal hypoxemia with associated acidemia leads to persistent elevations in plasma S100beta concentrations that strongly correlate with hemodynamic changes that are known to occur during fetal blood flow redistribution. These findings open up a new role for changes in fetal S100beta concentrations as a possible early marker of fetal hypoxia with associated acidemia in perinatal medicine.

  View details for DOI 10.1203/01.PDR.0000169999.66157.C0

  View details for Web of Science ID 000230995500002

  View details for PubMedID 16006424

• Calcitonin gene-related peptide antagonism attenuates the haemodynamic and glycaemic responses to acute hypoxaemia in the late gestation sheep fetus JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Bloomfield, M. R., Patterson, M., Giussani, D. A. 2005; 566 (2): 587-597

  Abstract

  The fetal defence to acute hypoxaemia involves cardiovascular and metabolic responses, which include peripheral vasoconstriction and hyperglycaemia. Both these responses are mediated via neuroendocrine mechanisms, which require the stimulation of the sympathetic nervous system. In the adult, accumulating evidence supports a role for calcitonin gene-related peptide (CGRP) in the activation of sympathetic outflow. However, the role of CGRP in stimulated cardiovascular and metabolic functions before birth is completely unknown. This study tested the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence responses to acute hypoxaemia by affecting sympathetic outflow. Under anaesthesia, five sheep fetuses at 0.8 of gestation were surgically instrumented with catheters and a femoral arterial Transonic flow-probe. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. Arterial samples were taken for blood gases, metabolic status and hormone analyses. CGRP antagonism did not alter basal arterial blood gas, metabolic, cardiovascular or endocrine status. During hypoxaemia, similar falls in Pa,O2 occurred in all fetuses. During saline infusion, hypoxaemia induced hypertension, bradycardia, femoral vasoconstriction, hyperglycaemia and an increase in haemoglobin, catecholamines and neuropeptide Y (NPY). In contrast, CGRP antagonism markedly diminished the femoral vasoconstrictor and glycaemic responses to hypoxaemia, and attenuated the increases in haemoglobin, catecholamines and NPY. Combined, these results strongly support the hypothesis that CGRP plays a role in the fetal cardiovascular and metabolic defence to hypoxaemia by affecting sympathetic outflow.

  View details for DOI 10.1113/jphysiol.2005.085431

  View details for Web of Science ID 000230909200023

  View details for PubMedID 15860534

• Calcitonin gene-related peptide contributes to the umbilical haemodynamic defence response to acute hypoxaemia JOURNAL OF PHYSIOLOGY-LONDON Thakor, A. S., Giussani, D. A. 2005; 563 (1): 309-317

  Abstract

  Despite clinical advances in obstetric practice, undiagnosed fetal hypoxaemia still contributes to a high incidence of perinatal morbidity. The fetal defence to hypoxaemia involves a redistribution of blood flow away from peripheral circulations towards essential vascular beds, such as the umbilical, cerebral, myocardial and adrenal circulations. In marked contrast to other essential vascular beds, the mechanisms mediating maintained perfusion of the umbilical circulation during hypoxaemia remain unknown. This study determined the role of calcitonin gene-related peptide (CGRP) in the maintenance of umbilical blood flow during basal and hypoxaemic conditions. Under anaesthesia, five sheep fetuses were instrumented with catheters and a Transonic probe around an umbilical artery, inside the fetal abdomen, at 0.8 of gestation. Five days later, fetuses were subjected to 0.5 h hypoxaemia during either i.v. saline or a selective CGRP antagonist in randomised order. Treatment started 30 min before hypoxaemia and ran continuously until the end of the challenge. The CGRP antagonist did not alter basal blood gas or cardiovascular status in the fetus. A similar fall in Pa,O2 occurred in fetuses during either saline (21 +/- 0.8 to 9 +/- 0.9 mmHg) or antagonist treatment (20 +/- 0.9 to 9 +/- 1.2 mmHg). Hypoxaemia during saline led to significant increases in arterial blood pressure, umbilical blood flow and umbilical vascular conductance. In marked contrast, hypoxaemia during CGRP antagonist treatment led to pronounced falls in both umbilical blood flow and umbilical vascular conductance without affecting the magnitude of the hypertensive response. In conclusion, CGRP plays an important role in the umbilical haemodynamic defence response to hypoxaemia in the late gestation fetus.

  View details for DOI 10.1113/jphysiol.2004.077024

  View details for Web of Science ID 000227224900023

  View details for PubMedID 15611032

• Effects of prolonged reduction in blood flow on submandibular secretory function in anesthetized sheep JOURNAL OF APPLIED PHYSIOLOGY Thakor, A. S., Brown, C. N., Edwards, A. V. 2003; 95 (2): 751-757

  Abstract

  Submandibular vascular and secretory responses to parasympathetic chorda-lingual (C-L) stimulation were investigated in anesthetized sheep before, during, and after an intracarotid (ic) infusion of endothelin-1 (ET-1). Stimulation of the peripheral end of the C-L nerve at 4 and 8 Hz produced a frequency-dependent reduction in submandibular vascular resistance (SVR) associated with a frequency-dependent increase in submandibular blood flow, salivary flow, and Na+, K+, and protein output from the gland. During stimulation at 4 Hz, ic ET-1 significantly increased SVR (P < 0.01), without significantly affecting either the aortic blood pressure or heart rate. Submandibular blood flow (SBF) was reduced by 48 +/- 4% and the flow of saliva by 50 +/- 1%. The effect on blood and salivary flow persisted for at least 30 min after the infusion of ET-1. The reduction in SBF was associated with a diminution in the output of Na+,K+, and protein in the saliva (P < 0.01). These effects persisted for 30 min after the infusion of ET-1 had been discontinued and were linearly related to the flow of plasma throughout.

  View details for DOI 10.1152/japplphysiol.00992.2002

  View details for Web of Science ID 000184016000039

  View details for PubMedID 12730153

• Effects of prolonged reduction in blood flow on submandibular secretory function in anaesthetized sheep Journal of Applied Physiology Thakor, A. S., Brown, C. N., Edwards, A. V. 2003; 95: 751-757