Morphine for the Treatment of Pain in Sickle Cell Disease.
; 2015: 540154
Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.
View details for DOI 10.1155/2015/540154
View details for PubMedID 25654130
The development of next-generation screening and diagnostic platforms will change diabetes care.
Expert review of molecular diagnostics
Diabetes mellitus is a common disease with a rising incidence and the findings of hyperglycemia and glucosuria. However, there are multiple types of diabetes, each with distinct etiologies. The two major types of diabetes are type 1, which is caused by an autoimmune process, and type 2, which is thought to be primarily metabolic, resulting from insulin resistance, often in the setting of obesity. Historically, the distinction between these two types was obvious. Here, we discuss how this paradigm has dramatically changed because of both the evolving epidemiology of diabetes mellitus and new and emerging tools, and therapies to diagnose and treat diabetes. As we believe that understanding these changes is critical to providing optimal care to patients with diabetes, we have developed a novel plasmonic gold chip platform that is able to meet the new and emerging demands of modern diabetes care.
View details for DOI 10.1586/14737159.2015.1002468
View details for PubMedID 25583407
E-013 endovascular management of pseudoaneurysms secondary to external ventricular drain placement: single center experience.
Journal of neurointerventional surgery
2014; 6: A43-4
Placement of external ventricular drains is a common, life-saving neurosurgical procedure indicated across a variety of settings. While advances have made the procedure quite safe, the potential for iatrogenic morbidity and mortality continues. Herein, we document our experience with the endovascular management of three pseudoaneurysms associated with EVD placement.We performed a retrospective analysis to identify all EVDs placed from 2008 through 2013 at our institution,. In instances of EVD-associated cerebrovascular injury, all admission and subsequent radiographic studies were reviewed, including cerebral angiograms and computed tomography (CT) scans. Angiograms were reviewed to record the extent of vascular injury and angiographic outcomes after treatment.One female and two male patients (40-75 years) were found to have developed vascular injuries associated with EVD placement. Three pseudoaneurysms, namely of the posterior communicating artery (PCOM), pericallosal artery branch and the middle meningeal artery, were treated by coil and/or glue embolization.Although EVD-associated cerebrovascular injury remains a rare phenomenon, such procedures are not entirely benign. Endovascular repair for such lesions proves a viable, effective option.arteriovenous fistula (AVF), computed tomography (CT), external ventricular drain (EVD), posterior communicating artery (PCOM), posterior cerebral artery (PCA) DISCLOSURES: O. Choudhri: None. M. Gupta: None. J. Heit: None. A. Feroze: None. H. Do: None.
View details for DOI 10.1136/neurintsurg-2014-011343.80
View details for PubMedID 25064928
O-034 Carotid Artery Angioplasty versus Stenting in Acute Ischemic Stroke.
Journal of neurointerventional surgery
2014; 6: A18-9
Acute ischemic stroke secondary to cervical carotid artery occlusion can lead to significant morbidity and mortality. Acute carotid occlusion may be managed by carotid angioplasty, stenting, or both. The use of carotid stents requires patients to be placed on dual antiplatelet agents, which may contribute to increased haemorrhage risk. We undertook this study to evaluate outcomes for angioplasty alone versus stenting in the setting of acute carotid occlusion.All patients treated from 2008 to 2013 with acute cervical internal carotid artery occlusions that had intervention within eight hours of symptom onset were included. NIHSS were recorded preceding intervention, and clinical outcomes were assessed using mRS at 90 days. All imaging and angiographic data were reviewed for pre-procedural ASPECT scores, pre- and post- TICI reperfusion scores, and intracranial haemorrhage as defined by PH grading score for haemorrhage. Demographic and treatment factors were correlated with good functional outcome (mRS < 2 at 90 days and a comparison was made for patients undergoing angioplasty alone versus stenting. All patients who underwent carotid stent were placed on dual antiplatelet agents while angioplasty patients received aspirin only.Twenty-four patients (15 males, 9 females; mean age, 67 years) satisfied the inclusion criteria. Seventeen patients underwent placement of carotid stent and 7 patients had angioplasty alone. Patients in both subgroups were comparable across characteristics including comorbidities, time for onset to recanalization, ASPECTS, and IV tPA use. 35% of patients who underwent stenting had good functional outcomes, versus 71% of patients treated with angioplasty alone, although these differences were not statistically significant. No differences were seen for the two treatment groups comparing time from onset to recanalization, baseline ASPECTS, and IV tPA use. Additionally, increased age (p = 0.049) and post-treatment parenchymal haemorrhage- PH1 or PH2 (p = 0.016) correlated with poor outcomes (mRS > 2). All parenchymal haemorrhages (6/17) and deaths (5/17) fell within the stenting subgroup (35.3% and 29.4%, respectively).This data suggest that patients undergoing angioplasty alone in the setting of acute internal carotid artery occlusion may have improved functional outcome at 90-day compared to those undergoing stenting. This study was limited by a small sample size and a larger study would be needed to confirm these findings.angioplasty, stenting, acute ischemic stroke, carotid occlusion.O. Choudhri: None. M. Gupta: None. A. Feroze: None. G. Albers: None. M. Lansberg: None. H. Do: None. R. Dodd: None. M. Marcellus: None. M. Marks: None.
View details for DOI 10.1136/neurintsurg-2014-011343.34
View details for PubMedID 25064877
Endovascular management of external ventricular drain-associated cerebrovascular injuries.
Surgical neurology international
2014; 5: 167-?
Placement of external ventricular drains (EVDs) is a common, life-saving neurosurgical procedure indicated across a variety of settings. While advances have made the procedure quite safe, the potential for iatrogenic morbidity and mortality continues. We document our experience with the endovascular management of three pseudoaneurysms associated with EVD placement and discuss the endovascular treatment options for EVD-associated cerebrovascular injury.We performed a retrospective analysis to identify all EVDs placed from 2008 through 2013 at our institution. In instances of EVD-associated cerebrovascular injury, all admission and subsequent radiographic studies were reviewed, including cerebral angiograms and computed tomography (CT) scans where available. Angiograms were reviewed to record the extent of vascular injury and outcomes after treatment.One female and two male patients (age range, 40-75 years) were found to have developed vascular injuries associated with EVD placement. Three pseudoaneurysms, of the posterior communicating artery (PCOM), pericallosal artery branch, and the middle meningeal artery, respectively, were treated by coil and/or glue embolization.Although EVD-associated cerebrovascular injury remains a rare phenomenon, such procedures are not entirely benign. Endovascular repair for such lesions proves a viable, effective option.
View details for DOI 10.4103/2152-7806.145930
View details for PubMedID 25558425
Topical fentanyl stimulates healing of ischemic wounds in diabetic rats.
Journal of diabetes
Topically applied opioids promote angiogenesis and healing of ischemic wounds in rats. We examined if topical fentanyl stimulates wound healing in diabetic rats by stimulating growth-promoting signaling, angiogenesis, lymphangiogenesis and nerve regeneration.We used Zucker diabetic fatty rats that develop obesity and diabetes on a high fat diet due to a mutation in the Leptin receptor. Fentanyl blended with hydrocream was applied topically on ischemic wounds twice daily, and wound closure was analyzed regularly. Wound histology was analyzed by hematoxylin and eosin staining. Angiogenesis, lymphangiogenesis, nerve fibers and phospho-platelet derived growth factor receptor-β (PDGFR-β) were visualized by CD31-, lymphatic vessel endothelium-1, protein gene product 9.5- and anti-phospho PDGFR-β-immunoreactivity, respectively. Nitric oxide synthase (NOS) and PDGFR-β signaling were analyzed using Western immunoblotting.Fentanyl significantly promoted wound closure as compared to phosphate-buffered saline (PBS). Histology scores were significantly higher in fentanyl-treated wounds, indicative of increased granulation tissue formation, reduced edema and inflammation, and increased matrix deposition. Fentanyl treatment resulted in increased wound angiogenesis, lymphatic vasculature, nerve fibers, nitric oxide, NOS and PDGFR-β signaling as compared to PBS. Phospho-PDGFR-β co-localized with CD31 co-staining for vasculature.Topically applied fentanyl promotes closure of ischemic wounds in diabetic rats. Increased angiogenesis, lymphangiogenesis, peripheral nerve regeneration, NO and PDGFR-β signaling are associated with fentanyl-induced tissue remodeling and wound healing.
View details for DOI 10.1111/1753-0407.12223
View details for PubMedID 25266258
Transient global amnesia associated with a unilateral infarction of the fornix: case report and review of the literature.
Frontiers in neurology
2014; 5: 291-?
Stroke is an extremely uncommon cause of transient global amnesia (TGA). Unilateral lesions of the fornix rarely cause amnesia and have not previously been reported to be associated with the distinctive amnesic picture of TGA. We describe the case of a 60-year-old woman who presented with acute onset, recent retrograde, and anterograde amnesia characteristic of TGA. Serial magnetic resonance imaging showed a persistent focal infarction of the body and left column of the fornix, without acute lesions in the hippocampus or other structures. Amnesia resolved in 6 h. Infarction of the fornix should thus be included in the differential diagnosis of TGA, as it changes the management of this otherwise self-limited syndrome.
View details for DOI 10.3389/fneur.2014.00291
View details for PubMedID 25628601
Mast cell activation contributes to sickle cell pathobiology and pain in mice
2013; 122 (11): 1853-1862
Sickle cell anemia (SCA) is an inherited disorder associated with severe lifelong pain and significant morbidity. The mechanisms of pain in SCA remain poorly understood. We show that mast cell activation/degranulation contributes to sickle pain pathophysiology by promoting neurogenic inflammation and nociceptor activation via the release of substance P in the skin and dorsal root ganglion. Mast cell inhibition with imatinib ameliorated cytokine release from skin biopsies and led to a correlative decrease in granulocyte-macrophage colony-stimulating factor and white blood cells in transgenic sickle mice. Targeting mast cells by genetic mutation or pharmacologic inhibition with imatinib ameliorates tonic hyperalgesia and prevents hypoxia/reoxygenation-induced hyperalgesia in sickle mice. Pretreatment with the mast cell stabilizer cromolyn sodium improved analgesia following low doses of morphine that were otherwise ineffective. Mast cell activation therefore underlies sickle pathophysiology leading to inflammation, vascular dysfunction, pain, and requirement for high doses of morphine. Pharmacological targeting of mast cells with imatinib may be a suitable approach to address pain and perhaps treat SCA.
View details for DOI 10.1182/blood-2013-04-498105
View details for Web of Science ID 000324570900008
View details for PubMedID 23775718
Biomarkers and Electrocardiographic Evidence of Myocardial Ischemia in Patients With Human Immunodeficiency Virus Infection
AMERICAN JOURNAL OF CARDIOLOGY
2013; 111 (5): 760-764
We assessed the relation of inflammatory and coagulation biomarkers with electrocardiographic (ECG) evidence of myocardial ischemia. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer levels were measured at study entry for 3,085 human immunodeficiency virus-infected participants (mean age 44 years; 26.4% women; 24.6% black) in the Strategies for Management of Antiretroviral Therapy trial. Logistic regression models were used to examine the associations of these biomarkers with prevalent and incident myocardial ischemia. The latter analyses were performed for 1,411 participants who were randomly assigned to receive continuous antiretroviral therapy during follow-up to suppress the human immunodeficiency virus viral load and had ≥1 ECG reading during the follow-up period. The median hsCRP, IL-6, and D-dimer level was 1.65 μg/ml (interquartile range 0.69 to 4.11), 1.60 pg/ml (interquartile range 1.00 to 2.75), and 0.18 μg/ml (interquartile range 0.11 to 0.32), respectively. At baseline, the prevalence of major or minor Q-QS or ST-T ECG abnormalities was 18.6%. The biomarker levels were associated with prevalent major or minor ischemic abnormalities on the univariate analyses; however, adjustment for traditional risk factors attenuated these associations. The adjusted odds ratio for major or minor ischemic abnormalities and 95% confidence intervals for the greatest versus lowest quartiles was 1.3 (95% confidence interval 0.9 to 1.7) for hsCRP, 1.0 (95% confidence interval 0.7 to 1.3) for IL-6, and 1.1 (95% confidence interval 0.9 to 1.5) for D-dimer. During a median follow-up of 2.3 years, new definite or probable ischemic ECG abnormalities developed in 11.7% of participants receiving continuous antiretroviral therapy. Biomarker levels were not associated with incident abnormalities on unadjusted or adjusted analyses. In conclusion, higher levels of hsCRP, IL-6, and D-dimer were not associated with ischemic ECG abnormalities. Elevated biomarker levels and ECG abnormalities indicating myocardial ischemia might reflect different risk pathways for cardiovascular disease.
View details for DOI 10.1016/j.amjcard.2012.11.032
View details for Web of Science ID 000315666600022
View details for PubMedID 23276469
- Why HIV, Why Now? An Assessment of HIV Testing at the Cambridge Health Alliance (Poster) 4th Annual Cambridge Health Alliance Academic Poster Session 2010
A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer
2009; 323 (5922): 1747-1750
Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2.
View details for DOI 10.1126/science.1163040
View details for Web of Science ID 000264559800045
View details for PubMedID 19251594
- AIDS at the Margin: Experiences and Lessons from Marginalized Groups in India (Part 2) The National Medical Journal of India 2009; 22 (3): 98-100
- AIDS at the Margin: Experiences and Lessons from Marginalized Groups in India (Part 1) The National Medical Journal of India 2009; 22 (2): 47-49
- Opioids as Promoters and Regulators of Angiogenesis Angiogenesis: Basic Science and Clinical Applications, Eds Maragoudakis ME and Papadimitriou E 2007: 303-318