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Other Publications (200)
- Pediatric Surgery International
- Pediatric Surgery International
- Expert Opinion on Drug Discovery
- Ayu
- Indian Heart Journal
- Neurology
- Shock (Augusta, Ga.)
- Pain Research and Treatment
- BJU International
- PloS One
- Frontiers in Microbiology
- Urology
- Urology
- Journal of Biomedical Semantics
- The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- Middle East African Journal of Ophthalmology
- Journal of Pharmacology & Pharmacotherapeutics
- IEEE Transactions on Visualization and Computer Graphics
- The Journal of Trauma and Acute Care Surgery
- Urology
- The Journal of Urology
- Frontiers in Integrative Neuroscience
- PloS One
- Nature
- PloS One
- Indian Pediatrics
- Neurocritical Care
- Sleep
- Pediatric Allergy, Immunology, and Pulmonology
- The British Journal of Ophthalmology
- Journal of the American Academy of Dermatology
- Neurology
- Case Reports in Radiology
- BMJ Open
- Journal of Ethnopharmacology
- Asian Journal of Neurosurgery
- Progress in Transplantation (Aliso Viejo, Calif.)
- Biomedical Informatics Insights
- American Journal of Physiology. Gastrointestinal and Liver Physiology
- Ultrasound Quarterly
- Expert Review of Medical Devices
- Frontiers in Microbiology
- Urology
- Urology
- Retina (Philadelphia, Pa.)
- Surgery
- Indian Journal of Dental Research : Official Publication of Indian Society for Dental Research
- PloS One
- Molecular Imaging
- Neurocritical Care
- Annals of the New York Academy of Sciences
- Neurology
- Intensive Care Medicine
- Hypertension
- American Journal of Human Genetics
- Neurosurgery Clinics of North America
- JACC. Cardiovascular Imaging
- Epilepsy & Behavior : E&B
- Imaging Science in Dentistry
- AJR. American Journal of Roentgenology
- Clinical Medicine Insights. Oncology
- Journal of Patient Safety
- PloS One
- World Neurosurgery
- Cerebral Cortex (New York, N.Y. : 1991)
- American Journal of Cardiovascular Disease
- Case Reports in Genetics
- Case Reports in Genetics
- Science (New York, N.Y.)
- Case Reports in Dermatological Medicine
- PloS One
- BMC Genomics
- Advances in Peritoneal Dialysis. Conference on Peritoneal Dialysis
- Case Reports in Genetics
- Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference
- Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference
- Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference
- Indian Journal of Pathology & Microbiology
- Journal of the Mississippi State Medical Association
- Journal of the Mississippi State Medical Association
- Seminars in Interventional Radiology
- Abdominal Imaging
- Journal of Neurointerventional Surgery
- Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery
- The Journal of Arthroplasty
- Brain Pathology (Zurich, Switzerland)
- International Journal of Dermatology
- The British Journal of Dermatology
- Journal of Gastroenterology and Hepatology
- Journal of Biomedical Informatics
- Neurocritical Care
- Journal of Neurointerventional Surgery
- Ophthalmology
- Pediatric Cardiology
- American Journal of Physiology. Gastrointestinal and Liver Physiology
- Neurosurgery
- Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
- IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society
- Drug and Alcohol Dependence
- Developmental Medicine and Child Neurology
- Journal of Neurosurgery
- The American Journal of Tropical Medicine and Hygiene
- Indian Pediatrics
- Magnetic Resonance Imaging
- Journal of Vascular and Interventional Radiology : JVIR
- International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics
- AIDS (London, England)
- Journal of Critical Care
- Current Opinion in Ophthalmology
- Fetal and Pediatric Pathology
- JAMA Ophthalmology
- Journal of Acquired Immune Deficiency Syndromes (1999)
- Psychophysiology
- Current Treatment Options in Neurology
- The Journal of Infectious Diseases
- Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
- ACS Nano
- Journal of Human Nutrition and Dietetics : the Official Journal of the British Dietetic Association
- Neurosurgery
- Journal of Neurosurgery
- Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
- Indian Pediatrics
- European Journal of Human Genetics : EJHG
- Neurocritical Care
- Autism Research : Official Journal of the International Society for Autism Research
- Alimentary Pharmacology & Therapeutics
- The Journal of the American Academy of Orthopaedic Surgeons
- The Open Ophthalmology Journal
- Neurocritical Care
- JACC. Cardiovascular Interventions
- Indian Journal of Orthopaedics
- Fertility and Sterility
- Alimentary Pharmacology & Therapeutics
- Photochemical & Photobiological Sciences : Official Journal of the European Photochemistry Association and the European Society for Photobiology
- International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics
- Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics
- American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
- Nature Protocols
- International Journal of Gynaecology and Obstetrics: the Official Organ of the International Federation of Gynaecology and Obstetrics
- Clinical & Experimental Ophthalmology
- Clinical Nuclear Medicine
- Fungal Genetics and Biology : FG & B
- Biotechnology and Bioengineering
- Analytical and Bioanalytical Chemistry
- Journal of Clinical Gastroenterology
- Development (Cambridge, England)
- Journal of Endourology / Endourological Society
- Magnetic Resonance in Medicine : Official Journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine
- Biochimica Et Biophysica Acta
- Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
- Antioxidants & Redox Signaling
- Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
- Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia
- Stroke; a Journal of Cerebral Circulation
- The American Journal of Gastroenterology
- American Journal of Hematology
- Journal of Magnetic Resonance Imaging : JMRI
- Ophthalmology
- Journal of Vascular and Interventional Radiology : JVIR
- PDA Journal of Pharmaceutical Science and Technology / PDA
- Ophthalmic Surgery, Lasers & Imaging Retina
- Oman Journal of Ophthalmology
- British Journal of Haematology
- JAMA Surgery
- Sleep
- Molecular Cytogenetics
- Pediatric Dermatology
- PloS One
- Journal of Drugs in Dermatology : JDD
- Neurocritical Care
- The Indian Journal of Medical Research
- JIMD Reports
- Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association
- The Annals of Thoracic Surgery
- Developmental Neurorehabilitation
- Journal of Biomedical Informatics
- Child's Nervous System : ChNS : Official Journal of the International Society for Pediatric Neurosurgery
- BMJ Case Reports
- International Journal of Pharmaceutics
- Developmental Dynamics : an Official Publication of the American Association of Anatomists
- Neurocritical Care
- JSLS : Journal of the Society of Laparoendoscopic Surgeons / Society of Laparoendoscopic Surgeons
- Pediatric Neurology
- Neurology
- The Journal of Urology
- BMJ Open
- Autism Research : Official Journal of the International Society for Autism Research
- Circulation. Heart Failure
- Journal of Neurosurgery
- Journal of Gastroenterology and Hepatology
- The Canadian Journal of Cardiology
- BMJ (Clinical Research Ed.)
- The Gastroenterology Report
- Journal of Neurotrauma
- Indian Journal of Gastroenterology : Official Journal of the Indian Society of Gastroenterology
- The Annals of Thoracic Surgery
- Disease Models & Mechanisms
- BJU International
- IEEE Journal of Biomedical and Health Informatics
- Journal of Neurosurgery
Articles by Heeral J. Sheth in JoVE
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Insertion of Flexible Neural Probes Using Rigid Stiffeners Attached with Biodissolvable Adhesive
Sarah H. Felix1, Kedar G. Shah1, Vanessa M. Tolosa1, Heeral J. Sheth1, Angela C. Tooker1, Terri L. Delima1, Shantanu P. Jadhav2, Loren M. Frank2, Satinderpall S. Pannu1
1Materials Engineering Division, Lawrence Livermore National Laboratory, 2UCSF Center for Integrative Neuroscience and the Department of Physiology, University of California, San Francisco
Insertion of flexible neural microelectrode probes is enabled by attaching probes to rigid stiffeners with polyethylene glycol (PEG). A unique assembly process ensures uniform and repeatable attachment. After insertion into tissue, the PEG dissolves and the stiffener is extracted. An in vitro test method evaluates the technique in agarose gel.
Other articles by Heeral J. Sheth on PubMed
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Antiobesity Effect of Stellaria Media Against Drug Induced Obesity in Swiss Albino Mice
Ayu.
Oct, 2011 |
Pubmed ID: 22661858 The whole plant of Stellaria media (family: Caryophyllaceae) has been tested for its antiobesity activity by using progesterone-induced obesity model in female albino mice. The effect of S. media on food consumption pattern, change in body weight, thermogenesis, lipid metabolism, and histology of fat pad. were examined. Methanolic and alcoholic extracts of the S. media were used in the study. Methanolic extract of S. media (MESM) have prevented the increase in body weight, adipose tissue weight and size, and upturned obesity and associated complications. MESM has also shown promising effects compared with alcoholic extract of S. media may be because of its multiple mechanisms. These findings suggest that antiobesity activity produced by MESM is because of its anorexic property mediated by saponin and flavonoid and partly of by its β-sitosterol content. β-Sitosterol in the plant extract was confirmed by thin-layer chromatography study. β-sitosterol is plant sterol having structural similarity with dietary fat which do the physical competition in the gastrointestinal tract and reduces fat absorption. Before carrying in vivo activity detail pharmacognostic and phytochemical analysis of the extracts was carried out. The plant has shown the presence of saponin, flavonoids, steroids and triterpenoids, glycosides, and anthocynidine. By this study, it can be concluded that, MESM is beneficial in suppression of obesity induced by progesterone.
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Activation of Toll-like Receptor 4 is Necessary for Trauma Hemorrhagic Shock-induced Gut Injury and Polymorphonuclear Neutrophil Priming
Shock (Augusta, Ga.).
Jul, 2012 |
Pubmed ID: 22575992 Interactions of toll-like receptors (TLRs) with nonmicrobial factors play a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4 mut) mice would be more resistant to T/HS-induced gut injury and polymorphonuclear neutrophil (PMN) priming than their wild-type littermates and found that both were significantly reduced in the TLR4 mut mice. In addition, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the wild-type mice was abrogated in TLR4 mut mice as well the TRIF mut-deficient mice and partially attenuated in Myd88 mice, suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymph-induced PMN priming. Polymorphonuclear neutrophil depletion studies showed that T/HS lymph-induced acute lung injury was PMN dependent, because lung injury was totally abrogated in PMN-depleted animals. Because the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous nonmicrobial TLR4 ligands. High-mobility group box 1 protein 1, heat shock protein 70, heat shock protein 27, and hyaluronic acid all have been implicated in ischemia-reperfusion-induced tissue injury. None of these "danger" proteins appeared to be involved, because their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.
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Efficacy and Tolerability of Fixed-dose Combination of Dexketoprofen and Dicyclomine Injection in Acute Renal Colic
Pain Research and Treatment.
2012 |
Pubmed ID: 22577544 Objective. To evaluate the efficacy and tolerability of a fixed-dose combination of dexketoprofen and dicyclomine (DXD) injection in patients with acute renal colic. Patients and Methods. Two hundred and seventeen patients were randomized to receive either DXD (n = 109) or fixed-dose combination of diclofenac and dicyclomine injection (DLD; n = 108), intramuscularly. Pain intensity (PI) was self-evaluated by patients on visual analogue scale (VAS) at baseline and at 1, 2, 4, 6, and 8 hours. Efficacy parameters were proportion of responders, difference in PI (PID) at 8 hours, and sum of analogue of pain intensity differences (SAPID). Tolerability was assessed by patients and physicians. Results. DXD showed superior efficacy in terms of proportion of responders (98.17% versus 81.48; P < 0.0001), PID at 8 hours (P = 0.002), and SAPID(0-8 hours) (P = 0.004). The clinical global impression for change in pain was significantly better for DXD than DLD. The incidence of adverse events was comparable in both groups. However, global assessment of tolerability was rated significantly better for DXD. Conclusion. DXD showed superior efficacy and tolerability than DLD in patients clinically diagnosed to be suffering from acute renal colic.
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Trace Elements Affect Methanogenic Activity and Diversity in Enrichments from Subsurface Coal Bed Produced Water
Frontiers in Microbiology.
2012 |
Pubmed ID: 22590465 Microbial methane from coal beds accounts for a significant and growing percentage of natural gas worldwide. Our knowledge of physical and geochemical factors regulating methanogenesis is still in its infancy. We hypothesized that in these closed systems, trace elements (as micronutrients) are a limiting factor for methanogenic growth and activity. Trace elements are essential components of enzymes or cofactors of metabolic pathways associated with methanogenesis. This study examined the effects of eight trace elements (iron, nickel, cobalt, molybdenum, zinc, manganese, boron, and copper) on methane production, on mcrA transcript levels, and on methanogenic community structure in enrichment cultures obtained from coal bed methane (CBM) well produced water samples from the Powder River Basin, Wyoming. Methane production was shown to be limited both by a lack of additional trace elements as well as by the addition of an overly concentrated trace element mixture. Addition of trace elements at concentrations optimized for standard media enhanced methane production by 37%. After 7 days of incubation, the levels of mcrA transcripts in enrichment cultures with trace element amendment were much higher than in cultures without amendment. Transcript levels of mcrA correlated positively with elevated rates of methane production in supplemented enrichments (R(2) = 0.95). Metabolically active methanogens, identified by clone sequences of mcrA mRNA retrieved from enrichment cultures, were closely related to Methanobacterium subterraneum and Methanobacterium formicicum. Enrichment cultures were dominated by M. subterraneum and had slightly higher predicted methanogenic richness, but less diversity than enrichment cultures without amendments. These results suggest that varying concentrations of trace elements in produced water from different subsurface coal wells may cause changing levels of CBM production and alter the composition of the active methanogenic community.
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Single-neuron Responses in the Human Nucleus Accumbens During a Financial Decision-making Task
The Journal of Neuroscience : the Official Journal of the Society for Neuroscience.
May, 2012 |
Pubmed ID: 22623676 Linking values to actions and evaluating expectations relative to outcomes are both central to reinforcement learning and are thought to underlie financial decision-making. However, neurophysiology studies of these processes in humans remain limited. Here, we recorded the activity of single human nucleus accumbens neurons while subjects performed a gambling task. We show that the nucleus accumbens encodes two signals related to subject behavior. First, we find that under relatively predictable conditions, single neuronal activity predicts future financial decisions on a trial-by-trial basis. Interestingly, we show that this activity continues to predict decisions even under conditions of uncertainty (e.g., when the probability of winning or losing is 50/50 and no particular financial choice predicts a rewarding outcome). Furthermore, we find that this activity occurs, on average, 2 s before the subjects physically manifest their decision. Second, we find that the nucleus accumbens encodes the difference between expected and realized outcomes, consistent with a prediction error signal. We show this activity occurs immediately after the subject has realized the outcome of the trial and is present on both the individual and population neuron levels. These results provide human single neuronal evidence that the nucleus accumbens is integral in making financial decisions.
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Energy Conservation for the Simulation of Deformable Bodies
IEEE Transactions on Visualization and Computer Graphics.
May, 2012 |
Pubmed ID: 22665723 We propose a novel technique that allows one to conserve energy using the time integration scheme of one’s choice. Traditionally, the time integration methods that deal with energy conservation, such as symplectic and variational integrators, have aimed to include damping in a manner independent of the time step size, stating that this gives more control over the look and feel of the simulation. Generally speaking, damping adds to the overall aesthetics of a numerical simulation, especially since it damps out the high frequency oscillations that occur on the level of the discretization mesh. We propose an alternative technique that allows one to use damping to obtain the desired look of a numerical simulation, while still exactly conserving the total energy - in stark contrast to previous methods where adding damping effects necessarily removes energy from the mesh. This allows, for example, a deformable bouncing ball with aesthetically pleasing damping to collide with the ground and return to its original height exactly conserving energy (see Figure 1). Furthermore, since our method works with any time integration scheme, the user can choose their favorite time integration method with regards to aesthetics and simply apply our method as a post-process to conserve all or as much of the energy as desired.
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Mechanisms of Deep Brain Stimulation for Obsessive Compulsive Disorder: Effects Upon Cells and Circuits
Frontiers in Integrative Neuroscience.
2012 |
Pubmed ID: 22712007 Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level.
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Human Dorsal Anterior Cingulate Cortex Neurons Mediate Ongoing Behavioural Adaptation
Nature.
Aug, 2012 |
Pubmed ID: 22722841 The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.
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Identification of Novel Mutations in HEXA Gene in Children Affected with Tay Sachs Disease from India
PloS One.
2012 |
Pubmed ID: 22723944 Tay Sachs disease (TSD) is a neurodegenerative disorder due to β-hexosaminidase A deficiency caused by mutations in the HEXA gene. The mutations leading to Tay Sachs disease in India are yet unknown. We aimed to determine mutations leading to TSD in India by complete sequencing of the HEXA gene. The clinical inclusion criteria included neuroregression, seizures, exaggerated startle reflex, macrocephaly, cherry red spot on fundus examination and spasticity. Neuroimaging criteria included thalamic hyperdensities on CT scan/T1W images of MRI of the brain. Biochemical criteria included deficiency of hexosaminidase A (less than 2% of total hexosaminidase activity for infantile patients). Total leukocyte hexosaminidase activity was assayed by 4-methylumbelliferyl-N-acetyl-β-D-glucosamine lysis and hexosaminidase A activity was assayed by heat inactivation method and 4-methylumbelliferyl-N-acetyl-β-D-glucosamine-6-sulphate lysis method. The exons and exon-intron boundaries of the HEXA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and looked up in public databases. In silico analysis for mutations was carried out using SIFT, Polyphen2, MutationT@ster and Accelrys Discovery Studio softwares. Fifteen families were included in the study. We identified six novel missense mutations, c.340 G>A (p.E114K), c.964 G>A (p.D322N), c.964 G>T (p.D322Y), c.1178C>G (p.R393P) and c.1385A>T (p.E462V), c.1432 G>A (p.G478R) and two previously reported mutations. c.1277_1278insTATC and c.508C>T (p.R170W). The mutation p.E462V was found in six unrelated families from Gujarat indicating a founder effect. A previously known splice site mutation c.805+1 G>C and another intronic mutation c.672+30 T>G of unknown significance were also identified. Mutations could not be identified in one family. We conclude that TSD patients from Gujarat should be screened for the common mutation p.E462V.
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The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research
Pediatric Allergy, Immunology, and Pulmonology.
Jun, 2012 |
Pubmed ID: 22768387 BACKGROUND: Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking. METHODS: In order to define subphenotypes of allergic disease accurately, we established an infrastructure to link and efficiently utilize clinical and epidemiologic data with biospecimens into a single biorepository called the Greater Cincinnati Pediatric Clinic Repository (GCPCR). Children with allergic disorders as well as healthy controls are followed longitudinally at hospital clinic, emergency department, and inpatient visits. Subjects' asthma, allergy, and skin symptoms; past medical, family, social, diet, and environmental histories; physical activity; medication adherence; perceived quality of life; and demographics are ascertained. DNA is collected from all participants, and other biospecimens such as blood, hair, and nasal epithelial cells are collected on a subset. RESULTS: To date, the GCPCR has 6,317 predominantly Caucasian and African American participants, and 93% have banked DNA. This large sample size supports adequately powered genetic, epidemiologic, environmental, and health disparities studies of childhood allergic diseases. CONCLUSIONS: The GCPCR is a unique biorepository that is continuously evaluated and refined to achieve and maintain rigorous clinical phenotype and biological data. Development of similar disease-specific repositories using common data elements is necessary to enable studies across multiple populations of comprehensively phenotyped patients.
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Identifying Risk Factors in Renal Allografts Before Transplant: Machine-measured Renal Resistance and Posttransplant Allograft Survival
Progress in Transplantation (Aliso Viejo, Calif.).
Jun, 2012 |
Pubmed ID: 22878075 Enhancement of renal allograft function and survival in an era where expanded criteria donors are increasingly used requires validated selection criteria. The goal of this retrospective study was to evaluate the significance of pretransplant donor and allograft parameters to identify risk factors that can be used in a model to predict 1-year allograft outcomes. Donor demographic factors, donor type, and allograft parameters such as biopsy results and machine-measured renal resistance were correlated with 1-year graft outcome. The Kaplan-Meier method was used to estimate graft survival using the categorical predictors of donor type, donor age, and machine measured renal resistance at 1.5, 3, and 5 hours. The log-rank test was used to test the difference in survival curves between cohorts. The Cox regression analysis was used to estimate hazard ratios for machine-measured renal resistance, donor age, donor terminal creatinine level, donor's estimated glomerular filtration rate, cold ischemia time, and percent glomerulosclerosis. The data show that machine-measured renal resistance at 3 and 5 hours has a statistically significant inverse relationship to 1-year graft survival. All other risk factors had no correlation with 1-year graft survival. The machine-measured renal resistance at 3 hours is the earliest significant predictor of 1-year allograft outcome.
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Role of Lipase-generated Free Fatty Acids in Converting Mesenteric Lymph from a Noncytotoxic to a Cytotoxic Fluid
American Journal of Physiology. Gastrointestinal and Liver Physiology.
Oct, 2012 |
Pubmed ID: 22899820 Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.
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Gene Expression Correlates with Process Rates Quantified for Sulfate- and Fe(III)-Reducing Bacteria in U(VI)-Contaminated Sediments
Frontiers in Microbiology.
2012 |
Pubmed ID: 22908009 Though iron- and sulfate-reducing bacteria are well known for mediating uranium(VI) reduction in contaminated subsurface environments, quantifying the in situ activity of the microbial groups responsible remains a challenge. The objective of this study was to demonstrate the use of quantitative molecular tools that target mRNA transcripts of key genes related to Fe(III) and sulfate reduction pathways in order to monitor these processes during in situ U(VI) remediation in the subsurface. Expression of the Geobacteraceae-specific citrate synthase gene (gltA) and the dissimilatory (bi)sulfite reductase gene (dsrA), were correlated with the activity of iron- or sulfate-reducing microorganisms, respectively, under stimulated bioremediation conditions in microcosms of sediments sampled from the U.S. Department of Energy's Oak Ridge Integrated Field Research Challenge (OR-IFRC) site at Oak Ridge, TN, USA. In addition, Geobacteraceae-specific gltA and dsrA transcript levels were determined in parallel with the predominant electron acceptors present in moderately and highly contaminated subsurface sediments from the OR-IFRC. Phylogenetic analysis of the cDNA generated from dsrA mRNA, sulfate-reducing bacteria-specific 16S rRNA, and gltA mRNA identified activity of specific microbial groups. Active sulfate reducers were members of the Desulfovibrio, Desulfobacterium, and Desulfotomaculum genera. Members of the subsurface Geobacter clade, closely related to uranium-reducing Geobacter uraniireducens and Geobacter daltonii, were the metabolically active iron-reducers in biostimulated microcosms and in situ core samples. Direct correlation of transcripts and process rates demonstrated evidence of competition between the functional guilds in subsurface sediments. We further showed that active populations of Fe(III)-reducing bacteria and sulfate-reducing bacteria are present in OR-IFRC sediments and are good potential targets for in situ bioremediation.
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Does Inhibiting Sur1 Complement Rt-PA in Cerebral Ischemia?
Annals of the New York Academy of Sciences.
Sep, 2012 |
Pubmed ID: 22994227 Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA-associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA-associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA-associated HT in stroke.
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Low-sodium Dietary Approaches to Stop Hypertension Diet Reduces Blood Pressure, Arterial Stiffness, and Oxidative Stress in Hypertensive Heart Failure with Preserved Ejection Fraction
Hypertension.
Nov, 2012 |
Pubmed ID: 23033371 Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155-138 mm Hg; P=0.02) and diastolic blood pressure (79-72 mm Hg; P=0.04), 24-hour ambulatory systolic (130-123 mm Hg; P=0.02) and diastolic blood pressure (67-62 mm Hg; P=0.02), and carotid-femoral pulse wave velocity (12.4-11.0 m/s; P=0.03). Urinary F2-isoprostanes decreased by 31% (209-144 pmol/mmol Cr; P=0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt-sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.
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Screening for Injurious Falls in Acute Care Hospitals
Journal of Patient Safety.
Nov, 2012 |
Pubmed ID: 23149691 BACKGROUND: Injurious fall is a serious hospital-acquired condition. Screening tools for injurious falls in hospitalized patients have received limited evaluation. OBJECTIVE: To compare operating characteristics of a succinct screening tool for injurious falls, the University of Pittsburgh Medical Center (UPMC) screening tool (based on mobility, fall history, and nursing judgment), with the ABCS injurious fall screening tool (based on Age, Bone, Coagulation, and recent Surgery). DESIGN: Case control study. METHODS: Hospitalized patients with injurious falls were identified from the UPMC adverse events database for 2007-2008 (N = 43). Controls (n = 86) matched for age, location, and period of fall event were selected from the hospital's administrative database. Tools were evaluated independently by 2 screeners using electronic charts. Interrater agreement, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and c-statistics for the screening tools were calculated. RESULTS: Case and control groups were similar in age, sex, and race. Interrater agreement was 71% for ABCS and 72% for UPMC screens. ABCS and UPMC screens had sensitivity of 60.5% (95% CI, 52.0%-68.9%) and 62.8% (95% CI, 54.5%-71.1%), specificity of 41.9% (95% CI, 33.4%-50.4%) and 58.1% (95% CI 49.6%-66.7%), and c-statistics of 51.2% and 59.3%, respectively. With a 33% prevalence of injurious fall, the PPV was 34.2%, and NPV was 67.9% for ABCS, and the PPV was 42.9%, and NPV was 75.8% for UPMC. Operating characteristics were not statistically significantly different, although the UPMC screen was 8% more accurate in predicting injurious falls and had a lower false-positive rate (44.2% versus 65.1%). CONCLUSIONS: Compared with the ABCS screen, the UPMC screen is a simple, practical tool. Prospective studies are needed to establish the UPMC tool's predictive value in hospital practices with lower rates of injurious falls. In general, better screening tools for injurious falls should be developed to meet quality standards.
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Dysregulation of IRP1-mediated Iron Metabolism Causes Gamma Ray-specific Radioresistance in Leukemia Cells
PloS One.
2012 |
Pubmed ID: 23155415 Iron is required for nearly all organisms, playing important roles in oxygen transport and many enzymatic reactions. Excess iron, however, can be cytotoxic. Emerging evidence suggests that radioresistance can be achieved in lower organisms by the protection of proteins, but not DNA, immediately following ionizing radiation (IR) exposure, allowing for improved DNA repair. One potential mechanism for protein protection is controlling and limiting the amount of free iron in cells, as has been demonstrated in the extremophile Deinococcus Radiodurans, reducing the potential for oxidative damage to proteins during exposure to IR. We found that iron regulatory protein 1 (IRP1) expression was markedly reduced in human myeloid leukemia HL60 cells resistant to low linear energy transfer (LET) gamma rays, but not to high LET alpha particles. Stable knockdown of IRP1 by short-hairpin RNA (shRNA) interference in radiosensitive parental cells led to radioresistance to low LET IR, reduced intracellular Fenton chemistry, reduced protein oxidation, and more rapid DNA double-strand break (DSB) repair. The mechanism of radioresistance appeared to be related to attenuated free radical-mediated cell death. Control of intracellular iron by IRPs may be a novel radioresistance mechanism in mammalian cells.
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Resveratrol Reduces Prostate Cancer Growth and Metastasis by Inhibiting the Akt/MicroRNA-21 Pathway
PloS One.
2012 |
Pubmed ID: 23272133 The consumption of foods containing resveratrol produces significant health benefits. Resveratrol inhibits cancer by reducing cell proliferation and metastasis and by inducing apoptosis. These actions could be explained by its ability to inhibit (ERK-1/2), Akt and suppressing the levels of estrogen and insulin growth factor -1 (IGF-1) receptor. How these processes are manifested into the antitumor actions of resveratrol is not clear. Using microarray studies, we show that resveratrol reduced the expression of various prostate-tumor associated microRNAs (miRs) including miR-21 in androgen-receptor negative and highly aggressive human prostate cancer cells, PC-3M-MM2. This effect of resveratrol was associated with reduced cell viability, migration and invasiveness. Additionally, resveratrol increased the expression of tumor suppressors, PDCD4 and maspin, which are negatively regulated by miR-21. Short interfering (si) RNA against PDCD4 attenuated resveratrol's effect on prostate cancer cells, and similar effects were observed following over expression of miR-21 with pre-miR-21 oligonucleotides. PC-3M-MM2 cells also exhibited high levels of phospho-Akt (pAkt), which were reduced by both resveratrol and LY294002 (a PI3-kinase inhibitor). MiR-21 expression in these cells appeared to be dependent on Akt, as LY294002 reduced the levels of miR-21 along with a concurrent increase in PDCD4 expression. These in vitro findings were further corroborated in a severe combined immunodeficient (SCID) mouse xenograft model of prostate cancer. Oral administration of resveratrol not only inhibited the tumor growth but also decreased the incidence and number of metastatic lung lesions. These tumor- and metastatic-suppressive effects of resveratrol were associated with reduced miR-21 and pAkt, and elevated PDCD4 levels. Similar anti-tumor effects of resveratrol were observed in DU145 and LNCaP prostate cancer cells which were associated with suppression of Akt and PDCD4, but independent of miR-21.These data suggest that resveratrol's anti-tumor actions in prostate cancer could be explained, in part, through inhibition of Akt/miR-21 signaling pathway.
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Species-level Classification of the Vaginal Microbiome
BMC Genomics.
2012 |
Pubmed ID: 23282177 The application of next-generation sequencing to the study of the vaginal microbiome is revealing the spectrum of microbial communities that inhabit the human vagina. High-resolution identification of bacterial taxa, minimally to the species level, is necessary to fully understand the association of the vaginal microbiome with bacterial vaginosis, sexually transmitted infections, pregnancy complications, menopause, and other physiological and infectious conditions. However, most current taxonomic assignment strategies based on metagenomic 16S rDNA sequence analysis provide at best a genus-level resolution. While surveys of 16S rRNA gene sequences are common in microbiome studies, few well-curated, body-site-specific reference databases of 16S rRNA gene sequences are available, and no such resource is available for vaginal microbiome studies.
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Examination of Survival After Transfer from Peritoneal Dialysis to Hemodialysis
Advances in Peritoneal Dialysis. Conference on Peritoneal Dialysis.
2012 |
Pubmed ID: 23311216 Data on survival after transfer from peritoneal dialysis (PD) to hemodialysis (HD) is conflicting. We reviewed two decades of outcomes in a PD program to examine short-term survival after transfer from PD to HD. Of 379 patients on PD, 33% transferred to HD. The reasons for transfer were PD-related infections (340%), uremia or failure to thrive (26%), PD catheter problems or loss of mechanical skills (15%), dementia or unable to train (7%), noncompliant with PD (7%), other (10%, including gastrointestinal complications, hernia, encapsulating peritoneal sclerosis, preference, loss of ultrafiltration), and cardiac (2%). All of those transferring for "other" reasons survived 6 months, and as did all except 1 who transferred for uremia (p = 0.035). Overall survival was 92% at 3 months and 85% at 6 months. Using multivariate logistic regression analysis, only score on the Charlson comorbidity index at PD start was a risk factor for dying in the first 6 months on HD: for each 1 point increase in CCI score, the hazard ratio for death was 1.4 (95% confidence interval: 1.16 to 1.74; p = 0.005). To summarize, starting a patient on PD and waiting until uremia to transfer to HD does not have a negative impact on survival. In a program with relatively low PD-related infectious complications, such complications accounted for only one third of transfers to HD.
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Optimization of Multi-layer Metal Neural Probe Design
Conference Proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference.
2012 |
Pubmed ID: 23367295 We present here a microfabrication process for multi-layer metal, multi-site, polymer-based neural probes. The process has been used to generate 1-, 2-, and 4-layer trace metal neural probes with highly uniform and reproducible electrode characteristics. Typically, increasing the number of metal layers is assumed to both reduce the width of the neural probes and minimize the injury and glial scarring caused at the implantation site. We show, however, that increasing the number of trace metal layers does not always result in the minimal probe cross-sectional area. A thorough design analysis reveals that the electrode size, along with other design parameters, have interacting effects on the probe cross-sectional area. Moreover, increasing the trace metal layers in the neural probes also increases the design and fabrication cost/time, as well as the likelihood of probe failure. Consequently, all of these factors must be considered when designing a multi-site, neural probe with the objective of minimizing tissue damage.
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Operative Treatment of Early Peri-prosthetic Femur Fractures Following Primary Total Hip Arthroplasty
The Journal of Arthroplasty.
Feb, 2013 |
Pubmed ID: 22868075 The risk factors for and results of operatively treated peri-prosthetic femoral fractures sustained within 90 days following primary THA were evaluated. 5,313 consecutive THAs were reviewed and 32 (0.60%) fractures were identified which included 9 A(g), 2 B(1), 18 B(2), 1 B(3), and 2 A(g)/B(2) fractures. 19 (61%) patients sustained 23 complications including 9 greater trochanter non-unions, 2 femoral shaft non-unions, 3 patients with Brooker III HO, and 2 deep infections. 7 patients (23%) required a second operative procedure and one patient required a third. Peri-prosthetic fractures were associated with advancing age, female gender, developmental hip dysplasia, and cementless metaphyseal engaging components, particularly flat wedge tapers. Overall, operative treatment of acute peri-prosthetic fractures is associated with a high rate of complications (61%) and re-operation (23%).
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Validation of the Innocor Device for Noninvasive Measurement of Oxygen Consumption in Children and Adults
Pediatric Cardiology.
Apr, 2013 |
Pubmed ID: 23108483 Outpatient measurements of oxygen consumption (VO2) and cardiac output (CO) are valuable in the management of pediatric cardiac disease. Current methods are inaccurate and cumbersome or require invasive procedures. New devices to measure these variables in adults have not been rigorously tested for children. The Innocor system uses a photoacoustic analyzer to measure gas content for noninvasive measurement of VO2 and CO. This study sought to validate Innocor-derived VO2 measurements in children and adults by comparing them against the gold standard Douglas bag method. Subjects were tested in an outpatient setting. Adaptations were made for pediatric patients based on weight. Resting VO2 measurements were obtained simultaneously by the Innocor system and Douglas bag during 3 min. The study enrolled 31 children (mean age, 12.2 years; range, 7-17 years, 17 girls) and 29 adults (mean age, 36.7 years; range, 19-57 years; 17 women). Strong correlation between the two techniques was seen for both the adults (R (2) = 0.88) and the children (R (2) = 0.82). The average discrepancy between the Innocor and Douglas bag measurements was 1.7 % (range, 0.6-19.1 %) for the adults, and 5.4 % (range, 0.1-32.2 %) for the children. The discrepancy was more than 15 % for 17 % of the adults and 22 % of the children, with the Innocor device tending to overestimate VO2 in children compared with the Douglas bag. This trend was not seen in adults. The Innocor system has excellent correlation with the Douglas bag and shows promise for noninvasive measurement of VO2 and CO in the school-age pediatric population.
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Oxidative Modification of the Intestinal Mucus Layer is a Critical but Unrecognized Component of Trauma Hemorrhagic Shock-induced Gut Barrier Failure
American Journal of Physiology. Gastrointestinal and Liver Physiology.
Jan, 2013 |
Pubmed ID: 23125158 Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radical-mediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS- and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.
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Dynamic Multi-channel TMS with Reconfigurable Coil
IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society.
May, 2013 |
Pubmed ID: 23193321 Investigations of the causal involvement of particular brain areas and interconnections in behavior require an external stimulation system with reasonable spatio-temporal resolution. Current transcranial magnetic stimulation (TMS) technology is limited to stimulating a single brain area once in a given trial. Here, we present a feasibility study for a novel TMS system based on multi-channel reconfigurable coils. With this hardware, researchers will be able to stimulate multiple brain sites in any temporal order in a trial. The system employs a wire-mesh coil, constructed using x- and y-directional wires. By varying the current direction and/or strength on each wire, we can configure the proposed mesh-wire coil into a standard loop coil and figure-eight coil of varying size. This provides maximum flexibility to the experimenter in that the location and extent of stimulation on the brain surface can be modified depending on experimental requirement. Moreover, one can dynamically and automatically modify the site(s) of stimulation several times within the span of seconds. By pre-storing various sequences of excitation patterns inside a control unit, one can explore the effect of dynamic TMS on behavior, in associative learning, and as rehabilitative therapy. Here, we present a computer simulation and bench experiments that show the feasibility of the dynamically-reconfigurable coil.
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Long-term Impact of Integration of Household Water Treatment and Hygiene Promotion with Antenatal Services on Maternal Water Treatment and Hygiene Practices in Malawi
The American Journal of Tropical Medicine and Hygiene.
Feb, 2013 |
Pubmed ID: 23243106 A clinic-based program to integrate antenatal services with distribution of hygiene kits including safe water storage containers, water treatment solution (brand name WaterGuard), soap, and hygiene education, was implemented in Malawi in 2007 and evaluated in 2010. We surveyed 389 participants at baseline in 2007, and found and surveyed 232 (60%) participants to assess water treatment, test stored drinking water for residual chlorine (an objective measure of treatment), and observe handwashing technique at follow-up in 2010. Program participants were more likely to know correct water treatment procedures (67% versus 36%; P < 0.0001), treat drinking water with WaterGuard (24% versus 2%; P < 0.0001), purchase and use WaterGuard (21% versus 1%; P < 0.001), and demonstrate correct handwashing technique (50% versus 21%; P < 0.001) at the three-year follow-up survey than at baseline. This antenatal-clinic-based program may have contributed to sustained water treatment and proper handwashing technique among program participants.
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Sound-induced Perturbations of the Brain Network in Non-REM Sleep, and Network Oscillations in Wake
Psychophysiology.
Mar, 2013 |
Pubmed ID: 23316945 During sleep, the brain network processes sensory stimuli without awareness. Stimulation must affect differently brain networks in sleep versus wake, but these differences have yet to be quantified. We recorded cortical activity in stage 2 (SII) sleep and wake using EEG while a tone was intermittently played. Zero-lag correlation measured input to pairs of sensors in the network; cross-correlation and phase-lag index measured pairwise corticocortical connectivity. Our analysis revealed that under baseline conditions, the cortical network, in particular the central regions of the frontoparietal cortex, interact at a characteristic latency of 50 ms, but only during wake, not sleep. Nonsalient auditory stimulation causes far greater perturbation of connectivity from baseline in sleep than wake, both in the response to common input and corticocortical connectivity. The findings have key implications for sensory processing.
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Fluorochrome-functionalized Nanoparticles for Imaging DNA in Biological Systems
ACS Nano.
Mar, 2013 |
Pubmed ID: 23373524 Attaching DNA binding fluorochromes to nanoparticles (NPs) provides a way of obtaining NPs that bind to DNA through fluorochrome mediated interactions. To obtain a nanoparticle (NP) that bound to the DNA in biological systems, we attached the DNA binding fluorochrome, TO-PRO 1 (TO), to the surface of the Feraheme (FH) NP, to obtain a fluorochrome-functionalized NP denoted TO-FH. When reacted with DNA in vitro, TO-FH formed microaggregates that were characterized by fluorescence, light scattering, and T2 changes. The formation of DNA/TO-FH microaggregates was also characterized by AFM, with microaggregates exhibiting a median size of 200 nm, and consisting of DNA and multiple TO-FH NPs whose individual diameters were only 25-35 nm. TO-FH failed to bind normal cells in culture, but treatment with chemotherapeutic agents or detergents yielded necrotic cells that bound TO-FH and vital fluorochromes similarly. The uptake of TO-FH by HT-29 xenografts (treated with 5-FU and oxaliplatin) was evident by surface fluorescence and MRI. Attaching multiple DNA binding fluorochromes to magnetic nanoparticles provides a way of generating DNA binding NPs that can be used to detect DNA detection by microaggregate formation in vitro, for imaging the DNA of necrotic cells in culture, and for imaging the DNA of a tumor treated with a chemotherapeutic agent. Fluorochrome functionalized NPs are a multimodal (magnetic and fluorescent), highly multivalent (n ≈ 10 fluorochromes/NP) nanomaterials useful for imaging the DNA of biological systems.
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Neurological Surgery: the Influence of Physical and Mental Demands on Humans Performing Complex Operations
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia.
Mar, 2013 |
Pubmed ID: 23394875 Performing neurological surgery is an inherently demanding task on the human body, both physically and mentally. Neurosurgeons routinely perform "high stakes" operations in the setting of mental and physical fatigue. These conditions may be not only the result of demanding operations, but also influential to their outcome. Similar to other performance-based endurance activities, training is paramount to successful outcomes. The inflection point, where training reaches the point of diminishing returns, is intensely debated. For the neurosurgeon, this point must be exploited to the maximum, as patients require both the best-trained and best-performing surgeon. In this review, we explore the delicate balance of training and performance, as well as some routinely used adjuncts to improve human performance.
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Dosage Changes of MED13L Further Delineate Its Role in Congenital Heart Defects and Intellectual Disability
European Journal of Human Genetics : EJHG.
Oct, 2013 |
Pubmed ID: 23403903 A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.
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Acetabular Bone Loss in Revision Total Hip Arthroplasty: Evaluation and Management
The Journal of the American Academy of Orthopaedic Surgeons.
Mar, 2013 |
Pubmed ID: 23457063 As the number of primary total hip arthroplasty (THA) procedures performed continues to rise, the burden of revision THA procedures is also expected to increase. Proper evaluation and management of acetabular bone loss at the time of revision surgery will be an increasing challenge facing orthopaedic surgeons. Proper preoperative patient assessment and detailed preoperative planning are essential in obtaining a good clinical result. Appropriate radiographs are critical in assessing acetabular bone loss, and specific classification schemes can identify bone loss patterns and guide available treatment options. Treatment options include impaction grafting and cementation of the acetabulum, noncemented hemispheric acetabular reconstruction, structural allograft reconstruction, noncemented reconstruction with modular porous metal augments, ring and cage reconstruction, oblong cup reconstruction, cup-cage reconstruction, and triflange reconstruction.
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Induced and Sustained Hypernatremia for the Prevention and Treatment of Cerebral Edema Following Brain Injury
Neurocritical Care.
Oct, 2013 |
Pubmed ID: 23468135 Cerebral edema develops in response to and as a result of a variety of neurologic insults such as ischemic stroke, traumatic brain injury, and tumor. It deforms brain tissue, resulting in localized mass effect and increase in intracranial pressure (ICP) that are associated with a high rate of morbidity and mortality. When administered in bolus form, hyperosmolar agents such as mannitol and hypertonic saline have been shown to reduce total brain water content and decrease ICP, and are currently the mainstays of pharmacological treatment. However, surprisingly, little is known about the increasingly common clinical practice of inducing a state of sustained hypernatremia. Herein, we review the available studies employing sustained hyperosmolar therapy to induce hypernatremia for the prevention and/or treatment of cerebral edema. Insufficient evidence exists to recommend pharmacologic induction of hypernatremia as a treatment for cerebral edema. The strategy of vigilant avoidance of hyponatremia is currently a safer, potentially more efficacious paradigm.
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Randomized, Double-masked, Placebo-controlled Study to Assess the Ocular Safety of Mirabegron in Healthy Volunteers
Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics.
Sep, 2013 |
Pubmed ID: 23586728 Abstract Purpose: This study assessed the effect of mirabegron on ocular safety in healthy volunteers. Methods: This was an 8-week, randomized, double-masked, placebo-controlled study. Participants: Consenting adults aged ≥18 years with a normal intraocular pressure (IOP, ≥10 to ≤21 mmHg) were eligible to enter the study. Of the 321 randomized subjects, 305 completed the study. Subjects were randomized 1:1 to a supratherapeutic dose of oral mirabegron 100 mg or placebo once daily for 56 days. The IOP was measured at screening, baseline, day 10, and day 56/end of treatment using Goldmann applanation tonometry. Visual acuity and biomicroscopy were also evaluated. The primary endpoint was the mean change from baseline in the IOP at 56 days or end of treatment with mirabegron versus placebo. Secondary outcome variables included change from baseline to day 10 in the IOP, and increases in the IOP of ≥6 mmHg and ≥10 mmHg in either eye from baseline to day 10 and day 56. Results: The mean (standard error, SE) IOP at baseline was 15.3 (0.16) mmHg for mirabegron and 15.4 (0.16) mmHg for placebo; values at day 56 were 15.0 (0.16) mmHg and 15.2 (0.17) mmHg, respectively. The adjusted mean IOP change from baseline to day 56 was -0.3 mmHg for mirabegron and -0.2 mmHg for placebo (-0.1 mmHg difference [95% confidence interval, CI, -0.4 to 0.3]). For the primary endpoint, mirabegron was noninferior to placebo, based on the prespecified limit of 1.5 mmHg. No statistically significant treatment effects on the IOP were seen at day 10. No subject discontinued due to increased IOP. Clinically significant increases from baseline in the IOP occurred rarely and only with placebo treatment. Changes in the visual acuity and biomicroscopy were not suggestive of a mirabegron effect. No treatment-emergent adverse event (AE) of glaucoma was reported. Conclusions: Mirabegron 100 mg orally once daily for 8 weeks of treatment does not increase the IOP, and was generally safe and well tolerated.
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Hemodialysis for the Treatment of Pulmonary Hemorrhage from Dabigatran Overdose
American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation.
Sep, 2013 |
Pubmed ID: 23597859 Dabigatran is an oral direct thrombin inhibitor indicated for thromboembolism prophylaxis in patients with nonvalvular atrial fibrillation. Since its approval in the United States in 2010, dabigatran-associated hemorrhages have garnered much attention because bleeding rates were higher than initially expected. Additionally, reversing anticoagulation remains challenging. Traditional modes of reversing warfarin-associated coagulopathies are ineffective in reversing anticoagulation from dabigatran. Although hemodialysis is proposed as a method to accelerate dabigatran elimination, evidence supporting its clinical utility remains unproved. We report the case of an 80-year-old man who presented with worsening hemoptysis in the setting of unintentional ingestion of excess dabigatran. Despite transfusion of 2 units of fresh frozen plasma, he continued to bleed, although his international normalized ratio improved from 8.8 to 7.2. He underwent hemodialysis, and serum dabigatran concentration decreased from 1,100 to 18 ng/mL over 4 hours, with an initial extraction ratio of 0.97 and blood clearance of 291 mL/min. Although his serum dabigatran concentration rebounded to 100 ng/mL 20 minutes after the cessation of dialysis, his bleeding stopped and he improved clinically. Hemorrhage in the setting of dabigatran anticoagulation remains a therapeutic predicament. Hemodialysis may play an adjunct role in accelerating the elimination of dabigatran in bleeding patients.
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Retinal Nerve Fibre Layer Imaging: Comparison of Cirrus Optical Coherence Tomography and Heidelberg Retinal Tomograph 3
Clinical & Experimental Ophthalmology.
Apr, 2013 |
Pubmed ID: 23601764 BACKGROUND: The propose of this study was to analyze the relationship between retinal nerve fibre layer (RNFL) thickness measured by spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope. DESIGN: Prospective, cross-sectional study. Hospital setting. PARTICIPANTS: One hundred seventy-three subjects (85 glaucoma and 88 normal subjects). METHODS: One eye from each individual was selected randomly for RNFLT imaging by the spectral domain Cirrus OCT and HRT3. MAIN OUTCOME MEASURES: Global RNFL thickness and measurements at the four quadrants around the optic disc were analyzed and compared for differences, agreement of the categorical classification, diagnostic sensitivities and specificities and the area under the receiver operating characteristic curves (AUC). RESULTS: RNFL thickness as determined by HRT3 were significantly thicker than measurements done by Cirrus OCT (respectively in μm, for global thickness: 200.0±87.2 and 80.7±14.7, for temporal quadrant: 75.3±31.9 and 59.1±13.8, for superior quadrant 223.2±128.4 and 97.7±20.9, for nasal quadrant 208.0±102.9 and 66.8±11.8, and for inferior quadrant 224.4±116.9 and 99.1±26.6, for all P
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Reporters for the Analysis of N-glycosylation in Candida Albicans
Fungal Genetics and Biology : FG & B.
Jul, 2013 |
Pubmed ID: 23608318 A large proportion of Candida albicans cell surface proteins are decorated post-translationally by glycosylation. Indeed N-glycosylation is critical for cell wall biogenesis in this major fungal pathogen and for its interactions with host cells. A detailed understanding of N-glycosylation will yield deeper insights into host-pathogen interactions. However, the analysis of N-glycosylation is extremely challenging because of the complexity and heterogeneity of these structures. Therefore, in an attempt to reduce this complexity and facilitate the analysis of N-glycosylation, we have developed new synthetic C. albicans reporters that carry a single N-linked glycosylation site derived from Saccharomyces cerevisiae Suc2. These glycosylation reporters, which carry C.albicans Hex1 or Sap2 signal sequences plus carboxy-terminal FLAG₃ and His₆ tags, were expressed in C.albicans from the ACT1 promoter. The reporter proteins were successfully secreted and hyperglycosylated by C.albicans cells, and their outer chain glycosylation was dependent on Och1 and Pmr1, which are required for N-mannan synthesis, but not on Mnt1 and Mnt2 which are only required for O-mannosylation. These reporters are useful tools for the experimental dissection of N-glycosylation and other related processes in C.albicans, such as secretion.
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Differential Linear Scan Voltammetry: Analytical Performance in Comparison with Pulsed Voltammetry Techniques
Analytical and Bioanalytical Chemistry.
Jun, 2013 |
Pubmed ID: 23624955 We report here on differential linear scan voltammetry, DLSV, that combines the working principles of linear scan voltammetry, LSV, and the numerous existing pulsed voltammetry techniques. DLSV preserves the information from continuous interrogation in voltage and high accuracy that LSV provides about electrochemical processes, and the much better sensitivity of differential pulsed techniques. DLSV also minimizes the background current compared to both LSV and pulsed voltammetry. An early version of DLSV, derivative stationary electrode polarography, DSEP, had been proposed in the 1960s but soon abandoned in favor of the emerging differential pulsed techniques. Relative to DSEP, DLSV takes advantage of the flexibility of discrete smoothing differentiation that was not available to early investigators. Also, DSEP had been explored in pure solutions and with reversible electrochemical reactions. DLSV is tested in this work in more challenging experimental contexts: the measurement of oxygen with a carbon fiber microelectrode in buffer, and with a gold microdisc electrode exposed to a live biological preparation. This work compares the analytical performance of DLSV and square wave voltammetry, the most popular pulsed voltammetry technique.
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Decompensated Cirrhotics Have Slower Intestinal Transit Times As Compared With Compensated Cirrhotics and Healthy Controls
Journal of Clinical Gastroenterology.
May, 2013 |
Pubmed ID: 23632359 BACKGROUND:: Altered small intestinal motility in cirrhotics may play a major role in the development of bacterial translocation (BT) by leading to small intestinal bacterial overgrowth. BT has been implicated in the development of several complications including spontaneous bacterial peritonitis, esophageal variceal hemorrhage, and hepatorenal syndrome. Prior studies using antroduodenal manometry to evaluate intestinal motility have shown discrepancies regarding the relationship between dysmotility and the severity of cirrhosis. OBJECTIVES:: (1) To characterize the frequency of small bowel motility disturbances in cirrhotic patients using a wireless motility capsule (SmartPill); (2) To assess the relationship of intestinal dysmotility with liver disease severity and cirrhosis complications; and (3) To compare intestinal transit times and motility indices among cirrhotics and healthy controls. METHODS:: We conducted a prospective study of 20 patients with cirrhosis (10 compensated, 10 decompensated) who were recruited from Yale New Haven Hospital and Hepatology clinics (February 2011 to July 2011). All patients underwent and completed SmartPill studies. Intestinal transit times were calculated, analyzed, and compared among compensated versus decompensated cirrhotics versus historical, healthy controls. Intestinal transit delays/motility indices were correlated with disease severity and complications. RESULTS:: Decompensated cirrhotics had significantly longer small bowel transit times (SBTT) as compared with compensated cirrhotics (6.17 vs. 3.56 h, P=0.036). There was a significant correlation (r=0.77, P=0.0003) between SBTT and cirrhosis severity as assessed by Child-Pugh score. There were no statistical differences noted between the groups for gastric or colonic transit times, although there was a trend toward prolonged transit throughout the gut in decompensated. Cirrhotics with spontaneous bacterial peritonitis and ascites also had significantly longer SBTT as compared with those without. CONCLUSIONS:: This study demonstrates that decompensated cirrhotics have slower intestinal transit times as compared with compensated cirrhotics and healthy controls. Additional prospective studies are needed to further characterize dysmotility in cirrhotics and its relationship to complications related to BT. This would aid in the identification of patients at risk for developing severe complications and who may benefit from prophylactic prokinetic and/or antimicrobial therapy.
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Decoupling the Function of Hox and Shh in Developing Limb Reveals Multiple Inputs of Hox Genes on Limb Growth
Development (Cambridge, England).
May, 2013 |
Pubmed ID: 23633510 Limb development relies on an exquisite coordination between growth and patterning, but the underlying mechanisms remain elusive. Anterior-posterior and proximal-distal specification initiates in early limb bud concomitantly with the proliferative expansion of limb cells. Previous studies have shown that limb bud growth initially relies on fibroblast growth factors (FGFs) produced in the apical ectodermal ridge (AER-FGFs), the maintenance of which relies on a positive-feedback loop involving sonic hedgehog (Shh) and the BMP antagonist gremlin 1 (Grem1). The positive cross-regulation between Shh and the HoxA and HoxD clustered genes identified an indirect effect of Hox genes on the maintenance of AER-FGFs but the respective function of Shh and Hox genes in this process remains unknown. Here, by uncoupling Hox and Shh function, we show that HoxA and HoxD genes are required for proper AER-FGFs expression, independently of their function in controlling Shh expression. In addition, we provide evidence that the Hox-dependent control of AER-FGF expression is achieved through the regulation of key mesenchymal signals, namely Grem1 and Fgf10, ensuring proper epithelial-mesenchymal interactions. Notably, HoxA and HoxD genes contribute to both the initial activation of Grem1 and the subsequent anterior expansion of its expression domain. We propose that the intricate interactions between Hox genes and the FGF and Shh signaling pathways act as a molecular network that ensures proper limb bud growth and patterning, probably contributing to the coordination of these two processes.
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Essential Role of NADPH Oxidase-Dependent Reactive Oxygen Species Generation in Regulating MicroRNA-21 Expression and Function in Prostate Cancer
Antioxidants & Redox Signaling.
Jul, 2013 |
Pubmed ID: 23682737 Abstract Aims: Oncogenic microRNAs (miRs) promote tumor growth and invasiveness. One of these, miR-21, contributes to carcinogenesis in prostate and other cancers. In the present study, we tested the hypothesis that NADPH oxidase-dependent reactive oxygen species (ROS) regulate the expression and function of miR-21 and its target proteins, maspin and programmed cell death 4 (PDCD4), in prostate cancer cells. Results: The highly aggressive androgen receptor negative PC-3M-MM2 prostate cancer cells demonstrated high expression of miR-21 and p47(phox) (an essential subunit of NADPH oxidase). Using loss-of-function strategy, we showed that transfection of PC-3M-MM2 cells with anti-miR-21- and p47(phox) siRNA (si-p47(phox)) led to reduced expression of miR-21 with concurrent increase in maspin and PDCD4, and decreased the invasiveness of the cells. Tail-vein injections of anti-miR-21- and si-p47(phox)-transfected PC-3M-MM2 cells in severe combined immunodeficient mice reduced lung metastases. Clinical samples from patients with advanced prostate cancer expressed high levels of miR-21 and p47(phox), and low expression of maspin and PDCD4. Finally, ROS activated Akt in these cells, the inhibition of which reduced miR-21 expression. Innovation: The levels of NADPH oxidase-derived ROS are high in prostate cancer cells, which have been shown to be involved in their growth and migration. This study demonstrates that ROS produced by this pathway is essential for the expression and function of an onco-miR, miR-21, in androgen receptor-negative prostate cancer cells. Conclusion: These data demonstrate that miR-21 is an important target of ROS, which contributes to the highly invasive and metastatic phenotype of prostate cancer cells. Antioxid. Redox Signal. 00, 000-000.
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Clinical Features of Brain Metastasis from Salivary Gland Tumors
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia.
May, 2013 |
Pubmed ID: 23685104 Salivary gland tumors comprise a group of 24 tumor subtypes with a wide range of clinical behaviors and propensities for metastasis. Several prognostic factors have been identified that help predict the development of systemic metastases, most commonly to the lung, liver, or bone. Metastases to the brain are rare. To better understand the behavior of salivary gland tumors that metastasise to the brain, we performed a retrospective cohort analysis on a series of patients to highlight features of their medical and surgical management. From 2007 to 2011, a database of 4117 elective craniotomies were queried at a single institution to identify patients surgically treated for salivary gland metastases to the brain. Three patients were identified. Histologic subtypes included salivary duct carcinoma, poorly differentiated carcinoma, and papillary mucinous adenocarcinoma. They had all undergone previous treatment for their primary malignancy. The mean time to intracranial metastasis was 48months from initial diagnosis (range, 14-91months). Treatment for intracranial metastases included surgical resection, whole brain radiation, stereotactic radiosurgery, and chemotherapy. Intracranial metastases from salivary gland tumors are rare, present years after diagnosis of the primary tumor, and are treatable with multimodality therapy.
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Non-contrast 3D Time-of-flight Magnetic Resonance Angiography for Visualization of Intracranial Aneurysms in Patients with Absolute Contraindications to CT or MRI Contrast
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia.
Aug, 2013 |
Pubmed ID: 23685107 The preoperative evaluation of patients with intracranial aneurysms typically includes a contrast-enhanced vascular study, such as computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography. However, there are numerous absolute and relative contraindications to the administration of imaging contrast agents, including pregnancy, severe contrast allergy, and renal insufficiency. Evaluation of patients with contrast contraindications thus presents a unique challenge. We identified three patients with absolute contrast contraindications who presented with intracranial aneurysms. One patient was pregnant, while the other two had previous severe anaphylactic reactions to iodinated contrast. Because of these contraindications to intravenous contrast, we performed non-contrast time-of-flight MRA with 3D reconstruction (TOF MRA with 3DR) with maximum intensity projections and volume renderings as part of the preoperative evaluation prior to successful open surgical clipping of the aneurysms. In the case of one paraclinoid aneurysm, a high-resolution non-contrast CT scan was also performed to assess the relationship of the aneurysm to the anterior clinoid process. TOF MRA with 3DR successfully identified the intracranial aneurysms and adequately depicted the surrounding microanatomy. Intraoperative findings were as predicted by the preoperative imaging studies. The aneurysms were successfully clip-obliterated, and the patients had uneventful post-operative courses. These cases demonstrate that non-contrast imaging is a viable modality to assess intracranial aneurysms as part of the surgical planning process in patients with contrast contraindications. TOF MRA with 3DR, in conjunction with high-resolution non-contrast CT when indicated, provides adequate visualization of the microanatomy of the aneurysm and surrounding structures.
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Defining the Accuracy of Secretin Pancreatic Function Testing in Patients With Suspected Early Chronic Pancreatitis
The American Journal of Gastroenterology.
May, 2013 |
Pubmed ID: 23711627 OBJECTIVES:The diagnosis of chronic pancreatitis in patients with characteristic symptoms but normal pancreatic imaging is challenging. Assessment of pancreatic function through secretin pancreatic function testing (SPFT) has been advocated in this setting, but its diagnostic accuracy is not fully known.METHODS:This was a retrospective review of patients who received SPFT at our tertiary care institution between January 1995 and December 2008 for suspected chronic pancreatitis. For all patients, medical records were reviewed for evidence of subsequent development of chronic pancreatitis by imaging and/or pathology. Patients were then categorized as "true positive" or "true negative" for chronic pancreatitis based on follow-up imaging or histologic evidence.RESULTS:In all, 116 patients underwent SPFT. Of the 27 patients who tested positive, 7 were lost to follow-up. Of the remaining 20 SPFT-positive patients, 9 (45%) developed radiologic or histologic evidence of chronic pancreatitis after a median of 4 years (1-11 years). Of the 89 patients who had negative SPFT testing, 19 were lost to follow-up. Of the remaining 70 patients, 2 were eventually diagnosed with chronic pancreatitis based on subsequent imaging/histology after a median follow-up period of 7 years (3-11 years). The sensitivity of the SPFT in diagnosing chronic pancreatitis was 82% with a specificity of 86%. The positive predictive value (PPV) of chronic pancreatitis was 45% with a negative predictive value (NPV) of 97%.CONCLUSIONS:In patients with suspected early chronic pancreatitis and normal pancreatic imaging, SPFT is highly accurate at ruling out early chronic pancreatitis with a NPV of 97%.Am J Gastroenterol advance online publication, 28 May 2013; doi:10.1038/ajg.2013.148.
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Regulatory B-cell Compartment in Transfused Alloimmunized and Non-alloimmunized Patients with Sickle Cell Disease
American Journal of Hematology.
Sep, 2013 |
Pubmed ID: 23720018 Transfusion therapy is a life-sustaining treatment for patients with sickle cell disease (SCD), but can cause serious complications including alloimmunization. We previously reported diminished regulatory T cells (Tregs) and skewed Th2 responses in alloimmunized SCD patients. We hypothesized that the B cell regulatory (Breg) compartment, which controls Treg and Th differentiation, may also be compromised in allosensitized SCD patients. Phenotypically, we did not find differences in the frequency or numbers of CD24(hi) CD38(hi) and CD24(hi) CD27(+) B cell subsets, both previously identified as human Bregs, between alloimmunized and non-alloimmunized SCD patients on regular transfusions. However, at the functional level, CD19+ B cells from alloimmunized SCD patients expressed lower levels of IL-10 following stimulation as compared with non-alloimmunized patients (P < 0.05), and had reduced ability in inhibiting autologous CD14+ monocyte TNF-α expression (P < 0.05). These findings suggest that Bregs from alloimmunized and non-alloimmunized SCD patients differ in their ability to produce IL-10 and dampen monocyte activation, all consistent with an altered immunoregulatory state in alloimmunized SCD patients. Am. J. Hematol. 88:736-740, 2013. © 2013 Wiley Periodicals, Inc.
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MR Characterization of Hepatic Storage Iron in Transfusional Iron Overload
Journal of Magnetic Resonance Imaging : JMRI.
May, 2013 |
Pubmed ID: 23720394 PURPOSE: To quantify the two principal forms of hepatic storage iron, diffuse, soluble iron (primarily ferritin), and aggregated, insoluble iron (primarily hemosiderin) using a new MRI method in patients with transfusional iron overload. MATERIALS AND METHODS: Six healthy volunteers and 20 patients with transfusion-dependent thalassemia syndromes and iron overload were examined. Ferritin- and hemosiderin-like iron were determined based on the measurement of two distinct relaxation parameters: the "reduced" transverse relaxation rate, RR2 , and the "aggregation index," A, using three sets of Carr-Purcell-Meiboom-Gill (CPMG) datasets with different interecho spacings. Agarose phantoms, simulating the relaxation and susceptibility properties of tissue with different concentrations of dispersed (ferritin-like) and aggregated (hemosiderin-like) iron, were used for validation. RESULTS: Both phantom and in vivo human data confirmed that transverse relaxation components associated with the dispersed and aggregated iron could be separated using the two-parameter (RR2 , A) method. The MRI-determined total hepatic storage iron was highly correlated (r = 0.95) with measurements derived from biopsy or biosusceptometry. As total hepatic storage iron increased, the proportion stored as aggregated iron became greater. CONCLUSION: This method provides a new means for noninvasive MRI determination of the partition of hepatic storage iron between ferritin and hemosiderin in iron overload disorders. J. Magn. Reson. Imaging 2013;. © 2013 Wiley Periodicals, Inc.
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Diagnostic Potential of Iris Cross-sectional Imaging in Albinism Using Optical Coherence Tomography
Ophthalmology.
May, 2013 |
Pubmed ID: 23725737 PURPOSE: To characterize in vivo anatomic abnormalities of the iris in albinism compared with healthy controls using anterior segment optical coherence tomography (AS-OCT) and to explore the diagnostic potential of this technique for albinism. We also investigated the relationship between iris abnormalities and other phenotypical features of albinism. DESIGN: Prospective cross-sectional study. PARTICIPANTS: A total of 55 individuals with albinism and 45 healthy controls. METHODS: We acquired 4.37×4.37-mm volumetric scans (743 A-scans, 50 B-scans) of the nasal and temporal iris in both eyes using AS-OCT (3-μm axial resolution). Iris layers were segmented and thicknesses were measured using ImageJ software. Iris transillumination grading was graded using Summers and colleagues' classification. Retinal OCT, eye movement recordings, best-corrected visual acuity (BCVA), visual evoked potential (VEP), and grading of skin and hair pigmentation were used to quantify other phenotypical features associated with albinism. MAIN OUTCOME MEASURES: Iris AS-OCT measurements included (1) total iris thickness, (2) stroma/anterior border (SAB) layer thickness, and (3) posterior epithelial layer (PEL) thickness. Correlation with other phenotypical measurements, including (1) iris transillumination grading, (2) retinal layer measurements at the fovea, (3) nystagmus intensity, (4) BCVA, (5) VEP asymmetry, (6) skin pigmentation, and (7) hair pigmentation (of head hair, lashes, and brows). RESULTS: The mean iris thickness was 10.7% thicker in controls (379.3±44.0 μm) compared with the albinism group (342.5±52.6 μm; P>0.001), SAB layers were 5.8% thicker in controls (315.1±43.8 μm) compared with the albinism group (297.7±50.0 μm; P=0.044), and PEL was 44.0% thicker in controls (64.1±11.7 μm) compared with the albinism group (44.5±13.9 μm; P
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Self-nanoemulsifying Drug Delivery System of Glimepiride: Design, Development, and Optimization
PDA Journal of Pharmaceutical Science and Technology / PDA.
May, 2013 |
Pubmed ID: 23752748 The objective of the present investigation was to develop and characterize the self-nanoemulsifying drug delivery system (SNEDDS) of glimepiride, a poorly soluble drug. Solubility of glimepiride in various vehicles was determined, and ternary phase diagrams were constructed using a suitable oil, surfactant, and cosurfactant system to find out the efficient self-emulsification system. A three factor, three level Box-Behnken statistical design was employed to explore the main and interaction effect of independent variables, namely X1 (amount of Capmul MCM), X2 (amount of Acrysol K 140), and X3 (amount of Transcutol P). Percent transmittance value (Y1), droplet diameter (Y2), and percent drug released at 5 min (Y3) were the dependent variables. Formulation optimization was carried out to optimize the droplet diameter and percent drug dissolved at 5 min. The batch prepared according to the optimized formulation showed a close agreement between observed and predicted values. Box-Behnken statistical design allowed us to understand the effect of formulation variables on the rapid dissolution of drug from SNEDDS and to optimize the formulation to obtain a rapid drug dissolution at 5 min.
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Sickle Cell Disease: Time for a Closer Look at Treatment Options?
British Journal of Haematology.
Aug, 2013 |
Pubmed ID: 23772687 Tremendous progress has been made in the care of individuals with sickle cell over the past several decades. Major successes have been comprehensive infection prophylaxis, prediction and prevention of stroke, and better transfusion care, the latter including both prevention of alloimmunization and treatment of iron overload. However, definitive therapies remain limited to hydroxycarbamide (hydroxyurea) and stem cell transplantation, both of which have been in use for at least two decades. Despite knowing the progressive natural history of the disease with organ dysfunction, failure, and ultimately death at a young age, definitive therapies are considered for only a small proportion of individuals. Consequently, while life expectancy has improved dramatically from the last century, the ongoing pace of advancement has slowed or stalled. We believe that it is time to broaden the use of definitive therapy for those with asymptomatic disease, being cautiously more aggressive in our approach.
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Chromosomal Imbalance Letter: Phenotypic Consequences of Combined Deletion 8pter and Duplication 15qter
Molecular Cytogenetics.
Jul, 2013 |
Pubmed ID: 23815819 Exact breakpoint determination by oligonucleotide array-CGH has improved the analysis of genotype-phenotype correlations in cases with chromosome aberrations allowing a more accurate definition of relevant genes, particularly their isolated or combined impact on the phenotype in an unbalanced state. Chromosomal imbalances have been identified as one of the major causes of mental retardation and/or malformation syndromes and they are observed in ~2-5 % of the cases. Here we report a female child born to non-consanguineous parents and having multiple congenital anomalies such as atrial septal defect and multiple ventricular septal defects, convergent strabismus, micropthalmia, seizures and mental retardation, with her head circumference and stature normal for her age. Cytogenetic study suggested 46,XX,add(8)(p23). Further analysis by array-CGH using 44 K oligonucleotide probe confirmed deletion on 8p23.3p23.1 of 7.1 Mb and duplication involving 15q23q26.3 of 30 Mb size leading to 46XX,der(8)t(8;15)(p23.3;q23)pat.arr 8p23.3p23.1(191,530-7,303,237)x1,15q23q26.3(72,338,961-102,351,195)x3. The unique phenotypic presentation in our case may have resulted from either loss or gain of a series of contiguous genes which may have resulted in a direct phenotypic effect and/or caused a genetic regulatory disturbance. Double segmental aberrations may have conferred phenotypic variability, as in our case, making it difficult to predict the characteristics that evolved as a result of the global gene imbalance, caused by the concomitant deletion and duplication.
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Burden of Lysosomal Storage Disorders in India: Experience of 387 Affected Children from a Single Diagnostic Facility
JIMD Reports.
Jul, 2013 |
Pubmed ID: 23852624 Lysosomal storage disorders (LSDs) are considered to be a rare metabolic disease for the national health forum, clinicians, and scientists. This study aimed to know the prevalence of different LSDs, their geographical variation, and burden on the society. It included 1,110 children from January 2002 to December 2012, having coarse facial features, hepatomegaly or hepatosplenomegaly, skeletal dysplasia, neuroregression, leukodystrophy, developmental delay, cerebral-cerebellar atrophy, and abnormal ophthalmic findings. All subjects were screened for I-cell disease, glycolipid storage disorders (Niemann-Pick disease A/B, Gaucher), and mucopolysaccharide disorders followed by confirmatory lysosomal enzymes study from leucocytes and/or fibroblasts. Niemann-Pick disease-C (NPC) was confirmed by fibroblasts study using filipin stain. Various storage disorders were detected in 387 children (34.8 %) with highest prevalence of glycolipid storage disorders in 48 %, followed by mucopolysaccharide disorders in 22 % and defective sulfatide degradation in 14 % of the children. Less common defects were glycogen degradation defect and protein degradation defect in 5 % each, lysosomal trafficking protein defect in 4 %, and transport defect in 3 % of the patients. This study demonstrates higher incidence of Gaucher disease (16 %) followed by GM2 gangliosidosis that includes Tay-Sachs disease (10 %) and Sandhoff disease (7.8 %) and mucopolysaccharide disorders among all LSDs. Nearly 30 % of the affected children were born to consanguineous parents and this was higher (72 %) in children with Batten disease. Our study also demonstrates two common mutations c.1277_1278insTATC in 14.28 % (4/28) and c.964G>T (p.D322Y) in 10.7 % (3/28) for Tay-Sachs disease in addition to the earlier reported c.1385A>T (p.E462V) mutation in 21.42 % (6/28).
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PREDOSE: A Semantic Web Platform for Drug Abuse Epidemiology Using Social Media
Journal of Biomedical Informatics.
Jul, 2013 |
Pubmed ID: 23892295 The role of social media in biomedical knowledge mining, including clinical, medical and healthcare informatics, prescription drug abuse epidemiology and drug pharmacology, has become increasingly significant in recent years. Social media offers opportunities for people to share opinions and experiences freely in online communities, which may contribute information beyond the knowledge of domain professionals. This paper describes the development of a novel semantic web platform called PREDOSE (PREscription Drug abuse Online Surveillance and Epidemiology), which is designed to facilitate the epidemiologic study of prescription (and related) drug abuse practices using social media. PREDOSE uses web forum posts and domain knowledge, modeled in a manually created Drug Abuse Ontology (DAO - pronounced dow), to facilitate the extraction of semantic information from User Generated Content (UGC), through combination of lexical, pattern-based and semantics-based techniques. In a previous study, PREDOSE was used to obtain the datasets from which new knowledge in drug abuse research was derived. Here, we report on various platform enhancements, including an updated DAO, new components for relationship and triple extraction, and tools for content analysis, trend detection and emerging patterns exploration, which enhance the capabilities of the PREDOSE platform. Given these enhancements, PREDOSE is now more equipped to impact drug abuse research by alleviating traditional labor-intensive content analysis tasks.
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The Influence of Initial Atomized Droplet Size on Residual Particle Size from Pressurized Metered Dose Inhalers
International Journal of Pharmaceutics.
Oct, 2013 |
Pubmed ID: 23911912 Pressurized metered dose inhalers (pMDIs) are widely used for the treatment of diseases of the lung, including asthma and chronic obstructive pulmonary disease. The mass median aerodynamic diameter of the residual particles (MMADR) delivered from a pMDI plays a key role in determining the amount and location of drug deposition in the lung and thereby the efficacy of the inhaler. The mass median diameter of the initial droplets (MMDI), upon atomization of a formulation, is a significant factor influencing the final particle size. The purpose of this study was to evaluate the extent that MMDI and initial droplet geometric standard deviation (GSD) influence the residual aerodynamic particle size distribution (APSDR) of solution and suspension formulations. From 48 solution pMDI configurations with varying ethanol concentrations, valve sizes and actuator orifice diameters, it was experimentally found that the effective MMDI ranged from 7.8 to 13.3μm. Subsequently, computational methods were utilized to determine the influence of MMDI on MMADR, by modulating the MMDI for solution and suspension pMDIs. For solution HFA-134a formulations of 0.5% drug in 10% ethanol, varying the MMDI from 7.5 to 13.5μm increased the MMADR from 1.4 to 2.5μm. For a suspension formulation with a representative particle size distribution of micronized drug (MMAD=2.5μm, GSD=1.8), the same increase in MMDI resulted in an increase in the MMADR from 2.7 to only 3.3μm. Hence, the same increase in MMDI resulted in a 79% increase in MMADR for the solution formulation compared to only a 22% increase for the suspension formulation. Similar trends were obtained for a range of drug concentrations and input micronized drug sizes. Thus, APSDR is more sensitive to changes in MMDI for solution formulations than suspension formulations; however, there are situations in which hypothetically small micronized drug in suspension (e.g. 500nm MMAD) could resemble trends observed for solution formulations. Furthermore, the relationship between APSDR and drug concentration and MMDI is predictable for solution pMDIs, but this is not as straightforward for suspension formulations. In addition, the MMADR was relatively insensitive to changes in initial droplet GSD (from 1.6 to 2.0) and the solution and suspension pMDI residual particle GSDs were essentially identical to the initial droplet GSDs.
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"Self-regulation," a New Facet of Hox Genes' Function
Developmental Dynamics : an Official Publication of the American Association of Anatomists.
Jul, 2013 |
Pubmed ID: 23913823 Background: Precise temporal and spatial expression of the clustered Hox genes is essential for patterning the developing embryo. Temporal activation of Hox genes was shown to be cluster-autonomous. However, gene clustering appears dispensable for spatial colinear expression. Generally, a set of Hox genes expressed in a group of cells instructs these cells about their fate such that the differential expression of Hox genes results in morphological diversity. The spatial colinearity is considered to rely both on local and long-range cis regulation. Results: Here, we report on the global deregulation of HoxA and HoxD expression patterns upon inactivation of a subset of HOXA and HOXD proteins. Conclusions: Our data suggest the existence of a "self-regulation" mechanism, a process by which HOX proteins establish and/or maintain the spatial domains of the Hox gene family and we propose that the functionally dominant HOX proteins could contribute to generating the spatial parameters of Hox expression in a given tissue, i.e., HOX controlling the establishment of the ultimate HOX code. Developmental Dynamics, 2013. © 2013 Wiley Periodicals, Inc.
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Interaction of Finger Representations in the Cortex of Individuals with Autism: A Functional Window into Cortical Inhibition
Autism Research : Official Journal of the International Society for Autism Research.
Aug, 2013 |
Pubmed ID: 23983203 An established neural biomarker of autism spectrum disorder (ASD) has the potential to provide novel biological and pharmacological targets for treatment. Lower level of inhibition in brain circuits is a leading biomarker candidate. A physiological investigation of the functional levels of inhibition in the cortex of individuals with autism can provide a strong test of the hypothesis. The amplitude of cortical response to the stimulation of adjacent fingers is controlled by the level of cortical inhibition and provides just such a test. Using magnetoencephalography, we recorded the response of the somatosensory cortex to the passive tactile stimulation of the thumb (D1), and index finger (D2), and to the simultaneous stimulation of both fingers combined (D1,D2) of the dominant (right) hand of young subjects with and without autism. For each participant, we measured the response to the stimulation of both fingers combined (D1,D2) relative to the post hoc sum of the responses to the stimulation of each finger alone (D1+D2) in multiple different ways and linearly regressed the ASD and neurotypical (NT) groups' responses. The resulting slopes were then compared: Smaller slope values imply attenuated response to paired finger stimulation, and enhanced levels of inhibition. The short-latency M40 and mid-latency M80 response slopes of the group with autism obtained in different ways were either significantly smaller, or statistically indistinguishable from NT. The result does not support reduced inhibition in the somatosensory cortex of individuals with autism, contrary to the seminal hypothesis of reduced inhibition. Implications are discussed including refinements of current theory. Autism Res 2013, â—â—: â—â—-â—â—. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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The Incidence of Complications in Elective Cranial Neurosurgery Associated with Dural Closure Material
Journal of Neurosurgery.
Sep, 2013 |
Pubmed ID: 24032702 Object Dural closure with synthetic grafts has been suggested to contribute to the incidence of infection and CSF leak. The objective of this study was to assess the contribution of choice of dural closure material, as well as other factors, to the incidence of infection and CSF leak. Methods A retrospective, consecutive cohort study of adult patients undergoing elective craniotomy was established between April 2010 and March 2011 at a single center. Exclusion criteria consisted of trauma, bur hole placement alone, and temporary CSF fluid diversion. Results Three hundred ninety-nine patients were included (mean follow-up 396.6 days). Nonautologous (synthetic) dural substitute was more likely to be used (n = 106) in cases of reoperation (p = 0.001). Seventeen patients developed a surgical site infection and 12 patients developed a CSF leak. Multivariate logistic regression modeling identified estimated blood loss (OR 1.002, 95% CI 1.001-1.003; p < 0.001) and cigarette smoking (OR 2.198, 95% CI 1.109-4.238; p = 0.019) as significant predictors of infection. Synthetic dural graft was not a predictor of infection in multivariate analysis. Infratentorial surgery (OR 4.348, 95% CI 1.234-16.722; p = 0.024) and more than 8 days of postoperative corticosteroid treatment (OR 3.886, 95% CI 1.052-16.607; p = 0.048) were significant predictors for the development of CSF leak. Synthetic dural graft was associated with a lower likelihood of CSF leak (OR 0.072, 95% CI 0.003-0.552; p = 0.036). Conclusions The use of synthetic dural closure material is not associated with surgical site infection and is associated with a reduced incidence of CSF leak. Modifiable risk factors exist for craniotomy complications that warrant vigilance and further study.
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Use of Brain Electrical Activity for the Identification of Hematomas in Mild Traumatic Brain Injury
Journal of Neurotrauma.
Sep, 2013 |
Pubmed ID: 24040943 Abstract This study investigates the potential clinical utility in the emergency department (ED) of an index of brain electrical activity to identify intracranial hematomas. The relationship between this index and depth, size, and type of hematoma was explored. Ten minutes of brain electrical activity was recorded from a limited montage in 38 adult patients with traumatic hematomas (CT scan positive) and 38 mild head injured controls (CT negative) in the ED. The volume of blood and distance from recording electrodes were measured by blinded independent experts. Brain electrical activity data was submitted to a classification algorithm independently developed TBI-Index to identify the probability of a CT+ traumatic event. There was no significant relationship between the TBI-index and type of hematoma, or distance of the bleed from recording sites. A significant correlation was found between TBI-Index and blood volume. Sensitivity to hematomas was 100%, positive predictive value (PPV) was 74.5%, and positive likelihood ratio (PLR) was 2.92. The TBI-index, derived from brain electrical activity, demonstrates high accuracy for identification of traumatic hematomas. Further, this was not influenced by distance of the bleed from the recording electrodes, blood volume, or type of hematoma. Distance and volume limitations noted with other methods, (such as that based on near-infrared spectroscopy, NIS), were not found, thus suggesting the TBI-Index to be a potentially important adjunct to acute assessment of head injury. Due to the life threatening risk of undetected hematomas (false negatives), specificity was permitted to be lower, 66%, in exchange for extremely high sensitivity.
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A Strategy for the Generation, Characterization and Distribution of Animal Models by The Michael J. Fox Foundation for Parkinson's Research
Disease Models & Mechanisms.
Sep, 2013 |
Pubmed ID: 24046356 Progress in Parkinson's disease (PD) research and therapeutic development is hindered by many challenges, including a need for robust preclinical animal models. Limited availability of these tools is due to technical hurdles, patent issues, licensing restrictions and the high costs associated with generating and distributing these animal models. Furthermore, the lack of standardization of phenotypic characterization and use of varying methodologies has made it difficult to compare outcome measures across laboratories. In response, The Michael J. Fox Foundation for Parkinson's Research (MJFF) is directly sponsoring the generation, characterization and distribution of preclinical rodent models, enabling increased access to these crucial tools in order to accelerate PD research. To date, MJFF has initiated and funded the generation of 30 different models, which include transgenic or knockout models of PD-relevant genes such as Park1 (also known as Park4 and SNCA), Park8 (LRRK2), Park7 (DJ-1), Park6 (PINK1), Park2 (Parkin), VPS35, EiF4G1 and GBA. The phenotypic characterization of these animals is performed in a uniform and streamlined manner at independent contract research organizations. Finally, MJFF created a central repository at The Jackson Laboratory (JAX) that houses both non-MJFF and MJFF-generated preclinical animal models. Funding from MJFF, which subsidizes the costs involved in transfer, rederivation and colony expansion, has directly resulted in over 2500 rodents being distributed to the PD community for research use.
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