tbuckley/cabot-search huggingface dataset:
Advances in the Medical Treatment of Epilepsy
Authors: Carl W. Bazil, Timothy A. Pedley
Journal: Annual Review of Medicine (1998)

Treatment options for epilepsy, especially using antiepileptic drugs, have increased substantially in the past five years. Since 1993, four novel antiepileptic drugs have been approved and marketed in the United States: felbamate, gabapentin, lamotrigine, and topiramate. Two others, tiagabine and vigabatrin, are likely to be approved in the near future. For many patients, these agents offer the realistic promise of improved seizure control, often with fewer adverse effects and less significant drug interactions compared with older agents. In addition, fosphenytoin, a water-soluble phenytoin prodrug with a number of advantages over intravenous phenytoin, has been released. There are new administration options for carbamazepine, diazepam, and valproic acid. For drug-resistant or -intolerant patients, there has been renewed interest in alternative therapies, especially the ketogenic diet. Taken together, these represent significant therapeutic advances that are benefiting patients with epilepsy. At the same time, improved understanding of the basic mechanisms of epileptogenesis, and of the cellular and molecular actions of available antiepileptic drugs, creates a framework for designing unique therapeutic strategies that are targeted at key sites of vulnerability involved in the development and maintenance of the epileptic state.
Cysteine scanning analysis of the IFM cluster in the inactivation gate of a human heart sodium channel
Authors: I Deschênes
Journal: Cardiovascular Research (1999)

The conserved isoleucine–phenylalanine–methionine (IFM) hydrophobic cluster located in the III–IV linker of voltage-gated sodium channels has been identified as a major component of the fast inactivation gate in these channels. Objectives: The aim of our study was to probe the contribution of each amino acids of the IFM cluster to the inactivation. Methods: A combination of site-directed mutagenesis, cysteine covalent modification and electrophysiological recording techniques were used to elucidate the role of isoleucine1485 and methionine1487 on hH1 sodium channels expressed in tsA20l cells. Results: Mutant I1485C behaves like mutant F1486C studied earlier: producing an incomplete inactivation (residual current), a slowing and change in the voltage-dependence of the time constants of current decay, a shift of the steady-state inactivation to more depolarized voltages, and a faster recovery from inactivation than the wild-type hH1. The electrophysiological parameters of mutant M1487C are similar to those of wild-type hH1 except for the presence of a residual current. Exposure of the cytoplasmic surface of the mutants to MTS reagents MTSES, MTSET and MTSBn further disrupted inactivation. In order to explain differences in the amplitude of the sustained currents recorded in the presence of MTSES or MTSET, we studied the effects of exposure of mutants I1485C, F1486C and M1487C to acidic and basic pH in the absence and presence of MTSES and MTSET. The effects of MTSES [negatively charged (−)] and MTSET (+) on the amplitude of the residual current of mutant F1486C were modulated by changes in intracellular pH. Conclusion: Isoleucine1487 and methionine1485, which surround phenylalanine1487 contribute to stabilizing the inactivation particle for fast inactivation.
Principles of Opioid Use in Cancer Pain
Authors: Russell K. Portenoy, Ebtesam Ahmed
Journal: Journal of Clinical Oncology (2014)

The management of pain is an essential aspect of comprehensive cancer care. Positive outcomes can be achieved in most patients with widely available therapies. There is a broad consensus that opioid-based pharmacotherapy is the first-line strategy for the treatment of moderate or severe chronic pain in populations with active disease, and treatment guidelines have been developed from the known pharmacology of these drugs, extant data, and extensive clinical experience. This article describes the major opioid analgesics available for the treatment of cancer-related pain and reviews the key elements for safe and effective prescribing, including selection of the best drug and route, approaches to titration and long-term administration of baseline and supplemental doses, rotation from one drug to another in poorly responsive patients, and management of opioid risks.
Controlled Clinical Trial of Interpersonal Psychotherapy Versus Parenting Education Program for Depressed Pregnant Women
Authors: Margaret G. Spinelli, Jean Endicott
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Antenatal depression is a significant risk factor for postpartum depression, with a 10%–12% prevalence in all pregnancies. Rates of depression are higher for pregnant women with chronic stressors, financial and housing problems, and inadequate social support. Despite the prevalence and associated family and infant morbidity, there are no controlled clinical treatment trials regarding this topic, to the authors' knowledge. APA has identified treatment of depression during pregnancy as a priority for clinical guidelines. METHOD: A 16-week bilingual controlled clinical trial compared a group receiving interpersonal psychotherapy for antepartum depression to a parenting education control program. Fifty outpatient antepartum women who met DSM-IV criteria for major depressive disorder were randomly assigned to interpersonal psychotherapy or a didactic parenting education program. Thirty-eight women remained in the study and were included in the data analysis. Depressed mood was measured with the Edinburgh Postnatal Depression Scale, the Beck Depression Inventory, and the Hamilton Depression Rating Scale. The Clinical Global Impression (CGI) and the Hamilton depression scale measured recovery. RESULTS: The interpersonal psychotherapy treatment group showed significant improvement compared to the parenting education control program on all three measures of mood at termination. Recovery criteria were met in 60% of the women treated with interpersonal psychotherapy, according to a CGI score of ≤2. In addition, there was a significant correlation between maternal mood and mother-infant interaction. CONCLUSIONS: Interpersonal psychotherapy is an effective method of antidepressant treatment during pregnancy and should be a first-line treatment in the hierarchy of treatment for antepartum depression.
Cerebral Blood Flow In Man at High Altitude
Authors: JOHN W. SEVERINGHAUS, HUGO CHIODI, E. I. EGER II, BERNARD BRANDSTATER, THOMAS F. HORNBEIN
Journal: Circulation Research (1966)

Cerebral blood flow was determined by an N 2 O method in 7 normal men at sea level and after 6 to 12 hr and 3 to 5 days at 3810 m altitude. An infrared N 2 O analyzer was used both to measure end-tidal PN 2 O so that it could be kept constant for 15 min and to determine blood N 2 O, for which a simple gas extraction method was devised. In addition, acute changes in cerebral blood flow were estimated from cerebral A-V O 2 differences. Control cerebral blood flow was 43 ml per 100 g per min; it increased 24% at 6 to 12 hours and 13% at 3 to 5 days at altitude. After 3 to 5 days, pH of cerebrospinal fluid was normal (7.31) in four subjects while arterial blood pH was alkaline (7.47); arterial blood Pco 2 had fallen from 41 to 30 mm Hg. Acute correction of hypoxia restored cerebral blood flow to control while mean Pco 2 was still 31 mm Hg. Addition of O 2 and CO 2 to inspired air raised cerebral blood flow 34% above control at Pao 2 = 170, Paco 2 = 35 mm Hg. Values obtained by extrapolation suggest that if arterial Pco 2 was raised to control (41 mm Hg), cerebral blood flow would have been 60% above control. Cerebral blood flow thus appears to return to normal at the prevailing Paco 2 , probably because the pH of cerebrospinal fluid and of the extracellular fluid of cerebral vascular smooth muscle is kept normal by active transport across the ‘blood-brain’ barrier. It is postulated that an ion-impermeable barrier separates the blood stream from extracellular fluid of the smooth muscle of cerebral arterioles.
Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study
Authors: C J Hawkey
Journal: Gut (2003)

<b>Background:</b> Previous studies in patients with osteoarthritis have suggested that the selective cyclooxygenase (COX)-2 inhibitor rofecoxib results in less gastrointestinal damage than non-selective non-steroidal antiinflammatory drugs (NSAIDs). This study compared the incidence of endoscopically detected gastroduodenal ulcers in rheumatoid arthritis patients treated with rofecoxib or a non-selective NSAID. <b>Methods:</b> In this multicentre, randomised, double blind, 12 week study, patients with rheumatoid arthritis were allocated to rofecoxib 50 mg once daily (n=219), naproxen 500 mg twice daily (n=220), or placebo (n=221). Endoscopy was performed at baseline and at six and 12 weeks. Lifetable analysis and log rank tests were used to analyse the incidence of gastroduodenal ulcers ≥3 mm. Gastric or duodenal ulcers ≥5 mm and erosions were also evaluated as secondary end points. Tolerability was assessed by adverse events. <b>Results:</b> The cumulative incidence of ulcers ≥3 mm at 12 weeks was significantly higher in patients on naproxen (25.5%) than in patients receiving rofecoxib (6.8%; difference 18.7% (95% confidence interval (CI) 11.7%, 25.7%); p&lt;0.001) or placebo (2.9%; difference 22.6% (95% CI 16.1%, 29.1%); p&lt;0.001). The difference between rofecoxib (6.8%) and placebo (2.9%) did not reach statistical significance (p=0.066). Results were similar for ulcers ≥5 mm and for mean changes from baseline in the number of gastroduodenal erosions. The overall incidence of clinical adverse events was similar among treatment groups (61% of patients on placebo, 62% in patients on rofecoxib, and 66% in patients on naproxen). <b>Conclusions:</b> Rofecoxib 50 mg daily (twice the dose recommended for this patient population) resulted in a lower incidence of endoscopically detected gastroduodenal ulcers and erosions than treatment with naproxen 500 mg twice daily.
Racial and Ethnic Health Disparities among Fifth-Graders in Three Cities
Authors: Mark A. Schuster, Marc N. Elliott, David E. Kanouse, Jan L. Wallander, Susan R. Tortolero, Jessica A. Ratner, David J. Klein, Paula M. Cuccaro, Susan L. Davies, Stephen W. Banspach
Journal: New England Journal of Medicine (2012)

For many health-related behaviors and outcomes, racial and ethnic disparities among adolescents are well documented, but less is known about health-related disparities during preadolescence.
Evidence for the biogenesis of more than 1,000 novel human microRNAs
Authors: Marc R Friedländer, Esther Lizano, Anna JS Houben, Daniela Bezdan, Mónica Báñez-Coronel, Grzegorz Kudla, Elisabet Mateu-Huertas, Birgit Kagerbauer, Justo González, Kevin C Chen, Emily M LeProust, Eulàlia Martí, Xavier Estivill
Journal: Genome biology (2014)

Abstract Background MicroRNAs (miRNAs) are established regulators of development, cell identity and disease. Although nearly two thousand human miRNA genes are known and new ones are continuously discovered, no attempt has been made to gauge the total miRNA content of the human genome. Results Employing an innovative computational method on massively pooled small RNA sequencing data, we report 2,469 novel human miRNA candidates of which 1,098 are validated by in-house and published experiments. Almost 300 candidates are robustly expressed in a neuronal cell system and are regulated during differentiation or when biogenesis factors Dicer, Drosha, DGCR8 or Ago2 are silenced. To improve expression profiling, we devised a quantitative miRNA capture system. In a kidney cell system, 400 candidates interact with DGCR8 at transcript positions that suggest miRNA hairpin recognition, and 1,000 of the new miRNA candidates interact with Ago1 or Ago2, indicating that they are directly bound by miRNA effector proteins. From kidney cell CLASH experiments, in which miRNA-target pairs are ligated and sequenced, we observe hundreds of interactions between novel miRNAs and mRNA targets. The novel miRNA candidates are specifically but lowly expressed, raising the possibility that not all may be functional. Interestingly, the majority are evolutionarily young and overrepresented in the human brain. Conclusions In summary, we present evidence that the complement of human miRNA genes is substantially larger than anticipated, and that more are likely to be discovered in the future as more tissues and experimental conditions are sequenced to greater depth.
Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells
Authors: Fiona J. Clark, Richard Gregg, Karen Piper, Debbie Dunnion, Lisa Freeman, Mike Griffiths, Gulnaz Begum, Premini Mahendra, Charles Craddock, Paul Moss, Ronjon Chakraverty
Journal: Blood (2003)
Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK
Authors: Klaus Dittmann, Claus Mayer, Rainer Kehlbach, H Peter Rodemann
Journal: Molecular Cancer (2008)

To elucidate the role of src kinase in caveolin-1 driven internalization and nuclear transport of EGFR linked to regulation of DNA-repair in irradiated cells.Ionizing radiation resulted in src kinase stabilization, activation and subsequent src mediated caveolin-1 Y14- and EGFR Y845-phosphorylations. Both phosphorylations were radiation specific and could not be observed after treatment with EGF. Inhibition of EGFR by the antibody Erbitux resulted in a strong accumulation of caveolin/EGFR complexes within the cytoplasm, which could not be further increased by irradiation. Radiation-induced caveolin-1- and EGFR-phosphorylations were associated with nuclear EGFR transport and activation of DNA-PK, as detected by phosphorylation at T2609. Blockage of src activity by the specific inhibitor PP2, decreased nuclear transport of EGFR and inhibited caveolin-1- and DNA-PK-phosphorylation. Knockdown of src by specific siRNA blocked EGFR phosphorylation at Y845, phosphorylation of caveolin-1 at Y14 and abolished EGFR transport into the nucleus and phosphorylation of DNA-PK. Consequently, both knockdown of src by specific siRNA and also inhibition of src activity by PP2 resulted in an enhanced residual DNA-damage as quantified 24 h after irradiation and increased radiosensitivity.Src kinase activation following irradiation triggered caveolin-1 dependent EGFR internalization into caveolae. Subsequently EGFR shuttled into the nucleus. As a consequence, inhibition of internalization and nuclear transport of EGFR blocked radiation-induced phosphorylation of DNA-PK and hampered repair of radiation-induced double strand breaks.
It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis
Authors: Robert G. Luke, John H. Galla
Journal: Journal of the American Society of Nephrology (2012)

Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO(3)(-) exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis.
Alternatives to warfarin for the treatment of pulmonary emboli: the EINSTEIN-PE Study
Authors: Gareth Hynes
Journal: Thorax (2012)

Alternatives to warfarin for the treatment of pulmonary emboli: the EINSTEIN-PE StudyThe last few years have seen new oral anticoagulant treatments emerge with a major advantage over conventional vitamin K antagonism with warfarin: they have a predictable dose response that negates the need for laboratory monitoring.Dabigatran (Pradaxa), a direct thrombin inhibitor, and rivaroxaban are two such medications licenced for the prevention of stroke in atrial fibrillation.Rivaroxaban (Xiralto) is a direct inhibitor of Factor Xa.The 2011 ROCKET-AF study showed its efficacy in stroke prevention. 1 The EINSTEIN-PE study was designed to compare efficacy and safety of fixed-dose oral rivaroxaban therapy against standard heparin plus warfarin in the treatment of symptomatic pulmonary emboli. 2 This Bayer-sponsored study was randomised, open-label and included 4833 patients, half of whom were given 15 mg rivaroxaban twice daily for 3 weeks, and 20 mg once daily thereafter, and half of whom received long-term warfarin and enoxaparin at 1 mg/ kg until their international normalised ratio (INR) exceeded 2 for 2 days.The primary efficacy outcome of recurrent venous thromboembolism (VTE) occurred in 50 patients (2.1%) taking rivaroxaban and 44 patients (1.8%) with standard therapy.The secondary safety outcome of major bleeding (haemoglobin drop of 2 g/dl; a 2-unit transfusion; or bleeding intracranially, retroperitoneally or contributing to death) occurred in 26 rivaroxaban patients (1.1%) and 52 standard-therapy patients (2.2%).Contraindications to rivaroxaban included creatinine clearance of <30 ml/min, pregnancy and breastfeeding.The authors conclude that this evidence supports the use of rivaroxaban in the treatment of VTE, being as effective as and potentially safer than warfarin therapy.Though dabigatran has been proven similarly effective by the RE-COVER trial, 3 neither rivaroxaban nor dabigatran have yet been licenced for VTE treatment.If they are, choosing between them will be difficult due to the lack of head-to-head trials, though it is worth noting that while both are renally excreted and removable through dialysis, only rivaroxaban has a proven reversal agent, prothrombin complex concentrate, known to immediately and completely reverse its anticoagulant effect.
TARP γ-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity
Authors: Nathalie Rouach, Keith Byrd, Ronald S Petralia, Guillermo M Elias, Hillel Adesnik, Susumu Tomita, Siavash Karimzadegan, Colin Kealey, David S Bredt, Roger A Nicoll
Journal: Nature Neuroscience (2005)
Risk of another basal cell carcinoma developing after treatment of a basal cell carcinoma
Authors: Ashfaq Marghoob, Alfred W. Kopf, Robert S. Bart, Louis Sanfilippo, Mark K. Silverman, Peter Lee, Elie Levy, Katrien A. Vossaert, Sandhya Yadav, Michelle Abadir
Journal: Journal of the American Academy of Dermatology (1993)

Background: There is an increased risk of new basal cell carcinomas (BCCs) developing in a person who has had a BCC. Objective: This study attempts to define the magnitude of this increased risk. Methods: The charts of 260 white patients with a histologically proven BCC were reviewed for the occurrence of new BCCs. The cumulative 5-year incidence (modified life-table method) for new BCCs developing in these patients was compared with the 5-year incidence in the general white population of the United States. Results: Of the 260 patients, new BCCs developed in 137 within an average of 38.3 months, a 5-year cumulative rate of one or more new BCCs of 45.2%. The yearly risk for new BCCs developing in the study population remained high during the 5-year interval. In the general white population of the United States, the maximal 5-year incidence was calculated to be 5% (p < 0.005, chi-square test). Conclusion: Patients with a history of BCC require life-long follow-up because of the high probability of new BCCs developing. Background: There is an increased risk of new basal cell carcinomas (BCCs) developing in a person who has had a BCC. Objective: This study attempts to define the magnitude of this increased risk. Methods: The charts of 260 white patients with a histologically proven BCC were reviewed for the occurrence of new BCCs. The cumulative 5-year incidence (modified life-table method) for new BCCs developing in these patients was compared with the 5-year incidence in the general white population of the United States. Results: Of the 260 patients, new BCCs developed in 137 within an average of 38.3 months, a 5-year cumulative rate of one or more new BCCs of 45.2%. The yearly risk for new BCCs developing in the study population remained high during the 5-year interval. In the general white population of the United States, the maximal 5-year incidence was calculated to be 5% (p < 0.005, chi-square test). Conclusion: Patients with a history of BCC require life-long follow-up because of the high probability of new BCCs developing.
Intellectual Impairment in Children with Blood Lead Concentrations below 10 μg per Deciliter
Authors: Richard L. Canfield, Charles R. Henderson, Deborah A. Cory-Slechta, Christopher Cox, Todd A. Jusko, Bruce P. Lanphear
Journal: New England Journal of Medicine (2003)

Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level.We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders.The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter.Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.