Fenfluramine and phentermine have been individually approved as anorectic agents by the Food and Drug Administration (FDA). When used in combination the drugs may be just as effective as either drug ...alone, with the added advantages of the need for lower doses of each agent and perhaps fewer side effects. Although the combination has not been approved by the FDA, in 1996 the total number of prescriptions in the United States for fenfluramine and phentermine exceeded 18 million.
We identified valvular heart disease in 24 women treated with fenfluramine-phentermine who had no history of cardiac disease. The women presented with cardiovascular symptoms or a heart murmur. As increasing numbers of these patients with similar clinical features were identified, there appeared to be an association between these features and fenfluramine-phentermine therapy.
Twenty-four women (mean +/-SD age, 44+/-8 years) were evaluated 12.3+/-7.1 months after the initiation of fenfluramine-phentermine therapy. Echocardiography demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved. Eight women also had newly documented pulmonary hypertension. To date, cardiac surgical intervention has been required in five patients. The heart valves had a glistening white appearance. Histopathological findings included plaque-like encasement of the leaflets and chordal structures with intact valve architecture. The histopathological features were identical to those seen in carcinoid or ergotamine-induced valve disease.
These cases arouse concern that fenfluramine-phentermine therapy may be associated with valvular heart disease. Candidates for fenfluramine-phentermine therapy should be informed about serious potential adverse effects, including pulmonary hypertension and valvular heart disease.
Approximately 21 million tons of steel industry slag are produced each year in the United States, and many productive commercial uses of slag have been developed (e.g., road bed, fill material). ...However, because slag contains heavy metals at concentrations that are higher than in most soil, questions have been raised regarding the need to evaluate the potential human health and environmental hazards associated with current applications. To enhance general understanding of the physical and chemical characteristics of this material, slag samples from 58 active mills with blast furnaces, basic oxygen furnaces, and/or electric arc furnaces were examined. This study profiles the major and minor constituents of slag from each furnace type and reports the leachability of metals from slag under neutral and acidic conditions. Particle size distributions and partitioning coefficients (K d) are also reported. Although concentrations of metals in slag are elevated relative to concentrations in soil, the metals in slag are tightly bound to the slag matrix and not readily leached. This study represents the most complete characterization of steel industry slag currently produced in North America, encompassing mills that collectively produce over 47% of steel industry slag. These data provide insights that may be useful for evaluating the marketability of steel industry slag and for human and ecological health risk assessment of environmental applications.
Neuronal injury in ischemic stroke is partly mediated by cytotoxic reactive oxygen species. Although the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier (BBB), ...its oxidized form, dehydroascorbic acid (DHA), enters the brain by means of facilitative transport. We hypothesized that i.v. DHA would improve outcome after stroke because of its ability to cross the BBB and augment brain antioxidant levels. Reversible or permanent focal cerebral ischemia was created by intraluminal middle cerebral artery occlusion in mice treated with vehicle, AA, or DHA (40, 250, or 500 mg/kg), either before or after ischemia. Given before ischemia, DHA caused dose-dependent increases in postreperfusion cerebral blood flow, with reductions in neurological deficit and mortality. In reperfused cerebral ischemia, mean infarct volume was reduced from 53% and 59% in vehicle- and AA-treated animals, respectively, to 15% in 250 mg/kg DHA-treated animals (P < 0.05). Similar significant reductions occurred in nonreperfused cerebral ischemia. Delayed postischemic DHA administration after 15 min or 3 h also mediated improved outcomes. DHA (250 mg/kg or 500 mg/kg) administered at 3 h postischemia reduced infarct volume by 6- to 9-fold, to only 5% with the highest DHA dose (P < 0.05). In contrast, AA had no effect on infarct volumes, mortality, or neurological deficits. No differences in the incidence of intracerebral hemorrhage occurred. Unlike exogenous AA, DHA confers in vivo, dose-dependent neuroprotection in reperfused and nonreperfused cerebral ischemia at clinically relevant times. As a naturally occurring interconvertible form of AA with BBB permeability, DHA represents a promising pharmacological therapy for stroke based on its effects in this model of cerebral ischemia.
The purpose of this study was to determine long-term outcome in adults with congenitally corrected transposition of the great arteries (CCTGA), with particular emphasis on systemic ventricular ...dysfunction and congestive heart failure (CHF).
Patients with CCTGA have the anatomical right ventricle as their systemic pumping chamber, with ventricular dysfunction and CHF being relatively common in older adults.
Retrospective analysis of records of 182 patients from 19 institutions were reviewed to determine current status and possible risk factors for systemic ventricular dysfunction and CHF. Factors considered included age, gender, associated cardiac defects, operative history, heart block, arrhythmias and tricuspid (i.e., systemic atrioventricular) regurgitation (TR).
Both CHF and systemic ventricular dysfunction were common in groups with or without associated cardiac lesions. By age 45, 67% of patients with associated lesions had CHF, and 25% of patients without associated lesions had this complication. The rates of systemic ventricular dysfunction and CHF were higher with increasing age, the presence of significant associated cardiac lesions, history of arrhythmia, pacemaker implantation, prior surgery of any type, and particularly with tricuspid valvuloplasty or replacement. Aortic regurgitation (a previously unreported problem) was also relatively common in this patient population.
Patients with CCTGA are increasingly subject to CHF with advancing age; this complication is extremely common by the fourth and fifth decades. Tricuspid (systemic atrioventricular) valvular regurgitation is strongly associated with RV (anatomical right ventricle connected to aorta in CCTGA patients; systemic ventricle in CCTGA) dysfunction and CHF; whether it is causative or a secondary complication remains speculative.
Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ...ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.
A search for the dinucleon decay pp → K+ K+ has been performed using 91.6 kton·yr data from Super-Kamiokande-I. This decay provides a sensitive probe of the R-parity-violating parameter λ112''. A ...boosted decision tree analysis found no signal candidates in the data. The expected background was 0.28±0.19 atmospheric neutrino induced events and the estimated signal detection efficiency was 12.6%±3.2%. A lower limit of 1.7×10(32) years has been placed on the partial lifetime of the decay O16 → C14K+ K+ at 90% C.L. A corresponding upper limit of 7.8×10(-9) has been placed on the parameter λ112''.
Calibration of the Super-Kamiokande detector Abe, K.; Iyogi, K.; Kameda, J. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2014, Letnik:
737
Journal Article
Recenzirano
Odprti dostop
Procedures and results on hardware-level detector calibration in Super-Kamiokande (SK) are presented in this paper. In particular, we report improvements made in our calibration methods for the ...experimental phase IV in which new readout electronics have been operating since 2008.
The topics are separated into two parts. The first part describes the determination of constants needed to interpret the digitized output of our electronics so that we can obtain physical numbers such as photon counts and their arrival times for each photomultiplier tube (PMT). In this context, we developed an in situ procedure to determine high-voltage settings for PMTs in large detectors like SK, as well as a new method for measuring PMT quantum efficiency and gain in such a detector.
The second part describes modeling of the detector in Monte Carlo simulations, including, in particular, the optical properties of the water target and their variability over time. Detailed studies on water quality are also presented.
As a result of this work, we have achieved a precision sufficient for physics analyses over a wide energy range (from a few MeV to above 1TeV). For example, charge determination was at the level of 1%, and the timing resolution was 2.1ns at the one-photoelectron charge level and 0.5ns at the 100-photoelectron charge level.
High risk strains of human papillomavirus (HPV), such as HPV 16, cause human cervical carcinoma. The E6 protein of HPV 16 mediates the rapid degradation of p53, although this is not the only function ...of E6 and cannot completely explain its transforming potential. Previous work in our laboratory has demonstrated that transfection of HPV 16 E6 into the tumor necrosis factor (TNF)-sensitive LM cell line protects expressing cells from TNF-induced apoptosis in a p53-independent manner, and the purpose of this study was to determine the molecular mechanism underlying this protection. Caspase 3 and caspase 8 activation were significantly reduced in E6-expressing cells, indicating that E6 acts early in the TNF apoptotic pathway. In fact, E6 binds directly to TNF R1, as shown both by co-immunoprecipitation and mammalian two-hybrid approaches. E6 requires the same C-terminal portion of TNF R1 for binding as does TNF R1-associated death domain, and TNF R1/TNF R1-associated death domain interactions are decreased in the presence of E6. HA-E6 also blocked cell death triggered by transfection of the death domain of TNF R1. Together, these results provide strong support for a model in which HPV E6 binding to TNF R1 interferes with formation of the death-inducing signaling complex and thus with transduction of proapoptotic signals. They also demonstrate that HPV, like several other viruses, has developed a method for evading the TNF-mediated host immune response.
The possible adverse effects on health of diet-derived advanced glycation endproducts (AGEs) and advanced lipoxidation endproducts (ALEs) is of current interest. This study had the objective of ...determining the effects of the addition of AGE/ALE inhibitors and different types of sugar and cooking oil on N ε-(carboxymethyl)lysine (CML) and N ε-(carboxyethyl)lysine (CEL) formation in model foods (sponge cakes). The cake baked using glucose produced the highest level of CML (2.07 ± 0.24 mmol/mol lysine), whereas the cake baked using fructose produced the highest concentration of CEL (25.1 ± 0.15 mmol/mol lysine). There were no significant differences between CML concentrations formed in the cakes prepared using different types of cooking oil, but significant differences (P < 0.001) were observed between the cakes prepared using different proportions of cooking oil. The cakes containing oil generated greater concentrations of CML than sucrose. α-Tocopherol and rutin did not inhibit CML and CEL formation. In contrast, ferulic acid and thiamin, thiamin monophosphate, and thiamin pyrophosphate reduced CML and CEL formation.
Combined with measurements made by very-long-baseline interferometry, the observations of fast TeV gamma-ray flares probe the structure and emission mechanism of blazar jets. However, only a handful ...of such flares have been detected to date, and only within the last few years have these flares been observed from lower-frequency-peaked BL Lac objects and flat-spectrum radio quasars. We report on a fast TeV gamma-ray flare from the blazar BL Lacertae observed by the Very Energetic Radiation Imaging Telescope Array System (VERITAS). with a rise time of ∼2.3 hr and a decay time of ∼36 min. The peak flux above 200 GeV is (4.2 0.6) × 10−6 photon m−2 s−1 measured with a 4-minute-binned light curve, corresponding to ∼180% of the flux that is observed from the Crab Nebula above the same energy threshold. Variability contemporaneous with the TeV gamma-ray flare was observed in GeV gamma-ray, X-ray, and optical flux, as well as in optical and radio polarization. Additionally, a possible moving emission feature with superluminal apparent velocity was identified in Very Long Baseline Array observations at 43 GHz, potentially passing the radio core of the jet around the time of the gamma-ray flare. We discuss the constraints on the size, Lorentz factor, and location of the emitting region of the flare, and the interpretations with several theoretical models that invoke relativistic plasma passing stationary shocks.
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