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Sample records for advanced disease phase

  1. [Phase-II-study with vindesine (desacetyl-vinblastine-amide-sulfate) in advanced malignant diseases].

    PubMed

    Goldhirsch, A; Beer, M; Sonntag, R W; Tschopp, L; Cavalli, F; Ryssel, H J; Brunner, K W

    1980-07-08

    53 patients with advanced and measurable cancerr were treated with vindesine in doses of 3 mg/m2 (pretreated) and 4 mg/m2 (non pretreated) i.v. once weekly. 48 patients are evaluable for response: of 14 patients with squamous cell carcinoma of the lung, 1 partial remission (PR), 1 minor response (MR) and 1 no change (NC) were observed. In 5 patients with large cell carcinoma of the lung: 1 NC. In 3 with adenocarcinoma of the lung: 1 MR. One patient with nasopharyngeal carcinoma had progressive disease. Stable disease was observed in a patient with carcinoma of the tongue and in a patient with adenocarcinoma of the esophagus. Four patients with colorectal carcinoma had progressive disease. One MR was observed in a patient with breast cancer, while all of the other 3 patients had progressive disease. One carcinoma of the penis was stable. One MR was observed in a patient with Hodgkin's disease. One PR was observed in a case with no-Hodgkin's lymphoma. A patient with acute leukemia had progressive disease. Among 9 patients with malignant melanoma, 3 had an MR and 1 patient had stable disease. A patient with fibrosarcoma had progressive disease. Observed toxicity included leukopenia, thrombocytopenia, anemia, paresthesias, constipation, jaw pain, nausea, stomatitis, alopecia, loss of taste, pruritus and skin rash, weakness and fatigue.

  2. Advanced Virgo phase cameras

    NASA Astrophysics Data System (ADS)

    van der Schaaf, L.; Agatsuma, K.; van Beuzekom, M.; Gebyehu, M.; van den Brand, J.

    2016-05-01

    A century after the prediction of gravitational waves, detectors have reached the sensitivity needed to proof their existence. One of them, the Virgo interferometer in Pisa, is presently being upgraded to Advanced Virgo (AdV) and will come into operation in 2016. The power stored in the interferometer arms raises from 20 to 700 kW. This increase is expected to introduce higher order modes in the beam, which could reduce the circulating power in the interferometer, limiting the sensitivity of the instrument. To suppress these higher-order modes, the core optics of Advanced Virgo is equipped with a thermal compensation system. Phase cameras, monitoring the real-time status of the beam constitute a critical component of this compensation system. These cameras measure the phases and amplitudes of the laser-light fields at the frequencies selected to control the interferometer. The measurement combines heterodyne detection with a scan of the wave front over a photodetector with pin-hole aperture. Three cameras observe the phase front of these laser sidebands. Two of them monitor the in-and output of the interferometer arms and the third one is used in the control of the aberrations introduced by the power recycling cavity. In this paper the working principle of the phase cameras is explained and some characteristic parameters are described.

  3. Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.

    PubMed

    Atkins, M B; Gould, J A; Allegretta, M; Li, J J; Dempsey, R A; Rudders, R A; Parkinson, D R; Reichlin, S; Mier, J W

    1986-09-01

    Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone

  4. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease.

    PubMed

    Coleman, Robert; Aksnes, Anne-Kirsti; Naume, Bjørn; Garcia, Camilo; Jerusalem, Guy; Piccart, Martine; Vobecky, Nancy; Thuresson, Marcus; Flamen, Patrick

    2014-06-01

    Radium-223 dichloride (radium-223) mimics calcium and emits high-energy, short-range alpha-particles resulting in an antitumor effect on bone metastases. This open-label, phase IIa nonrandomized study investigated safety and short-term efficacy of radium-223 in breast cancer patients with bone-dominant disease. Twenty-three advanced breast cancer patients with progressive bone-dominant disease, and no longer candidates for further endocrine therapy, were to receive radium-223 (50 kBq/kg IV) every 4 weeks for 4 cycles. The coprimary end points were change in urinary N-telopeptide of type 1 (uNTX-1) and serum bone alkaline phosphatase (bALP) after 16 weeks of treatment. Exploratory end points included sequential (18)F-fluorodeoxyglucose positron emission tomography and computed tomography (FDG PET/CT) to assess metabolic changes in osteoblastic bone metastases. Safety data were collected for all patients. Radium-223 significantly reduced uNTX-1 and bALP from baseline to end of treatment. Median uNTX-1 change was -10.1 nmol bone collagen equivalents/mmol creatinine (-32.8 %; P = 0.0124); median bALP change was -16.7 ng/mL (-42.0 %; P = 0.0045). Twenty of twenty-three patients had FDG PET/CT identifying 155 hypermetabolic osteoblastic bone lesions at baseline: 50 lesions showed metabolic decrease (≥25 % reduction of maximum standardized uptake value from baseline) after 2 radium-223 injections [32.3 % metabolic response rate (mRR) at week 9], persisting after the treatment period (41.5 % mRR at week 17). Radium-223 was safe and well tolerated. Radium-223 targets areas of increased bone metabolism and shows biological activity in advanced breast cancer patients with bone-dominant disease.

  5. Advanced Coats' disease.

    PubMed Central

    Haik, B G

    1991-01-01

    Advanced Coats' disease and retinoblastoma can both present with the triad of a retinal detachment, the appearance of a subretinal mass, and dilated retinal vessels. Thus, even the most experienced observer may not be able to differentiate these entities on ophthalmoscopic findings alone. Coats' disease is the most common reason for which eyes are enucleated with the misdiagnosis of retinoblastoma. Ultrasonography is the auxiliary diagnostic test most easily incorporated into the clinical examination, and can be utilized repeatedly without biologic tissue hazard. Ultrasonically identifiable features allowing differentiation between Coats' disease and retinoblastoma include the topography and character of retinal detachment and presence or absence of subretinal calcifications. Ultrasonography is of lesser use in poorly calcified retinoblastoma and in detecting optic nerve or extraocular extension in heavily calcified retinoblastoma. CT is perhaps the single most valuable test because of its ability to: (a) delineate intraocular morphology, (b) quantify subretinal densities, (c) identify vascularities within the subretinal space through the use of contrast enhancement, and (d) detected associated orbital or intracranial abnormalities. Optimal computed tomographic studies, however, require multiple thin slices both before and after contrast introduction and expose the child to low levels of radiation if studies are repeated periodically. MR imaging is valuable for its multiplanar imaging capabilities, its superior contrast resolution, and its ability to provide insights into the biochemical structure and composition of tissues. It is limited in its ability to detect calcium, which is the mainstay of ultrasonic and CT differentiation. Aqueous LDH and isoenzyme levels were not valuable in distinguishing between Coats' disease and retinoblastoma. The value of aqueous NSE levels in the differentiation of advanced Coats' disease and exophytic retinoblastoma deserves

  6. Phase I clinical trial of cell therapy in patients with advanced chronic obstructive pulmonary disease: follow-up of up to 3 years

    PubMed Central

    Stessuk, Talita; Ruiz, Milton Artur; Greco, Oswaldo Tadeu; Bilaqui, Aldemir; Ribeiro-Paes, Maria José de Oliveira; Ribeiro-Paes, João Tadeu

    2013-01-01

    Background Chronic obstructive pulmonary disease is a major inflammatory disease of the airways and an enormous therapeutic challenge. Within the spectrum of chronic obstructive pulmonary disease, pulmonary emphysema is characterized by the destruction of the alveolar walls with an increase in the air spaces distal to the terminal bronchioles but without significant pulmonary fibrosis. Therapeutic options are limited and palliative since they are unable to promote morphological and functional regeneration of the alveolar tissue. In this context, new therapeutic approaches, such as cell therapy with adult stem cells, are being evaluated. Objective This article aims to describe the follow-up of up to 3 years after the beginning of a phase I clinical trial and discuss the spirometry parameters achieved by patients with advanced pulmonary emphysema treated with bone marrow mononuclear cells. Methods Four patients with advanced pulmonary emphysema were submitted to autologous infusion of bone marrow mononuclear cells. Follow-ups were performed by spirometry up to 3 years after the procedure. Results The results showed that autologous cell therapy in patients having chronic obstructive pulmonary disease is a safe procedure and free of adverse effects. There was an improvement in laboratory parameters (spirometry) and a slowing down in the process of pathological degeneration. Also, patients reported improvements in the clinical condition and quality of life. Conclusions Despite being in the initial stage and in spite of the small sample, the results of the clinical protocol of cell therapy in advanced pulmonary emphysema as proposed in this study, open new therapeutic perspectives in chronic obstructive pulmonary disease. It is worth emphasizing that this study corresponds to the first study in the literature that reports a change in the natural history of pulmonary emphysema after the use of cell therapy with a pool of bone marrow mononuclear cells. PMID:24255620

  7. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY‐3+)

    PubMed Central

    Leroy, Vincent; Angus, Peter; Bronowicki, Jean‐Pierre; Dore, Gregory J.; Hezode, Christophe; Pianko, Stephen; Pol, Stanislas; Stuart, Katherine; Tse, Edmund; McPhee, Fiona; Bhore, Rafia; Jimenez‐Exposito, Maria Jesus

    2016-01-01

    Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY‐3+ study (N = 50) evaluated DCV‐SOF with ribavirin (RBV) in treatment‐naïve (n = 13) or treatment‐experienced (n = 37) genotype 3‐infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open‐label DCV‐SOF (60 + 400 mg daily) with weight‐based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post‐treatment week 12 (SVR12). SVR12 (intention‐to‐treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12‐week (91% observed) and 92% (24 of 26) in the 16‐week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12‐week (88% observed) and 89% (16 of 18) in the 16‐week group; for treatment‐experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12‐week group) did not enter post‐treatment follow‐up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment‐related serious AEs. Conclusion: The all‐oral regimen of DCV‐SOF‐RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3‐infected patients with advanced liver disease, irrespective of past HCV treatment experience. (Hepatology 2016

  8. Advanced thermoplastic resins, phase 1

    NASA Technical Reports Server (NTRS)

    Hendricks, C. L.; Hill, S. G.; Falcone, A.; Gerken, N. T.

    1991-01-01

    Eight thermoplastic polyimide resin systems were evaluated as composite matrix materials. Two resins were selected for more extensive mechanical testing and both were versions of LaRC-TPI (Langley Research Center - Thermoplastic Polyimide). One resin was made with LaRC-TPI and contained 2 weight percent of a di(amic acid) dopant as a melt flow aid. The second system was a 1:1 slurry of semicrystalline LaRC-TPI powder in a polyimidesulfone resin diglyme solution. The LaRC-TPI powder melts during processing and increases the melt flow of the resin. Testing included dynamic mechanical analysis, tension and compression testing, and compression-after-impact testing. The test results demonstrated that the LaRC-TPI resins have very good properties compared to other thermoplastics, and that they are promising matrix materials for advanced composite structures.

  9. Advanced thermoplastic resins, phase 2

    NASA Technical Reports Server (NTRS)

    Brown, A. M.; Hill, S. G.; Falcone, A.

    1991-01-01

    High temperature structural resins are required for use on advanced aerospace vehicles as adhesives and composite matrices. NASA-Langley developed polyimide resins were evaluated as high temperature structural adhesives for metal to metal bonding and as composite matrices. Adhesive tapes were prepared on glass scrim fabric from solutions of polyamide acids of the semicrystalline polyimide LARC-CPI, developed at the NASA-Langley Research Center. Using 6Al-4V titanium adherends, high lap shear bond strengths were obtained at ambient temperature (45.2 MPa, 6550 psi) and acceptable strengths were obtained at elevated temperature (14.0 MPa, 2030 psi) using the Pasa-Jell 107 conversion coating on the titanium and a bonding pressure of 1.38 MPa (200 psi). Average zero degree composite tensile and compressive strengths of 1290 MPa (187 ksi) and 883 MPa (128 ksi) respectively were obtained at ambient temperature with unsized AS-4 carbon fiber reinforcement.

  10. Recent advances in heartworm disease.

    PubMed

    Guerrero, J; McCall, J W; Genchi, C; Bazzocchi, C; Kramer, L; Simòn, F; Martarino, M

    2004-10-28

    This compilation of articles consists of four papers presented at the 19th International Conference of the World Association for the Advancement of Veterinary Parasitology (WAAVP) (held in New Orleans, LA, USA, on 10–14 August 2003) in a symposium session titled “ Recent Advances in Heartworm Disease,” organized and chaired by JohnW. McCall and Jorge Guerrero. The first paper(Guerrero) covered the American Heartworm Society’s most recent revision of their guidelines for the diagnosis, prevention, and management of heartworm infection in dogs, based on new research and clinical experience, particularly in the areas of heartworm chemoprophylaxis, adulticide therapy,and serologic testing and retesting. The entire updated 2003 “Guidelines” are presented herein.One paper (McCall) reviewed the “soft-kill” adulticidal and “safety-net” (reach-back, retroactive,clinical prophylactic) activity of prolonged dosing of prophylactic doses of macrocyclic lactones,concluding that ivermectin is the most effective in this way, milbemycin oxime is the least effective,and the activity of injectable moxidectin and selamectin lies between that of ivermectin and milbemycin oxime. The two remaining papers provided an overview of the discovery, rediscovery,phylogeny, and biological association between Wolbachia endosymbionts and filarial nematodes(Genchi and co-authors) and compelling evidence that Wolbachia may play a major role in the immunopathogenesis of filarial diseases of man and animals (Kramer and co-authors).

  11. Advances in Alcoholic Liver Disease

    PubMed Central

    Beier, Juliane I.; Arteel, Gavin E.

    2013-01-01

    Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States. In studies from the Veterans Administration, patients with cirrhosis and superimposed alcoholic hepatitis had greater than 60% mortality over a 4-year period, with most of those deaths occurring in the first month. Thus, the prognosis for this disease is more ominous than for many common types of cancer (eg, breast, prostate, and colon). Moreover, ALD imposes a significant economic burden from lost wages, health care costs, and lost productivity. Unfortunately, there is still no Food and Drug Administration–approved or widely accepted drug therapy for any stage of ALD. Thus, a pressing need exists for a more detailed understanding of mechanisms of liver injury. This article reviews recent advances in mechanisms and therapy related to five major areas of direct relevance to ALD: oxidative stress; gut-liver axis and cytokine signaling; malnutrition; fibrin/clotting; and stellate cell activation/fibrosis. We also review why therapies related to these mechanisms have performed well in experimental animals and in vitro systems, but have not necessarily translated into effective therapy for humans with ALD. PMID:21088999

  12. Mitochondrial diseases: advances and issues

    PubMed Central

    Scarpelli, Mauro; Todeschini, Alice; Volonghi, Irene; Padovani, Alessandro; Filosto, Massimiliano

    2017-01-01

    Mitochondrial diseases (MDs) are a clinically heterogeneous group of disorders caused by a dysfunction of the mitochondrial respiratory chain. They can be related to mutation of genes encoded using either nuclear DNA or mitochondrial DNA. The advent of next generation sequencing and whole exome sequencing in studying the molecular bases of MDs will bring about a revolution in the field of mitochondrial medicine, also opening the possibility of better defining pathogenic mechanisms and developing novel therapeutic approaches for these devastating disorders. The canonical rules of mitochondrial medicine remain milestones, but novel issues have been raised following the use of advanced diagnostic technologies. Rigorous validation of the novel mutations detected using deep sequencing in patients with suspected MD, and a clear definition of the natural history, outcome measures, and biomarkers that could be usefully adopted in clinical trials, are mandatory goals for the scientific community. Today, therapy is often inadequate and mostly palliative. However, important advances have been made in treating some clinical entities, eg, mitochondrial neuro-gastrointestinal encephalomyopathy, for which approaches using allogeneic hematopoietic stem cell transplantation, orthotopic liver transplantation, and carrier erythrocyte entrapped thymidine phosphorylase enzyme therapy have recently been developed. Promising new treatment methods are being identified so that researchers, clinicians, and patients can join forces to change the history of these untreatable disorders. PMID:28243136

  13. Recent Advances in Celiac Disease.

    PubMed

    Murch, Simon

    2016-11-01

    Recent diagnostic advances have demonstrated that celiac disease is relatively common although most patients have less florid symptoms than previously recognised. The mucosal lesion of this autoimmune disorder depends on both adaptive and innate immune responses. The characteristic antibodies to tissue transglutaminase-2 (tTG-2) and deamidated gliadin peptides may be produced in persons possessing the relevant HLA-DQ genotypes if intact gliadin peptides can penetrate the epithelial barrier to reach antigen presenting cells. Progression from celiac autoimmunity to overt disease may depend on innate immune mechanisms, not HLA-restricted, where IL-15 is generated within the epithelial compartment. A specific innate immune response previously thought restricted to invertebrates, the encapsulation reaction, may contribute to mucosal volume expansion through recruitment of syndecan-expressing leukocytes and stimulated matrix production. It is notable that tissue transglutaminase is critical in this reaction in insects, and that the very few insects that can predate wheat, possess specific salivary or intestinal enzymes that degrade gluten. Animal models in HLA-DQ transgenic mice suggest that the microbial flora of the intestine may play a role in host responses and modulate the evolution of the disease. This suggests that therapeutic modulation of the microbiome may contribute to management of celiac disease. In developing world countries, there is a potential difficulty in histological diagnosis because of the widespread incidence of environmental enteropathy amongst apparently healthy children. Thus, recognition of local patterns of enteropathy will be important for histopathologists, and high titre tTG-2 autoantibody titres may hold considerable diagnostic significance.

  14. Advances in motor neurone disease.

    PubMed

    Bäumer, Dirk; Talbot, Kevin; Turner, Martin R

    2014-01-01

    Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.

  15. Recent advances in oesophageal diseases.

    PubMed

    Al Dulaimi, David

    2014-01-01

    -quadrant biopsy protocol which may have led to an underestimation of BE prevalence. The review highlights an increasing incidence of esophageal adenocarcinoma in the West but unclear disease trend in Asia with inter-country variability. Similarly in Asian and Western countries BE is associated with the presence of hiatus hernia, advancing age, male gender, alcohol consumption, smoking, abdominal obesity and longer duration of gastro-esophageal reflux disease. The authors postulate that Helicobacter pylori infection, more prevalent in Asia than the West, may have a protective effect on BE. There is a need for larger, prospective studies to further clarify the disease pattern of BE in Asian countries. Clearly standardisation of the diagnostic process for BE is important to validate the differences in disease trends between Asian and Western countries. Kiadaliri AA. Gender and social disparities in esophagus cancer incidence in Iran, 2003-2009: a time trend province-level study.Asian Pac J Cancer Prev 2014;15(2):623-7 Esophageal cancer (EC) is a major cause of morbidity and mortality particuarly in Iran where the incidence rate exceeds the global average. An understanding of the factors influencing the province-specific incidence of EC in Iran is important to inform disease-prevention strategies and address health inequalities. This ecological study used cancer registry data to investigate the relationship between gender and social class and the incidence of EC in Iran at province-level between 2003 and 2009. The age standardised incidence rates (ASIR) of EC were greatest in the Northern provinces of Iran, specifically Razavi Khorasan in males and Kordestan in females. Overall the EC incidence did not significantly differ according to gender. Interestingly, during the study period the ASIR increased by 4.6% per year in females (p=0.08) and 6.5% per year in males (p=0.02). This may reflect increasing rates of establised risk factors for EC including obsesity and gastro

  16. Phase camera experiment for Advanced Virgo

    NASA Astrophysics Data System (ADS)

    Agatsuma, Kazuhiro; van Beuzekom, Martin; van der Schaaf, Laura; van den Brand, Jo

    2016-07-01

    We report on a study of the phase camera, which is a frequency selective wave-front sensor of a laser beam. This sensor is utilized for monitoring sidebands produced by phase modulations in a gravitational wave (GW) detector. Regarding the operation of the GW detectors, the laser modulation/demodulation method is used to measure mirror displacements and used for the position controls. This plays a significant role because the quality of controls affect the noise level of the GW detector. The phase camera is able to monitor each sideband separately, which has a great benefit for the manipulation of the delicate controls. Also, overcoming mirror aberrations will be an essential part of Advanced Virgo (AdV), which is a GW detector close to Pisa. Especially low-frequency sidebands can be affected greatly by aberrations in one of the interferometer cavities. The phase cameras allow tracking such changes because the state of the sidebands gives information on mirror aberrations. A prototype of the phase camera has been developed and is currently tested. The performance checks are almost completed and the installation of the optics at the AdV site has started. After the installation and commissioning, the phase camera will be combined to a thermal compensation system that consists of CO2 lasers and compensation plates. In this paper, we focus on the prototype and show some limitations from the scanner performance.

  17. NASA Bioreactors Advance Disease Treatments

    NASA Technical Reports Server (NTRS)

    2009-01-01

    the body. Experiments conducted by Johnson scientist Dr. Thomas Goodwin proved that the NASA bioreactor could successfully cultivate cells using simulated microgravity, resulting in three-dimensional tissues that more closely approximate those in the body. Further experiments conducted on space shuttle missions and by Wolf as an astronaut on the Mir space station demonstrated that the bioreactor s effects were even further expanded in space, resulting in remarkable levels of tissue formation. While the bioreactor may one day culture red blood cells for injured astronauts or single-celled organisms like algae as food or oxygen producers for a Mars colony, the technology s cell growth capability offers significant opportunities for terrestrial medical research right now. A small Texas company is taking advantage of the NASA technology to advance promising treatment applications for diseases both common and obscure.

  18. Palliation of advanced pelvic malignant disease with large fraction pelvic radiation and misonidazole: final report of RTOG phase I/II study

    SciTech Connect

    Spanos, W.J. Jr.; Wasserman, T.; Meoz, R.; Sala, J.; Kong, J.; Stetz, J.

    1987-10-01

    Between October 1979 and June 1982 forty-six patients were entered on a non-randomized Phase I-II protocol for the evaluation of Misonidazole combined with high dose per fraction radiation for the treatment of advanced pelvic malignancies. Pelvic radiation consisted of 1000 cGy in one fraction repeated at 4-week intervals for a total of three treatments. Oral Misonidazole at a dose of 4 gm/m2 was administered 4-6 hr prior to radiation (total dose 12 g/m2). The distribution of histology consisted of 20 gynecologic, 24 bowel, and 2 prostate malignancies. Of the thirty-seven patients completing the three treatments; there were 6 complete responses (14% CR), 10 partial responses (27% PR) 19 minimal or no response (32% NR), and 4 unevaluable. One patient remains NED 5.5 years following radiation. Toxicity directly related to Misonidazole was minimal and consisted primarily of transcient Grade 1, 2 peripheral neuropathy (20% Grade 1, 4% Grade 2) and Grade 2 ototoxicity (4%). Radiation toxicity was significant for late bowel damage. There were 4 (11%) Grade 3 and 7 (19%) Grade 4 gastro-intestinal (GI) toxicities. Kaplan-Meier plot of GI toxicity showed a progressive increase in incidence with time for projected rate of 49% Grade 3, 4 by 12-month. GI toxicity (Grade 3, 4) was also related to tumor response. The complication rate was 80% (4/6) for CR, 30% (3/10) for PR and 26% (5/19) for NR or progression. Because of the GI complication rate, this protocol for palliation of advanced pelvic malignancies has been replaced by a protocol that uses 4 fractions over 2 days (b.i.d.) of 370 cGy per fraction repeated at 3-week intervals for a total of 3 courses.

  19. Radiographic Differentiation of Advanced Fibrocystic Lung Diseases.

    PubMed

    Akira, Masanori

    2017-03-01

    The concept of end-stage lung disease suggests a final common pathway for most diffuse parenchymal lung diseases. In accordance with this concept, end-stage disease is characterized radiographically and pathologically by the presence of extensive honeycombing. However, sequential computed tomographic (CT) scans obtained from patients with chronic diffuse lung disease evolve over time to show various advanced lung disease patterns other than honeycombing. In addition, several radiographically distinct honeycomb patterns, including microcystic, macrocystic, mixed, and combined emphysema and honeycombing, differentiate one advanced lung disease from another. For example, usual interstitial pneumonia (IP) usually shows mixed microcystic and macrocystic honeycombing. In contrast, CT images of long-standing fibrotic nonspecific IP typically show only small, scattered foci of honeycombing; instead, most enlarged airspaces observed in the advanced stage of this disease represent dilatation of bronchioles. In desquamative IP and pulmonary Langerhans cell histiocytosis, focal opacities typically evolve into emphysema-like lesions seen on CT imaging. In combined pulmonary fibrosis and emphysema and sarcoidosis, the cysts tend to be larger than those observed in usual IP. Sequential CT scans in other chronic, diffuse lung diseases also show various distinctive changes. This article highlights radiographic patterns of lung destruction that belie a single common pathway to end-stage lung disease. Recognition of distinct radiographic patterns of lung destruction can help differentiate diffuse parenchymal lung diseases, even in advanced stages of disease evolution.

  20. Parkinson's Disease: The Newest Advances

    MedlinePlus

    ... on genetic findings, investigators have already developed improved animal models, so essential for our understanding of what causes the disease and for testing new treatments, and have made breakthroughs in cell ...

  1. Advanced Emissions Control Development Program: Phase III

    SciTech Connect

    G.T. Amrhein; R.T. Bailey; W. Downs; M.J. Holmes; G.A. Kudlac; D.A. Madden

    1999-07-01

    The primary objective of the Advanced Emissions Control Development Program (AECDP) is to develop practical, cost-effective strategies for reducing the emissions of air toxics from coal-fired boilers. The project goal is to effectively control air toxic emissions through the use of conventional flue gas clean-up equipment such as electrostatic precipitators (ESPs), fabric filters (baghouses - BH), and wet flue gas desulfurization systems (WFGD). Development work concentrated on the capture of trace metals, fine particulate, hydrogen chloride and hydrogen fluoride, with an emphasis on the control of mercury. The AECDP project is jointly funded by the US Department of Energy's Federal Energy Technology Center (DOE), the Ohio Coal Development Office within the Ohio Department of Development (OCDO), and Babcock and Wilcox, a McDermott company (B and W). This report discusses results of all three phases of the AECDP project with an emphasis on Phase III activities. Following the construction and evaluation of a representative air toxics test facility in Phase I, Phase II focused on characterization of the emissions of mercury and other air toxics and the control of these emissions for typical operating conditions of conventional flue gas clean-up equipment. Some general comments that can be made about the control of air toxics while burning a high-sulfur bituminous coal are as follows: (1) particulate control devices such as ESP's and baghouses do a good job of removing non-volatile trace metals, (2) particulate control devices (ESPs and baghouses) effectively remove the particulate-phase mercury, but the particulate-phase mercury was only a small fraction of the total for the coals tested, (3) wet scrubbing can effectively remove hydrogen chloride and hydrogen fluoride, and (4) wet scrubbers show good potential for the removal of mercury when operated under certain conditions, however, for certain applications, system enhancements can be required to achieve high

  2. [Advances in sickle cell disease].

    PubMed

    de Montalembert, Mariane

    2008-10-01

    Generation of transgenic mice have identified new pathophysiological mechanisms in sickle disease, including a permanent proinflammatory state and dysregulation of vascular tone. Treatment is no longer solely symptomatic. New agents target red cell hydration and the kinetics of deoxyhemoglobin S polymerization. Hydroxyurea, which reactivates fetal hemoglobin synthesis, is now widely used. Anti-adhesion molecules and agents modulating vascular tone are being tried in sickle mice. Bone marrow transplantation is widely used to cure patients with HLA-identical siblings, and gene therapy looks promising for those without a donor.

  3. Advanced magnetic resonance imaging of neurodegenerative diseases.

    PubMed

    Agosta, Federica; Galantucci, Sebastiano; Filippi, Massimo

    2017-01-01

    Magnetic resonance imaging (MRI) is playing an increasingly important role in the study of neurodegenerative diseases, delineating the structural and functional alterations determined by these conditions. Advanced MRI techniques are of special interest for their potential to characterize the signature of each neurodegenerative condition and aid both the diagnostic process and the monitoring of disease progression. This aspect will become crucial when disease-modifying (personalized) therapies will be established. MRI techniques are very diverse and go from the visual inspection of MRI scans to more complex approaches, such as manual and automatic volume measurements, diffusion tensor MRI, and functional MRI. All these techniques allow us to investigate the different features of neurodegeneration. In this review, we summarize the most recent advances concerning the use of MRI in some of the most important neurodegenerative conditions, putting an emphasis on the advanced techniques.

  4. Advanced imaging in equine dental disease.

    PubMed

    Selberg, Kurt; Easley, Jeremiah T

    2013-08-01

    Dental and sinus disorders are relatively common and of major clinical importance in equine medicine. Advanced diagnostic imaging has become an integral part of equine veterinary medicine. Advanced imaging has progressed the understanding, diagnosis, and treatment of dental- and sinus-related diseases. As a clinician, it is important to realize the value of advanced diagnostic imaging. Although computed tomography and magnetic resonance imaging are both significantly more expensive compared with other diagnostic tools, the financial cost of inaccurate diagnosis and treatment can often result in higher overall costs.

  5. Advances in identifying beryllium sensitization and disease.

    PubMed

    Middleton, Dan; Kowalski, Peter

    2010-01-01

    Beryllium is a lightweight metal with unique qualities related to stiffness, corrosion resistance, and conductivity. While there are many useful applications, researchers in the 1930s and 1940s linked beryllium exposure to a progressive occupational lung disease. Acute beryllium disease is a pulmonary irritant response to high exposure levels, whereas chronic beryllium disease (CBD) typically results from a hypersensitivity response to lower exposure levels. A blood test, the beryllium lymphocyte proliferation test (BeLPT), was an important advance in identifying individuals who are sensitized to beryllium (BeS) and thus at risk for developing CBD. While there is no true "gold standard" for BeS, basic epidemiologic concepts have been used to advance our understanding of the different screening algorithms.

  6. Demonstration Advanced Avionics System (DAAS), Phase 1

    NASA Technical Reports Server (NTRS)

    Bailey, A. J.; Bailey, D. G.; Gaabo, R. J.; Lahn, T. G.; Larson, J. C.; Peterson, E. M.; Schuck, J. W.; Rodgers, D. L.; Wroblewski, K. A.

    1981-01-01

    Demonstration advanced anionics system (DAAS) function description, hardware description, operational evaluation, and failure mode and effects analysis (FMEA) are provided. Projected advanced avionics system (PAAS) description, reliability analysis, cost analysis, maintainability analysis, and modularity analysis are discussed.

  7. Alzheimer's disease: research advances and medical reality.

    PubMed

    Seiguer, Erica

    2005-07-01

    Alzheimer's disease was the eighth-leading cause of death in 2001. There is no cure and no effective treatment. Alzheimer's disease presents policy-makers with several challenges, including the level of funding and direction of federally funded research, as well as the cost pressures on Medicare and Medicaid of long-term care. These challenges will increase in intensity as demographic changes, particularly the aging of baby boomers, take hold. Better prevention of Alzheimer's, advances in therapy, and appropriate care modalities will likely require significant investment.

  8. Cutaneous mucormycosis in advanced HIV disease.

    PubMed

    Moreira, José; Ridolfi, Felipe; Almeida-Paes, Rodrigo; Varon, Andrea; Lamas, Cristiane C

    Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease.

  9. Sialadenosis in Patients with Advanced Liver Disease

    PubMed Central

    Close, John M.; Eghtesad, Bijan

    2009-01-01

    Sialadenosis (sialosis) has been associated most often with alcoholic liver disease and alcoholic cirrhosis, but a number of nutritional deficiencies, diabetes, and bulimia have also been reported to result in sialadenosis. The aim of this study was to determine the prevalence of sialadenosis in patients with advanced liver disease. Patients in the study group consisted of 300 candidates for liver transplantation. Types of liver disease in subjects with clinical evidence of sialadenosis were compared with diagnoses in cases who had no manifestations of sialadenosis. The data were analyzed for significant association. Sialadenosis was found in 28 of the 300 subjects (9.3%). Among these 28 cases, 11 (39.3%) had alcoholic cirrhosis. The remaining 17 (60.7%) had eight other types of liver disease. There was no significant association between sialadenosis and alcoholic cirrhosis (P = 0.389). These findings suggest that both alcoholic and non-alcoholic cirrhosis may lead to the development of sialadenosis. Advanced liver disease is accompanied by multiple nutritional deficiencies which may be exacerbated by alcohol. Similar metabolic abnormalities may occur in patients with diabetes or bulimia. Malnutrition has been associated with autonomic neuropathy, the pathogenic mechanism that has been proposed for sialadenosis. PMID:19644542

  10. Sialadenosis in patients with advanced liver disease.

    PubMed

    Guggenheimer, James; Close, John M; Eghtesad, Bijan

    2009-06-01

    Sialadenosis (sialosis) has been associated most often with alcoholic liver disease and alcoholic cirrhosis, but a number of nutritional deficiencies, diabetes, and bulimia have also been reported to result in sialadenosis. The aim of this study was to determine the prevalence of sialadenosis in patients with advanced liver disease. Patients in the study group consisted of 300 candidates for liver transplantation. Types of liver disease in subjects with clinical evidence of sialadenosis were compared with diagnoses in cases who had no manifestations of sialadenosis. The data were analyzed for significant association. Sialadenosis was found in 28 of the 300 subjects (9.3%). Among these 28 cases, 11 (39.3%) had alcoholic cirrhosis. The remaining 17 (60.7%) had eight other types of liver disease. There was no significant association between sialadenosis and alcoholic cirrhosis (P = 0.389). These findings suggest that both alcoholic and non-alcoholic cirrhosis may lead to the development of sialadenosis. Advanced liver disease is accompanied by multiple nutritional deficiencies which may be exacerbated by alcohol. Similar metabolic abnormalities may occur in patients with diabetes or bulimia. Malnutrition has been associated with autonomic neuropathy, the pathogenic mechanism that has been proposed for sialadenosis.

  11. Myeloma Today: Disease Definitions and Treatment Advances

    PubMed Central

    Rajkumar, S. Vincent

    2015-01-01

    There have been major advances in the diagnosis, staging, risk-stratification, and management of multiple myeloma (MM). In addition to established CRAB (hypercalcemia, renal failure, anemia, and lytic bone lesions) features, new diagnostic criteria include 3 new biomarkers to diagnose the disease: bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain ratio ≥100, and >1 focal lesion on magnetic resonance imaging. MM can be classified into several subtypes based on baseline cytogenetics, and prognosis varies according to underlying cytogenetic abnormalities. A Revised International Staging System has been developed which combines markers of tumor burden (albumin, beta-2 microglobulin) with markers of aggressive disease biology (high risk cytogenetics and elevated serum lactate dehydrogenase). Although the approach to therapy remains largely the same, the treatment options at every stage of the disease have changed. Carfilzomib, pomalidomide, and panobinostat have been approved for the treatment of the disease. Elotuzumab, daratumumab, and ixazomib are expected to be approved shortly. These drugs combined with older agents such as cyclophosphamide, dexamethasone, thalidomide, bortezomib, and lenalidomide dramatically increase the repertoire of regimens available for the treatment of MM. This review provides a concise overview of recent advances in MM, including updates to diagnostic criteria, staging, risk-stratification, and management. PMID:26565896

  12. Glutathione peroxidase in early and advanced Parkinson's disease.

    PubMed Central

    Johannsen, P; Velander, G; Mai, J; Thorling, E B; Dupont, E

    1991-01-01

    A defective antioxidant scavenging system plays a major role in one of the theories of the pathogenesis of Parkinson's disease. The aim of this study was to investigate whether there is a general difference in antioxidant activity between early and advanced cases of Parkinson's disease. Twenty five recently diagnosed patients, without any clinical fluctuations (group A), and 25 patients in a late phase of the disease with severe fluctuations in response to levodopa therapy (group B) were included in the study. Erythrocyte glutathione peroxidase was determined as a measure of antioxidant activity and significantly lower values were found in group B than in group A. Regression analyses in groups A and B showed significant correlation between glutathione peroxidase and duration of disease, but not between glutathione peroxidase and age of patients. Images PMID:1940936

  13. New Advances in Polycystic Liver Diseases.

    PubMed

    Santos-Laso, A; Izquierdo-Sánchez, L; Lee-Law, P Y; Perugorria, M J; Marzioni, M; Marin, J J G; Bujanda, L; Banales, J M

    2017-02-01

    Polycystic liver diseases (PLDs) include a heterogeneous group of congenital disorders inherited as dominant or recessive genetic traits; they are manifested alone or in association with polycystic kidney disease. Ductal plate malformation during embryogenesis and the loss of heterozygosity linked to second-hit mutations may promote the dilatation and/or development of a large number (> 20) of biliary cysts, which are the main cause of morbidity in these patients. Surgical procedures aimed to eliminate symptomatic cysts show short-term beneficial effects, but are not able to block the disease progression. Therefore, liver transplantation is the only curative option. Intense studies on the molecular mechanisms involved in the pathogenesis of PLDs have resulted in different clinical trials, some of them with promising outcomes. Here the authors summarize the key aspects of PLD etiology, pathogenesis, and therapy, highlighting the most recent advances and future research directions.

  14. The effects of phase advances between interaction points

    SciTech Connect

    Luo, Y.; Tepekian, S.; Fischer, W.; Gu, X.; Trbojevic, D.

    2011-03-01

    In this note we perform simulation studies to investigate the effects of betatron phase advances between the beam-beam interaction points on half-integer resonance driving term, second order chromaticty and dynamic aperture in RHIC. The betatron phase advances are adjusted with artificial matrices inserted in the middle of arcs. The lattices for the 2011 RHIC polarized proton (p-p) run and 2010 RHIC Au-Au runs are used. We also scan the phase advances between IP8 and the electron lens for the proposed Blue ring lattice with head-on beam-beam compensation.

  15. OPTIMIZATION OF THE PHASE ADVANCE BETWEEN RHIC INTERACTION POINTS.

    SciTech Connect

    TOMAS, R.; FISCHER, W.

    2005-05-16

    The authors consider a scenario of having two identical Interaction Points (IPs) in the Relativistic Heavy Ion Collider (RHIC). The strengths of beam-beam resonances strongly depend on the phase advance between these two IPs and therefore certain phase advances could improve beam life-time and luminosity. The authors compute the dynamic aperture (DA) as function of the phase advance between these IPs to find the optimum settings.The beam-beam interaction is treated in the weak-strong approximation and a non-linear model of the lattice is used. For the current RHIC proton working point (0.69.0.685) [1] the design lattice is found to have the optimum phase advance. However this is not the case for other working points.

  16. Management of thrombocytopenia in advanced liver disease.

    PubMed

    Gangireddy, V G R; Kanneganti, P C; Sridhar, S; Talla, S; Coleman, T

    2014-11-01

    Thrombocytopenia (defined as a platelet count <150×10(9)) is a well-known complication in patients with liver cirrhosis and has been observed in 76% to 85% of patients. Significant thrombocytopenia (platelet count <50×10(9) to 75×10(9)) occurs in approximately 13% of patients with cirrhosis. Thrombocytopenia can negatively impact the care of patients with severe liver disease by potentially interfering with diagnostic and therapeutic procedures. Multiple factors can contribute to the development of thrombocytopenia including splenic platelet sequestration, immunological processes, bone marrow suppression by chronic viral infection, and reduced levels or activity of the hematopoietic growth factor thrombopoietin. The present review focuses on the etiologies and management options for severe thrombocytopenia in the setting of advanced liver disease.

  17. Advanced Microwave Ferrite Research (AMFeR): Phase Four

    DTIC Science & Technology

    2009-10-15

    COVERED (From - To) 28 Dec 2006 - 30 Sep 2009 4. TITLE AND SUBTITLE Advanced Microwave Ferrite Research (AMFeR): Phase Four 5a. CONTRACT NUMBER 5b...research endeavor is to devise ferrite materials for microwave , self-biased circulator applications. To this end, the research team focused on two key...Std Z39-18 Final Report Advanced Microwave Ferrite Research (AMFeR): Phase Four Dr. Jeffrey L. Young MRC Institute/Electrical and Computer

  18. Advanced Nanostructures for Two-Phase Fluid and Thermal Transport

    DTIC Science & Technology

    2014-08-07

    AFRL-OSR-VA-TR-2014-0183 (YIP 11) Advanced Nanostructures for Two-Phase Fluid and Thermal Transport Evelyn Wang MASSACHUSETTS INSTITUTE OF TECHNOLOGY...Advanced Nanostructures for Two-Phase Fluid and Thermal Transport AFOSR Grant FA9550-11-1-0059 Final Report Evelyn N. Wang Associate Professor...heated channel wall. Small fluctuations in the measured heater surface temperature (± 3-8 °C) indicated increased flow stability, and the heat transfer

  19. Advanced Gearless Drivetrain - Phase I Technical Report

    SciTech Connect

    Butterfield, Sandy; Smith, Jim; Petch, Derek; Sullivan, Brian; Smith, Peter; Pierce, Kirk

    2012-08-31

    Boulder Wind Power (BWP) collaborated with the National Renewable Energy Laboratory (NREL) in Golden, Colorado, to demonstrate the economics of scaling an advanced gearless drivetrain technology to 6MW (and larger) turbine applications. The project goal was to show that this advanced drivetrain technology enables a cost of energy of less than $0.10/kWH in offshore applications. This drivetrain technology achieves this Cost of Energy (COE) advantage via a 70% greater torque density versus current state-of-the-art drivetrain technologies. In addition, a new dynamically compliant design strategy is required to optimize turbine system-level COE. The BWP generator is uniquely suited for this new design strategy. This project developed a concept design for a 6MW drivetrain and culminated in a plan for a system-level test of this technology at 3MW scale. The project further demonstrated the advantage of the BWP drivetrain with increasing power ratings, with conceptual designs through 10 MW.

  20. Advances in Chagas disease drug development: 2009-2010

    PubMed Central

    Buckner, Frederick S.; Navabi, Nazlee

    2013-01-01

    Purpose of Review The need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past two years. Recent Findings Drug development efforts are almost exclusively occurring as preclinical research. The exceptions being Phase I safety studies for the cruzain inhibitor, K-777, and potential Phase II studies for the antifungal drug, posaconazole, and a prodrug of ravuconazole. Several recent laboratory investigations demonstrate anti-T. cruzi activity of novel small molecules in animal models. These include nonpeptidic cruzain inhibitors, novel inhibitors of the sterol 14α-demethylase enzyme, new compounds (arylimidamides) related to pentamidine, derivatives of nifurtimox, compounds using ruthenium complexes, and several natural products. The recent implementation of a high-throughput screen of >300,000 compounds against intracellular T. cruzi amastigotes done at the Broad Institute is an important development, yielding ~300 selective inhibitors, many of which may serve as leads for medicinal chemistry efforts. Summary Progress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Efforts to define a target product profile and to harmonize methodologies for testing drugs for Chagas disease are described herein. PMID:20885320

  1. Advanced supersonic propulsion study, phase 4

    NASA Technical Reports Server (NTRS)

    Howlett, R. A.

    1977-01-01

    Installation characteristics for a Variable Stream Control Engine (VSCE) were studied for three advanced supersonic airplane designs. Sensitivity of the VSCE concept to change in technology projections was evaluated in terms of impact on overall installed performance. Based on these sensitivity results, critical technology requirements were reviewed, resulting in the reaffirmation of the following requirements: low-noise nozzle system; a high performance, low emissions duct burner and main burner; hot section technology; variable geometry components; and propulsion integration features, including an integrated electronic control system.

  2. Advances in chronic obstructive pulmonary disease.

    PubMed

    McDonald, C F; Khor, Y

    2013-08-01

    Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation in the presence of identifiable risk factors. Inflammation is the central pathological feature in the pathogenesis of COPD. In addition to its pulmonary effects, COPD is associated with significant extrapulmonary manifestations, including ischaemic heart disease, osteoporosis, stroke and diabetes. Anxiety and depression are also common. Spirometry remains the gold standard diagnostic tool. Pharmacologic and non-pharmacologic therapy can improve symptoms, quality of life and exercise capacity and, through their effects on reducing exacerbations, have the potential to modify disease progression. Bronchodilators are the mainstay of pharmacotherapy, with guidelines recommending a stepwise escalating approach. Smoking cessation is paramount in managing COPD, with promotion of physical activity and pulmonary rehabilitation being other key factors in management. Comorbidities should be actively sought and managed in their own right. Given the chronicity and progressive nature of COPD, ongoing monitoring and support with timely discussion of advanced-care planning and end-of-life issues are recommended.

  3. Recent Advances in Autoimmune Thyroid Diseases

    PubMed Central

    Yoo, Won Sang

    2016-01-01

    Autoimmune thyroid disease (AITD) includes hyperthyroid Graves disease, hypothyroid autoimmune thyroiditis, and subtle subclinical thyroid dysfunctions. AITD is caused by interactions between genetic and environmental predisposing factors and results in autoimmune deterioration. Data on polymorphisms in the AITD susceptibility genes, related environmental factors, and dysregulation of autoimmune processes have accumulated over time. Over the last decade, there has been progress in the clinical field of AITD with respect to the available diagnostic and therapeutic methods as well as clinical consensus. The updated clinical guidelines allow practitioners to identify the most reasonable and current approaches for proper management. In this review, we focus on recent advances in understanding the genetic and environmental pathogenic mechanisms underlying AITD and introduce the updated set of clinical guidelines for AITD management. We also discuss other aspects of the disease such as management of subclinical thyroid dysfunction, use of levothyroxine plus levotriiodothyronine in the treatment of autoimmune hypothyroidism, risk assessment of long-standing antithyroid drug therapy in recurrent Graves' hyperthyroidism, and future research needs. PMID:27586448

  4. Advanced Stirling receiver development program, phase 1

    NASA Astrophysics Data System (ADS)

    Lurio, Charles A.

    1990-07-01

    Critical technology experiments were designed and developed to evaluate the Stirling cavity heat pipe receiver for a space solar power system. Theoretical criteria were applied to the design of a module for containing energy storage phase change material while avoiding thermal ratcheting. Zero-g drop tower tests, without phase change, were conducted to affirm that the bubble location required to avoid ratcheting could be achieved without the use of container materials that are wetted by the phase change material. A full scale module was fabricated, but not tested. A fabrication method was successfully developed for the sodium evaporator dome, with a sintered screen wick, to be used as the focal point for the receiver. Crushing of the screen during hydroforming was substantially reduced over the results of other researchers by using wax impregnation. Superheating of the sodium in the wick under average flux conditions is expected to be under 10K. A 2000K furnace which will simulate solar flux conditions for testing the evaporator dome was successfully built and tested.

  5. Recent theoretical advances on superradiant phase transitions

    NASA Astrophysics Data System (ADS)

    Baksic, Alexandre; Nataf, Pierre; Ciuti, Cristiano

    2013-03-01

    The Dicke model describing a single-mode boson field coupled to two-level systems is an important paradigm in quantum optics. In particular, the physics of ``superradiant phase transitions'' in the ultrastrong coupling regime is the subject of a vigorous research activity in both cavity and circuit QED. Recently, we explored the rich physics of two interesting generalizations of the Dicke model: (i) A model describing the coupling of a boson mode to two independent chains A and B of two-level systems, where chain A is coupled to one quadrature of the boson field and chain B to the orthogonal quadrature. This original model leads to a quantum phase transition with a double symmetry breaking and a fourfold ground state degeneracy. (ii) A generalized Dicke model with three-level systems including the diamagnetic term. In contrast to the case of two-level atoms for which no-go theorems exist, in the case of three-level system we prove that the Thomas-Reich-Kuhn sum rule does not always prevent a superradiant phase transition.

  6. Advanced Stirling receiver development program, phase 1

    NASA Technical Reports Server (NTRS)

    Lurio, Charles A.

    1990-01-01

    Critical technology experiments were designed and developed to evaluate the Stirling cavity heat pipe receiver for a space solar power system. Theoretical criteria were applied to the design of a module for containing energy storage phase change material while avoiding thermal ratcheting. Zero-g drop tower tests, without phase change, were conducted to affirm that the bubble location required to avoid ratcheting could be achieved without the use of container materials that are wetted by the phase change material. A full scale module was fabricated, but not tested. A fabrication method was successfully developed for the sodium evaporator dome, with a sintered screen wick, to be used as the focal point for the receiver. Crushing of the screen during hydroforming was substantially reduced over the results of other researchers by using wax impregnation. Superheating of the sodium in the wick under average flux conditions is expected to be under 10K. A 2000K furnace which will simulate solar flux conditions for testing the evaporator dome was successfully built and tested.

  7. Digital polarization holography advancing geometrical phase optics.

    PubMed

    De Sio, Luciano; Roberts, David E; Liao, Zhi; Nersisyan, Sarik; Uskova, Olena; Wickboldt, Lloyd; Tabiryan, Nelson; Steeves, Diane M; Kimball, Brian R

    2016-08-08

    Geometrical phase or the fourth generation (4G) optics enables realization of optical components (lenses, prisms, gratings, spiral phase plates, etc.) by patterning the optical axis orientation in the plane of thin anisotropic films. Such components exhibit near 100% diffraction efficiency over a broadband of wavelengths. The films are obtained by coating liquid crystalline (LC) materials over substrates with patterned alignment conditions. Photo-anisotropic materials are used for producing desired alignment conditions at the substrate surface. We present and discuss here an opportunity of producing the widest variety of "free-form" 4G optical components with arbitrary spatial patterns of the optical anisotropy axis orientation with the aid of a digital spatial light polarization converter (DSLPC). The DSLPC is based on a reflective, high resolution spatial light modulator (SLM) combined with an "ad hoc" optical setup. The most attractive feature of the use of a DSLPC for photoalignment of nanometer thin photo-anisotropic coatings is that the orientation of the alignment layer, and therefore of the fabricated LC or LC polymer (LCP) components can be specified on a pixel-by-pixel basis with high spatial resolution. By varying the optical magnification or de-magnification the spatial resolution of the photoaligned layer can be adjusted to an optimum for each application. With a simple "click" it is possible to record different optical components as well as arbitrary patterns ranging from lenses to invisible labels and other transparent labels that reveal different images depending on the side from which they are viewed.

  8. Advanced Lost Foam Casting Technology - Phase V

    SciTech Connect

    Wanliang Sun; Harry E. Littleton; Charles E. Bates

    2004-04-29

    Previous research, conducted under DOE Contracts DE-FC07-89ID12869, DE-FC07-93ID12230 and DE-FC07-95ID113358 made significant advances in understanding the Lost Foam Casting (LFC) Process and clearly identified areas where additional developments were needed to improve the process and make it more functional in industrial environments. The current project focused on eight tasks listed as follows: Task 1--Computational Model for the Process and Data Base to Support the Model; Task 2--Casting Dimensional Accuracy; Task 3--Pattern Production; Task 4--Improved Pattern Materials; Task 5--Coating Control; Task 6--In-Plant Case Studies; Task 7--Energy and the Environmental Data; and Task 8--Technology Transfer. This report summarizes the work done on all tasks in the period of October 1, 1999 through September 30, 2004. The results obtained in each task and subtask are summarized in this Executive Summary and details are provided in subsequent sections of the report.

  9. Advances in the prevention of Alzheimer's Disease

    PubMed Central

    Mangialasche, Francesca; Kivipelto, Miia

    2015-01-01

    Alzheimer's disease (AD), the leading cause of dementia, has reached epidemic proportions, with major social, medical and economical burdens. With no currently available curative treatments, both the World Health Organization and the G8 Dementia Summit recently identified dementia and AD prevention as a major public health priority. Dementia and AD have a wide range of risk factors (genetic, vascular/metabolic and lifestyle-related), which often co-occur and thus interact with each other. Previous intervention efforts aimed at preventing dementia and AD focused on the management of single risk factors, with relatively modest findings. Also, the effect of risk factors depends on age at exposure, indicating that the timing of preventive interventions needs to be carefully considered. In view of the complex multifactorial nature of AD, as well as its long pre-clinical (asymptomatic) phase, interventions simultaneously targeting multiple risk factors and disease mechanisms at an early stage of the disease are most likely to be effective. Three large European multidomain prevention trials have been launched with the goal of preventing cognitive decline, dementia and AD in older adults with different risk profiles. Pharmacological trials are also shifting towards prevention of Alzheimer dementia, by targeting at-risk individuals prior to the onset of cognitive symptoms. The current review will summarize and discuss the evidence on risk and protective factors from observational studies, ongoing lifestyle-related and pharmacological randomized controlled trials (RCTs), as well as future directions for dementia and AD prevention. PMID:26097723

  10. A phase II study of axitinib in advanced neuroendocrine tumors

    PubMed Central

    Strosberg, J R; Cives, M; Hwang, J; Weber, T; Nickerson, M; Atreya, C E; Venook, A; Kelley, R K; Valone, T; Morse, B; Coppola, D; Bergsland, E K

    2016-01-01

    Neuroendocrine tumors (NETs) are highly vascular neoplasms overexpressing vascular endothelial growth factor (VEGF) as well as VEGF receptors (VEGFR). Axitinib is a potent, selective inhibitor of VEGFR-1, -2 and -3, currently approved for the treatment of advanced renal cell carcinoma. We performed an open-label, two-stage design, phase II trial of axitinib 5 mg twice daily in patients with progressive unresectable/metastatic low-to-intermediate grade carcinoid tumors. The primary end points were progression-free survival (PFS) and 12-month PFS rate. The secondary end points included time to treatment failure (TTF), overall survival (OS), overall radiographic response rate (ORR), biochemical response rate and safety. A total of 30 patients were enrolled and assessable for toxicity; 22 patients were assessable for response. After a median follow-up of 29 months, we observed a median PFS of 26.7 months (95% CI, 11.4–35.1), with a 12-month PFS rate of 74.5% (±10.2). The median OS was 45.3 months (95% CI, 24.4–45.3), and the median TTF was 9.6 months (95% CI, 5.5–12). The best radiographic response was partial response (PR) in 1/30 (3%) and stable disease (SD) in 21/30 patients (70%); 8/30 patients (27%) were unevaluable due to early withdrawal due to toxicity. Hypertension was the most common toxicity that developed in 27 patients (90%). Grade 3/4 hypertension was recorded in 19 patients (63%), leading to treatment discontinuation in six patients (20%). Although axitinib appears to have an inhibitory effect on tumor growth in patients with advanced, progressive carcinoid tumors, the high rate of grade 3/4 hypertension may represent a potential impediment to its use in unselected patients. PMID:27080472

  11. Development of advanced fuel cell system, phase 2

    NASA Technical Reports Server (NTRS)

    Handley, L. M.; Meyer, A. P.; Bell, W. F.

    1973-01-01

    A multiple task research and development program was performed to improve the weight, life, and performance characteristics of hydrogen-oxygen alkaline fuel cells for advanced power systems. Development and characterization of a very stable gold alloy catalyst was continued from Phase I of the program. A polymer material for fabrication of cell structural components was identified and its long term compatibility with the fuel cell environment was demonstrated in cell tests. Full scale partial cell stacks, with advanced design closed cycle evaporative coolers, were tested. The characteristics demonstrated in these tests verified the feasibility of developing the engineering model system concept into an advanced lightweight long life powerplant.

  12. Advanced geothermal hydraulics model -- Phase 1 final report, Part 2

    SciTech Connect

    W. Zheng; J. Fu; W. C. Maurer

    1999-07-01

    An advanced geothermal well hydraulics model (GEODRIL) is being developed to accurately calculate bottom-hole conditions in these hot wells. In Phase 1, real-time monitoring and other improvements were added to GEODRIL. In Phase 2, GEODRIL will be integrated into Marconi's Intelligent Drilling Monitor (IDM) that will use artificial intelligence to detect lost circulation, fluid influxes and other circulation problems in geothermal wells. This software platform has potential for significantly reducing geothermal drilling costs.

  13. Advanced imaging in valvular heart disease.

    PubMed

    Bax, Jeroen J; Delgado, Victoria

    2017-04-01

    Although echocardiography remains the mainstay imaging technique for the evaluation of patients with valvular heart disease (VHD), innovations in noninvasive imaging in the past few years have provided new insights into the pathophysiology and quantification of VHD, early detection of left ventricular (LV) dysfunction, and advanced prognostic assessment. The severity grading of valve dysfunction has been refined with the use of Doppler echocardiography, cardiac magnetic resonance (CMR), and CT imaging. LV ejection fraction remains an important criterion when deciding whether patients should be referred for surgery. However, echocardiographic strain imaging can now detect impaired LV systolic function before LV ejection fraction reduces, thus provoking the debate on whether patients with severe VHD should be referred for surgery at an earlier stage (before symptom onset). Impaired LV strain correlates with the amount of myocardial fibrosis detected with CMR techniques. Furthermore, accumulating data show that the extent of fibrosis associated with severe VHD has important prognostic implications. The present Review focuses on using these novel imaging modalities to assess pathophysiology, early LV dysfunction, and prognosis of major VHDs, including aortic stenosis, mitral regurgitation, and aortic regurgitation.

  14. Biomarkers in Parkinson's disease: Advances and strategies.

    PubMed

    Delenclos, Marion; Jones, Daryl R; McLean, Pamela J; Uitti, Ryan J

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. PD is a complex syndrome with different clinical subtypes and a wide variability in disorder course. In order to deliver better clinical management of PD patients and discovery of novel therapies, there is an urgent need to find sensitive, specific, and reliable biomarkers. The development of biomarkers will not only help the scientific community to identify populations at risk, but also facilitate clinical diagnosis. Furthermore, these tools could monitor progression, which could ultimately deliver personalized therapeutic strategies. The field of biomarker discovery in PD has attracted significant attention and there have been numerous contributions in recent years. Although none of the parameters have been validated for clinical practice, some candidates hold promise. This review summarizes recent advances in the development of PD biomarkers and discusses new strategies for their utilization.

  15. Biomarkers in Parkinson's disease: Advances and strategies

    PubMed Central

    Delenclos, Marion; Jones, Daryl R.; McLean, Pamela J.; Uitti, Ryan J.

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor disturbances and affects more than 1% of the worldwide population. Despite considerable progress in understanding PD pathophysiology, including genetic and biochemical causes, diagnostic approaches lack accuracy and interventions are restricted to symptomatic treatments. PD is a complex syndrome with different clinical subtypes and a wide variability in disorder course. In order to deliver better clinical management of PD patients and discovery of novel therapies, there is an urgent need to find sensitive, specific, and reliable biomarkers. The development of biomarkers will not only help the scientific community to identify populations at risk, but also facilitate clinical diagnosis. Furthermore, these tools could monitor progression, which could ultimately deliver personalized therapeutic strategies. The field of biomarker discovery in PD has attracted significant attention and there have been numerous contributions in recent years. Although none of the parameters have been validated for clinical practice, some candidates hold promise. This review summarizes recent advances in the development of PD biomarkers and discusses new strategies for their utilization. PMID:26439946

  16. Altered Circadian Rhythm and Metabolic Gene Profile in Rats Subjected to Advanced Light Phase Shifts

    PubMed Central

    Herrero, Laura; Valcarcel, Lorea; da Silva, Crhistiane Andressa; Albert, Nerea; Diez-Noguera, Antoni; Cambras, Trinitat; Serra, Dolors

    2015-01-01

    The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT), brown adipose tissue (BAT) and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level. PMID:25837425

  17. Recent advances in echocardiography for valvular heart disease.

    PubMed

    Hahn, Rebecca

    2015-01-01

    Echocardiography is the imaging modality of choice for the assessment of patients with valvular heart disease. Echocardiographic advancements may have particular impact on the assessment and management of patients with valvular heart disease. This review will summarize the current literature on advancements, such as three-dimensional echocardiography, strain imaging, intracardiac echocardiography, and fusion imaging, in this patient population.

  18. Advancing frontiers in Alzheimer's disease research

    SciTech Connect

    Glenner, G.G.; Wurtman, R.J.

    1987-01-01

    This book contain 16 chapters. Some of the titles are: Transmitter Alterations in Alzheimer's Disease: Relation to Cortical Dysfunction as Suggested by Positron Emission Tomography; Single-Photon Emission Computed Tomography in the Clinical Evaluation of Dementia; Clinical Diagnosis of Alzheimer's Disease; Down's Syndrome and Alzheimer's Disease: What is the Relationship; and Beta Protein: A Possible Marker for Alzheimer's Disease.

  19. Advances in environmental and occupational respiratory diseases in 2009.

    PubMed

    Peden, David B; Bush, Robert K

    2010-03-01

    The year 2009 led to a number of significant advances in environmental and occupational allergic diseases. The role of exposure to environmental pollutants, respiratory viruses, and allergen exposure showed significant advances. New allergens were identified. Occupational asthma and the relationship of complementary and alternative medicine to allergic diseases were extensively reviewed. New approaches to immunotherapy, novel vaccine techniques, and methods to reduce risks for severe allergic disease were addressed.

  20. Thymostimulin in advanced hepatocellular carcinoma: A phase II trial

    PubMed Central

    Dollinger, Matthias M; Behrens, Christa M; Lesske, Joachim; Behl, Susanne; Behrmann, Curd; Fleig, Wolfgang E

    2008-01-01

    Background Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma in vitro. In a phase II trial, we investigated safety and efficacy including selection criteria for best response in advanced or metastasised hepatocellular carcinoma. Methods 44 patients (84 % male, median age 69 years) not suitable or refractory to conventional therapy received thymostimulin 75 mg subcutaneously five times per week for a median of 8.2 months until progression or complete response. 3/44 patients were secondarily accessible to local ablation or chemoembolisation. Primary endpoint was overall survival, secondary endpoint tumor response or progression-free survival. A multivariate Cox's regression model was used to identify variables affecting survival. Results Median survival was 11.5 months (95% CI 7.9–15.0) with a 1-, 2- and 3-year survival of 50%, 23% and 9%. In the univariate analysis, a low Child-Pugh-score (p = 0.01), a low score in the Okuda- and CLIP-classification (p < 0.001) or a low AFP-level (p < 0.001) were associated with better survival, but not therapy modalities other than thymostimulin (p = 0.1) or signs of an invasive HCC phenotype such as vascular invasion (p = 0.3) and metastases (p = 0.1). The only variables independently related to survival in the Cox's regression model were Okuda stage and presence of liver cirrhosis (p < 0.01) as well as response to thymostimulin (p < 0.05). Of 39/44 patients evaluable for response, two obtained complete responses (one after concomitant radiofrequency ablation), five partial responses (objective response 18%), twenty-four stable disease (tumor control rate 79%) and eight progressed. Median progression-free survival was 6.4 months (95% CI 0.8–12). Grade 1 local reactions following injection were the only side effects. Conclusion Outcome in our study rather depended on liver function and intrahepatic tumor growth (presence of liver cirrhosis and Okuda stage) in addition

  1. Successful Advance Directives through Quality Disease Management.

    PubMed

    Parke, Bob; Krajewski, Adam

    2010-01-01

    Recently there has been talk about the benefit of advance care planning. This is an issue which resurfaces from time to time, as is evident in recent New England Journal of Medicine articles and editorials (April 2010). It has also resurfaced in Canada in a recent document titled Advance Care Planning in Canada: National Framework for Consultation (Health Canada 2010). This document acknowledges that many of us believe in the value of advance directives, finding "that most of the general public (60-90%) is supportive of advance care planning. However, only 10-20% of the public in the US, Canada and Australia have completed an advance care plan of any kind" (Health Canada 2010: 6). In Muriel R. Gillick's editorial in the New England Journal Medicine, she strongly makes the point that few people complete advance directives and further states that "directives have been a resounding failure" (Gillick 2010: 1239). These statements, although not exhaustive on the subject, show that we have a problem translating the support for advance directives into actual plans.

  2. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks

    PubMed Central

    Wolff, Gretchen; Duncan, Marilyn J.

    2013-01-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  3. Advanced Turbine System Program: Phase 2 cycle selection

    SciTech Connect

    Latcovich, J.A. Jr.

    1995-10-01

    The objectives of the Advanced Turbine System (ATS) Phase 2 Program were to define a commercially attractive ATS cycle and to develop the necessary technologies required to meet the ATS Program goals with this cycle. This program is part of an eight-year Department of Energy, Fossil Energy sponsored ATS Program to make a significant improvement in natural gas-fired power generation plant efficiency while providing an environmentally superior and cost-effective system.

  4. [Advances in the diagnostics of Alzheimer's disease].

    PubMed

    Fiedler, U; Wiltfang, J; Peters, N; Benninghoff, J

    2012-05-01

    Due to the demographic developments, diagnosis and treatment, dementia constitutes an increasing medical challenge and is likely to have an increasing socioeconomic impact. Dementia does not reflect a single disease but encompasses a variety of underlying conditions, heterogeneous clinical courses and therapeutic approaches, among which Alzheimer's disease represents the most common cause. Therefore, a thorough differential diagnosis of dementia is of major importance. To date the current diagnosis of dementia according to ICD-10/DMS-IV is based on clinical criteria. In addition, the concept of mild cognitive impairment comprises early cognitive dysfunction without clinically apparent dementia. Alzheimer's disease is more and more conceptualized as a disease continuum with mild cognitive impairment as an early and manifest dementia as the later stage of the disease. This review gives an overview on the current diagnostic approaches and the proposed revisions of diagnostic and research criteria for Alzheimer's disease.

  5. Interdisciplinary Management of Patient with Advanced Periodontal Disease.

    PubMed

    Kochar, Gagan Deep; Jayan, B; Chopra, S S; Mechery, Reenesh; Goel, Manish; Verma, Munish

    2016-01-01

    This case report describes the interdisciplinary management of an adult patient with advanced periodontal disease. Treatment involved orthodontic and periodontal management. Good esthetic results and dental relationships were achieved by the treatment.

  6. Advanced Crystallographic Data Collection Protocols for Experimental Phasing.

    PubMed

    Finke, Aaron D; Panepucci, Ezequiel; Vonrhein, Clemens; Wang, Meitian; Bricogne, Gérard; Oliéric, Vincent

    2016-01-01

    Experimental phasing by single- or multi-wavelength anomalous dispersion (SAD or MAD) has become the most popular method of de novo macromolecular structure determination. Continuous advances at third-generation synchrotron sources have enabled the deployment of rapid data collection protocols that are capable of recording SAD or MAD data sets. However, procedural simplifications driven by the pursuit of high throughput have led to a loss of sophistication in data collection strategies, adversely affecting measurement accuracy from the viewpoint of anomalous phasing. In this chapter, we detail optimized strategies for collecting high-quality data for experimental phasing, with particular emphasis on minimizing errors from radiation damage as well as from the instrument. This chapter also emphasizes data processing for "on-the-fly" decision-making during data collection, a critical process when data quality depends directly on information gathered while at the synchrotron.

  7. Advancing swine models for human health and diseases.

    PubMed

    Walters, Eric M; Prather, Randall S

    2013-01-01

    Swine models are relatively new kids on the block for modeling human health and diseases when compared to rodents and dogs. Because of the similarity to humans in size, physiology, and genetics, the pig has made significant strides in advancing the understanding of the human condition, and is thus an excellent choice for an animal model. Recent technological advances to genetic engineering of the swine genome enhance the utility of swine as models of human genetic diseases.

  8. Advances in designs for Alzheimer's disease clinical trials.

    PubMed

    Cummings, Jeffrey; Gould, Heath; Zhong, Kate

    2012-01-01

    There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer's disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer's Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development.

  9. Advances in designs for Alzheimer’s disease clinical trials

    PubMed Central

    Cummings, Jeffrey; Gould, Heath; Zhong, Kate

    2012-01-01

    There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer’s disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer’s Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development. PMID:23383393

  10. Collaborative Advanced Gas Turbine Program: Phase 1. Final report

    SciTech Connect

    Hollenbacher, R.; Kesser, K.; Beishon, D.

    1994-12-01

    The Collaborative Advanced Gas Turbine (CAGT) Program is an advanced gas turbine research and development program whose goal is to accelerate the commercial availability, to within the turn of the century, of high efficiency aeroderivative gas turbines for electric power generating applications. In the first project phase, research was conducted to prove or disprove the research hypothesis that advanced aeroderivative gas turbine systems can provide a promising technology alternative, offering high efficiency and good environmental performance characteristics in modular sizes, for utility applications. This $5 million, Phase 1 research effort reflects the collaborative efforts of a broad and international coalition of industries and organizations, both public and private, that have pooled their resources to assist in this research. Included in this coalition are: electric and gas utilities, the Electric Power Research Institute, the Gas Research Institute and the principal aircraft engine manufacturers. Additionally, the US Department of Energy (DOE) and the California Energy Commission have interacted with the CAGT on both technical and executive levels as observers and sources of funding. The three aircraft engine manufacturer-led research teams participating in this research include: Rolls-Royce, Inc., and Bechtel; the Turbo Power and Marine Division of United Technologies and Fluor Daniel; and General Electric Power Generation, Stewart and Stevenson, and Bechtel. Each team has investigated advanced electric power generating systems based on their high-thrust (60,000 to 100,000 pounds) aircraft engines. The ultimate goal of the CAGT program is that the community of stakeholders in the growing market for natural-gas-fueled, electric power generation can collectively provide the right combination of market-pull and technology-push to substantially accelerate the commercialization of advanced, high efficiency aeroderivative technologies.

  11. Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

    PubMed Central

    Jain, Rajul K; Hong, David S; Naing, Aung; Wheler, Jennifer; Helgason, Thorunn; Shi, Nai-Yi; Gad, Yash; Kurzrock, Razelle

    2015-01-01

    PURPOSE: Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells - G1, S, and G2/M. METHODS: Temsirolimus (G1 inhibitor), topotecan (S inhibitor), and bortezomib (G2/M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen. RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m2 IV D1, 8; and bortezomib 0.9 mg/m2 IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G2/M and S phases to G1 phase and the quiescent G0 phase. Eighteen percent of subjects (11/62) achieved partial response (n = 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n = 9). CONCLUSION: Combining drugs with inhibitory activity of G1 phase, S phase, and G2/M phase is safe and warrants further evaluation. PMID:26467427

  12. Advances in management of sickle cell disease.

    PubMed

    Agarwal, M B

    2003-08-01

    Sickle cell disease is numerically as common as thalassaemia. However, it affects relatively under privileged population i.e. tribal population belonging to economically poor class and having inadequate access to education and modern health facilities. A recent explosion acknowledged in understanding the pathogenesis of this disease has lead to newer dimensions in treatment. Some of these viz. prevention of overwhelming bacterial infection, present indications and controversies regarding blood transfusion, prevention of stroke, acute chest syndrome, hydroxyurea therapy--probably the best disease modifying agent at the moment, stem cell transplantation--a cure and certain promising experimental therapies including gene therapy have been discussed in this review.

  13. Advances in Biomarker Research in Parkinson's Disease.

    PubMed

    Mehta, Shyamal H; Adler, Charles H

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease, and the numbers are projected to double in the next two decades with the increase in the aging population. An important focus of current research is to develop interventions to slow the progression of the disease. However, prerequisites to it include the development of reliable biomarkers for early diagnosis which would identify at-risk groups and disease progression. In this review, we present updated evidence of already known clinical biomarkers (such as hyposmia and rapid eye movement (REM) sleep behavior disorder (RBD)) and neuroimaging biomarkers, as well as newer possible markers in the blood, CSF, and other tissues. While several promising candidates and methods to assess these biomarkers are on the horizon, it is becoming increasingly clear that no one candidate will clearly fulfill all the roles as a single biomarker. A multimodal and combinatorial approach to develop a battery of biomarkers will likely be necessary in the future.

  14. Advances in the genetics of Parkinson disease.

    PubMed

    Trinh, Joanne; Farrer, Matt

    2013-08-01

    Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.

  15. Chemotherapy in advanced malignant diseases in Iraq

    PubMed Central

    Talib, Hussein

    1971-01-01

    This work discusses the experience of one surgical team in the Third Surgical Unit at the Republican Teaching Hospital, Baghdad, from 1967 to 1970. 112 patients with advanced malignant lesions in various parts of the body were dealt with. In 84, the intra-arterial route was adopted; in the remaining, systemic administration of cytotoxic agents either singly or in combination was employed. The results are reported in terms of subjective and objective response, and the various complications are discussed. ImagesFig. 1Fig. 2 PMID:5137574

  16. [Advances in chronic obstructive pulmonary disease].

    PubMed

    Jiménez, Belén Arnalich; Pumarega, Irene Cano; Ausiró, Anna Mola; Izquierdo Alonso, José Luis

    2009-01-01

    Although chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible, chronic airflow obstruction, from the clinical point of view we must continue to make progress in the diagnosis and management of these patients so that spirometry is not the only technique used. Understanding that COPD is a heterogeneous process and that patient complexity usually increases due to the presence of comorbidities will allow more individualized strategies to be designed, which may improve control of the process. The TORCH and UPLIFT trials have shown that current treatment can improve important aspects of the disease, including mortality. However, the finalizing of these two large trials has generated a current of opinion favoring a more individually-tailored approach that should include all the factors -both pulmonary and extrapulmonary- that can modify the patient's form of presentation. Although we are witnessing a change in the therapeutic approach to COPD, future treatment will probably be based on studies performed in specific patient subgroups and on clarifying the interrelation between COPD and other diseases that are common in these patients. Greater knowledge of the pathogenesis of the disease may improve pharmacological treatment but drugs that, by themselves, alter the short- and longterm course of COPD are not on the horizon. However, a more patient-focussed approach may be the main tool available to physicians to increase quality of life -and possibly survival- in these patients.

  17. Advances in Pediatric Nonalcoholic Fatty Liver Disease

    PubMed Central

    Loomba, Rohit; Sirlin, Claude B.; Schwimmer, Jeffrey B.; Lavine, Joel E.

    2009-01-01

    Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease in children and adolescents in the United States. A two- to three-fold rise in the rates of obesity and overweight in children over the last 2 decades is probably responsible for the epidemic of NAFLD. Emerging data suggest that children with NASH progress to cirrhosis which may ultimately increase liver-related mortality. More worrisome is the recognition that cardiovascular risk and morbidity in children and adolescents is associated with fatty liver. Pediatric fatty liver disease often displays a histologic pattern distinct from that found in adults. Liver biopsy remains the gold standard for diagnosis of NASH. Non-invasive biomarkers are needed to identify individuals with progressive liver injury. Targeted therapies to improve liver histology and metabolic abnormalities associated with fatty liver are needed. Currently, randomized-controlled trials are underway in the pediatric population to define pharmacologic therapy for NAFLD. Public health awareness and intervention are needed to promote healthy diet, exercise, and lifestyle modifications to prevent and reduce the burden of disease in the community. PMID:19637286

  18. Refractory gastroesophageal reflux disease: advances and treatment.

    PubMed

    Ates, Fehmi; Francis, David O; Vaezi, Michael F

    2014-08-01

    'Refractory gastroesophageal reflux disease' is one of the most common misnomers in the area of gastroesophageal reflux disease. The term implies reflux as the underlying etiology despite unresponsiveness to aggressive proton pump inhibitor therapy. The term should be replaced with 'refractory symptoms.' We must acknowledge that in many patients symptoms of reflux often overlap with non-GERD causes such as gastroparesis, dyspepsia, hypersensitive esophagus and functional disorders. Lack of response to aggressive acid suppressive therapy often leads to diagnostic testing. In majority of patients these tests are normal. The role of non-acid reflux in this group is uncertain and patients should not undergo surgical fundoplication based on this parameter. In patients unresponsive to acid suppressive therapy GERD is most commonly not causal and a search for non-GERD causes must ensue.

  19. Prostate cancer: 9. Treatment of advanced disease

    PubMed Central

    Gleave, M E; Bruchovsky, N; Moore, M J; Venner, P

    1999-01-01

    A 70-year-old man is referred to a urologist for recommendations on the management of metastatic prostate cancer. His cancer was diagnosed 5 years ago, and he underwent radical prostatectomy at that time. The tumour was confined to the prostate gland (Gleason score 7), and during surgery the lymph nodes were assessed as being clear of cancer. Before the surgery, the patient's prostate-specific antigen (PSA) level had been 8 ng/mL. After the prostatectomy, PSA was at first undetectable, but recently the PSA level rose to 2 ng/mL and then, at the most recent test, to 16 ng/mL. A bone scan was ordered to investigate back discomfort, which has been persistent but easily controlled with acetaminophen. Unfortunately, the bone scan shows several sites of metastatic disease. The man's medical history includes type 2 diabetes, which has developed during the past 3 years and which is controlled by diet, as well as asymptomatic hypertension, which is managed by means of a thiazide diuretic. The patient asks what treatments are available, what impact they are likely to have on his disease and what risks are associated with the therapies. PMID:9951446

  20. Recent advances in small bowel diseases: Part II

    PubMed Central

    Thomson, Alan BR; Chopra, Angeli; Clandinin, Michael Tom; Freeman, Hugh

    2012-01-01

    As is the case in all areas of gastroenterology and hepatology, in 2009 and 2010 there were many advances in our knowledge and understanding of small intestinal diseases. Over 1000 publications were reviewed, and the important advances in basic science as well as clinical applications were considered. In Part II we review six topics: absorption, short bowel syndrome, smooth muscle function and intestinal motility, tumors, diagnostic imaging, and cystic fibrosis. PMID:22807605

  1. The prediagnostic phase of Parkinson's disease

    PubMed Central

    Noyce, Alastair John; Lees, Andrew John; Schrag, Anette-Eleonore

    2016-01-01

    The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those ‘at risk’. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis. We discuss imaging markers across a range of modalities, and the emerging literature on fluid and peripheral tissue biomarkers. We then explore current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials, what we are learning from these initiatives, and how these studies will bring the field closer to realistically commencing primary or secondary preventive trials for PD. Further progress in this field hinges on greater clinical and biological description, and understanding of the prediagnostic, peridiagnostic and immediate postdiagnostic stages of PD. Identifying subjects 3–5 years before they are currently diagnosed may be an ideal group for neuroprotective trials. At the very least, these initiatives will help clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of disease. PMID:26848171

  2. Advances in environmental and occupational respiratory disease in 2010.

    PubMed

    Peden, David B; Bush, Robert K

    2011-03-01

    2010 Found a number of significant advances in environmental and occupational respiratory disease. The role of sensitization and the subsequent production of allergic disease have been explored. New allergens and their T- and B-cell epitopes have been characterized. Novel approaches to the diagnosis and evaluation of food allergy have been described. The role of pollutants as they affect respiratory disease and the effects of age extremes on sensitization and asthma have been addressed. Significant advances in the understanding of inflammatory changes in both the upper and lower respiratory systems occurred. Novel therapeutic approaches have been explored, including the development of hypoallergens from improved molecular biology techniques. New effective approaches to asthma therapy have been identified. Exposure reduction through air filtration and novel immunotherapy approaches, such as sublingual therapy, have made significant advances.

  3. Alzheimer's disease: recent advances and future perspectives.

    PubMed

    Ubhi, Kiren; Masliah, Eliezer

    2013-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterized by the progressive loss of basal forebrain cholinergic neurons that innervate the hippocampus and cortex and the abnormal extracellular accumulation of amyloid-β and intracellular tau protein. Current research on AD is focused on the mechanisms underlying the abnormal oligomerization, fibrillation, and accumulation of the amyloid-β and tau proteins, mechanisms that may alter the dynamics of this accumulation and on experimental therapeutics approaches aimed at the clearance of the abnormally folded proteins and other potentially neuroprotective interventions. This review will summarize the main areas of investigation in AD and present ways forward for future work.

  4. Kidney disease in children: latest advances and remaining challenges.

    PubMed

    Bertram, John F; Goldstein, Stuart L; Pape, Lars; Schaefer, Franz; Shroff, Rukshana C; Warady, Bradley A

    2016-03-01

    To mark World Kidney Day 2016, Nature Reviews Nephrology invited six leading researchers to highlight the key advances and challenges within their specialist field of paediatric nephrology. Here, advances and remaining challenges in the fields of prenatal patterning, acute kidney injury, renal transplantation, genetics, cardiovascular health, and growth and nutrition, are all discussed within the context of paediatric and neonatal patients with kidney disease. Our global panel of researchers describe areas in which further studies and clinical advances are needed, and suggest ways in which research in these areas should progress to optimize renal care and long-term outcomes for affected patients.

  5. Development of Advanced Fuel Cell System (Phase 4)

    NASA Technical Reports Server (NTRS)

    Meyer, A. P.; Bell, W. F.

    1976-01-01

    A multiple-task research and development program was performed to improve the weight, life, and performance characteristics of hydrogen-oxygen alkaline fuel cells for advanced power systems. During Phase 4, the lowest stabilized degradation rate observed in all the testing completed during four phases of the program, 1 microvolt/hour, was demonstrated. This test continues after 5,000 hours of operation. The cell incorporates a PPf anode, a 90Au/10Pt cathode, a hybrid frame, and a Fybex matrix. These elements were developed under this program to extend cell life. The result demonstrated that the 80Au/20Pt cathode is as stable as a 90Au/10Pt cathode of twice the precious metal loading, was confirmed in full-scale cells. A hybrid frame two-cell plaque with dedicated flow fields and manifolds for all fluids was demonstrated to prevent the cell-to cell electrolyte transfer that limited the endurance of multicell plaques. At the conclusion of Phase 4, more than 90,900 hours of testing had been completed and twelve different cell designs had been evaluated. A technology base has been established which is ready for evaluation at the powerplant level.

  6. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them.

  7. Hypercalcemia of advanced chronic liver disease: a forgotten clinical entity!

    PubMed Central

    Kuchay, Mohammad Shafi; Mishra, Sunil Kumar; Farooqui, Khalid Jamal; Bansal, Beena; Wasir, Jasjeet Singh; Mithal, Ambrish

    2016-01-01

    Summary Hypercalcemia caused by advanced chronic liver disease (CLD) without hepatic neoplasia is uncommonly reported and poorly understood condition. We are reporting two cases of advanced CLD who developed hypercalcemia in the course of the disease. This diagnosis of exclusion was made only after meticulous ruling out of all causes of hypercalcemia. The unique feature of this type of hypercalcemia is its transient nature that may or may not require treatment. This clinical condition in patients with CLD should be kept in mind while evaluating the cause of hypercalcemia in them. PMID:27252737

  8. Glucocerebrosidase and Parkinson disease: Recent advances.

    PubMed

    Schapira, Anthony H V

    2015-05-01

    Mutations of the glucocerebrosidase (GBA) gene are the most important risk factor yet discovered for Parkinson disease (PD). Homozygous GBA mutations result in Gaucher disease (GD), a lysosomal storage disorder. Heterozygous mutations have not until recently been thought to be associated with any pathological process. However, it is clear that the presence of a GBA mutation in homozygous or heterozygous form is associated with an approximately 20-fold increase in the risk for PD, with little if any difference in risk burden related to gene dose. Most studies suggest that 5-10% of PD patients have GBA mutations, although this figure is greater in the Ashkenazi population and may be an underestimate overall if the entire exome is not sequenced. GBA-associated PD is clinically indistinguishable from idiopathic PD, except for slightly earlier age of onset and a greater frequency of cognitive impairment. Pathological and imaging features, and response to pharmacotherapy are identical to idiopathic PD. GBA mutations result in reduced enzyme activity and mutant protein may become trapped in the endoplasmic reticulum (ER) leading to unfolded protein response and ER associated degradation and stress. Both mechanisms may be relevant in GD and PD pathogenesis and lead to impaired lysosomal function. Of particular relevance to PD is the interaction of glucocerebrosidase enzyme (GCase) with alpha-synuclein (SNCA). There appears to be a bi-directional reciprocal relationship between GCase levels and those of SNCA. Thus reduced GCase in GBA mutation PD brain is associated with increased SNCA, and increased SNCA deposition is associated with reduced GCase even in GBA wild-type PD brains. It is noteworthy that GBA mutations are also associated with an increase in risk for dementia with Lewy bodies, another synucleinopathy. It has been suggested that the relationship between GCase and SNCA may be leveraged to reduce SNCA levels in PD by enhancing GCase levels and activity. This

  9. Phase 1 Study of Erlotinib Plus Radiation Therapy in Patients With Advanced Cutaneous Squamous Cell Carcinoma

    SciTech Connect

    Heath, C. Hope; Deep, Nicholas L.; Nabell, Lisle; Carroll, William R.; Desmond, Renee; Clemons, Lisa; Spencer, Sharon; Magnuson, J. Scott; Rosenthal, Eben L.

    2013-04-01

    Purpose: To assess the toxicity profile of erlotinib therapy combined with postoperative adjuvant radiation therapy in patients with advanced cutaneous squamous cell carcinoma. Methods and Materials: This was a single-arm, prospective, phase 1 open-label study of erlotinib with radiation therapy to treat 15 patients with advanced cutaneous head-and-neck squamous cell carcinoma. Toxicity data were summarized, and survival was analyzed with the Kaplan-Meier method. Results: The majority of patients were male (87%) and presented with T4 disease (93%). The most common toxicity attributed to erlotinib was a grade 2-3 dermatologic reaction occurring in 100% of the patients, followed by mucositis (87%). Diarrhea occurred in 20% of the patients. The 2-year recurrence rate was 26.7%, and mean time to cancer recurrence was 10.5 months. Two-year overall survival was 65%, and disease-free survival was 60%. Conclusions: Erlotinib and radiation therapy had an acceptable toxicity profile in patients with advanced cutaneous squamous cell carcinoma. The disease-free survival in this cohort was comparable to that in historical controls.

  10. [Recent advances in immunologic laboratory testing for rheumatic diseases].

    PubMed

    Akahoshi, Tohru

    2004-09-01

    Immunologic laboratory tests serve critical roles in the care of patients with various rheumatic diseases. These tests can provide relevant information of rheumatic diseases based on their immunopathophysiological condition. Although immunologic laboratory tests are quite useful for the determination of diagnosis and the estimation of disease activity, organ involvement and prognosis, they are frequently misused and resulted in an inappropriate diagnosis and treatment. Appropriate use of immunologic laboratory tests and accurate clinical interpretation of the test results can prevent false diagnosis and unnecessary treatment. In order to improve clinical care of patients with rheumatic diseases, clinicians caring patients with rheumatic disease should recognize meanings, characteristics and limitations of each result of immunologic laboratory testing. This article reviewed recent advances in immunologic laboratory testing such as antinuclear antibody, anti-DNA antibody and anti-neutrophil cytoplasmic antibody, and introduced guidelines for these testing. These guidelines based on evidences of EBM may contribute to the appropriate use of immunologic laboratory tests for rheumatic diseases.

  11. Emerging and Neglected Infectious Diseases: Insights, Advances, and Challenges

    PubMed Central

    2017-01-01

    Infectious diseases are a significant burden on public health and economic stability of societies all over the world. They have for centuries been among the leading causes of death and disability and presented growing challenges to health security and human progress. The threat posed by infectious diseases is further deepened by the continued emergence of new, unrecognized, and old infectious disease epidemics of global impact. Over the past three and half decades at least 30 new infectious agents affecting humans have emerged, most of which are zoonotic and their origins have been shown to correlate significantly with socioeconomic, environmental, and ecological factors. As these factors continue to increase, putting people in increased contact with the disease causing pathogens, there is concern that infectious diseases may continue to present a formidable challenge. Constant awareness and pursuance of effective strategies for controlling infectious diseases and disease emergence thus remain crucial. This review presents current updates on emerging and neglected infectious diseases and highlights the scope, dynamics, and advances in infectious disease management with particular focus on WHO top priority emerging infectious diseases (EIDs) and neglected tropical infectious diseases. PMID:28286767

  12. Advances in environmental and occupational respiratory disease in 2007.

    PubMed

    Bush, Robert K; Peden, David

    2008-06-01

    This review of key articles appearing in the Journal in 2008 represents significant advances in the understanding of the interrelationships between the environment and allergic respiratory diseases. New allergens have been identified and characterized. Improvements in diagnostic techniques and methods to assess environmental allergen exposure have been developed. The novel therapeutics and refinements of allergen avoidance approaches will improve patient care. A fuller appreciation of the complexities of environmental factors in allergic diseases can lead to better preventative measures. Lastly, the increasingly important role of pollutants on inflammatory processes is evolving. The articles discussed will add to our increasing knowledge base and advance the ability to more effectively treat patients with allergic respiratory diseases and expand research opportunities.

  13. Recent advances in metabolomics in neurological disease, and future perspectives.

    PubMed

    Zhang, Ai-hua; Sun, Hui; Wang, Xi-jun

    2013-10-01

    Discovery of clinically relevant biomarkers for diseases has revealed metabolomics has potential advantages that classical diagnostic approaches do not. The great asset of metabolomics is that it enables assessment of global metabolic profiles of biofluids and discovery of biomarkers distinguishing disease status, with the possibility of enhancing clinical diagnostics. Most current clinical chemistry tests rely on old technology, and are neither sensitive nor specific for a particular disease. Clinical diagnosis of major neurological disorders, for example Alzheimer's disease and Parkinson's disease, on the basis of current clinical criteria is unsatisfactory. Emerging metabolomics is a powerful technique for discovering novel biomarkers and biochemical pathways to improve diagnosis, and for determination of prognosis and therapy. Identifying multiple novel biomarkers for neurological diseases has been greatly enhanced with recent advances in metabolomics that are more accurate than routine clinical practice. Cerebrospinal fluid (CSF), which is known to be a rich source of small-molecule biomarkers for neurological and neurodegenerative diseases, and is in close contact with diseased areas in neurological disorders, could potentially be used for disease diagnosis. Metabolomics will drive CSF analysis, facilitate and improve the development of disease treatment, and result in great benefits to public health in the long-term. This review covers different aspects of CSF metabolomics and discusses their significance in the postgenomic era, emphasizing the potential importance of endogenous small-molecule metabolites in this emerging field.

  14. Advanced drug delivery and targeting technologies for the ocular diseases

    PubMed Central

    Barar, Jaleh; Aghanejad, Ayuob; Fathi, Marziyeh; Omidi, Yadollah

    2016-01-01

    Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies

  15. Recent advances in small bowel diseases: Part I

    PubMed Central

    Thomson, Alan BR; Chopra, Angeli; Clandinin, Michael Tom; Freeman, Hugh

    2012-01-01

    As is the case in all parts of gastroenterology and hepatology, there have been many advances in our knowledge and understanding of small intestinal diseases. Over 1000 publications were reviewed for 2008 and 2009, and the important advances in basic science as well as clinical applications were considered. In Part I of this Editorial Review, seven topics are considered: intestinal development; proliferation and repair; intestinal permeability; microbiotica, infectious diarrhea and probiotics; diarrhea; salt and water absorption; necrotizing enterocolitis; and immunology/allergy. These topics were chosen because of their importance to the practicing physician. PMID:22807604

  16. Advances in non-dopaminergic treatments for Parkinson's disease

    PubMed Central

    Stayte, Sandy; Vissel, Bryce

    2014-01-01

    Since the 1960's treatments for Parkinson's disease (PD) have traditionally been directed to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has resulted in extensive efforts to develop new therapies that work in ways other than restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a detailed account of their success in animal models and their translation to human clinical trials. We then consider how advances in understanding the mechanisms of PD, genetics, the possibility that PD may consist of multiple disease states, understanding of the etiology of PD in non-dopaminergic regions as well as advances in clinical trial design will be essential for ongoing advances. We conclude that despite the challenges ahead, patients have much cause for optimism that novel therapeutics that offer better disease management and/or which slow disease progression are inevitable. PMID:24904259

  17. Advances in celiac disease and gluten-free diet.

    PubMed

    Niewinski, Mary M

    2008-04-01

    Celiac disease is becoming an increasingly recognized autoimmune enteropathy caused by a permanent intolerance to gluten. Once thought to be a rare disease of childhood characterized by diarrhea, celiac disease is actually a multisystemic disorder that occurs as a result of an immune response to ingested gluten in genetically predisposed individuals. Screening studies have revealed that celiac disease is most common in asymptomatic adults in the United States. Although considerable scientific progress has been made in understanding celiac disease and in preventing or curing its manifestations, a strict gluten-free diet is the only treatment for celiac disease to date. Early diagnosis and treatment, together with regular follow-up visits with a dietitian, are necessary to ensure nutritional adequacy and to prevent malnutrition while adhering to the gluten-free diet for life. The purpose of this review is to provide clinicians with current updated information about celiac disease, its diverse clinical presentation and increased prevalence, the complex pathophysiology and strong genetic predisposition to celiac disease, and its diagnosis. This review focuses in detail on the gluten-free diet and the importance of intense expert dietary counseling for all patients with celiac disease. Recent advances in the gluten-free diet include food allergen labeling as well as the US Food and Drug Administration's proposed definition of the food-labeling term gluten-free. The gluten-free diet is complex and patients need comprehensive nutrition education from a skilled dietitian.

  18. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.

    PubMed

    Braun, Thorsten; Itzykson, Raphael; Renneville, Aline; de Renzis, Benoit; Dreyfus, François; Laribi, Kamel; Bouabdallah, Krimo; Vey, Norbert; Toma, Andrea; Recher, Christian; Royer, Bruno; Joly, Bertrand; Vekhoff, Anne; Lafon, Ingrid; Sanhes, Laurence; Meurice, Guillaume; Oréar, Cédric; Preudhomme, Claude; Gardin, Claude; Ades, Lionel; Fontenay, Michaela; Fenaux, Pierre; Droin, Nathalie; Solary, Eric

    2011-10-06

    Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084.

  19. Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study

    PubMed Central

    André, T; Reyes-Vidal, J M; Fartoux, L; Ross, P; Leslie, M; Rosmorduc, O; Clemens, M R; Louvet, C; Perez, N; Mehmud, F; Scheithauer, W

    2008-01-01

    Advanced biliary tract carcinomas (BTCs) are often diagnosed at an advanced/metastatic stage and have a poor prognosis. The combination of gemcitabine and oxaliplatin (GEMOX) has shown promising activity in this setting. This international phase II study evaluated the efficacy and safety of GEMOX as first-line therapy in patients with advanced BTCs. Eligible patients with previously untreated locally advanced or metastatic BTC received gemcitabine 1000 mg m−2 (day 1) and oxaliplatin 100 mg m−2 (day 2), every 2 weeks. Seventy patients were enroled; 72.9% had metastatic disease. Sixty-seven patients were treated. There were 10 confirmed partial responses (14.9%; 95% confidence interval (CI), 7.4–25.7%) in the treated population (RECIST). Twenty-four patients (35.8 %) had stable disease. The objective response rate was 20.5% in patients with non-gallbladder cancers (9/44 patients) and 4.3% in patients with gallbladder cancers (1/23). Median overall survival for the intent-to-treat population was 8.8 months (95% CI, 6.9–11.1%) and progression-free survival was 3.4 months (95% CI, 2.5–4.6%). Grade 3/4 toxicities included thrombocytopenia (14.9% of patients), alanine aminotransferase elevation (13.4%), anaemia (10.4%), neutropenia (11.9%) and pain (11.9%). In this study, GEMOX demonstrated activity in non-gallbladder carcinoma, but poor activity in gallbladder carcinoma. GEMOX is well tolerated in advanced BTCs. PMID:19238628

  20. Advanced Simulation Capability for Environmental Management (ASCEM) Phase II Demonstration

    SciTech Connect

    Freshley, M.; Hubbard, S.; Flach, G.; Freedman, V.; Agarwal, D.; Andre, B.; Bott, Y.; Chen, X.; Davis, J.; Faybishenko, B.; Gorton, I.; Murray, C.; Moulton, D.; Meyer, J.; Rockhold, M.; Shoshani, A.; Steefel, C.; Wainwright, H.; Waichler, S.

    2012-09-28

    In 2009, the National Academies of Science (NAS) reviewed and validated the U.S. Department of Energy Office of Environmental Management (EM) Technology Program in its publication, Advice on the Department of Energy’s Cleanup Technology Roadmap: Gaps and Bridges. The NAS report outlined prioritization needs for the Groundwater and Soil Remediation Roadmap, concluded that contaminant behavior in the subsurface is poorly understood, and recommended further research in this area as a high priority. To address this NAS concern, the EM Office of Site Restoration began supporting the development of the Advanced Simulation Capability for Environmental Management (ASCEM). ASCEM is a state-of-the-art scientific approach that uses an integration of toolsets for understanding and predicting contaminant fate and transport in natural and engineered systems. The ASCEM modeling toolset is modular and open source. It is divided into three thrust areas: Multi-Process High Performance Computing (HPC), Platform and Integrated Toolsets, and Site Applications. The ASCEM toolsets will facilitate integrated approaches to modeling and site characterization that enable robust and standardized assessments of performance and risk for EM cleanup and closure activities. During fiscal year 2012, the ASCEM project continued to make significant progress in capabilities development. Capability development occurred in both the Platform and Integrated Toolsets and Multi-Process HPC Simulator areas. The new Platform and Integrated Toolsets capabilities provide the user an interface and the tools necessary for end-to-end model development that includes conceptual model definition, data management for model input, model calibration and uncertainty analysis, and model output processing including visualization. The new HPC Simulator capabilities target increased functionality of process model representations, toolsets for interaction with the Platform, and model confidence testing and verification for

  1. Advancing digital methods in the fight against communicable diseases.

    PubMed

    Chabot-Couture, Guillaume; Seaman, Vincent Y; Wenger, Jay; Moonen, Bruno; Magill, Alan

    2015-03-01

    Important advances are being made in the fight against communicable diseases by using new digital tools. While they can be a challenge to deploy at-scale, GPS-enabled smartphones, electronic dashboards and computer models have multiple benefits. They can facilitate program operations, lead to new insights about the disease transmission and support strategic planning. Today, tools such as these are used to vaccinate more children against polio in Nigeria, reduce the malaria burden in Zambia and help predict the spread of the Ebola epidemic in West Africa.

  2. Nutrition Intervention for Advanced Stages of Diabetic Kidney Disease

    PubMed Central

    Kalantar-Zadeh, Kamyar

    2015-01-01

    IN BRIEF For the goals of reducing diabetic kidney disease (DKD) onset and progression, approaches to nutritional therapy are a subject of much debate. This article discusses selected nutrients that have a role in affecting DKD outcomes and introduces application of newer, individualized concepts for healthful eating, as supported by clinical evidence relevant to patients with DKD. Selected aspects of management of advanced DKD are also reviewed. PMID:26300611

  3. Nutrition Intervention for Advanced Stages of Diabetic Kidney Disease.

    PubMed

    Goldstein-Fuchs, Jordi; Kalantar-Zadeh, Kamyar

    2015-08-01

    IN BRIEF For the goals of reducing diabetic kidney disease (DKD) onset and progression, approaches to nutritional therapy are a subject of much debate. This article discusses selected nutrients that have a role in affecting DKD outcomes and introduces application of newer, individualized concepts for healthful eating, as supported by clinical evidence relevant to patients with DKD. Selected aspects of management of advanced DKD are also reviewed.

  4. Linear and Curvilinear Trajectories of Cortical Loss with Advancing Age and Disease Duration in Parkinson's Disease.

    PubMed

    Claassen, Daniel O; Dobolyi, David G; Isaacs, David A; Roman, Olivia C; Herb, Joshua; Wylie, Scott A; Neimat, Joseph S; Donahue, Manus J; Hedera, Peter; Zald, David H; Landman, Bennett A; Bowman, Aaron B; Dawant, Benoit M; Rane, Swati

    2016-05-01

    Advancing age and disease duration both contribute to cortical thinning in Parkinson's disease (PD), but the pathological interactions between them are poorly described. This study aims to distinguish patterns of cortical decline determined by advancing age and disease duration in PD. A convenience cohort of 177 consecutive PD patients, identified at the Vanderbilt University Movement Disorders Clinic as part of a clinical evaluation for Deep Brain Stimulation (age: M= 62.0, SD 9.3), completed a standardized clinical assessment, along with structural brain Magnetic Resonance Imaging scan. Age and gender matched controls (n=53) were obtained from the Alzheimer Disease Neuroimaging Initiative and Progressive Parkinson's Marker Initiative (age: M= 63.4, SD 12.2). Estimated changes in cortical thickness were modeled with advancing age, disease duration, and their interaction. The best-fitting model, linear or curvilinear (2(nd), or 3(rd) order natural spline), was defined using the minimum Akaike Information Criterion, and illustrated on a 3-dimensional brain. Three curvilinear patterns of cortical thinning were identified: early decline, late decline, and early-stable-late. In contrast to healthy controls, the best-fit model for age related changes in PD is curvilinear (early decline), particularly in frontal and precuneus regions. With advancing disease duration, a curvilinear model depicts accelerating decline in the occipital cortex. A significant interaction between advancing age and disease duration is evident in frontal, motor, and posterior parietal areas. Study results support the hypothesis that advancing age and disease duration differentially affect regional cortical thickness and display regional dependent linear and curvilinear patterns of thinning.

  5. Determination of Stabiliser Contents in Advanced Gun Propellants by Reverse Phase High Performance Liquid Chromatography

    DTIC Science & Technology

    1994-03-01

    HIGH PERFORMANCE LIQUID CHROMATOGRAPHY N"m A.R. TURNER AND A. WHITE...TO biEPROOU.; AND SELL THIS REPORT Determination of Stabiliser Contents in Advanced Gun Propellants by Reverse Phase High Performance Liquid Chromatography A.R...8217/......... .. Availability Cooes Dist Avaiardlo A-i Determination of Stabiliser Contents in Advanced Gun Propellants by Reverse Phase High Performance Liquid Chromatography

  6. Cerebrovascular Disease in Children: Recent Advances in Diagnosis and Management

    PubMed Central

    Bowers, Karen J.; deVeber, Gabrielle A.; Ferriero, Donna M.; Roach, E. Steve; Vexler, Zinaida S.; Maria, Bernard L.

    2017-01-01

    Cerebrovascular disease in children manifests in many forms, all of which have devastating and long-lasting effects. Recent advances in diagnostic imaging have revealed that this condition is much more common in the pediatric population than previously believed, affecting as many as 1 in 1500 neonates and 1 in 3000 children. The underlying mechanisms that cause stroke—ischemic stroke, sinovenous thrombosis, and hemorrhagic stroke—are only beginning to be understood; however, progress has been made toward better understanding the mechanisms of disease, particularly in the fields of genetics, inflammation, and thrombus formation. Furthermore, new imaging techniques, and better understanding of how to use imaging in managing stroke, have enabled practitioners to more quickly and accurately identify cerebrovascular disease type in children, which is key to mitigation of negative outcomes. The 2010 Neurobiology of Disease in Children symposium, held in conjunction with the 39th annual meeting of the Child Neurology Society, aimed to (1) describe clinical issues surrounding childhood stroke, including diagnosis and acute care; (2) discuss recent advances in the understanding of the pathogenesis of childhood stroke; (3) review current management of and therapies for childhood stroke, including controversial therapies; and (4) establish research directions for investigators. This article summarizes the speakers’ presentations and includes an edited transcript of question-and-answer sessions. PMID:21778188

  7. Advances in epigenetics and epigenomics for neurodegenerative diseases.

    PubMed

    Qureshi, Irfan A; Mehler, Mark F

    2011-10-01

    In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.

  8. High-speed multilevel phase/amplitude spatial light modulator advances

    NASA Astrophysics Data System (ADS)

    Bauchert, Kipp A.; Serati, Steven A.

    1999-03-01

    Recent and near-term advancements in our multi-level (analog) phase/amplitude liquid crystal spatial light modulators will be presented. These advancements include higher resolution, smaller pixel pitch, planarized pixel pads, and higher speed modulation for phase-only, amplitude-only, and phase- amplitude-coupled modulation. These devices have applications in optical processing, optical storage, holographic display, and beam steering. Design criteria and experimental data will be presented.

  9. FreedomCAR Advanced Traction Drive Motor Development Phase I

    SciTech Connect

    Ley, Josh; Lutz, Jon

    2006-09-01

    The overall objective of this program is to design and develop an advanced traction motor that will meet the FreedomCAR and Vehicle Technologies (FCVT) 2010 goals and the traction motor technical targets. The motor specifications are given in Section 1.3. Other goals of the program include providing a cost study to ensure the motor can be developed within the cost targets needed for the automotive industry. The program has focused on using materials that are both high performance and low costs such that the performance can be met and cost targets are achieved. In addition, the motor technologies and machine design features must be compatible with high volume manufacturing and able to provide high reliability, efficiency, and ruggedness while simultaneously reducing weight and volume. Weight and volume reduction will become a major factor in reducing cost, material cost being the most significant part of manufacturing cost at high volume. Many motor technology categories have been considered in the past and present for traction drive applications, including: brushed direct current (DC), PM (PM) brushless dc (BLDC), alternating current (AC) induction, switched reluctance and synchronous reluctance machines. Of these machine technologies, PM BLDC has consistently demonstrated an advantage in terms of power density and efficiency. As rare earth magnet cost has declined, total cost may also be reduced over the other technologies. Of the many different configurations of PM BLDC machines, those which incorporate power production utilizing both magnetic torque as well as reluctance torque appear to have the most promise for traction applications. There are many different PM BLDC machine configurations which employ both of these torque producing mechanisms; however, most would fall into one of two categories--some use weaker magnets and rely more heavily on reluctance torque (reluctance-dominant PM machines), others use strong PMs and supplement with reluctance torque

  10. Recent advances in the medical treatment of Cushing's disease.

    PubMed

    Fleseriu, Maria

    2014-01-01

    Cushing's disease is a condition of hypercortisolism caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. While rare, it is associated with significant morbidity and mortality, which suggests that early and aggressive intervention is required. The primary, definitive therapy for patients with Cushing's disease in the majority of patients is pituitary surgery, generally performed via a transsphenoidal approach. However, many patients will not achieve remission or they will have recurrences. The consequences of persistent hypercortisolism are severe and, as such, early identification of those patients at risk of treatment failure is exigent. Medical management of Cushing's disease patients plays an important role in achieving long-term remission after failed transsphenoidal surgery, while awaiting effects of radiation or before surgery to decrease the hypercortisolemia and potentially reducing perioperative complications and improving outcome. Medical therapies include centrally acting agents, adrenal steroidogenesis inhibitors and glucocorticoid receptor blockers. Furthermore, several new agents are in clinical trials. To normalize the devastating disease effects of hypercortisolemia, it is paramount that successful patient disease management includes individualized, multidisciplinary care, with close collaboration between endocrinologists, neurosurgeons, radiation oncologists, and general surgeons. This commentary will focus on recent advances in the medical treatment of Cushing's, with a focus on newly approved ACTH modulators and glucocorticoid receptor blockers.

  11. Inspecting Composite Ceramic Armor Using Advanced Signal Processing Together with Phased Array Ultrasound

    DTIC Science & Technology

    2010-01-08

    processing techniques have been developed to help improve phased array ultrasonic inspection and analysis of multi-layered ceramic armor panels. The...INSPECTING COMPOSITE CERAMIC ARMOR USING ADVANCED SIGNAL PROCESSING TOGETHER WITH PHASED ARRAY ULTRASOUND J. S. Steckenrider Illinois College...immersion phased array ultrasound system. Some of these specimens had intentional design defects inserted interior to the specimens. Because of the very

  12. Recent advances in treating Parkinson’s disease

    PubMed Central

    Oertel, Wolfgang H.

    2017-01-01

    This article summarizes (1) the recent achievements to further improve symptomatic therapy of motor Parkinson’s disease (PD) symptoms, (2) the still-few attempts to systematically search for symptomatic therapy of non-motor symptoms in PD, and (3) the advances in the development and clinical testing of compounds which promise to offer disease modification in already-manifest PD. However, prevention (that is, slowing or stopping PD in a prodromal stage) is still a dream and one reason for this is that we have no consensus on primary endpoints for clinical trials which reflect the progression in prodromal stages of PD, such as in rapid eye movement sleep behavior disorder (RBD) —a methodological challenge to be met in the future. PMID:28357055

  13. [Advances in the researches of lutein and alzheimer's disease].

    PubMed

    Xu, Xianrong; Lin, Xiaoming

    2015-05-01

    Lutein, a kind of oxycarotenoid, can pass the blood brain barrier and preferentially accumulate in the human brain, which is the most abundant carotenoid in human brain. Evidence from multiple studies suggested that lutein was closely related to age-related cognitive decline and risk of Alzheimer's disease (AD) in human. Dietary, plasma and brain concentrations of lutein were negatively associated with age-related cognitive decline. Lutein concentrations in plasma and brain were significantly lower in AD patients than those of health control. In human brain, lutein was the sole carotenoid which consistently associated with a range of cognitive function measures. In elderly women, lutein supplement can improve the cognitive function. In this article, we systematically reviewed the literature on the role of lutein in age-related cognitive decline and alzheimer's disease and its possible mechanisms. It may prove some benefit information for the advanced research and prevention of AD.

  14. Two-phase flow measurements with advanced instrumented spool pieces

    SciTech Connect

    Turnage, K.C.

    1980-09-01

    A series of two-phase, air-water and steam-water tests performed with instrumented piping spool pieces is described. The behavior of the three-beam densitometer, turbine meter, and drag flowmeter is discussed in terms of two-phase models. Results from application of some two-phase mass flow models to the recorded spool piece data are shown. Results of the study are used to make recommendations regarding spool piece design, instrument selection, and data reduction methods to obtain more accurate measurements of two-phase flow parameters. 13 refs., 23 figs., 1 tab.

  15. The effects of betatron phase advances on beam-beam and its compensation in RHIC

    SciTech Connect

    Luo, Y.; Fischer, W.; Gu, X.; Tepikian, S.; Trbojevic, D.

    2011-03-28

    In this article we perform simulation studies to investigate the effects of betatron phase advances between the beam-beam interaction points on half-integer resonance driving term, second order chromaticty and dynamic aperture in RHIC. The betatron phase advances are adjusted with artificial matrices inserted in the middle of arcs. The lattices for the 2011 RHIC polarized proton (p-p) run and 2010 RHIC Au-Au runs are used in this study. We also scan the betatron phase advances between IP8 and the electron lens for the proposed Blue ring lattice with head-on beam-beam compensation.

  16. Febuxostat for hyperuricemia in patients with advanced chronic kidney disease.

    PubMed

    Akimoto, Tetsu; Morishita, Yoshiyuki; Ito, Chiharu; Iimura, Osamu; Tsunematsu, Sadao; Watanabe, Yuko; Kusano, Eiji; Nagata, Daisuke

    2014-01-01

    Febuxostat is a nonpurine xanthine oxidase (XO) inhibitor, which recently received marketing approval. However, information regarding the experience with this agent among advanced chronic kidney disease (CKD) patients is limited. In the current study, we investigated the effects of oral febuxostat in patients with advanced CKD with asymptomatic hyperuricemia. We demonstrated, for the first time, that not only the serum levels of uric acid (UA) but also those of 8-hydroxydeoxyguanosine, an oxidative stress marker, were significantly reduced after six months of febuxostat treatment, with no adverse events. These results encouraged us to pursue further investigations regarding the clinical impact of lowering the serum UA levels with febuxostat in advanced CKD patients in terms of concomitantly reducing oxidative stress via the blockade of XO. More detailed studies with a larger number of subjects and assessments of the effects of multiple factors affecting hyperuricemia, such as age, sex, and dietary habits, would shed light on the therapeutic challenges of treating asymptomatic hyperuricemia in patients with various stages of CKD.

  17. [Device-aided therapies in advanced Parkinson's disease].

    PubMed

    Timofeeva, A A

    2016-01-01

    Advanced stages of Parkinson's disease (PD) is a consequence of the severe neurodegenerative process and are characterized by the development of motor fluctuations and dyskinesia, aggravation of non-motor symptoms. Treatment with peroral and transdermal drugs can't provide an adequate control of PD symptoms and quality-of-life of the patients at this stage of disease. Currently, three device-aided therapies: deep brain stimulation (DBS), intrajejunal infusion of duodopa, subcutaneous infusion of apomorphine can be used in treatment of patients with advanced stages of PD. Timely administration of device-aided therapies and right choice of the method determine, to a large extent, the efficacy and safety of their use. Despite the high efficacy of all three methods with respect to the fluctuation of separate symptoms, each method has its own peculiarities. The authors reviewed the data on the expediency of using each method according to the severity of motor and non-motor symptoms, patient's age, PD duration, concomitant pathology and social support of the patients.

  18. Advances in vaccine research against economically important viral diseases of food animals: Infectious bursal disease virus.

    PubMed

    Jackwood, Daral J

    2016-11-22

    Numerous reviews have been published on infectious bursal disease (IBD) and infectious bursal disease virus (IBDV). Many high quality vaccines are commercially available for the control of IBD that, when used correctly, provide solid protection against infection and disease caused by IBDV. Viruses are not static however; they continue to evolve and vaccines need to keep pace with them. The evolution of IBDV has resulted in very virulent strains and new antigenic types of the virus. This review will discuss some of the limitations associated with existing vaccines, potential solutions to these problems and advances in new vaccines for the control of IBD.

  19. Advances in the assessment of disease activity in inflammatory bowel disease

    SciTech Connect

    Camilleri, M.; Proano, M. )

    1989-07-01

    Knowledge of the severity and extent of the inflammation in inflammatory bowel diseases provides a means of determining rational therapeutic strategies in affected patients. During the past 3 decades, several clinical, laboratory, and combined indices have been proposed for the assessment of inflammatory bowel disease; refinements in radiologic methods and the availability of endoscopy and biopsy have facilitated the accurate assessment of the extent and severity of the disease. In relapsing conditions such as inflammatory bowel disease, however, the use of such procedures is limited by the radiation exposure or the relatively invasive nature of the technique. In this article, we review the proposed methods and recent advances in assessment of patients with inflammatory bowel disease; we also discuss possible strategies at the time of diagnosis, during recurrence, and in evaluation of the efficacy of drug or dietic therapy. 58 references.

  20. Advanced mast cell disease: an Italian Hematological Multicenter experience.

    PubMed

    Pagano, Livio; Valentini, Caterina Giovanna; Caira, Morena; Rondoni, Michela; Van Lint, Maria Teresa; Candoni, Anna; Allione, Bernardino; Cattaneo, Chiara; Marbello, Laura; Caramatti, Cecilia; Pogliani, Enrico Maria; Iannitto, Emilio; Giona, Fiorina; Ferrara, Felicetto; Invernizzi, Rosangela; Fanci, Rosa; Lunghi, Monia; Fianchi, Luana; Sanpaolo, Grazia; Stefani, Pietro Maria; Pulsoni, Alessandro; Martinelli, Giovanni; Leone, Giuseppe; Musto, Pellegrino

    2008-12-01

    The aim of the study is to evaluate clinical features, treatments and outcome of patients with systemic mast cell disease (MCD) who arrived to the attention of hematologists. A retrospective study was conducted over 1995-2006 in patients admitted in 18 Italian hematological divisions. Twenty-four cases of advanced MCD were collected: 12 aggressive SM (50%), 8 mast cell leukemia (33%), 4 SM with associated clonal non-mast cell-lineage hematologic disease (17%). Spleen and liver were the principal extramedullary organ involved. The c-kit point mutation D816V was found in 13/18 patients in which molecular biology studies were performed (72%). Treatments were very heterogeneous: on the whole Imatinib was administered in 17 patients, alpha-Interferon in 8, 2-CdA in 3; 2 patients underwent allogeneic hematopoietic stem cell transplantation. The overall response rate to Imatinib, the most frequently employed drugs, was of 29%, registering one complete remission and four partial remission; all responsive patients did not present D816V c-kit mutation. Overall three patients (12%) died for progression of disease. We conclude that MCD is characterized by severe mediator-related symptoms but with a moderate mortality rate. D816V c-kit mutation is frequent and associated with resistance against Imatinib. Because of the rarity of these forms, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies.

  1. Advances in stem cell therapy for cardiovascular disease (Review)

    PubMed Central

    SUN, RONGRONG; LI, XIANCHI; LIU, MIN; ZENG, YI; CHEN, SHUANG; ZHANG, PEYING

    2016-01-01

    Cardiovascular disease constitutes the primary cause of mortality and morbidity worldwide, and represents a group of disorders associated with the loss of cardiac function. Despite considerable advances in the understanding of the pathologic mechanisms of the disease, the majority of the currently available therapies remain at best palliative, since the problem of cardiac tissue loss has not yet been addressed. Indeed, few therapeutic approaches offer direct tissue repair and regeneration, whereas the majority of treatment options aim to limit scar formation and adverse remodeling, while improving myocardial function. Of all the existing therapeutic approaches, the problem of cardiac tissue loss is addressed uniquely by heart transplantation. Nevertheless, alternative options, particularly stem cell therapy, has emerged as a novel and promising approach. This approach involves the transplantation of healthy and functional cells to promote the renewal of damaged cells and repair injured tissue. Bone marrow precursor cells were the first cell type used in clinical studies, and subsequently, preclinical and clinical investigations have been extended to the use of various populations of stem cells. This review addresses the present state of research as regards stem cell therapy for cardiovascular disease. PMID:27220939

  2. Looking forward: novel therapeutic approaches in chronic and advanced phases of myelofibrosis.

    PubMed

    Mascarenhas, John

    2015-01-01

    Myelofibrosis (MF) is complex at the pathobiologic level and heterogeneous at the clinical level. The advances in molecular characterization of MF provide important insight into the mechanisms driving this chronic myeloid malignancy, refine risk stratification, offer novel therapeutic targets, and serve to measure therapeutic response. Although JAK2 inhibition has been the focus of laboratory and clinical efforts over the last decade, current experimental therapeutic approaches have broadened to include inhibitors of key alternative signaling pathways, epigenetic modulators, anti-fibrotics, and immunotherapies. Based on compelling preclinical rationale, a number of JAK2 inhibitor based combination therapies are now actively being evaluated in the clinic with the goal of disease course modification. The role and timing of hematopoietic stem cell transplant (HSCT) for MF has been challenged with the availability of commercial ruxolitinib and the plethora of experimental treatment options that exist. Integration of preconditioning JAK2 inhibition, reduced intensity conditioning regimens, and alternative donor sources are all being explored in an attempt to optimize this potentially curative modality. This review will summarize modern MF risk stratification, current clinical research approaches to chronic and advance phase MF focusing on novel agents alone and in combination, and update the reader on new directions in HSCT.

  3. Advanced worker protection system. Topical report, Phase I

    SciTech Connect

    Myers, J.

    1995-07-01

    The Department of Energy (DOE) is in the process of defining the magnitude and diversity of Decontamination and Decommissioning (D&D) obligations at its numerous sites. The DOE believes that existing technologies are inadequate to solve many challenging problems such as how to decontaminate structures and equipment cost effectively, what to do with materials and wastes generated, and how to adequately protect workers and the environment. Preliminary estimates show a tremendous need for effective use of resources over a relatively long period (over 30 years). Several technologies are being investigated which can potentially reduce D&D costs while providing appropriate protection to DOE workers. The DOE recognizes that traditional methods used by the EPA in hazardous waste site clean up activities are insufficient to provide the needed protection and worker productivity demanded by DOE D&D programs. As a consequence, new clothing and equipment which can adequately protect workers while providing increases in worker productivity are being sought for implementation at DOE sites. This project will result in the development of an Advanced Worker Protection System (AWPS). The AWPS will be built around a life support backpack that uses liquid air to provide cooling as well as breathing gas to the worker. The backpack will be combined with advanced protective garments, advanced liquid cooling garment, respirator, communications, and support equipment to provide improved worker protection, simplified system, maintenance, and dramatically improve worker productivity through longer duration work cycles.

  4. Advanced gastrointestinal endoscopic imaging for inflammatory bowel diseases

    PubMed Central

    Tontini, Gian Eugenio; Rath, Timo; Neumann, Helmut

    2016-01-01

    Gastrointestinal luminal endoscopy is of paramount importance for diagnosis, monitoring and dysplasia surveillance in patients with both, Crohn’s disease and ulcerative colitis. Moreover, with the recent recognition that mucosal healing is directly linked to the clinical outcome of patients with inflammatory bowel disorders, a growing demand exists for the precise, timely and detailed endoscopic assessment of superficial mucosal layer. Further, the novel field of molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy, now encompassing not only diagnosis, surveillance, and treatment but also the prediction of individual therapeutic responses. Within this review, we describe how novel endoscopic approaches and advanced endoscopic imaging methods such as high definition and high magnification endoscopy, dye-based and dye-less chromoendoscopy, confocal laser endomicroscopy, endocytoscopy and molecular imaging now allow for the precise and ultrastructural assessment of mucosal inflammation and describe the potential of these techniques for dysplasia detection. PMID:26811662

  5. Advances in Nanotechnology for the Management of Coronary Artery Disease

    PubMed Central

    Rhee, June-Wha; Wu, Joseph C.

    2013-01-01

    Nanotechnology holds tremendous potential to advance the current treatment of coronary artery disease. Nanotechnology may assist medical therapies by providing a safe and efficacious delivery platform for a variety of drugs aimed at modulating lipid disorders, decreasing inflammation and angiogenesis within atherosclerotic plaques, and preventing plaque thrombosis. Nanotechnology may improve coronary stent applications by promoting endothelial recovery on a stent surface utilizing bio-mimetic nanofibrous scaffolds, and also by preventing in-stent restenosis using nanoparticle-based delivery of drugs that are decoupled from stents. Additionally, nanotechnology may enhance tissue-engineered graft materials for application in coronary artery bypass grafting by facilitating cellular infiltration and remodeling of a graft matrix. PMID:23245913

  6. Nursing staff's understanding expressions of people with advanced dementia disease.

    PubMed

    Eggers, Thomas; Ekman, Sirkka-Liisa; Norberg, Astrid

    2013-01-01

    People with advanced dementia disease (ADD) are known to have communication difficulties and thus it presents a challenge in understanding the expressions of these people. Because successful communication presupposes cooperation at least between 2 individuals, both individual's actions must be acknowledged. The aim of this study is to describe nursing staff's ways of understanding the expressions of people with ADD when communicating with them. Interviews from 8 nursing staff were analyzed using qualitative content analysis. Two themes were constructed: "Being in communication" and "Doing communication." Being in communication means that nursing staff perceive people with ADD as being capable of communication. Doing communication means that nursing staff attempt different individualized strategies to understand what people with ADD communicate. Good care of people with ADD presupposes nursing staff that are willing and able to relate to other people and to maintain good care for people with ADD continuous education and supervision are needed.

  7. CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

    PubMed

    Reiman, Eric M; Langbaum, Jessica B; Tariot, Pierre N; Lopera, Francisco; Bateman, Randall J; Morris, John C; Sperling, Reisa A; Aisen, Paul S; Roses, Allen D; Welsh-Bohmer, Kathleen A; Carrillo, Maria C; Weninger, Stacie

    2016-01-01

    If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

  8. CAP—advancing the evaluation of preclinical Alzheimer disease treatments

    PubMed Central

    Reiman, Eric M.; Langbaum, Jessica B.; Tariot, Pierre N.; Lopera, Francisco; Bateman, Randall J.; Morris, John C.; Sperling, Reisa A.; Aisen, Paul S.; Roses, Allen D.; Welsh-Bohmer, Kathleen A.; Carrillo, Maria C.; Weninger, Stacie

    2016-01-01

    If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer’s Prevention (CAP)—a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact—and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials. PMID:26416539

  9. Advances in the genetic mechanisms of mitochondrial disease.

    PubMed

    Vladutiu, G D

    1997-12-01

    During the past 16 years since the delineation of the human mitochondrial genome, substantial advances have been made in identifying pathogenic mutations causing mitochondrial disorders. However, just as we have come to accept the unexpected in the nontraditional aspects of Mendelian inheritance with the discovery of trinucleotide expansions, imprinting and uniparental disomy, unusual characteristics of mitochondrial inheritance also have been found that defy existing laws. For example, we now know that the nuclear genetic background of an individual might influence the expression and tissue specificity of mitochondrial mutations. Pathogenic mitochondrial DNA mutations contribute to the generation of new mutations by compromising mitochondrial function and increasing free radical production. Evidence for recombination raises new questions about repair mechanisms of mitochondrial DNA. It appears that the more we learn about the bases of mitochondrial disease, the more complex diagnosis, treatment, and genetic counseling become.

  10. Recent advancement of therapeutic endoscopy in the esophageal benign diseases

    PubMed Central

    Bechara, Robert; Inoue, Haruhiro

    2015-01-01

    Over the past 30 years, the field of endoscopy has witnessed several advances. With the advent of endoscopic mucosal resection, removal of large mucosal lesions have become possible. Thereafter, endoscopic submucosal resection was refined, permitting en bloc removal of large superficial neoplasms. Such techniques have facilitated the development of antireflux mucosectomy, a promising novel treatment for gastroesophageal reflux. The introduction and use of over the scope clips has allowed for endoscopic closure of defects in the gastrointestinal tract, which were traditionally treated with surgical intervention. With the development of per-oral endoscopic myotomy (POEM), the treatment of achalasia and spastic disorders of the esophagus have been revolutionized. From the submucosal tunnelling technique developed for POEM, Per oral endoscopic tumor resection of subepithelial tumors was made possible. Simultaneously, advances in biotechnology have expanded esophageal stenting capabilities with the introduction of fully covered metal and plastic stents, as well as biodegradable stents. Once deemed a primarily diagnostic tool, endoscopy has quickly transcended to a minimally invasive intervention and therapeutic tool. These techniques are reviewed with regards to their application to benign disease of the esophagus. PMID:25992187

  11. A novel mouse model of advanced diabetic kidney disease.

    PubMed

    Thibodeau, Jean-Francois; Holterman, Chet E; Burger, Dylan; Read, Naomi C; Reudelhuber, Timothy L; Kennedy, Christopher R J

    2014-01-01

    Currently available rodent models exhibit characteristics of early diabetic nephropathy (DN) such as hyperfiltration, mesangial expansion, and albuminuria yet features of late DN (hypertension, GFR decline, tubulointerstitial fibrosis) are absent or require a significant time investment for full phenotype development. Accordingly, the aim of the present study was to develop a mouse model of advanced DN with hypertension superimposed (HD mice). Mice transgenic for human renin cDNA under the control of the transthyretin promoter (TTRhRen) were employed as a model of angiotensin-dependent hypertension. Diabetes was induced in TTRhRen mice through low dose streptozotocin (HD-STZ mice) or by intercrossing with OVE26 diabetic mice (HD-OVE mice). Both HD-STZ and HD-OVE mice displayed more pronounced increases in urinary albumin levels as compared with their diabetic littermates. Additionally, HD mice displayed renal hypertrophy, advanced glomerular scarring and evidence of tubulointerstitial fibrosis. Both HD-OVE and HD-STZ mice showed evidence of GFR decline as FITC-inulin clearance was decreased compared to hyperfiltering STZ and OVE mice. Taken together our results suggest that HD mice represent a robust model of type I DN that recapitulates key features of human disease which may be significant in studying the pathogenesis of DN and in the assessment of putative therapeutics.

  12. Advanced glycation end products contribute to amyloidosis in Alzheimer disease.

    PubMed Central

    Vitek, M P; Bhattacharya, K; Glendening, J M; Stopa, E; Vlassara, H; Bucala, R; Manogue, K; Cerami, A

    1994-01-01

    Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble beta AP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated beta-amyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified beta AP-nucleation seeds further accelerated aggregation of soluble beta AP compared to non-modified "seed" material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of posttranslational covalent adducts on long-lived proteins in vivo. In a standardized competitive ELISA, plaque fractions of AD brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of beta-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid. PMID:8197133

  13. Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective

    PubMed Central

    Ho, AK; Hocaoglu, MB

    2011-01-01

    Ho AK, Hocaoglu MB for the European Huntington's Disease Network Quality of Life Working Group. Impact of Huntington disease across the entire disease spectrum: the phases and stages of disease from the patient perspective. Although Huntington's disease (HD) is a neurodegenerative disease characterized by motor, cognitive and behavioural disturbances, there has been little empirical data examining what patients are most concerned about throughout the different stages of disease, which can span many years. Semi-structured face-to-face interviews were individually conducted with 31 people living with different stages of Huntington's, from pre-clinical gene carriers to advanced stage. We examined how often participants raised issues and concerns regarding the impact of Huntington's on everyday life. The Physical/functional theme hardly featured pre-clinically, but was strongly present from Stage 1, rose steadily and peaked at Stage 5. There were no significant changes between stages for the Emotional, Social, and Self themes that all featured across all stages, indicating that these issues were not raised more frequently over the course of the disease. Likewise, the more rarely mentioned Financial and Legal themes also remained similar across stages. However, the Cognitive theme only featured between Stages 1 and 4, and hardly at all pre-clinically and at Stage 5. These findings provide insight into patients' important and unique perspective and have implications for the management and development of interventions across the spectrum of HD stages. Section Editor: Aad Tibben, email: a.Tibben@lumc.nl PMID:21736564

  14. Three-phase bone scintigraphy in Pellegrini-Stieda disease.

    PubMed

    Liu, R S; Chou, C S; Yeh, S H

    1987-01-01

    In a patient with Pellegrini-Stieda disease, radiographs of the knees were unremarkable at the time the three-phase bone scintigraphy was abnormal. The results of follow-up radiographs three months later remained normal in the left knee, where local steroid injection was given, but revealed typical positive results in the right knee with no treatment. The three-phase bone scintigraphic pattern is rather typical and antedates the radiographic changes. Thus, the radionuclide technique would provide a useful procedure for the early diagnosis and treatment of Pellegrini-Stieda disease.

  15. Sulfatinib, a novel kinase inhibitor, in patients with advanced solid tumors: Results from a phase I study.

    PubMed

    Xu, Jian Ming; Wang, Yan; Chen, Yu Ling; Jia, Ru; Li, Jie; Gong, Ji Fang; Li, Jing; Qi, Chuan; Hua, Ye; Tan, Cui Rong; Wang, Jian; Li, Ke; Sai, Yang; Zhou, Feng; Ren, Yong Xin; Qing, Wei Guo; Jia, Hong; Su, Wei Guo; Shen, Lin

    2017-02-01

    Sulfatinib is a small molecule kinase inhibitor that targets tumor angiogenesis and immune modulation. This phase I study (NCT02133157) investigated the safety, pharmacokinetic characteristics, and preliminary anti-tumor activity of sulfatinib in patients with advanced solid tumors. The study included a dose-escalation phase (50-350 mg/day, 28-day cycle) with a Fibonacci (3+3) design, and a tumor-specific expansion phase investigating the tumor response to treatment. Two sulfatinib formulations were assessed: formulation 1 (5, 25, and 50 mg capsules) and formulation 2 (50 and 200 mg capsules). Seventy-seven Chinese patients received oral sulfatinib; the maximum tolerated dose was not reached. Dose-limiting toxicities included abnormal hepatic function and coagulation tests, and upper gastrointestinal hemorrhage. The most common treatment-related adverse events were proteinuria, hypertension and diarrhea. Among 34 patients receiving sulfatinib formulation 2, one patient with hepatocellular carcinoma and eight with neuroendocrine tumors exhibited a partial response; 15 had stable disease. The objective response rate was 26.5% (9/34) and the disease control rate was 70.6% (24/34). Pharmacokinetic, safety, and efficacy data supported continuous oral administration of sulfatinib at 300 mg as the recommended phase II dose. Sulfatinib exhibited an acceptable safety profile and encouraging antitumor activity in patients with advanced solid tumors, particularly neuroendocrine tumors.

  16. A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans.

    PubMed

    Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali

    2016-04-15

    Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.

  17. A phase I trial of chlorambucil administered in short pulses in patients with advanced malignancies.

    PubMed

    Blumenreich, M S; Woodcock, T M; Sherrill, E J; Richman, S P; Gentile, P S; Epremian, B E; Kubota, T T; Allegra, J C

    1988-01-01

    We carried out a phase I trial with chlorambucil. Thirty patients with advanced cancer were entered in six dose levels: 36, 48, 60, 84, 108, and 144 mg/m2. The drug was given in six divided oral doses every 6 hours and the regimen was repeated every 3 weeks. The median age was 62 years (31-84), median Karnofsky performance status (KPS) 60 (40-90). All patients but one had received prior radiation therapy, chemotherapy, or both. Central nervous system toxicity was dose limiting, occurring in 5 of 6 patients at 144 mg/m2. It was characterized by transient seizures, hallucinations, lethargy, stupor, and coma. Metoclopramide was successful in controlling nausea and vomiting, which was severe if the antiemetic was not used. Leukopenia (3 patients) and thrombocytopenia (2 patients) were mild. One patient with colorectal carcinoma had a minor response, and two patients with non-small cell lung cancer had stable disease. A safe dose for phase II trials is 108 mg/m2 in six 6-hourly oral doses.

  18. Phase I study of tanespimycin in combination with bortezomib in patients with advanced solid malignancies

    PubMed Central

    Schenk, Erin; Wahner Hendrickson, Andrea E.; Northfelt, Donald; Toft, David O.; Ames, Matthew M.; Menefee, Michael; Satele, Daniel; Qin, Rui; Erlichman, Charles

    2014-01-01

    Summary Purpose To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of tanespimycin when given in combination with bortezomib. Experimental design Phase I dose-escalating trial using a standard cohort “3+3” design performed in patients with advanced solid tumors. Patients were given tanespimycin and bortezomib twice weekly for 2 weeks in a 3 week cycle (days 1, 4, 8, 11 every 21 days). Results Seventeen patients were enrolled in this study, fifteen were evaluable for toxicity, and nine patients were evaluable for tumor response. The MTD was 250 mg/m2 of tanespimycin and 1.0 mg/m2 of bortezomib when used in combination. DLTs of abdominal pain (13%), complete atrioventricular block (7%), fatigue (7%), encephalopathy (7%), anorexia (7%), hyponatremia (7%), hypoxia (7%), and acidosis (7%) were observed. There were no objective responses. One patient had stable disease. Conclusions The recommended phase II dose for twice weekly 17-AAG and PS341 are 250 mg/m2 and 1.0 mg/m2respectively, on days 1, 4, 8 and 11 of a 21 day cycle. PMID:23543109

  19. Efficacy, safety, pharmacokinetics and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: A phase II study

    PubMed Central

    Zhu, Andrew X.; Ancukiewicz, Marek; Supko, Jeffrey G.; Sahani, Dushyant V.; Blaszkowsky, Lawrence S.; Meyerhardt, Jeffrey A.; Abrams, Thomas A.; McCleary, Nadine Jackson; Bhargava, Pankaj; Muzikansky, Alona; Sheehan, Susan; Regan, Eileen; Vasudev, Eamala; Knowles, Michelle; Fuchs, Charles S.; Ryan, David P.; Jain, Rakesh K.; Duda, Dan G.

    2013-01-01

    Purpose We performed a single-arm phase II study of cediranib, a pan-VEGFR tyrosine kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC). Patients and Methods Patients with histologically confirmed measurable advanced HCC and adequate hematologic, hepatic, and renal functions received cediranib 30-mg orally once daily (4 weeks/cycle). The primary endpoint was progression-free survival (PFS) rate at 3 months. Other endpoints included response rates, overall survival (OS), pharmacokinetics (PK) and biomarkers for cediranib. Results Cediranib treatment resulted in an estimated 3-month-PFS rate of 77% [60%, 99%]. Median PFS was 5.3 [3.5,9.7] months, stable disease was seen in 5/17 patients (29%), and median OS was 11.7 [7.5–13.6] months. Grade 3 toxicities included hypertension (29%), hyponatremia (29%) and hyperbilirubinemia (18%). Cediranib PK were comparable to those seen in cancer patients with normal hepatic function. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased after cediranib treatment. PFS was inversely correlated with baseline levels of VEGF, sVEGFR2, and bFGF and with on-treatment levels of bFGF and IGF-1, and directly associated with on-treatment levels of IFN-γ. OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-α, CAIX and CD34+CD133+CD45dim circulating progenitor cells and on-treatment levels of sVEGFR2. Conclusions Despite the limitations of primary endpoint selection, cediranib at 30-mg daily showed a high incidence of toxicity and preliminary evidence of antitumor activity in advanced HCC. Hepatic dysfunction did not appear to affect the steady-state PK of cediranib. Exploratory studies suggested pro-angiogenic and inflammatory factors as potential biomarkers of anti-VEGF therapy in HCC. PMID:23362324

  20. Design of Digital Phase-Locked Loops For Advanced Digital Transponders

    NASA Technical Reports Server (NTRS)

    Nguyen, Tien M.

    1994-01-01

    For advanced digital space transponders, the Digital Phased-Locked Loops (DPLLs) can be designed using the available analog loops. DPLLs considered in this paper are derived from the Analog Phase-Locked Loop (APLL) using S-domain mapping techniques.

  1. Effect of phase advance on the brushless dc motor torque speed respond

    NASA Astrophysics Data System (ADS)

    Mohd, M. S.; Karsiti, M. N.; Mohd, M. S.

    2015-12-01

    Brushless direct current (BLDC) motor is widely used in small and medium sized electric vehicles as it exhibit highest specific power and thermal efficiency as compared to the induction motor. Permanent magnets BLDC rotor create a constant magnetic flux, which limit the motor top speed. As the back electromotive force (EMF) voltage increases proportionally with motor rotational speed and it approaches the amplitude of the input voltage, the phase current amplitude will reach zero. By advancing the phase current, it is possible to extend the maximum speed of the BLDC motor beyond the rated top speed. This will allow smaller BLDC motor to be used in small electric vehicles (EV) and in larger applications will allow the use of BLDC motor without the use of multispeed transmission unit for high speed operation. However, increasing the speed of BLDC will affect the torque speed response. The torque output will decrease as speed increases. Adjusting the phase angle will affect the speed of the motor as each coil is energized earlier than the corresponding rise in the back emf of the coil. This paper discusses the phase advance strategy of Brushless DC motor by phase angle manipulation approaches using external hall sensors. Tests have been performed at different phase advance angles in advance and retard positions for different voltage levels applied. The objective is to create the external hall sensor system to commutate the BLDC motor, to establish the phase advance of the BLDC by varying the phase angle through external hall sensor manipulation, observe the respond of the motor while applying the phase advance by hall sensor adjustment.

  2. Acute Phase Reactants as Novel Predictors of Cardiovascular Disease

    PubMed Central

    Ahmed, M. S.; Jadhav, A. B.; Hassan, A.; Meng, Qing H.

    2012-01-01

    Acute phase reaction is a systemic response which usually follows a physiological condition that takes place in the beginning of an inflammatory process. This physiological change usually lasts 1-2 days. However, the systemic acute phase response usually lasts longer. The aim of this systemic response is to restore homeostasis. These events are accompanied by upregulation of some proteins (positive acute phase reactants) and downregulation of others (negative acute phase reactants) during inflammatory reactions. Cardiovascular diseases are accompanied by the elevation of several positive acute phase reactants such as C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, white blood cell count, secretory nonpancreatic phospholipase 2-II (sPLA2-II), ferritin, and ceruloplasmin. Cardiovascular disease is also accompanied by the reduction of negative acute phase reactants such as albumin, transferrin, transthyretin, retinol-binding protein, antithrombin, and transcortin. In this paper, we will be discussing the biological activity and diagnostic and prognostic values of acute phase reactants with cardiovascular importance. The potential therapeutic targets of these reactants will be also discussed. PMID:24049653

  3. Drosophila models of Alzheimer's disease: advances, limits, and perspectives.

    PubMed

    Bouleau, Sylvina; Tricoire, Hervé

    2015-01-01

    Amyloid-β protein precursor (AβPP) and the microtubule-associated protein tau (MAPT) are the two key players involved in Alzheimer's disease (AD) and are associated with amyloid plaques and neurofibrillary tangles respectively, two key hallmarks of the disease. Besides vertebrate models, Drosophila models have been widely used to understand the complex events leading to AD in relation to aging. Drosophila benefits from the low redundancy of the genome which greatly simplifies the analysis of single gene disruption, sophisticated molecular genetic tools, and reduced cost compared to mammals. The aim of this review is to describe the recent advances in modeling AD using fly and to emphasize some limits of these models. Genetic studies in Drosophila have revealed some key aspects of the normal function of Appl and Tau, the fly homologues of AβPP and MAPT that may be disrupted during AD. Drosophila models have also been useful to uncover or validate several pathological pathways or susceptibility genes, and have been readily implemented in drug screening pipelines. We discuss some limitations of the current models that may arise from differences in structure of Appl and Tau compared to their human counterparts or from missing AβPP or MAPT protein interactors in flies. The advent of new genome modification technologies should allow the development of more realistic fly models and to better understand the relationship between AD and aging, taking advantage of the fly's short lifespan.

  4. Advances in pleural disease management including updated procedural coding.

    PubMed

    Haas, Andrew R; Sterman, Daniel H

    2014-08-01

    Over 1.5 million pleural effusions occur in the United States every year as a consequence of a variety of inflammatory, infectious, and malignant conditions. Although rarely fatal in isolation, pleural effusions are often a marker of a serious underlying medical condition and contribute to significant patient morbidity, quality-of-life reduction, and mortality. Pleural effusion management centers on pleural fluid drainage to relieve symptoms and to investigate pleural fluid accumulation etiology. Many recent studies have demonstrated important advances in pleural disease management approaches for a variety of pleural fluid etiologies, including malignant pleural effusion, complicated parapneumonic effusion and empyema, and chest tube size. The last decade has seen greater implementation of real-time imaging assistance for pleural effusion management and increasing use of smaller bore percutaneous chest tubes. This article will briefly review recent pleural effusion management literature and update the latest changes in common procedural terminology billing codes as reflected in the changing landscape of imaging use and percutaneous approaches to pleural disease management.

  5. Recent Advances in Conjugated Polymer Materials for Disease Diagnosis.

    PubMed

    Lv, Fengting; Qiu, Tian; Liu, Libing; Ying, Jianming; Wang, Shu

    2016-02-10

    The extraordinary optical amplification and light-harvesting properties of conjugated polymers impart sensing systems with higher sensitivity, which meets the primary demands of early cancer diagnosis. Recent advances in the detection of DNA methylation and mutation with polyfluorene derivatives based fluorescence resonance energy transfer (FRET) as a means to modulate fluorescent responses attest to the great promise of conjugated polymers as powerful tools for the clinical diagnosis of diseases. To facilitate the ever-changing needs of diagnosis, the development of detection approaches and FRET signal analysis are highlighted in this review. Due to their exceptional brightness, excellent photostability, and low or absent toxicity, conjugated polymers are verified as superior materials for in-vivo imaging, and provide feasibility for future clinical molecular-imaging applications. The integration of conjugated polymers with clinical research has shown profound effects on diagnosis for the early detection of disease-related biomarkers, as well as in-vivo imaging, which leads to a multidisciplinary scientific field with perspectives in both basic research and application issues.

  6. Advanced Microwave Ferrite Research (AMFeR): Phase Two

    DTIC Science & Technology

    2006-12-31

    well with the measured longitudinal-plane and normal-plane hysteresis and torque curve data. Since the micromagnetic modeling effort has reach maturation...temperature/slow furnace cooling process The hysteresis loops in Fig. 7 show the magnetization curves of different samples measured in perpendicular... Hysteresis loops of sintered Co0 .8Zn 1 2Z ferrite phases were identified by x-ray disks with 5 wt% Bi 20 3 sintering agent at diffraction pattern for low

  7. Advanced Microwave Ferrite Research (AMFeR): Phase Three

    DTIC Science & Technology

    2008-07-31

    10 GHz. Certain deviations from simulation The ferrite hysteresis and ferromagnetic resonance proper- are apparent particularly in the insertion loss...Field (Oe) 12 Frequency (GHz) Fig. 7. Measured hysteresis curve of TT1-1000. Fig. 10. Simulation and measurement Wwrtion loss and isolation of the 0...quality simulation of a ferrite phase shifter. The key team members of this project are divided into two functional groups: Material Science and Microwave

  8. Recent advances in two-phase flow numerics

    SciTech Connect

    Mahaffy, J.H.; Macian, R.

    1997-07-01

    The authors review three topics in the broad field of numerical methods that may be of interest to individuals modeling two-phase flow in nuclear power plants. The first topic is iterative solution of linear equations created during the solution of finite volume equations. The second is numerical tracking of macroscopic liquid interfaces. The final area surveyed is the use of higher spatial difference techniques.

  9. An advanced phase retrieval algorithm in N-step phase-shifting interferometry with unknown phase shifts

    PubMed Central

    Li, Jiaosheng; Zhong, Liyun; Liu, Shengde; Zhou, Yunfei; Xu, Jie; Tian, Jindong; Lu, Xiaoxu

    2017-01-01

    In phase-shifting interferometry with unknown phase shifts, a normalization and orthogonalization phase-shifting algorithm (NOPSA) is proposed to achieve phase retrieval. The background of interferogram is eliminated through using the orthogonality of complex sinusoidal function; and the influence of phase shifts deviation on accuracy of phase retrieval is avoided through both normalization and orthogonalization processing. Compared with the current algorithms with unknown phase shifts, the proposed algorithm reveals significantly faster computation speed, higher accuracy, better stability and non-sensitivity of phase shifts deviation. PMID:28290494

  10. An advanced phase retrieval algorithm in N-step phase-shifting interferometry with unknown phase shifts

    NASA Astrophysics Data System (ADS)

    Li, Jiaosheng; Zhong, Liyun; Liu, Shengde; Zhou, Yunfei; Xu, Jie; Tian, Jindong; Lu, Xiaoxu

    2017-03-01

    In phase-shifting interferometry with unknown phase shifts, a normalization and orthogonalization phase-shifting algorithm (NOPSA) is proposed to achieve phase retrieval. The background of interferogram is eliminated through using the orthogonality of complex sinusoidal function; and the influence of phase shifts deviation on accuracy of phase retrieval is avoided through both normalization and orthogonalization processing. Compared with the current algorithms with unknown phase shifts, the proposed algorithm reveals significantly faster computation speed, higher accuracy, better stability and non-sensitivity of phase shifts deviation.

  11. Advances in Fmoc solid‐phase peptide synthesis

    PubMed Central

    Behrendt, Raymond; White, Peter

    2016-01-01

    Today, Fmoc SPPS is the method of choice for peptide synthesis. Very‐high‐quality Fmoc building blocks are available at low cost because of the economies of scale arising from current multiton production of therapeutic peptides by Fmoc SPPS. Many modified derivatives are commercially available as Fmoc building blocks, making synthetic access to a broad range of peptide derivatives straightforward. The number of synthetic peptides entering clinical trials has grown continuously over the last decade, and recent advances in the Fmoc SPPS technology are a response to the growing demand from medicinal chemistry and pharmacology. Improvements are being continually reported for peptide quality, synthesis time and novel synthetic targets. Topical peptide research has contributed to a continuous improvement and expansion of Fmoc SPPS applications. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. PMID:26785684

  12. Phase 1 Development Testing of the Advanced Manufacturing Demonstrator Engine

    NASA Technical Reports Server (NTRS)

    Case, Nicholas L.; Eddleman, David E.; Calvert, Marty R.; Bullard, David B.; Martin, Michael A.; Wall, Thomas R.

    2016-01-01

    The Additive Manufacturing Development Breadboard Engine (BBE) is a pressure-fed liquid oxygen/pump-fed liquid hydrogen (LOX/LH2) expander cycle engine that was built and operated by NASA at Marshall Space Flight Center's East Test Area. The breadboard engine was conceived as a technology demonstrator for the additive manufacturing technologies for an advanced upper stage prototype engine. The components tested on the breadboard engine included an ablative chamber, injector, main fuel valve, turbine bypass valve, a main oxidizer valve, a mixer and the fuel turbopump. All parts minus the ablative chamber were additively manufactured. The BBE was successfully hot fire tested seven times. Data collected from the test series will be used for follow on demonstration tests with a liquid oxygen turbopump and a regeneratively cooled chamber and nozzle.

  13. Magnetic suspension and balance system advanced study, phase 2

    NASA Technical Reports Server (NTRS)

    Boom, R. W.; Abdelsalam, M. K.; Eyssa, Y. M.; Mcintosh, G. E.

    1990-01-01

    The design improvements for the system encompass 14 or 18 external superconductive coils mounted on a 8 x 8 foot wind tunnel, a superconductive model core magnet on a holmium mandrel to fit an F-16 model, model wings of permanent magnet material Nd2Fe14B, and fiber glass epoxy structure. The Magnetic Suspension and Balance System (MSBS) advanced design is confirmed by the successful construction and test of a full size superconductive model core solenoid with holmium mandrel. The solenoid is 75 cm long and 12.6 cm in diameter and produces 6.1 tesla for a hold time of 47 minutes. An integrated coil system design of a new compact configuration without specific coils for roll or pitch shows promise of simplicity; magnet reductions of 30 percent compared to the most recent 1985 design are possible.

  14. Advanced Packaging and Integration Technologies for Microsensors. Phase 1

    DTIC Science & Technology

    1994-08-12

    CV VU CW %so - U Advanced Packaging & Integration Technologies for " icrosensors Final Report A.AUTN0I) i A. A. Ned and A. D. Kurtz 7. P.i-• N - 0-1O... N •AnMN NAME(SI AND .----- •S$() 6L P•,•E•_-_G •---•wWaOu Kulite Semiconductor Products, Inc. NPOW u•NeUMBE One Willow Tree Rd. Leonia, NJ 07605 I1...T I YaAU W 16UJNU S 17. S ý " cu. . t lmV IC .M N . I& . SO ,-,- C L, •.A T 1% ý, . . C L . ... ... L O • .A .. _ w un Unclassified Unclassified

  15. Field testing advanced geothermal turbodrill (AGT). Phase 1 final report

    SciTech Connect

    Maurer, W.C.; Cohen, J.H.

    1999-06-01

    Maurer Engineering developed special high-temperature geothermal turbodrills for LANL in the 1970s to overcome motor temperature limitations. These turbodrills were used to drill the directional portions of LANL`s Hot Dry Rock Geothermal Wells at Fenton Hill, New Mexico. The Hot Dry Rock concept is to drill parallel inclined wells (35-degree inclination), hydraulically fracture between these wells, and then circulate cold water down one well and through the fractures and produce hot water out of the second well. At the time LANL drilled the Fenton Hill wells, the LANL turbodrill was the only motor in the world that would drill at the high temperatures encountered in these wells. It was difficult to operate the turbodrills continuously at low speed due to the low torque output of the LANL turbodrills. The turbodrills would stall frequently and could only be restarted by lifting the bit off bottom. This allowed the bit to rotate at very high speeds, and as a result, there was excessive wear in the bearings and on the gauge of insert roller bits due to these high rotary speeds. In 1998, Maurer Engineering developed an Advanced Geothermal Turbodrill (AGT) for the National Advanced Drilling and Excavation Technology (NADET) at MIT by adding a planetary speed reducer to the LANL turbodrill to increase its torque and reduce its rotary speed. Drilling tests were conducted with the AGT using 12 1/2-inch insert roller bits in Texas Pink Granite. The drilling tests were very successful, with the AGT drilling 94 ft/hr in Texas Pink Granite compared to 45 ft/hr with the LANL turbodrill and 42 ft/hr with a rotary drill. Field tests are currently being planned in Mexico and in geothermal wells in California to demonstrate the ability of the AGT to increase drilling rates and reduce drilling costs.

  16. Advances in solid-phase extraction disks for environmental chemistry

    USGS Publications Warehouse

    Thurman, E.M.; Snavely, K.

    2000-01-01

    The development of solid-phase extraction (SPE) for environmental chemistry has progressed significantly over the last decade to include a number of new sorbents and new approaches to SPE. One SPE approach in particular, the SPE disk, has greatly reduced or eliminated the use of chlorinated solvents for the analysis of trace organic compounds. This article discusses the use and applicability of various SPE disks, including micro-sized disks, prior to gas chromatography-mass spectrometry for the analysis of trace organic compounds in water. Copyright (C) 2000 Elsevier Science B.V.

  17. Advanced microelectronics research for space applications, phase 2

    NASA Technical Reports Server (NTRS)

    Gaertner, W. W.

    1971-01-01

    Negative-resistance circuits with possible space flight applications are discussed. The basic design approach is to use impedance rotation, i.e., the conversion from capacitance to negative resistance, and from resistance to inductance by the phase shift of the transistor current gain at high frequencies. The subjects discussed in detail are the following: hybrid fabrication of VHF and UHF negative-resistance stages with lumped passive elements; formulation of measurement techniques to characterize transistors and to extend the frequency of negative-resistance transistor amplifiers to higher microwave frequencies; and derivation of transistor characteristics required to increase the frequency range of negative-resistance transistor stages.

  18. Advanced Swimming, Phase II--Advanced Swimmer; Physical Education: 5551.48.

    ERIC Educational Resources Information Center

    Gutting, Dick

    GRADES OR AGES: Grades 7-12. SUBJECT MATTER: Advanced swimming. ORGANIZATION AND PHYSICAL APPEARANCE: The first two sections of the guides are devoted to course guidelines, description, and broad goal statement. The next two sections list behavioral and skill objectives and course content. The fifth section presents learning activities and…

  19. Advanced two-phase digestion of sewage sludge

    SciTech Connect

    Ghosh, S.

    1984-01-01

    This paper describes the development and operating results of a novel configuration of the two-phase digestion concept. The two-phase system, comprises two custom-designed upflow digesters, which were operated in tandem to optimize the liquefying-acidification and acetogenesis-methanation reactions. The results are based on system operation for more than one year with a high-metal-content sewage sludge. During the operating period, the system exhibited an increasing methane yield at hydraulic retention times (HRT) of less than 6 days. With continuing culture enrichment and improvements in reactor design, the methane yield increased from 5 to 6.8 SCF/lb VS added, and then to 7.7 SCF/lb VS added. This methane yield was about 80% of the theoretical methane yield achievable with this sewage sludge--and the highest methane yield reported for sludge at this HRT. Operation of the novel process configuration was very stable and superior to that of conventional single-stage digestion in terms of methane yield, gas generation rate, and net energy production. About 75 weight percent of the organic solids was gasified; this could be the maximum attainable feed conversion efficiency for sludge, considering that between 75% and 80% of this feed is normally biodegradable. 3 references, 7 tables.

  20. Advances in kinase inhibition: treating rheumatic diseases and beyond

    PubMed Central

    Gadina, Massimo

    2014-01-01

    Purpose of review Kinases inhibitors are now used for the treatment of autoimmune diseases. Here are reviewed the most recent findings related to their mechanism of action and some of the newest molecules and targets which are being investigated for autoimmune and inflammatory disorders. Recent findings Similarly to p38 inhibitors, Syk inhibitors have not fulfilled the expectations of researchers and clinicians and will likely not be used therapeutically in autoimmunity. BTK inhibitors remain in the preclinical phase. Studies on the mechanism of action of successful Jak inhibitors have revealed that besides T and B cells, bone cells such as osteoclasts and innate immunity cells such as dendritic cells are positively affected. More specific, novel Jak inhibitors are now in clinical trials and newer Jak inhibitors are being developed. Other kinases are emerging from basic studies as potentially druggable and will surely be investigated. Summary First generation pan-Jak inhibitors can be useful for a wide variety of pathologies. They act on innate immune cells and can promote tolerance. More specific inhibitors will soon be available and these may be used in a disease-specific manner. PMID:24419749

  1. Development of advanced fuel cell system, phase 3

    NASA Technical Reports Server (NTRS)

    Handley, L. M.; Meyer, A. P.; Bell, W. F.

    1975-01-01

    A multiple task research and development program was performed to improve the weight, life, and performance characteristics of hydrogen-oxygen alkaline fuel cells for advanced power systems. Gradual wetting of the anode structure and subsequent long-term performance loss was determined to be caused by deposition of a silicon-containing material on the anode. This deposit was attributed to degradation of the asbestos matrix, and attention was therefore placed on development of a substitute matrix of potassium titanate. An 80 percent gold 20 percent platinum catalyst cathode was developed which has the same performance and stability as the standard 90 percent gold - 10 percent platinum cathode but at half the loading. A hybrid polysulfone/epoxy-glass fiber frame was developed which combines the resistance to the cell environment of pure polysulfone with the fabricating ease of epoxy-glass fiber laminate. These cell components were evaluated in various configurations of full-size cells. The ways in which the baseline engineering model system would be modified to accommodate the requirements of the space tug application are identified.

  2. Advanced catalytic combustors for low pollutant emissions, phase 1

    NASA Technical Reports Server (NTRS)

    Dodds, W. J.

    1979-01-01

    The feasibility of employing the known attractive and distinguishing features of catalytic combustion technology to reduce nitric oxide emissions from gas turbine engines during subsonic, stratospheric cruise operation was investigated. Six conceptual combustor designs employing catalytic combustion were defined and evaluated for their potential to meet specific emissions and performance goals. Based on these evaluations, two parallel-staged, fixed-geometry designs were identified as the most promising concepts. Additional design studies were conducted to produce detailed preliminary designs of these two combustors. Results indicate that cruise nitric oxide emissions can be reduced by an order of magnitude relative to current technology levels by the use of catalytic combustion. Also, these combustors have the potential for operating over the EPA landing-takeoff cycle and at cruise with a low pressure drop, high combustion efficiency and with a very low overall level of emission pollutants. The use of catalytic combustion, however, requires advanced technology generation in order to obtain the time-temperature catalytic reactor performance and durability required for practical aircraft engine combustors.

  3. Design of an advanced two-phase capillary cold plate

    NASA Technical Reports Server (NTRS)

    Chalmers, D. R.; Kroliczek, E. J.; Ku, J.

    1986-01-01

    The functional principles and implementation of capillary pumped loop (CPL) two phase heat transport system for various elements of the Space Station program are described. Circulation of the working fluid by the surface-tension forces in a fine-pore capillary wick is the core principle of CPL systems. The liquid, usually NH3 at the moment, is changed into a vapor by heat absorption at one end of the loop, and the vapor is carrried back along the wick by the surface tension within the wick. NASA specifications and the results of mechanical and thermal tests for prototype cold plate and the capillary pump designs are outlined. The CPL is targeted for installation on free-flying platforms, attached payloads, and power subsystem thermal control systems.

  4. ADVANCED COMPUTATIONAL MODEL FOR THREE-PHASE SLURRY REACTORS

    SciTech Connect

    Goodarz Ahmadi

    2004-10-01

    In this project, an Eulerian-Lagrangian formulation for analyzing three-phase slurry flows in a bubble column was developed. The approach used an Eulerian analysis of liquid flows in the bubble column, and made use of the Lagrangian trajectory analysis for the bubbles and particle motions. The bubble-bubble and particle-particle collisions are included the model. The model predictions are compared with the experimental data and good agreement was found An experimental setup for studying two-dimensional bubble columns was developed. The multiphase flow conditions in the bubble column were measured using optical image processing and Particle Image Velocimetry techniques (PIV). A simple shear flow device for bubble motion in a constant shear flow field was also developed. The flow conditions in simple shear flow device were studied using PIV method. Concentration and velocity of particles of different sizes near a wall in a duct flow was also measured. The technique of Phase-Doppler anemometry was used in these studies. An Eulerian volume of fluid (VOF) computational model for the flow condition in the two-dimensional bubble column was also developed. The liquid and bubble motions were analyzed and the results were compared with observed flow patterns in the experimental setup. Solid-fluid mixture flows in ducts and passages at different angle of orientations were also analyzed. The model predictions were compared with the experimental data and good agreement was found. Gravity chute flows of solid-liquid mixtures were also studied. The simulation results were compared with the experimental data and discussed A thermodynamically consistent model for multiphase slurry flows with and without chemical reaction in a state of turbulent motion was developed. The balance laws were obtained and the constitutive laws established.

  5. Development of Sensors for Ceramic Components in Advanced Propulsion Systems. Phase 2; Temperature Sensor Systems Evaluation

    NASA Technical Reports Server (NTRS)

    Atkinson, W. H.; Cyr, M. A.; Strange, R. R.

    1994-01-01

    The 'development of sensors for ceramic components in advanced propulsion systems' program is divided into two phases. The objectives of Phase 1 were to analyze, evaluate and recommend sensor concepts for the measurement of surface temperature, strain and heat flux on ceramic components for advanced propulsion systems. The results of this effort were previously published in NASA CR-182111. As a result of Phase 1, three approaches were recommended for further development: pyrometry, thin-film sensors, and thermographic phosphors. The objective of Phase 2 were to fabricate and conduct laboratory demonstration tests of these systems. Six materials, mutually agreed upon by NASA and Pratt & Whitney, were investigated under this program. This report summarizes the Phase 2 effort and provides conclusions and recommendations for each of the categories evaluated.

  6. Recent Advances in Traditional Chinese Medicine for Kidney Disease.

    PubMed

    Zhong, Yifei; Menon, Madhav C; Deng, Yueyi; Chen, Yiping; He, John Cijiang

    2015-09-01

    Because current treatment options for chronic kidney disease (CKD) are limited, many patients seek out alternative therapies such as traditional Chinese medicine. However, there is a lack of evidence from large clinical trials to support the use of traditional medicines in patients with CKD. Many active components of traditional medicine formulas are undetermined and their toxicities are unknown. Therefore, there is a need for research to identify active compounds from traditional medicines and understand the mechanisms of action of these compounds, as well as their potential toxicity, and subsequently perform well-designed, randomized, controlled, clinical trials to study the efficacy and safety of their use in patients with CKD. Significant progress has been made in this field within the last several years. Many active compounds have been identified by applying sophisticated techniques such as mass spectrometry, and more mechanistic studies of these compounds have been performed using both in vitro and in vivo models. In addition, several well-designed, large, randomized, clinical trials have recently been published. We summarize these recent advances in the field of traditional medicines as they apply to CKD. In addition, current barriers for further research are also discussed. Due to the ongoing research in this field, we believe that stronger evidence to support the use of traditional medicines for CKD will emerge in the near future.

  7. QUANTITATIVE 7T PHASE IMAGING IN PREMOTOR HUNTINGTON DISEASE

    PubMed Central

    Apple, Alexandra C.; Possin, Katherine L.; Satris, Gabriela; Johnson, Erica; Lupo, Janine M.; Jakary, Angela; Wong, Katherine; Kelley, Douglas A. C.; Kang, Gail A.; Sha, Sharon J.; Kramer, Joel H.; Geschwind, Michael; Nelson, Sarah J.; Hess, Christopher P.

    2014-01-01

    Background and Purpose In vivo MRI and postmortem neuropathological studies have demonstrated elevated iron concentration and atrophy within the striatum of patients with Huntington disease (HD), implicating neuronal loss and iron accumulation in the pathogenesis of this neurodegenerative disorder. We used 7T MRI to determine whether quantitative phase, a putative marker of these endpoints, is altered in subjects with premotor HD. Materials and Methods Local field shift (LFS), calculated from 7T MR phase images, was quantified in 13 subjects with premotor HD and 13 age- and gender-matched controls. All participants underwent 3T and 7T MRI, including volumetric 3T T1 and 7T gradient-recalled echo sequences. LFS maps were created from 7T phase data and registered to caudate ROIs automatically parcellated from the 3T T1 images. HD-specific neurocognitive assessment was also performed and compared to LFS. Results Subjects with premotor HD had smaller caudate nuclear volume and higher LFS than controls. A significant correlation between these measurements was not detected, and prediction accuracy for disease state improved with inclusion of both variables. A positive correlation between LFS and genetic disease burden was also found, and there was a trend towards significant correlations between LFS and neurocognitive tests of working memory and executive function. Conclusion Subjects with premotor HD exhibit differences in 7T MRI phase within the caudate nuclei that correlate with genetic disease burden and trend with neurocognitive assessments. Ultra-high field MRI of quantitative phase may be a useful marker for monitoring neurodegeneration in premanifest HD. PMID:24742810

  8. Estimating disease prevalence in two-phase studies.

    PubMed

    Alonzo, Todd A; Pepe, Margaret Sullivan; Lumley, Thomas

    2003-04-01

    Disease prevalence is ideally estimated using a 'gold standard' to ascertain true disease status on all subjects in a population of interest. In practice, however, the gold standard may be too costly or invasive to be applied to all subjects, in which case a two-phase design is often employed. Phase 1 data consisting of inexpensive and non-invasive screening tests on all study subjects are used to determine the subjects that receive the gold standard in the second phase. Naive estimates of prevalence in two-phase studies can be biased (verification bias). Imputation and re-weighting estimators are often used to avoid this bias. We contrast the forms and attributes of the various prevalence estimators. Distribution theory and simulation studies are used to investigate their bias and efficiency. We conclude that the semiparametric efficient approach is the preferred method for prevalence estimation in two-phase studies. It is more robust and comparable in its efficiency to imputation and other re-weighting estimators. It is also easy to implement. We use this approach to examine the prevalence of depression in adolescents with data from the Great Smoky Mountain Study.

  9. Behavioral and Genetic Dissection of a Mouse Model for Advanced Sleep Phase Syndrome

    PubMed Central

    Jiang, Peng; Striz, Martin; Wisor, Jonathan P.; O'Hara, Bruce F.

    2011-01-01

    Study Objective: The adaptive value of the endogenous circadian clock arises from its ability to synchronize (i.e., entrain) to external light-dark (LD) cycles at an appropriate phase. Studies have suggested that advanced circadian phase alignment might result from shortening of the period length of the clock. Here we explore mechanisms that contribute to an early activity phase in CAST/EiJ (CAST) mice. Methods: We investigated circadian rhythms of wheel-running activity in C57BL/6J (B6), CAST and 2 strains of B6.CAST congenic mice, which carry CAST segments introgressed in a B6 genome. Results: When entrained, all CAST mice initiate daily activity several hours earlier than normal mice. This difference could not be explained by alterations in the endogenous period, as activity onset did not correlate with period length. However, the photic phase-shifting responses in these mice were phase-lagged by 3 hours relative to their activity. Attenuated light masking responses were also found in CAST mice, which allow for activity normally inhibited by light. A previously identified quantitative trait locus (QTL), Era1, which contributes to the early activity trait, was confirmed and refined here using two B6.CAST congenic strains. Surprisingly, these B6.CAST mice exhibited longer rather than shorter endogenous periods, further demonstrating that the advanced phase in these mice is not due to alterations in period. Conclusions: CAST mice have an advanced activity phase similar to human advanced sleep phase syndrome. This advanced phase is not due to its shorter period length or smaller light-induced phase shifts, but appears to be related to both light masking and altered coupling of the circadian pacemaker with various outputs. Lastly, a QTL influencing this trait was confirmed and narrowed using congenic mice as a first step toward gene identification. Citation: Jiang P; Striz M; Wisor JP; O'Hara BF. Behavioral and genetic dissection of a mouse model for advanced sleep

  10. Phase I study of a systemically delivered p53 nanoparticle in advanced solid tumors.

    PubMed

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-05-01

    Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions.

  11. Phase I Study of a Systemically Delivered p53 Nanoparticle in Advanced Solid Tumors

    PubMed Central

    Senzer, Neil; Nemunaitis, John; Nemunaitis, Derek; Bedell, Cynthia; Edelman, Gerald; Barve, Minal; Nunan, Robert; Pirollo, Kathleen F; Rait, Antonina; Chang, Esther H

    2013-01-01

    Selective delivery of therapeutic molecules to primary and metastatic tumors is optimal for effective cancer therapy. A liposomal nanodelivery complex (scL) for systemic, tumor-targeting delivery of anticancer therapeutics has been developed. scL employs an anti-transferrin receptor (TfR), scFv as the targeting molecule. Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, is present in most human cancers. Rather than being transiently permissive for tumor initiation, persistence of p53 dysfunction is a continuing requirement for maintaining tumor growth. Herein, we report results of a first-in-man Phase I clinical trial of restoration of the normal human tumor suppressor gene p53 using the scL nanocomplex (SGT-53). Minimal side effects were observed in this trial in patients with advanced solid tumors. Furthermore, the majority of patients demonstrated stable disease. One patient with adenoid cystic carcinoma had his status changed from unresectable to resectable after one treatment cycle. More significantly, we observed an accumulation of the transgene in metastatic tumors, but not in normal skin tissue, in a dose-related manner. These results show not only that systemically delivered SGT-53 is well tolerated and exhibits anticancer activity, but also supply evidence of targeted tumor delivery of SGT-53 to metastatic lesions. PMID:23609015

  12. An advanced case of indium lung disease with progressive emphysema

    PubMed Central

    Nakano, Makiko; Tanaka, Akiyo; Hirata, Miyuki; Kumazoe, Hiroyuki; Wakamatsu, Kentaro; Kamada, Dan; Omae, Kazuyuki

    2016-01-01

    Objectives: To report the occurrence of an advanced case of indium lung disease with severely progressive emphysema in an indium-exposed worker. Case report: A healthy 42-year-old male smoker was employed to primarily grind indium-tin oxide (ITO) target plates, exposing him to indium for 9 years (1998-2008). In 2004, an epidemiological study was conducted on indium-exposed workers at the factory in which he worked. The subject's serum indium concentration (In-S) was 99.7 μg/l, while his serum Krebs von den Lungen-6 level was 2,350 U/ml. Pulmonary function tests showed forced vital capacity (FVC) of 4.17 l (91.5% of the JRS predicted value), forced expiratory volume in 1 s (FEV1) of 3.19 l (80.8% of predicted), and an FEV1-to-FVC ratio of 76.5%. A high-resolution chest computed tomography (HRCT) scan showed mild interlobular septal thickening and mild emphysematous changes. In 2008, he was transferred from the ITO grinding workplace to an inspection work section, where indium concentrations in total dusts had a range of 0.001-0.002 mg/m3. In 2009, the subject's In-S had increased to 132.1 μg/l, and pulmonary function tests revealed obstructive changes. In addition, HRCT scan showed clear evidence of progressive lung destruction with accompanying severe centrilobular emphysema and interlobular septal thickening in both lung fields. The subject's condition gradually worsened, and in 2015, he was registered with the Japan Organ Transplant Network for lung transplantation (LTx). Conclusions: Heavy indium exposure is a risk factor for emphysema, which can lead to a severity level that requires LTx as the final therapeutic option. PMID:27488043

  13. Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.

    PubMed

    Case, Laura E; Koeberl, Dwight D; Young, Sarah P; Bali, Deeksha; DeArmey, Stephanie M; Mackey, Joanne; Kishnani, Priya S

    2008-12-01

    Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.

  14. Advanced Tracers in PET Imaging of Cardiovascular Disease

    PubMed Central

    Zhang, Wei; Wu, Hua; Liu, Gang

    2014-01-01

    Cardiovascular disease is the leading cause of death worldwide. Molecular imaging with targeted tracers by positron emission tomography (PET) allows for the noninvasive detection and characterization of biological changes at the molecular level, leading to earlier disease detection, objective monitoring of therapies, and better prognostication of cardiovascular diseases progression. Here we review, the current role of PET in cardiovascular disease, with emphasize on tracers developed for PET imaging of cardiovascular diseases. PMID:25389529

  15. Enabling Roles to Reclaim Teacher Agency: Insights from the Advanced Certificate in Teaching (Foundation Phase)

    ERIC Educational Resources Information Center

    Ebrahim, H. B.; Verbeek, D. C.; Mashiya, J. N.

    2011-01-01

    In developing the Advanced Certificate in Teaching (ACT) as a professional qualification for continuing teacher education for early schooling at the University of KwaZulu-Natal we asked the following: "What are the enabling roles foundation phase teachers need to play in order to reclaim their space as agents who significantly influence their…

  16. Phase I Study of LY2606368, a Checkpoint Kinase 1 Inhibitor, in Patients With Advanced Cancer

    PubMed Central

    Infante, Jeffrey; Janku, Filip; Jones, Suzanne; Nguyen, Ly M.; Burris, Howard; Naing, Aung; Bauer, Todd M.; Piha-Paul, Sarina; Johnson, Faye M.; Kurzrock, Razelle; Golden, Lisa; Hynes, Scott; Lin, Ji; Lin, Aimee Bence; Bendell, Johanna

    2016-01-01

    Purpose The primary objective was to determine safety, toxicity, and a recommended phase II dose regimen of LY2606368, an inhibitor of checkpoint kinase 1, as monotherapy. Patients and Methods This phase I, nonrandomized, open-label, dose-escalation trial used a 3 + 3 dose-escalation scheme and included patients with advanced solid tumors. Intravenous LY2606368 was dose escalated from 10 to 50 mg/m2 on schedule 1 (days 1 to 3 every 14 days) or from 40 to 130 mg/m2 on schedule 2 (day 1 every 14 days). Safety measures and pharmacokinetics were assessed, and pharmacodynamics were measured in blood, hair follicles, and circulating tumor cells. Results Forty-five patients were treated; seven experienced dose-limiting toxicities (all hematologic). The maximum-tolerated doses (MTDs) were 40 mg/m2 (schedule 1) and 105 mg/m2 (schedule 2). The most common related grade 3 or 4 treatment-emergent adverse events were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. Grade 4 neutropenia occurred in 73.3% of patients and was transient (typically < 5 days). Febrile neutropenia incidence was low (7%). The LY2606368 exposure over the first 72 hours (area under the curve from 0 to 72 hours) at the MTD for each schedule coincided with the exposure in mouse xenografts that resulted in maximal tumor responses. Minor intra- and intercycle accumulation of LY2606368 was observed at the MTDs for both schedules. Two patients (4.4%) had a partial response; one had squamous cell carcinoma (SCC) of the anus and one had SCC of the head and neck. Fifteen patients (33.3%) had a best overall response of stable disease (range, 1.2 to 6.7 months), six of whom had SCC. Conclusion An LY2606368 dose of 105 mg/m2 once every 14 days is being evaluated as the recommended phase II dose in dose-expansion cohorts for patients with SCC. PMID:27044938

  17. Nutrition for Advanced Chronic Kidney Disease in Adults

    MedlinePlus

    ... peanut oil canola oil Why is knowing about sodium important for someone with advanced CKD? Too much ... who have high blood pressure. High- and Low-sodium Foods High-sodium Foods Low-sodium Alternatives Salt ...

  18. New MS Drug Shows 'Breakthrough' Promise for Advanced Disease

    MedlinePlus

    ... News) -- A new drug slows the progress of multiple sclerosis, including an advanced form of the degenerative nerve ... also proved superior in treating people with relapsing multiple sclerosis, the most common form of MS, compared with ...

  19. Current advances on genetic resistance to rice blast disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rice blast disease caused by the fungal pathogen Magnaporthe oryzae is one of the most threatening fungal diseases resulting in significant annual crop losses worldwide. Blast disease has been effectively managed by a combination of resistant (R) gene deployment, application of fungicides, and suita...

  20. Drug nanocarrier, the future of atopic diseases: Advanced drug delivery systems and smart management of disease.

    PubMed

    Shao, Mei; Hussain, Zahid; Thu, Hnin Ei; Khan, Shahzeb; Katas, Haliza; Ahmed, Tarek A; Tripathy, Minaketan; Leng, Jing; Qin, Hua-Li; Bukhari, Syed Nasir Abbas

    2016-11-01

    Atopic dermatitis (AD) is a chronically relapsing skin inflammatory disorder characterized by perivascular infiltration of immunoglobulin-E (IgE), T-lymphocytes and mast cells. The key pathophysiological factors causing this disease are immunological disorders and the compromised epidermal barrier integrity. Pruritus, intense itching, psychological stress, deprived physical and mental performance and sleep disturbance are the hallmark features of this dermatological complication. Preventive interventions which include educational programs, avoidance of allergens, exclusive care towards skin, and the rational selection of therapeutic regimen play key roles in the treatment of dermatosis. In last two decades, it is evident from a plethora of studies that scientific focus is being driven from conventional therapies to the advanced nanocarrier-based regimen for an effective management of AD. These nanocarriers which include polymeric nanoparticles (NPs), hydrogel NPs, liposomes, ethosomes, solid lipid nanoparticles (SLNs) and nanoemulsion, provide efficient roles for the target specific delivery of the therapeutic payload. The success of these targeted therapies is due to their pharmaceutical versatility, longer retention time at the target site, avoiding off-target effects and preventing premature degradation of the incorporated drugs. The present review was therefore aimed to summarise convincing evidence for the therapeutic superiority of advanced nanocarrier-mediated strategies over the conventional therapies used in the treatment of AD.

  1. Advances in surveillance of periodontitis: the Centers for Disease Control and Prevention periodontal disease surveillance project.

    PubMed

    Eke, Paul I; Thornton-Evans, Gina; Dye, Bruce; Genco, Robert

    2012-11-01

    The Centers for Disease Control and Prevention (CDC) has as one of its strategic goals to support and improve surveillance of periodontal disease. In 2003, the CDC initiated the CDC Periodontal Disease Surveillance Project in collaboration with the American Academy of Periodontology to address population-based surveillance of periodontal disease at the local, state, and national levels. This initiative has made significant advancements toward the goal of improved surveillance, including developing valid self-reported measures that can be obtained from interview-based surveys to predict prevalence of periodontitis in populations. This will allow surveillance of periodontitis at the state and local levels and in countries where clinical resources for surveillance are scarce. This work has produced standard case definitions for surveillance of periodontitis that are now widely recognized and applied in population studies and research. At the national level, this initiative has evaluated the validity of previous clinical examination protocols and tested new protocols on the National Health and Nutrition Examination Survey (NHANES), recommending and supporting funding for the gold-standard full-mouth periodontal examination in NHANES 2009 to 2012. These examinations will generate accurate estimates of the prevalence of periodontitis in the US adult population and provide a superior dataset for surveillance and research. Also, this data will be used to generate the necessary coefficients for our self-report questions for use in subsets of the total US population. The impact of these findings on population-based surveillance of periodontitis and future directions of the project are discussed along with plans for dissemination and translation efforts for broader public health use.

  2. Lifted linear phase filter banks and the polyphase-with-advance representation

    SciTech Connect

    Brislawn, C. M.; Wohlberg, B. E.

    2004-01-01

    A matrix theory is developed for the noncausal polyphase-with-advance representation that underlies the theory of lifted perfect reconstruction filter banks and wavelet transforms as developed by Sweldens and Daubechies. This theory provides the fundamental lifting methodology employed in the ISO/IEC JPEG-2000 still image coding standard, which the authors helped to develop. Lifting structures for polyphase-with-advance filter banks are depicted in Figure 1. In the analysis bank of Figure 1(a), the first lifting step updates x{sub 0} with a filtered version of x{sub 1} and the second step updates x{sub 1} with a filtered version of x{sub 0}; gain factors 1/K and K normalize the lowpass- and highpass-filtered output subbands. Each of these steps is inverted by the corresponding operations in the synthesis bank shown in Figure 1(b). Lifting steps correspond to upper- or lower-triangular matrices, S{sub i}(z), in a cascade-form decomposition of the polyphase analysis matrix, H{sub a}(z). Lifting structures can also be implemented reversibly (i.e., losslessly in fixed-precision arithmetic) by rounding the lifting updates to integer values. Our treatment of the polyphase-with-advance representation develops an extensive matrix algebra framework that goes far beyond the results of. Specifically, we focus on analyzing and implementing linear phase two-channel filter banks via linear phase lifting cascade schemes. Whole-sample symmetric (WS) and half-sample symmetric (HS) linear phase filter banks are characterized completely in terms of the polyphase-with-advance representation. The theory benefits significantly from a number of new group-theoretic structures arising in the polyphase-with-advance matrix algebra from the lifting factorization of linear phase filter banks.

  3. Advancing the understanding of autism disease mechanisms through genetics

    PubMed Central

    de la Torre-Ubieta, Luis; Won, Hyejung; Stein, Jason L; Geschwind, Daniel H

    2016-01-01

    Progress in understanding the genetic etiology of autism spectrum disorders (ASD) has fueled remarkable advances in our understanding of its potential neurobiological mechanisms. Yet, at the same time, these findings highlight extraordinary causal diversity and complexity at many levels ranging from molecules to circuits and emphasize the gaps in our current knowledge. Here we review current understanding of the genetic architecture of ASD and integrate genetic evidence, neuropathology and studies in model systems with how they inform mechanistic models of ASD pathophysiology. Despite the challenges, these advances provide a solid foundation for the development of rational, targeted molecular therapies. PMID:27050589

  4. Performance evaluation of digital phase-locked loops for advanced deep space transponders

    NASA Technical Reports Server (NTRS)

    Nguyen, T. M.; Hinedi, S. M.; Yeh, H.-G.; Kyriacou, C.

    1994-01-01

    The performances of the digital phase-locked loops (DPLL's) for the advanced deep-space transponders (ADT's) are investigated. DPLL's considered in this article are derived from the analog phase-locked loop, which is currently employed by the NASA standard deep space transponder, using S-domain to Z-domain mapping techniques. Three mappings are used to develop digital approximations of the standard deep space analog phase-locked loop, namely the bilinear transformation (BT), impulse invariant transformation (IIT), and step invariant transformation (SIT) techniques. The performance in terms of the closed loop phase and magnitude responses, carrier tracking jitter, and response of the loop to the phase offset (the difference between in incoming phase and reference phase) is evaluated for each digital approximation. Theoretical results of the carrier tracking jitter for command-on and command-off cases are then validated by computer simulation. Both theoretical and computer simulation results show that at high sampling frequency, the DPLL's approximated by all three transformations have the same tracking jitter. However, at low sampling frequency, the digital approximation using BT outperforms the others. The minimum sampling frequency for adequate tracking performance is determined for each digital approximation of the analog loop. In addition, computer simulation shows that the DPLL developed by BT provides faster response to the phase offset than IIT and SIT.

  5. Emittance and Phase Space Exchange for Advanced Beam Manipulation and Diagnostics

    SciTech Connect

    Xiang, Dao; Chao, Alex; /SLAC

    2012-04-27

    Alternative chicane-type beam lines are proposed for exact emittance exchange between transverse phase space (x,x') and longitudinal phase space (z,{delta}), where x is the transverse position, x' is the transverse divergence, and z and {delta} are relative longitudinal position and energy deviation with respect to the reference particle. Methods to achieve exact phase space exchanges, i.e., mapping x to z, x' to {delta}, z to x, and {delta} to x', are suggested. Schemes to mitigate and completely compensate for the thick-lens effect of the transverse cavity on emittance exchange are studied. Some applications of the phase space exchange for advanced beam manipulation and diagnostics are discussed.

  6. Recent advances in synchrotron-based hard x-ray phase contrast imaging

    NASA Astrophysics Data System (ADS)

    Liu, Y.; Nelson, J.; Holzner, C.; Andrews, J. C.; Pianetta, P.

    2013-12-01

    Ever since the first demonstration of phase contrast imaging (PCI) in the 1930s by Frits Zernike, people have realized the significant advantage of phase contrast over conventional absorption-based imaging in terms of sensitivity to ‘transparent’ features within specimens. Thus, x-ray phase contrast imaging (XPCI) holds great potential in studies of soft biological tissues, typically containing low Z elements such as C, H, O and N. Particularly when synchrotron hard x-rays are employed, the favourable brightness, energy tunability, monochromatic characteristics and penetration depth have dramatically enhanced the quality and variety of XPCI methods, which permit detection of the phase shift associated with 3D geometry of relatively large samples in a non-destructive manner. In this paper, we review recent advances in several synchrotron-based hard x-ray XPCI methods. Challenges and key factors in methodological development are discussed, and biological and medical applications are presented.

  7. Advances and Limitations of Disease Biogeography Using Ecological Niche Modeling.

    PubMed

    Escobar, Luis E; Craft, Meggan E

    2016-01-01

    Mapping disease transmission risk is crucial in public and animal health for evidence based decision-making. Ecology and epidemiology are highly related disciplines that may contribute to improvements in mapping disease, which can be used to answer health related questions. Ecological niche modeling is increasingly used for understanding the biogeography of diseases in plants, animals, and humans. However, epidemiological applications of niche modeling approaches for disease mapping can fail to generate robust study designs, producing incomplete or incorrect inferences. This manuscript is an overview of the history and conceptual bases behind ecological niche modeling, specifically as applied to epidemiology and public health; it does not pretend to be an exhaustive and detailed description of ecological niche modeling literature and methods. Instead, this review includes selected state-of-the-science approaches and tools, providing a short guide to designing studies incorporating information on the type and quality of the input data (i.e., occurrences and environmental variables), identification and justification of the extent of the study area, and encourages users to explore and test diverse algorithms for more informed conclusions. We provide a friendly introduction to the field of disease biogeography presenting an updated guide for researchers looking to use ecological niche modeling for disease mapping. We anticipate that ecological niche modeling will soon be a critical tool for epidemiologists aiming to map disease transmission risk, forecast disease distribution under climate change scenarios, and identify landscape factors triggering outbreaks.

  8. Advances and Limitations of Disease Biogeography Using Ecological Niche Modeling

    PubMed Central

    Escobar, Luis E.; Craft, Meggan E.

    2016-01-01

    Mapping disease transmission risk is crucial in public and animal health for evidence based decision-making. Ecology and epidemiology are highly related disciplines that may contribute to improvements in mapping disease, which can be used to answer health related questions. Ecological niche modeling is increasingly used for understanding the biogeography of diseases in plants, animals, and humans. However, epidemiological applications of niche modeling approaches for disease mapping can fail to generate robust study designs, producing incomplete or incorrect inferences. This manuscript is an overview of the history and conceptual bases behind ecological niche modeling, specifically as applied to epidemiology and public health; it does not pretend to be an exhaustive and detailed description of ecological niche modeling literature and methods. Instead, this review includes selected state-of-the-science approaches and tools, providing a short guide to designing studies incorporating information on the type and quality of the input data (i.e., occurrences and environmental variables), identification and justification of the extent of the study area, and encourages users to explore and test diverse algorithms for more informed conclusions. We provide a friendly introduction to the field of disease biogeography presenting an updated guide for researchers looking to use ecological niche modeling for disease mapping. We anticipate that ecological niche modeling will soon be a critical tool for epidemiologists aiming to map disease transmission risk, forecast disease distribution under climate change scenarios, and identify landscape factors triggering outbreaks. PMID:27547199

  9. [Advances in research of dihydroartemisinin against parasitic diseases].

    PubMed

    Li, Hong-Jun; Wang, Wei; Liang, You-Sheng

    2011-08-01

    Dihydroartemisinin, the main metabolite of artemisinin and two artemisinin derivatives, artemether and artesunate, is a broad-spectrum anti-parasitic drug. The present paper systematically reviews the advances in research of dihydroartemisinin against Plasmodium, Schistosoma, Pneumocystis, Toxoplasma, Trichomonas vaginalis, Leishmania, Giardia lamblia.

  10. Advances in Raman spectroscopy for the diagnosis of Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Sudworth, Caroline D.; Archer, John K. J.; Black, Richard A.; Mann, David

    2006-02-01

    Within the next 50 years Alzheimer's disease is expected to affect 100 million people worldwide. The progressive decline in the mental health of the patient is caused by severe brain atrophy generated by the breakdown and aggregation of proteins, resulting in β-amyloid plaques and neurofibrillary tangles. The greatest challenge to Alzheimer's disease lies in the pursuit of an early and definitive diagnosis, in order that suitable treatment can be administered. At the present time, definitive diagnosis is restricted to post-mortem examination. Alzheimer's disease also remains without a long-term cure. This research demonstrates the potential role of Raman spectroscopy, combined with principle components analysis (PCA), as a diagnostic method. Analyses of ethically approved ex vivo post-mortem brain tissues (originating from frontal and occipital lobes) from control (3 normal elderly subjects and 3 Huntingdon's disease subjects) and Alzheimer's disease (12 subjects) brain sections, and a further set of 12 blinded samples are presented. Spectra originating from these tissues are highly reproducible, and initial results indicate a vital difference in protein content and conformation, relating to the abnormally high levels of aggregated proteins in the diseased tissues. Further examination of these spectra using PCA allows for the separation of control from diseased tissues. The validation of the PCA models using blinded samples also displays promise for the identification of Alzheimer's disease, in conjunction with secondary information regarding other brain diseases and dementias. These results provide a route for Raman spectroscopy as a possible non-invasive, non-destructive tool for the early diagnosis of Alzheimer's disease.

  11. UTILITY ADVANCED TURBINE SYSTEMS (ATS) TECHNOLOGY READINESS TESTING: PHASE 3R

    SciTech Connect

    1999-09-01

    The overall objective of the Advanced Turbine System (ATS) Phase 3 Cooperative Agreement between GE and the US Department of Energy (DOE) is the development of the GE 7H and 9H combined cycle power systems. The major effort will be expended on detail design. Validation of critical components and technologies will be performed, including: hot gas path component testing, sub-scale compressor testing, steam purity test trials, and rotational heat transfer confirmation testing. Processes will be developed to support the manufacture of the first system, which was to have been sited and operated in Phase 4 but will now be sited and operated commercially by GE. This change has resulted from DOE's request to GE for deletion of Phase 4 in favor of a restructured Phase 3 (as Phase 3R) to include full speed, no load (FSNL) testing of the 7H gas turbine. Technology enhancements that are not required for the first machine design but will be critical for future ATS advances in performance, reliability, and costs will be initiated. Long-term tests of materials to confirm design life predictions will continue. A schematic of the GE H machine is shown. This report summarizes work accomplished in 2Q99.

  12. Orbit transfer rocket engine technology program. Phase 2: Advanced engine study

    NASA Technical Reports Server (NTRS)

    Erickson, C.; Martinez, A.; Hines, B.

    1987-01-01

    In Phase 2 of the Advanced Engine Study, the Failure Modes and Effects Analysis (FMEA) maintenance-driven engine design, preliminary maintenance plan, and concept for space operable disconnects generated in Phase 1 were further developed. Based on the results of the vehicle contractors Orbit Transfer Vehicle (OTV) Concept Definition and System Analysis Phase A studies, minor revisions to the engine design were made. Additional refinements in the engine design were identified through further engine concept studies. These included an updated engine balance incorporating experimental heat transfer data from the Enhanced Heat Load Thrust Chamber Study and a Rao optimum nozzle contour. The preliminary maintenance plan of Phase 1 was further developed through additional studies. These included a compilation of critical component lives and life limiters and a review of the Space Shuttle Main Engine (SSME) operations and maintenance manual in order to begin outlining the overall maintenance procedures for the Orbit Transfer Vehicle Engine and identifying technology requirements for streamlining space-based operations. Phase 2 efforts also provided further definition to the advanced fluid coupling devices including the selection and preliminary design of a preferred concept and a preliminary test plan for its further development.

  13. Assessment of impact of advanced energy transmission fluids on district heating and cooling systems (Phase 1)

    SciTech Connect

    Kasza, K.E.; Chen, M.M.

    1987-09-01

    Argonne National Laboratory (ANL), under sponsorship of the US Department of Energy (DOE) Office of Buildings and Community Systems, has embarked upon a comprehensive, long-range program to develop high-performance advanced energy transmission fluids for use in district heating and cooling (DHC) systems. ANL has the lead technical role in this DOE program. These advanced fluids will substantially reduce flow frictional losses and enhance energy transfer. In system enhancement scoping studies conducted by ANL, the fluids yielded potentially significant upfront capital equipment cost reductions by allowing the use of smaller pipes, pumps, heat exchangers, and storage tanks as well as reductions in operational costs. This report presents the first-phase results of assessment of impact of the advanced fluids on DHC systems. Future reports will focus on assessment of impact on hardware performance, capital eqiupment, and operation costs. 9 refs., 30 figs., 2 tab.

  14. Advanced conceptual design report. Phase II. Liquid effluent treatment and disposal Project W-252

    SciTech Connect

    1995-01-31

    This Advanced Conceptual Design Report (ACDR) provides a documented review and analysis of the Conceptual Design Report (CDR), WHC-SD-W252-CDR-001, June 30, 1993. The ACDR provides further design evaluation of the major design approaches and uncertainties identified in the original CDR. The ACDR will provide a firmer basis for the both the design approach and the associated planning for the performance of the Definitive Design phase of the project.

  15. Aircrew Training Devices: Utility and Utilization of Advanced Instructional Features. Phase III. Electronic Warfare Trainers.

    DTIC Science & Technology

    1986-04-01

    Devices: Utility and Utilization of Advanced Instructional Features (Phase III- Electronic Warfare Trainers) 12 PERSONAL AUTHOR(S) Polzella . Donald J...Features, addressed a portion of this subthrust. Dr. Wayne Waag (AFHRL/OTU) was the Contract Monitor and Dr. Donald J. Polzella and Dr. David C. Hubbard...training is practicable (see Polzella , 1983, p.8). However, instructional features are expensive to implement, especially those features that require the

  16. Aspirin-exacerbated respiratory disease: pathophysiological insights and clinical advances

    PubMed Central

    Steinke, John W; Wilson, Jeff M

    2016-01-01

    Asthma and chronic rhinosinusitis are heterogeneous airway diseases of the lower and upper airways, respectively. Molecular and cellular studies indicate that these diseases can be categorized into unique endotypes, which have therapeutic implications. One such endotype is aspirin-exacerbated respiratory disease (AERD), which encompasses the triad of asthma, aspirin (or nonsteroidal anti-inflammatory drug) hypersensitivity, and nasal polyposis. AERD has unique pathophysiological features that distinguish it from aspirin-tolerant asthma and other forms of chronic rhinosinusitis. This review details molecular and cellular features of AERD and highlights current and future therapies that are based on these insights. PMID:27022293

  17. The advance of tomato disease-related microRNAs.

    PubMed

    Wang, Weichen; Luan, Yushi

    2015-07-01

    Tomato is a model plant for studying plant-pathogen interactions. As regulatory factors, microRNAs (miRNAs) have been widely identified and play crucial roles in tomato-pathogen interactions, including host defense and pathogen counter-defense. Here, the review summarizes the discoveries and highlights of miRNAs in tomato diseases. Roles of artificial miRNAs in disease resistance are further discussed. Hence, a better understanding of the contribution of miRNAs in tomato disease will shed light on strategies in enhancing tomato-pathogen resistance.

  18. Periodontitis and Buerger’s Disease: Recent Advances

    PubMed Central

    Pavlic, Verica; Vujic-Aleksic, Vesna; Zubovic, Nina; Gojkov-Vukelic, Mirjana

    2013-01-01

    Buerger’s disease (BD) is a relatively rare thrombotic, occlusive and non-atherosclerotic clinical syndrome of unknown etiology. In recent years, numerous epidemiological studies confirmed the strong association between chronic anaerobic periodontal infection and development of cardiovascular diseases, including BD. Therefore, the aim of this study is to clarify association between periodontal pathogens and Buerger’s disease. Confirmation of presence and identification of periopathogens in patients with BD can be considered crucial in developing novel therapies for BD. Further, periodontal therapy will lead to eventual improvement of BD patients’ condition. PMID:24554799

  19. Advances in the genetically-complex autoinflammatory diseases

    PubMed Central

    Ombrello, Michael J.

    2015-01-01

    Monogenic diseases usually demonstrate Mendelian inheritance and are caused by highly penetrant genetic variants of a single gene. In contrast, genetically-complex diseases arise from a combination of multiple genetic and environmental factors. The concept of autoinflammation originally emerged from the identification of individual, activating lesions of the innate immune system as the molecular basis of the hereditary periodic fever syndromes. In addition to these rare, monogenic forms of autoinflammation, genetically-complex autoinflammatory diseases like the periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, chronic recurrent multifocal osteomyelitis (CRMO), Behçet’s disease, and systemic arthritis also fulfill the definition of autoinflammatory diseases - namely the development of apparently unprovoked episodes of inflammation without identifiable exogenous triggers and in the absence of autoimmunity. Interestingly, investigations of these genetically-complex autoinflammatory diseases have implicated both innate and adaptive immune abnormalities, blurring the line between autoinflammation and autoimmunity. This reinforces the paradigm of concerted innate and adaptive immune dysfunction leading to genetically-complex autoinflammatory phenotypes. PMID:26077134

  20. Advances in the pharmacological management of Huntington's disease.

    PubMed

    Frank, Samuel; Jankovic, Joseph

    2010-03-26

    There is inevitable physical, cognitive and behavioural decline in Huntington's disease (HD), a dominantly inherited progressive neurological disorder. The hallmark of the disease is chorea, an involuntary brief movement that tends to flow between body regions. HD is diagnosed clinically with genetic confirmation. Predictive testing is available; however, it should be undertaken with caution in patients at risk for the disease but without clinical disease expression. Ongoing observational trials have identified not only early subtle motor signs, but also striatal volume, verbal memory and olfaction as possible early manifestations of clinical disease. Multiple areas of the brain degenerate, with dopamine, glutamate and GABA being the predominant neurotransmitters affected in HD. Although many pharmacotherapies have been evaluated targeting these neurotransmitters, few well conducted trials for symptomatic or neuroprotective interventions have yielded positive results. Tetrabenazine is one of the better studied and more effective agents for reducing chorea, although with a risk of potentially serious adverse effects. Newer antipsychotic agents such as olanzapine and aripiprazole may have adequate efficacy with a more favourable adverse-effect profile than older antipsychotics for treating chorea and psychosis. In this review, the pathogenesis, epidemiology and diagnosis of HD are discussed as background for understanding potential pharmacological treatment options. Potential strategies to delay the progression of HD that have been studied and are planned for the future are summarized. Although there is no current method to change the course of this devastating disease, education and symptomatic therapies are effective tools available to clinicians and the families affected by HD.

  1. Combination of Light and Melatonin Time Cues for Phase Advancing the Human Circadian Clock

    PubMed Central

    Burke, Tina M.; Markwald, Rachel R.; Chinoy, Evan D.; Snider, Jesse A.; Bessman, Sara C.; Jung, Christopher M.; Wright, Kenneth P.

    2013-01-01

    Study Objectives: Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure. Design: Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m2)-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m2)-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time. Setting: Sleep and chronobiology laboratory environment free of time cues. Participants: Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD). Results: Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances. Conclusion: Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders. Citation: Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian

  2. Disease evaluations and agronomic traits of advanced peanut breeding lines in 2016

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Peanut disease evaluations of advanced breeding lines are conducted annually to compare the agronomic traits (crop value, yield, seed grade, and characteristics) and disease resistance of cultivars that are currently available or close to being released for the Southwest. In 2016, a total of 21 com...

  3. A class of optimum digital phase locked loops for the DSN advanced receiver

    NASA Technical Reports Server (NTRS)

    Hurd, W. J.; Kumar, R.

    1985-01-01

    A class of optimum digital filters for digital phase locked loop of the deep space network advanced receiver is discussed. The filter minimizes a weighted combination of the variance of the random component of the phase error and the sum square of the deterministic dynamic component of phase error at the output of the numerically controlled oscillator (NCO). By varying the weighting coefficient over a suitable range of values, a wide set of filters are obtained such that, for any specified value of the equivalent loop-noise bandwidth, there corresponds a unique filter in this class. This filter thus has the property of having the best transient response over all possible filters of the same bandwidth and type. The optimum filters are also evaluated in terms of their gain margin for stability and their steady-state error performance.

  4. A multicenter phase II study of irinotecan in patients with advanced colorectal cancer previously treated with 5-fluorouracil.

    PubMed

    Méndez, Miguel; Salut, Antonieta; García-Girón, Carlos; Navalon, Marta; Diz, Pilar; García López, Maria José; España, Pilar; de la Torre, Ascensión; Martínez del Prado, Purificación; Duarte, Isabel; Pujol, Eduardo; Arizcun, Alberto; Cruz, Juan Jesús

    2003-11-01

    This multicenter, open-label, phase II study was performed to assess the efficacy and toxicity of irinotecan 350 mg/m2 intravenously every 3 weeks in patients with advanced colorectal cancer (CRC) previously treated with 5-fluorouracil (5-FU). The study enrolled 115 patients and a total of 558 cycles (median, 6 per patient) were administered. The overall objective response rate on an intent-to-treat basis was 18% (with 1 complete response and 20 partial responses), whereas 42 patients (37%) showed stable disease. Median time to progression was 4.8 months and median survival was 13.6 months. Grade 3/4 toxicities included delayed diarrhea (19.1%), nausea/vomiting (10.4%), and neutropenia (8.7%). There were 2 toxic deaths, 1 from delayed diarrhea and 1 from hemorrhage and grade 4 mucositis. In conclusion, the present study confirms the antitumor efficacy of irinotecan monotherapy in patients with CRC pretreated with 5-FU.

  5. Advances in the treatment of visual hallucinations in neurodegenerative diseases

    PubMed Central

    Collerton, Daniel; Taylor, John-Paul

    2013-01-01

    Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any single one may be of limited efficacy. Reducing medication, with the careful introduction of antidementia medication if needed, is the mainstay of current management. Antipsychotic medication leads to excessive morbidity and mortality and should only be used in cases of high distress that do not otherwise respond. Education, reduction of risk factors and psychological treatments have limited evidence of efficacy, but are unlikely to cause harm. PMID:23882162

  6. Advanced Dispersed Fringe Sensing Algorithm for Coarse Phasing Segmented Mirror Telescopes

    NASA Technical Reports Server (NTRS)

    Spechler, Joshua A.; Hoppe, Daniel J.; Sigrist, Norbert; Shi, Fang; Seo, Byoung-Joon; Bikkannavar, Siddarayappa A.

    2013-01-01

    Segment mirror phasing, a critical step of segment mirror alignment, requires the ability to sense and correct the relative pistons between segments from up to a few hundred microns to a fraction of wavelength in order to bring the mirror system to its full diffraction capability. When sampling the aperture of a telescope, using auto-collimating flats (ACFs) is more economical. The performance of a telescope with a segmented primary mirror strongly depends on how well those primary mirror segments can be phased. One such process to phase primary mirror segments in the axial piston direction is dispersed fringe sensing (DFS). DFS technology can be used to co-phase the ACFs. DFS is essentially a signal fitting and processing operation. It is an elegant method of coarse phasing segmented mirrors. DFS performance accuracy is dependent upon careful calibration of the system as well as other factors such as internal optical alignment, system wavefront errors, and detector quality. Novel improvements to the algorithm have led to substantial enhancements in DFS performance. The Advanced Dispersed Fringe Sensing (ADFS) Algorithm is designed to reduce the sensitivity to calibration errors by determining the optimal fringe extraction line. Applying an angular extraction line dithering procedure and combining this dithering process with an error function while minimizing the phase term of the fitted signal, defines in essence the ADFS algorithm.

  7. Final Report - Advanced Conceptual Models for Unsaturated and Two-Phase Flow in Fractured Rock

    SciTech Connect

    Nicholl, Michael J.

    2006-07-10

    The Department of Energy Environmental Management Program is faced with two major issues involving two-phase flow in fractured rock; specifically, transport of dissolved contaminants in the Vadose Zone, and the fate of Dense Nonaqueous Phase Liquids (DNAPLs) below the water table. Conceptual models currently used to address these problems do not correctly include the influence of the fractures, thus leading to erroneous predictions. Recent work has shown that it is crucial to understand the topology, or ''structure'' of the fluid phases (air/water or water/DNAPL) within the subsurface. It has also been shown that even under steady boundary conditions, the influence of fractures can lead to complex and dynamic phase structure that controls system behavior, with or without the presence of a porous rock matrix. Complicated phase structures within the fracture network can facilitate rapid transport, and lead to a sparsely populated and widespread distribution of concentrated contaminants; these qualities are highly difficult to describe with current conceptual models. The focus of our work is to improve predictive modeling through the development of advanced conceptual models for two-phase flow in fractured rock.

  8. Advances in nutritional therapy in inflammatory bowel diseases: Review

    PubMed Central

    Wędrychowicz, Andrzej; Zając, Andrzej; Tomasik, Przemysław

    2016-01-01

    Inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease are chronic, life-long, and relapsing diseases of the gastrointestinal tract. Currently, there are no complete cure possibilities, but combined pharmacological and nutritional therapy may induce remission of the disease. Malnutrition and specific nutritional deficiencies are frequent among IBD patients, so the majority of them need nutritional treatment, which not only improves the state of nutrition of the patients but has strong anti-inflammatory activity as well. Moreover, some nutrients, from early stages of life are suspected as triggering factors in the etiopathogenesis of IBD. Both parenteral and enteral nutrition is used in IBD therapy, but their practical utility in different populations and in different countries is not clearly established, and there are sometimes conflicting theories concerning the role of nutrition in IBD. This review presents the actual data from research studies on the influence of nutrition on the etiopathogenesis of IBD and the latest findings regarding its mechanisms of action. The use of both parenteral and enteral nutrition as therapeutic methods in induction and maintenance therapy in IBD treatment is also extensively discussed. Comparison of the latest research data, scientific theories concerning the role of nutrition in IBD, and different opinions about them are also presented and discussed. Additionally, some potential future perspectives for nutritional therapy are highlighted. PMID:26811646

  9. [Non-motor symptoms in premotor phase of Parkinson disease].

    PubMed

    Takahashi, Kazushi

    2013-01-01

    Non-motor symptoms are common in patients with newly diagnosed Parkinson's disease (PD), and some even predate the emergence of the classic motor features. The premotor phase of PD is characterized by several important non-motor features, including constipation, olfactory dysfunction, REM sleep behavior disorder (RBD), depression, etc. The basis of this prodromal stage is that the pathological process related to Lewy bodies, may start outside of the substantia nigra. We investigated 469 Japanese PD patients in our multicenter study, using the Japanese version of the RBD screening questionnaire. Probable RBD was detected in 146 patients (31%) and the RBD symptoms of 53 patients preceded the onset of PD motor symptoms. With the probable exception of RBD, non-motor clinical markers can be sensitive for an impending diagnosis of PD, but these features are common and non-specific. The combination of non-motor clinical markers and more specific markers (e.g., imaging or genetic markers) may achieve sufficient utility in PD diagnosis and prediction in future. Being able to diagnose that a patient has PD at an earlier time point than is currently possible, would be allowed to introduce potential disease-modifying therapies at a time when it could have fundamental and long-lasting effects.

  10. Advances in Diagnosis and Management of Salivary Gland Diseases

    PubMed Central

    Rice, Dale H.

    1984-01-01

    Salivary glands may be involved in a wide variety of diseases, which may be broadly grouped into (1) inflammatory, (2) noninflammatory, nonneoplastic and (3) neoplastic categories. Most inflammatory and noninflammatory, nonneoplastic diseases should be managed conservatively and symptomatically. The common exceptions are first-arch branchialcleft cysts and calculi. Neoplastic lesions always require resection if that is feasible. For benign tumors, simple excision with a cuff of normal tissue around it will usually suffice. The prevailing trend for treatment of malignant neoplasms is conservatism. No longer is the facial nerve routinely sacrificed. The resection done is dictated by the tumor size and the facial nerve is spared unless directly invaded. Postoperative radiation therapy is increasingly used. PMID:6328773

  11. Advancing the cellular and molecular therapy for intervertebral disc disease.

    PubMed

    Sakai, Daisuke; Grad, Sibylle

    2015-04-01

    The healthy intervertebral disc (IVD) fulfils the essential function of load absorption, while maintaining multi-axial flexibility of the spine. The interrelated tissues of the IVD, the annulus fibrosus, the nucleus pulposus, and the cartilaginous endplate, are characterised by their specific niche, implying avascularity, hypoxia, acidic environment, low nutrition, and low cellularity. Anabolic and catabolic factors balance a slow physiological turnover of extracellular matrix synthesis and breakdown. Deviations in mechanical load, nutrient supply, cellular activity, matrix composition and metabolism may initiate a cascade ultimately leading to tissue dehydration, fibrosis, nerve and vessel ingrowth, disc height loss and disc herniation. Spinal instability, inflammation and neural sensitisation are sources of back pain, a worldwide leading burden that is challenging to cure. In this review, advances in cell and molecular therapy, including mobilisation and activation of endogenous progenitor cells, progenitor cell homing, and targeted delivery of cells, genes, or bioactive factors are discussed.

  12. Advances in paediatric pulmonary vascular disease associated with bronchopulmonary dysplasia.

    PubMed

    Rossor, Thomas; Greenough, Anne

    2015-02-01

    Pulmonary hypertension (PH) is a common finding in infants with bronchopulmonary dysplasia (BPD). The aim of this review is to describe recent advances in the diagnosis and treatment of PH and discuss whether they will benefit infants and children with BPD related PH. Echocardiography remains the mainstay of diagnosis but has limitations, further developments in diagnostic techniques and identification of biomarkers are required. There are many potential therapies for PH associated with BPD. Inhaled nitric oxide has been shown to improve short term outcomes only. Sidenafil in resource limited settings was shown in three randomized trials to significantly reduce mortality. The efficacy of other therapies including prostacyclin, PDE3 inhibitors and endothelin receptor blockers has only been reported in case reports or case series. Randomized controlled trials with long term follow up are required to appropriately assess the efficacy of therapies aimed at improving the outcome of children with PH.

  13. Presence of novel compound BCR-ABL mutations in late chronic and advanced phase imatinib sensitive CML patients indicates their possible role in CML progression.

    PubMed

    Akram, Afia Muhammad; Iqbal, Zafar; Akhtar, Tanveer; Khalid, Ahmed Mukhtar; Sabar, Muhammad Farooq; Qazi, Mahmood Hussain; Aziz, Zeba; Sajid, Nadia; Aleem, Aamer; Rasool, Mahmood; Asif, Muhammad; Aloraibi, Saleh; Aljamaan, Khaled; Iqbal, Mudassar

    2017-02-21

    BCR-ABL kinase domain (KD) mutations are well known for causing resistance against tyrosine kinase inhibitors (TKIs) and disease progression in chronic myeloid leukemia (CML). In recent years, compound BCR-ABL mutations have emerged as a new threat to CML patients by causing higher degrees of resistance involving multiple TKIs, including ponatinib. However, there are limited reports about association of compound BCR-ABL mutations with disease progression in imatinib (IM) sensitive CML patients. Therefore, we investigated presence of ABL-KD mutations in chronic phase (n = 41), late chronic phase (n = 33) and accelerated phase (n = 16) imatinib responders. Direct sequencing analysis was employed for this purpose. Eleven patients (12.22%) in late-CP CML were detected having total 24 types of point mutations, out of which eight (72.72%) harbored compound mutated sites. SH2 contact site mutations were dominant in our study cohort, with E355G (3.33%) being the most prevalent. Five patients (45%) all having compound mutated sites, progressed to advanced phases of disease during follow up studies. Two novel silent mutations G208G and E292E/E were detected in combination with other mutants, indicating limited tolerance for BCR-ABL1 kinase domain for missense mutations. However, no patient in early CP of disease manifested mutated ABL-KD. Occurrence of mutations was found associated with elevated platelet count (p = 0.037) and patients of male sex (p = 0.049). The median overall survival and event free survival of CML patients (n = 90) was 6.98 and 5.8 years respectively. The compound missense mutations in BCR-ABL kinase domain responsible to elicit disease progression, drug resistance or disease relapse in CML, can be present in yet Imatinib sensitive patients. Disease progression observed here, emphasizes the need of ABL-KD mutation screening in late chronic phase CML patients for improved clinical management of disease.

  14. Radiosensitization of Chemotherapy-Refractory, Locally Advanced or Locally Recurrent Breast Cancer With Trastuzumab: A Phase II Trial

    SciTech Connect

    Horton, Janet K.; Halle, Jan; Ferraro, Madlyn; Carey, Lisa; Moore, Dominic T.; Ollila, David; Sartor, Carolyn I.

    2010-03-15

    Purpose: Trastuzumab (Herceptin), an anti-human epidermal growth factor receptor 2 (HER2) antibody, has been shown to be an effective radiosensitizer in preclinical studies. The present Phase II trial evaluated trastuzumab plus radiotherapy in patients with HER2-positive, chemotherapy-refractory, locally advanced or locoregionally recurrent breast cancer. Methods and Materials: Eligible patients had measurable disease, normal cardiac function, and biopsy-confirmed residual HER2-positive disease. Patients received weekly trastuzumab (2 mg/kg intravenously), concurrent with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks. If feasible, surgery followed radiotherapy. The primary endpoint was safety, and the secondary endpoint was efficacy (pathologic response and interval to symptomatic local progression). Results: Of the 19 patients enrolled, 7 were ineligible and received radiotherapy alone and 12 received therapy per protocol. Of these 12 patients, 11 had a Stage T4 diagnosis. Grade 3 toxicities included skin (n = 2) and lymphopenia (n = 1). One patient experienced delayed wound healing after surgery. No patients developed symptomatic cardiac dysfunction. Of the 7 patients who had undergone mastectomy, 3 (43%) had a substantial pathologic response (complete response or microscopic residual disease), significantly more than a comparison cohort (2 of 38 or 5%, p = .02). The median interval to symptomatic local progression was not reached. The median overall survival was 39 months. Conclusion: This is the first prospective trial providing evidence for a radiosensitizing effect of trastuzumab in breast cancer. The combination of trastuzumab and radiotherapy was well tolerated.

  15. Advanced Envelope Research for Factory Built Housing, Phase 3 -- Whole-House Prototyping

    SciTech Connect

    Levy, E.; Mullens, M.; Rath, P.

    2014-04-01

    The Advanced Envelope Research effort will provide factory homebuilders with high performance, cost-effective envelope designs that can be effectively integrated into the plant production process while meeting the thermal requirements of the 2012 IECC standards. Given the affordable nature of manufactured homes, impact on first cost is a major consideration in developing new envelope technologies. This work is part of a multi-phase effort. Phase 1 identified seven envelope technologies and provided a preliminary assessment of three methods for building high performance walls. Phase 2 focused on developing viable product designs, manufacturing strategies, addressing code and structural issues, and cost analysis of the three selected options. An industry advisory committee helped narrow the research focus to perfecting a stud wall design with exterior continuous insulation (CI). Phase 3, completed in two stages, continued the design development effort, exploring and evaluating a range or methods for applying CI to factory built homes. The scope also included material selection, manufacturing and cost analysis, and prototyping and testing. During this phase, a home was built with CI, evaluated, and placed in service. The experience of building a mock up wall section with CI and then constructing on line a prototype home resolved important concerns about how to integrate the material into the production process. First steps were taken toward finding least expensive approaches for incorporating CI in standard factory building practices and a preliminary assessment suggested that even at this early stage the technology is attractive when viewed from a life cycle cost perspective.

  16. Advances in Gene Therapy for Diseases of the Eye

    PubMed Central

    Petit, Lolita; Khanna, Hemant; Punzo, Claudio

    2016-01-01

    Over the last few years, huge progress has been made with regard to the understanding of molecular mechanisms underlying the pathogenesis of neurodegenerative diseases of the eye. Such knowledge has led to the development of gene therapy approaches to treat these devastating disorders. Challenges regarding the efficacy and efficiency of therapeutic gene delivery have driven the development of novel therapeutic approaches, which continue to evolve the field of ocular gene therapy. In this review article, we will discuss the evolution of preclinical and clinical strategies that have improved gene therapy in the eye, showing that treatment of vision loss has a bright future. PMID:27178388

  17. Advances in metal-induced oxidative stress and human disease.

    PubMed

    Jomova, Klaudia; Valko, Marian

    2011-05-10

    Detailed studies in the past two decades have shown that redox active metals like iron (Fe), copper (Cu), chromium (Cr), cobalt (Co) and other metals undergo redox cycling reactions and possess the ability to produce reactive radicals such as superoxide anion radical and nitric oxide in biological systems. Disruption of metal ion homeostasis may lead to oxidative stress, a state where increased formation of reactive oxygen species (ROS) overwhelms body antioxidant protection and subsequently induces DNA damage, lipid peroxidation, protein modification and other effects, all symptomatic for numerous diseases, involving cancer, cardiovascular disease, diabetes, atherosclerosis, neurological disorders (Alzheimer's disease, Parkinson's disease), chronic inflammation and others. The underlying mechanism of action for all these metals involves formation of the superoxide radical, hydroxyl radical (mainly via Fenton reaction) and other ROS, finally producing mutagenic and carcinogenic malondialdehyde (MDA), 4-hydroxynonenal (HNE) and other exocyclic DNA adducts. On the other hand, the redox inactive metals, such as cadmium (Cd), arsenic (As) and lead (Pb) show their toxic effects via bonding to sulphydryl groups of proteins and depletion of glutathione. Interestingly, for arsenic an alternative mechanism of action based on the formation of hydrogen peroxide under physiological conditions has been proposed. A special position among metals is occupied by the redox inert metal zinc (Zn). Zn is an essential component of numerous proteins involved in the defense against oxidative stress. It has been shown, that depletion of Zn may enhance DNA damage via impairments of DNA repair mechanisms. In addition, Zn has an impact on the immune system and possesses neuroprotective properties. The mechanism of metal-induced formation of free radicals is tightly influenced by the action of cellular antioxidants. Many low-molecular weight antioxidants (ascorbic acid (vitamin C), alpha

  18. Advance in the pathogenesis and treatment of Wilson disease

    PubMed Central

    2012-01-01

    Wilson disease is an autosomal recessive disorder of copper metabolism. Diagnosis depends primarily on clinical features, biochemical parameters and the presence of the Kayser-Fleischer ring. Genetic analysis for mutations within ATP7B is a convincing diagnostic tool. The traditional treatment for WD includes chelation of excessive copper accumulation and reduction of copper intake. Medical therapy is effective but WD is not yet curable. Liver transplantation is especially helpful for patients who fail to respond to medical therapy or present with fulminant liver failure, although evaluation of its long-term effect are still in need. PMID:23210912

  19. Advances in non-invasive imaging of intracranial vascular disease.

    PubMed Central

    Jäger, H. R.; Grieve, J. P.

    2000-01-01

    Intra-arterial catheter angiography has, in the past, been the mainstay for the investigation of intracranial vascular disease. It is, however, invasive, usually requires in-patients admission, and is associated with a rate of neurological complications between 1% and 3%. In recent years, magnetic resonance angiography (MRA) and CT angiography (CTA) have emerged as non-invasive alternatives for imaging blood vessels and have made a significant impact on neuroradiological investigations. It is the purpose of this article to explain the basic technical principles of these two methods and to give an overview of their current clinical applications. PMID:10700757

  20. Advances in chest drain management in thoracic disease

    PubMed Central

    George, Robert S.

    2016-01-01

    An adequate chest drainage system aims to drain fluid and air and restore the negative pleural pressure facilitating lung expansion. In thoracic surgery the post-operative use of the conventional underwater seal chest drainage system fulfills these requirements, however they allow great variability amongst practices. In addition they do not offer accurate data and they are often inconvenient to both patients and hospital staff. This article aims to simplify the myths surrounding the management of chest drains following chest surgery, review current experience and explore the advantages of modern digital chest drain systems and address their disease-specific use. PMID:26941971

  1. Special low-protein foods ameliorate postprandial off in patients with advanced Parkinson's disease.

    PubMed

    Barichella, Michela; Marczewska, Agnieszka; De Notaris, Roberta; Vairo, Antonella; Baldo, Cinzia; Mauri, Andrea; Savardi, Chiara; Pezzoli, Gianni

    2006-10-01

    Protein intake interferes with levodopa therapy. Patients with advanced Parkinson's disease (PD) should restrict daily protein intake and shift protein intake to the evening. For further reduction of protein intake in the first part of the day, special low-protein products (LPP) should be used instead of normal food products at breakfast and lunch. We studied the efficacy of LPP on postprandial off periods, in PD patients on levodopa therapy. The methods included a randomized, cross-over, single-blind, pilot clinical trial comparing a 2-month balanced diet with a 2-month LPP diet in 18 PD patients with motor fluctuations. The off phases were significantly shorter after LPP diet than after balanced diet (postprandial off, 49 +/- 73 min vs. 79 +/- 72 min and total off, 164 +/- 148 min vs. 271 +/- 174 min, both P < 0.0001). Moreover, a reduction in total off time during LPP diet (3.3 +/- 2.7 hr vs. 4.7 +/- 3.3 hr, P < 0.0001), occurred also in the 9 patients who did not experience subjective benefit. No significant changes in hematological and biochemical variables or body composition were recorded; a slight reduction in body weight (mean, -1.8%) was observed. Consumption of LPP in the first part of the day ameliorates off periods in PD patients, but additional studies including pharmacokinetics are needed.

  2. Eligibility of patients with advanced non-small cell lung cancer for phase III chemotherapy trials

    PubMed Central

    2009-01-01

    Background Evidence that chemotherapy improves survival and quality of life in patients with stage IIIB & IV non small cell lung cancer (NSCLC) is based on large randomized controlled trials. The purpose of this study was to determine eligibility of patients with advanced NSCLC for major chemotherapy trials. Methods Physicians treating stage IIIB/IV NSCLC at Sydney Cancer Centre assessed patient eligibility for the E1594, SWOG9509 and TAX326 trials for patients presenting from October 2001 to December 2002. A review of the centre's registry was used to obtain missing data. Results 199 patients with advanced NSCLC were registered during the 14-month period. Characteristics of 100 patients were defined prospectively, 85 retrospectively: 77% males, median age 68 (range 32–88), 64% stage IV disease. Only 35% met trial eligibility for E1594 and 28% for SWOG9509 and TAX326. Common reasons for ineligibility were: co-morbidities 75(40%); ECOG Performance Status ≥2 72(39%); symptomatic brain metastasis 15(8%); and previous cancers 21(11%). Many patients were ineligible by more than one criterion. Conclusion The majority of patients with advanced NSCLC were ineligible for the large chemotherapy trials. The applicability of trial results to advanced lung cancer populations may be limited. Future trials should be conducted in a more representative population. PMID:19402889

  3. Gas-phase advanced oxidation for effective, efficient in situ control of pollution.

    PubMed

    Johnson, Matthew S; Nilsson, Elna J K; Svensson, Erik A; Langer, Sarka

    2014-01-01

    In this article, gas-phase advanced oxidation, a new method for pollution control building on the photo-oxidation and particle formation chemistry occurring in the atmosphere, is introduced and characterized. The process uses ozone and UV-C light to produce in situ radicals to oxidize pollution, generating particles that are removed by a filter; ozone is removed using a MnO2 honeycomb catalyst. This combination of in situ processes removes a wide range of pollutants with a comparatively low specific energy input. Two proof-of-concept devices were built to test and optimize the process. The laboratory prototype was built of standard ventilation duct and could treat up to 850 m(3)/h. A portable continuous-flow prototype built in an aluminum flight case was able to treat 46 m(3)/h. Removal efficiencies of >95% were observed for propane, cyclohexane, benzene, isoprene, aerosol particle mass, and ozone for concentrations in the range of 0.4-6 ppm and exposure times up to 0.5 min. The laboratory prototype generated a OH(•) concentration derived from propane reaction of (2.5 ± 0.3) × 10(10) cm(-3) at a specific energy input of 3 kJ/m(3), and the portable device generated (4.6 ± 0.4) × 10(9) cm(-3) at 10 kJ/m(3). Based on these results, in situ gas-phase advanced oxidation is a viable control strategy for most volatile organic compounds, specifically those with a OH(•) reaction rate higher than ca. 5 × 10(-13) cm(3)/s. Gas-phase advanced oxidation is able to remove compounds that react with OH and to control ozone and total particulate mass. Secondary pollution including formaldehyde and ultrafine particles might be generated, depending on the composition of the primary pollution.

  4. Advances in Diagnosis and Management of Celiac Disease

    PubMed Central

    Kelly, Ciarán P.; Bai, Julio C.; Liu, Edwin; Leffler, Daniel A.

    2015-01-01

    Celiac disease is an autoimmune disorder induced by dietary gluten in genetically predisposed individuals. It has a prevalence of ∼1% in many populations worldwide. New diagnoses have increased substantially, due to increased awareness, better diagnostic tools, and probable, real increases in incidence. The breadth of recognized clinical presentations continues to expand, making the disorder highly relevant to all physicians. Newer diagnostic tools, including serologic tests for antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptide, greatly facilitate diagnosis. Tests for celiac-permissive HLA DQ2 and DQ8 molecules are useful in defined clinical situations. Celiac disease is diagnosed by histopathologic examination of duodenal biopsies. However, according to recent controversial guidelines, a diagnosis can be made without biopsy in certain circumstances, especially for children. Symptoms, mortality, and risk for malignancy can each be reduced by adherence to a gluten-free diet. This treatment is a challenge, however, as the diet is expensive, socially isolating, and not always effective in controlling symptoms or intestinal damage. Hence, there is increasing interest in developing non-dietary therapies. PMID:25662623

  5. Advances in alcoholic liver disease: An update on alcoholic hepatitis

    PubMed Central

    Liang, Randy; Liu, Andy; Perumpail, Ryan B; Wong, Robert J; Ahmed, Aijaz

    2015-01-01

    Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality (25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material (Mallory’s hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey’s discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline. PMID:26576078

  6. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy.

    PubMed

    Lillicrap, David

    2013-01-01

    von Willebrand disease (VWD) is the most common autosomally inherited bleeding disorder. The disease represents a range of quantitative and qualitative pathologies of the adhesive glycoprotein von Willebrand factor (VWF). The pathogenic mechanisms responsible for the type 2 qualitative variants of VWF are now well characterized, with most mutations representing missense substitutions influencing VWF multimer structure and interactions with platelet GPIbα and collagen and with factor VIII. The molecular pathology of type 3 VWD has been similarly well characterized, with an array of different mutation types producing either a null phenotype or the production of VWF that is not secreted. In contrast, the pathogenetic mechanisms responsible for type 1 VWD remain only partially resolved. In the hemostasis laboratory, the measurement of VWF:Ag and VWF:RCo are key components in the diagnostic algorithm for VWD, although the introduction of direct GPIbα-binding assays may become the functional assay of choice. Molecular genetic testing can provide additional benefit, but its utility is currently limited to type 2 and 3 VWD. The treatment of bleeding in VWD involves the use of desmopressin and plasma-derived VWF concentrates and a variety of adjunctive agents. Finally, a new recombinant VWF concentrate has just completed clinical trial evaluation and has demonstrated excellent hemostatic efficacy and safety.

  7. Advances in alcoholic liver disease: An update on alcoholic hepatitis.

    PubMed

    Liang, Randy; Liu, Andy; Perumpail, Ryan B; Wong, Robert J; Ahmed, Aijaz

    2015-11-14

    Alcoholic hepatitis is a pro-inflammatory chronic liver disease that is associated with high short-term morbidity and mortality (25%-35% in one month) in the setting of chronic alcohol use. Histopathology is notable for micro- and macrovesicular steatosis, acute inflammation with neutrophil infiltration, hepatocellular necrosis, perivenular and perisinusoidal fibrosis, and Mallory hyaline bodies found in ballooned hepatocytes. Other findings include the characteristic eosinophilic fibrillar material (Mallory's hyaline bodies) found in ballooned hepatocytes. The presence of focal intense lobular infiltration of neutrophils is what typically distinguishes alcoholic hepatitis from other forms of hepatitis, in which the inflammatory infiltrate is primarily composed of mononuclear cells. Management consists of a multidisciplinary approach including alcohol cessation, fluid and electrolyte correction, treatment of alcohol withdrawal, and pharmacological therapy based on the severity of the disease. Pharmacological treatment for severe alcoholic hepatitis, as defined by Maddrey's discriminant factor ≥ 32, consists of either prednisolone or pentoxifylline for a period of four weeks. The body of evidence for corticosteroids has been greater than pentoxifylline, although there are higher risks of complications. Recently head-to-head trials between corticosteroids and pentoxifylline have been performed, which again suggests that corticosteroids should strongly be considered over pentoxifylline.

  8. Phase II trial of 4'-epi-doxorubicin in locally advanced or metastatic gastric cancer.

    PubMed

    Cazap, E; Estevez, R; Bruno, M; Levy, D; Algamiz, C; Chacon, R; Badano, C; Romero, A; Desimone, G; Roca, E

    1988-06-30

    Patients with locally advanced or metastatic gastric adenocarcinoma received an i.v. bolus of 4'-epi-doxorubicin, 75/mg/m2/cycle, every 21 days. Partial responses were observed in 5 of 23 evaluable patients (21.7%). Treatment was generally well tolerated and toxicity was mild. The response rate to epirubicin appears to be very similar to that reported for doxorubicin. Larger doses of epirubicin could be safely used in future studies, and further evaluation of epirubicin in phase III trials is indicated.

  9. Performance characteristics of advanced volume phase holographic gratings for operation in the near infrared

    NASA Astrophysics Data System (ADS)

    Arns, James A.

    2016-07-01

    Volume phase holographic (VPH) gratings are proven dispersing elements in astronomical spectrographs over the visible spectrum. VPH gratings have also been successfully deployed for use at cryogenic temperatures. Recent advances in production technology now permit the production of gratings for use in the near infrared up to 2450 nm at cryogenic conditions. This paper describes the requirements of VPH gratings for use in the H (wavelengths from 1500 nm to 1800 nm) and K (wavelengths from 1950 nm to 2450 nm) bands, gives the theoretical performances of diffraction efficiency for the production designs and presents the measured performances on the production gratings

  10. Subsonic Ultra Green Aircraft Research Phase II: N+4 Advanced Concept Development

    NASA Technical Reports Server (NTRS)

    Bradley, Marty K.; Droney, Christopher K.

    2012-01-01

    This final report documents the work of the Boeing Subsonic Ultra Green Aircraft Research (SUGAR) team on Task 1 of the Phase II effort. The team consisted of Boeing Research and Technology, Boeing Commercial Airplanes, General Electric, and Georgia Tech. Using a quantitative workshop process, the following technologies, appropriate to aircraft operational in the N+4 2040 timeframe, were identified: Liquefied Natural Gas (LNG), Hydrogen, fuel cell hybrids, battery electric hybrids, Low Energy Nuclear (LENR), boundary layer ingestion propulsion (BLI), unducted fans and advanced propellers, and combinations. Technology development plans were developed.

  11. Review: gas-phase ion chemistry of the noble gases: recent advances and future perspectives.

    PubMed

    Grandinetti, Felice

    2011-01-01

    This review article surveys recent experimental and theoretical advances in the gas-phase ion chemistry of the noble gases. Covered issues include the interaction of the noble gases with metal and non-metal cations, the conceivable existence of covalent noble-gas anions, the occurrence of ion-molecule reactions involving singly-charged xenon cations, and the occurrence of bond-forming reactions involving doubly-charged cations. Research themes are also highlighted, that are expected to attract further interest in the future.

  12. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Leone, Robert; Chang, Yunyoung C; Fecher, Leslie A; Schuchter, Lynn M; Kramer, Amy; Tan, Kay-See; Heitjan, Daniel F; Rodgers, Glenda; Gallagher, Maryann; Piao, Shengfu; Troxel, Andrea B; Evans, Tracey L; DeMichele, Angela M; Nathanson, Katherine L; O'Dwyer, Peter J; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; Amaravadi, Ravi K

    2014-08-01

    Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m (2) daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.

  13. Technology Reinvestment Program/Advanced ``Zero Emission'' Control Valve (Phase II)

    SciTech Connect

    J. Napoleon

    1998-12-01

    The objectives of this effort are to determine, develop and demonstrate the feasibility of significantly reducing the cost and expanding the applications for a family of Advanced Zero Emissions Control Valves that meets the fugitive emissions requirements of the 1990 Amendments to the Clean Air Act. This program is a direct technology spin-off from the valve technology that is critical to the US Navy's Nuclear Powered Fleet. These zero emissions valves will allow the Hydrocarbon and Chemical Processing Industries, etc., to maintain their competitiveness and still meet environmental and safety requirements. Phase 2 is directed at refining the basic technologies developed during Phase 1 so that they can be more readily selected and utilized by the target market. In addition to various necessary certifications, the project will develop a full featured digital controller with ``smart valve'' growth capability, expanding valve sizes/applications and identifying valve materials to permit applications in severe operational environments.

  14. Advances in the treatment of diseased equine cheek teeth.

    PubMed

    Tremaine, Henry

    2013-08-01

    The last decade has seen a number of studies that have illuminated our knowledge of hypsodont dental disease and re-examined some of the traditionally performed practices. In addition there has been a major interest in routine preventative dentistry and non-traumatic treatments. These have highlighted some potential risks of the use of modern tools when applied to traditional techniques. This has also led to a reflective review of equine dentistry with the emphasis on attempting to preserve and salvage dental and periodontal tissues, with minimal trauma. In addition, precise imaging and instrumentation have facilitated minimally invasive techniques in conscious sedated horses, and there is renewed interest in comparative dentistry leading to trials with restorative techniques that are practiced in other species.

  15. Recent advances in understanding cardiac contractility in health and disease

    PubMed Central

    MacLeod, Ken T.

    2016-01-01

    The aim of this review is to provide the reader with a synopsis of some of the emerging ideas and experimental findings in cardiac physiology and pathophysiology that were published in 2015. To provide context for the non-specialist, a brief summary of cardiac contraction and calcium (Ca) regulation in the heart in health and disease is provided. Thereafter, some recently published articles are introduced that indicate the current thinking on (1) the Ca regulatory pathways modulated by Ca/calmodulin-dependent protein kinase II, (2) the potential influences of nitrosylation by nitric oxide or S-nitrosated proteins, (3) newly observed effects of reactive oxygen species (ROS) on contraction and Ca regulation following myocardial infarction and a possible link with changes in mitochondrial Ca, and (4) the effects of some of these signaling pathways on late Na current and pro-arrhythmic afterdepolarizations as well as the effects of transverse tubule disturbances. PMID:27508064

  16. Radical irradiation and misonidazole in the treatment of advanced cervical carcinoma: results of a phase II trial

    SciTech Connect

    Girinski, T.; Pejovic, M.H.; Haie, C.; Bonnay, M.; Gerbaulet, A.; Mazeron, J.J.; Malaise, E.; Chassagne, D.

    1985-10-01

    Between February 1979 and January 1982, a Phase II study of misonidazole as a radiosensitizer was performed in 34 patients with advanced carcinoma of the uterine cervix. Twenty-nine patients were treated with conventional fractionated radiation and five patients with a twice daily fractionation schedule, 3 days a week. The total dose to the whole pelvis was 5000 cGy delivered in 5.5 weeks. Intracavitary curietherapy delivered an additional boost to the tumor. Misonidazole was given to all patients during external radiation and to 25 patients during intracavitary treatment for a total dose of 11 to 14 g/mS. All patients were followed for at least 28 months after treatment with a median follow-up of 52 months. Misonidazole toxicity included peripheral neuropathy (18%) and central nervous system toxicity (3%). The 3-year survival rate is 74% and the 3-year disease-free survival is 57%. When compared to our historical group survival, 42 and 12% for Stage III and IV, respectively, our data suggest that there is a probable advantage from using misonidazole in advanced carcinoma of the cervix.

  17. Recent advances in the molecular analysis of inherited disease.

    PubMed

    Malcolm, S

    1990-12-12

    Many important human genes have been cloned during the last ten years. In some cases, using reverse genetic techniques [Orkin, S. H. (1986) Cell 47, 845-850], disease-causing genes have been isolated whose product was previously unknown. Important examples include the dystrophin protein which, when mutated, gives rise to either Duchenne or Becker muscular dystrophy [Koenig, M., Hoffman, E. P., Bertelson, C. J., Monaco, A. P., Feener, C. and Kunkel, L. M. (1987) Cell 50, 509-517; Monaco, A. P., Bertelson, C. J., Liechti-Gallati, S. & Kunkel, L. M. (1988) Genomics 2, 90-95; Koenig, M., Monaco, A. P. & Kunkel, L. M. (1988) Cell 53, 219-228] and the cystic fibrosis transmembrane conductance regulator (CFTR) [Riordan, J. R., Rommens, J. M., Kerem, B.-S., Alon, N., Rozmahel, R., Grzelczak, Z., Zielenski, J., Lok, S., Plavsic, N., Chou, J.-L., Drumm, M. L., Ianuzzi, M. C., Collins, F. S. & Tsui, L.-C. (1989) Science 245, 1066-1073]. Recently the technology for systematically detecting single base-pair changes by chemical methods, enzymatic methods or direct DNA sequencing has greatly expanded and simplified. In addition to providing structural information about these clinically important genes and information on disease-causing mutations, these studies have led to an increased understanding of mechanisms of mutation, to the discovery of novel genetic mechanisms and to important clinical applications of carrier detection and pre-natal diagnosis. The recent rapid progress has been made possible by the development of DNA amplification using the polymerase chain reaction (pcr) invented by Saiki and colleagues [Saiki, R. K., Chang, C-A., Levenson, C. H., Warren, T. C., Boehm, C. D., Kazazian, H. H. & Ehrlich, H. A. (1988) N. Engl. J. Med. 319, 537-541].

  18. X-ray imaging in advanced studies of ophthalmic diseases

    SciTech Connect

    Antunes, Andrea; Safatle, Angelica M. V.; Barros, Paulo S. M.; Morelhao, Sergio L.

    2006-07-15

    Microscopic characterization of pathological tissues has one major intrinsic limitation, the small sampling areas with respect to the extension of the tissues. Mapping possible changes on vast tissues and correlating them with large ensembles of clinical cases is not a feasible procedure for studying most diseases, as for instance vision loss related diseases and, in particular, the cataract. Although intraocular lens implants are successful treatments, cataract still is a leading public-health issue that grows in importance as the population increases and life expectancy is extended worldwide. In this work we have exploited the radiation-tissue interaction properties of hard x-rays--very low absorption and scattering--to map distinct lesions on entire eye lenses. At the used synchrotron x-ray photon energy of 20 keV (wavelength {lambda}=0.062 nm), scattering and refraction are angular resolved effects. It allows the employed x-ray image technique to efficiently characterize two types of lesions in eye lenses under cataractogenesis: distributions of tiny scattering centers and extended areas of fiber cell compaction. The data collection procedure is relatively fast; allowing dozens of samples to be totally imaged (scattering, refraction, and mass absorption images) in a single day of synchrotron beam time. More than 60 cases of canine cataract, not correlated to specific causes, were investigated in this first application of x-rays to image entire lenses. Cortical opacity cases, or partial opacity, could be related to the presence of calcificated tissues at the cortical areas, clearly visible in the images, whose elemental contents were verified by micro x-ray fluorescence as very rich in calcium. Calcificated tissues were also observed at nuclear areas in some cases of hypermature cataract. Total opacity cases without distinguishable amount of scattering centers consist in 70% of the analyzed cases, where remarkable fissure marks owing to extended areas of fiber

  19. Phase I/II Study of Erlotinib Combined With Cisplatin and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

    SciTech Connect

    Herchenhorn, Daniel; Dias, Fernando L.; Viegas, Celia M.P.; Federico, Miriam H.; Araujo, Carlos Manoel M.; Small, Isabelle; Bezerra, Marcos; Fontao, Karina M.D.; Knust, Renata E.; Ferreira, Carlos G.; Martins, Renato G.

    2010-11-01

    Purpose: Erlotinib, an oral tyrosine kinase inhibitor, is active against head-and-neck squamous cell carcinoma (HNSCC) and possibly has a synergistic interaction with chemotherapy and radiotherapy. We investigated the safety and efficacy of erlotinib added to cisplatin and radiotherapy in locally advanced HNSCC. Methods and Materials: In this Phase I/II trial 100 mg/m{sup 2} of cisplatin was administered on Days 8, 29, and 50, and radiotherapy at 70 Gy was started on Day 8. During Phase I, the erlotinib dose was escalated (50 mg, 100 mg, and 150 mg) in consecutive cohorts of 3 patients, starting on Day 1 and continuing during radiotherapy. Dose-limiting toxicity was defined as any Grade 4 event requiring radiotherapy interruptions. Phase II was initiated 8 weeks after the last Phase I enrollment. Results: The study accrued 9 patients in Phase I and 28 in Phase II; all were evaluable for efficacy and safety. No dose-limiting toxicity occurred in Phase I, and the recommended Phase II dose was 150 mg. The most frequent nonhematologic toxicities were nausea/vomiting, dysphagia, stomatitis, xerostomia and in-field dermatitis, acneiform rash, and diarrhea. Of the 31 patients receiving a 150-mg daily dose of erlotinib, 23 (74%; 95% confidence interval, 56.8%-86.3%) had a complete response, 3 were disease free after salvage surgery, 4 had inoperable residual disease, and 1 died of sepsis during treatment. With a median 37 months' follow-up, the 3-year progression-free and overall survival rates were 61% and 72%, respectively. Conclusions: This combination appears safe, has encouraging activity, and deserves further studies in locally advanced HNSCC.

  20. Nondestructive Evaluation of Advanced Materials with X-ray Phase Mapping

    NASA Technical Reports Server (NTRS)

    Hu, Zhengwei

    2005-01-01

    X-ray radiation has been widely used for imaging applications since Rontgen first discovered X-rays over a century ago. Its large penetration depth makes it ideal for the nondestructive visualization of the internal structure and/or defects of materials unobtainable otherwise. Currently used nondestructive evaluation (NDE) tools, X-ray radiography and tomography, are absorption-based, and work well in heavy-element materials where density or composition variations due to internal structure or defects are high enough to produce appreciable absorption contrast. However, in many cases where materials are light-weight and/or composites that have similar mass absorption coefficients, the conventional absorption-based X-ray methods for NDE become less useful. Indeed, the light-weight and ultra-high-strength requirements for the most advanced materials used or developed for current flight mission and future space exploration pose a great challenge to the standard NDE tools in that the absorption contrast arising from the internal structure of these materials is often too weak to be resolved. In this presentation, a solution to the problem, the use of phase information of X-rays for phase contrast X-ray imaging, will be discussed, along with a comparison between the absorption-based and phase-contrast imaging methods. Latest results on phase contrast X-ray imaging of lightweight Space Shuttle foam in 2D and 3D will be presented, demonstrating new opportunities to solve the challenging issues encountered in advanced materials development and processing.

  1. Phase I trial outcomes in older patients with advanced solid tumours

    PubMed Central

    Khan, K H; Yap, T A; Ring, A; Molife, L R; Bodla, S; Thomas, K; Zivi, A; Smith, A; Judson, I; Banerji, U; de Bono, J S; Kaye, S B

    2016-01-01

    Background: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. Methods: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. Results: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3–5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4% P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. Conclusions: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients. PMID:26757260

  2. Moments of homecoming among people with advanced dementia disease in a residential care facility.

    PubMed

    Norberg, Astrid; Ternestedt, Britt-Marie; Lundman, Berit

    2015-10-26

    This study concerns moments of homecoming among people with advanced dementia disease living in a residential care facility. Our main finding from participant observations with nine residents was that the residents showed moments of homecoming, i.e. they alternated between verbal and/or nonverbal expressions of feeling at home and of not feeling at home. If care providers understand that they can help people with advanced dementia disease experience moments of homecoming, they can focus on aspects of care that can promote these experiences.

  3. Reaching Those Most in Need – A Call to Action for Advanced Parkinson’s Disease

    PubMed Central

    Agarwal, Shashank; Fleisher, Jori E

    2016-01-01

    Much of the clinical and research attention for Parkinson's Disease (PD) has focused on mild to moderate stages. As the disease advances, it can become difficult for patients to attend clinical visits. These patients are often lost to follow-up, and consequently, vanish from the pool of potential research subjects who could inform our management of this understudied population. We aim to increase awareness about this population and potential interventions to improve continuity of care and foster research in advanced PD. PMID:27708720

  4. Advanced Envelope Research for Factory Built Housing, Phase 3. Design Development and Prototyping

    SciTech Connect

    Levy, E.; Kessler, B.; Mullens, M.; Rath, P.

    2014-01-01

    The Advanced Envelope Research effort will provide factory homebuilders with high performance, cost-effective alternative envelope designs. In the near term, these technologies will play a central role in meeting stringent energy code requirements. For manufactured homes, the thermal requirements, last updated by statute in 1994, will move up to the more rigorous IECC 2012 levels in 2013, the requirements of which are consistent with site built and modular housing. This places added urgency on identifying envelope technologies that the industry can implement in the short timeframe. The primary goal of this research is to develop wall designs that meet the thermal requirements based on 2012 IECC standards. Given the affordable nature of manufactured homes, impact on first cost is a major consideration in developing the new envelope technologies. This work is part of a four-phase, multi-year effort. Phase 1 identified seven envelope technologies and provided a preliminary assessment of three selected methods for building high performance wall systems. Phase 2 focused on the development of viable product designs, manufacturing strategies, addressing code and structural issues, and cost analysis of the three selected options. An industry advisory committee helped critique and select the most viable solution to move further in the research -- stud walls with continuous exterior insulation. Phase 3, the subject of the current report, focused on the design development of the selected wall concept and explored variations on the use of exterior foam insulation. The scope also included material selection, manufacturing and cost analysis, and prototyping and testing.

  5. Advanced Envelope Research for Factory Built Housing, Phase 3. Whole-House Prototyping

    SciTech Connect

    Levy, E.; Mullens, M.; Rath, P.

    2014-04-01

    The Advanced Envelope Research effort will provide factory homebuilders with high performance, cost-effective envelope designs that can be effectively integrated into the plant production process while meeting the thermal requirements of the 2012 IECC standards. This work is part of a multiphase effort. Phase 1 identified seven envelope technologies and provided a preliminary assessment of three methods for building high performance walls. Phase 2 focused on developing viable product designs, manufacturing strategies, addressing code and structural issues, and cost analysis of the three selected options. An industry advisory committee helped narrow the research focus to perfecting a stud wall design with exterior continuous insulation (CI). This report describes Phase 3, which was completed in two stages and continued the design development effort, exploring and evaluating a range or methods for applying CI to factory built homes. The scope also included material selection, manufacturing and cost analysis, and prototyping and testing. During this phase, a home was built with CI, evaluated, and placed in service. The experience of building a mock up wall section with CI and then constructing on line a prototype home resolved important concerns about how to integrate the material into the production process. First steps were taken toward finding least expensive approaches for incorporating CI in standard factory building practices and a preliminary assessment suggested that even at this early stage the technology is attractive when viewed from a life cycle cost perspective.

  6. Advanced Envelope Research for Factory Built Housing, Phase 3 -- Design Development and Prototyping

    SciTech Connect

    Levy, E.; Kessler, B.; Mullens, M.; Rath, P.

    2014-01-01

    The Advanced Envelope Research effort will provide factory homebuilders with high performance, cost-effective alternative envelope designs. In the near term, these technologies will play a central role in meeting stringent energy code requirements. For manufactured homes, the thermal requirements, last updated by statute in 1994, will move up to the more rigorous IECC 2012 levels in 2013, the requirements of which are consistent with site built and modular housing. This places added urgency on identifying envelope technologies that the industry can implement in the short timeframe. The primary goal of this research is to develop wall designs that meet the thermal requirements based on 2012 IECC standards. Given the affordable nature of manufactured homes, impact on first cost is a major consideration in developing the new envelope technologies. This work is part of a four-phase, multi-year effort. Phase 1 identified seven envelope technologies and provided a preliminary assessment of three selected methods for building high performance wall systems. Phase 2 focused on the development of viable product designs, manufacturing strategies, addressing code and structural issues, and cost analysis of the three selected options. An industry advisory committee helped critique and select the most viable solution to move further in the research -- stud walls with continuous exterior insulation. Phase 3, the subject of the current report, focused on the design development of the selected wall concept and explored variations on the use of exterior foam insulation. The scope also included material selection, manufacturing and cost analysis, and prototyping and testing.

  7. Metronomic treatment of advanced non-small-cell lung cancer with daily oral vinorelbine – a Phase I trial

    PubMed Central

    Guetz, Sylvia; Tufman, Amanda; von Pawel, Joachim; Rittmeyer, Achim; Borgmeier, Astrid; Ferré, Pierre; Edlich, Birgit; Huber, Rudolf Maria

    2017-01-01

    Micro-abstract In a Phase I dose-finding study of metronomic daily oral vinorelbine in advanced non-small-cell lung cancer, a recommended dose was established for this therapeutic approach. In addition, this trial revealed promising efficacy data and an acceptable tolerability profile. The observed vinorelbine blood concentrations suggest continuous anti-angiogenic coverage. Introduction We present a Phase I dose-finding study investigating metronomic daily oral vinorelbine (Navelbine® Oral, NVBo) in advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients with stage III/IV NSCLC received daily NVBo at fixed dose levels of 20–50 mg/d for 21 days of each 4-week cycle. Primary end point was the maximum tolerated dose. Secondary end points included tumor response, time to progression (TTP), overall survival (OS) and tolerability. Results Twenty-seven patients with advanced NSCLC were enrolled. Most of them were extensively pretreated. Daily NVBo was well tolerated up to 30 mg/d. At 40 mg/d, two of five patients experienced dose-limiting toxicities (DLTs). Three of six patients had DLTs at the 50 mg/d level. The recommended dose was established at 30 mg/d in cycle 1, with escalation to 40 mg/d in cycle 2, if tolerated. Pharmacokinetic analyses showed continuous blood exposure over 21 days and only marginal accumulation. The tolerability profile was acceptable (all dose levels – all grades: decreased appetite 33%, diarrhea 33%, leukopenia 33%, nausea 30%, vomiting 26%; ≥grade 3: leukopenia 30%, lymphopenia 19%, neutropenia 19%, febrile neutropenia 15%). Disease control rate, OS and TTP signaled a treatment effect. Conclusion Daily metronomic NVBo therapy in extensively pretreated patients with advanced NSCLC is feasible and safe at the recommended dose of 30 mg/d. Escalation to 40 mg/d in the second cycle is possible. The blood concentrations of vinorelbine after daily metronomic dosing reached lower peaks than intravenous or oral conventional

  8. Building a multicenter telehealth network to advance chronic disease management.

    PubMed

    Khairat, Saif; Wijesinghe, Namal; Wolfson, Julian; Scott, Rob; Simkus, Ray

    2014-01-01

    The use of telehealth solutions has proved to improve clinical management of chronic diseases, expand access to healthcare services and clinicians, and reduce healthcare-related costs. The project aims at improving Heart Failure (HF) management through the utilization of a Telemedicine and Personal Health Records systems that will assist HF specialist in Colombo, Sri Lanka to monitor and consult with remote HF patients. A telehealth network will be built at an international site that connects five remote telehealth clinics to a central clinic at a major University Hospital in Sri Lanka where HF specialists are located. In this study, 200 HF patients will be recruited for nine months, 100 patients will be randomly selected for the treatment group and the other 100 will be selected for the control group. Pre, mid, and post study surveys will be conducted to assess the efficacy and satisfaction levels of patients with both care models. Moreover, clinical outcomes will be collected to evaluate the impact of the intervention on the treatment patients compared to control patients. The research aims at enhancing Heart Failure management through eliminating current health challenges and healthcare-related financial burdens.

  9. Recent advances in herbal medicines treating Parkinson's disease.

    PubMed

    Li, Xu-Zhao; Zhang, Shuai-Nan; Liu, Shu-Min; Lu, Fang

    2013-01-01

    Herbal medicines have attracted considerable attention in recent years, which are used to treat Parkinson's disease (PD) in China based on traditional Chinese medicine or modern pharmacological theories. We summarized and analyzed the anti-Parkinsonian activities of herbal medicines and herbal formulations investigated in PD models and provide future references for basic and clinical investigations. All the herbal medicines and herbal formulations were tested on PD models in vitro and in vivo. The relevant compounds and herbal extracts with anti-Parkinsonian activities were included and analyzed according to their genera or pharmacological activities. A total of 38 herbal medicines and 11 herbal formulations were analyzed. The relevant compounds, herbal extracts and formulations were reported to be effective on PD models by modulating multiple key events or signaling pathways implicated in the pathogenesis of PD. The plant species of these herbal medicines belong to 24 genera and 18 families, such as Acanthopanax, Alpinia and Astragalus, etc. These herbal medicines can be an alternative and valuable source for anti-Parkinsonian drug discovery. The plant species in these genera and families may be the most promising candidates for further investigation and deserve further consideration in clinical trials. Active components in some of the herbal extracts and the compatibility law of herbal formulations remain to be further investigated.

  10. Recent advances in understanding and managing Crohn’s disease

    PubMed Central

    Stange, Eduard F.; Wehkamp, Jan

    2016-01-01

    There is consensus that inflammatory bowel diseases (IBDs) are the result of “dysregulated” immune reactivity towards commensal microorganisms in the intestine. This gut microbiome is clearly altered in IBD, but its primary or secondary role is still debated. The focus has shifted from adaptive to innate immunity, with its multitude of receptor molecules (Toll-like and NOD receptors) and antibacterial effector molecules (defensins, cathelicidin, and others). The latter appear to be at least partly deficient at different intestinal locations. Host genetics also support the notion that microbe–host interaction at the mucosa is the prime site of pathogenesis. In contrast, even the latest therapeutic antibodies are directed against secondary targets like cytokines and integrins identified decades ago. These so-called “biologicals” have disappointing long-term results, with the majority of patients not achieving remission in the long run. A promising approach is the development of novel drugs like defensin-derived molecules that substitute for the missing endogenous antibacterials. PMID:28163902

  11. Advanced algorithms for the identification of mixtures using condensed-phase FT-IR spectroscopy

    NASA Astrophysics Data System (ADS)

    Arnó, Josep; Andersson, Greger; Levy, Dustin; Tomczyk, Carol; Zou, Peng; Zuidema, Eric

    2011-06-01

    FT-IR spectroscopy is the technology of choice to identify solid and liquid phase unknown samples. Advances in instrument portability have made possible the use of FT-IR spectroscopy in emergency response and military field applications. The samples collected in those harsh environments are rarely pure and typically contain multiple chemical species in water, sand, or inorganic matrices. In such critical applications, it is also desired that in addition to broad chemical identification, the user is warned immediately if the sample contains a threat or target class material (i.e. biological, narcotic, explosive). The next generation HazMatID 360 combines the ruggedized design and functionality of the current HazMatID with advanced mixture analysis algorithms. The advanced FT-IR instrument allows effective chemical assessment of samples that may contain one or more interfering materials like water or dirt. The algorithm was the result of years of cumulative experience based on thousands of real-life spectra sent to our ReachBack spectral analysis service by customers in the field. The HazMatID 360 combines mixture analysis with threat detection and chemical hazard classification capabilities to provide, in record time, crucial information to the user. This paper will provide an overview of the software and algorithm enhancements, in addition to examples of improved performance in mixture identification.

  12. [Chronic diseases and complexity: new roles in nursing. Advanced practice nurses and chronic patient].

    PubMed

    Sánchez-Martín, C Inmaculada

    2014-01-01

    The increase in chronic diseases and the progressive ageing of the population is a source of concern for the different agencies with responsibility for health care. This has led to the creation of many documents focused on the analysis of the current situation and care of chronic diseases, including the WHO recommendations intended to assist countries and health services design and implement strategies that will address the existing demand, control and prevention of chronic diseases. In addition, there is a need to respond to the demand generated by chronic diseases in every sense, and from the different systems it is becoming more difficult to get enough support from multidisciplinary teams where the nurse has a central importance. While chronic diseases are becoming a threat due to the costs they generate, it is also an opportunity for nursing to be at the forefront for advanced care requirements, performed by professionals with recognized advanced clinical skills and ability for case management while monitoring and controlling complex chronic patients. The different services of the National Health System have introduced nurses that play different roles (cases managers, liaison nurses, advanced practice nurses and so on). However, it could be argued that they are not being trained to a desirable development level. It is therefore time for health care authorities to determine the role of the advanced practice nurse in relation to functional positions, and allow them to make an advance in the development of unified skills for the whole National Health System. From our experience we have learned that the advanced practice nurse is a resource that helps in the sustainability of services, thanks to the efficiency shown in the results obtained from the care given to both chronic and complex chronic patients.

  13. Liposomal cisplatin combined with gemcitabine in pretreated advanced pancreatic cancer patients: a phase I-II study.

    PubMed

    Stathopoulos, George P; Boulikas, Teni; Vougiouka, Maria; Rigatos, Sotirios K; Stathopoulos, John G

    2006-05-01

    The present trial is a phase I-II study based on a new liposomal cisplatin (lipoplatin). Previous preclinical and clinical data (phase I pharmacokinetics) led to the investigation of a combined treatment modality involving lipoplatin and gemcitabine. The gemcitabine dose was kept standard at 1000 mg/m2 and the lipoplatin dose was escalated from 25 mg/m2 to 125 mg/m2. The treatment was administered to advanced pretreated pancreatic cancer patients who were refractory to previous chemotherapy which included gemcitabine. Lipoplatin at 125 mg/m2 was defined as dose limiting toxicity (DLT) and 100 mg/m2 as the maximum tolerated dose (MTD) in combination with 1000 mg/m2 of gemcitabine. Preliminary objective response rate data showed a partial response in 2/24 patients (8.3%), disease stability in 14 patients (58.3%) for a median duration of 3 months (range 2-7 months) and clinical benefit in 8 patients (33.3%). Liposomal cisplatin is a non-toxic alternative agent to bare cisplatin. In combination with gemcitabine, it has an MTD of 100 mg/m2 and shows promising efficacy in refractory pancreatic cancer.

  14. Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma

    PubMed Central

    Abida, Wassim; Milowsky, Matthew I.; Ostrovnaya, Irina; Gerst, Scott R.; Rosenberg, Jonathan E.; Voss, Martin H.; Apolo, Andrea B.; Regazzi, Ashley M.; McCoy, Asia S.; Boyd, Mariel E.; Bajorin, Dean F.

    2016-01-01

    Background: Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs. Objective: We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting. Methods: Patients received gemcitabine 800 mg/m2 and cisplatin 35 mg/m2 on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination. Results: 12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1 *(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1 * had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached). Conclusions: The maximum tolerated dose was reached at the lowest dose level, 5 mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity. PMID:27376132

  15. Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: a phase II study.

    PubMed

    Yamazaki, Naoya; Kiyohara, Yoshio; Uhara, Hisashi; Uehara, Jiro; Fujimoto, Manabu; Takenouchi, Tatsuya; Otsuka, Masaki; Uchi, Hiroshi; Ihn, Hironobu; Minami, Hironobu

    2017-03-25

    Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation via overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has demonstrated promising anti-cancer activity in various cancers. We conducted a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received intravenous nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval [CI]: 20.8, 51.9), and the overall survival rate at 18 months was 56.5% (90% CI: 38.0, 71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab demonstrated favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. This article is protected by copyright. All rights reserved.

  16. Advances in MR imaging assessment of adults with congenital heart disease.

    PubMed

    Kathiria, Nazima N; Higgins, Charles B; Ordovas, Karen G

    2015-02-01

    Many novel cardiac MR sequences can be used for assessment of adult patients with congenital heart disease. Although most of these techniques are still primarily used in the research arena, there are many potential applications in clinical practice. Advanced cardiac MR assessment of myocardial tissue characterization, flow hemodynamics, and myocardial strain are promising tools for diagnostic and prognostic assessment late after repair of congenital heart diseases.

  17. Advances in sickle cell disease treatment: from drug discovery until the patient monitoring.

    PubMed

    dos Santos, Jean Leandro; Lanaro, Carolina; Chin, Chung Man

    2011-04-01

    Sickle cell disease (SCD) is one of the most prevalent hematological diseases in the world. Despite the immense progress in molecular knowledge about SCD in last years few therapeutical sources are currently available. Nowadays the treatment is performed mainly with drugs such as hydroxyurea or other fetal hemoglobin inducers and chelating agents. This review summarizes current knowledge about the treatment and the advancements in drug design in order to discover more effective and safe drugs. Patient monitoring methods in SCD are also discussed.

  18. Phase III Advanced Anodes and Cathodes Utilized in Energy Efficient Aluminum Production Cells

    SciTech Connect

    R.A. Christini; R.K. Dawless; S.P. Ray; D.A. Weirauch, Jr.

    2001-11-05

    During Phase I of the present program, Alcoa developed a commercial cell concept that has been estimated to save 30% of the energy required for aluminum smelting. Phase ii involved the construction of a pilot facility and operation of two pilots. Phase iii of the Advanced Anodes and Cathodes Program was aimed at bench experiments to permit the resolution of certain questions to be followed by three pilot cells. All of the milestones related to materials, in particular metal purity, were attained with distinct improvements over work in previous phases of the program. NiO additions to the ceramic phase and Ag additions to the Cu metal phase of the cermet improved corrosion resistance sufficiently that the bench scale pencil anodes met the purity milestones. Some excellent metal purity results have been obtained with anodes of the following composition: Further improvements in anode material composition appear to be dependent on a better understanding of oxide solubilities in molten cryolite. For that reason, work was commissioned with an outside consultant to model the MeO - cryolite systems. That work has led to a better understanding of which oxides can be used to substitute into the NiO-Fe2O3 ceramic phase to stabilize the ferrites and reduce their solubility in molten cryolite. An extensive number of vertical plate bench electrolysis cells were run to try to find conditions where high current efficiencies could be attained. TiB2-G plates were very inconsistent and led to poor wetting and drainage. Pure TiB2 did produce good current efficiencies at small overlaps (shadowing) between the anodes and cathodes. This bench work with vertical plate anodes and cathodes reinforced the importance of good cathode wetting to attain high current efficiencies. Because of those conclusions, new wetting work was commissioned and became a major component of the research during the third year of Phase III. While significant progress was made in several areas, much work needs to be

  19. Advances in the Diagnosis and Management of Inflammatory Bowel Disease: Challenges and Uncertainties

    PubMed Central

    Mosli, Mahmoud; Al Beshir, Mohammad; Al-Judaibi, Bandar; Al-Ameel, Turki; Saleem, Abdulaziz; Bessissow, Talat; Ghosh, Subrata; Almadi, Majid

    2014-01-01

    Over the past two decades, several advances have been made in the management of patients with inflammatory bowel disease (IBD) from both evaluative and therapeutic perspectives. This review discusses the medical advancements that have recently been made as the standard of care for managing patients with ulcerative colitis (UC) and Crohn's Disease (CD) and to identify the challenges associated with implementing their use in clinical practice. A comprehensive literature search of the major databases (PubMed and Embase) was conducted for all recent scientific papers (1990–2013) giving the recent updates on the management of IBD and the data were extracted. The reported advancements in managing IBD range from diagnostic and evaluative tools, such as genetic tests, biochemical surrogate markers of activity, endoscopic techniques, and radiological modalities, to therapeutic advances, which encompass medical, endoscopic, and surgical interventions. There are limited studies addressing the cost-effectiveness and the impact that these advances have had on medical practice. The majority of the advances developed for managing IBD, while considered instrumental by some IBD experts in improving patient care, have questionable applications due to constraints of cost, lack of availability, and most importantly, insufficient evidence that supports their role in improving important long-term health-related outcomes. PMID:24705146

  20. Advances in the diagnosis and management of inflammatory bowel disease: challenges and uncertainties.

    PubMed

    Mosli, Mahmoud; Al Beshir, Mohammad; Al-Judaibi, Bandar; Al-Ameel, Turki; Saleem, Abdulaziz; Bessissow, Talat; Ghosh, Subrata; Almadi, Majid

    2014-01-01

    Over the past two decades, several advances have been made in the management of patients with inflammatory bowel disease (IBD) from both evaluative and therapeutic perspectives. This review discusses the medical advancements that have recently been made as the standard of care for managing patients with ulcerative colitis (UC) and Crohn's Disease (CD) and to identify the challenges associated with implementing their use in clinical practice. A comprehensive literature search of the major databases (PubMed and Embase) was conducted for all recent scientific papers (1990-2013) giving the recent updates on the management of IBD and the data were extracted. The reported advancements in managing IBD range from diagnostic and evaluative tools, such as genetic tests, biochemical surrogate markers of activity, endoscopic techniques, and radiological modalities, to therapeutic advances, which encompass medical, endoscopic, and surgical interventions. There are limited studies addressing the cost-effectiveness and the impact that these advances have had on medical practice. The majority of the advances developed for managing IBD, while considered instrumental by some IBD experts in improving patient care, have questionable applications due to constraints of cost, lack of availability, and most importantly, insufficient evidence that supports their role in improving important long-term health-related outcomes.

  1. Legionnaires' disease bacteria in power plant cooling systems: Phase 2

    SciTech Connect

    Tyndall, R.L.; Christensen, S.W.; Solomon, J.A.

    1985-04-01

    Legionnaires' Disease Bacteria (Legionella) are a normal component of the aquatic community. The study investigated various environmental factors that affect Legionella profiles in power plant cooling waters. The results indicate that each of the four factors investigated (incubation temperature, water quality, the presence and type of associated biota, and the nature of the indigenous Legionella population) is important in determining the Legionella profile of these waters. Simple predictive relationships were not found. At incubation temperatures of 32/sup 0/ and 37/sup 0/C, waters from a power plant where infectious Legionella were not observed stimulated the growth of stock Legionella cultures more than did waters from plants where infectious Legionella were prevalent. This observation is consistent with Phase I results, which showed that densities of Legionella were frequently reduced in closed-cycle cooling systems despite the often higher infectivity of Legionella in closed-cycle waters. In contrast, water from power plants where infectious Legionella were prevalent supported the growth of indigenous Legionella pneumophila at 42/sup 0/C, while water from a power plant where infectious Legionella were absent did not support growth of indigenous Legionella. Some Legionella are able to withstand a water temperature of 85/sup 0/C for several hours, thus proving more tolerant than was previously realized. Finally, the observation that water from two power plants where infectious Legionella were prevalent usually supported the growth of Group A Legionella at 45/sup 0/C indicates the presence, of soluble Legionella growth promoters in these waters. This test system could allow for future identification and control of these growth promoters and, hence, of Legionella. 25 refs., 23 figs., 10 tabs.

  2. Advanced Therapeutic Strategies for Chronic Lung Disease Using Nanoparticle-Based Drug Delivery

    PubMed Central

    Yhee, Ji Young; Im, Jintaek; Nho, Richard Seonghun

    2016-01-01

    Chronic lung diseases include a variety of obstinate and fatal diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and lung cancers. Pharmacotherapy is important for the treatment of chronic lung diseases, and current progress in nanoparticles offers great potential as an advanced strategy for drug delivery. Based on their biophysical properties, nanoparticles have shown improved pharmacokinetics of therapeutics and controlled drug delivery, gaining great attention. Herein, we will review the nanoparticle-based drug delivery system for the treatment of chronic lung diseases. Various types of nanoparticles will be introduced, and recent innovative efforts to utilize the nanoparticles as novel drug carriers for the effective treatment of chronic lung diseases will also be discussed. PMID:27657144

  3. Identifying human disease genes: advances in molecular genetics and computational approaches.

    PubMed

    Bakhtiar, S M; Ali, A; Baig, S M; Barh, D; Miyoshi, A; Azevedo, V

    2014-07-04

    The human genome project is one of the significant achievements that have provided detailed insight into our genetic legacy. During the last two decades, biomedical investigations have gathered a considerable body of evidence by detecting more than 2000 disease genes. Despite the imperative advances in the genetic understanding of various diseases, the pathogenesis of many others remains obscure. With recent advances, the laborious methodologies used to identify DNA variations are replaced by direct sequencing of genomic DNA to detect genetic changes. The ability to perform such studies depends equally on the development of high-throughput and economical genotyping methods. Currently, basically for every disease whose origen is still unknown, genetic approaches are available which could be pedigree-dependent or -independent with the capacity to elucidate fundamental disease mechanisms. Computer algorithms and programs for linkage analysis have formed the foundation for many disease gene detection projects, similarly databases of clinical findings have been widely used to support diagnostic decisions in dysmorphology and general human disease. For every disease type, genome sequence variations, particularly single nucleotide polymorphisms are mapped by comparing the genetic makeup of case and control groups. Methods that predict the effects of polymorphisms on protein stability are useful for the identification of possible disease associations, whereas structural effects can be assessed using methods to predict stability changes in proteins using sequence and/or structural information.

  4. Disease evaluations and agronomic traits of advanced peanut breeding lines in 2014

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A total of 23 commercially available peanut cultivars and high-oleic advanced breeding lines were evaluated in small field plots in 2014 for agronomic traits (crop value, yield, seed grade, and characteristics) and resistance to soilborne diseases. Among the 16 runner entries evaluated, Tamrun OL11...

  5. Disease evaluations and agronomic traits of advanced peanut breeding lines in 2013

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A total of 21 peanut cultivars and high-oleic advanced breeding lines were evaluated in small field plots in 2013 for agronomic traits (crop value, yield, seed grade, and characteristics) and resistance to diseases (Sclerotinia blight, southern blight, and Pythium and Rhizoctonia pod rot). Among th...

  6. The Care Needs of Community-Dwelling Seniors Suffering from Advanced Chronic Obstructive Pulmonary Disease

    ERIC Educational Resources Information Center

    Wilson, Donna M.; Ross, Carolyn; Goodridge, Donna; Davis, Penny; Landreville, Alison; Roebuck, Kim

    2008-01-01

    Aim: This study was undertaken to determine the care needs of Canadian seniors living at home with advanced chronic obstructive pulmonary disease (COPD). Background: COPD is a leading cause of morbidity and mortality worldwide. Although hospitalizations for illness exacerbations and end-stage care may be common, most persons with COPD live out…

  7. Future care planning: a first step to palliative care for all patients with advanced heart disease.

    PubMed

    Denvir, M A; Murray, S A; Boyd, K J

    2015-07-01

    Palliative care is recommended for patients with end-stage heart failure with several recent, randomised trials showing improvements in symptoms and quality of life and more studies underway. Future care planning provides a framework for discussing a range of palliative care problems with patients and their families. This approach can be introduced at any time during the patient's journey of care and ideally well in advance of end-of-life care. Future care planning is applicable to a wide range of patients with advanced heart disease and could be delivered systematically by cardiology teams at the time of an unplanned hospital admission, akin to cardiac rehabilitation for myocardial infarction. Integrating cardiology care and palliative care can benefit many patients with advanced heart disease at increased risk of death or hospitalisation. Larger, randomised trials are needed to assess the impact on patient outcomes and experiences.

  8. Overview and Accomplishments of Advanced Mirror Technology Development Phase 2 (AMTD-2) Project

    NASA Technical Reports Server (NTRS)

    Stahl, H. Philip

    2015-01-01

    The Advance Mirror Technology Development (AMTD) project is in Phase 2 of a multiyear effort, initiated in FY12, to mature by at least a half TRL step critical technologies required to enable 4 meter or larger UVOIR space telescope primary mirror assemblies for both general astrophysics and ultra-high contrast observations of exoplanets. AMTD Phase 1 completed all of its goals and accomplished all of its milestones. AMTD Phase 2 started in 2014. Key accomplishments include deriving primary mirror engineering specifications from science requirements; developing integrated modeling tools and using those tools to perform parametric design trades; and demonstrating new mirror technologies via sub-scale fabrication and test. AMTD-1 demonstrated the stacked core technique by making a 43-cm diameter 400 mm thick 'biscuit-cut' of a 4-m class mirror. AMTD-2 is demonstrating lateral scalability of the stacked core method by making a 1.5 meter 1/3rd scale model of a 4-m class mirror.

  9. Overview and accomplishments of advanced mirror technology development phase 2 (AMTD-2) project

    NASA Astrophysics Data System (ADS)

    Stahl, H. Philip

    2015-09-01

    The Advance Mirror Technology Development (AMTD) project is in Phase 2 of a multiyear effort, initiated in FY12, to mature by at least a half TRL step critical technologies required to enable 4 meter or larger UVOIR space telescope primary mirror assemblies for both general astrophysics and ultra-high contrast observations of exoplanets. AMTD Phase 1 completed all of its goals and accomplished all of its milestones. AMTD Phase 2 started in 2014. Key accomplishments include deriving primary mirror engineering specifications from science requirements; developing integrated modeling tools and using those tools to perform parametric design trades; and demonstrating new mirror technologies via sub-scale fabrication and test. AMTD-1 demonstrated the stacked core technique by making a 43-cm diameter 400 mm thick `biscuit-cut' of a 4-m class mirror. AMTD-2 is demonstrating lateral scalability of the stacked core method by making a 1.5 meter 1/3rd scale model of a 4-m class mirror

  10. Early Detection of Amyloid Plaque in Alzheimer’s Disease Via X-ray Phase CT

    DTIC Science & Technology

    2015-06-01

    SUBTITLE 5a. CONTRACT NUMBER W81XWH-12-1-0138 Early Detection of Amyloid Plaque in Alzheimer’s Disease Via X-ray Phase CT 5b. GRANT NUMBER 5c...ray phase contrast CT imaging method for early detection of amyloid plaque in Alzheimer’s disease. As specified in SA#1 and the project timeline, the

  11. Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study.

    PubMed

    Suzuki, Nobuaki; Hazama, Shoichi; Iguchi, Haruo; Uesugi, Kazuhiro; Tanaka, Hiroaki; Hirakawa, Kosei; Aruga, Atsushi; Hatori, Takashi; Ishizaki, Hidenobu; Umeda, Yuzo; Fujiwara, Toshiyoshi; Ikemoto, Tetsuya; Shimada, Mitsuo; Yoshimatsu, Kazuhiko; Shimizu, Ryoichi; Hayashi, Hiroto; Sakata, Koichiro; Takenouchi, Hiroko; Matsui, Hiroto; Shindo, Yoshitaro; Iida, Michihisa; Koki, Yasunobu; Arima, Hideki; Furukawa, Hiroyuki; Ueno, Tomio; Yoshino, Shigefumi; Nakamura, Yusuke; Oka, Masaaki; Nagano, Hiroaki

    2017-01-01

    We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

  12. Long-term evaluation of a phase 1 study of AADC gene therapy for Parkinson's disease.

    PubMed

    Mittermeyer, Gabriele; Christine, Chadwick W; Rosenbluth, Kathryn H; Baker, Suzanne L; Starr, Philip; Larson, Paul; Kaplan, Paul L; Forsayeth, John; Aminoff, Michael J; Bankiewicz, Krystof S

    2012-04-01

    We report the results of a long-term follow-up of subjects in a phase 1 study of AAV2-hAADC (adeno-associated virus type 2-human aromatic L-amino acid decarboxylase) gene therapy for the treatment of Parkinson's disease (PD). Ten patients with moderately advanced PD received bilateral putaminal infusions of either a low or a high dose of AAV2-hAADC vector. An annual positron emission tomography (PET) imaging with [(18)F]fluoro-L-m-tyrosine tracer was used for evaluation of AADC expression, and a standard clinical rating scale [Unified Parkinson's Disease Rating Scale (UPDRS)] was used to assess effect. Our previous analysis of the 6-month data suggested that this treatment was acutely safe and well tolerated. We found that the elevated PET signal observed in the first 12 months persisted over 4 years in both dose groups. A significantly increased PET value compared with the presurgery baseline was maintained over the 4-year monitoring period. The UPDRS in all patients off medication for 12 hr improved in the first 12 months, but displayed a slow deterioration in subsequent years. This analysis demonstrates that apparent efficacy continues through later years with an acceptable safety profile. These data indicate stable transgene expression over 4 years after vector delivery and continued safety, but emphasize the need for a controlled efficacy trial and the use of a higher vector dose.

  13. Advances in understanding and treating liver diseases during pregnancy: A review.

    PubMed

    Kamimura, Kenya; Abe, Hiroyuki; Kawai, Hirokazu; Kamimura, Hiroteru; Kobayashi, Yuji; Nomoto, Minoru; Aoyagi, Yutaka; Terai, Shuji

    2015-05-07

    Liver disease in pregnancy is rare but pregnancy-related liver diseases may cause threat to fetal and maternal survival. It includes pre-eclampsia; eclampsia; haemolysis, elevated liver enzymes, and low platelets syndrome; acute fatty liver of pregnancy; hyperemesis gravidarum; and intrahepatic cholestasis of pregnancy. Recent basic researches have shown the various etiologies involved in this disease entity. With these advances, rapid diagnosis is essential for severe cases since the decision of immediate delivery is important for maternal and fetal survival. The other therapeutic options have also been shown in recent reports based on the clinical trials and cooperation and information sharing between hepatologist and gynecologist is important for timely therapeutic intervention. Therefore, correct understandings of diseases and differential diagnosis from the pre-existing and co-incidental liver diseases during the pregnancy will help to achieve better prognosis. Therefore, here we review and summarized recent advances in understanding the etiologies, clinical courses and management of liver disease in pregnancy. This information will contribute to physicians for diagnosis of disease and optimum management of patients.

  14. Acute-phase reactants in periodontal disease: current concepts and future implications.

    PubMed

    Archana, Vilasan; Ambili, Ranjith; Nisha, Krishnavilasam Jayakumary; Seba, Abraham; Preeja, Chandran

    2015-05-01

    Periodontal disease has been linked to adverse cardiovascular events by unknown mechanisms. C-reactive protein is a systemic marker released during the acute phase of an inflammatory response and is a prognostic marker for cardiovascular disease, with elevated serum levels being reported during periodontal disease. Studies also reported elevated levels of various other acute-phase reactants in periodontal disease. It has been reported extensively in the literature that treatment of periodontal infections can significantly lower serum levels of C-reactive protein. Therefore, an understanding of the relationship between acute-phase response and the progression of periodontal disease and other systemic health complications would have a profound effect on the periodontal treatment strategies. In view of this fact, the present review highlights an overview of acute-phase reactants and their role in periodontal disease.

  15. Safety and feasibility of transendocardial autologous bone marrow cell transplantation in patients with advanced heart disease.

    PubMed

    Fuchs, Shmuel; Kornowski, Ran; Weisz, Giora; Satler, Lowell F; Smits, Peter C; Okubagzi, Petros; Baffour, Richard; Aggarwal, Anita; Weissman, Neil J; Cerqueira, Manuel; Waksman, Ron; Serrruys, Parrick; Battler, Alexander; Moses, Jeffrey W; Leon, Martin B; Epstein, Stephen E

    2006-03-15

    The present report contains the final results of a Phase I study that evaluated the feasibility, safety, and potential efficacy of intramyocardial injection of autologous bone marrow (BM) in "no-option" patients with refractory angina and myocardial ischemia. Twenty-seven patients underwent electromechanic mapping-guided transendomyocardial injections (n = 12, 0.2 ml each) of unfractionated autologous BM cells directed to ischemic, noninfarcted myocardial territory. Patients were injected with 28 +/- 27 x 10(6)/ml nucleated cells containing 2.2 +/- 1.4% CD34+ cells. The autologous BM injection procedure was successful in all patients and was associated with no adverse events. At 3 months, the Canadian Cardiovascular Society angina score (3.2 +/- 0.5 vs 2.0 +/- 0.91, p = 0.001) and treadmill exercise duration (418 +/- 136 vs 489 +/- 142 seconds, p = 0.017) had improved significantly. The stress-induced ischemia score within the injected territories (118 segments) had also improved (2.2 +/- 0.8 vs 1.7 +/- 1.1, p < 0.001). At 1 year, the clinical improvement was sustained, although 5 patients had undergone revascularization procedures. The number of total injected nucleated cells (CD45+), progenitor cells (CD34+), and the magnitude of secreted vascular endothelial growth factor and macrophage chemoattractant protein-1 by cultured BM cells failed to predict the clinical response. In conclusion, the 3- and 12-month study results have indicated the safety of catheter-based transendocardial delivery of autologous BM cells in patients with advanced symptomatic ischemic heart disease and may suggest sustained potential efficacy. The cellular and humeral characteristics of autologous BM cells did not predict the clinical response, underscoring the advisability of additional mechanistic exploration.

  16. Long-Term PEG-J Tube Safety in Patients With Advanced Parkinson's Disease

    PubMed Central

    Epstein, Michael; Johnson, David A; Hawes, Robert; Schmulewitz, Nathan; Vanagunas, Arvydas D; Gossen, E Roderich; Robieson, Weining Z; Eaton, Susan; Dubow, Jordan; Chatamra, Krai; Benesh, Janet

    2016-01-01

    OBJECTIVES: The objectives of this study were to present procedure- and device-associated adverse events (AEs) identified with long-term drug delivery via percutaneous endoscopic gastrojejunostomy (PEG-J). Levodopa-carbidopa intestinal gel (LCIG, also known in US as carbidopa-levodopa enteral suspension, CLES) is continuously infused directly to the proximal small intestine via PEG-J in patients with advanced Parkinson's disease (PD) to overcome slow and erratic gastric emptying and treat motor fluctuations that are not adequately controlled by oral or other pharmacological therapy. METHODS: An independent adjudication committee of three experienced (>25 years each) gastroenterologists reviewed gastrointestinal procedure- and device-associated AEs reported for PD patients (total n=395) enrolled in phase 3 LCIG studies. The rate, clinical significance, and causality of the procedure/device events were determined. RESULTS: The patient median exposure to PEG-J at the data cutoff was 480 days. Procedure- and device-associated serious AEs (SAEs) occurred in 67 (17%) patients. A total of 42% of SAEs occurred during the first 4 weeks following PEG-J placement. SAEs of major clinical significance with the highest procedural incidence were peritonitis (1.5%), pneumonia (1.5%), and abdominal pain (1.3%). The most common non-serious procedure- and device-associated AEs were abdominal pain (31%), post-operative wound infection (20%), and procedural pain (23%). In all, 17 (4.3%) patients discontinued treatment owing to an AE. CONCLUSIONS: In conclusion, incidences of PEG-J AEs with the LCIG delivery system and PEG-J longevity were compared favorably with ranges described in the PEG/PEG-J literature. A low discontinuation rate in this study suggests acceptable procedural outcomes and AE rates in PD patients treated with this PEG-J drug delivery system. PMID:27030949

  17. Regolith Advanced Surface Systems Operations Robot (RASSOR) Phase 2 and Smart Autonomous Sand-Swimming Excavator

    NASA Technical Reports Server (NTRS)

    Sandy, Michael

    2015-01-01

    The Regolith Advanced Surface Systems Operations Robot (RASSOR) Phase 2 is an excavation robot for mining regolith on a planet like Mars. The robot is programmed using the Robotic Operating System (ROS) and it also uses a physical simulation program called Gazebo. This internship focused on various functions of the program in order to make it a more professional and efficient robot. During the internship another project called the Smart Autonomous Sand-Swimming Excavator was worked on. This is a robot that is designed to dig through sand and extract sample material. The intern worked on programming the Sand-Swimming robot, and designing the electrical system to power and control the robot.

  18. Advanced conceptual design report solid waste retrieval facility, phase I, project W-113

    SciTech Connect

    Smith, K.E.

    1994-03-21

    Project W-113 will provide the equipment and facilities necessary to retrieve suspect transuranic (TRU) waste from Trench 04 of the 218W-4C burial ground. As part of the retrieval process, waste drums will be assayed, overpacked, vented, head-gas sampled, and x-rayed prior to shipment to the Phase V storage facility in preparation for receipt at the Waste Receiving and Processing Facility (WRAP). Advanced Conceptual Design (ACD) studies focused on project items warranting further definition prior to Title I design and areas where the potential for cost savings existed. This ACD Report documents the studies performed during FY93 to optimize the equipment and facilities provided in relation to other SWOC facilities and to provide additional design information for Definitive Design.

  19. Summary of the Advanced Reactor Design Criteria (ARDC) Phase 2 Activities

    SciTech Connect

    Holbrook, Mark Raymond

    2015-09-01

    This report provides an end-of-year summary reflecting the progress and status of proposed regulatory design criteria for advanced non-LWR designs in accordance with the Level 3 milestone in M3AT-15IN2001017 in work package AT-15IN200101. These criteria have been designated as ARDC, and they provide guidance to future applicants for addressing the GDC that are currently applied specifically to LWR designs. The report provides a summary of Phase 2 activities related to the various tasks associated with ARDC development and the subsequent development of example adaptations of ARDC for Sodium Fast Reactor (SFR) and modular High Temperature Gas-cooled Reactor (HTGR) designs.

  20. Diffusion, Thermal Properties and Chemical Compatibilities of Select MAX Phases with Materials For Advanced Nuclear Systems

    SciTech Connect

    Barsoum, Michel; Bentzel, Grady; Tallman, Darin J.; Sindelar, Robert; Garcia-Diaz, Brenda; Hoffman, Elizabeth

    2016-04-04

    The demands of Gen IV nuclear power plants for long service life under neutron irradiation at high temperature are severe. Advanced materials that would withstand high temperatures (up to 1000+ ºC) to high doses in a neutron field would be ideal for reactor internal structures and would add to the long service life and reliability of the reactors. The objective of this work is to investigate the chemical compatibility of select MAX with potential materials that are important for nuclear energy, as well as to measure the thermal transport properties as a function of neutron irradiation. The chemical counterparts chosen for this work are: pyrolytic carbon, SiC, U, Pd, FLiBe, Pb-Bi and Na, the latter 3 in the molten state. The thermal conductivities and heat capacities of non-irradiated MAX phases will be measured.

  1. MANIFOLD DAMPING OF WAKEFIELDS IN HIGH PHASE ADVANCE LINACS FOR THE NLC

    SciTech Connect

    Jones, Roger M

    2002-06-20

    Earlier RDDS (Rounded Damped Detuned Structures) [1,2], designed, fabricated and tested at SLAC, in collaboration with KEK, have been shown to damp wakefields successfully. However, electrical breakdown has been found to occur in these structures and this makes them inoperable at the desired gradient. Recent results [3] indicate that lowering the group velocity of the accelerating mode reduces electrical breakdown events. In order to preserve the filling time of each structure a high synchronous phase advance (150 degrees as opposed to 120 used in previous NLC designs) has been chosen. Here, damping of the wakefield is analyzed. Manifold damping and interleaving of structure cell frequencies is discussed. These wakefields impose alignment tolerances on the cells and on the structure as a whole. Tolerance calculations are performed and these are compared with analytic estimations.

  2. Time-temperature-stress capabilities of composite materials for advanced supersonic technology application, phase 1

    NASA Technical Reports Server (NTRS)

    Kerr, J. R.; Haskins, J. F.

    1980-01-01

    Implementation of metal and resin matrix composites into supersonic vehicle usage is contingent upon accelerating the demonstration of service capacity and design technology. Because of the added material complexity and lack of extensive service data, laboratory replication of the flight service will provide the most rapid method of documenting the airworthiness of advanced composite systems. A program in progress to determine the time temperature stress capabilities of several high temperature composite materials includes thermal aging, environmental aging, fatigue, creep, fracture, and tensile tests as well as real time flight simulation exposure. The program has two parts. The first includes all the material property determinations and aging and simulation exposures up through 10,000 hours. The second continues these tests up to 50,000 cumulative hours. Results are presented of the 10,000 hour phase, which has now been completed.

  3. A phase I trial investigating pulsatile erlotinib in combination with gemcitabine and oxaliplatin in advanced biliary tract cancers.

    PubMed

    Goff, Laura W; Cardin, Dana B; Whisenant, Jennifer G; Du, Liping; Koyama, Tatsuki; Dahlman, Kimberly B; Salaria, Safia N; Young, Ruth T; Ciombor, Kristen K; Gilbert, Jill; Smith, Stephen James; Chan, Emily; Berlin, Jordan

    2017-02-01

    Advanced biliary tract cancers (ABTC) are among the deadliest malignancies with limited treatment options after progression on standard-of-care chemotherapy, which includes gemcitabine (GEM) and oxaliplatin (OX). The epidermal growth factor receptor inhibitor erlotinib has been explored in ABTC with modest efficacy. Erlotinib given continuously may antagonize the action of chemotherapy against cycling tumor cells, but pulsatile dosing of erlotinib with chemotherapy may improve efficacy. The purpose of this study was to assess the safety of pulsatile erlotinib with GEMOX. This was a single-institution phase Ib study that enrolled adult patients with unresectable or metastatic biliary tract, pancreas, duodenal, or ampullary carcinomas that have not received any prior treatment for their disease. Dose escalation followed a standard 3 + 3 design, and dose-limiting toxicities (DLTs) were any treatment-related, first course non-hematologic grade ≥ 3 toxicity, except nausea/vomiting, or grade 4 hematologic toxicity. A dose expansion cohort in ABTC was treated at the MTD. Twenty-eight patients were enrolled and 4 dose levels were explored. The MTD was erlotinib 150 mg + GEM 800 mg/m(2) + OX 85 mg/m(2). DLTs were diarrhea and anemia. Most frequent toxicities were nausea (78 %), fatigue (71 %), neuropathy (68 %), and diarrhea (61 %), predominantly grade 1-2. In the ABTC patients, the objective response and disease control rates were 29 % and 94 %, respectively, and median overall survival was 18 months. Erlotinib plus GEMOX was well tolerated. Encouraging anti-tumor activity was seen as evidenced by a high disease control rate and longer median OS than standard chemotherapy in the patients with ABTC.

  4. Phase II study of capecitabine (Xeloda (registered) ) and concomitant boost radiotherapy in patients with locally advanced rectal cancer

    SciTech Connect

    Krishnan, Sunil; Janjan, Nora A.; Skibber, John M.; Rodriguez-Bigas, Miguel A.; Wolff, Robert A.; Das, Prajnan; Delclos, Marc E.; Chang, George J.; Hoff, Paulo M.; Eng, Cathy; Brown, Thomas D.; Crane, Christopher H.; Feig, Barry W.; Morris, Jeffrey; Vadhan-Raj, Saroj; Hamilton, Stanley R.; Lin, Edward H. . E-mail: elin@u.washington.edu

    2006-11-01

    Purpose: The aim of this study was to determine the efficacy of capecitabine (Xeloda (registered) ), an oral fluoropyrimidine, as a radiosensitizer in the neoadjuvant treatment of locally advanced rectal cancer (LARC). Methods and Materials: We conducted a phase II study of capecitabine (825 mg/m{sup 2} orally, twice daily continuous) with radiotherapy (52.5 Gy/30 fractions to the primary tumor and perirectal nodes) in 54 patients with LARC (node-negative {>=}T3 or any node-positive tumor) staged by endoscopic ultrasound (EUS). The primary endpoint was pathologic response rate; secondary endpoints included toxicity profiles and survival parameters. Results: Of the 54 patients (median age, 56.7 years; range, 21.3-78.7 years; male:female ratio, 1.7; Eastern Cooperative Oncology Group performance status 0-1: 100%), 51 patients (94%) had T3N0 or T3N1 disease by EUS. Surgery was not performed in 3 patients; 2 of these patients had metastatic disease, and the third patient refused after a complete clinical response. Of the 51 patients evaluable for pathologic response, 9 patients (18%) achieved complete response, and 12 patients (24%) had microscopic residual disease (<10% viable cells). In addition, 26 patients of all 54 patients (51%) achieved T-downstaging, and 15 patients of 29 patients (52%) achieved N-downstaging. Grade 3/4 toxicities were radiation dermatitis (9%) and diarrhea (2%). Sphincter preservation rate for tumor {<=}5 cm from the anal verge was 67% (18/27). Conclusion: This regimen of radiotherapy plus capecitabine is well tolerated and is more convenient than protracted venous infusion of 5-FU. The pathologic response rate is comparable to our previous experience using protracted venous infusion 5-FU for LARC.

  5. A Phase II Study of Sorafenib in Advanced Uterine Carcinoma / Carcinosarcoma: A Trial of the Chicago, PMH, and California Phase II Consortia

    PubMed Central

    Nimeiri, Halla S.; Oza, Amit M.; Morgan, Robert J.; Huo, Dezheng; Elit, Laurie; Knost, James A.; Wade, James L.; Agamah, Edem; Vokes, Everett E.; Fleming, Gini F.

    2010-01-01

    Objectives To determine the efficacy and safety of single agent sorafenib, an oral multi-targeted tyrosine kinase inhibitor, in patients with advanced uterine carcinoma and carcinosarcoma. Methods This multi-institutional non-randomized phase II trial enrolled two cohorts: patients with uterine carcinoma (cohort A) and uterine carcinosarcoma (cohort B). Eligibility criteria included measurable disease, 0–1 prior chemotherapy regimens, and ECOG performance status ≤ 2. Sorafenib at a dose of 400 mg was administered orally twice daily. A cycle was defined as 28 days. Objective tumor response was the primary endpoint and was assessed following every two cycles. Results Fifty–six patients (40 with carcinoma, 16 with carcinosarcoma) were enrolled between March 2005 and August 2007. Two (5%) patients with uterine carcinoma had a partial response (PR) and 17 (42.5%) achieved stable disease (SD). Five had SD lasting at least 4 months. The 6-month progression free survival rate for patients with carcinoma was 29%, and the median overall survival was 11.4 months. No patients with carcinosarcoma had an objective response. Four (25%) had SD, and one had SD lasting 18 months. The 6-month progression free survival rate was 13%, and the median overall survival was 5.0 months. Grade 3/4 drug related toxicities included: hypertension (13%), hand-foot syndrome (13%), hypophosphatemia (7%), anemia (5%), rash (5%), diarrhea (5%), thrombosis (5%), fatigue (5%) and bleeding (5%). Conclusion Sorafenib had minimal activity in patients with uterine carcinoma. Predictive factors for potential benefit are needed. PMID:20117828

  6. Aspirin-Exacerbated Diseases: Advances in Asthma with Nasal Polyposis, Urticaria, Angioedema, and Anaphylaxis.

    PubMed

    Stevens, Whitney; Buchheit, Kathleen; Cahill, Katherine N

    2015-12-01

    Aspirin-exacerbated diseases are important examples of drug hypersensitivities and include aspirin-exacerbated respiratory disease (AERD), aspirin- or non-steroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema, and aspirin- or NSAID-induced anaphylaxis. While each disease subtype may be distinguished by unique clinical features, the underlying mechanisms that contribute to these phenotypes are not fully understood. However, the inhibition of the cyclooxygenase-1 enzyme is thought to play a significant role. Additionally, eosinophils, mast cells, and their products, prostaglandins and leukotrienes, have been identified in the pathogenesis of AERD. Current diagnostic and treatment strategies for aspirin-exacerbated diseases remain limited, and continued research focusing on each of the unique hypersensitivity reactions to aspirin is essential. This will not only advance the understanding of these disease processes, but also lead to the subsequent development of novel therapeutics that patients who suffer from aspirin-induced reactions desperately need.

  7. A review of advances in the study of diseases of fish: 1954-1964

    USGS Publications Warehouse

    Post, G.

    1965-01-01

    STUDY OF DISEASE IN ANIMALS, INCLUDING MAN, has progressed rapidly in the past decade. Looking back, we find amazing success in the study of man's diseases and possibly only a little less success in studies of diseases of domesticated homeothermic animals. We who are interested in the poikilothermic animals may feel at times that we have not advanced so rapidly in our field. The reason for this may be closely associated with economics. The market for drugs and therapeutic agents is greater for domestic livestock than for cultured fishes. A larger income is derived from rearing domestic livestock. Therefore, more public funds are available for study of diseases of man and domestic livestock, while such funds are limited for the study of diseases of fish. The Federal and State fish-cultural systems, as well as colleges and universities, have been most active in research on fish disease and probably will continue to be so.

  8. Advanced simulation model for IPM motor drive with considering phase voltage and stator inductance

    NASA Astrophysics Data System (ADS)

    Lee, Dong-Myung; Park, Hyun-Jong; Lee, Ju

    2016-10-01

    This paper proposes an advanced simulation model of driving system for Interior Permanent Magnet (IPM) BrushLess Direct Current (BLDC) motors driven by 120-degree conduction method (two-phase conduction method, TPCM) that is widely used for sensorless control of BLDC motors. BLDC motors can be classified as SPM (Surface mounted Permanent Magnet) and IPM motors. Simulation model of driving system with SPM motors is simple due to the constant stator inductance regardless of the rotor position. Simulation models of SPM motor driving system have been proposed in many researches. On the other hand, simulation models for IPM driving system by graphic-based simulation tool such as Matlab/Simulink have not been proposed. Simulation study about driving system of IPMs with TPCM is complex because stator inductances of IPM vary with the rotor position, as permanent magnets are embedded in the rotor. To develop sensorless scheme or improve control performance, development of control algorithm through simulation study is essential, and the simulation model that accurately reflects the characteristic of IPM is required. Therefore, this paper presents the advanced simulation model of IPM driving system, which takes into account the unique characteristic of IPM due to the position-dependent inductances. The validity of the proposed simulation model is validated by comparison to experimental and simulation results using IPM with TPCM control scheme.

  9. Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing.

    PubMed

    Peters, Brock A; Kermani, Bahram G; Alferov, Oleg; Agarwal, Misha R; McElwain, Mark A; Gulbahce, Natali; Hayden, Daniel M; Tang, Y Tom; Zhang, Rebecca Yu; Tearle, Rick; Crain, Birgit; Prates, Renata; Berkeley, Alan; Munné, Santiago; Drmanac, Radoje

    2015-03-01

    Currently, the methods available for preimplantation genetic diagnosis (PGD) of in vitro fertilized (IVF) embryos do not detect de novo single-nucleotide and short indel mutations, which have been shown to cause a large fraction of genetic diseases. Detection of all these types of mutations requires whole-genome sequencing (WGS). In this study, advanced massively parallel WGS was performed on three 5- to 10-cell biopsies from two blastocyst-stage embryos. Both parents and paternal grandparents were also analyzed to allow for accurate measurements of false-positive and false-negative error rates. Overall, >95% of each genome was called. In the embryos, experimentally derived haplotypes and barcoded read data were used to detect and phase up to 82% of de novo single base mutations with a false-positive rate of about one error per Gb, resulting in fewer than 10 such errors per embryo. This represents a ∼ 100-fold lower error rate than previously published from 10 cells, and it is the first demonstration that advanced WGS can be used to accurately identify these de novo mutations in spite of the thousands of false-positive errors introduced by the extensive DNA amplification required for deep sequencing. Using haplotype information, we also demonstrate how small de novo deletions could be detected. These results suggest that phased WGS using barcoded DNA could be used in the future as part of the PGD process to maximize comprehensiveness in detecting disease-causing mutations and to reduce the incidence of genetic diseases.

  10. Proteomics and plant disease: advances in combating a major threat to the global food supply.

    PubMed

    Rampitsch, Christof; Bykova, Natalia V

    2012-02-01

    The study of plant disease and immunity is benefiting tremendously from proteomics. Parallel streams of research from model systems, from pathogens in vitro and from the relevant pathogen-crop interactions themselves have begun to reveal a model of how plants succumb to invading pathogens and how they defend themselves without the benefit of a circulating immune system. In this review, we discuss the contribution of proteomics to these advances, drawing mainly on examples from crop-fungus interactions, from Arabidopsis-bacteria interactions, from elicitor-based model systems and from pathogen studies, to highlight also the important contribution of non-crop systems to advancing crop protection.

  11. Phase Transitions in Antibody Solutions: from Pharmaceuticals to Human Disease

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Lomakin, Aleksey; Benedek, George; Dana Farber Cancer Institute Collaboration; Amgen Inc. Collaboration

    2014-03-01

    Antibodies are very important proteins. Natural antibodies play essential role in the immune system of human body. Pharmaceutical antibodies are used as drugs. Antibodies are also indispensable tools in biomedical research and diagnostics. Recently, a number of observations of phase transitions of pharmaceutical antibodies have been reported. These phase transitions are undesirable from the perspective of colloid stability of drug solutions in processing and storage, but can be used for protein purification, X-ray crystallography, and improving pharmokinetics of drugs. Phase transitions of antibodies can also take place in human body, particularly in multiple myeloma patients who overproduce monoclonal antibodies. These antibodies, in some cases, crystallize at body temperature and cause severe complications called cryoglobulinemia. I will present the results of our current studies on phase transitions of both pharmaceutical antibodies and cryoglobulinemia-associated antibodies. These studies have shown that different antibodies have different propensity to undergo phase transitions, but their phase behavior has universal features which are remarkably different from those of spherical proteins. I will discuss how studies of phase behavior can be useful in assessing colloid stability of pharmaceutical antibodies and in early diagnostics of cryoglobulinemia, as well as general implications of the fact that some antibodies can precipitate at physiological conditions.

  12. Recent Advances in Kawasaki Disease - Proceedings of the 3rd Kawasaki Disease Summit, Chandigarh, 2014.

    PubMed

    Singh, Surjit; Sharma, Dhrubajyoti; Bhattad, Sagar; Phillip, Saji

    2016-01-01

    Kawasaki disease (KD) is the most common cause of acquired heart disease in children in Japan, North America and Europe. It is now being increasingly recognized from the developing countries as well. If not diagnosed and treated in time, KD can result in coronary artery abnormalities in approximately 15-25% cases. The long-term consequences of these abnormalities may manifest in adults as myocardial ischemia and congestive heart failure. Intravenous immunoglobulin (IVIg) remains the drug of choice for treatment of KD, but several new agents like infliximab, cyclosporine, glucocorticoids and statins are now being increasingly used in these patients. While echocardiography has been the preferred imaging modality hitherto, CT coronary angiography has emerged as an exciting new supplementary option and provides an entirely new dimension to this disease. The incidence of KD has shown a progressive increase in several countries and it is likely that this disease would impact public health programmes in the near future even in the developing countries.

  13. Advanced Communication and Control for Distributed Energy Resource Integration: Phase 2 Scientific Report

    SciTech Connect

    BPL Global

    2008-09-30

    The objective of this research project is to demonstrate sensing, communication, information and control technologies to achieve a seamless integration of multivendor distributed energy resource (DER) units at aggregation levels that meet individual user requirements for facility operations (residential, commercial, industrial, manufacturing, etc.) and further serve as resource options for electric and natural gas utilities. The fully demonstrated DER aggregation system with embodiment of communication and control technologies will lead to real-time, interactive, customer-managed service networks to achieve greater customer value. Work on this Advanced Communication and Control Project (ACCP) consists of a two-phase approach for an integrated demonstration of communication and control technologies to achieve a seamless integration of DER units to reach progressive levels of aggregated power output. Phase I involved design and proof-of-design, and Phase II involves real-world demonstration of the Phase I design architecture. The scope of work for Phase II of this ACCP involves demonstrating the Phase I design architecture in large scale real-world settings while integrating with the operations of one or more electricity supplier feeder lines. The communication and control architectures for integrated demonstration shall encompass combinations of software and hardware components, including: sensors, data acquisition and communication systems, remote monitoring systems, metering (interval revenue, real-time), local and wide area networks, Web-based systems, smart controls, energy management/information systems with control and automation of building energy loads, and demand-response management with integration of real-time market pricing. For Phase II, BPL Global shall demonstrate the Phase I design for integrating and controlling the operation of more than 10 DER units, dispersed at various locations in one or more Independent System Operator (ISO) Control Areas, at

  14. Neoadjuvant radiochemotherapy for locally advanced gastric cancer: Long-term results of a phase I trial

    SciTech Connect

    Allal, Abdelkarim S. . E-mail: abdelkarim.allal@hcuge.ch; Zwahlen, Daniel; Bruendler, Marie-Anne; Peyer, Raymond de; Morel, Philippe; Huber, Olivier; Roth, Arnaud D.

    2005-12-01

    Purpose: To assess the long-term results of radiation therapy (RT) when added preoperatively to systemic chemotherapy in patients with locally advanced gastric cancer. Methods and Materials: Patients presenting with T3-4 or N+ gastric cancer received two cycles of cisplatin 100 mg/m{sup 2} d1, 5FU 800 mg/m{sup 2} d1-4, and Leucovorin 60 mg twice daily d1-4; one cycle before and one concomitantly with hyperfractionated RT (median dose, 38.4; range, 31.2-45.6 Gy). All patients underwent a total or subtotal gastrectomy with D2 lymph node resection. Results: Nineteen patients were accrued and 18 completed the neoadjuvant therapeutic program. All patients were subsequently operated and no fatality occurred. At a mean follow-up of 8 years for the surviving patients, no severe late toxicity was observed. The 5-year locoregional control, disease-free, and overall survival were of 85%, 41%, and 35%, respectively. The peritoneum was the most frequent site of relapse. Among long terms survivors, no severe (Radiation Therapy Oncology Group Grade 3-4) late complication was reported. Conclusions: The present neoadjuvant treatment does not seem to increase the operative risk, nor the late side effects. The encouraging locoregional control rate suggests that the neoadjuvant approach should be considered for future trials in locally advanced gastric cancer. Also, the frequency of peritoneal recurrence stresses the need for a more efficient systemic or intraperitoneal treatment.

  15. Advanced Systems development: New materials/systems for interior gas distribution. Phase 1. Advanced Systems Specifications. Final report, January 1989-May 1991

    SciTech Connect

    Peters, E.; Scocca, M.; Topping, R.

    1991-05-01

    As part of the Gas Research Institute's overall program to develop safe, low cost, semi rigid gas piping systems, their project is aimed at identifying and evaluating advanced high performance materials and components suitable for interior gas piping by the year 2000 and beyond. The report summarizes the results of Phase I - Advanced Systems Specifications Studies, which developed performance criteria, installed cost goals and a database of promising new metallic and non-metallic piping materials. Several candidate materials and systems are identified as well as the current status of gas monitoring, sensing and control technologies.

  16. Emergence of the advancing neuromechanical phase in a resistive force dominated medium

    PubMed Central

    Ding, Yang; Sharpe, Sarah S.; Wiesenfeld, Kurt; Goldman, Daniel I.

    2013-01-01

    Undulatory locomotion, a gait in which thrust is produced in the opposite direction of a traveling wave of body bending, is a common mode of propulsion used by animals in fluids, on land, and even within sand. As such, it has been an excellent system for discovery of neuromechanical principles of movement. In nearly all animals studied, the wave of muscle activation progresses faster than the wave of body bending, leading to an advancing phase of activation relative to the curvature toward the tail. This is referred to as “neuromechanical phase lags” (NPL). Several multiparameter neuromechanical models have reproduced this phenomenon, but due to model complexity, the origin of the NPL has proved difficult to identify. Here, we use perhaps the simplest model of undulatory swimming to predict the NPL accurately during sand-swimming by the sandfish lizard, with no fitting parameters. The sinusoidal wave used in sandfish locomotion, the friction-dominated and noninertial granular resistive force environment, and the simplicity of the model allow detailed analysis, and reveal the fundamental mechanism responsible for the phenomenon: the combination of synchronized torques from distant points on the body and local traveling torques. This general mechanism should help explain the NPL in organisms in other environments; we therefore propose that sand-swimming could be an excellent system with which to generate and test other neuromechanical models of movement quantitatively. Such a system can also provide guidance for the design and control of robotic undulatory locomotors in complex environments. PMID:23733931

  17. Emergence of the advancing neuromechanical phase in a resistive force dominated medium.

    PubMed

    Ding, Yang; Sharpe, Sarah S; Wiesenfeld, Kurt; Goldman, Daniel I

    2013-06-18

    Undulatory locomotion, a gait in which thrust is produced in the opposite direction of a traveling wave of body bending, is a common mode of propulsion used by animals in fluids, on land, and even within sand. As such, it has been an excellent system for discovery of neuromechanical principles of movement. In nearly all animals studied, the wave of muscle activation progresses faster than the wave of body bending, leading to an advancing phase of activation relative to the curvature toward the tail. This is referred to as "neuromechanical phase lags" (NPL). Several multiparameter neuromechanical models have reproduced this phenomenon, but due to model complexity, the origin of the NPL has proved difficult to identify. Here, we use perhaps the simplest model of undulatory swimming to predict the NPL accurately during sand-swimming by the sandfish lizard, with no fitting parameters. The sinusoidal wave used in sandfish locomotion, the friction-dominated and noninertial granular resistive force environment, and the simplicity of the model allow detailed analysis, and reveal the fundamental mechanism responsible for the phenomenon: the combination of synchronized torques from distant points on the body and local traveling torques. This general mechanism should help explain the NPL in organisms in other environments; we therefore propose that sand-swimming could be an excellent system with which to generate and test other neuromechanical models of movement quantitatively. Such a system can also provide guidance for the design and control of robotic undulatory locomotors in complex environments.

  18. Development and characterization of advanced phase-shift mask blanks for 14nm node and beyond

    NASA Astrophysics Data System (ADS)

    Kim, Chang-Jun; Jang, Kyu-Jin; Choi, Min-Ki; Yang, Chul-Kyu; Lee, Jae-Chul; Lee, Jong-Keun; Kang, Byung-Sun; Lee, Jong-Hwa; Shin, Cheol; Nam, Kee-Soo

    2014-10-01

    Recently, the development of semiconductor process for 14nm node and beyond is in progress. The mask-making process demands higher resolution and CD accuracy to meet requirements. Current conventional ArF PSM has several problems such as higher 3D effect and higher loading effect due to the thicker film. These problems cause the CD performance degradation. This study is about the manufacturing of advance ArF PSM, which has thinner phase shift layer and higher etch rate Cr absorber film. The thickness of phase shift film is less than 60nm and the total etch-time for the Cr absorber film is reduced more than 30%. The mask CD performance of this new blank was evaluated in terms of CD uniformity, CD linearity, pattern resolution, and loading effect and so on. Adapting to this new blank, we can achieve better CD performance by reducing the loading effect. In addition, the chemical durability and ArF exposure durability were also improved. In conclusion, the mask-making process margin was extended by using this new blank, and it is expected that we can achieve the required specifications for 14nm node and beyond.

  19. Advanced emissions control development project. Phase I, Final report, November 1, 1993--February 19, 1996

    SciTech Connect

    1996-02-29

    The primary objective of the Advanced Emissions Control Development Program (AECDP) is to develop practical, cost-effective strategies for reducing the emissions of air toxics from coal-fired boilers. Ideally, the project aim is to effectively control air toxic emissions through the use of conventional flue gas cleanup equipment such as electrostatic precipitators (ESP`s), fabric filters (baghouse), and wet flue gas desulfurization. B&W`s Clean Environment Development Facility (CEDF) and the AECDP equipment combined to form a state-of-the-art facility for integrated evaluation of combustion and post-combustion emissions control options. Phase 1 activities were primarily aimed at providing a reliable, representative test facility for conducting air toxic emissions control development work later in the project. This report summarizes the AECDP Phase I activities which consisted of the design, installation, shakedown, verification, and air toxics benchmarking of the AECDP facility. All verification and air toxic tests were conducted with a high sulfur, bituminous Ohio coal.

  20. Advanced emissions control development project. Final report, November 1, 1993--February 29, 1996. Phase I

    SciTech Connect

    Farthing, G.A.

    1996-02-29

    The primary objective of the Advanced Emissions Control Development Program (AECDP) is to develop practical, cost-effective strategies for reducing the emissions of air toxics from coal-fired boilers. Ideally, the project aim is to effectively control air toxic emissions through the use of conventional flue gas cleanup equipment such as electrostatic precipitators (ESPs), fabric filters (baghouses), and wet flue gas desulfurization. B&W`s Clean Environment Development Facility (CEDF) and the AECDP equipment combined to form a state-of-the-art facility for integrated evaluation of combustion and post-combustion emissions control options. Phase I activities were primarily directed at providing a reliable, representative test facility for conducting air toxic emission control development work later in the project. This report summarizes the AECDP Phase I activities which consisted of the design, installation, shakedown, verification, and air toxics benchmarking of the AECDP facility. The AECDP facility consists of an ESP, pulse-jet baghouse, and wet scrubber. All verification and air toxic tests were conducted with a high sulfur, bituminous Ohio coal. In order to successfully apply the results of the program to utility systems, the relationship between the performance of the CEDF/AECDP test equipment and commercial units had to be established. The first step in the verification process was to validate that the flue gas treatment devices - boiler/convection pass simulator, ESP, baghouse, and wet SO{sub 2} scrubber - operate in a manner representative of commercial units.

  1. Recent advances in host defense mechanisms/therapies against oral infectious diseases and consequences for systemic disease.

    PubMed

    Gaffen, S L; Herzberg, M C; Taubman, M A; Van Dyke, T E

    2014-05-01

    The innate and adaptive immune systems are both crucial to oral disease mechanisms and their impact on systemic health status. Greater understanding of these interrelationships will yield opportunities to identify new therapeutic targets to modulate disease processes and/or increase host resistance to infectious or inflammatory insult. The topics addressed reflect the latest advances in our knowledge of the role of innate and adaptive immune systems and inflammatory mechanisms in infectious diseases affecting the oral cavity, including periodontitis and candidiasis. In addition, several potential links with systemic inflammatory conditions, such as cardiovascular disease, are explored. The findings elucidate some of the defense mechanisms utilized by host tissues, including the role of IL-17 in providing immunity to oral candidiasis, the antimicrobial defense of mucosal epithelial cells, and the pro-resolution effects of the natural inflammatory regulators, proresolvins and lipoxins. They also describe the role of immune cells in mediating pathologic bone resorption in periodontal disease. These insights highlight the potential for therapeutic benefit of immunomodulatory interventions that bolster or modulate host defense mechanisms in both oral and systemic disease. Among the promising new therapeutic approaches discussed here are epithelial cell gene therapy, passive immunization against immune cell targets, and the use of proresolvin agents.

  2. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

    PubMed Central

    Gulliford, T.; English, J.; Colston, K. W.; Menday, P.; Moller, S.; Coombes, R. C.

    1998-01-01

    Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3. PMID:9662243

  3. Combined radiotherapy, 5-fluorouracil continuous infusion and weekly oxaliplatin in advanced rectal cancer: a phase I study.

    PubMed

    François, Eric; Ychou, Marc; Ducreux, Michel; Bertheault-Cvitkovic, Frédérique; Giovannini, Marc; Conroy, Thierry; Lemanski, Claire; Thomas, Olivier; Magnin, Valérie

    2005-12-01

    The aim of this study was to determine the maximum-tolerated dose (MTD) of weekly oxaliplatin combined with 5-fluorouracil (5FU) continuous infusion administered concomitantly with fractionated radiotherapy in patients presenting advanced rectal cancer. Forty-three patients with rectal cancer (stage T3/T4 (n = 24), metastatic (n = 17) and 2 with local recurrence), were included. The radiotherapy dose delivered was 45 Gy over 5 weeks (1.8 Gy/fraction/day, 5 days per week). The initial weekly oxaliplatin dosage was 30 mg/m2 and the 5FU dosage 150 mg/m2/d. The oxaliplatin and 5FU doses were escalated. Eight dose levels were tested. At dose level 8 (oxaliplatin 80 mg/m2, 5FU 225 mg/m2/d), 2 patients out of 4 presented dose-limiting toxicity (severe diarrhoea with dehydration and fatal shock, rectovesical fistula). At dose level 7, 2 further patients presented with grade 3 diarrhoea. The main toxicity of the combination was diarrhoea. The hematological and neurological toxicities were not severe and were not dose-limiting. Out of the 30 patients undergoing surgery, 4 (13.3%) presented with pathological complete response and 4 (13.3%) only presented with microscopic residual disease. The results from this study enabled determination of the recommended weekly oxaliplatin dose (60 mg/m2) combined with 5FU continuous infusion (225 mg/m2) and fractionated radiotherapy (45 Gy) in the pre-operative treatment of advanced rectal cancer. The good safety profile of the regimen, associated with promising results in terms of histological response, suggest that the regimen could be developed in future phase II/III studies.

  4. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

    PubMed

    Gulliford, T; English, J; Colston, K W; Menday, P; Moller, S; Coombes, R C

    1998-07-01

    Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3.

  5. Advanced Multi-Phase Flow CFD Model Development for Solid Rocket Motor Flowfield Analysis

    NASA Technical Reports Server (NTRS)

    Liaw, Paul; Chen, Y. S.; Shang, H. M.; Doran, Denise

    1993-01-01

    It is known that the simulations of solid rocket motor internal flow field with AL-based propellants require complex multi-phase turbulent flow model. The objective of this study is to develop an advanced particulate multi-phase flow model which includes the effects of particle dynamics, chemical reaction and hot gas flow turbulence. The inclusion of particle agglomeration, particle/gas reaction and mass transfer, particle collision, coalescence and breakup mechanisms in modeling the particle dynamics will allow the proposed model to realistically simulate the flowfield inside a solid rocket motor. The Finite Difference Navier-Stokes numerical code FDNS is used to simulate the steady-state multi-phase particulate flow field for a 3-zone 2-D axisymmetric ASRM model and a 6-zone 3-D ASRM model at launch conditions. The 2-D model includes aft-end cavity and submerged nozzle. The 3-D model represents the whole ASRM geometry, including additional grain port area in the gas cavity and two inhibitors. FDNS is a pressure based finite difference Navier-Stokes flow solver with time-accurate adaptive second-order upwind schemes, standard and extended k-epsilon models with compressibility corrections, multi zone body-fitted formulations, and turbulence particle interaction model. Eulerian/Lagrangian multi-phase solution method is applied for multi-zone mesh. To simulate the chemical reaction, penalty function corrected efficient finite-rate chemistry integration method is used in FDNS. For the AL particle combustion rate, the Hermsen correlation is employed. To simulate the turbulent dispersion of particles, the Gaussian probability distribution with standard deviation equal to (2k/3)(exp 1/2) is used for the random turbulent velocity components. The computational results reveal that the flow field near the juncture of aft-end cavity and the submerged nozzle is very complex. The effects of the turbulent particles affect the flow field significantly and provide better

  6. Phase 1 environmental report for the Advanced Neutron Source at Oak Ridge National Laboratory

    SciTech Connect

    Blasing, T.J.; Brown, R.A.; Cada, G.F.; Easterly, C.; Feldman, D.L.; Hagan, C.W.; Harrington, R.M.; Johnson, R.O.; Ketelle, R.H.; Kroodsma, R.L.; McCold, L.N.; Reich, W.J.; Scofield, P.A.; Socolof, M.L.; Taleyarkhan, R.P.; Van Dyke, J.W.

    1992-02-01

    The US Department of Energy (DOE) has proposed the construction and operation of the Advanced Neutron Source (ANS), a 330-MW(f) reactor, at Oak Ridge National Laboratory (ORNL) to support neutron scattering and nuclear physics experiments. ANS would provide a steady-state source of neutrons that are thermalized to produce sources of hot, cold, and very coal neutrons. The use of these neutrons in ANS experiment facilities would be an essential component of national research efforts in basic materials science. Additionally, ANS capabilities would include production of transplutonium isotopes, irradiation of potential fusion and fission reactor materials, activation analysis, and production of medical and industrial isotopes such as {sup 252}Cf. Although ANS would not require licensing by the US Nuclear Regulatory Commission (NRC), DOE regards the design, construction, and operation of ANS as activities that would produce a licensable facility; that is, DOE is following the regulatory guidelines that NRC would apply if NRC were licensing the facility. Those guidelines include instructions for the preparation of an environmental report (ER), a compilation of available data and preliminary analyses regarding the environmental impacts of nuclear facility construction and operation. The ER, described and outlined in NRC Regulatory Guide 4.2, serves as a background document to facilitate the preparation of environmental impact statements (EISs). Using Regulatory Guide 4.2 as a model, this ANS ER provides analyses and information specific to the ANS site and area that can be adopted (and modified, if necessary) for the ANS EIS. The ER is being prepared in two phases. Phase 1 ER includes many of the data and analyses needed to prepare the EIS but does not include data or analyses of alternate sites or alternate technologies. Phase 2 ER will include the additional data and analyses stipulated by Regulatory Guide 4.2.

  7. ADVANCED SIMULATION CAPABILITY FOR ENVIRONMENTAL MANAGEMENT- CURRENT STATUS AND PHASE II DEMONSTRATION RESULTS

    SciTech Connect

    Seitz, R.

    2013-02-26

    The U.S. Department of Energy (USDOE) Office of Environmental Management (EM), Office of Soil and Groundwater, is supporting development of the Advanced Simulation Capability for Environmental Management (ASCEM). ASCEM is a state-of-the-art scientific tool and approach for understanding and predicting contaminant fate and transport in natural and engineered systems. The modular and open source high-performance computing tool facilitates integrated approaches to modeling and site characterization that enable robust and standardized assessments of performance and risk for EM cleanup and closure activities. The ASCEM project continues to make significant progress in development of computer software capabilities with an emphasis on integration of capabilities in FY12. Capability development is occurring for both the Platform and Integrated Toolsets and High-Performance Computing (HPC) Multiprocess Simulator. The Platform capabilities provide the user interface and tools for end-to-end model development, starting with definition of the conceptual model, management of data for model input, model calibration and uncertainty analysis, and processing of model output, including visualization. The HPC capabilities target increased functionality of process model representations, toolsets for interaction with Platform, and verification and model confidence testing. The Platform and HPC capabilities are being tested and evaluated for EM applications in a set of demonstrations as part of Site Applications Thrust Area activities. The Phase I demonstration focusing on individual capabilities of the initial toolsets was completed in 2010. The Phase II demonstration completed in 2012 focused on showcasing integrated ASCEM capabilities. For Phase II, the Hanford Site deep vadose zone (BC Cribs) served as an application site for an end-to-end demonstration of capabilities, with emphasis on integration and linkages between the Platform and HPC components. Other demonstrations

  8. ADVANCED SIMULATION CAPABILITY FOR ENVIRONMENTAL MANAGEMENT – CURRENT STATUS AND PHASE II DEMONSTRATION RESULTS

    SciTech Connect

    Seitz, Roger; Freshley, Mark D.; Dixon, Paul; Hubbard, Susan S.; Freedman, Vicky L.; Flach, Gregory P.; Faybishenko, Boris; Gorton, Ian; Finsterle, Stefan A.; Moulton, John D.; Steefel, Carl I.; Marble, Justin

    2013-06-27

    The U.S. Department of Energy (USDOE) Office of Environmental Management (EM), Office of Soil and Groundwater, is supporting development of the Advanced Simulation Capability for Environmental Management (ASCEM). ASCEM is a state-of-the-art scientific tool and approach for understanding and predicting contaminant fate and transport in natural and engineered systems. The modular and open source high-performance computing tool facilitates integrated approaches to modeling and site characterization that enable robust and standardized assessments of performance and risk for EM cleanup and closure activities. The ASCEM project continues to make significant progress in development of computer software capabilities with an emphasis on integration of capabilities in FY12. Capability development is occurring for both the Platform and Integrated Toolsets and High-Performance Computing (HPC) Multiprocess Simulator. The Platform capabilities provide the user interface and tools for end-to-end model development, starting with definition of the conceptual model, management of data for model input, model calibration and uncertainty analysis, and processing of model output, including visualization. The HPC capabilities target increased functionality of process model representations, toolsets for interaction with Platform, and verification and model confidence testing. The Platform and HPC capabilities are being tested and evaluated for EM applications in a set of demonstrations as part of Site Applications Thrust Area activities. The Phase I demonstration focusing on individual capabilities of the initial toolsets was completed in 2010. The Phase II demonstration completed in 2012 focused on showcasing integrated ASCEM capabilities. For Phase II, the Hanford Site deep vadose zone (BC Cribs) served as an application site for an end-to-end demonstration of capabilities, with emphasis on integration and linkages between the Platform and HPC components. Other demonstrations

  9. Advanced Circadian Phase in Mania and Delayed Circadian Phase in Mixed Mania and Depression Returned to Normal after Treatment of Bipolar Disorder.

    PubMed

    Moon, Joung-Ho; Cho, Chul-Hyun; Son, Gi Hoon; Geum, Dongho; Chung, Sooyoung; Kim, Hyun; Kang, Seung-Gul; Park, Young-Min; Yoon, Ho-Kyoung; Kim, Leen; Jee, Hee-Jung; An, Hyonggin; Kripke, Daniel F; Lee, Heon-Jeong

    2016-09-01

    Disturbances in circadian rhythms have been suggested as a possible cause of bipolar disorder (BD). Included in this study were 31 mood episodes of 26 BD patients, and 18 controls. Circadian rhythms of BD were evaluated at admission, at 2-week intervals during hospitalization, and at discharge. All participants wore wrist actigraphs during the studies. Saliva and buccal cells were obtained at 8:00, 11:00, 15:00, 19:00, and 23:00 for two consecutive days. Collected saliva and buccal cells were used for analysis of the cortisol and gene circadian rhythm, respectively. Circadian rhythms had different phases during acute mood episodes of BD compared to recovered states. In 23 acute manic episodes, circadian phases were ~7hour advanced (equivalent to ~17hour delayed). Phases of 21 out of these 23 cases returned to normal by ~7hour delay along with treatment, but two out of 23 cases returned to normal by ~17hour advance. In three cases of mixed manic episodes, the phases were ~6-7hour delayed. For five cases of depressive episodes, circadian rhythms phases were ~4-5hour delayed. After treatment, circadian phases resembled those of healthy controls. Circadian misalignment due to circadian rhythm phase shifts might be a pathophysiological mechanism of BD.

  10. Advanced laparoscopic surgery for colorectal disease: NOTES/NOSE or single port?

    PubMed

    Sehgal, Rishabh; Cahill, Ronan A

    2014-02-01

    Laparoscopic surgery for colorectal disease is an evolving, dynamic subject undergoing constant adaptation. Hence there are significant ongoing advances in technique and technology as has been seen with the emergence of single port and Natural Orifice Transluminal Endoscopic operations with already considerable ramifications for many aspects of minimal access surgery. Most recently single port technologies and expertise have synergized with Transanal Endoscopic (TEM/TEO) experience to allow their convergence out of their respective niches so that pelvic surgery can be laparoendoscopically performed from both its abdominal and perineal aspects. Distinct from wound-related benefits, such capacity for high resolution and multi-dimensional imaging relates significant benefit to the operating team and patient. This state of the art review demonstrates the crucial perspective that advanced practices and performance capabilities are intrinsically complimentary rather than competitive. All surgeons need therefore to participate in adapting their practice styles to allow technical step-advance across the discipline.

  11. Low Circulating Levels of Dehydroepiandrosterone in Histologically Advanced Nonalcoholic Fatty Liver Disease

    PubMed Central

    Charlton, Michael; Angulo, Paul; Chalasani, Naga; Merriman, Ralph; Viker, Kimberly; Charatcharoenwitthaya, Phunchai; Sanderson, Schuyler; Gawrieh, Samer; Krishnan, Anuradha; Lindor, Keith

    2010-01-01

    The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone(DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator-activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0–2] or advanced (NASH with fibrosis stage 3–4). Serum levels of sulfated DHEA (DHEA-S) were measured by enzyme-linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA-S than patients with mild NAFLD in both the initial (0.25 ± 0.07 versus 1.1 ± 0.09 µg/mL, P < 0.001) and validation cohorts (0.47 ± 0.06 versus 0.99 ± 0.04 µg/mL, P < 0.001). A “dose effect” of decreasing DHEA-S and incremental fibrosis stage was observed with a mean DHEA-S of 1.03 ± 0.05, 0.96 ± 0.07, 0.83 ± 0.11, 0.66 ± 0.11, and 0.35 ± 0.06 µg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA-S levels, with the majority in the hypoadrenal range. The association between DHEA-S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA-S levels was not seen in patients with cholestatic liver diseases. Conclusion More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA-S. These data provide novel evidence for relative DHEA-S deficiency in patients with

  12. Congenital heart disease and rheumatic heart disease in Africa: recent advances and current priorities.

    PubMed

    Zühlke, Liesl; Mirabel, Mariana; Marijon, Eloi

    2013-11-01

    Africa has one of the highest prevalence of heart diseases in children and young adults, including congenital heart disease (CHD) and rheumatic heart disease (RHD). We present here an extensive review of recent data from the African continent highlighting key studies and information regarding progress in CHD and RHD since 2005. Main findings include evidence that the CHD burden is underestimated mainly due to the poor outcome of African children with CHD. The interest in primary prevention for RHD has been recently re-emphasised, and new data are available regarding echocardiographic screening for subclinical RHD and initiation of secondary prevention. There is an urgent need for comprehensive service frameworks to improve access and level of care and services for patients, educational programmes to reinforce the importance of prevention and early diagnosis and a relevant research agenda focusing on the African context.

  13. Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours

    PubMed Central

    Martin, L P; Kozloff, M F; Herbst, R S; Samuel, T A; Kim, S; Rosbrook, B; Tortorici, M; Chen, Y; Tarazi, J; Olszanski, A J; Rado, T; Starr, A; Cohen, R B

    2012-01-01

    Background: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy. Methods: A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m–2 weekly), docetaxel (100 mg m–2 every 3 weeks) or capecitabine (1000 or 1250 mg m–2 b.i.d., days 1–14). Results: Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand–foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents. Conclusions: Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types. PMID:22996612

  14. Phase I study of TAC-101, an oral synthetic retinoid, in Japanese patients with advanced hepatocellular carcinoma.

    PubMed

    Okusaka, Takuji; Ueno, Hideki; Ikeda, Masafumi; Takezako, Yoriko; Morizane, Chigusa

    2012-08-01

    Preclinical models have shown that TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid), an oral synthetic retinoid, has antitumor activity in hepatocellular carcinoma (HCC). We conducted a phase I study in Japanese patients with advanced HCC to examine the pharmacokinetics, recommended dose, safety, and efficacy of TAC-101. The administered dose of TAC-101 was 10 mg/day in four patients (level 1), 20 mg/day in six (level 2), and 30 mg/day in three (level 3). There was no dose-limiting toxicity at level 1. Only one patient each had dose-limiting toxicity at level 2 (grade 2 fatigue, recovery requiring eight or more consecutive days of rest) and at level 3 (grade 3 splenic vein thrombosis). Level 3 (30 mg/day) was considered the maximum tolerated dose and 20 mg/day the recommended dose by a panel of medical experts, placing maximum emphasis on safety. The most frequent adverse events were fatigue, headache, and dermal symptoms such as rash. Pharmacokinetic parameters in Japanese patients with HCC were similar to those in patients in the United States, most of whom were Caucasian. Although no patient had a complete or partial response, the disease control rate was 38.5%. In conclusion, the recommended dose of TAC-101 for patients with HCC is 20 mg/day. TAC-101 had an acceptable toxicity profile, warranting further evaluation in clinical trials.

  15. Phase II trial of pegylated liposomal doxorubicin (Caelyx) plus Gemcitabine in chemotherapeutically pretreated patients with advanced breast cancer.

    PubMed

    Ulrich-Pur, Herbert; Kornek, Gabriela V; Haider, Karin; Kwasny, Werner; Payrits, Thomas; Dworan, Nina; Vormittag, Laurenz; Depisch, Dieter; Lang, Fritz; Scheithauer, Werner

    2007-01-01

    A phase II trial was performed to investigate the efficacy and tolerance of combined gemcitabine and liposomal doxorubicin +/- recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapeutically pretreated metastatic breast cancer. Thirty-four patients were entered in this trial. Chemotherapy consisted of gemcitabine and liposomal doxorubicin +/- G-CSF. Twenty seven patients received this regimen as 2nd line therapy, five patients as 3rd line and two patients as 4th line therapy after having failed taxane- and/or anthracycline-based chemotherapy or other drug combinations. After a median of six courses, an overall response rate of 26% (9 PR in 34 enrolled patients) was observed; 14 patients had disease stabilization (41%), and eight (24%) progressed. Three patients were not evaluable for response due to anaphylaxis after the first course and protracted thrombocytopenia. The median TTP was 7.5 months, and median overall survival was 15 months. Myelosuppression was the most frequently observed toxicity. Non-haematological side effects were generally mild to moderate. Our data suggest that gemcitabine and liposomal doxorubicin +/- G-CSF is an effective and fairly well tolerated regimen for chemotherapeutically pretreated patients with advanced breast cancer.

  16. A phase I trial of temsirolimus and pemetrexed in patients with advanced non-small cell lung cancer

    PubMed Central

    Waqar, Saiama N.; Baggstrom, Maria Q.; Morgensztern, Daniel; Williams, Kristina; Rigden, Caron; Govindan, Ramaswamy

    2017-01-01

    Background Pemetrexed is an anti-folate chemotherapeutic agent approved for use in non-small cell lung cancer. Mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development, and is inhibited by temsirolimus. Methods We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous non-small cell lung cancer (NSCLC). Results Eight patients were enrolled in this study. The dose limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutopenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m2 intravenously on day 1 and temsirolimus 25 mg intravenously on days 1,8 and 15. No objective responses were noted, and 3 patients had stable disease as the best response. Conclusion The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in patients with TSC1 or STK11 mutations. PMID:26780363

  17. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.

    PubMed

    Dubois, Bruno; Feldman, Howard H; Jacova, Claudia; Hampel, Harald; Molinuevo, José Luis; Blennow, Kaj; DeKosky, Steven T; Gauthier, Serge; Selkoe, Dennis; Bateman, Randall; Cappa, Stefano; Crutch, Sebastian; Engelborghs, Sebastiaan; Frisoni, Giovanni B; Fox, Nick C; Galasko, Douglas; Habert, Marie-Odile; Jicha, Gregory A; Nordberg, Agneta; Pasquier, Florence; Rabinovici, Gil; Robert, Philippe; Rowe, Christopher; Salloway, Stephen; Sarazin, Marie; Epelbaum, Stéphane; de Souza, Leonardo C; Vellas, Bruno; Visser, Pieter J; Schneider, Lon; Stern, Yaakov; Scheltens, Philip; Cummings, Jeffrey L

    2014-06-01

    In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD.

  18. Biliary atresia and other cholestatic childhood diseases: Advances and future challenges.

    PubMed

    Verkade, Henkjan J; Bezerra, Jorge A; Davenport, Mark; Schreiber, Richard A; Mieli-Vergani, Georgina; Hulscher, Jan B; Sokol, Ronald J; Kelly, Deirdre A; Ure, Benno; Whitington, Peter F; Samyn, Marianne; Petersen, Claus

    2016-09-01

    Biliary Atresia and other cholestatic childhood diseases are rare conditions affecting the function and/or anatomy along the canalicular-bile duct continuum, characterised by onset of persistent cholestatic jaundice during the neonatal period. Biliary atresia (BA) is the most common among these, but still has an incidence of only 1 in 10-19,000 in Europe and North America. Other diseases such as the genetic conditions, Alagille syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC), are less common. Choledochal malformations are amenable to surgical correction and require a high index of suspicion. The low incidence of such diseases hinder patient-based studies that include large cohorts, while the limited numbers of animal models of disease that recapitulate the spectrum of disease phenotypes hinders both basic research and the development of new treatments. Despite their individual rarity, collectively BA and other cholestatic childhood diseases are the commonest indications for liver transplantation during childhood. Here, we review the recent advances in basic research and clinical progress in these diseases, as well as the research needs. For the various diseases, we formulate current key questions and controversies and identify top priorities to guide future research.

  19. Advances in Cardiovascular MRI for Diagnostics: Applications in Coronary Artery Disease and Cardiomyopathies

    PubMed Central

    Salerno, Michael; Kramer, Christopher M

    2010-01-01

    Background Cardiac magnetic resonance (CMR) imaging has emerged as an important cardiac imaging technique for the evaluation of multiple cardiac pathologies. Objective/Method The goal of this review is to describe recent advances in techniques which have extended the potential applications of CMR. The focus will be on the clinical applications of CMR for the evaluation of coronary artery disease and heart failure/cardiomyopathies which are major causes of morbidity and mortality worldwide. Conclusion CMR provides unique tissue characterization which is not available from other imaging modalities and has demonstrated important diagnostic and prognostic information in many forms of heart disease. PMID:21113233

  20. Advanced biomaterials and their potential applications in the treatment of periodontal disease.

    PubMed

    Chen, Xi; Wu, Guofeng; Feng, Zhihong; Dong, Yan; Zhou, Wei; Li, Bei; Bai, Shizhu; Zhao, Yimin

    2016-08-01

    Periodontal disease is considered as a widespread infectious disease and the most common cause of tooth loss in adults. Attempts for developing periodontal disease treatment strategies, including drug delivery and regeneration approaches, provide a useful experimental model for the evaluation of future periodontal therapies. Recently, emerging advanced biomaterials including hydrogels, films, micro/nanofibers and particles, hold great potential to be utilized as cell/drug carriers for local drug delivery and biomimetic scaffolds for future regeneration therapies. In this review, first, we describe the pathogenesis of periodontal disease, including plaque formation, immune response and inflammatory reactions caused by bacteria. Second, periodontal therapy and an overview of current biomaterials in periodontal regenerative medicine have been discussed. Third, the roles of state-of-the-art biomaterials, including hydrogels, films, micro/nanofibers and micro/nanoparticles, developed for periodontal disease treatment and periodontal tissue regeneration, and their fabrication methods, have been presented. Finally, biological properties, including biocompatibility, biodegradability and immunogenicity of the biomaterials, together with their current applications strategies are given. Conclusive remarks and future perspectives for such advanced biomaterials are discussed.

  1. Advances in the prevention of oral disease; the role of the International Association for Dental Research

    PubMed Central

    2015-01-01

    Abstract Background Since its foundation in 1920, prevention of oral disease has been a priority for the International Association for Dental Research (IADR) and the commitment of the organisation to the subject area is clearly expressed in its mission to improve oral health worldwide. The IADR has a current global membership of almost 11,000 people who share an interest in oral and craniofacial research. Contribution of IADR This paper provides an overview of the contribution of IADR to supporting research and associated activities in disease prevention, in disseminating knowledge and in advocating for better oral health for all citizens of the world. It looks back over time and summarises current supports. Two more recent initiatives in disease prevention are described in more detail, the Global Oral Health Inequalities Research Agenda (GOHIRA) and the proceedings at the 2013 World Conference on Preventive Dentistry (WCPD, 2013), a joint initiative between IADR and WHO. Through organisational structure, meetings, publications, scientific groups and networks and external relations, IADR has been at the forefront of advancing research for the prevention of oral diseases. Conclusions IADR is committed to ensuring research advances get disseminated and implemented and at the same time encourages and advocates for basic, clinical and translational research across disciplines so that we may uncover the major breakthrough in prevention of oral disease. PMID:26391001

  2. Dynamic tension EMG to characterize the effects of DBS treatment of advanced Parkinson's disease.

    PubMed

    Ruonala, V; Pekkonen, E; Rissanen, S; Airaksinen, O; Miroshnichenko, G; Kankaanpää, M; Karjalainen, P

    2014-01-01

    Deep brain stimulation (DBS) is an effective treatment method for motor symptoms of advanced Parkinson's disease. DBS-electrode is implanted to subthalamic nucleus to give precisely allocated electrical stimuli to brain. The optimal stimulus type has to be adjusted individually. Disease severity, main symptoms and biological factors play a role in correctly setting up the device. Currently there are no objective methods to assess the efficacy of DBS, hence the adjustment is based solely on clinical assessment. In optimal case an objectively measurable feature would point the right settings of DBS. Surface electromyographic and kinematic measurements have been used in Parkinson's disease research. As Parkinson's disease symptoms are known to change the EMG signal properties, these methods could be helpful aid in the clinical adjustment of DBS. In this study, 13 patients with advanced Parkinson's disease who received DBS treatment were measured. The patients were measured with seven different settings of the DBS in clinical range including changes in stimulation amplitude, frequency and pulse width. The EMG analysis was based on parameters that characterize EMG signal morphology. Correlation dimension and recurrence rate made the most significant difference in relation to optimal settings. In conclusion, EMG analysis is able to detect differences between the DBS setups, and can help in finding the correct parameters.

  3. ATYPICAL MACULOPATHY IN A PATIENT WITH LIGHT CHAIN DEPOSITION DISEASE MIMICKING ADVANCED GEOGRAPHIC ATROPHY

    PubMed Central

    Oshry, Lauren J.; Reichel, Elias

    2017-01-01

    Purpose: To report a previously unreported presentation of advanced geographic atrophy of the macula mimicking nonneovascular (dry) age-related macular degeneration in a patient with light chain deposition disease. Methods: Ocular examination included dilated fundus examination, fundus autofluorescence, full-field electroretinography, and spectral domain optical coherence tomography. Patients: Single-patient case report. Results: Dilated fundus examination demonstrated diffuse loss of the retinal pigment epithelium in a geographic atrophy pattern in the macula and drusenlike deposits localized to the outer retina and retinal pigment epithelium. There were no signs of choroidal neovascularization or retinal pigment epithelium detachments. Fundus autofluorescence demonstrated wide areas of retinal pigment epithelium loss. Full-field electroretinography was normal. Spectral domain optical coherence tomography displayed atrophy of the outer retinal layers. Discussion: This is the first documented case of drusenlike deposits and maculopathy in a patient with light chain deposition disease that mimics advanced geographic atrophy that is typically observed in nonneovascular age-related macular degeneration. Physicians should be aware of the macular changes that can be associated with light chain deposition disease, and patients with light chain deposition disease should be regularly evaluated for associated macular disease. PMID:26934302

  4. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

    PubMed

    Rangwala, Reshma; Chang, Yunyoung C; Hu, Janice; Algazy, Kenneth M; Evans, Tracey L; Fecher, Leslie A; Schuchter, Lynn M; Torigian, Drew A; Panosian, Jeffrey T; Troxel, Andrea B; Tan, Kay-See; Heitjan, Daniel F; DeMichele, Angela M; Vaughn, David J; Redlinger, Maryann; Alavi, Abass; Kaiser, Jonathon; Pontiggia, Laura; Davis, Lisa E; O'Dwyer, Peter J; Amaravadi, Ravi K

    2014-08-01

    The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

  5. Phase I study of TP300 in patients with advanced solid tumors with pharmacokinetic, pharmacogenetic and pharmacodynamic analyses

    PubMed Central

    2012-01-01

    Background A Phase I dose escalation first in man study assessed maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended Phase II dose of TP300, a water soluble prodrug of the Topo-1 inhibitor TP3076, and active metabolite, TP3011. Methods Eligible patients with refractory advanced solid tumors, adequate performance status, haematologic, renal, and hepatic function. TP300 was given as a 1-hour i.v. infusion 3-weekly and pharmacokinetic (PK) profiles of TP300, TP3076 and TP3011 were analysed. Polymorphisms in CYP2D6, AOX1 and UGT1A1 were studied and DNA strand-breaks measured in peripheral blood mononuclear cells (PBMCs). Results 32 patients received TP300 at 1, 2, 4, 6, 8, 10, 12 mg/m2. MTD was 10 mg/m2; DLTs at 12 (2/4 patients) and 10 mg/m2 (3/12) included thrombocytopenia and febrile neutropenia; diarrhoea was uncommon. Six patients (five had received irinotecan), had stable disease for 1.5-5 months. TP3076 showed dose proportionality in AUC and Cmax from 1–10 mg/m2. Genetic polymorphisms had no apparent influence on exposure. DNA strand-breaks were detected after TP300 infusion. Conclusions TP300 had predictable hematologic toxicity, and diarrhoea was uncommon. AUC at MTD is substantially greater than for SN38. TP3076 and TP3011 are equi-potent with SN38, suggesting a PK advantage. Trial registration EU-CTR2006-001345-33 PMID:23170896

  6. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms.

    PubMed

    Mooney, Michael A; Simon, Elias D; Little, Andrew S

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  7. Managing uncertainty in advanced liver disease: a qualitative, multiperspective, serial interview study

    PubMed Central

    Kimbell, Barbara; Boyd, Kirsty; Kendall, Marilyn; Iredale, John; Murray, Scott A

    2015-01-01

    Objective To understand the experiences and support needs of people with advanced liver disease and those of their lay and professional carers to inform improvements in the supportive and palliative care of this rapidly growing but currently neglected patient group. Design Multiperspective, serial interviews. We conducted up to three qualitative in-depth interviews with each patient and lay carer over 12 months and single interviews with case-linked healthcare professionals. Data were analysed using grounded theory techniques. Participants Patients with advanced liver disease of diverse aetiologies recruited from an inpatient hepatology ward, and their lay carers and case-linked healthcare professionals nominated by the patients. Setting Primary and secondary care in South-East Scotland. Results 37 participants (15 patients, 11 lay and 11 professional carers) completed 51 individual and 13 joint patient-carer interviews. Nine patients died during the study. Uncertainty dominated experiences throughout the course of the illness, across patients’ considerable physical, psychological, social and existential needs and affected patients, lay carers and professionals. This related to the nature of the condition, the unpredictability of physical deterioration and prognosis, poor communication and information-sharing, and complexities of care. The pervasive uncertainty also shaped patients’ and lay carers’ strategies for coping and impeded care planning. While patients’ acute medical care was usually well coordinated, their ongoing care lacked structure and focus. Conclusions Living, dying and caring in advanced liver disease is dominated by pervasive, enduring and universally shared uncertainty. In the face of high levels of multidimensional patient distress, professionals must acknowledge this uncertainty in constructive ways that value its contribution to the person's coping approach. Pervasive uncertainty makes anticipatory care planning in advanced liver

  8. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms

    PubMed Central

    Mooney, Michael A.; Simon, Elias D.; Little, Andrew S.

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment. PMID:27517036

  9. Differential induction and localization of mPer1 and mPer2 during advancing and delaying phase shifts

    PubMed Central

    Yan, Lily; Silver, Rae

    2012-01-01

    The mechanism whereby brief light exposure resets the mammalian circadian clock in a phase dependent manner is not known, but is thought to involve Per gene expression. At the behavioural level, a light pulse produces phase delays in early subjective night, phase advances in late subjective night, and no phase shifts in mid-subjective night or subjective day. To understand the relationship between Per gene activity and behavioural phase shifts, we examined light-induced mPer1 and mPer2 expression in the suprachiasmatic nucleus (SCN) of the mouse, in the subjective night, with a view to understanding SCN heterogeneity. In the VIP-containing region of the SCN (termed `core'), light-induced mPer1 expression occurs at all times of the subjective night, while mPer2 induction is seen only in early subjective night. In the remaining regions of the SCN (termed `shell'), a phase delaying light pulse produces no mPer1 but significant mPer2 expression, while a phase advancing light pulse produces no mPer2 but substantial mPer1 induction. Moreover, following a light pulse during mid-subjective night, neither mPer1 nor mPer2 are induced in the shell. The results reveal that behavioural phase shifts occur only when light-induced Per gene expression spreads from the core to the shell SCN, with mPer1 expression in shell corresponding to phase advances, and mPer2 corresponding to phase delays. The results indicate that the time course and the localization of light-induced Per gene expression in SCN reveals important aspects of intra-SCN communication. PMID:12405967

  10. Deep Assessment: A Novel Framework for Improving the Care of People with Very Advanced Alzheimer's Disease

    PubMed Central

    Lyons, Gordon; Arthur-Kelly, Michael; Eidels, Ami; Mavratzakis, Aimee

    2015-01-01

    Best practice in understanding and caring for people with advanced Alzheimer's disease presents extraordinary challenges. Their severe and deteriorating cognitive impairments are such that carers find progressive difficulty in authentically ascertaining and responding to interests, preferences, and needs. Deep assessment, a novel multifaceted framework drawn from research into the experiences of others with severe cognitive impairments, has potential to empower carers and other support professionals to develop an enhanced understanding of people with advanced Alzheimer's disease and so deliver better calibrated care in attempts to maximize quality of life. Deep assessment uses a combination of techniques, namely, Behaviour State Observation, Triangulated Proxy Reporting, and Startle Reflex Modulation Measurement, to deliver a comprehensive and deep assessment of the inner states (awareness, preferences, likes, and dislikes) of people who cannot reliably self-report. This paper explains deep assessment and its current applications. It then suggests how it can be applied to people with advanced Alzheimer's disease to develop others' understanding of their inner states and to help improve their quality of life. An illustrative hypothetical vignette is used to amplify this framework. We discuss the potential utility and efficacy of this technique for this population and we also propose other human conditions that may benefit from research using a deep assessment approach. PMID:26688817

  11. [Application of levodopa/carbidopa intestinal gel in advanced Parkinson's disease].

    PubMed

    Toth, Adrián; Nagy, Helga; Wacha, Judit; Bereczki, Dániel; Takáts, Annamária

    2015-12-01

    Parkinson's disease is the second most common neurodegenerative disorder around the world. Levodopa has remained the "gold standard" of the therapy even several decades after its introduction. Chronic levodopa treatment is associated with the development of motor complications in most patients. Advanced Parkinson's disease is characterized by these complications: motor and non-motor fluctuation and disturbing dyskinesia. Continuous dopaminergic stimulation might reduce these complications. In advanced Parkinson's disease levodopa is still effective. In the treatment of this stage there are several advanced or device-aided therapies: apomorphine pump, deep brain stimulation and levodopa/carbidopa intestinal gel. Levodopa/carbidopa intestinal gel is an aqueous gel that can be delivered to the jejunum via a percutaneous gastrojejunostomy tube which is connected to an infusion pump dosing the levodopa gel continuously to the place of absorption. Levodopa/carbidopa gel infusion can be used as monotherapy, can be tested, can be used individually and this therapy is reversible. Several clinical trials demonstrated that levodopa/carbidopa intestinal gel therapy is of long-term benefit, improves the quality of life of the patients and can reduce motor fluctuation and dyskinesia.

  12. Deep Assessment: A Novel Framework for Improving the Care of People with Very Advanced Alzheimer's Disease.

    PubMed

    Lyons, Gordon; Arthur-Kelly, Michael; Eidels, Ami; Mavratzakis, Aimee

    2015-01-01

    Best practice in understanding and caring for people with advanced Alzheimer's disease presents extraordinary challenges. Their severe and deteriorating cognitive impairments are such that carers find progressive difficulty in authentically ascertaining and responding to interests, preferences, and needs. Deep assessment, a novel multifaceted framework drawn from research into the experiences of others with severe cognitive impairments, has potential to empower carers and other support professionals to develop an enhanced understanding of people with advanced Alzheimer's disease and so deliver better calibrated care in attempts to maximize quality of life. Deep assessment uses a combination of techniques, namely, Behaviour State Observation, Triangulated Proxy Reporting, and Startle Reflex Modulation Measurement, to deliver a comprehensive and deep assessment of the inner states (awareness, preferences, likes, and dislikes) of people who cannot reliably self-report. This paper explains deep assessment and its current applications. It then suggests how it can be applied to people with advanced Alzheimer's disease to develop others' understanding of their inner states and to help improve their quality of life. An illustrative hypothetical vignette is used to amplify this framework. We discuss the potential utility and efficacy of this technique for this population and we also propose other human conditions that may benefit from research using a deep assessment approach.

  13. ‘Reality and desire’ in the care of advanced chronic kidney disease

    PubMed Central

    Marrón, Belén; Craver, Lourdes; Remón, César; Prieto, Mario; Gutiérrez, Josep Mª; Ortiz, Alberto

    2010-01-01

    There is a long distance between the actual worldwide reality in advanced chronic kidney disease care and the desire of how these patients should be managed to decrease cardiovascular and general morbidity and mortality. Implementation of adequate infrastructures may improve clinical outcomes and increase the use of home renal replacement therapies (RRT). Current pitfalls should be addressed to optimise care: inadequate medical training for nephrological referral and RRT selection, late referral to nephrologists, inadequate patient education for choice of RRT modality, lack of multidisciplinary advanced kidney disease clinics and lack of programmed RRT initiation. These deficiencies generate unintended consequences, such as inequality of care and limitations in patient education and selection-choice for RRT technique with limited use of peritoneal dialysis. Multidisciplinary advanced kidney disease clinics may have a direct impact on patient survival, morbidity and quality of life. There is a common need to reduce health care costs and scenarios increasing PD incidence show better efficiency. The following proposals may help to improve the current situation: defining the scope of the problem, disseminating guidelines with specific targets and quality indicators, optimising medical speciality training, providing adequate patient education, specially through the use of general decision making tools that will allow patients to choose the best possible RRT in accordance with their values, preferences and medical advice, increasing planned dialysis starts and involving all stakeholders in the process. PMID:25984045

  14. Advanced direct liquefaction concepts for PETC generic units. Final report, Phase I

    SciTech Connect

    1995-03-01

    The Advanced Concepts for Direct Coal Liquefaction program was initiated by the Department of Energy in 1991 to develop technologies that could significantly reduce the cost of producing liquid fuels by the direct liquefaction of coal. The advanced 2-stage liquefaction technology that was developed at Wilsonville over the past 10 years has contributed significantly toward decreasing the cost of producing liquids from coal to about $33/bbl. It remains, however, the objective of DOE to further reduce this cost to a level more competitive with petroleum based products. This project, among others, was initiated to investigate various alternative approaches to develop technologies that might ultimately lead to a 25 % reduction in cost of product. In this project a number of novel concepts were investigated, either individually or in a coupled configuration that had the potential to contribute toward meeting the DOE goal. The concepts included mature technologies or ones closely related to them, such as coal cleaning by oil agglomeration, fluid coking and distillate hydrotreating and dewaxing. Other approaches that were either embryonic or less developed were chemical pretreatment of coal to remove oxygen, and dispersed catalyst development for application in the 2-stage liquefaction process. This report presents the results of this project. It is arranged in four sections which were prepared by participating organizations responsible for that phase of the project. A summary of the overall project and the principal results are given in this section. First, however, an overview of the process economics and the process concepts that were developed during the course of this program is presented.

  15. Innovative grinding wheel design for cost-effective machining of advanced ceramics. Phase I, final report

    SciTech Connect

    Licht, R.H.; Ramanath, S.; Simpson, M.; Lilley, E.

    1996-02-01

    Norton Company successfully completed the 16-month Phase I technical effort to define requirements, design, develop, and evaluate a next-generation grinding wheel for cost-effective cylindrical grinding of advanced ceramics. This program was a cooperative effort involving three Norton groups representing a superabrasive grinding wheel manufacturer, a diamond film manufacturing division and a ceramic research center. The program was divided into two technical tasks, Task 1, Analysis of Required Grinding Wheel Characteristics, and Task 2, Design and Prototype Development. In Task 1 we performed a parallel path approach with Superabrasive metal-bond development and the higher technical risk, CVD diamond wheel development. For the Superabrasive approach, Task 1 included bond wear and strength tests to engineer bond-wear characteristics. This task culminated in a small-wheel screening test plunge grinding sialon disks. In Task 2, an improved Superabrasive metal-bond specification for low-cost machining of ceramics in external cylindrical grinding mode was identified. The experimental wheel successfully ground three types of advanced ceramics without the need for wheel dressing. The spindle power consumed by this wheel during test grinding of NC-520 sialon is as much as to 30% lower compared to a standard resin bonded wheel with 100 diamond concentration. The wheel wear with this improved metal bond was an order of magnitude lower than the resin-bonded wheel, which would significantly reduce ceramic grinding costs through fewer wheel changes for retruing and replacements. Evaluation of ceramic specimens from both Tasks 1 and 2 tests for all three ceramic materials did not show evidence of unusual grinding damage. The novel CVD-diamond-wheel approach was incorporated in this program as part of Task 1. The important factors affecting the grinding performance of diamond wheels made by CVD coating preforms were determined.

  16. Characterization and Suppression of the Electromagnetic Interference Induced Phase Shift in the JLab FEL Photo - Injector Advanced Drive Laser System

    SciTech Connect

    F. G. Wilson, D. Sexton, S. Zhang

    2011-09-01

    The drive laser for the photo-cathode gun used in the JLab Free Electron Laser (FEL) facility had been experiencing various phase shifts on the order of tens of degrees (>20{sup o} at 1497 MHz or >40ps) when changing the Advanced Drive Laser (ADL) [2][3][4] micro-pulse frequencies. These phase shifts introduced multiple complications when trying to setup the accelerator for operation, ultimately inhibiting the robustness and overall performance of the FEL. Through rigorous phase measurements and systematic characterizations, we determined that the phase shifts could be attributed to electromagnetic interference (EMI) coupling into the ADL phase control loop, and subsequently resolved the issue of phase shift to within tenths of a degree (<0.5{sup o} at 1497 MHz or <1ps). The diagnostic method developed and the knowledge gained through the entire process will prove to be invaluable for future designs of similar systems.

  17. Short-Course Accelerated Radiotherapy in Palliative Treatment of Advanced Pelvic Malignancies: A Phase I Study

    SciTech Connect

    Caravatta, Luciana; Padula, Gilbert D.A.; Macchia, Gabriella; Ferrandina, Gabriella; Bonomo, Pierluigi; Deodato, Francesco; Massaccesi, Mariangela; Mignogna, Samantha; Tambaro, Rosa; Rossi, Marco; Flocco, Mariano; Scapati, Andrea; and others

    2012-08-01

    Purpose: To define the maximum tolerated dose of a conformal short-course accelerated radiotherapy in patients with symptomatic advanced pelvic cancer. Methods and Materials: A phase I trial in 3 dose-escalation steps was designed: 14 Gy (3.5-Gy fractions), 16 Gy (4-Gy fractions), and 18 Gy (4.5-Gy fractions). The eligibility criteria included locally advanced and/or metastatic pelvic cancer and Eastern Cooperative Oncology Group performance status of {<=}3. Treatment was delivered in 2 days with twice-daily fractionation and at least an 8-hour interval. Patients were treated in cohorts of 6-12 to define the maximum tolerated dose. The dose-limiting toxicity was defined as any acute toxicity of grade 3 or greater, using the Radiation Therapy Oncology Group scale. Pain was recorded using a visual analog scale. The effect on quality of life was evaluated according to Cancer Linear Analog Scale (CLAS). Results: Of the 27 enrolled patients, 11 were male and 16 were female, with a median age of 72 years (range 47-86). The primary tumor sites were gynecologic (48%), colorectal (33.5%), and genitourinary (18.5%). The most frequent baseline symptoms were bleeding (48%) and pain (33%). Only grade 1-2 acute toxicities were recorded. No patients experienced dose-limiting toxicity. With a median follow-up time of 6 months (range 3-28), no late toxicities were observed. The overall (complete plus partial) symptom remission was 88.9% (95% confidence interval 66.0%-97.8%). Five patients (41.7%) had complete pain relief, and six (50%) showed >30% visual analog scale reduction. The overall response rate for pain was 91.67% (95% confidence interval 52.4%-99.9%). Conclusions: Conformal short course radiotherapy in twice-daily fractions for 2 consecutive days was well tolerated up to a total dose of 18 Gy. A phase II study is ongoing to confirm the efficacy on symptom control and quality of life indexes.

  18. A two-phase model for chronic disease processes under intermittent inspection.

    PubMed

    Wu, Ying; Cook, Richard J

    2017-02-26

    A model is developed for chronic diseases with an indolent phase that is followed by a phase with more active disease resulting in progression and damage. The time scales for the intensity functions for the active phase are more naturally based on the time since the start of the active phase, corresponding to a semi-Markov formulation. This two-phase model enables one to fit a separate regression model for the duration of the indolent phase and intensity-based models for the more active second phase. In cohort studies for which the disease status is only known at a series of clinical assessment times, transition times are interval-censored, which means the time origin for phase II is interval-censored. Weakly parametric models with piecewise constant baseline hazard and rate functions are specified, and an expectation-maximization algorithm is described for model fitting. Simulation studies examining the performance of the proposed model show good performance under maximum likelihood and two-stage estimation. An application to data from the motivating study of disease progression in psoriatic arthritis illustrates the procedure and identifies new human leukocyte antigens associated with the duration of the indolent phase. Copyright © 2017 John Wiley & Sons, Ltd.

  19. Phase 2 Multi-institutional Trial Evaluating Gemcitabine and Stereotactic Body Radiotherapy for Patients With Locally Advanced Unresectable Pancreatic Adenocarcinoma

    PubMed Central

    Herman, Joseph M; Chang, Daniel T; Goodman, Karyn A; Dholakia, Avani S; Raman, Siva P; Hacker-Prietz, Amy; Iacobuzio-Donahue, Christine A; Griffith, Mary E; Pawlik, Timothy M; Pai, Jonathan S; O'Reilly, Eileen; Fisher, George A; Wild, Aaron T; Rosati, Lauren M; Zheng, Lei; Wolfgang, Christopher L; Laheru, Daniel A; Columbo, Laurie A; Sugar, Elizabeth A; Koong, Albert C

    2015-01-01

    Background This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). Methods A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. Results The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P<.001]). The median overall survival was 13.9 months (95% confidence interval, 10.2 months-16.7 months). Freedom from local disease progression at 1 year was 78%. Four patients (8%) underwent margin-negative and lymph node-negative surgical resections. Conclusions

  20. Advances in huntington disease drug discovery: novel approaches to model disease phenotypes.

    PubMed

    Bard, Jonathan; Wall, Michael D; Lazari, Ovadia; Arjomand, Jamshid; Munoz-Sanjuan, Ignacio

    2014-02-01

    Huntington disease is a monogenic, autosomal dominant, progressive neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in exon 1 of the huntingtin (HTT) gene; age of onset of clinical symptoms inversely correlates with expanded CAG repeat length. HD leads to extensive degeneration of the basal ganglia, hypothalamic nuclei, and selected cortical areas, and a wide range of molecular mechanisms have been implicated in disease pathology in animal or cellular models expressing mutated HTT (mHTT) proteins, either full-length or amino-terminal fragments. However, HD cellular models that recapitulate the slow progression of the disease have not been available due to the toxicity of overexpressed exogenous mHTT or to limitations with using primary cells for long-term studies. Most investigations of the effects of mHTT relied on cytotoxicity or aggregation end points in heterologous systems or in primary embryonic neuroglial cultures derived from HD mouse models. More innovative approaches are currently under active investigation, including screening using electrophysiological endpoints, as well as the recent use of primary blood mononuclear cells and of human embryonic stem cells derived from a variety of HD research participants. Here we describe how these cellular systems are being used to investigate HD biology as well as to identify mechanisms with therapeutic potential.

  1. Phase I study of a new cancer vaccine of ten mixed peptides for advanced cancer patients.

    PubMed

    Iwasa, Satoru; Yamada, Yasuhide; Heike, Yuji; Shoji, Hirokazu; Honma, Yoshitaka; Komatsu, Nobukazu; Matsueda, Satoko; Yamada, Akira; Morita, Michi; Yamaguchi, Rin; Tanaka, Natsuki; Kawahara, Akihiko; Kage, Masayoshi; Shichijo, Shigeki; Sasada, Tetsuro; Itoh, Kyogo

    2016-05-01

    A phase I study of a new cancer vaccine (KRM-10), consisting of a mixture of 10 different short peptides, was conducted for patients with advanced gastrointestinal cancers. Primary or secondary endpoints included the dose-limiting toxicity (DLT), or safety and immune responses, respectively. Peptide-specific cytotoxic T lymphocytes (CTL) and immunoglobulin G (IgG), together with soluble inflammatory factors, were measured before and after vaccination. Twenty-one patients were vaccinated with KRM-10 at dose levels of 10 (n = 6), 20 (n = 8) or 30 mg (n = 7) of peptides every week for 6 weeks. No DLT were observed in the dose range evaluated. Common treatment-related adverse events were a grade 1 injection site reaction in 15 patients, and fever in three patients (grade 1 in two patients and grade 2 in one patient). CTL activity to at least one peptide at the time of the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively. IgG levels, at the third and sixth vaccination, were also increased in 1 and 1 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 1 and 3 of 6 (30 mg) patients, respectively. The KRM-10 vaccine consisting of 20 mg of peptides was determined as the optimal dose for a coming phase II trial because of its safety, and also for demonstrating the most potent activity for augmenting the immune response of the three doses tested. This trial was registered at the UMIN Clinical Trials Registry as UMIN000008820.

  2. Advanced hydrogen/methanol utilization technology demonstration. Phase II: Hydrogen cold start of a methanol vehicle

    SciTech Connect

    1995-05-01

    This is the Phase 11 Final Report on NREL Subcontract No. XR-2-11175-1 {open_quotes}Advanced Hydrogen/Methane Utilization Demonstration{close_quotes} between the National Renewable Energy Laboratory (NREL), Alternative Fuels Utilization Program, Golden, Colorado and Hydrogen Consultants, Inc. (HCI), Littleton, Colorado. Mr. Chris Colucci was NREL`s Technical Monitor. Colorado State University`s (CSU) Engines and Energy Conversion Laboratory was HCI`s subcontractor. Some of the vehicle test work was carried out at the National Center for Vehicle Emissions Control and Safety (NCVECS) at CSU. The collaboration of the Colorado School of Mines is also gratefully acknowledged. Hydrogen is unique among alternative fuels in its ability to burn over a wide range of mixtures in air with no carbon-related combustion products. Hydrogen also has the ability to burn on a catalyst, starting from room temperature. Hydrogen can be made from a variety of renewable energy resources and is expected to become a widely used energy carrier in the sustainable energy system of the future. One way to make a start toward widespread use of hydrogen in the energy system is to use it sparingly with other alternative fuels. The Phase I work showed that strong affects could be achieved with dilute concentrations of hydrogen in methane (11). Reductions in emissions greater than the proportion of hydrogen in the fuel provide a form of leverage to stimulate the early introduction of hydrogen. Per energy unit or per dollar of hydrogen, a greater benefit is derived than simply displacing fossil-fueled vehicles with pure hydrogen vehicles.

  3. Low vitamin D status is associated with advanced liver fibrosis in patients with nonalcoholic fatty liver disease.

    PubMed

    Yang, Bing-Bing; Chen, Yuan-Hua; Zhang, Cheng; Shi, Chang-E; Hu, Kai-Feng; Zhou, Ju; Xu, De-Xiang; Chen, Xi

    2017-02-01

    Several studies explored the association between vitamin D status and nonalcoholic fatty liver disease with contradictory results. We aimed to investigate the association between vitamin D status, inflammatory cytokines and liver fibrosis in nonalcoholic fatty liver disease patients. Two hundred nineteen nonalcoholic fatty liver disease patients and 166 age- and gender- matched healthy controls were recruited for this study. Serum 25(OH)D was measured by radioimmunoassay. Serum interleukin-8 and transforming growth factor-β1 were measured using ELISA. Serum 25(OH)D was only marginally decreased in nonalcoholic fatty liver disease patients. Interestingly, serum 25(OH)D was markedly reduced in nonalcoholic fatty liver disease patients with advanced liver fibrosis compared to nonalcoholic fatty liver disease patients with indeterminate liver fibrosis and no advanced fibrosis. Logistic regression analysis showed that there was an inverse association between serum 25(OH)D and severity of liver fibrosis in nonalcoholic fatty liver disease patients. Further analysis showed that serum interleukin-8 was elevated in nonalcoholic fatty liver disease patients, the highest interleukin-8 in patients with advanced fibrosis. An inverse correlation between serum 25(OH)D and interleukin-8 was observed in nonalcoholic fatty liver disease patients with and without liver fibrosis. Although serum transforming growth factor-β1 was slightly elevated in nonalcoholic fatty liver disease patients, serum transforming growth factor-β1 was reduced in nonalcoholic fatty liver disease patients with advanced fibrosis. Unexpectedly, a positive correlation between serum 25(OH)D and transforming growth factor-β1 was observed in nonalcoholic fatty liver disease patients with advanced fibrosis. In conclusion, low vitamin D status is associated with advanced liver fibrosis in nonalcoholic fatty liver disease patients. Interleukin-8 may be an important mediator for hepatic fibrosis in nonalcoholic

  4. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

    PubMed Central

    Weidemann, F; Niemann, M; Störk, S; Breunig, F; Beer, M; Sommer, C; Herrmann, S; Ertl, G; Wanner, C

    2013-01-01

    Objective The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease. Methods A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. Results During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. Conclusion Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease. PMID:23586858

  5. [Advance in application of syndromic surveillance for detection of emerging infectious diseases and outbreak alerts].

    PubMed

    Lin, Mei; Wang, Xin; Liang, Dabin

    2015-07-01

    Over the past decade, syndromic surveillance, as supplementation of disease surveillance, has provided possibility of early alert in a real-time way for detection of emerging infectious diseases and outbreaks of widespread infectious diseases, resulting in improvement in sensitivity of outbreak detection and public health alert capacity. This tool has been highly valued and widely used in the world, and effective implementation has been observed in China. Upon abundant literature search, the authors reviewed the progress and advance of syndromic surveillance in early alert of emerging infectious diseases and outbreaks, and analyzed the problem met in the current situation in China when implementing syndromic surveillance in local facilities, which are high cost, lack of medical information platform, lack of real-time digital alert system and lack of a comprehensive information exchange platform. The authors suggested that syndromic surveillance should be implemented considering the local situation and performed in a more effective way in the current situation. Syndromic surveillance has to be integrated into the conventional public health surveillance systems and advanced laboratory networks. Digital information system is urgently needed to achieve real-time alert.

  6. Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson's Disease

    ClinicalTrials.gov

    2017-02-22

    Idiopathic Parkinson's Disease; Parkinson's Disease; Basal Ganglia Disease; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Nervous System Diseases; Neurodegenerative Diseases; Parkinsonian Disorders

  7. GPs’ views on managing advanced chronic kidney disease in primary care: a qualitative study

    PubMed Central

    Tonkin-Crine, Sarah; Santer, Miriam; Leydon, Geraldine M; Murtagh, Fliss EM; Farrington, Ken; Caskey, Fergus; Rayner, Hugh; Roderick, Paul

    2015-01-01

    Background Chronic kidney disease (CKD) has become a significant part of the GP’s workload since the introduction of the National Institute for Health and Care Excellence guidelines in 2008. Patients with advanced CKD (stages G4 and G5) often have comorbidities, varied disease progression, and are likely to be older. GPs may experience difficulties with management decisions for patients with advanced CKD, including when to refer to nephrology. Aim To explore GPs’ views of managing patients with advanced CKD and referral to secondary care. Design and setting Qualitative study with GPs in four areas of England: London, Bristol, Birmingham, and Stevenage. Method Semi-structured interviews with 19 GPs. Transcribed interviews were thematically analysed. Results GPs had little experience of managing patients with advanced CKD, including those on dialysis or having conservative care (treatment without dialysis or a transplant), and welcomed guidance. Some GPs referred patients based on renal function alone and some used wider criteria including age and multimorbidity. GPs reported a tension between national guidance and local advice, and some had learnt from experience that patients were discharged back to primary care. GPs with more experience of managing CKD referred patients later, or sometimes not at all, if there were no additional problems and if dialysis was seen as not in the patient’s interests. Conclusion GPs want guidance on managing older patients with advanced CKD and comorbidities, which better incorporates agreement between local and national recommendations to clarify referral criteria. GPs are not generally aware of conservative care programmes provided by renal units, however, they appear happy to contribute to such care or alternatively, lead conservative management with input from renal teams. PMID:26120137

  8. Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers

    PubMed Central

    Downs-Canner, Stephanie; Guo, Zong Sheng; Ravindranathan, Roshni; Breitbach, Caroline J; O'Malley, Mark E; Jones, Heather L; Moon, Anne; McCart, Judith Andrea; Shuai, Yongli; Zeh, Herbert J; Bartlett, David L

    2016-01-01

    We have conducted a phase 1 study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on 11 patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses, and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15–30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted. PMID:27203445

  9. Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

    PubMed Central

    Brennan, K. C.; Bates, Emily A.; Shapiro, Robert E.; Zyuzin, Jekaterina; Hallows, William C.; Huang, Yong; Lee, Hsien-Yang; Jones, Christopher R.; Fu, Ying-Hui; Charles, Andrew C.; Ptáček, Louis J.

    2014-01-01

    Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine. PMID:23636092

  10. An advanced Ka band phased array communication system at commercial frequencies

    NASA Astrophysics Data System (ADS)

    Wald, Lawrence; Kacpura, Thomas; Kershner, Dennis

    2000-01-01

    The Glenn Research Center (GRC) Direct Data Distribution (D3) project will demonstrate an advanced, high-performance communication system that transmits information from a technology payload carried by the Space Shuttle in low-Earth orbit (LEO) to a small receiving terminal on the Earth. The Shuttle-based communications package will utilize a solid-state, Ka-band phased array antenna that electronically steers the 19.05 Ghz RF signal toward a low-cost, tracking ground terminal, thereby providing agile, vibration-free, electronic steering at reduced size and weight with increased reliability. The project will also demonstrate new digital modulation and processing technology that will allow transmission of user/platform data at rates up to 1200 Mbits per second. This capability will enable the management of the substantially increased amounts of data to be collected from the International Space Station (ISS) or other LEO platforms directly to NASA field centers, principal investigators, or into the commercial terrestrial communications network. .

  11. Advanced Si solid phase crystallization for vertical channel in vertical NANDs

    SciTech Connect

    Lee, Sangsoo; Son, Yong-Hoon; Hwang, Kihyun; Shin, Yoo Gyun; Yoon, Euijoon

    2014-07-01

    The advanced solid phase crystallization (SPC) method using the SiGe/Si bi-layer structure is proposed to obtain high-mobility poly-Si thin-film transistors in next generation vertical NAND (VNAND) devices. During the SPC process, the top SiGe thin film acts as a selective nucleation layer to induce surface nucleation and equiaxial microstructure. Subsequently, this SiGe thin film microstructure is propagated to the underlying Si thin film by epitaxy-like growth. The initial nucleation at the SiGe surface was clearly observed by in situ transmission electron microscopy (TEM) when heating up to 600 °C. The equiaxial microstructures of both SiGe nucleation and Si channel layers were shown in the crystallized bi-layer plan-view TEM measurements. Based on these experimental results, the large-grained and less-defective Si microstructure is expected to form near the channel region of each VNAND cell transistor, which may improve the electrical characteristics.

  12. Application of phase congruency for discriminating some lung diseases using chest radiograph.

    PubMed

    Rijal, Omar Mohd; Ebrahimian, Hossein; Noor, Norliza Mohd; Hussin, Amran; Yunus, Ashari; Mahayiddin, Aziah Ahmad

    2015-01-01

    A novel procedure using phase congruency is proposed for discriminating some lung disease using chest radiograph. Phase congruency provides information about transitions between adjacent pixels. Abrupt changes of phase congruency values between pixels may suggest a possible boundary or another feature that may be used for discrimination. This property of phase congruency may have potential for deciding between disease present and disease absent where the regions of infection on the images have no obvious shape, size, or configuration. Five texture measures calculated from phase congruency and Gabor were shown to be normally distributed. This gave good indicators of discrimination errors in the form of the probability of Type I Error (δ) and the probability of Type II Error (β). However, since 1 -  δ is the true positive fraction (TPF) and β is the false positive fraction (FPF), an ROC analysis was used to decide on the choice of texture measures. Given that features are normally distributed, for the discrimination between disease present and disease absent, energy, contrast, and homogeneity from phase congruency gave better results compared to those using Gabor. Similarly, for the more difficult problem of discriminating lobar pneumonia and lung cancer, entropy and homogeneity from phase congruency gave better results relative to Gabor.

  13. Application of Phase Congruency for Discriminating Some Lung Diseases Using Chest Radiograph

    PubMed Central

    Rijal, Omar Mohd; Ebrahimian, Hossein; Noor, Norliza Mohd; Yunus, Ashari; Mahayiddin, Aziah Ahmad

    2015-01-01

    A novel procedure using phase congruency is proposed for discriminating some lung disease using chest radiograph. Phase congruency provides information about transitions between adjacent pixels. Abrupt changes of phase congruency values between pixels may suggest a possible boundary or another feature that may be used for discrimination. This property of phase congruency may have potential for deciding between disease present and disease absent where the regions of infection on the images have no obvious shape, size, or configuration. Five texture measures calculated from phase congruency and Gabor were shown to be normally distributed. This gave good indicators of discrimination errors in the form of the probability of Type I Error (δ) and the probability of Type II Error (β). However, since 1 −  δ is the true positive fraction (TPF) and β is the false positive fraction (FPF), an ROC analysis was used to decide on the choice of texture measures. Given that features are normally distributed, for the discrimination between disease present and disease absent, energy, contrast, and homogeneity from phase congruency gave better results compared to those using Gabor. Similarly, for the more difficult problem of discriminating lobar pneumonia and lung cancer, entropy and homogeneity from phase congruency gave better results relative to Gabor. PMID:25918551

  14. Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

    PubMed Central

    Borad, Mitesh J.; Reddy, Shantan G.; Bahary, Nathan; Uronis, Hope E.; Sigal, Darren; Cohn, Allen L.; Schelman, William R.; Stephenson, Joe; Chiorean, E. Gabriela; Rosen, Peter J.; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A.; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P.

    2015-01-01

    Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study

  15. Treatment of Parkinson disease: a 64-year-old man with motor complications of advanced Parkinson disease.

    PubMed

    Tarsy, Daniel

    2012-06-06

    In early stages, Parkinson disease typically begins with asymmetric or unilateral motor symptoms due to combinations of mild bradykinesia, rigidity, and tremor. In most cases, with progression, signs of more generalized bradykinesia appear, which include facial masking, reduced voice volume, and slowing of activities of daily living. In more advanced Parkinson disease, other disabling manifestations may follow, such as impaired balance, gait freezing, falls, speech disturbance, and cognitive impairment. Levodopa is the most effective medical treatment for Parkinson disease. However, motor complications uniquely related to levodopa treatment may emerge that may be difficult to manage. These include fluctuating levodopa responses and involuntary movements and postures known as dyskinesia and dystonia. Medication adjustments are usually effective, but in some cases surgical intervention with deep brain stimulation becomes necessary to alleviate motor complications. The case of Mr L, a man with an 11-year history of Parkinson disease, illustrates these emerging motor complications and the manner in which they may be managed both medically and surgically.

  16. Advanced Simulation Capability for Environmental Management - Current Status and Phase II Demonstration Results - 13161

    SciTech Connect

    Seitz, Roger R.; Flach, Greg; Freshley, Mark D.; Freedman, Vicky; Gorton, Ian; Dixon, Paul; Moulton, J. David; Hubbard, Susan S.; Faybishenko, Boris; Steefel, Carl I.; Finsterle, Stefan; Marble, Justin

    2013-07-01

    The U.S. Department of Energy (US DOE) Office of Environmental Management (EM), Office of Soil and Groundwater, is supporting development of the Advanced Simulation Capability for Environmental Management (ASCEM). ASCEM is a state-of-the-art scientific tool and approach for understanding and predicting contaminant fate and transport in natural and engineered systems. The modular and open source high-performance computing tool facilitates integrated approaches to modeling and site characterization that enable robust and standardized assessments of performance and risk for EM cleanup and closure activities. The ASCEM project continues to make significant progress in development of computer software capabilities with an emphasis on integration of capabilities in FY12. Capability development is occurring for both the Platform and Integrated Tool-sets and High-Performance Computing (HPC) Multi-process Simulator. The Platform capabilities provide the user interface and tools for end-to-end model development, starting with definition of the conceptual model, management of data for model input, model calibration and uncertainty analysis, and processing of model output, including visualization. The HPC capabilities target increased functionality of process model representations, tool-sets for interaction with Platform, and verification and model confidence testing. The Platform and HPC capabilities are being tested and evaluated for EM applications in a set of demonstrations as part of Site Applications Thrust Area activities. The Phase I demonstration focusing on individual capabilities of the initial tool-sets was completed in 2010. The Phase II demonstration completed in 2012 focused on showcasing integrated ASCEM capabilities. For Phase II, the Hanford Site deep vadose zone (BC Cribs) served as an application site for an end-to-end demonstration of capabilities, with emphasis on integration and linkages between the Platform and HPC components. Other demonstrations

  17. Nonsurgical Management of Cervical Cancer: Locally Advanced, Recurrent, and Metastatic Disease, Survivorship, and Beyond

    PubMed Central

    Mackay, Helen J.; Wenzel, Lari; Mileshkin, Linda

    2016-01-01

    Overview Despite the declining incidence of cervical cancer as a result of the introduction of screening programs, globally it remains a leading cause of cancer-related death in women. Outcomes for patients who are diagnosed with anything but early-stage disease remain poor. Here we examine emerging strategies to improve the treatment of locally advanced disease. We discuss emerging biologic data, which are informing our investigation of new therapeutic interventions in persistent, recurrent, and metastatic cervical cancer. We recognize the importance of interventions to improve quality of life and to prevent long-term sequelae in women undergoing treatment. Finally, and perhaps most importantly, we recognize the need for global collaboration and advocacy to improve the outcome for all women at risk of and diagnosed with this disease. PMID:25993189

  18. Kienböck Disease: Recent Advances in the Basic Science, Assessment and Treatment.

    PubMed

    Bain, Gregory Ian; Yeo, Chong Jin; Morse, Levi Philip

    2015-10-01

    Kienböck disease is a disorder of impaired lunate vascularity which ultimately has the potential to lead to marked degeneration of the wrist and impaired wrist function. The aetiology of the avascular necrosis is uncertain, but theories relate to ulnar variance, variability in lunate vascularity and intraosseous pressures. Clinical symptoms can be subtle and variable, requiring a high index of suspicion for the diagnosis. The Lichtmann classification has historically been used to guide management. We present a review of Kienböck disease, with a focus on the recent advances in assessment and treatment. Based on our understanding thus far of the pathoanatomy of Kienböck's disease, we are proposing a pathological staging system founded on the vascularity, osseous and chondral health of the lunate. We also propose an articular-based approach to treatment, with an arthroscopic grading system to guide management.

  19. Update on celiac disease – etiology, differential diagnosis, drug targets, and management advances

    PubMed Central

    Scanlon, Samantha A; Murray, Joseph A

    2011-01-01

    Celiac disease (CD) is an immune-mediated enteropathy triggered by exposure to wheat gluten and similar proteins found in rye and barley that affects genetically susceptible persons. This immune-mediated enteropathy is characterized by villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia. Once thought a disease that largely presented with malnourished children, the wide spectrum of disease activity is now better recognized and this has resulted in a shift in the presenting symptoms of most patients with CD. New advances in testing, both serologic and endoscopic, have dramatically increased the detection and diagnosis of CD. While the gluten-free diet is still the only treatment for CD, recent investigations have explored alternative approaches, including the use of altered nonimmunogenic wheat variants, enzymatic degradation of gluten, tissue transglutaminase inhibitors, induction of tolerance, and peptides to restore integrity to intestinal tight junctions. PMID:22235174

  20. Development and proof-testing of advanced absorption refrigeration cycle concepts. Report on Phases 1 and 1A

    SciTech Connect

    Modahl, R.J.; Hayes, F.C.

    1992-03-01

    The overall objectives of this project are to evaluate, develop, and proof-test advanced absorption refrigeration cycles that are applicable to residential and commercial heat pumps for space conditioning. The heat pump system is to be direct-fired with natural gas and is to use absorption working fluids whose properties are known. Target coefficients of performance (COPs) are 1.6 at 47{degrees}F and 1.2 at 17{degrees} in the heating mode, and 0.7 at 95{degree}F in the cooling mode, including the effect of flue losses. The project is divided into three phases. Phase I entailed the analytical evaluation of advanced cycles and included the selection of preferred concepts for further development. Phase II involves the development and testing of critical components and of a complete laboratory breadboard version of the selected system. Phase III calls for the development of a prototype unit and is contingent on the successful completion of Phase II. This report covers Phase I work on the project. In Phase 1, 24 advanced absorption cycle/fluid combinations were evaluated, and computer models were developed to predict system performance. COP, theoretical pump power, and internal heat exchange were calculated for each system, and these calculations were used as indicators of operating and installed costs in order to rank the relative promise of each system. The highest ranking systems involve the cycle concept of absorber/generator heat exchange, generator heat exchanger/absorber heat exchange, regeneration, and resorption/desorption, in combination with the NH{sub 3}/H{sub 2}O/LiBr ternary absorption fluid mixture or with the NH{sub 3}/H{sub 2}O binary solution. Based upon these conclusions, the recommendation was made to proceed to Phase II, the laboratory breadboard proof-of- concept.

  1. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component.

    PubMed

    Yang, James Chih-Hsin; Ahn, Myung-Ju; Kim, Dong-Wan; Ramalingam, Suresh S; Sequist, Lecia V; Su, Wu-Chou; Kim, Sang-We; Kim, Joo-Hang; Planchard, David; Felip, Enriqueta; Blackhall, Fiona; Haggstrom, Daniel; Yoh, Kiyotaka; Novello, Silvia; Gold, Kathryn; Hirashima, Tomonori; Lin, Chia-Chi; Mann, Helen; Cantarini, Mireille; Ghiorghiu, Serban; Jänne, Pasi A

    2017-02-21

    Purpose Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing ( EGFRm) and T790M resistance mutations. AURA (NCT01802632) is a phase I/II clinical trial to determine the dose, safety, and efficacy of osimertinib. This article reports the results from the phase II extension component. Patients and Methods Patients with EGFR-TKI-pretreated EGFRm- and T790M-positive advanced non-small-cell lung cancer (NSCLC) received once-daily osimertinib 80 mg. T790M status was confirmed by central testing from a tumor sample taken after the most recent disease progression. Patients with asymptomatic, stable CNS metastases that did not require corticosteroids were allowed to enroll. The primary end point was objective response rate (ORR) by independent radiology assessment. Secondary end points were disease control rate, duration of response, progression-free survival (PFS), and safety. Patient-reported outcomes comprised an exploratory objective. Results In total, 201 patients received treatment, with a median treatment duration of 13.2 months at the time of data cutoff (November 1, 2015). In evaluable patients (n = 198), ORR was 62% (95% CI, 54% to 68%), and the disease control rate was 90% (95% CI, 85 to 94). Median duration of response in 122 responding patients was 15.2 months (95% CI, 11.3 to not calculable). Median PFS was 12.3 months (95% CI, 9.5 to 13.8). The most common possibly causally related adverse events (investigator assessed) were diarrhea (43%; grade ≥ 3, < 1%) and rash (grouped terms; 40%; grade ≥ 3, < 1%). Interstitial lung disease (grouped terms) was reported in eight patients (4%; grade 1, n = 2; grade 3, n = 3; grade 5, n = 3). Conclusion In patients with EGFRm T790M advanced NSCLC who progress after EGFR-TKI treatment, osimertinib provides a high ORR, encouraging PFS, and durable response.

  2. Phase I Study of Capecitabine, Oxaliplatin, Bevacizumab, and Everolimus in Advanced Solid Tumors

    PubMed Central

    Rangwala, F.; Bendell, J.; Kozloff, M.; Arrowood, C.; Dellinger, A.; Meadows, J.; Tourt-Uhlig, S.; Murphy, J.; Meadows, K.L.; Starr, A.; Broderick, S.; Brady, J.C.; Cushman, S. M.; Morse, M.; Uronis, H.; Hsu, S.D.; Zafar, S.Y.; Wallace, J.; Starodub, A.; Strickler, J.; Pang, H.; Nixon, A.B.; Hurwitz, H.

    2014-01-01

    Purpose To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design This was a standard “3+3” dose-escalation trial. All subjects received bevacizumab 7.5mg/kg on day one of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; eight of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5mg daily; capecitabine 680mg/m2 BID days 1-14; oxaliplatin 100mg/m2 and bevacizumab 7.5mg/kg, day one. Activity was noted in mCRC. PMID:24711126

  3. Phasic Dopaminergic Signaling and the Presymptomatic Phase of Parkinson’s Disease

    DTIC Science & Technology

    2004-07-01

    disease . The overall hypothesis is that, in rats with partial dopamine lesions mimicking the preclinical phase of Parkinson’s disease , deficits in...The purpose of this project is to investigate the relationship between phasic dopaminergic signaling and behavior in an animal model of Parkinson’s

  4. Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases.

    PubMed

    Byun, Kyunghee; Yoo, YongCheol; Son, Myeongjoo; Lee, Jaesuk; Jeong, Goo-Bo; Park, Young Mok; Salekdeh, Ghasem Hosseini; Lee, Bonghee

    2017-02-13

    Advanced glycation end products (AGEs) and their receptor have been implicated in the progressions of many intractable diseases, such as diabetes and atherosclerosis, and are also critical for pathologic changes in chronic degenerative diseases, such as Alzheimer's disease, Parkinson's disease, and alcoholic brain damage. Recently activated macrophages were found to be a source of AGEs, and the most abundant form of AGEs, AGE-albumin excreted by macrophages has been implicated in these diseases and to act through common pathways. AGEs inhibition has been shown to prevent the pathogenesis of AGEs-related diseases in human, and therapeutic advances have resulted in several agents that prevent their adverse effects. Recently, anti-inflammatory molecules that inhibit AGEs have been shown to be good candidates for ameliorating diabetic complications as well as degenerative diseases. This review was undertaken to present, discuss, and clarify current understanding regarding AGEs formation in association with macrophages, different diseases, therapeutic and diagnostic strategy and links with RAGE inhibition.

  5. Is gardening a stimulating activity for people with advanced Huntington's disease?

    PubMed

    Spring, Josephine A; Viera, Marc; Bowen, Ceri; Marsh, Nicola

    2014-11-01

    This study evaluated adapted gardening as an activity for people with advanced Huntington's disease (HD) and explored its therapeutic aspects. Visitors and staff completed a questionnaire and participated in structured interviews to capture further information, whereas a pictorial questionnaire was designed for residents with communication difficulties. Staff reported that gardening was a constructive, outdoor activity that promoted social interaction, physical activity including functional movement and posed cognitive challenges. Half the staff thought the activity was problem free and a third used the garden for therapy. Visitors used the garden to meet with residents socially. Despite their disabilities, HD clients enjoyed growing flourishing flowers and vegetables, labelling plants, being outside in the sun and the quiet of the garden. The garden is valued by all three groups. The study demonstrates the adapted method of gardening is a stimulating and enjoyable activity for people with advanced HD.

  6. Advances and challenges in biosensor-based diagnosis of infectious diseases

    PubMed Central

    Sin, Mandy LY; Mach, Kathleen E; Wong, Pak Kin; Liao, Joseph C

    2014-01-01

    Rapid diagnosis of infectious diseases and timely initiation of appropriate treatment are critical determinants that promote optimal clinical outcomes and general public health. Conventional in vitro diagnostics for infectious diseases are time-consuming and require centralized laboratories, experienced personnel and bulky equipment. Recent advances in biosensor technologies have potential to deliver point-of-care diagnostics that match or surpass conventional standards in regards to time, accuracy and cost. Broadly classified as either label-free or labeled, modern biosensors exploit micro- and nanofabrication technologies and diverse sensing strategies including optical, electrical and mechanical transducers. Despite clinical need, translation of biosensors from research laboratories to clinical applications has remained limited to a few notable examples, such as the glucose sensor. Challenges to be overcome include sample preparation, matrix effects and system integration. We review the advances of biosensors for infectious disease diagnostics and discuss the critical challenges that need to be overcome in order to implement integrated diagnostic biosensors in real world settings. PMID:24524681

  7. Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis.

    PubMed

    Moujalled, Diane; White, Anthony R

    2016-03-01

    Amyotrophic lateral sclerosis (ALS) is a progressive adult-onset, neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. Over recent years, numerous genes ha ve been identified that promote disease pathology, including SOD1, TARDBP, and the expanded hexanucleotide repeat (GGGGCC) within C9ORF72. However, despite these major advances in identifying genes contributing to ALS pathogenesis, there remains only one currently approved therapeutic: the glutamate antagonist, riluzole. Seminal breakthroughs in the pathomechanisms and genetic factors associated with ALS have heavily relied on the use of rodent models that recapitulate the ALS phenotype; however, while many therapeutics have proved to be significant in animal models by prolonging life and rescuing motor deficits, they have failed in human clinical trials. This may be due to fundamental differences between rodent models and human disease, the fact that animal models are based on overexpression of mutated genes, and confounding issues such as difficulties mimicking the dosing schedules and regimens implemented in mouse models to humans. Here, we review the major pathways associated with the pathology of ALS, the rodent models engineered to test efficacy of candidate drugs, the advancements being made in stem cell therapy for ALS, and what strategies may be important to circumvent the lack of successful translational studies in the clinic.

  8. Clinical and Genetic Advances in Paget's Disease of Bone: a Review.

    PubMed

    Alonso, N; Calero-Paniagua, I; Del Pino-Montes, J

    2017-01-01

    Paget's disease of bone (PDB) is the second most common metabolic bone disorder, after osteoporosis. It is characterised by focal areas of increased and disorganised bone turnover, coupled with increased bone formation. This disease usually appears in the late stages of life, being slightly more frequent in men than in women. It has been reported worldwide, but primarily affects individuals of British descent. Majority of PDB patients are asymptomatic, but clinical manifestations include pain, bone deformity and complications, like pathological fractures and deafness. The causes of the disease are poorly understood and it is considered as a complex trait, combining genetic predisposition with environmental factors. Linkage analysis identified SQSTM1, at chromosome 5q35, as directly related to the disease. A number of mutations in this gene have been reported, pP392L being the most common variant among different populations. Most of these variants affect the ubiquitin-associated (UBA) domain of the protein, which is involved in autophagy processes. Genome-wide association studies enlarged the number of loci associated with PDB, and further fine-mapping studies, combined with functional analysis, identified OPTN and RIN3 as causal genes for Paget's disease. A combination of risk alleles identified by genome-wide association studies led to the development of a score to predict disease severity, which could improve the management of the disease. Further studies need to be conducted to elucidate other important aspects of the trait, such as its focal nature and the epidemiological changes found in some populations. In this review, we summarize the clinical characteristics of the disease and the latest genetic advances to identify susceptibility genes. We also list current available treatments and prospective options.

  9. Phase II study of induction chemotherapy followed by chemoradiotherapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer

    PubMed Central

    Fiore, Michele; Ramella, Sara; Valeri, Sergio; Caputo, Damiano; Floreno, Barnaba; Trecca, Pasquale; Trodella, Luca Eolo; Trodella, Lucio; D’Angelillo, Rolando Maria; Coppola, Roberto

    2017-01-01

    There is not a clear consensus regarding the optimal treatment of locally advanced pancreatic disease. There is a potential role for neoadjuvant therapy to treat micrometastatic disease with chemotherapy, as well as for the treatment of local disease with radiotherapy. We evaluated the safety and efficacy of induction chemotherapy with oxaliplatin and gemcitabine followed by a high weekly dose of gemcitabine concurrent to radiation therapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer. In our study, 41 patients with pancreatic cancer were evaluated. In all cases an accurate pre-treatment staging was performed. Patients with evidence of metastatic disease were excluded, and thus a total of 34 patients were consequently enrolled. Of these, twenty-seven patients (80%) had locally advanced unresectable tumours, seven patients (20%) had borderline resectable disease. This protocol treatment represents a well-tolerated promising approach. Fifteen patients (55.5%) underwent surgical radical resection. With a median follow-up of 20 months, the median PFS and OS were 20 months and 19.2 months, respectively. The median OS for borderline resectable patients was 21.5 months compared with 14 months for unresectable patients (p = 0.3). Continued optimization in multimodality therapy and an accurate patient selection remain crucial points for the appropriate treatment of these patients. PMID:28378800

  10. A phase I study of intravenous bryostatin 1 in patients with advanced cancer.

    PubMed Central

    Prendiville, J.; Crowther, D.; Thatcher, N.; Woll, P. J.; Fox, B. W.; McGown, A.; Testa, N.; Stern, P.; McDermott, R.; Potter, M.

    1993-01-01

    Bryostatin 1 is a novel antitumour agent derived from Bugula neritina of the marine phylum Ectoprocta. Nineteen patients with advanced solid tumours were entered into a phase I study to evaluate the toxicity and biological effects of bryostatin 1. Bryostatin 1 was given as a one hour intravenous infusion at the beginning of each 2 week treatment cycle. A maximum of three treatment cycles were given. Doses were escalated in steps from 5 to 65 micrograms m-2 in successive patient groups. The maximum tolerated dose was 50 micrograms m-2. Myalgia was the dose limiting toxicity and was of WHO grade 3 in all three patients treated at 65 micrograms m-2. Flu-like symptoms were common but were of maximum WHO grade 2. Hypotension, of maximum WHO grade 1, occurred in six patients treated at doses up to and including 20 micrograms m-2 and may not have been attributable to treatment with bryostatin 1. Cellulitis and thrombophlebitis occurred at the bryostatin 1 infusion site of patients treated at all dose levels up to 50 micrograms m-2, attributable to the 60% ethanol diluent in the bryostatin 1 infusion. Subsequent patients treated at 50 and 65 micrograms m-2 received treatment with an intravenous normal saline flush and they did not develop these complications. Significant decreases of the platelet count and total leucocyte, neutrophil and lymphocyte counts were seen in the first 24 h after treatment at the dose of 65 micrograms m-2. Immediate decreases in haemoglobin of up to 1.9g dl-1 were also noted in patients treated with 65 micrograms m-2, in the absence of clinical evidence of bleeding or haemodynamic compromise. No effect was observed on the incidence of haemopoietic progenitor cells in the marrow. Some patients' neutrophils demonstrated enhanced superoxide radical formation in response to in vitro stimulation with opsonised zymosan (a bacterial polysaccharide) but in the absence of this additional stimulus, no bryostatin 1 effect was observed. Lymphocyte natural

  11. Phase I dose-finding study of sorafenib with FOLFOX4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer

    PubMed Central

    Chi, Yihebali; Yang, Jianliang; Yang, Sheng; Sun, Yongkun; Jia, Bo

    2015-01-01

    Objective To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and efficacy of sorafenib in combination with FOLFOX4 (oxaliplatin/leucovorin (LV)/5-fluorouracil) as first-line treatment for advanced gastric cancer, we performed a phase I dose-finding study in nine evaluable patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Methods According to modified Fibonacci method, the design of this study was to guide elevation of the sorafenib dosage to the next level (from 200 mg twice daily to 400 mg twice daily and then, if tolerated, 600 mg twice daily). If the patient achieved complete response (CR), partial response (PR) or stable disease (SD) after eight cycles of treatment, combination chemotherapy was scheduled to be discontinued and sorafenib monotherapy continued at the original dose until either disease progression or unacceptable toxicity. Results In sorafenib 200 mg twice daily group, DLT was observed in 1 of 6 patients, and in 400 mg twice daily group, it was observed in 2 of 3 patients. Seven of 9 (77.8%) evaluable patients achieved PR, with a median overall survival (OS) of 11.8 [95% confidence interval (CI): 8.9-14.7] months. Common adverse effects include hand-foot syndrome, leukopenia, neutropenia, anorexia, and nausea. Conclusions Twice-daily dosing of sorafenib 200 mg in combination with FOLFOX4 was proven effective and safe for the treatment of advanced gastric cancer, and could be an appropriate dosage for subsequent phase II clinical studies. PMID:26157320

  12. Phase 1 Clinical Trial of Ipilimumab In Pediatric Patients With Advanced Solid Tumors

    PubMed Central

    Merchant, Melinda S.; Wright, Matthew; Baird, Kristin; Wexler, Leonard H.; Rodriguez-Galindo, Carlos; Bernstein, Donna; Delbrook, Cindy; Lodish, Maya; Bishop, Rachel; Wolchok, Jedd D.; Streicher, Howard; Mackall, Crystal L.

    2016-01-01

    Purpose Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. Experimental Design This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Results Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half–life of 8-15 days. At day 21, subjects had increased levels of cycling T cells, but no change in regulatory T cell populations. Six subjects had confirmed stable disease for 4-10 cycles (melanoma, osteosarcoma, clear cell sarcoma, and synovial sarcoma). Conclusions Ipilimumab was safely administered to pediatric patients using management algorithms for immune-related toxicities. The spectrum of immune-related adverse events is similar to those described in adults; however, many of the pediatric toxicities were evident after a single dose. Although no objective tumor regressions were observed with ipilimumab as a single agent, subjects with immune related toxicities had an increased overall survival compared to those who showed no evidence of breaking tolerance. PMID:26534966

  13. Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies

    PubMed Central

    Kim, Duk Hwan

    2017-01-01

    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with an unknown etiology. IBD is composed of two different disease entities: Crohn's disease (CD) and ulcerative colitis (UC). IBD has been thought to be idiopathic but has two main attributable causes that include genetic and environmental factors. The gastrointestinal tract in which this disease occurs is central to the immune system, and the innate and the adaptive immune systems are balanced in complex interactions with intestinal microbes under homeostatic conditions. However, in IBD, this homeostasis is disrupted and uncontrolled intestinal inflammation is perpetuated. Recently, the pathogenesis of IBD has become better understood owing to advances in genetic and immunologic technology. Moreover, new therapeutic strategies are now being implemented that accurately target the pathogenesis of IBD. Beyond conventional immunesuppressive therapy, the development of biological agents that target specific disease mechanisms has resulted in more frequent and deeper remission in IBD patients, with mucosal healing as a treatment goal of therapy. Future novel biologics should overcome the limitations of current therapies and ensure that individual patients can be treated with optimal drugs that are safe and precisely target IBD. PMID:28261018

  14. CT angiography after 20 years: a transformation in cardiovascular disease characterization continues to advance.

    PubMed

    Rubin, Geoffrey D; Leipsic, Jonathon; Joseph Schoepf, U; Fleischmann, Dominik; Napel, Sandy

    2014-06-01

    Through a marriage of spiral computed tomography (CT) and graphical volumetric image processing, CT angiography was born 20 years ago. Fueled by a series of technical innovations in CT and image processing, over the next 5-15 years, CT angiography toppled conventional angiography, the undisputed diagnostic reference standard for vascular disease for the prior 70 years, as the preferred modality for the diagnosis and characterization of most cardiovascular abnormalities. This review recounts the evolution of CT angiography from its development and early challenges to a maturing modality that has provided unique insights into cardiovascular disease characterization and management. Selected clinical challenges, which include acute aortic syndromes, peripheral vascular disease, aortic stent-graft and transcatheter aortic valve assessment, and coronary artery disease, are presented as contrasting examples of how CT angiography is changing our approach to cardiovascular disease diagnosis and management. Finally, the recently introduced capabilities for multispectral imaging, tissue perfusion imaging, and radiation dose reduction through iterative reconstruction are explored with consideration toward the continued refinement and advancement of CT angiography.

  15. Inflammation Biomarkers of Advanced Disease in Nongingival Tissues of Chronic Periodontitis Patients.

    PubMed

    da Costa, Thiago Alvares; Silva, Marcelo José Barbosa; Alves, Polyanna Miranda; Chica, Javier Emílio Lazo; Barcelos, Emilio Zorzo; Giani, Max Antonio Alves; Garlet, Gustavo Pompermaier; da Silva, João Santana; Rodrigues Júnior, Virmondes; Rodrigues, Denise Bertulucci Rocha; Cardoso, Cristina Ribeiro de Barros

    2015-01-01

    Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17(+) and TRAP(+) cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression.

  16. Inflammation Biomarkers of Advanced Disease in Nongingival Tissues of Chronic Periodontitis Patients

    PubMed Central

    da Costa, Thiago Alvares; Silva, Marcelo José Barbosa; Alves, Polyanna Miranda; Chica, Javier Emílio Lazo; Barcelos, Emilio Zorzo; Giani, Max Antonio Alves; Garlet, Gustavo Pompermaier; da Silva, João Santana; Rodrigues Júnior, Virmondes; Rodrigues, Denise Bertulucci Rocha; Cardoso, Cristina Ribeiro de Barros

    2015-01-01

    Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17+ and TRAP+ cells. The levels of TNF-α and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-α and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression. PMID:26063981

  17. Phase II Trial of Neoadjuvant Bevacizumab, Capecitabine, and Radiotherapy for Locally Advanced Rectal Cancer

    SciTech Connect

    Crane, Christopher H.; Eng, Cathy; Feig, Barry W.; Das, Prajnan; Skibber, John M.; Chang, George J.; Wolff, Robert A.; Krishnan, Sunil; Hamilton, Stanley; Janjan, Nora A.; Maru, Dipen M.; Ellis, Lee M.; Rodriguez-Bigas, Miguel A.

    2010-03-01

    Purpose: We designed this Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabine-based chemoradiation in locally advanced rectal cancer. Methods: Between April 2004 and December 2007, 25 patients with clinically staged T3N1 (n = 20) or T3N0 (n = 5) rectal cancer received neoadjuvant therapy with radiotherapy (50.4 Gy in 28 fractions over 5.5 weeks), bevacizumab every 2 weeks (3 doses of 5 mg/kg), and capecitabine (900 mg/m{sup 2} orally twice daily only on days of radiation), followed by surgical resection a median of 7.3 weeks later. Results: Procedures included abdominoperineal resection (APR; 6 patients), proctectomy with coloanal anastamosis (8 patients), low anterior resection (10 patients), and local excision (1 patient). Eight (32%) of 25 patients had a pathologic complete response, and 6 (24%) of 25 had <10% viable tumor cells in the specimen. No patient had Grade 3 hand-foot syndrome, gastrointestinal toxicity, or significant hematologic toxicity. Three wound complications required surgical intervention (one coloanal anastamostic dehiscence requiring completion APR and two perineal wound dehiscences after initial APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, 4.5-32.4 months), all patients were alive; one patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. Conclusions: The addition of bevacizumab to neoadjuvant chemoradiation resulted in encouraging pathologic complete response without an increase in acute toxicity. The impact of bevacizumab on perineal wound and anastamotic healing due to concurrent bevacizumab requires further study.

  18. On-the-Fly Kinetic Monte Carlo Simulation of Aqueous Phase Advanced Oxidation Processes.

    PubMed

    Guo, Xin; Minakata, Daisuke; Crittenden, John

    2015-08-04

    We have developed an on-the-fly kinetic Monte Carlo (KMC) model to predict the degradation mechanisms and fates of intermediates and byproducts that are produced during aqueous-phase advanced oxidation processes (AOPs). The on-the-fly KMC model is composed of a reaction pathway generator, a reaction rate constant estimator, a mechanistic reduction module, and a KMC solver. The novelty of this work is that we develop the pathway as we march forward in time rather than developing the pathway before we use the KMC method to solve the equations. As a result, we have fewer reactions to consider, and we have greater computational efficiency. We have verified this on-the-fly KMC model for the degradation of polyacrylamide (PAM) using UV light and titanium dioxide (i.e., UV/TiO2). Using the on-the-fly KMC model, we were able to predict the time-dependent profiles of the average molecular weight for PAM. The model provided detailed and quantitative insights into the time evolution of the molecular weight distribution and reaction mechanism. We also verified our on-the-fly KMC model for the destruction of (1) acetone, (2) trichloroethylene (TCE), and (3) polyethylene glycol (PEG) for the ultraviolet light and hydrogen peroxide AOP. We demonstrated that the on-the-fly KMC model can achieve the same accuracy as the computer-based first-principles KMC (CF-KMC) model, which has already been validated in our earlier work. The on-the-fly KMC is particularly suitable for molecules with large molecular weights (e.g., polymers) because the degradation mechanisms for large molecules can result in hundreds of thousands to even millions of reactions. The ordinary differential equations (ODEs) that describe the degradation pathways cannot be solved using traditional numerical methods, but the KMC can solve these equations.

  19. Phase I Study of CKD-516, a Novel Vascular Disrupting Agent, in Patients with Advanced Solid Tumors

    PubMed Central

    Oh, Do-Youn; Kim, Tae-Min; Han, Sae-Won; Shin, Dong-Yeop; Lee, Yun Gyoo; Lee, Keun-Wook; Kim, Jee Hyun; Kim, Tae-You; Jang, In-Jin; Lee, Jong-Seok; Bang, Yung-Jue

    2016-01-01

    Purpose CKD-516 is a newly developed vascular disrupting agent. This phase I dose-escalation study of CKD-516 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors. Materials and Methods Patients received CKD-516 intravenously on D1 and D8 every 3 weeks, in a standard 3+3 design. Safety was evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.02 and response was assessed by Response Evaluation Criteria in Solid Tumor ver. 1.1. Results Twenty-three patients were treated with CKD-516 at seven dosing levels: 1 mg/m2/day (n=3), 2 mg/m2/day (n=3), 3.3 mg/m2/day (n=3), 5 mg/m2/day (n=3), 7 mg/m2/day (n=3), 9 mg/m2/day (n=6), and 12 mg/m2/day (n=2). Mean age was 54 and 56.5% of patients were male. Two dose-limiting toxicities, which were both grade 3 hypertension, were observed in two patients at 12 mg/m2/day. The MTD was determined as 12 mg/m2/day. Most common adverse events were gastrointestinal adverse events (diarrhea, 34.8% [30.4% grade 1/2, 13.0% grade 3]; nausea, 21.7% [all grade 1/2]; vomiting, 21.7% [all grade 1/2]), myalgia (17.4%, all grade 1/2), and abdominal pain (21.7% [21.7% grade 1/2, 4.3% grade 3]). The pharmacokinetic study showed the dose-linearity of all dosing levels. Among 23 patients, six patients (26.1%) showed stable disease. Median progression-free survival was 39 days (95% confidence interval, 37 to 41 days). Conclusion This study demonstrates feasibility of CKD-516, novel vascular disrupting agent, in patients with advanced solid tumor. MTD of CKD-516 was defined as 12 mg/m2/day on D1 and D8 every 3 weeks. PMID:25715767

  20. Immediately loaded fixed maxillary implant treatment for a patient with advanced periodontal disease: a clinical report.

    PubMed

    Binon, Paul

    2010-12-01

    Patients with a failing maxillary dentition typically require an extended treatment sequence that involves extractions, interim prosthesis wear, grafting and subsequent implant placement, and restoration with an implant-supported fixed or bar-retained prosthesis. Established maxillary implant protocols can take up to 15 or more months to complete. The purpose of this report is to describe a treatment sequence using zygomatic implants in a patient with advanced periodontal disease. A fixed prosthesis was fabricated without grafting, resulting in a shortened treatment time.

  1. Phase I trial of arginine deprivation therapy with ADI-PEG 20 plus docetaxel in patients with advanced malignant solid tumors

    PubMed Central

    Tomlinson, Benjamin K.; Thomson, James A.; Bomalaski, John S.; Diaz, Monica; Akande, Taiwo; Mahaffey, Nichole; Li, Tianhong; Dutia, Mrinal P.; Kelly, Karen; Gong, I-Yeh; Semrad, Thomas; Gandara, David R.; Pan, Chong-Xian; Lara, Primo N.

    2015-01-01

    Purpose This phase I study examined the toxicity and tolerability, of pegylated arginine deiminase (ADI-PEG 20) in combination with docetaxel in patients with advanced solid malignancies. Experimental Design Eligible patients had histologically proven advanced solid malignancies, with any number of prior therapies, zubrod performance status 0–2 and adequate organ function. Patients received ADI-PEG 20 weekly intramuscular injection ranging from 4.5–36 mg/m2, and up to ten doses of docetaxel 75 mg/m2 every three weeks. Primary endpoints were safety, toxicity and a recommended phase II dose. Circulating arginine levels were measured prior to each cycle. Tumor response was measured as a secondary endpoint every six weeks on study. Results Eighteen patients received a total of 116 cycles of therapy through four dose levels of ADI-PEG 20. A single dose-limiting toxicity (grade 3 urticarial rash) was observed at the 1st dose level, with no additional dose-limiting toxicities observed. Hematologic toxicities were common with 14 patients experiencing at least one grade 3–4 leukopenia. Fatigue was the most prevalent toxicity reported by 16 patients. Arginine was variably suppressed with ten patients achieving at least a 50% reduction in baseline values. In 14 patients with evaluable disease, four partial responses (including two patients with PSA response) were documented and seven patients had stable disease. Conclusions ADI-PEG 20 demonstrated reasonable toxicity in combination with docetaxel. Promising clinical activity was noted and expansion cohorts are now accruing for both castrate resistant prostate cancer and non-small cell lung cancer at a recommended phase II dose of 36 mg/m2. PMID:25739672

  2. In search of an advance directive that works for end-stage renal disease patients.

    PubMed

    Bartlow, Bruce

    2006-10-01

    Although loss, disability, and death are constant possibilities for any end-stage renal disease patient, very few have planned for the last of life. Currently available Advance Directives (ADs) are refusal of specific therapies in only specific but nebulous circumstances. They fail to provide positive guidance for a patient's remaining time. Without addressing goals, quality of life, reversibility of medical problems, and desired end-of-life (EOL) care, such ADs are useless. End-stage renal disease providers are generally untrained and unsupported in offering guidance. Financial, emotional, and structural factors collude to justify ignoring EOL planning. Several alternative ADs are offered, along with a goal-directed approach to EOL counseling for patients and staff.

  3. Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management.

    PubMed

    Mulshine, James L; Avila, Rick; Yankelevitz, David; Baer, Thomas M; Estépar, Raul San Jose; Ambrose, Laurie Fenton; Aldigé, Carolyn R

    2015-05-01

    The Prevent Cancer Foundation Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management was held in New York, NY on May 16 and 17, 2014. The two goals of the Workshop were to define strategies to drive innovation in precompetitive quantitative research on the use of imaging to assess new therapies for management of early lung cancer and to discuss a process to implement a national program to provide high quality computed tomography imaging for lung cancer and other tobacco-induced disease. With the central importance of computed tomography imaging for both early detection and volumetric lung cancer assessment, strategic issues around the development of imaging and ensuring its quality are critical to ensure continued progress against this most lethal cancer.

  4. Recent advances in biomarkers for Parkinson's disease focusing on biochemicals, omics and neuroimaging.

    PubMed

    Ren, Rutong; Sun, Yi; Zhao, Xin; Pu, Xiaoping

    2015-09-01

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders, involving progressive loss of the nigro-striatal dopaminergic neurons. Cardinal symptoms including tremors, muscle rigidity, drooping posture, drooping, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons have already been destroyed. Hence, reliable biomarkers are needed for early and accurate diagnosis to measure disease progression and response to therapy. We review the current status of protein and small molecule biomarkers involved in oxidative stress, protein aggregation and inflammation etc. which are present in cerebrospinal fluid, human blood, urine or saliva. In recent years, advances in genomics, proteomics, metabolomics, and functional brain imaging techniques have led to new insights into the pathoetiology of PD. Further studies in the novel discovery of PD biomarkers will provide avenues to treat PD patients more effectively with few or no side effects.

  5. Nitric Oxide Dysregulation in Platelets from Patients with Advanced Huntington Disease

    PubMed Central

    Maglione, Vittorio; Damato, Antonio; Amico, Enrico; Formisano, Luigi; Vecchione, Carmine; Squitieri, Ferdinando

    2014-01-01

    Nitric oxide (NO) is a biologically active inorganic molecule involved in the regulation of many physiological processes, such as control of blood flow, platelet adhesion, endocrine function, neurotransmission and neuromodulation. In the present study, for the first time, we investigated the modulation of NO signaling in platelets of HD patients. We recruited 55 patients with manifest HD and 28 gender- and age-matched healthy controls. Our data demonstrated that NO-mediated vasorelaxation, when evoked by supernatant from insulin-stimulated HD platelets, gradually worsens along disease course. The defective vasorelaxation seems to stem from a faulty release of NO from platelets of HD patients and, it is associated with impairment of eNOS phosphorylation (Ser1177) and activity. This study provides important insights about NO metabolism in HD and raises the hypothesis that the decrease of NO in platelets of HD individuals could be a good tool for monitoring advanced stages of the disease. PMID:24587005

  6. Advances in imaging-genetic relationships for Alzheimer's disease: clinical implications.

    PubMed

    Bagnoli, Silvia; Piaceri, Irene; Sorbi, Sandro; Nacmias, Benedetta

    2014-01-01

    Alzheimer's disease (AD) is the most common cause of dementia and represents a major public health problem. From a clinical perspective, AD is devastating to patients and their families. The genetic approach to the study of dementia undoubtedly continues to provide a significant contribution to understanding the pathogenesis, diagnosis and therapeutic perspectives, but also raises important ethical implications. With advances in new technology, including genetics and PET/MRI scanning, the role of genetic studies and neuroimaging is being redefined as an aid in the clinical diagnosis of AD, and also in presymptomatic evaluation. Here, we review some of the issues related to the neuroimaging-genetic relationship in AD with a possible clinical implication as a preclinical biomarker for dementia and also for tracking disease progression.

  7. Cardioproteomics: advancing the discovery of signaling mechanisms involved in cardiovascular diseases

    PubMed Central

    Cui, Ziyou; Dewey, Shannamar; Gomes, Aldrin V

    2011-01-01

    Cardioproteomics (Cardiovascular proteomics) is fast becoming an indispensible technique in deciphering changes in signaling pathways that occur in cardiovascular diseases (CVDs). The quality and availability of the instruments and bioinformatics software used for cardioproteomics continues to improve, and these techniques are now available to most cardiovascular researchers either directly or indirectly via university core centers. The heart and aorta are specialized tissues which present unique challenges to investigate. Currently, the diverse range of proteomic techniques available for cardiovascular research makes the choice of the best method or best combination of methods for the disease parameter(s) being investigated as important as the equipment used. This review focuses on proteomic techniques and their applications which have advanced our understanding of the signaling mechanisms involved in CVDs at the levels of protein complex/protein-protein interaction, post-translational modifications and signaling induced protein changes. PMID:22254205

  8. Advances in Microfluidic PCR for Point-of-Care Infectious Disease Diagnostics

    PubMed Central

    Park, Seungkyung; Zhang, Yi; Lin, Shin; Wang, Tza-Huei; Yang, Samuel

    2011-01-01

    Global burdens from existing or emerging infectious diseases emphasize the need for point-of-care (POC) diagnostics to enhance timely recognition and intervention. Molecular approaches based on PCR methods have made significant inroads by improving detection time and accuracy but are still largely hampered by resource-intensive processing in centralized laboratories, thereby precluding their routine bedside- or field-use. Microfluidic technologies have enabled miniaturization of PCR processes onto a chip device with potential benefits including speed, cost, portability, throughput, and automation. In this review, we provide an overview of recent advances in microfluidic PCR technologies and discuss practical issues and perspectives related to implementing them into infectious disease diagnostics. PMID:21741465

  9. Advances with microRNAs in Parkinson’s disease research

    PubMed Central

    Ma, Liuqing; Wei, Liangming; Wu, Fei; Hu, Zhenhua; Liu, Zhenguo; Yuan, Weien

    2013-01-01

    Parkinson’s disease (PD) is the second-most common age-dependent neurodegenerative disorder and is caused by severe degeneration of dopaminergic neurons in the substantia nigra pars compacta. Unfortunately, current treatment only targets symptoms and involves dopamine replacement therapy, which does not counteract progressive degeneration. MicroRNAs (miRNAs) are a class of small RNA molecules implicated in post-transcriptional regulation of gene expression during development. Recent studies show that miRNAs are playing an important role in the pathophysiology of PD. miRNA-based therapy is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we focus on the recent advances of the use of miRNAs in the pathogenesis of PD. PMID:24109179

  10. Process Modeling Phase I Summary Report for the Advanced Gas Reactor Fuel Development and Qualification Program

    SciTech Connect

    Pannala, Sreekanth; Daw, C Stuart; Boyalakuntla, Dhanunjay S; FINNEY, Charles E A

    2006-09-01

    This report summarizes the results of preliminary work at Oak Ridge National Laboratory (ORNL) to demonstrate application of computational fluid dynamics modeling to the scale-up of a Fluidized Bed Chemical Vapor Deposition (FBCVD) process for nuclear fuels coating. Specifically, this work, referred to as Modeling Scale-Up Phase I, was conducted between January 1, 2006 and March 31, 2006 in support of the Advanced Gas Reactor (AGR) Program. The objective was to develop, demonstrate and "freeze" a version of ORNL's computational model of the TRI ISOtropic (TRISO) fuel-particle coating process that can be specifically used to assist coater scale-up activities as part of the production of AGR-2 fuel. The results in this report are intended to serve as input for making decisions about initiating additional FBCVD modeling work (referred to as Modeling Scale-Up Phase II) in support of AGR-2. The main computational tool used to implement the model is the general-purpose multiphase fluid-dynamics computer code known as MFIX (Multiphase Flow with Interphase eXchanges), which is documented in detail on the DOE-sponsored website http://www.mfix.org. Additional computational tools are also being developed by ORNL for post-processing MFIX output to efficiently summarize the important information generated by the coater simulations. The summarized information includes quantitative spatial and temporal measures (referred to as discriminating characteristics, or DCs) by which different coater designs and operating conditions can be compared and correlated with trends in product quality. The ORNL FBCVD modeling work is being conducted in conjunction with experimental coater studies at ORNL with natural uranium CO (NUCO) and surrogate fuel kernels. Data are also being obtained from ambient-temperature, spouted-bed characterization experiments at the University of Tennessee and theoretical studies of carbon and silicon carbide chemical vapor deposition kinetics at Iowa State

  11. A phase II study of laquinimod in Crohn's disease

    PubMed Central

    D'Haens, Geert; Sandborn, William J; Colombel, Jean Frederic; Rutgeerts, Paul; Brown, Kurt; Barkay, Hadas; Sakov, Anat; Haviv, Asi; Feagan, Brian G

    2015-01-01

    Objective Laquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD. Design Multicentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF). Results 117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses. Conclusions Laquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD. Trial registration number NCT00737932. PMID:25281416

  12. Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

    PubMed Central

    Mochiki, E; Ohno, T; Kamiyama, Y; Aihara, R; Haga, N; Ojima, H; Nakamura, J; Ohsawa, H; Nakabayashi, T; Takeuchi, K; Asao, T; Kuwano, H

    2006-01-01

    Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m−2 day−1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m−2 day−1. The dose was increased in a stepwise manner to 70 mg m−2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m−2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m−2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1–17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer. PMID:17133268

  13. [Management of coronary artery disease at the acute phase].

    PubMed

    Chatot, Marion; Schiele, François

    2015-03-01

    In patients with acute coronary syndrome (ACS), early management is of prime importance. However, the median time taken by the patient to call the emergency services is often very long, up to 2 hours. The presence of a physician as first responder ensures good quality resuscitation in case of cardiac arrest, and allows recording of a first ECG, which can be very informative, especially in ACS without ST segment elevation. Treatment at this stage is limited to sublingual nitroglycerin and aspirin. If the first ECG shows ST segment elevation, the patient should be immediately oriented for reperfusion, usually by percutaneous coronary intervention. in the absence of ST segment elevation, the diagnosis of ACS remains unconfirmed. This does not imply that the risk is lesser, but rather that the risk cannot be evaluated accurately in the pre-hospital setting. The use of risk scores can guide the choice of management towards an invasive strategy, including coronary angiography (immediately, or within 24-72 hours). Low-risk patients are candidates for an invasive strategy, provided non-invasive tests demonstrate the presence of ischemia. During the hospital phase, antiplatelet treatment should be initiated and must be adapted to the patient bleeding and thrombotic risk. Clopidogrel is recommended only in patients who are not amenable to prasugrel or ticagrelor. Statin therapy should be initiated from day one, regardless of the initial cholesterol level, preferably with 80 mg atorvastatin. Angiotensin-converting enzyme inhibitors and beta-blockers should also be prescribed to complete the medical prescription both in-hospital and in the long term.

  14. Utility advanced turbine systems (ATS) technology readiness testing -- Phase 3. Technical progress report, October 1--December 31, 1997

    SciTech Connect

    1997-12-31

    The overall objective of the Advanced Turbine System (ATS) Phase 3 Cooperative Agreement between GE and US Department of Energy (DOE) is the development of the GE 7H and 9H combined cycle power systems. The major effort will be expended on detail design. Validation of critical components and technologies will be performed including: hot gas path component testing, sub-scale compressor testing, steam purity test trials, and rotational heat transfer confirmation testing. Processes will be developed to support the manufacture of the first system, which was to have been sited and operated in Phase 4 but will now be sited and operated commercially by GE. This change has resulted from DOE`s request to GE for deletion of Phase 4 in favor of a restructured Phase 3 (as Phase 3R) to include full speed, no load (FSNL) testing of the 7H gas turbine. Technology enhancements that are not required for the first machine design but will be critical for future ATS advances in performance, reliability, and costs will be initiated. Long-term tests of materials to confirm design life predictions will continue. A schematic of the GE H machine is shown. This report summarizes work accomplished in 4Q97.

  15. Advanced glycation endproducts are increased in rheumatoid arthritis patients with controlled disease

    PubMed Central

    2011-01-01

    Introduction Advanced glycation end products (AGEs) are produced and can accumulate during chronic inflammation, as might be present in patients with rheumatoid arthritis (RA). AGEs are involved in the development of cardiovascular disease. The aim of this study is to evaluate whether AGEs are increased in patients with long-standing RA and whether AGE accumulation is related to disease activity, disease severity and measures of (premature) atherosclerosis, such as endothelial activation, endothelial dysfunction and intima media thickness (IMT). Methods In a cross-sectional study, 49 consecutive RA patients with longstanding disease (median disease duration of 12.3 years (range 9.3 to 15.1)), receiving standard of care, were included and compared with 49 age- and sex-matched healthy controls (HC). AGEs were determined by skin autofluorescence. Disease activity was evaluated by the Disease Activity Score of 28 joints (DAS-28) score and joint damage by modified Sharp-v.d. Heijde score. Endothelial activation (soluble vascular cellular adhesion molecule-1) sVCAM-1, von Willebrand factor (vWF), thrombomodulin), endothelial dysfunction (determined by small artery elasticity (SAE)) and IMT were measured and related to AGE accumulation. Results AGEs were increased in RA patients (median 2.4 arbitrary units (a.u.), range 1.6 to 4.2) compared to HC (2.2, 1.3 to 3.8). RA patients had a DAS-28 score of 2.9 (0.8 to 6.9) and a modified Sharp-v.d. Heijde score of 19 (0 to 103). sVCAM-1 and vWF levels were higher in RA patients. SAE was significantly decreased in RA (3.9 ml/mmHg (1.4 to 12.2) vs. 6.1 in HC (1.7 to 12.9). IMT did not differ between the two groups. Combining both groups' AGEs correlated with vWF, sVCAM-1 and IMT, and was inversely related to SAE. In RA, AGEs had an inverse relation with SAE, but did not relate to disease activity or radiological damage. In multivariate analysis for both groups, smoking, glucose levels, vWF, SAE and male gender were significantly

  16. Advanced extravehicular activity systems requirements definition study. Phase 2: Extravehicular activity at a lunar base

    NASA Technical Reports Server (NTRS)

    Neal, Valerie; Shields, Nicholas, Jr.; Carr, Gerald P.; Pogue, William; Schmitt, Harrison H.; Schulze, Arthur E.

    1988-01-01

    The focus is on Extravehicular Activity (EVA) systems requirements definition for an advanced space mission: remote-from-main base EVA on the Moon. The lunar environment, biomedical considerations, appropriate hardware design criteria, hardware and interface requirements, and key technical issues for advanced lunar EVA were examined. Six remote EVA scenarios (three nominal operations and three contingency situations) were developed in considerable detail.

  17. Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells

    PubMed Central

    Kawser Hossain, Mohammed; Abdal Dayem, Ahmed; Han, Jihae; Kumar Saha, Subbroto; Yang, Gwang-Mo; Choi, Hye Yeon; Cho, Ssang-Goo

    2016-01-01

    Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any cell type, including insulin-secreting pancreatic β cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic βcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs) are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic β cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies. PMID:26907255

  18. Recent Advances in Disease Modeling and Drug Discovery for Diabetes Mellitus Using Induced Pluripotent Stem Cells.

    PubMed

    Kawser Hossain, Mohammed; Abdal Dayem, Ahmed; Han, Jihae; Kumar Saha, Subbroto; Yang, Gwang-Mo; Choi, Hye Yeon; Cho, Ssang-Goo

    2016-02-19

    Diabetes mellitus (DM) is a widespread metabolic disease with a progressive incidence of morbidity and mortality worldwide. Despite extensive research, treatment options for diabetic patients remains limited. Although significant challenges remain, induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any cell type, including insulin-secreting pancreatic β cells, highlighting its potential as a treatment option for DM. Several iPSC lines have recently been derived from both diabetic and healthy donors. Using different reprogramming techniques, iPSCs were differentiated into insulin-secreting pancreatic βcells. Furthermore, diabetes patient-derived iPSCs (DiPSCs) are increasingly being used as a platform to perform cell-based drug screening in order to develop DiPSC-based cell therapies against DM. Toxicity and teratogenicity assays based on iPSC-derived cells can also provide additional information on safety before advancing drugs to clinical trials. In this review, we summarize recent advances in the development of techniques for differentiation of iPSCs or DiPSCs into insulin-secreting pancreatic β cells, their applications in drug screening, and their role in complementing and replacing animal testing in clinical use. Advances in iPSC technologies will provide new knowledge needed to develop patient-specific iPSC-based diabetic therapies.

  19. Utility of the advanced chronic kidney disease patient management tools: case studies.

    PubMed

    Patwardhan, Meenal B; Matchar, David B; Samsa, Gregory P; Haley, William E

    2008-01-01

    Appropriate management of advanced chronic kidney disease (CKD) delays or limits its progression. The Advanced CKD Patient Management Toolkit was developed using a process-improvement technique to assist patient management and address CKD-specific management issues. We pilot tested the toolkit in 2 community nephrology practices, assessed the utility of individual tools, and evaluated the impact on conformance to an advanced CKD guideline through patient chart abstraction. Tool use was distinct in the 2 sites and depended on the site champion's involvement, the extent of process reconfiguration demanded by a tool, and its perceived value. Baseline conformance varied across guideline recommendations (averaged 54%). Posttrial conformance increased in all clinical areas (averaged 59%). Valuable features of the toolkit in real-world settings were its ability to: facilitate tool selection, direct implementation efforts in response to a baseline performance audit, and allow selection of tool versions and customizing them. Our results suggest that systematically created, multifaceted, and customizable tools can promote guideline conformance.

  20. Inherited retinal diseases in dogs: advances in gene/mutation discovery.

    PubMed

    Miyadera, Keiko

    1. Inherited retinal diseases (RDs) are vision-threatening conditions affecting humans as well as many domestic animals. Through many years of clinical studies of the domestic dog population, a wide array of RDs has been phenotypically characterized. Extensive effort to map the causative gene and to identify the underlying mutation followed. Through candidate gene, linkage analysis, genome-wide association studies, and more recently, by means of next-generation sequencing, as many as 31 mutations in 24 genes have been identified as the underlying cause for canine RDs. Most of these genes have been associated with human RDs providing opportunities to study their roles in the disease pathogenesis and in normal visual function. The canine model has also contributed in developing new treatments such as gene therapy which has been clinically applied to human patients. Meanwhile, with increasing knowledge of the molecular architecture of RDs in different subpopulations of dogs, the conventional understanding of RDs as a simple monogenic disease is beginning to change. Emerging evidence of modifiers that alters the disease outcome is complicating the interpretation of DNA tests. In this review, advances in the gene/mutation discovery approaches and the emerging genetic complexity of canine RDs are discussed.

  1. Inherited retinal diseases in dogs: advances in gene/mutation discovery

    PubMed Central

    Miyadera, Keiko

    2015-01-01

    1. Inherited retinal diseases (RDs) are vision-threatening conditions affecting humans as well as many domestic animals. Through many years of clinical studies of the domestic dog population, a wide array of RDs has been phenotypically characterized. Extensive effort to map the causative gene and to identify the underlying mutation followed. Through candidate gene, linkage analysis, genome-wide association studies, and more recently, by means of next-generation sequencing, as many as 31 mutations in 24 genes have been identified as the underlying cause for canine RDs. Most of these genes have been associated with human RDs providing opportunities to study their roles in the disease pathogenesis and in normal visual function. The canine model has also contributed in developing new treatments such as gene therapy which has been clinically applied to human patients. Meanwhile, with increasing knowledge of the molecular architecture of RDs in different subpopulations of dogs, the conventional understanding of RDs as a simple monogenic disease is beginning to change. Emerging evidence of modifiers that alters the disease outcome is complicating the interpretation of DNA tests. In this review, advances in the gene/mutation discovery approaches and the emerging genetic complexity of canine RDs are discussed. PMID:26120276

  2. Recent Advances in Nucleic Acid-Based Delivery: From Bench to Clinical Trials in Genetic Diseases.

    PubMed

    Oliveira, Cláudia; Ribeiro, António J; Veiga, Francisco; Silveira, Isabel

    2016-05-01

    Delivery of nucleic acids is the most promising therapy for many diseases that remain untreatable. Therefore, many research efforts have been put on finding a safe and efficient delivery system able to provide a sustained response. Viral vectors have proved to be the most efficient for delivery of nucleic acids and, thus, stand as the foremost vector used in current clinical trials. However, safety issues arise as a main concern and mitigate their use, impelling the improvement of non-viral alternatives. This review focuses on the recent advances in pre-clinical development of non-viral polyplexes and lipoplexes for nucleic acid-based delivery, in contrast with vectors being used in present clinical trials. Nucleic acid vectors for neurodegenerative ataxias, Parkinson's disease, retinitis pigmentosa, cystic fibrosis, hemophilia, pancreatic and lung cancer, and rheumatoid arthritis are discussed to illustrate current state of pre-clinical and clinical studies. Thereby, denoting the prospects for treatment of genetic diseases and elucidating the trend in non-viral vector development and improvement which is expected to significantly increase disease rescue exceeding the modest clinical successes observed so far.

  3. Recent advances in the application of metabolomics to Alzheimer’s Disease

    PubMed Central

    Trushina, Eugenia; Mielke, Michelle M.

    2013-01-01

    The pathophysiological changes associated with Alzheimer’s Disease (AD) begin decades before the emergence of clinical symptoms. Understanding the early mechanisms associated with AD pathology is, therefore, especially important for identifying disease-modifying therapeutic targets. While the majority of AD clinical trials to date have focused on anti-amyloid-beta (Aβ) treatments, other therapeutic approaches may be necessary. The ability to monitor changes in cellular networks that include both Aβ and non-Aβ pathways is essential to advance our understanding of the etiopathogenesis of AD and subsequent development of cognitive symptoms and dementia. Metabolomics is a powerful tool that detects perturbations in the metabolome, a pool of metabolites that reflects changes downstream of genomic, transcriptomic and proteomic fluctuations, and represents an accurate biochemical profile of the organism in health and disease. The application of metabolomics could help to identify biomarkers for early AD diagnosis, to discover novel therapeutic targets, and to monitor therapeutic response and disease progression. Moreover, given the considerable parallel between mouse and human metabolism, the use of metabolomics provides ready translation of animal research into human studies for accelerated drug design. In this review, we will summarize current progress in the application of metabolomics in both animal models and in humans to further understanding of the mechanisms involved in AD pathogenesis. PMID:23816564

  4. Advances in the Evaluation of Respiratory Pathophysiology during Exercise in Chronic Lung Diseases

    PubMed Central

    O'Donnell, Denis E.; Elbehairy, Amany F.; Berton, Danilo C.; Domnik, Nicolle J.; Neder, J. Alberto

    2017-01-01

    Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple “non-invasive” assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions. PMID:28275353

  5. Phase 1 study of intravenous rigosertib (ON 01910.Na), a novel benzyl styryl sulfone structure producing G2/M arrest and apoptosis, in adult patients with advanced cancer

    PubMed Central

    Ohnuma, Takao; Lehrer, Deborah; Ren, Chen; Cho, Sool Yeon; Maniar, Manoj; Silverman, Lewis; Sung, Max; Gretz, Herbert F; Benisovich, Vladimir; Navada, Shyamala; Akahoho, Eugene; Wilck, Eric; Taft, David R; Roboz, John; Wilhelm, Francois; Holland, James F

    2013-01-01

    Rigosertib (ON 01910.Na), a synthetic novel benzyl styryl sulfone, was administered to 28 patients with advanced cancer in a Phase I trial in order to characterize its pharmacokinetic profile, determine the dose-limiting toxicities (DLT), define the recommended phase II dose (RPTD) and to document any antitumor activity. Patients with advanced malignant neoplasms refractory to standard therapy were given escalating doses of rigosertib (50, 100, 150, 250, 325, 400, 650, 850, 1,050, 1,375, 1,700 mg/m2/24h) as a 3-day continuous infusion (CI) every 2 weeks. An accelerated Fibonacci titration schedule with specified decreases for toxicities was used for escalation until grade ≥2 toxicity occurred. Intrapatient dose escalation was allowed if toxicity was grade ≤2 and the disease remained stable. Plasma pharmacokinetics (PK) and urinary PK assessments were studied in the 1st and 4th cycles. Twenty-nine patients (12 men and 17 women; age 36-87 y with a median of 63 y) were registered, but one died before study drug was given. Twenty-eight patients received a median of 3 cycles of therapy. Most common grade ≥2 toxicities attributable to rigosertib included fatigue, anorexia, vomiting and constipation. DLTs included muscular weakness, hyponatremia, neutropenia, delirium and confusional state. Risk factors for severe toxicities include pre-existing neurological dysfunction or advanced gynecologic cancer after pelvic surgery. Rigosertib pharmacokinetics showed rapid plasma distribution phases and urinary excretion. Elevations in plasma Cmax and AUC due to decreases in plasma clearance were associated with acute grade ≥3 toxicities. Of 22 evaluable patients, 9 (41%) achieved a best overall response of stable disease; all other patients (n=13; 59%) progressed. The median progression-free survival time was 50 days (95% confidence interval [CI]: 37-80 days). Nine (41%) patients survived for over 1 y. In summary, prolonged IV infusions of rigosertib were generally well

  6. Dietary advanced glycation end products and their role in health and disease.

    PubMed

    Uribarri, Jaime; del Castillo, María Dolores; de la Maza, María Pía; Filip, Rosana; Gugliucci, Alejandro; Luevano-Contreras, Claudia; Macías-Cervantes, Maciste H; Markowicz Bastos, Deborah H; Medrano, Alejandra; Menini, Teresita; Portero-Otin, Manuel; Rojas, Armando; Sampaio, Geni Rodrigues; Wrobel, Kazimierz; Wrobel, Katarzyna; Garay-Sevilla, Ma Eugenia

    2015-07-01

    Over the past 2 decades there has been increasing evidence supporting an important contribution from food-derived advanced glycation end products (AGEs) to the body pool of AGEs and therefore increased oxidative stress and inflammation, processes that play a major role in the causation of chronic diseases. A 3-d symposium (1st Latin American Symposium of AGEs) to discuss this subject took place in Guanajuato, Mexico, on 1-3 October 2014 with the participation of researchers from several countries. This review is a summary of the different presentations and subjects discussed, and it is divided into 4 sections. The first section deals with current general knowledge about AGEs. The second section dwells on mechanisms of action of AGEs, with special emphasis on the receptor for advanced glycation end products and the potential role of AGEs in neurodegenerative diseases. The third section discusses different approaches to decrease the AGE burden. The last section discusses current methodologic problems with measurement of AGEs in different samples. The subject under discussion is complex and extensive and cannot be completely covered in a short review. Therefore, some areas of interest have been left out because of space. However, we hope this review illustrates currently known facts about dietary AGEs as well as pointing out areas that require further research.

  7. Long-term clinical results and MRI changes after tendon ball arthroplasty for advanced Kienbock's disease.

    PubMed

    Mariconda, M; Soscia, E; Sirignano, C; Smeraglia, F; Soldati, A; Balato, G

    2013-06-01

    The purpose of this study was to assess the long-term clinical results and morphological changes after tendon ball arthroplasty for advanced Kienböck's disease. Twenty-six patients were reviewed, with a mean follow-up interval of 125 months (range 50-226). At follow-up, mean score on the Disabilities of the Arm, Shoulder, and Hand questionnaire was 7.7 and mean visual analogue scale score for pain was 1. Mean carpal height ratio was significantly reduced with respect to the pre-operative value. On magnetic resonance imaging scans, cartilage damage, synovitis, and erosive or oedematous changes in the bones were detected in most patients. Calcification in the defect filled by the tendon ball was seen in all patients. Narrowing of the radioscaphoid joint and the presence of intercarpal synovitis were negatively associated with clinical outcome. Tendon ball arthroplasty in advanced Kienböck's disease results in long-term satisfactory clinical outcomes, despite widespread changes in the bones and joints within the wrist.

  8. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2007.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2008-06-01

    This review highlights some of the research advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects that were reported primarily in the Journal in 2007. Advances in diagnosis include possible biomarkers for anaphylaxis, improved understanding of the relevance of food-specific serum IgE tests, identification of possibly discriminatory T-cell responses for drug allergy, and an elucidation of irritant responses for vaccine allergy diagnostic skin tests. Mechanistic studies are discerning T-cell and cytokine responses central to eosinophilic gastroenteropathies and food allergy, including the identification of multiple potential therapeutic targets. Regarding treatment, clinical studies of oral immunotherapy and allergen vaccination strategies show promise, whereas several clinical studies raise questions about whether oral allergen avoidance reduces atopic risks and whether probiotics can prevent or treat atopic disease. The importance of skin barrier dysfunction has been highlighted in the pathogenesis of atopic dermatitis (AD), particularly as it relates to allergen sensitization and eczema severity. Research has also continued to identify immunologic defects that contribute to the propensity of patients with AD to have viral and bacterial infections. New therapeutic approaches to AD, urticaria, and angioedema have been reported, including use of sublingual immunotherapy, anti-IgE, and a kallikrein inhibitor.

  9. Recent advances in managing chronic HCV infection: focus on therapy in patients with severe liver disease

    PubMed Central

    Maan, Raoel; van der Meer, Adriaan J.

    2016-01-01

    Chronic hepatitis C virus (HCV) infection still represents a major public health problem, as it is thought to be responsible for more than 350,000 deaths around the globe on a yearly basis. Fortunately, successful eradication of the virus has been associated with improved clinical outcome and reduced mortality rates. In the past few years, treatment has improved considerably by the implementation of direct-acting antivirals (DAAs). From 2014 onwards, sofosbuvir, simeprevir, daclatasvir, ledipasvir, paritaprevir, ombitasvir, and dasabuvir have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Regimens with various combinations of these new drugs, without the use of interferon (IFN), proved to be very effective and well tolerated, even among patients with advanced liver disease. Moreover, treatment duration could be shortened to 12 weeks in the majority of patients. The high costs of these DAAs, however, limit the availability of IFN-free therapy worldwide. Even in wealthy countries, it is deemed necessary to prioritize DAA treatment in order to limit the immediate impact on the health budget. As patients with advanced liver disease are in most need of HCV clearance, many countries decided to treat those patients first. In the current review, we focus on the currently available IFN-free treatment options for patients with cirrhosis. We discuss the virological efficacy as well as the clinical relevance of these regimens among this specific patient population. PMID:27006761

  10. Proteinuria as a Therapeutic Target in Advanced Chronic Kidney Disease: a Retrospective Multicenter Cohort Study

    PubMed Central

    Chen, Chang-Hsu; Wu, Hon-Yen; Wang, Chieh-Li; Yang, Feng-Jung; Wu, Pei-Chen; Hung, Szu-Chun; Kan, Wei-Chih; Yang, Chung-Wei; Chiang, Chih-Kang; Huang, Jenq-Wen; Hung, Kuan-Yu

    2016-01-01

    Current evidence of proteinuria reduction as a surrogate target in advanced chronic kidney disease (CKD) is incomplete due to lack of patient-pooled database. We retrospectively studied a multicenter cohort of 1891 patients who were enrolled in the nationwide multidisciplinary pre-end stage renal disease care program with a baseline glomerular filtration rate (GFR) <45 mL/min/1.73 m2 and followed longitudinally to investigate the effect of the change in proteinuria on renal death (defined as composite of dialysis and death occurring before initiation of dialysis). The group with a change in proteinuria ≤0.30 g/g (n = 1261) had lower cumulative probabilities of renal death (p < 0.001). In a linear regression model, a higher baseline proteinuria and a greater increase in proteinuria were associated with faster annual GFR decline. Cox’s analysis showed that every 1 unit increase in natural log(baseline proteinuria, 10 g/g) and every 0.1 g/g increase in the change in proteinuria resulted in 67% (HR = 1.67, 95% CI: 1.46–1.91) and 1% (HR = 1.01, 95% CI: 1.01–1.01) greater risk of renal death respectively after adjusting for the effects of the other covariates. Our study provided a patient-based evidence to support proteinuria as a therapeutic target in advanced CKD. PMID:27198863

  11. Dietary Advanced Glycation End Products and Their Role in Health and Disease12

    PubMed Central

    Uribarri, Jaime; del Castillo, María Dolores; de la Maza, María Pía; Filip, Rosana; Gugliucci, Alejandro; Luevano-Contreras, Claudia; Macías-Cervantes, Maciste H; Markowicz Bastos, Deborah H; Medrano, Alejandra; Menini, Teresita; Portero-Otin, Manuel; Rojas, Armando; Sampaio, Geni Rodrigues; Wrobel, Kazimierz; Wrobel, Katarzyna; Garay-Sevilla, Ma Eugenia

    2015-01-01

    Over the past 2 decades there has been increasing evidence supporting an important contribution from food-derived advanced glycation end products (AGEs) to the body pool of AGEs and therefore increased oxidative stress and inflammation, processes that play a major role in the causation of chronic diseases. A 3-d symposium (1st Latin American Symposium of AGEs) to discuss this subject took place in Guanajuato, Mexico, on 1–3 October 2014 with the participation of researchers from several countries. This review is a summary of the different presentations and subjects discussed, and it is divided into 4 sections. The first section deals with current general knowledge about AGEs. The second section dwells on mechanisms of action of AGEs, with special emphasis on the receptor for advanced glycation end products and the potential role of AGEs in neurodegenerative diseases. The third section discusses different approaches to decrease the AGE burden. The last section discusses current methodologic problems with measurement of AGEs in different samples. The subject under discussion is complex and extensive and cannot be completely covered in a short review. Therefore, some areas of interest have been left out because of space. However, we hope this review illustrates currently known facts about dietary AGEs as well as pointing out areas that require further research. PMID:26178030

  12. Recent advances in understanding and preventing human papillomavirus-related disease

    PubMed Central

    Hellner, Karin; Dorrell, Lucy

    2017-01-01

    High-risk human papillomaviruses (hrHPV) are responsible for anogenital and oropharyngeal cancers, which together account for at least 5% of cancers worldwide. Industrialised nations have benefitted from highly effective screening for the prevention of cervical cancer in recent decades, yet this vital intervention remains inaccessible to millions of women in low- and middle-income countries (LMICs), who bear the greatest burden of HPV disease. While there is an urgent need to increase investment in basic health infrastructure and rollout of prophylactic vaccination, there are now unprecedented opportunities to exploit recent scientific and technological advances in screening and treatment of pre-invasive hrHPV lesions and to adapt them for delivery at scale in resource-limited settings. In addition, non-surgical approaches to the treatment of cervical intraepithelial neoplasia and other hrHPV lesions are showing encouraging results in clinical trials of therapeutic vaccines and antiviral agents. Finally, the use of next-generation sequencing to characterise the vaginal microbial environment is beginning to shed light on host factors that may influence the natural history of HPV infections. In this article, we focus on recent advances in these areas and discuss their potential for impact on HPV disease. PMID:28357043

  13. Advancing research with Alzheimer disease subjects: investigators' perceptions and ethical issues.

    PubMed

    High, D M

    1993-01-01

    Advancement of Alzheimer disease (AD) research will not only depend on increased participation of patients with AD as subjects, but researchers will likely face increasingly difficult ethical issues. Presented are the results of a survey of researchers at the 15 federally funded Alzheimer Disease Research Centers concerning the ethical issues for subjects with AD participating in research. Experiences from 99 projects are assessed. Major findings include a significant lack of uniformity on the assessment of competency of subjects to consent to research, proxy informed consent overwhelmingly provided informally by family members, no wide use of durable powers of attorney and guardians, perception by the investigators that most projects present only minimal risks to the subjects, and Institutional Review Boards not being viewed by the investigators as preventing or inhibiting the advancement of AD research. It is recommended that research is needed to develop greater clarity in assessment of capacity of subjects to provide informed consent, that ethical and legal empowerment of family members to provide proxy consent be sustained, and that the issue of risk/benefit ratios for AD participants in research be reevaluated in the light of potentially greater risks to subjects.

  14. Phase contrast medical imaging with compact X-ray sources at the Munich-Centre for Advance Photonics (MAP)

    NASA Astrophysics Data System (ADS)

    Coan, P.; Gruener, F.; Glaser, C.; Schneider, T.; Bravin, A.; Reiser, M.; Habs, D.

    2009-09-01

    In this paper, the excellence cluster "Munich-Centre for Advance Photonics" (MAP) is presented. One of the aims of the project is the development of innovative X-ray-based diagnostics imaging techniques to be implemented at an ultra-compact high-energy and high-brilliance X-ray source. The basis of the project and the developments towards the clinical application of phase contrast imaging applied to mammography and cartilage studies will be presented and discussed.

  15. Advanced Life Support Water Recycling Technologies Case Studies: Vapor Phase Catalytic Ammonia Removal and Direct Osmotic Concentration

    NASA Technical Reports Server (NTRS)

    Flynn, Michael

    2004-01-01

    Design for microgravity has traditionally not been well integrated early on into the development of advanced life support (ALS) technologies. NASA currently has a many ALS technologies that are currently being developed to high technology readiness levels but have not been formally evaluated for microgravity compatibility. Two examples of such technologies are the Vapor Phase Catalytic Ammonia Removal Technology and the Direct Osmotic Concentration Technology. This presentation will cover the design of theses two systems and will identify potential microgravity issues.

  16. Safety and Efficacy in Advanced Solid Tumors of a Targeted Nanocomplex Carrying the p53 Gene Used in Combination with Docetaxel: A Phase 1b Study.

    PubMed

    Pirollo, Kathleen F; Nemunaitis, John; Leung, Po Ki; Nunan, Robert; Adams, Jana; Chang, Esther H

    2016-09-01

    Loss of p53 suppressor function, through mutations or inactivation of the p53 pathway, occurs in most human cancers. SGT-53 is a liposomal nanocomplex designed for systemic, tumor-targeting delivery of the wt p53 gene. In this nanodelivery system, an anti-transferrin receptor single-chain antibody fragment serves as the targeting moiety. In an initial phase 1 trial in patients with advanced solid tumors, SGT-53 demonstrated tumor-specific targeting, was shown to be well tolerated, and was associated with an antitumor effect in several patients. Our preclinical studies have also demonstrated enhanced antitumor activity with the combination of SGT-53 and docetaxel. Thus, this dose-escalation trial was undertaken to assess the combination of SGT-53 and docetaxel for safety and potential efficacy in 14 advanced cancer patients. Results reveal that the combination of SGT-53 (maximum dose, 3.6 mg DNA/infusion) and docetaxel (75 mg/m(2)/infusion) was well tolerated. Moreover, clinical activity involving 12 evaluable patients was observed. Three of these patients achieved RECIST-verified partial responses with tumor reductions of -47%, -51%, and -79%. Two others had stable disease with significant shrinkage (-25% and -16%). These results support phase 2 testing of SGT-53 in combination with docetaxel.

  17. Phase 2 Study of Combined Sorafenib and Radiation Therapy in Patients With Advanced Hepatocellular Carcinoma

    SciTech Connect

    Chen, Shang-Wen; Lin, Li-Ching; Kuo, Yu-Cheng; Liang, Ji-An; Kuo, Chia-Chun; Chiou, Jeng-Fong

    2014-04-01

    Purpose: This phase 2 study evaluated the efficacy of radiation therapy (RT) with concurrent and sequential sorafenib therapy in patients with unresectable hepatocellular carcinoma (HCC). Methods and Materials: Forty patients with unresectable HCC unfit for transarterial chemoembolization were treated with RT with concurrent and sequential sorafenib. Sorafenib was administered from the commencement of RT at a dose of 400 mg twice daily and continued to clinical or radiologic progression, unacceptable adverse events, or death. All patients had underlying Child-Pugh A cirrhosis. The maximal tumor diameter ranged from 3.0 cm to 15.5 cm. Coexisting portal vein thrombosis was found in 24 patients and was irradiated simultaneously. The cumulative RT dose ranged from 40 Gy to 60 Gy (median, 50 Gy). Image studies were done 1 month after RT and then every 3 months thereafter. Results: Thirty-three (83%) completed the allocated RT. During RT, the incidence of hand-foot skin reactions ≥ grade 2 and diarrhea were 37.5% and 25%, respectively, and 35% of patients had hepatic toxicities grade ≥2. Twenty-two (55.0%) patients achieved complete or partial remission at the initial assessment, and 18 (45%) had stable or progressive disease. The 2-year overall survival and infield progression-free survival (IFPS) were 32% and 39%, respectively. A Cancer of the Liver Italian Program (CLIP) score ≥2 was associated with an inferior outcome in overall survival. Six patients (15%) developed treatment-related hepatic toxicity grade ≥3 during the sequential phase, and 3 of them were fatal. Conclusions: When RT and sorafenib therapy were combined in patients with unresectable HCC, the initial complete or partial response rate was 55% with a 2-year IFPS of 39%. A CLIP score ≥2 was associated with an inferior outcome in overall survival. Hepatic toxicities are a major determinant of the safety; the combination should be used with caution and needs further investigation.

  18. Advanced, phase-locked, 100 kW, 1.3 GHz magnetron

    NASA Astrophysics Data System (ADS)

    Read, Michael; Ives, R. Lawrence; Bui, Thuc; Pasquinelli, Ralph; Chase, Brian; Walker, Chris; Conant, Jeff

    2017-03-01

    Calabazas Creek Research, Inc., in collaboration with Fermilab and Communications & Power Industries, LLC, is developing a phase-locked, 100 kW peak, 10 kW average power magnetron-based RF system for driving accelerators. Phase locking will be achieved using an approach originating at Fermilab that includes control of both amplitude and phase on a fast time scale.

  19. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2009.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2010-01-01

    This review highlights some of the research advances in anaphylaxis and hypersensitivity reactions to foods, drugs, and insects, as well as advances in allergic skin disease that were reported in the Journal in 2009. Among key epidemiologic observations, several westernized countries report that more than 1% of children have peanut allergy, and there is some evidence that environmental exposure to peanut is a risk factor. The role of regulatory T cells, complement, platelet-activating factor, and effector cells in the development and expression of food allergy were explored in several murine models and human studies. Delayed anaphylaxis to mammalian meats appears to be related to IgE binding to the carbohydrate moiety galactose-alpha-1,3-galactose, which also has implications for hypersensitivity to murine mAb therapeutics containing this oligosaccharide. Oral immunotherapy studies continue to show promise for the treatment of food allergy, but determining whether the treatment causes tolerance (cure) or temporary desensitization remains to be explored. Increased baseline serum tryptase levels might inform the risk of venom anaphylaxis and might indicate a risk for mast cell disorders in persons who have experienced such episodes. Reduced structural and immune barrier function contribute to local and systemic allergen sensitization in patients with atopic dermatitis, as well as increased propensity of skin infections in these patients. The use of increased doses of nonsedating antihistamines and potential usefulness of omalizumab for chronic urticaria was highlighted. These exciting advances reported in the Journal can improve patient care today and provide insights on how we can improve the diagnosis and treatment of these allergic diseases in the future.

  20. The role of the Istituto Superiore di Sanità as the competent authority for Phase I trials in the translation of advanced therapies.

    PubMed

    Popoli, Patrizia; Cometa, Maria Francesca; Fabi, Fulvia; Meneguz, Annarita

    2011-01-01

    Advanced therapy medicinal products (ATMP) can offer new, effective therapeutic options for the treatment of severe illnesses, including cancer, neurodegenerative and cardiovascular diseases. Translation of advanced therapies to the clinic has been slow despite significant academic research from academia and foundations. The implementation of 2001/20 Directive in Italy established that the development of an ATMP should follow the GXP rules - good manufacturing practice (GMP) for production, good laboratory practice (GLP) for non clinical safety studies and good clinical practice (GCP) for clinical trials. The high costs of GCP application and the needs for GMP facilities are perceived as the most important bottlenecks for the development of ATMP. Here it is pointed out that a strategic cooperation between different actors (academia, industry and experts in regulatory issues) is strongly needed. In particular, it is highlighted that the Istituto Superiore di Sanità, as the competent authority for the authorization of Phase I clinical trials, has a specific responsibility in fostering the translation of safe and effective therapies for human diseases.

  1. Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

    PubMed

    Stuurman, F E; Voest, E E; Awada, A; Witteveen, P O; Bergeland, T; Hals, P-A; Rasch, W; Schellens, J H M; Hendlisz, A

    2013-08-01

    CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

  2. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review.

    PubMed

    de la Morena, M Teresa; Nelson, Robert P

    2014-04-01

    Hematopoietic cell transplantation (HCT) is a curative therapeutic option for severe combined immunodeficiency (SCID), a group of diseases which otherwise carry life expectancies that are of limited duration and quality. Survival following HCT for SCID has improved from approximately 23 to 91 % over the last 40 years. Success with SCID prompted efforts to apply HCT to the therapeutic challenge of well over 20 molecularly defined primary immune deficiency diseases (PID). Such success is due to both early recognition of PIDs and advances in the field of transplantation. Such advances include high-resolution HLA DNA donor-recipient matching, expansion of donor sources, better tolerated conditioning, new antibiotics, and wider availability. International collaborative efforts have provided patients and caregivers information that permit better treatment decisions now, and direct clinicians and investigators to ensure progress in the future. Pioneers in screening for SCID have taken steps to correct the fundamental challenge to successful treatment, which is the rapid discovery and characterization of cases and offering the transplant option to an affected child early in life; blood spot testing for T and B cell receptor quantification is now available to a growing fraction of newborns. Organizations including the Primary Immune Deficiency Treatment Consortium in the USA, The European Society for Primary Immunodeficiency, the European Group for Blood and Marrow Transplantation, the Pediatric Blood and Marrow Transplant Consortium, the United States Immunodeficiency Network, the Immune Deficiency Foundation, and the Jeffrey Modell Foundation are contributing mightily to increase awareness and standardize optimal utilization to the benefit of patients. This review will update the allergist-immunologist concerning disease presentations, indications for transplantation, methodologies, conditioning regimens, and clinical outcomes for patients with PID for which timely HCT is

  3. Phase advance of circadian rhythms in Smith-Magenis syndrome: a case study in an adult man.

    PubMed

    Kocher, Laurence; Brun, Jocelyne; Devillard, Françoise; Azabou, Eric; Claustrat, Bruno

    2015-01-12

    Melatonin secretion is usually increased during the daytime and decreased at night in Smith-Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24h profiles of core temperature, sleep-wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin.

  4. Industrialization study, phase 2. [assessment of advanced photovoltaic technologies for commerical development

    NASA Technical Reports Server (NTRS)

    1979-01-01

    The potentials and requirements of advanced photovoltaic technologies still in their early developmental stages were evaluated and compared to the present day single crystal silicon wafer technology and to each other. The major areas of consideration include polycrystalline and amorphous silicon, single crystal and polycrystalline gallium arsenide, and single crystal and polycrystalline cadmium sulfide. A rank ordering of the advanced technologies is provided. The various ranking schemes were based upon present-day efficiency levels, their stability and long-term reliability prospects, material availability, capital investments both at the laboratory and production level, and associated variable costs. An estimate of the timing of the possible readiness of these advanced technologies for technology development programs and industrialization is presented along with a set of recommended government actions concerning the various advanced technologies.

  5. Life prediction methodology for ceramic components of advanced heat engines. Phase 1: Volume 1, Final report

    SciTech Connect

    Cuccio, J.C.; Brehm, P.; Fang, H.T.

    1995-03-01

    Emphasis of this program is to develop and demonstrate ceramics life prediction methods, including fast fracture, stress rupture, creep, oxidation, and nondestructive evaluation. Significant advancements were made in these methods and their predictive capabilities successfully demonstrated.

  6. Results of two different surgical techniques in the treatment of advanced-stage Freiberg's disease

    PubMed Central

    Özkul, Emin; Gem, Mehmet; Alemdar, Celil; Arslan, Hüseyin; Boğatekin, Ferit; Kişin, Bülent

    2016-01-01

    Background: Freiberg's disease is an osteochondrosis most commonly seen in adolescent women and characterized by pain, swelling and motion restriction in the second metatarsal. The early stages of this disease can be managed with semirigid orthoses, metatarsal bars and short leg walking cast. Number of operative methods are suggested which can be used depending on the pathophysiology of the disease, including abnormal biomechanics, joint congruence and degenerative process. We evaluated the outcomes of the patients with Freiberg's disease who were treated with dorsal closing-wedge osteotomy and resection of the metatarsal head. Patients and Methods: 16 patients (11 female, 5 male) with a mean age of 24.5 (range 13–49 years) years who underwent dorsal closing wedge osteotomy or resection of the metatarsal head were included in this retrospective study. Second metatarsal was affected in 13 and third metatarsal in three patients. According to the Smillie's classification system, ten patients had type IV osteonecrosis and six patients had type V. The results of the patients were evaluated using the lesser metatarsophalangeal-interphalangeal (LMPI) scale. Results: According to the LMPI scale, the postoperative scores for the osteotomy and excision groups were 86 (range 64–100) and 72.6 (range 60–85), respectively. In the osteotomy group, mean passive flexion restriction was 18° (range 0°–35°) and mean passive extension restriction was 12° (range 0°–25°). Mean metatarsal shortening was 2.2 mm (range 2–4 mm) in the osteotomy group as opposed to 9.8 mm (range 7–14 mm) in the excision group. Significant pain relief was obtained in both groups following the surgery. Conclusions: The decision of performing osteotomy or resection arthroplasty in the patients with advanced-stage Freiberg's disease should be based on the joint injury and the patients should be informed about the cosmetic problems like shortening which may arise from resection. PMID:26955180

  7. Aircrew Training Devices: Utility and Utilization of Advanced Instructional Features. Phase 4. Summary Report.

    DTIC Science & Technology

    1987-11-01

    the automated instructional system on the Advanced Simulator for Pilot Training ( ASPT ) at Williams AF8, Arizona (Faconti & Epps, 1975; Faconti...Nortimer, & Simpson, 1970; Fuller, Waag, & Martin, 1980; Knoop, 1973). The ASPT is a sophisticated research device that incorporates advanced visual and...potential of the ASPT , Gray, Chun, Warner, and Eubanks (1981) found that SIs tended to use the device in a fairly conventional manner. with few

  8. Concomitant Chemoradiotherapy With Mitomycin C and Cisplatin in Advanced Unresectable Carcinoma of the Head and Neck: Phase I-II Clinical Study

    SciTech Connect

    Strojan, Primoz Karner, Katarina; Smid, Lojze; Soba, Erika; Fajdiga, Igor; Jancar, Boris; Anicin, Aleksandar; Budihna, Marjan; Zakotnik, Branko

    2008-10-01

    Purpose: To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. Patients and Methods: Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m{sup 2} IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m{sup 2}/d IV, applied during the last 10 fractions of irradiation ('chemoboost'). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m{sup 2}/d up to the maximum tolerated dose (MTD) or at the most 14 mg/m{sup 2}/d (Phase I study), which was tested in the subsequent Phase II study. Results: All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m{sup 2}/d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m{sup 2}/d, the corresponding rates were 40%, 20%, and 22%, respectively. Conclusion: Concomitant chemoradiotherapy with mitomycin C and cisplatin 'chemoboost' at 14 mg/m{sup 2}/d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

  9. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications.

    PubMed

    Ponziani, Francesca Romana; Gerardi, Viviana; Pecere, Silvia; D'Aversa, Francesca; Lopetuso, Loris; Zocco, Maria Assunta; Pompili, Maurizio; Gasbarrini, Antonio

    2015-11-21

    Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint", characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.

  10. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications

    PubMed Central

    Ponziani, Francesca Romana; Gerardi, Viviana; Pecere, Silvia; D’Aversa, Francesca; Lopetuso, Loris; Zocco, Maria Assunta; Pompili, Maurizio; Gasbarrini, Antonio

    2015-01-01

    Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial “fingerprint”, characterized by the reduced ratio of “good” to “potentially pathogenic” bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease. PMID:26604640

  11. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2012.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2013-01-01

    This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2012. Studies support an increase in peanut allergy prevalence in children and exposure to the antibacterial agent triclosan and having filaggrin (FLG) loss-of-function mutations as risk factors for food sensitization. The role of specific foods in causing eosinophilic esophagitis is elucidated by several studies, and microRNA analysis is identified as a possible noninvasive disease biomarker. Studies on food allergy diagnosis emphasize the utility of component testing and the possibility of improved diagnosis through stepped approaches, epitope-binding analysis, and bioinformatics. Treatment studies of food allergy show promise for oral immunotherapy, but tolerance induction remains elusive, and additional therapies are under study. Studies on anaphylaxis suggest an important role for platelet-activating factor and its relationship to the need for prompt treatment with epinephrine. Insights on the pathophysiology and diagnosis of non-IgE-mediated drug allergy are offered, with novel data regarding the interaction of drugs with HLA molecules. Numerous studies support influenza vaccination of persons with egg allergy using modest precautions. Evidence continues to mount that there is cross-talk between skin barrier defects and immune responses in patients with atopic dermatitis. Augmentation of the skin barrier with reduction in skin inflammatory responses will likely lead to the most effective intervention in patients with this common skin disease.

  12. Recent advances in understanding the role of lamins in health and disease

    PubMed Central

    Reddy, Sita; Comai, Lucio

    2016-01-01

    Lamins are major components of the nuclear lamina, a network of proteins that supports the nuclear envelope in metazoan cells. Over the past decade, biochemical studies have provided support for the view that lamins are not passive bystanders providing mechanical stability to the nucleus but play an active role in the organization of the genome and the function of fundamental nuclear processes. It has also become apparent that lamins are critical for human health, as a large number of mutations identified in the gene that encodes for A-type lamins are associated with tissue-specific and systemic genetic diseases, including the accelerated aging disorder known as Hutchinson-Gilford progeria syndrome. Recent years have witnessed great advances in our understanding of the role of lamins in the nucleus and the functional consequences of disease-associated A-type lamin mutations. Many of these findings have been presented in comprehensive reviews. In this mini-review, we discuss recent breakthroughs in the role of lamins in health and disease and what lies ahead in lamin research. PMID:27803806

  13. UTILITY ADVANCED TURBINE SYSTEMS (ATS) TECHNOLOGY READINESS TESTING PHASE 3 RESTRUCTURED (3R)

    SciTech Connect

    Unknown

    2000-03-17

    This scope document defines the work scope for accomplishing the design of the GE MS7001H and MS9001H (7H and 9H) combined-cycle power systems under the original ATS Phase 3 DOE Cooperative Agreement No. DE-FC21-95MC31176, and incorporates changes in scope required to convert Phase 3 to the ''restructured'' Phase 3R as defined in Amendment A012 to the Cooperative Agreement.

  14. A phase 1 dose-escalation study of the oral histone deacetylase inhibitor abexinostat in combination with standard hypofractionated radiotherapy in advanced solid tumors.

    PubMed

    Deutsch, Eric; Cohen-Jonathan Moyal, Elizabeth; Gregorc, Vanesa; Zucali, Paolo Andrea; Menard, Jean; Soria, Jean-Charles; Kloos, Ioana; Hsu, Jeff; Luan, Ying; Liu, Emily; Vezan, Remus; Graef, Thorsten; Rivera, Sofia

    2016-12-24

    Current treatments for advanced solid tumors tend to be only palliative. Although radiotherapy is administered with a curative intent, radioresistance and dose-limiting toxicities pose limitations to treatment. Abexinostat, an oral pan-histone deacetylase inhibitor, demonstrated enhanced sensitivity to radiation in various solid tumor cell lines. We conducted an exploratory, phase 1, dose-escalation study of abexinostat in combination with standard hypofractionated radiotherapy in patients with advanced solid tumors treated in a palliative setting. Among 58 treated patients, the median age was 61.5 years (range, 20-82); 47% of the patients had M1 stage disease, and 95% had received previous chemotherapy alone or chemotherapy in combination with surgery and/or radiotherapy. The recommended phase 2 dose was determined to be 90 mg/m2 (140 mg). Of the 51 patients evaluable for response, best overall response was 8% (1 complete response [CR], 3 partial responses [PRs]), and best loco-regional response was 12% (1 CR and 5 PRs) at a median follow-up of 16 weeks. Of note, patients with target or non-target brain lesions showed encouraging responses, with 1 patient achieving a best loco-regional response of CR. Treatment-emergent grade ≥3 adverse events (AEs) were few, with most common being thrombocytopenia (17%), lymphopenia (12%), and hypokalemia (7%). Six patients (10%) discontinued treatment due to AEs. No grade ≥3 prolongation of the QTc interval was observed, with no treatment discontinuations due to this AE. Oral abexinostat combined with radiotherapy was well tolerated in patients with advanced solid tumors. The combination may have potential for treatment of patients with brain lesions.

  15. Advances in Scanning Reflectarray Antennas Based on Ferroelectric Thin Film Phase Shifters for Deep Space Communications

    NASA Technical Reports Server (NTRS)

    Romanofsky, Robert R.

    2007-01-01

    Though there are a few examples of scanning phased array antennas that have flown successfully in space, the quest for low-cost, high-efficiency, large aperture microwave phased arrays continues. Fixed and mobile applications that may be part of a heterogeneous exploration communication architecture will benefit from the agile (rapid) beam steering and graceful degradation afforded by phased array antennas. The reflectarray promises greater efficiency and economy compared to directly-radiating varieties. Implementing a practical scanning version has proven elusive. The ferroelectric reflectarray, under development and described herein, involves phase shifters based on coupled microstrip patterned on Ba(x)Sr(1-x)TiO3 films, that were laser ablated onto LaAlO3 substrates. These devices outperform their semiconductor counterparts from X- through and K-band frequencies. There are special issues associated with the implementation of a scanning reflectarray antenna, especially one realized with thin film ferroelectric phase shifters. This paper will discuss these issues which include: relevance of phase shifter loss; modulo 2(pi) effects and phase shifter transient effects on bit error rate; scattering from the ground plane; presentation of a novel hybrid ferroelectric-semiconductor phase shifter; and the effect of mild radiation exposure on phase shifter performance.

  16. Daily oscillation of gene expression in the retina is phase-advanced with respect to the pineal gland.

    PubMed

    Bai, Lin; Zimmer, Sybille; Rickes, Oliver; Rohleder, Nils; Holthues, Heike; Engel, Lydia; Leube, Rudolf; Spessert, Rainer

    2008-04-08

    The photoreceptive retina and the non-photoreceptive pineal gland are components of the circadian and the melatonin forming system in mammals. To contribute to our understanding of the functional integrity of the circadian system and the melatonin forming system we have compared the daily oscillation of the two tissues under various seasonal lighting conditions. For this purpose, the 24-h profiles of the expression of the genes coding for arylalkylamine N-acetyltransferase (AA-NAT), nerve growth factor inducible gene-A (NGFI-A), nerve growth factor inducible gene-B (NGFI-B), retinoic acid related orphan receptor beta (RORbeta), dopamine D4 receptor, and period2 (Per2) have been simultaneously recorded in the retina and the pineal gland of rats under short day (light/dark 8:16) and long day (light/dark 16:8) conditions. We have found that the cyclical patterns of all genes are phase-advanced in the retina, often with a lengthened temporal interval under short day conditions. In both tissues, the AA-NAT gene expression represents an indication of the output of the relevant pacemakers. The temporal phasing in the AA-NAT transcript amount between the retina and the pineal gland is retained under constant darkness suggesting that the intrinsic self-cycling clock of the retina oscillates in a phase-advanced manner with respect to the self-cycling clock in the suprachiasmatic nucleus, which controls the pineal gland. We therefore conclude that daily rhythms in gene expression in the retina are phase-advanced with respect to the pineal gland, and that the same temporal relationship appears to be valid for the self-cycling clocks influencing the tissues.

  17. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Ko, Andrew H.; Venook, Alan P.

    2007-07-01

    Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

  18. Micromechanics of plastic deformation and phase transformation in a three-phase TRIP-assisted advanced high strength steel: Experiments and modeling

    NASA Astrophysics Data System (ADS)

    Srivastava, Ankit; Ghassemi-Armaki, Hassan; Sung, Hyokyung; Chen, Peng; Kumar, Sharvan; Bower, Allan F.

    2015-05-01

    The micromechanics of plastic deformation and phase transformation in a three-phase advanced high strength steel are analyzed both experimentally and by microstructure-based simulations. The steel examined is a three-phase (ferrite, martensite and retained austenite) quenched and partitioned sheet steel with a tensile strength of ~980 MPa. The macroscopic flow behavior and the volume fraction of martensite resulting from the austenite-martensite transformation during deformation were measured. In addition, micropillar compression specimens were extracted from the individual ferrite grains and the martensite particles, and using a flat-punch nanoindenter, stress-strain curves were obtained. Finite element simulations idealize the microstructure as a composite that contains ferrite, martensite and retained austenite. All three phases are discretely modeled using appropriate crystal plasticity based constitutive relations. Material parameters for ferrite and martensite are determined by fitting numerical predictions to the micropillar data. The constitutive relation for retained austenite takes into account contributions to the strain rate from the austenite-martensite transformation, as well as slip in both the untransformed austenite and product martensite. Parameters for the retained austenite are then determined by fitting the predicted flow stress and transformed austenite volume fraction in a 3D microstructure to experimental measurements. Simulations are used to probe the role of the retained austenite in controlling the strain hardening behavior as well as internal stress and strain distributions in the microstructure.

  19. Big data to smart data in Alzheimer's disease: Real-world examples of advanced modeling and simulation.

    PubMed

    Haas, Magali; Stephenson, Diane; Romero, Klaus; Gordon, Mark Forrest; Zach, Neta; Geerts, Hugo

    2016-09-01

    Many disease-modifying clinical development programs in Alzheimer's disease (AD) have failed to date, and development of new and advanced preclinical models that generate actionable knowledge is desperately needed. This review reports on computer-based modeling and simulation approach as a powerful tool in AD research. Statistical data-analysis techniques can identify associations between certain data and phenotypes, such as diagnosis or disease progression. Other approaches integrate domain expertise in a formalized mathematical way to understand how specific components of pathology integrate into complex brain networks. Private-public partnerships focused on data sharing, causal inference and pathway-based analysis, crowdsourcing, and mechanism-based quantitative systems modeling represent successful real-world modeling examples with substantial impact on CNS diseases. Similar to other disease indications, successful real-world examples of advanced simulation can generate actionable support of drug discovery and development in AD, illustrating the value that can be generated for different stakeholders.

  20. Aluminum-centered tetrahedron-octahedron transition in advancing Al-Sb-Te phase change properties.

    PubMed

    Xia, Mengjiao; Ding, Keyuan; Rao, Feng; Li, Xianbin; Wu, Liangcai; Song, Zhitang

    2015-02-24

    Group IIIA elements, Al, Ga, or In, etc., doped Sb-Te materials have proven good phase change properties, especially the superior data retention ability over popular Ge2Sb2Te5, while their phase transition mechanisms are rarely investigated. In this paper, aiming at the phase transition of Al-Sb-Te materials, we reveal a dominant rule of local structure changes around the Al atoms based on ab initio simulations and nuclear magnetic resonance evidences. By comparing the local chemical environments around Al atoms in respective amorphous and crystalline Al-Sb-Te phases, we believe that Al-centered motifs undergo reversible tetrahedron-octahedron reconfigurations in phase transition process. Such Al-centered local structure rearrangements significantly enhance thermal stability of amorphous phase compared to that of undoped Sb-Te materials, and facilitate a low-energy amorphization due to the weak links among Al-centered and Sb-centered octahedrons. Our studies may provide a useful reference to further understand the underlying physics and optimize performances of all IIIA metal doped Sb-Te phase change materials, prompting the development of NOR/NAND Flash-like phase change memory technology.

  1. Advanced image processing for optical coherence tomographic angiography of macular diseases

    PubMed Central

    Zhang, Miao; Wang, Jie; Pechauer, Alex D.; Hwang, Thomas S.; Gao, Simon S.; Liu, Liang; Liu, Li; Bailey, Steven T.; Wilson, David J.; Huang, David; Jia, Yali

    2015-01-01

    This article provides an overview of advanced image processing for three dimensional (3D) optical coherence tomographic (OCT) angiography of macular diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR). A fast automated retinal layers segmentation algorithm using directional graph search was introduced to separates 3D flow data into different layers in the presence of pathologies. Intelligent manual correction methods are also systematically addressed which can be done rapidly on a single frame and then automatically propagated to full 3D volume with accuracy better than 1 pixel. Methods to visualize and analyze the abnormalities including retinal and choroidal neovascularization, retinal ischemia, and macular edema were presented to facilitate the clinical use of OCT angiography. PMID:26713185

  2. Challenges in Facing the Lung Cancer Epidemic and Treating Advanced Disease in Latin America.

    PubMed

    Raez, Luis E; Santos, Edgardo S; Rolfo, Christian; Lopes, Gilberto; Barrios, Carlos; Cardona, Andres; Mas, Luis A; Arrieta, Oscar; Richardet, Eduardo; Vallejos S, Carlos; Wistuba, Ignacio; Gandara, David; Hirsch, Fred R

    2017-01-01

    Lung cancer, the deadliest cancer worldwide, is of particular concern in Latin America. The rising incidence poses a myriad of challenges for the region, which struggles with limited resources to meet the health care needs of its low- and middle-income populations. In this environment, we are concerned that governments are relatively unaware of the pressing need to implement effective strategies for screening, diagnosis, and treatment of lung cancer. The region has also been slow in adopting molecularly-based therapies in the treatment of advanced disease: testing for epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements are not routine, and access to targeted agents such as monoclonal antibodies and tyrosine kinase inhibitors is problematic. In this paper, we review the current situation in the management of lung cancer in Latin America, hoping that this initiative will help physicians, patient associations, industry, governments, and other stakeholders better face this epidemic in the near future.

  3. Liver transplantation for chronic liver disease: advances and controversies in an era of organ shortages

    PubMed Central

    Prince, M; Hudson, M

    2002-01-01

    Since liver transplantation was first performed in 1968 by Starzl et al, advances in case selection, liver surgery, anaesthetics, and immunotherapy have significantly increased the indications for and success of this operation. Liver transplantation is now a standard therapy for many end stage liver disorders as well as acute liver failure. However, while demand for cadaveric organ grafts has increased, in recent years the supply of organs has fallen. This review addresses current controversies resulting from this mismatch. In particular, methods for increasing graft availability and difficulties arising from transplantation in the context of alcohol related cirrhosis, primary liver tumours, and hepatitis C are reviewed. Together these three indications accounted for 42% of liver transplants performed for chronic liver disease in the UK in 2000. Ethical frameworks for making decisions on patients' suitability for liver transplantation have been developed in both the USA and the UK and these are also reviewed. PMID:11884694

  4. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™

    PubMed Central

    Qiu, Xiangguo; Wong, Gary; Audet, Jonathan; Bello, Alexander; Fernando, Lisa; Alimonti, Judie B.; Fausther-Bovendo, Hugues; Wei, Haiyan; Aviles, Jenna; Hiatt, Ernie; Johnson, Ashley; Morton, Josh; Swope, Kelsi; Bohorov, Ognian; Bohorova, Natasha; Goodman, Charles; Kim, Do; Pauly, Michael H.; Velasco, Jesus; Pettitt, James; Olinger, Gene G.; Whaley, Kevin; Xu, Bianli; Strong, James E.; Zeitlin, Larry; Kobinger, Gary P.

    2014-01-01

    Without an approved vaccine or treatment, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp™), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viremia, and abnormalities in blood count and chemistry were evident in many animals before ZMapp™ intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal hemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp™ is cross-reactive with the Guinean variant of Ebola. ZMapp™ currently exceeds all previous descriptions of efficacy with other therapeutics, and results warrant further development of this cocktail for clinical use. PMID:25171469

  5. Examining the Role of Gender in Career Advancement at the Centers for Disease Control and Prevention

    PubMed Central

    Roy, Kakoli; Gotway Crawford, Carol A.

    2010-01-01

    During the past decade, efforts to promote gender parity in the healing and public health professions have met with only partial success. We provide a critical update regarding the status of women in the public health profession by exploring gender-related differences in promotion rates at the nation's leading public health agency, the Centers for Disease Control and Prevention (CDC). Using personnel data drawn from CDC, we found that the gender gap in promotion has diminished across time and that this reduction can be attributed to changes in individual characteristics (e.g., higher educational levels and more federal work experience). However, a substantial gap in promotion that cannot be explained by such characteristics has persisted, indicating continuing barriers in women's career advancement. PMID:20075327

  6. Examining the role of gender in career advancement at the Centers for Disease Control and Prevention.

    PubMed

    Chen, Zhuo; Roy, Kakoli; Gotway Crawford, Carol A

    2010-03-01

    During the past decade, efforts to promote gender parity in the healing and public health professions have met with only partial success. We provide a critical update regarding the status of women in the public health profession by exploring gender-related differences in promotion rates at the nation's leading public health agency, the Centers for Disease Control and Prevention (CDC). Using personnel data drawn from CDC, we found that the gender gap in promotion has diminished across time and that this reduction can be attributed to changes in individual characteristics (e.g., higher educational levels and more federal work experience). However, a substantial gap in promotion that cannot be explained by such characteristics has persisted, indicating continuing barriers in women's career advancement.

  7. The search for neuroimaging biomarkers of Alzheimer's disease with advanced MRI techniques.

    PubMed

    Li, Tie-Qiang; Wahlund, Lars-Olof

    2011-03-01

    The aim of this review is to examine the recent literature on using advanced magnetic resonance imaging (MRI) techniques for finding neuroimaging biomarkers that are sensitive to the detection of risks for Alzheimer's disease (AD). Since structural MRI techniques, such as brain structural volumetry and voxel-based morphometry (VBM), have been widely used for AD studies and extensively reviewed, we will only briefly touch on the topics of volumetry and morphometry. The focus of the current review is about the more recent developments in the search for AD neuroimaging biomarkers with functional MRI (fMRI), resting-state functional connectivity MRI (fcMRI), diffusion tensor imaging (DTI), arterial spin-labeling (ASL), and magnetic resonance spectroscopy (MRS).

  8. Research Advance in Intestinal Mucosal Barrier and Pathogenesis of Crohn's Disease

    PubMed Central

    Dou, Chuan-zi; Guan, Xin; Wu, Huan-gan

    2016-01-01

    To date, the etiology and pathogenesis of Crohn's disease (CD) have not been fully elucidated. It is widely accepted that genetic, immune, and environment factors are closely related to the development of CD. As an important defensive line for human body against the environment, intestinal mucosa is able to protect the homeostasis of gut bacteria and alleviate the intestinal inflammatory and immune response. It is evident that the dysfunction of intestinal mucosa barriers plays a crucial role in CD initiation and development. Yet researches are insufficient on intestinal mucosal barrier's action in the prevention of CD onset. This article summarizes the research advances about the correlations between the disorders of intestinal mucosal barriers and CD. PMID:27651792

  9. Tremor reduction by subthalamic nucleus stimulation and medication in advanced Parkinson's disease.

    PubMed

    Blahak, Christian; Wöhrle, Johannes C; Capelle, Hans-Holger; Bäzner, Hansjörg; Grips, Eva; Weigel, Ralf; Hennerici, Michael G; Krauss, Joachim K

    2007-02-01

    Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor in Parkinson's disease (PD). Most of the recent studies used only clinical data to analyse tremor reduction. The objective of our study was to quantify tremor reduction by STN DBS and antiparkinsonian medication in elderly PD patients using an objective measuring system. Amplitude and frequency of resting tremor and re-emergent resting tremor during postural tasks were analysed using an ultrasound-based measuring system and surface electromyography. In a prospective study design nine patients with advanced PD were examined preoperatively off and on medication, and twice postoperatively during four treatment conditions: off treatment, on STN DBS, on medication, and on STN DBS plus medication. While both STN DBS and medication reduced tremor amplitude, STN DBS alone and the combination of medication and STN DBS were significantly superior to pre- and postoperative medication. STN DBS but not medication increased tremor frequency, and off treatment tremor frequency was significantly reduced postoperatively compared to baseline. These findings demonstrate that STN DBS is highly effective in elderly patients with advanced PD and moderate preoperative tremor reduction by medication. Thus, with regard to the advanced impact on the other parkinsonian symptoms, STN DBS can replace thalamic stimulation in this cohort of patients. Nevertheless, medication was still effective postoperatively and may act synergistically. The significantly superior efficacy of STN DBS on tremor amplitude and its impact on tremor frequency in contrast to medication might be explained by the influence of STN DBS on additional neural circuits independent from dopaminergic neurotransmission.

  10. Levodopa-carbidopa enteral suspension in advanced Parkinson’s disease: clinical evidence and experience

    PubMed Central

    Virhammar, Johan; Nyholm, Dag

    2016-01-01

    The duration of action of oral levodopa becomes shorter as Parkinson’s disease (PD) progresses. Patients with advanced PD may develop potentially disabling motor fluctuations and abnormal involuntary movement (dyskinesia), which cannot be managed with optimized oral or transdermal PD medications. The progressively worsening symptoms can have a substantial impact on the patient quality of life (QoL). Levodopa–carbidopa intestinal gel (LCIG) is delivered continuously via a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J). LCIG is licensed for the treatment of levodopa-responsive advanced PD in individuals experiencing severe motor fluctuations and dyskinesia when available combinations of antiparkinsonian medications have not given satisfactory results. Initial evidence for the efficacy and tolerability of LCIG came from a number of small-scale studies, but recently, three prospective studies have provided higher quality evidence. A 12-week double-blind comparison of LCIG with standard levodopa therapy, a 52-week open-label study extension of the double-blind study, and a 54-week open-label safety study, demonstrated significant improvements in ‘off’ time and ‘on’ time without troublesome dyskinesia, and QoL measures that were maintained in the longer term. There are also observations that LCIG may be effective treatment for nonmotor symptoms (NMS) although the evidence is limited. There is a need for further research on the efficacy of LCIG in reducing NMS, dyskinesia and improving QoL. This review surveys the clinical evidence for the effectiveness and tolerability of LCIG in the management of advanced PD and highlights some practical considerations to help optimize treatment. PMID:28344656

  11. Real-Time Volumetric Phase Monitoring: Advancing Chemical Analysis by Countercurrent Separation.

    PubMed

    Pauli, Guido F; Pro, Samuel M; Chadwick, Lucas R; Burdick, Thomas; Pro, Luke; Friedl, Warren; Novak, Nick; Maltby, John; Qiu, Feng; Friesen, J Brent

    2015-07-21

    Countercurrent separation (CCS) utilizes the differential partitioning behavior of analytes between two immiscible liquid phases. We introduce the first platform ("CherryOne") capable of real-time monitoring, metering, and control of the dynamic liquid-liquid CCS process. Automated phase monitoring and volumetrics are made possible with an array of sensors, including the new permittivity-based phase metering apparatus (PMA). Volumetric data for each liquid phase are converted into a dynamic real-time display of stationary phase retention (Sf) and eluent partition coefficients (K), which represent critical parameters of CCS reproducibility. When coupled with the elution-extrusion operational mode (EECCC), automated Sf and K determination empowers untargeted and targeted applications ranging from metabolomic analysis to preparative purifications.

  12. Relationship of Advanced Glycation End Products With Cardiovascular Disease in Menopausal Women.

    PubMed

    Pertynska-Marczewska, Magdalena; Merhi, Zaher

    2015-07-01

    Cardiovascular disease (CVD) represents the most significant cause of death in postmenopausal women. Advanced glycation end products (AGEs) are formed by nonenzymatic modification of proteins, lipids, and nucleic acids by glucose. This review focuses on the contribution of AGEs and their receptors to the development of CVD in menopause. Advanced glycation end products circulate and activate the proinflammatory endothelial cell surface receptor called RAGE, bind to the extracellular matrix of the cardiovascular system, or bind to the circulating anti-inflammatory soluble form of RAGE (sRAGE). Data emerging from human and animal studies suggest that AGEs and both receptors (RAGE and sRAGE) are implicated in the pathophysiology of CVD. Particular emphasis has been given to the role of AGE-RAGE axis in oxidative stress, inflammation, endothelial cell toxicity, and progression of atherosclerosis in menopause. Data accruing from human and animal studies suggest that RAGE expression level and circulating sRAGE level are associated with estradiol and are correlated with CVD risk factors, such as adiposity, dyslipidemia, insulin resistance, diabetes, and metabolic syndrome. By recognizing the impact of AGEs on atherosclerosis, pharmacological strategies targeting the AGE-RAGE pathway hold therapeutic potential for CVD in menopausal women.

  13. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2010.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2011-02-01

    This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin disease that were reported in the Journal in 2010. Key epidemiologic observations include an apparent increase in peanut allergy, with more than 1% of children affected, and increasing evidence that early food allergen exposure, rather than avoidance, might improve allergy outcomes. Advances in food allergy diagnosis include improved insights into prognosis and estimation of severity through component-resolved diagnostics and characterization of IgE binding to specific epitopes. Regarding treatment, oral and epicutaneous immunotherapy show promise. Studies of drug allergies show insights into pathophysiology, and studies on insect hypersensitivity reveal improved diagnostic methods. Genetic and functional studies have revealed the important role of epidermal differentiation products in the pathogenesis of atopic dermatitis. Cross-talk between the atopic immune response with the innate immune response have also been found to predispose to infection in patients with atopic dermatitis. New therapeutic approaches to control chronic urticaria have also been identified during the past year.

  14. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2014.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2015-02-01

    This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2014. Studies on food allergy suggest worrisomely high rates of peanut allergy and food-induced anaphylaxis-related hospitalizations. Evidence is mounting to support the theory that environmental exposure to peanut, such as in house dust, especially with an impaired skin barrier attributed to atopic dermatitis (AD) and loss of function mutations in the filaggrin gene, is a risk factor for sensitization and allergy. Diagnostic tests are improving, with early studies suggesting the possibility of developing novel cellular tests with increased diagnostic utility. Treatment trials continue to show the promise and limitations of oral immunotherapy, and mechanistic studies are elucidating pathways that might define the degree of efficacy of this treatment. Studies have also provided insights into the prevalence and characteristics of anaphylaxis and insect venom allergy, such as suggesting that baseline platelet-activating factor acetylhydrolase activity levels are related to the severity of reactions. Advances in drug allergy include identification of HLA associations for penicillin allergy and a microRNA biomarker/mechanism for toxic epidermal necrolysis. Research identifying critical events leading to skin barrier dysfunction and the polarized immune pathways that drive AD have led to new therapeutic approaches in the prevention and management of AD.

  15. A Novel Procedure for the Immediate Reconstruction of Severely Resorbed Alveolar Sockets for Advanced Periodontal Disease

    PubMed Central

    2017-01-01

    Background. Several clinical techniques and a variety of biomaterials have been introduced over the years in an effort to overcome bone remodeling and resorption after tooth extraction. However, the predictability of these procedures in sockets with severely resorbed buccal/lingual plate due to periodontal disease is still unknown. Case Description. A patient with advanced periodontitis underwent extraction of upper right lateral and central incisors. The central incisor exhibited complete buccal bone plate loss and a 9 mm vertical bone deficiency on its palatal side. The alveolar sockets were filled with collagen sponge and covered with a nonresorbable high-density PTFE membrane. Primary closure was not attained and any rigid scaffold material was not used. Histologic analysis provided evidence of new bone formation. At 12 months a cone-beam computed tomographic scan revealed enough bone volume to insert two conventional dental implants in conjunction with minor horizontal bone augmentation procedures. Clinical Implications. This case report would seem to support the potential of the proposed reconstructive approach in changing the morphology of severely resorbed alveolar sockets, minimizing the need for advanced bone regeneration procedures during implant placement. PMID:28250998

  16. Therapeutic interventions for Advanced Glycation-End Products and its Receptor-Mediated Cardiovascular Disease.

    PubMed

    Prasad, Kailash; Tiwari, Shuchita

    2016-10-06

    Advanced glycation end products (AGEs) are heterogeneous group of molecules formed from non-enzymatic reaction of reducing sugars with amino group of proteins, lipids, and nucleic acid. Interaction of AGEs with its cell-bound receptor (RAGE) results in generation of oxygen radicals, nuclear factor kappa-β, pro-inflammatory cytokines and cell adhesion molecules, and is involved in the pathophysiology of cardiovascular diseases (CVD). Circulating soluble forms of RAGE (sRAGE) and endo-secretory RAGE (esRAGE) compete with RAGE for ligand binding and function as a decoy. This paper describes the endogenous and exogenous (high dietary AGEs, cooking food under high dry heat, elevated pH, and long period) sources of AGEs. AGE-RAGE-mediated CVD includes atherosclerosis, coronary artery disease, carotid artery disease, hypertension, peripheral vascular diseases, heart failure, cardiomyopathy, and microangiopathy. The therapeutic intervention with reduction in AGEs and RAGE, and elevation in sRAGE has been reported for the treatment of AGE-RAGE-mediated CVD. Reduction in levels of AGEs can be achieved by reduction in consumption of food containing low amount of AGEs, cooking food at low temperature, moist heat, and shorter duration. AGE formation can be reduced with drugs, vitamins and stoppage of cigarette smoking. Statins, telmisartan, and curcumin have been used for suppression of RAGE. Statins, ACE-inhibitors, Rosiglitazone and vitamin D have been used to increase levels of sRAGE. Finally exogenous administration of sRAGE can be helpful in amelioration of CVD. In conclusion, AGE-RAGE-mediated CVD could be attenuated with reduction in consumption of AGEs, suppression of RAGE and elevation of sRAGE.

  17. Oral cancer treatment costs in Greece and the effect of advanced disease

    PubMed Central

    Zavras, Athanasios; Andreopoulos, Nikos; Katsikeris, Nikos; Zavras, Dimitrios; Cartsos, Vassiliki; Vamvakidis, Athanasios

    2002-01-01

    Background The main purpose of the study was to quantify the direct costs of oral cancer treatment to the healthcare system of Greece. Another aim was to identify factors that affect costs and potential cost reduction items. More specifically, we examined the relationship between stage of disease, modality of treatment and total direct costs. Methods The medical records and clinic files of the Oral and Maxillofacial Clinic of the Athens General Hospital "Genimatas" were abstracted to investigate clinical treatment characteristics, including length of hospitalization, modes of treatment, stage of disease etc. Records of 95 patients with oral squamous cell carcinoma (OSSC), with at least six months of follow-up, were examined. The clinical data was then used to calculate actual direct costs, based on 2001 market values. Results The mean total direct costs for OSSC treatment estimated at euro 8,450 or approximately US$ 7,450. Costs depended on the stage of the disease, with significant increases in stages III and IV, as compared with stages I and II (p < 0.05). Multi-modality treatment applied mainly to patients in stages III and IV was the factor that affected the cost. Disease stage was also associated with the total duration of hospitalization (p < 0.05). Conclusions The clinical management of advanced oral cancer is strongly associated with higher costs. Although the ideal would be to prevent cancer, the combination of high-risk screening, early diagnosis and early treatment seems the most efficient way to reduce costs, and most importantly, prolong life. PMID:12133170

  18. The chronic kidney disease - Mineral bone disorder (CKD-MBD): Advances in pathophysiology.

    PubMed

    Hruska, Keith A; Sugatani, Toshifumi; Agapova, Olga; Fang, Yifu

    2017-01-21

    The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. New advances in the causes of the CKD-MBD are discussed in this review. They demonstrate that repair and disease processes in the kidneys release factors to the circulation that cause the systemic complications of CKD. The discovery of WNT inhibitors, especially Dickkopf 1 (Dkk1), produced during renal repair as participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical. This lead to the discovery that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, wherein it stimulates fibrosis, and decreases tubular klotho expression. Activin A binds to the type 2 activin A receptor, ActRIIA, which is variably affected by CKD in the vasculature. In diabetic/atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC), ActRIIA signaling is inhibited and contributes to CKD induced VSMC dedifferentiation, osteogenic transition and neointimal atherosclerotic calcification. In nondiabetic/nonatherosclerotic aortas, CKD increases VSMC ActRIIA signaling, and vascular fibroblast signaling causing the latter to undergo osteogenic transition and stimulate vascular calcification. In both vascular situations, a ligand trap for ActRIIA prevented vascular calcification. In the skeleton, activin A is responsible for CKD stimulation of osteoclastogenesis and bone remodeling increasing bone turnover. These studies demonstrate that circulating renal repair and injury factors are causal of the CKD-MBD and CKD associated cardiovascular disease.

  19. Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease

    PubMed Central

    Devos, D; Krystkowiak, P; Clement, F; Dujardin, K; Cottencin, O; Waucquier, N; Ajebbar, K; Thielemans, B; Kroumova, M; Duhamel, A; Destée, A; Bordet, R; Defebvre, L

    2007-01-01

    Background Therapeutic management of gait disorders in patients with advanced Parkinson's disease (PD) can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus (STN) stimulation are more effective for limb‐related parkinsonian signs than for gait disorders. Gait disorders could also be partly related to norepinephrine system impairment, and the pharmacological modulation of both dopamine and norepinephrine pathways could potentially improve the symptomatology. Aim To assess the clinical value of chronic, high doses of methylphenidate (MPD) in patients with PD having gait disorders, despite their use of optimal dopaminergic doses and STN stimulation parameters. Methods Efficacy was blindly assessed on video for 17 patients in the absence of l‐dopa and again after acute administration of the drug, both before and after a 3‐month course of MPD, using a Stand–Walk–Sit (SWS) Test, the Tinetti Scale, the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and the Dyskinesia Rating Scale. Results An improvement was observed in the number of steps and time in the SWS Test, the number of freezing episodes, the Tinetti Scale score and the UPDRS part III score in the absence of l‐dopa after 3 months of taking MPD. The l‐dopa‐induced improvement in these various scores was also stronger after the 3‐month course of MPD than before. The Epworth Sleepiness Scale score fell dramatically in all patients. No significant induction of adverse effects was found. Interpretation Chronic, high doses of MPD improved gait and motor symptoms in the absence of l‐dopa and increased the intensity of response of these symptoms to l‐dopa in a population with advanced PD. PMID:17098845

  20. Advance market commitments for vaccines against neglected diseases: estimating costs and effectiveness.

    PubMed

    Berndt, Ernst R; Glennerster, Rachel; Kremer, Michael R; Lee, Jean; Levine, Ruth; Weizsäcker, Georg; Williams, Heidi

    2007-05-01

    The G8 is considering committing to purchase vaccines against diseases concentrated in low-income countries (if and when desirable vaccines are developed) as a way to spur research and development on vaccines for these diseases. Under such an 'advance market commitment,' one or more sponsors would commit to a minimum price to be paid per person immunized for an eligible product, up to a certain number of individuals immunized. For additional purchases, the price would eventually drop to close to marginal cost. If no suitable product were developed, no payments would be made. We estimate the offer size which would make revenues similar to the revenues realized from investments in typical existing commercial pharmaceutical products, as well as the degree to which various model contracts and assumptions would affect the cost-effectiveness of such a commitment. We make adjustments for lower marketing costs under an advance market commitment and the risk that a developer may have to share the market with subsequent developers. We also show how this second risk could be reduced, and money saved, by introducing a superiority clause to a commitment. Under conservative assumptions, we document that a commitment comparable in value to sales earned by the average of a sample of recently launched commercial products (adjusted for lower marketing costs) would be a highly cost-effective way to address HIV/AIDS, malaria, and tuberculosis. Sensitivity analyses suggest most characteristics of a hypothetical vaccine would have little effect on the cost-effectiveness, but that the duration of protection conferred by a vaccine strongly affects potential cost-effectiveness. Readers can conduct their own sensitivity analyses employing a web-based spreadsheet tool.

  1. Mary S. Easton Center of Alzheimer's Disease Research at UCLA: advancing the therapeutic imperative.

    PubMed

    Cummings, Jeffrey L; Ringman, John; Metz, Karen

    2010-01-01

    The Mary S. Easton Center for Alzheimer's Disease Research (UCLA-Easton Alzheimer's Center) is committed to the "therapeutic imperative" and is devoted to finding new treatments for Alzheimer's disease (AD) and to developing technologies (biomarkers) to advance that goal. The UCLA-Easton Alzheimer's Center has a continuum of research and research-related activities including basic/foundational studies of peptide interactions; translational studies in transgenic animals and other animal models of AD; clinical research to define the phenotype of AD, characterize familial AD, develop biomarkers, and advance clinical trials; health services and outcomes research; and active education, dissemination, and recruitment activities. The UCLAEaston Alzheimer's Center is supported by the National Institutes on Aging, the State of California, and generous donors who share our commitment to developing new therapies for AD. The naming donor (Jim Easton) provided substantial funds to endow the center and to support projects in AD drug discovery and biomarker development. The Sidell-Kagan Foundation supports the Katherine and Benjamin Kagan Alzheimer's Treatment Development Program, and the Deane F. Johnson Alzheimer's Research Foundation supports the Deane F. Johnson Center for Neurotherapeutics at UCLA. The John Douglas French Alzheimer's Research Foundation provides grants to junior investigators in critical periods of their academic development. The UCLA-Easton Alzheimer's Center partners with community organizations including the Alzheimer's Association California Southland Chapter and the Leeza Gibbons memory Foundation. Collaboration with pharmaceutical companies, biotechnology companies, and device companies is critical to developing new therapeutics for AD and these collaborations are embraced in the mission of the UCLA-Easton Alzheimer's Center. The Center supports excellent senior 3 investigators and serves as an incubator for new scientists, agents, models, technologies

  2. Understanding the impact of deep brain stimulation on ambulatory activity in advanced Parkinson's disease.

    PubMed

    Rochester, Lynn; Chastin, Sebastien Francois Martin; Lord, Sue; Baker, Katherine; Burn, David John

    2012-06-01

    Whilst deep brain stimulation of the subthalamic nucleus (DBS-STN) improves the motor symptoms of Parkinson's disease (PD), its effect on daily activity is unknown. We aimed to quantify changes in ambulatory activity following DBS-STN in advanced PD using novel accelerometry based measures that describe changes to the volume and pattern of walking. Seventeen participants with advanced PD were measured over a 7-day period using an activPAL (™) activity monitor. Data were collected 6 weeks before and 6 months after surgery and included measures that describe the volume and pattern of ambulatory activity (number of steps per day, accumulation, diversity and variability of walking time), alongside standard measures for disease severity, freezing of gait, gait speed, and extended activities of daily living. Activity outcomes were compared pre- and 6 months post-surgery using linear mixed models and correlated with standard outcomes. The results of this study are despite significant improvements in motor symptoms after surgery, the volume of ambulatory activity (total number of steps per day) did not change (P = 0.468). However, significant increases in length and variability of walking bouts emerged, suggesting improvements in diversity and flexibility of walking patterns. Motor severity and extended activities of daily living scores were significantly correlated with walking bout variability but not with volume of walking. Thus, the conclusions are reduction in motor symptom severity after DBS-STN translated into selective improvements in daily activity. Novel measures derived from accelerometry provide a discrete measure of performance and allow closer interpretation of the impact of DBS-STN on real-world activity.

  3. A home environment test battery for status assessment in patients with advanced Parkinson's disease.

    PubMed

    Westin, Jerker; Dougherty, Mark; Nyholm, Dag; Groth, Torgny

    2010-04-01

    A test battery for assessing patient state in advanced Parkinson's disease, consisting of self-assessments and motor tests, was constructed and implemented on a hand computer with touch screen in a telemedicine setting. The aim of this work was to construct an assessment device, applicable during motor fluctuations in the patient's home environment. Selection of self-assessment questions was based on questions from an e-diary, previously used in a clinical trial. Both un-cued and cued tapping tests and spiral drawing tests were designed for capturing upper limb stiffnes, slowness and involuntary movements. The patient interface gave an audible signal at scheduled response times and was locked otherwise. Data messages in an XML-format were sent from the hand unit to a central server for storage, processing and presentation. In tapping tests, speed and accuracy were calculated and in spiral tests, standard deviation of frequency filtered radial drawing velocity was calculated. An overall test score, combining repeated assessments of the different test items during a test period, was defined based on principal component analysis and linear regression. An evaluation with two pilot patients before and after receiving new types of treatments was performed. Compliance and usability was assessed in a clinical trial (65 patients with advanced Parkinson's disease) and correlations between different test items and internal consistency were investigated. The test battery could detect treatment effect in the two pilot patients, both in self-assessments, tapping tests' results and spiral scores. It had good patient compliance and acceptable usability according to nine nurses. Correlation analysis showed that tapping results provided different information as compared to diary responses. Internal consistency of the test battery was good and learning effects in the tapping tests were small.

  4. Recent advances in understanding the biomolecular basis of chronic beryllium disease: a review.

    PubMed

    McCleskey, T Mark; Buchner, Virginia; Field, R William; Scott, Brian L

    2009-01-01

    In this review we summarize the work conducted over the past decade that has advanced our knowledge of pulmonary diseases associated with exposure to beryllium that has provided a molecular-based understanding of the chemistry, immunopathology, and immunogenetics of beryllium toxicity. Beryllium is a strong and lightweight metal that generates and reflects neutrons, resists corrosion, is transparent to X-rays, and conducts electricity. Beryllium is one of the most toxic elements on the periodic table, eliciting in susceptible humans (a) an allergic immune response known as beryllium sensitization (BeS); (b) acute beryllium disease, an acutely toxic, pneumonitis-like lung condition resulting from exposure to high beryllium concentrations that are rarely seen in modern industry; and (c) chronic beryllium disease (CBD) following either high or very low levels of exposure. Because of its exceptional strength, stability, and heat-absorbing capability, beryllium is used in many important technologies in the modern world. In the early 1940s, beryllium was recognized as posing an occupational hazard in manufacturing and production settings. Although acute beryllium disease is now rare, beryllium is an insidious poison with a latent toxicity and the risk of developing CBD persists. Chronic beryllium disease-a systemic granulomatous lung disorder caused by a specific delayed immune response to beryllium within a few months to several decades after exposure-has been called the "unrecognized epidemic". Although not a disease in itself, BeS, the innate immune response to beryllium identified by an abnormal beryllium lymphocyte proliferation test result, is a population-based predictor of CBD. Genetic susceptibility to CBD is associated with alleles of the major histocompatibility gene, human leukocyte antigen DP (HLA-DP) containing glutamic acid at the 69th position of the beta chain (HLA-DPbeta-E69). Other genes are likely to be involved in the disease process, and research on

  5. Prevalence of non-alcoholic fatty liver disease and risk factors for advanced fibrosis and mortality in the United States

    PubMed Central

    Le, Michael H.; Devaki, Pardha; Ha, Nghiem B.; Jun, Dae Won; Te, Helen S.; Cheung, Ramsey C.

    2017-01-01

    In the United States, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and associated with higher mortality according to data from earlier National Health and Nutrition Examination Survey (NHANES) 1988–1994. Our goal was to determine the NAFLD prevalence in the recent 1999–2012 NHANES, risk factors for advanced fibrosis (stage 3–4) and mortality. NAFLD was defined as having a United States Fatty Liver Index (USFLI) > 30 in the absence of heavy alcohol use and other known liver diseases. The probability of low/high risk of having advanced fibrosis was determined by the NAFLD Fibrosis Score (NFS). In total, 6000 persons were included; of which, 30.0% had NAFLD and 10.3% of these had advanced fibrosis. Five and eight-year overall mortality in NAFLD subjects with advanced fibrosis was significantly higher than subjects without NAFLD ((18% and 35% vs. 2.6% and 5.5%, respectively) but not NAFLD subjects without advanced fibrosis (1.1% and 2.8%, respectively). NAFLD with advanced fibrosis (but not those without) is an independent predictor for mortality on multivariate analysis (HR = 3.13, 95% CI 1.93–5.08, p<0.001). In conclusion, in this most recent NHANES, NAFLD prevalence remains at 30% with 10.3% of these having advanced fibrosis. NAFLD per se was not a risk factor for increased mortality, but NAFLD with advanced fibrosis was. Mexican American ethnicity was a significant risk factor for NAFLD but not for advanced fibrosis or increased mortality. PMID:28346543

  6. [Periods and phases of disease in the context of predictive-preventive medicine, significance and principles of "integrative" diagnostics].

    PubMed

    Kats, Ia A; Parkhoniuk, E V

    2013-01-01

    The authors emphasize the necessity of more exact staging of disease formation with special reference to distinguishing "pre-disease" and "post-disease" periods with the phases of rehabilitation, recovery or transition to the "inter-disease" period in case of a chronic process. Diagnostics of the latter period is of great importance for the identification of the pre-active phase and prevention of activation of the pathological process. The integrative diagnostics method is proposed for distinguishing between stages and phases of diseases.

  7. Advance care planning uptake among patients with severe lung disease: a randomised patient preference trial of a nurse-led, facilitated advance care planning intervention

    PubMed Central

    Sinclair, Craig; Auret, Kirsten Anne; Evans, Sharon Frances; Williamson, Fiona; Dormer, Siobhan; Greeve, Kim; Koay, Audrey; Price, Dot; Brims, Fraser

    2017-01-01

    Objective Advance care planning (ACP) clarifies goals for future care if a patient becomes unable to communicate their own preferences. However, ACP uptake is low, with discussions often occurring late. This study assessed whether a systematic nurse-led ACP intervention increases ACP in patients with advanced respiratory disease. Design A multicentre open-label randomised controlled trial with preference arm. Setting Metropolitan teaching hospital and a rural healthcare network. Participants 149 participants with respiratory malignancy, chronic obstructive pulmonary disease or interstitial lung disease. Intervention Nurse facilitators offered facilitated ACP discussions, prompted further discussions with doctors and loved ones, and assisted participants to appoint a substitute medical decision-maker (SDM) and complete an advance directive (AD). Outcome measures The primary measure was formal (AD or SDM) or informal (discussion with doctor) ACP uptake assessed by self-report (6 months) and medical notes audit. Secondary measures were the factors predicting baseline readiness to undertake ACP, and factors predicting postintervention ACP uptake in the intervention arm. Results At 6 months, formal ACP uptake was significantly higher (p<0.001) in the intervention arm (54/106, 51%), compared with usual care (6/43, 14%). ACP discussions with doctors were also significantly higher (p<0.005) in the intervention arm (76/106, 72%) compared with usual care (20/43, 47%). Those with a strong preference for the intervention were more likely to complete formal ACP documents than those randomly allocated. Increased symptom burden and preference for the intervention predicted later ACP uptake. Social support was positively associated with ACP discussion with loved ones, but negatively associated with discussion with doctors. Conclusions Nurse-led facilitated ACP is acceptable to patients with advanced respiratory disease and effective in increasing ACP discussions and completion

  8. Social support and adjustment in patients with sarcoma: the moderator effect of the disease phase.

    PubMed

    Paredes, Tiago F; Canavarro, Maria C; Simões, Mário R

    2012-01-01

    This study examined the association between different types of perceived social support and adjustment of patients with sarcoma, and if these relationships would differ depending on the outcome measure and phase of disease. Forty-nine patients in the diagnostic phase, 43 in the treatment phase, and 59 in the follow-up phase were recruited. Participants completed the Medical Outcomes Study Social Support Survey Questionnaire, the Hospital Anxiety and Depression Scale, and World Health Organization Quality of Life Assessment. Positive social interaction, emotional/informational, affectionate, and tangible supports were significantly associated with depression scores, but not with anxiety. Except for affectionate support, all the associations with overall quality of life were significant. A moderating effect of the phase of the disease was also found in the association between tangible support and anxiety, and between affectionate support, depression, and overall quality of life. In clinical practice it is important to implement phase-specific psychosocial interventions and to take into consideration other factors beyond perceived social support while handling patients with sarcoma.

  9. Immunosuppressants in advanced clinical development for organ transplantation and selected autoimmune diseases.

    PubMed

    Kovarik, John M; Burtin, Pascale

    2003-05-01

    Immunosuppressants dampen the immune response or restore balance among immune system components. They are primarily used to prevent allograft rejection after organ transplantation and to prevent or treat disease flares in autoimmune diseases. Immunosuppressants available at present include the calcineurin inhibitors (cyclosporin, tacrolimus), antimetabolites (azathioprine, leflunomide, methotrexate, mycophenolate mofetil), antiproliferatives (sirolimus), monoclonal antibodies to T lymphocyte (basiliximab, daclizumab, muromonab-CD3) and anticytokines (anakinra, etanercept, infliximab). The immunosuppressive market grows at a rate of > 10% yearly, with total sales in 2001 of US$2.7 billion. Immunotherapy in transplantation and autoimmune diseases is tending towards the use of multi-drug regimens tailored for the individual patient. At least 23 new immunosuppressants are currently in advanced clinical testing or preregistration, and can be divided into three groups. First, emerging drugs targeting intracellular ligands in immune cells are primarily analogues of currently-marketed agents, which attempt to provide improved pharmaceutical or safety profiles compared with the prototype compound. They are largely being developed in organ transplantation. Second, emerging drugs targeting cell surface ligands on immune cells attempt to antagonise novel molecular sites to interfere with immune cell activation via costimulatory signals, immune cell adhesion to tissues or the vasculature and immune cell trafficking. These agents are being primarily developed in rheumatoid arthritis, psoriasis and/or multiple sclerosis. Finally, emerging drugs acting as anticytokines, which largely follow on from the success of those on the market, by antagonising the function of tumour necrosis factor or a narrow selection of interleukins. All are being assessed in rheumatoid arthritis. Drug development of immunosuppressants is increasingly attempting to intervene in disease progression over

  10. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

    PubMed Central

    Riches, Marcie L.; Kernan, Nancy A.; Brochstein, Joel A.; Mineishi, Shin; Termuhlen, Amanda M.; Arai, Sally; Grupp, Stephan A.; Guinan, Eva C.; Martin, Paul L.; Steinbach, Gideon; Krishnan, Amrita; Nemecek, Eneida R.; Giralt, Sergio; Rodriguez, Tulio; Duerst, Reggie; Doyle, John; Antin, Joseph H.; Smith, Angela; Lehmann, Leslie; Champlin, Richard; Gillio, Alfred; Bajwa, Rajinder; D’Agostino, Ralph B.; Massaro, Joseph; Warren, Diane; Miloslavsky, Maja; Hume, Robin L.; Iacobelli, Massimo; Nejadnik, Bijan; Hannah, Alison L.; Soiffer, Robert J.

    2016-01-01

    Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P = .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P = .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #NCT00358501. PMID:26825712

  11. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure.

    PubMed

    Richardson, Paul G; Riches, Marcie L; Kernan, Nancy A; Brochstein, Joel A; Mineishi, Shin; Termuhlen, Amanda M; Arai, Sally; Grupp, Stephan A; Guinan, Eva C; Martin, Paul L; Steinbach, Gideon; Krishnan, Amrita; Nemecek, Eneida R; Giralt, Sergio; Rodriguez, Tulio; Duerst, Reggie; Doyle, John; Antin, Joseph H; Smith, Angela; Lehmann, Leslie; Champlin, Richard; Gillio, Alfred; Bajwa, Rajinder; D'Agostino, Ralph B; Massaro, Joseph; Warren, Diane; Miloslavsky, Maja; Hume, Robin L; Iacobelli, Massimo; Nejadnik, Bijan; Hannah, Alison L; Soiffer, Robert J

    2016-03-31

    Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

  12. A Phase Ib/II Study Evaluating the Combination of Weekly Docetaxel and Cisplatin Together with Capecitabine and Bevacizumab in Patients with Advanced Esophago-Gastric Cancer

    PubMed Central

    Sarfaty, Michal; Purim, Ofer; Kundel, Yulia; Amit, Limor; Abramovich, Amir; Sadeh Gonik, Udi; Idelevich, Efraim; Gordon, Noa; Medalia, Gal; Sulkes, Aaron

    2016-01-01

    Introduction Current treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC. Methods Patients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25–35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1–14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part). Results The study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5–52.2 months) and the median progression-free survival was 7.6 months (range, 1.3–26.6 months). The 2-year OS rate reached 23.7%. Conclusions AVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further

  13. Advanced Power Electronic Interfaces for Distributed Energy Systems, Part 2: Modeling, Development, and Experimental Evaluation of Advanced Control Functions for Single-Phase Utility-Connected Inverter

    SciTech Connect

    Chakraborty, S.; Kroposki, B.; Kramer, W.

    2008-11-01

    Integrating renewable energy and distributed generations into the Smart Grid architecture requires power electronic (PE) for energy conversion. The key to reaching successful Smart Grid implementation is to develop interoperable, intelligent, and advanced PE technology that improves and accelerates the use of distributed energy resource systems. This report describes the simulation, design, and testing of a single-phase DC-to-AC inverter developed to operate in both islanded and utility-connected mode. It provides results on both the simulations and the experiments conducted, demonstrating the ability of the inverter to provide advanced control functions such as power flow and VAR/voltage regulation. This report also analyzes two different techniques used for digital signal processor (DSP) code generation. Initially, the DSP code was written in C programming language using Texas Instrument's Code Composer Studio. In a later stage of the research, the Simulink DSP toolbox was used to self-generate code for the DSP. The successful tests using Simulink self-generated DSP codes show promise for fast prototyping of PE controls.

  14. Utility advanced turbine systems (ATS) technology readiness testing -- Phase 3. Annual report, October 1, 1996--September 30, 1997

    SciTech Connect

    1997-12-31

    The overall objective of the Advanced Turbine System (ATS) Phase 3 Cooperative Agreement between GE and the US Department of Energy (DOE) is the development of the GE 7H and 9H combined cycle power systems. The major effort will be expended on detail design. Validation of critical components and technologies will be performed including: hot gas path component testing, sub-scale compressor testing, steam purity test trials, and rotational heat transfer confirmation testing. Processes will be developed to support the manufacture of the first system. Technology enhancements that are not required for the first machine design but will be critical for future ATS advances in performance, reliability, and costs will be initiated. Long-term tests of materials to confirm design life predictions will continue. A schematic of the GE H machine is shown.

  15. Advanced Light Source First-Phase Scientific Program, 1993/1994

    SciTech Connect

    Not Available

    1992-08-01

    This composite document outlines ten different experiments planned for the beamline at the Advanced Light Source. Researchers from various parts of the country have detailed their methods and equipment to be used in experiments in biology and physics. X-ray spectroscopy and microscopy are the common topics to these experiments. (GHH)

  16. Aircrew Training Devices: Utility and Utilization of Advanced Instructional Features (Phase IV--Summary Report).

    ERIC Educational Resources Information Center

    Polzella, Donald J.; And Others

    Modern aircrew training devices (ATDs) are equipped with sophisticated hardware and software capabilities, known as advanced instructional features (AIFs), that permit a simulator instructor to prepare briefings, manage training, vary task difficulty/fidelity, monitor performance, and provide feedback for flight simulation training missions. The…

  17. Advanced Swimming, Phase One--Swimmer; Physical Education: 5551.48.

    ERIC Educational Resources Information Center

    Gutting, Dick

    GRADES OR AGES: Grades 7-12. SUBJECT MATTER: Advanced swimming. ORGANIZATION AND PHYSICAL APPEARANCE: The first five sections of the guide list course guidelines, course description, broad goal statement, behavioral objectives, course content, learning activities, and teaching procedures. The guide also contains evaluation forms and a five-item…

  18. [Congenital heart disease: Recent technical advances in three-dimensional echocardiography].

    PubMed

    Karsenty, Clement; Hadeed, Khaled; Acar, Philippe

    2017-01-04

    The recent technical advances allow the use in practice of three-dimensional echocardiography in children especially through the new high frequency matrix probe. It is difficult or even impossible to hold breathing during children' acquisition so to avoid motion full volume artifact, one beat and live 3D modes are suitable. 3D echocardiography is more accurate than 2D to assess the size, location, and relationship with surrounding structures of atrial and ventricular septal defects and thus helps in the therapeutic decision. 3D echocardiography enables to guide precisely percutaneous procedure. The morphology of the valve leaflets, chordal support apparatus, papillary muscle and the annulus are particularly well described in 3D and allows assessment of the regurgitation before repair and after as well for the common valve of the atrioventricular septal defect or in the Ebstein anomaly. Complex heart diseases such as double outlet right ventricle are suitable to a tridimensional assessment to plan surgical strategy. 3D printing, fusion imaging in cathlab and automated volume quantification embody recent innovations of new techniques in congenital heart disease.

  19. Receptor for Advanced Glycation End Products and Its Involvement in Inflammatory Diseases

    PubMed Central

    Talib, Herni; Tie, Tung Hing; Nordin, Norshariza

    2013-01-01

    The receptor for advanced glycation end products (RAGE) is a transmembrane receptor of the immunoglobulin superfamily, capable of binding a broad repertoire of ligands. RAGE-ligands interaction induces a series of signal transduction cascades and lead to the activation of transcription factor NF-κB as well as increased expression of cytokines, chemokines, and adhesion molecules. These effects endow RAGE with the role in the signal transduction from pathogen substrates to cell activation during the onset and perpetuation of inflammation. RAGE signaling and downstream pathways have been implicated in a wide spectrum of inflammatory-related pathologic conditions such as arteriosclerosis, Alzheimer's disease, arthritis, acute respiratory failure, and sepsis. Despite the significant progress in other RAGE studies, the functional importance of the receptor in clinical situations and inflammatory diseases still remains to be fully realized. In this review, we will summarize current understandings and lines of evidence on the molecular mechanisms through which RAGE signaling contributes to the pathogenesis of the aforementioned inflammation-associated conditions. PMID:24102034

  20. Advances in the Endoscopic Assessment of Inflammatory Bowel Diseases: Cooperation between Endoscopic and Pathologic Evaluations

    PubMed Central

    Cheon, Jae Hee

    2015-01-01

    Endoscopic assessment has a crucial role in the management of inflammatory bowel disease (IBD). It is particularly useful for the assessment of IBD disease extension, severity, and neoplasia surveillance. Recent advances in endoscopic imaging techniques have been revolutionized over the past decades, progressing from conventional white light endoscopy to novel endoscopic techniques using molecular probes or electronic filter technologies. These new technologies allow for visualization of the mucosa in detail and monitor for inflammation/dysplasia at the cellular or sub-cellular level. These techniques may enable us to alter the IBD surveillance paradigm from four quadrant random biopsy to targeted biopsy and diagnosis. High definition endoscopy and dye-based chromoendoscopy can improve the detection rate of dysplasia and evaluate inflammatory changes with better visualization. Dye-less chromoendoscopy, including narrow band imaging, iScan, and autofluorescence imaging can also enhance surveillance in comparison to white light endoscopy with optical or electronic filter technologies. Moreover, confocal laser endomicroscopy or endocytoscopy have can achieve real-time histology evaluation in vivo and have greater accuracy in comparison with histology. These new technologies could be combined with standard endoscopy or further histologic confirmation in patients with IBD. This review offers an evidence-based overview of new endoscopic techniques in patients with IBD. PMID:26018512

  1. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2011.

    PubMed

    Sicherer, Scott H; Leung, Donald Y M

    2012-01-01

    This review highlights some of the research advances in anaphylaxis; hypersensitivity reactions to foods, drugs, and insects; and allergic skin diseases that were reported in the Journal in 2011. Food allergy appears to be increasing in prevalence and carries a strong economic burden. Risk factors can include dietary ones, such as deficiency of vitamin D and timing of complementary foods, and genetic factors, such as filaggrin loss-of-function mutations. Novel mechanisms underlying food allergy include the role of invariant natural killer T cells and influences of dietary components, such as isoflavones. Among numerou