Science.gov

Sample records for long-term enzyme replacement

  1. Long-term galsulfase enzyme replacement therapy in Taiwanese mucopolysaccharidosis VI patients: A case series

    PubMed Central

    Lin, Hsiang-Yu; Chuang, Chih-Kuang; Wang, Chung-Hsing; Chien, Yin-Hsiu; Wang, Yu-Mei; Tsai, Fuu-Jen; Chou, Yen-Yin; Lin, Shio Jean; Pan, Hui-Ping; Niu, Dau-Ming; Hwu, Wuh-Liang; Ke, Yu-Yuan; Lin, Shuan-Pei

    2016-01-01

    Background Information regarding the long-term outcome of enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase (rhASB, galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.) for Taiwanese patients with mucopolysaccharidosis (MPS) VI is limited. Methods Nine Taiwanese patients with MPS VI (4 males and 5 females; age range, 1.4 to 21.1 years) treated with weekly intravenous infusions of galsulfase (1.0 mg/kg) in 5 medical centers in Taiwan were reviewed. A set of biochemical and clinical assessments were evaluated annually. Results After 6.2 to 11.2 years of galsulfase treatment, 6 patients experienced improvement over baseline in the 6-minute walk test by a mean of 150 m (59% change over time), and 3 patients also increased the 3-minute stair climb test by a mean of 60 steps (46%). In a manual dexterity test, 3 patients decreased the time required to pick up 10 coins and put the coins into a cup by 15 s (33%). Shoulder range of motion in all 9 patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.42 points (21%). Four patients showed improved pulmonary function. Five patients had positive effects on cardiac-wall diameters. Four patients had improved cardiac diastolic function. Liver and spleen sizes as measured by abdominal ultrasonography remained the same or decreased in all 9 patients. However, the severity degree of valvular stenosis or regurgitation did not show improvement despite ERT. A mean overall 69% decrease in urinary glycosaminoglycan (GAG) excretion indicated a satisfactory biomarker response. Conclusions Long-term ERT was beneficial and safe for Taiwanese patients with MPS VI. This treatment reduced urinary GAG and had positive effects on a wide range of clinical functional assessments including endurance, mobility, joint function, pulmonary function, liver and spleen size, cardiac hypertrophy and diastolic dysfunction. PMID:27134829

  2. Long Term Treatment with Enzyme Replacement Therapy in Patients with Fabry Disease.

    PubMed

    Oder, Daniel; Nordbeck, Peter; Wanner, Christoph

    2016-01-01

    Anderson-Fabry disease is a potentially life-threatening hereditary lysosomal storage disorder taking origin in over 1,000 known pathogenic mutations in the alpha-galactosidase A encoding gene. Over the past 15 years, intravenous replacement therapy of the deficient alpha agalsidase A enzyme has been well-established retarding the progression of a multisystemic disease and organ involvement. Despite this innovative treatment approach, premature deaths still do occur. The response to enzyme replacement therapy (ERT) varies considerably and appears to depend on gender, genotype (classic or later onset/non-classic), stage of disease or age and agalsidase inhibition by anti-agalsidase antibodies. Early ERT treatment at young age, a personalized approach, and adjunctive therapies for specific disease manifestations appear to impact on prognosis and are currently favored with the expectance of more effective intravenous and oral treatments in the short future. PMID:27576727

  3. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials.

    PubMed

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-07-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3-62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2-4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427. PMID:25801797

  4. Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials

    PubMed Central

    Hughes, Derralynn A; Gonzalez, Derlis E; Lukina, Elena A; Mehta, Atul; Kabra, Madhulika; Elstein, Deborah; Kisinovsky, Isaac; Giraldo, Pilar; Bavdekar, Ashish; Hangartner, Thomas N; Wang, Nan; Crombez, Eric; Zimran, Ari

    2015-01-01

    Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; http://www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. © 2015 Wiley Periodicals, Inc. PMID:25801797

  5. Long-term enzyme replacement therapy in beta-glucuronidase--deficient mice by allogeneic bone marrow transplantation

    SciTech Connect

    Yatziv, S.; Weiss, L.; Morecki, S.; Fuks, Z.; Slavin, S.

    1982-06-01

    Enzyme replacement therapy was successfully accomplished in beta-Glu-deficient C3H/HeJ mice after transplantation of BM cells obtained from normal BALB/c donors. Marrow recipients were prepared for transplantation by fractionated TLI. Enzyme activity increased from 20.5 +/- 7.0 nmol/mg of protein per hour to 180 +/- 30.2 in the liver (p less than 0.001) and from 8.2 +/- 2.0 to 17.5 +/- 5.0 nmol/ml/hr in the plasma (p less than 0.05) at 50 days after marrow infusion. Normal enzyme activity was maintained in treated mice for at least 100 days after marrow transplantation, as documented by repeated liver biopsies and examination of plasma samples. The marrow donors and the recipients were fully histoincompatible. Both immunologic rejection of the marrow allograft and GVHD were prevented by the prior conditioning of the recipients with TLI, resulting in bilateral transplantation tolerance of host vs. graft and graft vs. host. The data suggest that allogeneic BM transplantation may provide a possible therapeutic approach for certain enzyme deficiency syndromes.

  6. Targeted gene transfer into ependymal cells through intraventricular injection of AAV1 vector and long-term enzyme replacement via the CSF.

    PubMed

    Yamazaki, Yoshiyuki; Hirai, Yukihiko; Miyake, Koichi; Shimada, Takashi

    2014-01-01

    Enzyme replacement via the cerebrospinal fluid (CSF) has been shown to ameliorate neurological symptoms in model animals with neuropathic metabolic disorders. Gene therapy via the CSF offers a means to achieve a long-term sustainable supply of therapeutic proteins within the central nervous system (CNS) by setting up a continuous source of transgenic products. In the present study, a serotype 1 adeno-associated virus (AAV1) vector was injected into a lateral cerebral ventricle in adult mice to transduce the gene encoding human lysosomal enzyme arylsulfatase A (hASA) into the cells of the CNS. Widespread transduction and stable expression of hASA in the choroid plexus and ependymal cells was observed throughout the ventricles for more than 1 year after vector injection. Although humoral immunity to hASA developed after 6 weeks, which diminished the hASA levels detected in CSF from AAV1-injected mice, hASA levels in CSF were maintained for at least 12 weeks when the mice were tolerized to hASA prior of vector injection. Our results suggest that the cells lining the ventricles could potentially serve as a biological reservoir for long-term continuous secretion of lysosomal enzymes into the CSF following intracerebroventricular injection of an AAV1 vector. PMID:24981028

  7. Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase.

    PubMed

    Harmatz, Paul; Yu, Zi-Fan; Giugliani, Roberto; Schwartz, Ida Vanessa D; Guffon, Nathalie; Teles, Elisa Leão; Miranda, M Clara Sá; Wraith, J Edmond; Beck, Michael; Arash, Laila; Scarpa, Maurizio; Ketteridge, David; Hopwood, John J; Plecko, Barbara; Steiner, Robert; Whitley, Chester B; Kaplan, Paige; Swiedler, Stuart J; Hardy, Karen; Berger, Kenneth I; Decker, Celeste

    2010-02-01

    Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients. PMID:20140523

  8. Oxidative and nitrative stress and pro-inflammatory cytokines in Mucopolysaccharidosis type II patients: effect of long-term enzyme replacement therapy and relation with glycosaminoglycan accumulation.

    PubMed

    Jacques, Carlos Eduardo Diaz; Donida, Bruna; Mescka, Caroline P; Rodrigues, Daiane G B; Marchetti, Desirèe P; Bitencourt, Fernanda H; Burin, Maira G; de Souza, Carolina F M; Giugliani, Roberto; Vargas, Carmen Regla

    2016-09-01

    Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a deficient activity of iduronate-2-sulfatase, leading to abnormal accumulation of glycosaminoglycans (GAG). The main treatment for MPS II is enzyme replacement therapy (ERT). Previous studies described potential benefits of six months of ERT against oxidative stress in patients. Thus, the aim of this study was to investigate oxidative, nitrative and inflammatory biomarkers in MPS II patients submitted to long term ERT. It were analyzed urine and blood samples from patients on ERT (mean time: 5.2years) and healthy controls. Patients presented increased levels of lipid peroxidation, assessed by urinary 15-F2t-isoprostane and plasmatic thiobarbituric acid-reactive substances. Concerning to protein damage, urinary di-tyrosine (di-Tyr) was increased in patients; however, sulfhydryl and carbonyl groups in plasma were not altered. It were also verified increased levels of urinary nitrate+nitrite and plasmatic nitric oxide (NO) in MPS II patients. Pro-inflammatory cytokines IL-1β and TNF-α were increased in treated patients. GAG levels were correlated to di-Tyr and nitrate+nitrite. Furthermore, IL-1β was positively correlated with TNF-α and NO. Contrastingly, we did not observed alterations in erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, in reduced glutathione content and in the plasmatic antioxidant capacity. Although some parameters were still altered in MPS II patients, these results may suggest a protective role of long-term ERT against oxidative stress, especially upon oxidative damage to protein and enzymatic and non-enzymatic defenses. Moreover, the redox imbalance observed in treated patients seems to be GAG- and pro-inflammatory cytokine-related. PMID:27251652

  9. Short Communication Impact of early enzyme-replacement therapy for mucopolysaccharidosis VI: results of a long-term follow-up of Brazilian siblings.

    PubMed

    Franco, J F; Soares, D C; Torres, L C; Leal, G N; Cunha, M T; Honjo, R S; Bertola, D R; Kim, C A

    2016-01-01

    Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive multisystem lysosomal storage disorder, which is characterized by the deficiency of the enzyme arylsulfatase B encoded by the ARSB gene. Treatment of this disease with enzyme-replacement therapy (ERT) improves the clinical status of and generates hope for MPS VI patients. However, only few reports on patients with MPS VI treated before 5 years of age have been published. Thus, the objective of this study was to compare the clinical parameters of two sisters affected by MPS VI who started ERT at different ages (9 years and 1 year 5 months, respectively) and to determine the most relevant clinical impacts of early treatment after 85 months of evaluation. The treatment was well tolerated by both siblings. ERT in the younger sibling resulted in increased growth, an improved 6-minute walk test, less coarse face, slower progression of cardiac valve disease, and the absence of compressive myelopathy compared to that in her older sister. On the other hand, the older sibling had typical MPS VI phenotypic features before the commencement of ERT. Corneal clouding, clawed hands, and progressive skeletal changes were observed in both siblings despite the treatment. Both siblings displayed reduced frequencies of upper respiratory infections and apnea indices. This study emphasizes that early diagnosis and treatment of MPS VI are critical for a better disease outcome and to enhance the quality of life for these patients. PMID:26910003

  10. Esophageal replacement in children: Challenges and long-term outcomes

    PubMed Central

    Soccorso, Giampiero; Parikh, Dakshesh H.

    2016-01-01

    Replacement of a nonexistent or damaged esophagus continues to pose a significant challenge to pediatric surgeons. Various esophageal replacement grafts and techniques have not produced consistently good outcomes to emulate normal esophagus. Therefore, many techniques are still being practiced and recommended with no clear consensus. We present a concise literature review of the currently used techniques and with discussions on the advantages and anticipated morbidity. There are no randomized controlled pediatric studies to compare different types of esophageal replacements. Management and graft choice are based on geographical and personal predilections rather than on any discernible objective data. The biggest series with long-term outcome are reported for gastric transposition and colonic replacement. Comparison of different studies shows no significant difference in early (graft necrosis and anastomotic leaks) or late complications (strictures, poor feeding, gastro-esophageal reflux, tortuosity of the graft, and Barrett's esophagus). The biggest series seem to have lower complications than small series reflecting the decennials experience in their respective centers. Long-term follow-up is recommended following esophageal replacement for the development of late strictures, excessive tortuosity, and Barrett's changes within the graft. Once child overcomes initial morbidity and establishes oral feeding, long-term consequences and complications of pediatric esophageal replacement should be monitored and managed in adult life. PMID:27365900

  11. Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long-term enzyme replacement therapy

    PubMed Central

    Gruhn, Kai Michael; Heyer, Christoph Malte; Güttsches, Anne-Katrin; Rehmann, Robert; Nicolas, Volkmar; Schmidt-Wilcke, Tobias; Tegenthoff, Martin; Vorgerd, Matthias; Kley, Rudolf Andre

    2015-01-01

    Background Late-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD. Objective We analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters. Methods Three symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations. Results We detected a decrease in thigh muscle volume of 6.7% (p < 0.001) and an increase in lower leg muscle volume of 8.2% (p = 0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R2 = 0.68, p < 0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles. Conclusions The results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome. PMID:26937398

  12. 75 FR 53976 - Risks and Benefits of Long-Term Use of Nicotine Replacement Therapy Products; Public Workshop...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-02

    ... Therapy Products; Public Workshop; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION... risks and benefits associated with the long- term use of nicotine replacement therapy (NRT)...

  13. Regional analgesia for improvement of long-term functional outcome after elective large joint replacement

    PubMed Central

    Atchabahian, Arthur; Schwartz, Gary; Hall, Charles B; Lajam, Claudette M; Andreae, Michael H

    2015-01-01

    Background Regional analgesia is more effective than conventional analgesia for controlling pain and may facilitate rehabilitation after large joint replacement in the short term. It remains unclear if regional anaesthesia improves functional outcomes after joint replacement beyond three months after surgery. Objectives To assess the effects of regional anaesthesia and analgesia on long-term functional outcomes 3, 6 and 12 months after elective major joint (knee, shoulder and hip) replacement surgery. Search methods We performed an electronic search of several databases (CENTRAL, MEDLINE, EMBASE, CINAHL), and handsearched reference lists and conference abstracts. We updated our search in June 2015. Selection criteria We included randomized controlled trials (RCTs) comparing regional analgesia versus conventional analgesia in patients undergoing total shoulder, hip or knee replacement. We included studies that reported a functional outcome with a follow-up of at least three months after surgery. Data collection and analysis We used standard methodological procedures expected by Cochrane. We contacted study authors for additional information. Main results We included six studies with 350 participants followed for at least three months. All of these studies enrolled participants undergoing total knee replacement. Studies were at least partially blinded. Three studies had a high risk of performance bias and one a high risk of attrition bias, but the risk of bias was otherwise unclear or low. Only one study assessed joint function using a global score. Due to heterogeneity in outcome and reporting, we could only pool three out of six RCTs, with range of motion assessed at three months after surgery used as a surrogate for joint function. All studies had a high risk of detection bias. Using the random-effects model, there was no statistically significant difference between the experimental and control groups (mean difference 3.99 degrees, 95% confidence interval (CI)

  14. Long-Term Behavior of Simulated Partial Lead Service Line Replacements

    PubMed Central

    St. Clair, Justin; Cartier, Clement; Triantafyllidou, Simoni; Clark, Brandi; Edwards, Marc

    2016-01-01

    Abstract In this 48-month pilot study, long-term impacts of copper:lead galvanic connections on lead release to water were assessed without confounding differences in pipe exposure prehistory or disturbances arising from cutting lead pipe. Lead release was tracked from three lead service line configurations, including (1) 100% lead, (2) traditional partial replacement with 50% copper upstream of 50% lead, and (3) 50% lead upstream of 50% copper as a function of flow rate, connection types, and sampling methodologies. Elevated lead from galvanic corrosion worsened with time, with 140% more lead release from configurations representing traditional partial replacement configurations at 14 months compared to earlier data in the first 8 months. Even when sampled consistently at moderate flow rate (8 LPM) and collecting all water passing through service lines, conditions representing traditional partial service line configurations were significantly worse (≈40%) when compared to 100% lead pipe. If sampled at a high flow rate (32 LPM) and collecting 2 L samples from service lines, 100% of samples collected from traditional partial replacement configurations exceeded thresholds posing an acute health risk versus a 0% risk for samples from 100% lead pipe. Temporary removal of lead accumulations near Pb:Cu junctions and lead deposits from other downstream plastic pipes reduced risk of partial replacements relative to that observed for 100% lead. When typical brass compression couplings were used to connect prepassivated lead pipes, lead release spiked up to 10 times higher, confirming prior concerns raised at bench and field scale regarding adverse impacts of crevices and service line disturbances on lead release. To quantify semirandom particulate lead release from service lines in future research, whole-house filters have many advantages compared to other approaches. PMID:26989344

  15. Damage evolution in acetabular replacements under long-term physiological loading conditions.

    PubMed

    Wang, J-Y; Heaton-Adegbile, P; New, A; Hussell, J G; Tong, J

    2009-05-29

    Damage development in cemented acetabular replacements has been studied in bovine pelvic bones under long-term physiological loading conditions, including normal walking, stair climbing and a combined block loading with representative routine activities. The physiological loading conditions were achieved using a specially designed hip simulator for fixation endurance testing. Damage was detected and monitored using micro-CT scanning at regular intervals of the experiments, and verified by microscopic studies post testing. The results show that debonding at the bone-cement interface defined the failure of cement fixation in all cases, and debondings initiated near the dome of the acetabulum in the superior-posterior quadrant, consistent with the high-stress region identified from the finite element analysis of implanted acetabular models Zant, N.P., Heaton-Adegbile, P., Hussell, J.G., Tong, J., 2008b. In-vitro fatigue failure of cemented acetabular replacements-a hip simulator study. Journal of Biomechanical Engineering, Transactions of the ASME, 130, 021019-1-9]; [Tong, J., Zant, N.P., Wang, J-Y., Heaton-Adegbile, P., Hussell, J.G., 2008. Fatigue in cemented acetabulum. International Journal of Fatigue, 30(8), 1366-1375]. PMID:19345357

  16. Detect Long-term Complications After ICD Replacement (DECODE): Rationale and Study Design of a Multicenter Italian Registry.

    PubMed

    Diemberger, Igor; Parisi, Quintino; De Filippo, Paolo; Narducci, Maria Lucia; Zanon, Francesco; Potenza, Domenico Rosario; Ciaramitaro, Gianfranco; Malacrida, Maurizio; Boriani, Giuseppe; Biffi, Mauro

    2015-10-01

    The replacement of implantable cardioverter-defibrillators (ICDs) may give rise to considerable clinical consequences, the importance of which is underrated by the medical community. Replacement-related adverse events are difficult to identify and require monitoring of both short-term complications and long-term patient outcome. The aim of this study is to perform a structured evaluation of both short- and long-term adverse events and a cost analysis of consecutive ICD replacement procedures. Detect Long-term Complications After ICD Replacement (DECODE) is a prospective, single-arm, multicenter cohort study designed to estimate long-term complication rates (at 12 months and 5 years) in patients undergoing ICD generator replacement. The study will also evaluate predictors of complications, patient management before and during the replacement procedure in clinical practice, and the costs related to use of health care resources. About 800 consecutive patients with standard indications for ICD generator replacement will be enrolled in this study. The decision to undertake generator replacement/upgrade will be made according to the investigators' own judgment (which will be recorded). Patients will be followed for 60 months through periodic in-hospital examinations or remote monitoring. Detailed data on complications related to ICD replacement in current clinical practice are still lacking. The analysis of adverse events will reveal the value of new preventive strategies, thereby yielding both clinical and economic benefits. Moreover, assessment of complication rates after ICD replacement in a real-life setting will help estimate the actual long-term cost of ICD therapy and assess the real impact of increasing ICD longevity on cost-effectiveness. PMID:26282191

  17. Long-Term DHEA Replacement in Primary Adrenal Insufficiency: A Randomized, Controlled Trial

    PubMed Central

    Gurnell, Eleanor M.; Hunt, Penelope J.; Curran, Suzanne E.; Conway, Catherine L.; Pullenayegum, Eleanor M.; Huppert, Felicia A.; Compston, Juliet E.; Herbert, Joseph; Chatterjee, V. Krishna K.

    2008-01-01

    Context: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are the major circulating adrenal steroids and substrates for peripheral sex hormone biosynthesis. In Addison’s disease, glucocorticoid and mineralocorticoid deficiencies require lifelong replacement, but the associated near-total failure of DHEA synthesis is not typically corrected. Objective and Design: In a double-blind trial, we randomized 106 subjects (44 males, 62 females) with Addison’s disease to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months to evaluate its longer-term effects on bone mineral density, body composition, and cognitive function together with well-being and fatigue. Results: Circulating DHEAS and androstenedione rose significantly in both sexes, with testosterone increasing to low normal levels only in females. DHEA reversed ongoing loss of bone mineral density at the femoral neck (P < 0.05) but not at other sites; DHEA enhanced total body (P = 0.02) and truncal (P = 0.017) lean mass significantly with no change in fat mass. At baseline, subscales of psychological well-being in questionnaires (Short Form-36, General Health Questionnaire-30), were significantly worse in Addison’s patients vs. control populations (P < 0.001), and one subscale of SF-36 improved significantly (P = 0.004) after DHEA treatment. There was no significant benefit of DHEA treatment on fatigue or cognitive or sexual function. Supraphysiological DHEAS levels were achieved in some older females who experienced mild androgenic side effects. Conclusion: Although further long-term studies of DHEA therapy, with dosage adjustment, are desirable, our results support some beneficial effects of prolonged DHEA treatment in Addison’s disease. PMID:18000094

  18. Pediatric Cardiopulmonary Bypass Adaptations for Long-Term Survival of Baboons Undergoing Pulmonary Artery Replacement

    PubMed Central

    Whittaker, Carrie; Grist, Gary; Bert, Arthur; Brasky, Kathleen; Neighbors, Stacy; McFall, Christopher; Hilbert, Stephen L.; Drake, William B.; Cromwell, Michael; Mueller, Barbara; Lofland, Gary K.; Hopkins, Richard A.

    2010-01-01

    Abstract: Cardiopulmonary bypass (CPB) protocols of the baboon (Papio cynocephalus anubis) are limited to obtaining experimental data without concern for long-term survival. In the evaluation of pulmonary artery tissue engineered heart valves (TEHVs), pediatric CPB methods are adapted to accommodate the animals’ unique physiology enabling survival up to 6 months until elective sacrifice. Aortic access was by a 14F arterial cannula and atrial access by a single 24F venous cannula. The CPB circuit includes a 3.3 L/min flow rated oxygenator, ¼″ × ⅜″ arterial-venous loop, ⅜″ raceway, and bubble trap. The prime contains 700 mL Plasma-Lyte, 700 units heparin, 5 mL of 50% dextrose, and 20 mg amiodarone. Heparinization (200 u/kg) targets an activated clotting time of 350 seconds. Normothermic CPB was initiated at a 2.5 L/m2/min cardiac index with a mean arterial pressure of 55–80 mmHg. Weaning was monitored with transesophageal echocardiogram. Post-CPB circuit blood was re-infused. Chest tubes were removed with cessation of bleeding. Extubation was performed upon spontaneous breathing. The animals were conscious and upright 3 hours post-CPB. Bioprosthetic valves or TEHVs were implanted as pulmonary replacements in 20 baboons: weight = 27.5 ± 5.6 kg, height = 73 ± 7 cm, body surface area = 0.77 m2 ± 0.08, mean blood flow = 1.973 ± .254 L/min, core temperature = 37.1 ± .1°C, and CPB time = 60 ± 40 minutes. No acidosis accompanied CPB. Sixteen animals survived, four expired. Three died of right ventricular failure and one of an anaphylactoid reaction. Surviving animals had normally functioning replacement valves and ventricles. Baboon CPB requires modifications to include high systemic blood pressure for adequate perfusion into small coronary arteries, careful CPB weaning to prevent ventricular distention, and drug and fluid interventions to abate variable venous return related to a muscularized spleno-splanchnic venous capacity. PMID:21114226

  19. The appearance of newly identified intraocular lesions in Gaucher disease type 3 despite long-term glucocerebrosidase replacement therapy

    PubMed Central

    Sawicka-Gutaj, Nadia; Machaczka, Maciej; Kulińska-Niedziela, Izabela; Bernardczyk-Meller, Jadwiga; Gutaj, Paweł; Sowiński, Jerzy; Ruchała, Marek

    2016-01-01

    Background Gaucher disease (GD) is an autosomal recessive lipid storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase. The presence of central nervous system disease is a hallmark of the neuronopathic forms of GD (types 2 and 3). Intraocular lesions (e.g. corneal clouding, retinal lesions, and vitreous opacities) have been infrequently reported in GD type 3 (GD3). Moreover, there are virtually no published data on the occurrence and natural course of intraocular lesions in GD3 patients treated with enzyme replacement therapy (ERT). Case presentation We describe the case of a 26-year-old Polish male with L444P homozygous GD3 (mutation c.1448T > C in the GBA1 gene) who developed fundus lesions despite 10 years of ERT. At the age of 23 years, a spectral domain optical coherence tomography (OCT) examination was performed which disclosed the presence of discrete lesions located preretinally, intraretinally in the nerve fiber layer, and in the vitreous body. A 3-year follow-up OCT examination has not shown any significant progression of the fundus lesions. Conclusions To the best of our knowledge, this is the first published report describing the occurrence of newly identified retinal and preretinal lesions occurring during long-term ERT in GD3. We recommend that a careful ophthalmic assessment, including a dilated fundus examination, should be included as part of annual follow-up in patients with GD3. Further studies are needed to understand the nature and clinical course of these changes and whether or not these intraocular findings have any predictive value in the context of neurologic and skeletal progression in GD3. PMID:27064303

  20. Obesity and long term functional outcomes following elective total hip replacement

    PubMed Central

    2012-01-01

    Introduction Obesity rates continue to rise and more total hip arthroplasty procedures are being performed in progressively younger, obese patients. Hence, maintenance of long term physical function will become very important for quality of life, functional independence and hip prosthesis survival. Presently, there are no reviews of the long term efficacy of total hip arthroplasty on physical function. This review: 1) synopsized available data regarding obesity effects on long term functional outcomes after total hip arthroplasty, and 2) suggested future directions for research. Methods A literature search was conducted from 1965 to January of 2011 for studies that evaluated long term functional outcomes at one year or longer after THA in obese (body mass index values ≥30 kg/m2) and non-obese patients (body mass index <30 kg/m2). Results Five retrospective studies and 18 prospective studies were identified as those that assessed physical function before surgery out to ≥ one year after total hip arthroplasty. Study sample sizes ranged from 108–18,968 and followed patients from one to twenty years. Total hip arthroplasty confers significant pain reduction and improvement in quality of life irrespective of body mass index. Functional improvement occurred after total hip arthroplasty among all studies, but obese patients generally did not attain the same level of physical function by the follow-up time point. Discussion Uncontrolled obesity after total hip arthroplasty is related to worsening of comorbidities and excessive health care costs over the long term. Aggressive and sustainable rehabilitation strategies that include physical exercise, psychosocial components and behavior modification may be highly useful in maximizing and maintaining weight loss after total hip arthroplasty. PMID:22533938

  1. Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study

    PubMed Central

    Wells, Michael; Sturdee, David W; Barlow, David H; Ulrich, Lian G; O'Brien, Karen; Campbell, Michael J; Vessey, Martin P; Bragg, Anthony J

    2002-01-01

    Objective To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17β-oestradiol and 1 mg norethisterone acetate on endometrial histology in postmenopausal women. Design Follow up study in postmenopausal women. Setting 31 menopause clinics in the United Kingdom. Participants 534 postmenopausal women, all with an intact uterus, who had completed nine months of treatment with oral continuous combined 2 mg 17β-oestradiol and 1 mg norethisterone acetate agreed to take part in a long term follow up study. Women were assigned to different groups on the basis of the treatment status immediately before entering the original study: 360 women had taken sequential oestrogen-progestogen hormone replacement therapy, 164 had taken no hormone replacement therapy, and 10 had taken unopposed oestrogen therapy. Methods Endometrial aspiration specimens were taken before the women started the continuous combined regimen, after 9 and 24-36 months, and at the end of the five year treatment period or on withdrawal from the study. Main outcome measure Results of endometrial histology. Results The duration of treatment with continuous combined hormone replacement therapy was 4.4 (range 1.1-5.9) years. Data on endometrial specimens were available for 526 women after nine months of treatment, 465 women after 24-36 months of treatment, and 398 women who completed the five years treatment (345 women) or were withdrawn between the two latter visits for biopsies (53 women). No cases of endometrial hyperplasia or malignancy were detected at biopsy; 69% of women had an endometrium classified as atrophic or unassessable on completion of the study or withdrawal from it. Before the continuous combined therapy was started, complex hyperplasia was detected in 21 women who had taken sequential hormone replacement therapy before the study and in one who had taken unopposed oestrogen. All of these women had normal results on histological examination of

  2. [Abdominal secondary aorto-enteric fistulae complicating aortic graft replacement: postoperative and long-term outcomes in 32 patients].

    PubMed

    Vaillant, Jean-christophe; Schoell, Thibaut; Karoui, Mehdi; Chiche, Laurent; Gaudric, Julien; Gibert, Hadrien; Tresallet, Christophe; Koskas, Fabien; Hannoun, Laurent

    2013-01-01

    Management of patients with abdominal secondary aorto-entericfistulae (SAEF) complicating aortic graft replacement is controversial. We retrospectively analyzed the postope- rative and long-term outcomes of all consecutive patients operated on for SAEF betwveen 2002 and2012. All were managed by in situ replacement with a cryopreserved allograft and treatment of the affected digestive tract. Thirty-two patients (median age 65 years) underwent aortic replacement for SAEFa median of 5 years after initial aortic surgery. The fistulae were located in the duodenum (n = 20), small bowel (n = 6), colon (n = 5) or stomach (n = 1). Treatment of the digestive tract included suture (n = 16), resection with anastomosis (n = 12) covered by a defunctioning stoma (n = 1), and Hartmann's procedure (n = 3). Omentoplasty was performed in 18 patients (56 %), and 17 patients (53 %) had afeedingjejunostomy. Eight patients (25 %) died post-operatively, 3 with a recurrent aorto-enteric fistula. Fifteen (62.5 %) of the remaining patients developed 27 complications, including 6 patients (19 %) with severe morbidity (Dindo III-IV). The reoperation rate was 21 %. The median hospital stay was 33 days. During follow-up (median 15 months), no further patients had a recurrent aorto-enteric fistula. We conclude that surgery for SAEF is a major procedure associated with high mortality and morbidity. Good long-term results can be obtained by excision of the prosthetic graft with cryopreserved allograft replacement, and by management in a tertialy referral center with expertise in both vascular and digestive surgery. PMID:25518163

  3. Combined enzyme replacement and haematopoietic stem cell transplantation in Hurler syndrome.

    PubMed

    Bijarnia, Sunita; Shaw, Peter; Vimpani, Anne; Smith, Robert; Pacey, Verity; O'Grady, Helen; Christodoulou, John; Sillence, David

    2009-01-01

    We report the long-term follow-up of successful treatment of mucopolysaccharidosis type I H (MPS IH, Hurler syndrome) with combined enzyme replacement therapy and haematopoietic progenitor stem cell transplant. PMID:19712183

  4. Long-term survival after surgical aortic valve replacement among patients over 65 years of age

    PubMed Central

    Sharabiani, Mansour T A; Fiorentino, Francesca; Angelini, Gianni D; Patel, Nishith N

    2016-01-01

    Objective Surgical aortic valve replacement (AVR) remains the gold standard therapy for severe aortic stenosis. Long-term survival data following AVR is required. Our objective was to provide a detailed contemporary benchmark of long-term survival following AVR among elderly patients (≥65 years) in the UK. Methods We conducted a retrospective cohort study of 1815 adult patients undergoing surgical AVR± coronary artery bypass graft (CABG) surgery at a single UK centre between 1996 and 2011. Our main outcome was patient survival, which was assessed by linkage to census records at the Office for National Statistics. Results The mean age of the cohort was 75 (±5.6) years. Patients in the AVR alone group had a slightly higher median survival of 10.9 (95% CI 10.5 to 11.8) years than the AVR+CABG group which had a median survival of 9.6 (95% CI 8.7 to 10.1) years (p=0.001 of log-rank test (LRT) for equality of survivor functions). The presence of chronic kidney disease, severely impaired left ventricular function or being a current smoker were each associated with a ≥50% increased risk of long-term mortality. Comparison of our study cohort patients and the reference (operation year, age and gender matched) UK population suggested no difference in survival probability up to 8 years (p=0.55). However, for longer periods of follow-up, the difference became increasingly significant (p<0.0001). Conclusions Long-term survival following surgical AVR in patients over 65 years of age is excellent and up to 8 years is comparable to the matched general population. PMID:27042318

  5. Impact of obesity on long-term survival after aortic valve replacement with a small prosthesis

    PubMed Central

    Wang, Biao; Yang, Hongyang; Wang, Tao; Zhang, Xiquan; Zhu, Wenjie; Cao, Guangqing; Wu, Shuming

    2013-01-01

    OBJECTIVES Although many studies have evaluated the impact of obesity on various medical treatments, it is not known whether obesity is related to late mortality with implantation of small aortic prostheses. This study evaluated the effect of obesity on the late survival of patients after aortic valve replacement (AVR) with implantation of a small aortic prosthesis (size ≤21 mm). METHODS From January 1998 to December 2008, 307 patients in our institution who underwent primary AVR with smaller prostheses survived 30 days after surgery. Patients were categorized as normal weight if body mass index (BMI) was <24 kg/m2, overweight if BMI 24–27.9 kg/m2 and obese if BMI ≥28 kg/m2. Data of the New York Heart Association (NYHA) functional classification, left ventricular ejection fraction (LVEF), effective orifice area index (EOAI) and left ventricular mass index of the patients were collected at the third month, sixth month, first year, third year, fifth year and eighth year after operation. RESULTS By multivariable analysis, obesity was a significant independent factor of late mortality (hazard ratio: 1.62; P = 0.01). The obese and overweight groups of patients exhibited lower survival (P < 0.001) and a higher proportion in NYHA Class III/IV (P < 0.01) compared with the normal group. A lower EOAI and higher left ventricular mass index were found in the obese and overweight groups, but we saw no significant variance in LVEF among the three groups. CONCLUSIONS Obesity is associated with increased late mortality of patients after AVR with implantation of small aortic prosthesis. Obesity or/and overweight may also affect the NYHA classification, even in the longer term. EOAI should be improved where possible, as it may reduce late mortality and improve quality of life in obese or overweight patients. PMID:23529754

  6. Uncemented Total Hip Replacement Stem Loosening after Long Term Compressive Stress Application: A Simulated FEA Study of Cortical Bone Remodeling

    NASA Astrophysics Data System (ADS)

    Jung, Duk-Young; Tsutsumi, Sadami; Nakai, Ryusuke; Ikeuchi, Ken; Sekel, Ron

    The purpose of this study is to predict with the use of FEA, the differing predisposition to cortical bone resorption and subsequent distal migration of an un-cemented femoral hip replacement stem subjected to long term biomechanical high compressive stresses, while varying the load angles, the material properties of the stem, and the stem length. A two-dimensional hip model was constructed to estimate the minimum principle stresses (P3) and migration magnitudes. Bone remodeling at the interface between the bone and the prosthesis was performed by comparison of the local compressive stress to physiological stress values governing bone resorption. With respect to load angles, migrations of the hip prosthesis did not occur with load angles between 63° and 74° load angle in relation to the longitudinal axis of the bony femur, as the compressive stress generated on the cortical bone was under the criteria threshold for bone resorption (-50MPa). In addition, the magnitude of migration (17%decrease) was relatively more sensitive to changes in stem length than those (92%decrease) of changes of material properties. In conclusion, using an FEA model for bone remodeling, based on the high compressive stresses exerted on distal cortical bone, it is possible to estimate migration magnitudes of cementless hip prostheses in the long term. The load angles have been shown to be an important parameter affecting the migration magnitudes and furthermore, it can be demonstrated that the stiffer materials and reduction of stem length can decrease the migration of cementless hip prosthesis in the long term.

  7. Effect of long-term industrial waste effluent pollution on soil enzyme activities and bacterial community composition.

    PubMed

    Subrahmanyam, Gangavarapu; Shen, Ju-Pei; Liu, Yu-Rong; Archana, Gattupalli; Zhang, Li-Mei

    2016-02-01

    Although numerous studies have addressed the influence of exogenous pollutants on microorganisms, the effect of long-term industrial waste effluent (IWE) pollution on the activity and diversity of soil bacteria was still unclear. Three soil samples characterized as uncontaminated (R1), moderately contaminated (R2), and highly contaminated (R3) receiving mixed organic and heavy metal pollutants for more than 20 years through IWE were collected along the Mahi River basin, Gujarat, western India. Basal soil respiration and in situ enzyme activities indicated an apparent deleterious effect of IWE on microbial activity and soil function. Community composition profiling of soil bacteria using 16S rRNA gene amplification and denaturing gradient gel electrophoresis (DGGE) method indicated an apparent bacterial community shift in the IWE-affected soils. Cloning and sequencing of DGGE bands revealed that the dominated bacterial phyla in polluted soil were affiliated with Firmicutes, Acidobacteria, and Actinobacteria, indicating that these bacterial phyla may have a high tolerance to pollutants. We suggested that specific bacterial phyla along with soil enzyme activities could be used as relevant biological indicators for long-term pollution assessment on soil quality. Graphical Abstract Bacterial community profiling and soil enzyme activities in long-term industrial waste effluent polluted soils. PMID:26803661

  8. Long-term in vitro culture of bovine preantral follicles: Effect of base medium and medium replacement methods.

    PubMed

    Araújo, V R; Gastal, M O; Wischral, A; Figueiredo, J R; Gastal, E L

    2015-10-01

    Two culture media and replacement methods were compared during long-term in vitro culture of secondary follicles of cattle using α-MEM(+) or TCM-199(+) as base media. The medium replacement methods were: Conventional - removal and subsequent addition of the same amount (60μl) in a 100μl aliquot (MEM-C and TCM-C), and Small Supplementation - addition of 5μl of fresh medium to an initial small aliquot (50μl), resulting in a final volume of 125μl on the last day of culture (MEM-S and TCM-S). A total of 207 secondary follicles were cultured individually for 32 days at 38.5°C in 5% CO2 and medium replacement was performed every other day. The MEM-S treatment resulted in a larger (P<0.01) follicular diameter, greater (P<0.02) growth rate, greater (P<0.02) antrum formation, as well as greater (P<0.0001) estradiol concentrations when compared with the MEM-C treatment. The medium change methods did not affect (P>0.05) the follicular and estradiol end points for TCM-199(+). The expression of the FSHR gene was greater (P<0.03) with the TCM-C than TCM-S treatment, while the relative amounts of mRNA for IGF1 was greater (P<0.02) with MEM-S than TCM-S treatments and for VEGF was greater (P<0.02) with MEM-C than TCM-C treatment. In conclusion, the type of base medium and the effect of periodic addition of medium differentially affected follicle development, estradiol production, and gene expression. Furthermore, α-MEM(+) can be used to replace TCM-199(+) for culture of preantral follicles of cattle if progressive addition of medium is used for medium change. PMID:26304751

  9. Mid-to long-term results of revision total hip replacement in patients aged 50 years or younger.

    PubMed

    Lee, P T H; Lakstein, D L; Lozano, B; Safir, O; Backstein, J; Gross, A E

    2014-08-01

    Revision total hip replacement (THR) for young patients is challenging because of technical complexity and the potential need for subsequent further revisions. We have assessed the survivorship, functional outcome and complications of this procedure in patients aged < 50 years through a large longitudinal series with consistent treatment algorithms. Of 132 consecutive patients (181 hips) who underwent revision THR, 102 patients (151 hips) with a mean age of 43 years (22 to 50) were reviewed at a mean follow-up of 11 years (2 to 26) post-operatively. We attempted to restore bone stock with allograft where indicated. Using further revision for any reason as an end point, the survival of the acetabular component was 71% (sd 4) and 54% (sd 7) at ten- and 20 years. The survival of the femoral component was 80% (sd 4) and 62% (sd 6) at ten- and 20 years. Complications included 11 dislocations (6.1%), ten periprosthetic fractures (5.5%), two deep infections (1.1%), four sciatic nerve palsies (2.2%; three resolved without intervention, one improved after exploration and freeing from adhesions) and one vascular injury (0.6%). The mean modified Harris Hip Score was 41 (10 to 82) pre-operatively, 77 (39 to 93) one year post-operatively and 77 (38 to 93) at the latest review. This overall perspective on the mid- to long-term results is valuable when advising young patients on the prospects of revision surgery at the time of primary replacement. PMID:25086120

  10. Long-term tocotrienol supplementation and glutathione-dependent enzymes during hepatocarcinogenesis in the rat.

    PubMed

    Rahmat, A; Wan Ngah, W Z; Gapor, A; Khalid, B A

    1993-09-01

    The effects of long-term administration of tocotrienol on hepatocarcinogenesis in rats induced by diethyl nitrosamine (DEN) and 2-acetylaminofluorene (AAF) were investigated by the determination of plasma and liver gamma-glutamyl transpeptidase (GGT), cytosolic glutathione reductase (GSSG-Rx), glutathione peroxidase (GSH-Px) and glutathione S-transferase (GST). Twenty-eight male Rattus norwegicus rats (120-160g) were divided according to treatments into four groups: control group, tocotrienol - supplemented diet group (30mg/kg food), DEN/AAF-treated group and DEN/AAF treated plus tocotrienol-supplemented-diet group (30mg/kg food). The rats were sacrificed after nine months. The results obtained indicated no difference in the morphology and histology of the livers of control and tocotrienol-treated rats. Greyish-white neoplastic nodules (two per liver) were found in all the DEN/ AAF treated rats (n-10) whereas only one nodule was found in one of the carcinogen treated rats receiving tocotrienol supplementation (n-6). Histological examination showed obvious cellular damage for both the DEN/AAF-treated rats and the tocotrienol-supplemented rats but were less severe in the latter. Treatment with DEN/AAF caused increases in GGT, GSH-Px, GST and GSSG-Rx activities when compared to controls. These increases were also observed when tocotrienol was supplemented with DEN/AAF but the increases were less when compared to the rats receiving DEN/AAF only. PMID:24352144

  11. Mineralogical impact on long-term patterns of soil nitrogen and phosphorus enzyme activities

    NASA Astrophysics Data System (ADS)

    Mikutta, Robert; Turner, Stephanie; Meyer-Stüve, Sandra; Guggenberger, Georg; Dohrmann, Reiner; Schippers, Axel

    2014-05-01

    Soil chronosequences provide a unique opportunity to study microbial activity over time in mineralogical diverse soils of different ages. The main objective of this study was to test the effect of mineralogical properties, nutrient and organic matter availability over whole soil pro-files on the abundance and activity of the microbial communities. We focused on microbio-logical processes involved in nitrogen and phosphorus cycling at the 120,000-year Franz Josef soil chronosequence. Microbial abundances (microbial biomass and total cell counts) and enzyme activities (protease, urease, aminopeptidase, and phosphatase) were determined and related to nutrient contents and mineralogical soil properties. Both, microbial abundances and enzyme activities decreased with soil depth at all sites. In the organic layers, microbial biomass and the activities of N-hydrolyzing enzymes showed their maximum at the intermediate-aged sites, corresponding to a high aboveground biomass. In contrast, the phosphatase activity increased with site age. The activities of N-hydrolyzing enzymes were positively correlated with total carbon and nitrogen contents, whereas the phosphatase activity was negatively correlated with the phosphorus content. In the mineral soil, the enzyme activities were generally low, thus reflecting the presence of strongly sorbing minerals. Sub-strate-normalized enzyme activities correlated negatively to clay content as well as poorly crystalline Al and Fe oxyhydroxides, supporting the view that the evolution of reactive sec-ondary mineral phases alters the activity of the microbial communities by constraining sub-strate availability. Our data suggest a strong mineralogical influence on nutrient cycling par-ticularly in subsoil environments.

  12. Long-term anti-FVIII antibody response in Bethesda-negative haemophilia A patients receiving continuous replacement therapy.

    PubMed

    Klintman, Jenny; Hillarp, Andreas; Berntorp, Erik; Astermark, Jan

    2013-11-01

    It has previously been shown that patients with haemophilia A may develop non-neutralizing anti-factor VIII (FVIII) antibodies (NNA) that escape detection by the Bethesda assay, but are detected using immune-based assays. We and others found NNAs to be directed not only towards non-functional parts of the protein, but towards all regions of the FVIII protein. We also showed a heterogeneous antibody response towards different FVIII products. However, the clinical relevance and the natural history of NNA remain unclear. Therefore, we followed a cohort of unrelated subjects with haemophilia A for 4 years with the goal of exploring the long-term development of NNA using an enzyme-linked immunosorbent assay (ELISA). Ten of 78 subjects (12·8%) exhibited an immune response that was transient and heterogeneous, and none of the subjects developed an FVIII inhibitor. The result of the ELISA was examined in relation to clinical variables and no significant associations between a positive ELISA and age, F8 mutation, port-à-cath implantation and HCV infection were shown. Interestingly, patients with NNA had significantly fewer bleeding episodes (P = 0·048) compared with NNA-negative subjects. The results indicate that the immune response to FVIII products within an individual may vary over time. However, the clinical impact of NNA remains unclear. PMID:24032553

  13. Effects of long term irrigation with polluted water and sludge amendment on some soil enzyme activities

    SciTech Connect

    Topac, F.O.; Baskaya, H.S.; Alkan, U.; Katkat, A.V.

    2008-01-15

    The objective of this study was to determine the effects of wastewater sludge-fly ash mixtures on urease, dehydrogenase, alkaline phosphatase and beta-glucosidase activities in soils. In order to evaluate the probable effects of previous soil management practices (irrigation with polluted water) on soil enzymes, two different soil samples which were similar in physical properties, but different in irrigation practice were used. The application of wastewater sludges supplemented with varying doses of fly ash increased potential enzyme activities for a short period of time (3 months) in comparison to unamended soils. However, the activity levels generally showed a decreasing trend with increasing ash ratios indicating the inhibitory effect of fly ash. The urease and dehydrogenase activities were particularly lower in soils irrigated from a polluted stream, indicating the negative effects of the previous soil management on soil microbial activity.

  14. Responses of absolute and specific soil enzyme activities to long term additions of organic and mineral fertilizer.

    PubMed

    Zhang, Xinyu; Dong, Wenyi; Dai, Xiaoqin; Schaeffer, Sean; Yang, Fengting; Radosevich, Mark; Xu, Lili; Liu, Xiyu; Sun, Xiaomin

    2015-12-01

    Long-term phosphorus (P) and nitrogen (N) applications may seriously affect soil microbial activity. A long-term field fertilizer application trial was established on reddish paddy soils in the subtropical region of southern China in 1998. We assessed the effects of swine manure and seven different rates or ratios of NPK fertilizer treatments on (1) the absolute and specific enzyme activities per unit of soil organic carbon (SOC) or microbial biomass carbon (MBC) involved in C, N, and P transformations and (2) their relationships with soil environmental factors and soil microbial community structures. The results showed that manure applications led to increases in the absolute and specific activities of soil β-1,4-glucosidase(βG), β-1,4-N-acetylglucosaminidase (NAG), and leucine aminopeptidase (LAP). The absolute and specific acid phosphatase (AP) activities decreased as mineral P fertilizer application rates and ratios increased. Redundancy analysis (RDA) showed that there were negative correlations between absolute and specific AP activities, pH, and total P contents, while there were positive correlations between soil absolute and specific βG, NAG, and LAP enzyme activities, and SOC and total N contents. RDA showed that the contents of actinomycete and Gram-positive bacterium PLFA biomarkers are more closely related to the absolute and specific enzyme activities than the other PLFA biomarkers (P<0.01). Our results suggest that both the absolute and specific enzyme activities could be used as sensitive soil quality indicators that provide useful linkages with the microbial community structures and environmental factors. To maintain microbial activity and to minimize environmental impacts, P should be applied as a combination of inorganic and organic forms, and total P fertilizer application rates to subtropical paddy soils should not exceed 44 kg P ha(-1) year(-1). PMID:26196069

  15. Cervical artificial disc replacement with ProDisc-C: clinical and radiographic outcomes with long-term follow-up.

    PubMed

    Malham, Gregory M; Parker, Rhiannon M; Ellis, Ngaire J; Chan, Philip G; Varma, Dinesh

    2014-06-01

    Cervical artificial disc replacement (ADR) is indicated for the treatment of severe radiculopathy permitting neural decompression and maintenance of motion. We evaluated the clinical and radiographic outcomes in cervical ADR patients using the ProDisc-C device (DePuy Synthes, West Chester, PA, USA) with a 5-9 year follow-up. Data were collected through a prospective registry, with retrospective analysis performed on 24 consecutive patients treated with cervical ADR by a single surgeon. All patients underwent single- or two-level ADR with the ProDisc-C device. Outcome measures included neck and arm pain (visual analogue scale), disability (neck disability index [NDI]), complications and secondary surgery rates. Flexion-extension cervical radiographs were performed to assess range of motion (ROM) of the device and adjacent segment disease (ASD). Average follow-up was 7.7 years. Neck and arm pain improved 60% and 79%, respectively, and NDI had an improvement of 58%. There were no episodes of device migration or subsidence. Mean ROM of the device was 6.4°. Heterotopic ossification was present in seven patients (37%). Radiographic ASD below the device developed in four patients (21%) (one single-level and three two-level ADR). No patient required secondary surgery (repeat operations at the index level or adjacent levels). Fourteen out of 19 patients (74%) were able to return to employment, with a median return to work time of 1.3 months. The ProDisc-C device for cervical ADR is a safe option for patients providing excellent clinical outcomes, satisfactory return to work rates and maintenance of segmental motion despite radiographic evidence of heterotopic ossification and ASD on long-term follow-up. PMID:24417795

  16. Alterations in antioxidant enzyme activities and proline content in pea leaves under long-term drought stress.

    PubMed

    Karataş, Ilhami; Öztürk, Lokman; Demir, Yavuz; Unlükara, Ali; Kurunç, Ahmet; Düzdemir, Oral

    2014-09-01

    The effects of long-term drought stress on chlorophyll, proline, protein and hydrogen peroxide (H2O2) contents, malondialdehyde (MDA) in terms of lipid peroxidation and on the changes in the activities of antioxidant enzymes such as superoxide dismutase (SOD, EC 1.15.1.1), ascorbate peroxidase (APX, EC 1.11.1.11), catalase (CAT, EC 1.11.1.6) and peroxidase (POX; EC 1.11.1.7) in the leaves of pea (Pisum sativum L.) were studied in field conditions. Chlorophyll and protein contents in leaves decreased significantly with increased drought stress. The proline content increased markedly under water deficit. MDA amounts were elevated as a result of water shortage, whereas H(2)O(2) content changed slightly in pea leaves exposed to drought stress. Drought stress markedly enhanced the activities of SOD, CAT and POX but slightly changed the activity of APX. We conclude that in field conditions, long-term water shortage increased the susceptibility to drought in peas. PMID:23047611

  17. Longitudinal Blood Pressure Control, Long-Term Mortality, and Predictive Utility of Serum Liver Enzymes and Bilirubin in Hypertensive Patients.

    PubMed

    McCallum, Linsay; Panniyammakal, Jeemon; Hastie, Claire E; Hewitt, Jonathan; Patel, Rajan; Jones, Gregory C; Muir, Scott; Walters, Matthew; Sattar, Naveed; Dominiczak, Anna F; Padmanabhan, Sandosh

    2015-07-01

    There is accruing evidence from general population studies that serum bilirubin and liver enzymes affect blood pressure (BP) and cardiovascular risk, but it is unclear whether these have an impact on hypertensive patients in terms of long-term survival or BP control. We analyzed 12 000 treated hypertensive individuals attending a tertiary care clinic followed up for 35 years for association between baseline liver function tests and cause-specific mortality after adjustment for conventional cardiovascular covariates. Generalized estimating equations were used to study the association of liver tests and follow-up BP. The total time at risk was 173 806 person years with median survival 32.3 years. Follow-up systolic BP over 5 years changed by -0.4 (alanine transaminase and bilirubin), +2.1(alkaline phosphatase), +0.9(γ-glutamyl transpeptidase) mm Hg for each standard deviation increase. Serum total bilirubin and alanine transaminase showed a significant negative association with all-cause and cardiovascular mortality, whereas alkaline phosphatase and γ-glutamyl transpeptidase showed a positive association and aspartate transaminase showed a U-shapedassociation. Serum bilirubin showed an incremental improvement of continuous net reclassification improvement by 8% to 26% for 25 year and 35 year cardiovascular mortality, whereas all liver markers together improved continuous net reclassification improvement by 19% to 47% compared with reference model. In hypertensive patients, serum liver enzymes and bilirubin within 4 standard deviations of the mean show independent effects on mortality and BP control. Our findings would support further studies to elucidate the mechanisms by which liver enzymes and bilirubin may exert an effect on BP and cardiovascular risk, but there is little support for using them in risk stratification. PMID:25941342

  18. Long-Term Changes in the Distal Aorta after Aortic Arch Replacement in Acute DeBakey Type I Aortic Dissection

    PubMed Central

    Cho, Kwangjo; Jeong, Jeahwa; Park, Jongyoon; Yun, Sungsil; Woo, Jongsu

    2016-01-01

    Background We analyzed the long-term results of ascending aortic replacement and arch aortic replacement in acute DeBakey type I aortic dissections to measure the differences in the distal aortic changes with extension of the aortic replacement. Methods We reviewed 142 cases of acute DeBakey type I aortic dissections (1996–2015). Seventy percent of the cases were ascending aortic replacements, and 30% of the cases underwent total arch aortic replacement, which includes the aorta from the root to the beginning of the descending aorta with the 3 arch branches. Fourteen percent (20 cases) resulted in surgical mortality and 86% of cases that survived had a mean follow-up period of 6.6±4.6 years. Among these cases, 64% of the patients were followed up with computed tomography (CT) angiograms with the duration of the final CT check period of 4.9±2.9 years. Results There were 15 cases of reoperation in 13 patients. Of these 15 cases, 13 cases were in the ascending aortic replacement group and 2 cases were in the total arch aortic replacement group. Late mortality occurred in 13 cases; 10 cases were in the ascending aortic replacement group and 3 cases were in the total arch aortic replacement group. Eight patients died of a distal aortic problem in the ascending aortic replacement group, and 1 patient died of distal aortic rupture in the total arch aortic replacement group. The follow-up CT angiogram showed that 69.8% of the ascending aortic replacement group and 35.7% of the total arch aortic replacement group developed distal aortic dilatation (p=0.0022). Conclusion The total arch aortic replacement procedure developed fewer distal remnant aortic problems from dilatation than the ascending aortic replacement procedure in acute type I aortic dissections. PMID:27525235

  19. Enzyme replacement in Tay-Sachs disease.

    PubMed

    von Specht, B U; Geiger, B; Arnon, R; Passwell, J; Keren, G; Goldman, B; Padeh, B

    1979-06-01

    Enzyme replacement therapy was attempted with two Tay-Sachs-diseased individuals--a 14-month-old child and a 7-week-old infant. Treatment consisted of repeated weekly intrathecal injections of pure hexosaminidase A. Injection of this enzyme resulted in almost complete disappearance of GM2 from the serum, but did not bring about dissolution of the GM2 membranous cytoplasmic bodies in the brain, as detected by electronmicroscopy. Both patients tolerated the treatment without apparent clinical complications, but no clear-cut improvement was noted as a result of prolonged injections of hexosaminidase A. Since this treatment was initiated in both an advanced stage and a very early stage of the disease, we conclude that enzyme replacement treatment by this route is not beneficial for patients with Tay-Sachs disease. PMID:572006

  20. Imaging of enzyme replacement therapy using PET

    PubMed Central

    Phenix, Christopher P.; Rempel, Brian P.; Colobong, Karen; Doudet, Doris J.; Adam, Michael J.; Clarke, Lorne A.; Withers, Stephen G.

    2010-01-01

    Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucher disease, Fabry disease, Hurler syndrome, Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid β-glucocerebrosidase (GCase), the recombinant enzyme formulated in Cerezyme® used to treat Gaucher disease, using an 18F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue 18F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to 18F-label GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs. PMID:20534487

  1. Diagnostic imaging methods applied in long-term surveillance after EVAR. Will computed tomography angiography be replaced by other methods?

    PubMed Central

    Stefaniak, Karolina; Gabriel, Marcin; Oszkinis, Grzegorz

    2016-01-01

    Endovascular implantation of a stent graft in the abdominal aorta (endovascular aneurysm repair – EVAR) is a widely accepted alternative to open surgery in treatment of abdominal aortic aneurysms. Although EVAR is connected with a significant reduction in the risk of peri- and post-operative complications, it does not eliminate them totally. Long-term surveillance of post-EVAR patients is aimed at early detection of and fast reaction to a group of complications called endovascular leaks. Currently, the gold standard in leak diagnostics is computed tomography angiography (CTA). The other methods are ultrasonography, magnetic resonance (MR) angiography, intra-aneurysm sac pressure measurement, X-ray, and digital subtraction angiography (DSA). Despite many analyses based on long-term research, emphasising the high value and competitiveness of less invasive tests such as US or X-ray compared to CTA, it is still difficult for them to win the trust and acceptance of clinicians. The persisting view is that computed tomography is the test that finally resolves any inaccuracies. Consequently, a patient with a number of concurrent diseases is subject to absurdly high radiation exposure and effects of a radiocontrast agent within a short time. It is therefore logical to acknowledge that the EVAR-related risk is catching up with the open surgery risk, while the endovascular procedure is much more costly. Nevertheless, the status of CTA as the gold standard ultimately seems to be unthreatened. This paper presents a description of the diagnostic imaging tests that make it possible to detect any vascular leaks and to develop strategies for therapeutic processes. PMID:26966443

  2. Encapsulation of a Nerve Agent Detoxifying Enzyme by a Mesoporous Zirconium Metal-Organic Framework Engenders Thermal and Long-Term Stability.

    PubMed

    Li, Peng; Moon, Su-Young; Guelta, Mark A; Harvey, Steven P; Hupp, Joseph T; Farha, Omar K

    2016-07-01

    Immobilized enzymes typically have greater thermal and operational stability than their soluble form. Here we report that for the first time, a nerve agent detoxifying enzyme, organophosphorus acid anhydrolase (OPAA), has been successfully encapsulated into a water-stable zirconium metal-organic framework (MOF). This MOF features a hierarchical mesoporous channel structure and exhibits a 12 wt % loading capacity of OPAA. The thermal and long-term stabilities of OPAA are both significantly enhanced after immobilization. PMID:27341436

  3. Old Myths, New Concerns: the Long-Term Effects of Ascending Aorta Replacement with Dacron Grafts. Not All That Glitters Is Gold.

    PubMed

    Spadaccio, Cristiano; Nappi, Francesco; Al-Attar, Nawwar; Sutherland, Fraser W; Acar, Christophe; Nenna, Antonio; Trombetta, Marcella; Chello, Massimo; Rainer, Alberto

    2016-08-01

    Synthetic grafts are widely used in cardiac and vascular surgery since the mid-1970s. Despite their general good performance, inability of mimicking the elastomechanical characteristics of the native arterial tissue, and the consequent lack of adequate compliance, leads to a cascade of hemodynamic and biological alterations deeply affecting cardiovascular homeostasis. Those concerns have been reconsidered in more contemporaneous surgical and experimental reports which also triggered some research efforts in the tissue engineering field towards the realization of biomimetic arterial surrogates. The present review focuses on the significance of the "compliance mismatch" phenomenon occurring after aortic root or ascending aorta replacement with prosthetic grafts and discusses the clinical reflexes of this state of tissue incompatibility, as the loss of the native elastomechanical properties of the aorta can translate into detrimental effects on the normal efficiency of the aortic root complex with impact in the long-term results of patients undergoing aortic replacement. PMID:27245785

  4. The inherent properties of enzymes can only lead to a negative temperature response of soil C decomposition on the long-term.

    NASA Astrophysics Data System (ADS)

    Alvarez, Gaël; Fontaine, Sébastien

    2015-04-01

    More than one century after the pioneer work of Arrhenius on the temperature dependence of chemical reactions, the response of soil C decomposition to global warming remains uncertain. The majority of lab experiments, generally conducted at short term (months to years), suggest that the decomposition of soil C accelerates with temperature. In contrast, long-term (> 5 years) ecosystem warming experiments show that stimulation of soil respiration is only transitory. Moreover, studies on ecosystem C fluxes along a latitudinal gradient even suggest that, for a given amount of C fixed by the ecosystem, the decomposition flux decreases with temperature leading to higher C storage in warmer ecosystems (Giardina and Ryan, 2000; Sanderman, 2003). To understand this discrepancy between short-term and long-term temperature responses of C decomposition, we re-analysed the thermo-dependence of decomposition in a theory distinguishing enzyme-limited and substrate-limited reactions. Indeed, it is increasingly recognized that decomposition of the largest pool of soil C (humified organic C, HOC) is limited by the amount of soil (extracellular) enzymes. The substrate-limited reaction and its dependence to temperature were classically modelled with the first order kinetics dC/dt=-kC where reaction velocity k is modelled by an Arrhenius equation. The thermo-dependence of enzyme-limited reactions was studied in models where the reaction velocity depends on the specific activity of enzymes and the dynamics of enzyme pool, each of which may display distinct temperature sensitivities. The dynamics of the enzyme pool depended on (1) the inactivation of enzymes and its dependence to time and temperature and (2) the microbial production of enzymes, which is limited by the energy available to soil microorganisms. These models were analysed mathematically and through simulations using data on thermodynamics properties of enzymes (activation energies) and ecosystem C fluxes. Our results show

  5. Effects of Cr(VI) long-term and low-dose action on mammalian antioxidant enzymes (an in vitro study)

    SciTech Connect

    Asatiani, N.; Sapojnikova, N.; Abuladze, M.; Kartvelishvili, T.L.; Kulikova, N.; Kiziria, E.; Namchevadze, E.; Holman, H.-Y.N.

    2003-08-01

    In order to investigate the low-dose long-term Cr(VI) action on antioxidant enzymes in cultured mammalian cells we estimated the activity of glutathione dependent antioxidant enzymes, catalase and superoxide dismutase (SOD) under various chromium concentrations in human epithelial-like L-41 cells. The long-term action of 20 mu-M causes the toxicity that results in losing of the cell viability by activating the apoptotic process, as identified by morphological analysis, the activation of caspase-3, and DNA fragmentation. The toxic chromium concentration totally destroys glutathione antioxidant system, and diminishes the activity of catalase and cytosolic Cu, ZnSOD. The non-toxic concentration (2 mu-M) causes the activation of the antioxidant defense systems, and they neutralize the oxidative impact.

  6. Effectiveness of estrogen replacement in restoration of cognitive function after long-term estrogen withdrawal in aging rats.

    PubMed

    Markowska, Alicja L; Savonenko, Alena V

    2002-12-15

    Recent studies suggest that some aspects of learning and memory may be altered by a midlife loss of estrogen, indicating a potential causal relationship between the deficiency of ovarian hormones and cognitive aging. In this study, the effects of estrogen withdrawal and replacement were tested in middle-aged Fischer-344 rats using different memory tasks. Estrogen withdrawal accelerated the rate of cognitive aging. A deficit first occurred 4 months after ovariectomy in working memory, which was tested in a delayed-nonmatching-to-position task, and progressed from long-delay to short-delay trials. Reference memory, which was tested in a place discrimination task and a split-stem T-maze, was not affected by aging or ovariectomy. The efficacy of estrogen in ameliorating the cognitive deficit in old rats depended on the type of treatment (acute vs chronic) and whether the aging-related decline in a particular cognitive process was aggravated by estrogen withdrawal. Chronic estrogen treatment (implants) was effective in improving working memory only when primed with repeated injections of estrogen, indicating that simulating the estrogen fluctuations of the estrous cycle may be more effective than the widely used mode of chronic pharmacological treatment. A challenge with scopolamine revealed that ovariectomy-induced cognitive deterioration coincided with a compromised cholinergic system. Importantly, the estrogen treatment that had restored effectively the cognitive abilities of old ovariectomized rats did not reduce their sensitivity to scopolamine. Taking into consideration that estrogen was highly effective against the amnestic action of scopolamine when tested in young-adult rats, these data emphasize that mechanisms of the protective effect of estrogen differ in young and old rats. PMID:12486194

  7. 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. PMID:18930676

  8. Exploring the Impact of Short- and Long-Term Hydrocortisone Replacement on Cognitive Function, Quality of Life and Catecholamine Secretion: A Pilot Study.

    PubMed

    Harbeck, Birgit; Danneberg, Sven; Rahvar, Amir-Hossein; Haas, Christian S; Lehnert, Hendrik; Kropp, Peter; Mönig, Heiner

    2016-09-01

    Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL. PMID:27170300

  9. A proposal of "core enzyme" bioindicator in long-term Pb-Zn ore pollution areas based on topsoil property analysis.

    PubMed

    Yang, JinShui; Yang, FengLong; Yang, Yang; Xing, GuanLan; Deng, ChunPing; Shen, YaTing; Luo, LiQiang; Li, BaoZhen; Yuan, HongLi

    2016-06-01

    To study the effects of long-term mining activities on the agricultural soil quality of Mengnuo town in Yunnan province, China, the heavy metal and soil enzyme activities of soil samples from 47 sites were examined. The results showed that long-term mining processes led to point source heavy metal pollution and Pb, Cd, Zn and As were the primary metal pollutants. Polyphenoloxidase was found the most sensitive soil enzyme activity and significantly correlated with almost all the metals (P < 0.05). Amylase (for C cycling), acid phosphatase (for P cycling) and catalase (for redox reaction) activities showed significantly positive correlations (P < 0.05) with Pb, Cd, Zn and As contents. The correlations between soil enzymes activities and Cd, Pb and Zn contents were verified in microcosm experiments, it was found that catalase activity had significant correlations (P < 0.05) with these three metals in short-term experiments using different soils under different conditions. Based on both field investigation and microcosm simulation analysis, oxidoreductases activities (rather than a specific enzyme activity) were suggested to be used as "core enzyme", which could simply and universally indicate the heavy metal pollution degrees of different environments. And hydrolases (for C, N, P and S recycling) could be used as a supplement to improve correlation accuracy for heavy metal indication in various polluted environments. PMID:27038207

  10. [Long-term results after lunate replacement by the vascularised os pisiform for treatment of Kienböck's disease III b].

    PubMed

    von Maydell, B; Brüser, P

    2008-06-01

    Saffar's procedure is used only rarely today. In order to assess the value of this operation in the treatment of advanced Kienböck's disease, after a mean follow-up period of 19 years we could review 7 of 12 patients who had had their lunate replaced by the vascularised pisiform. At the time of follow-up all patients were fully employed without restrictions, and no patient had had to change his job. The mean DASH score was 5.9. The average pain level by VAS was 0.9 and four patients were totally free of pain. Grip strength of the affected arm was reduced to 77% of the opposite side, the active range of motion (extension/flection) was 97 degrees, which was 72% of that of the not affected side. All patients reported high satisfaction with the results of the operation. Although the clinical results were very good, we found substantial radiographical alterations: In 5 patients we found an advanced intercarpal osteoarthritis. Four patients presented a spontaneous synostosis between the pisiform and the triquetrum. The average CHR (carpal height ratio) was 0.43. The presented long-term results after lunate replacement by the vascularised pisiform indicate a high patient satisfaction and very good functional results in spite of significant radiological changes. PMID:18548357

  11. The long-term outcome of the cemented Weber acetabular component in total hip replacement using a second-generation cementing technique.

    PubMed

    de Jong, P T; de Man, F H R; Haverkamp, D; Marti, R K

    2009-01-01

    We report the long-term outcome of a modified second-generation cementing technique for fixation of the acetabular component of total hip replacement. An earlier report has shown the superiority of this technique assessed by improved survival compared with first-generation cementing. The acetabular preparation involved reaming only to the subchondral plate, followed by impaction of the bone in the anchorage holes. Between 1978 and 1993, 287 total hip replacements were undertaken in 244 patients with a mean age of 65.3 years (21 to 90) using a hemispherical Weber acetabular component with this modified technique for cementing and a cemented femoral component. The survival with acetabular revision for aseptic loosening as the endpoint was 99.1% (95% confidence interval 97.9 to 100 after ten years and 85.5% (95% confidence interval 74.7 to 96.2) at 20 years. Apart from contributing to a long-lasting fixation of the component, this technique also preserved bone, facilitating revision surgery when necessary. PMID:19092001

  12. Long-Term Rescue of Retinal Structure and Function by Rhodopsin RNA Replacement with a Single Adeno-Associated Viral Vector in P23H RHO Transgenic Mice

    PubMed Central

    Mao, Haoyu; Gorbatyuk, Marina S.; Rossmiller, Brian; Hauswirth, William W.

    2012-01-01

    Abstract Many mutations in the human rhodopsin gene (RHO) cause autosomal dominant retinitis pigmentosa (ADRP). Our previous studies with a P23H (proline-23 substituted by histidine) RHO transgenic mouse model of ADRP demonstrated significant improvement of retinal function and preservation of retinal structure after transfer of wild-type rhodopsin by AAV. In this study we demonstrate long-term rescue of retinal structure and function by a single virus expressing both RHO replacement cDNA and small interfering RNA (siRNA) to digest mouse Rho and human P23H RHO mRNA. This combination should prevent overexpression of rhodopsin, which can be deleterious to photoreceptors. On the basis of the electroretinogram (ERG) response, degeneration of retinal function was arrested at 2 months postinjection, and the response was maintained at this level until termination at 9 months. Preservation of the ERG response in P23H RHO mice reflected survival of photoreceptors: both the outer nuclear layer (ONL) and outer segments of photoreceptor cells maintained the same thickness as in nontransgenic mice, whereas the control injected P23H eyes exhibited severe thinning of the ONL and outer segments. These findings suggest that delivery of both a modified cDNA and an siRNA by a single adeno-associated viral vector provided long-term rescue of ADRP in this model. Because the siRNA targets human as well as mouse rhodopsin mRNAs, the combination vector may be useful for the treatment of human disease. PMID:22289036

  13. Local anaesthetic infiltration for peri-operative pain control in total hip and knee replacement: systematic review and meta-analyses of short- and long-term effectiveness

    PubMed Central

    2014-01-01

    mobilisation, and lower incidence of vomiting. Few studies reported long-term outcomes. Conclusions Local anaesthetic infiltration is effective in reducing short-term pain and hospital stay in patients receiving THR and TKR. Studies should assess whether local anaesthetic infiltration can prevent long-term pain. Enhanced pain control with additional analgesia through a catheter should be weighed against a possible infection risk. PMID:24996539

  14. Molecular pathologies of and enzyme replacement therapies for lysosomal diseases.

    PubMed

    Sakuraba, Hitoshi; Sawada, Makoto; Matsuzawa, Fumiko; Aikawa, Sei-ichi; Chiba, Yasunori; Jigami, Yoshifumi; Itoh, Kohji

    2006-08-01

    Lysosomal diseases comprise a group of inherited disorders resulting from defects of lysosomal enzymes and their cofactors, and in many of them the nervous system is affected. Recently, enzyme replacement therapy with recombinant lysosomal enzymes has been clinically available for several lysosomal diseases. Such enzyme replacement therapies can improve non-neurological disorders but is not effective for neurological ones. In this review, we discuss the molecular pathologies of lysosomal diseases from the protein structural aspect, current enzyme replacement therapies, and attempts to develop enzyme replacement therapies effective for lysosomal diseases associated with neurological disorders, i.e., production of enzymes, brain-specific delivery and incorporation of lysosomal enzymes into cells. PMID:16918392

  15. Enzyme Changes in the Offspring of Female Rats due to Long-Term Administration of Cyclic AMP and Insulin before Pregnancy.

    PubMed

    Strumilo, S A; Czyzewska, U; Siemieniuk, M; Strumilo, J; Tylicki, A

    2016-07-01

    We studied the effects of insulin and cAMP on the offspring of female rats after daily treatment with these substances over 4 weeks. In adult offspring from cAMP-treated females, activities of pyruvate kinase and glucose-6-phosphate dehydrogenase decreased in the liver and brain and activities of NADP-dependent malate dehydrogenase and 6-phosphogluconate dehydrogenase decreased in the liver. In the offspring of insulin-treated females, we observed only activation of glucose-6-phosphate dehydrogenase and malate dehydrogenase in the liver and only in females. Enzyme activity probably correlates with their content, as no changes in their kinetic properties were observed under these conditions. Long-term hormone treatment before pregnancy can affect the expression of genes for some enzymes in the offspring due to transmission of epigenetic signals by the ovum. However, further studies are required to confirm this mechanism. PMID:27502537

  16. Long-term effects of growth hormone (GH) replacement therapy on hematopoiesis in a large cohort of children with GH deficiency.

    PubMed

    Esposito, Andrea; Capalbo, Donatella; De Martino, Lucia; Rezzuto, Martina; Di Mase, Raffaella; Pignata, Claudio; Salerno, Mariacarolina

    2016-07-01

    The aim of our prospective case-control study was to evaluate long-term effects of GH replacement therapy on erythrocytes parameters, leukocytes, and platelets numbers in a large cohort of children with isolated GH deficiency (GHD). Hemoglobin (Hb) concentration, hematocrit (Hct), mean corpuscular volume, mean corpuscular hemoglobin, red cell distribution width, number of erythrocytes, leukocytes, neutrophils, lymphocytes, monocytes and platelets, ferritin, and C-reactive protein were evaluated in 85 children with isolated GHD (10.20 ± 3.50 years) before and annually during the first 5 years of GH replacement therapy and in 85 healthy children age and sex comparable to patients during 5 years of follow-up. Compared with controls, GHD children at study entry showed lower Hb (-1.18 ± 0.87 vs. -0.40 ± 0.90 SDS, p < 0.0001), red cells number (-0.24 ± 0.81 vs. 0.25 ± 1.14 SDS, p < 0.0001), and Hct (-1.18 ± 0.86 vs. -0.68 ± 0.99 SDS, p < 0.0001). Twelve GHD patients (14 %) showed a normocytic anemia. GH therapy was associated with a significant increase in Hb, Hct, and red cells number which became all comparable to controls within the first 2 years of treatment. Moreover, hemoglobin levels normalized in all anemic GHD patients after 5 years of therapy. No difference between patients and controls was found in leukocytes and platelets numbers neither at baseline nor during the study. GHD in childhood is associated with an impairment of erythropoiesis which causes a normocytic anemia in a considerable percentage of patients. GH replacement therapy exerts a beneficial effect leading to a significant increase of erythrocytes parameters and recovery from anemia. Neither GHD nor GH replacement treatment exerts effects on leukocytes or platelets numbers. PMID:26511947

  17. Long-Term Care

    MedlinePlus

    ... this page please turn Javascript on. Long-Term Care What Is Long-Term Care? Long-term care involves a variety of services ... the Escape (Esc) button on your keyboard.) Most Care Provided at Home Long-term care is provided ...

  18. Changes in soil carbon and enzyme activity as a result of different long-term fertilization regimes in a greenhouse field.

    PubMed

    Zhang, Lili; Chen, Wei; Burger, Martin; Yang, Lijie; Gong, Ping; Wu, Zhijie

    2015-01-01

    In order to discover the advantages and disadvantages of different fertilization regimes and identify the best management practice of fertilization in greenhouse fields, soil enzyme activities involved in carbon (C) transformations, soil chemical characteristics, and crop yields were monitored after long-term (20-year) fertilization regimes, including no fertilizer (CK), 300 kg N ha-1 and 600 kg N ha-1 as urea (N1 and N2), 75 Mg ha-1 horse manure compost (M), and M with either 300 or 600 kg N ha-1 urea (MN1 and MN2). Compared with CK, fertilization increased crop yields by 31% (N2) to 69% (MN1). However, compared with CK, inorganic fertilization (especially N2) also caused soil acidification and salinization. In the N2 treatment, soil total organic carbon (TOC) decreased from 14.1±0.27 g kg-1 at the beginning of the long-term experiment in 1988 to 12.6±0.11 g kg-1 (P<0.05). Compared to CK, N1 and N2 exhibited higher soil α-galactosidase and β-galactosidase activities, but lower soil α-glucosidase and β-glucosidase activities (P<0.05), indicating that inorganic fertilization had different impacts on these C transformation enzymes. Compared with CK, the M, MN1 and MN2 treatments exhibited higher enzyme activities, soil TOC, total nitrogen, dissolved organic C, and microbial biomass C and N. The fertilization regime of the MN1 treatment was identified as optimal because it produced the highest yields and increased soil quality, ensuring sustainability. The results suggest that inorganic fertilizer alone, especially in high amounts, in greenhouse fields is detrimental to soil quality. PMID:25706998

  19. Changes in Soil Carbon and Enzyme Activity As a Result of Different Long-Term Fertilization Regimes in a Greenhouse Field

    PubMed Central

    Zhang, Lili; Chen, Wei; Burger, Martin; Yang, Lijie; Gong, Ping; Wu, Zhijie

    2015-01-01

    In order to discover the advantages and disadvantages of different fertilization regimes and identify the best management practice of fertilization in greenhouse fields, soil enzyme activities involved in carbon (C) transformations, soil chemical characteristics, and crop yields were monitored after long-term (20-year) fertilization regimes, including no fertilizer (CK), 300 kg N ha-1 and 600 kg N ha-1 as urea (N1 and N2), 75 Mg ha-1 horse manure compost (M), and M with either 300 or 600 kg N ha-1 urea (MN1 and MN2). Compared with CK, fertilization increased crop yields by 31% (N2) to 69% (MN1). However, compared with CK, inorganic fertilization (especially N2) also caused soil acidification and salinization. In the N2 treatment, soil total organic carbon (TOC) decreased from 14.1±0.27 g kg-1 at the beginning of the long-term experiment in 1988 to 12.6±0.11 g kg-1 (P<0.05). Compared to CK, N1 and N2 exhibited higher soil α-galactosidase and β-galactosidase activities, but lower soil α-glucosidase and β-glucosidase activities (P<0.05), indicating that inorganic fertilization had different impacts on these C transformation enzymes. Compared with CK, the M, MN1 and MN2 treatments exhibited higher enzyme activities, soil TOC, total nitrogen, dissolved organic C, and microbial biomass C and N. The fertilization regime of the MN1 treatment was identified as optimal because it produced the highest yields and increased soil quality, ensuring sustainability. The results suggest that inorganic fertilizer alone, especially in high amounts, in greenhouse fields is detrimental to soil quality. PMID:25706998

  20. Long-term feeding a plant-based diet devoid of marine ingredients strongly affects certain key metabolic enzymes in the rainbow trout liver.

    PubMed

    Véron, Vincent; Panserat, Stéphane; Le Boucher, Richard; Labbé, Laurent; Quillet, Edwige; Dupont-Nivet, Mathilde; Médale, Françoise

    2016-04-01

    Incorporation of a plant blend in the diet can affect growth parameters and metabolism in carnivorous fish. We studied for the first time the long-term (1 year) metabolic response of rainbow trout fed from first feeding with a plant-based diet totally devoid of marine ingredients. Hepatic enzymes were analyzed at enzymatic and molecular levels, at 3, 8 and 24 h after the last meal to study both the short-term effects of the last meal and long-term effects of the diet. The results were compared with those of fish fed a control diet of fish meal and fish oil. Growth, feed intake, feed efficiency and protein retention were lower in the group fed the plant-based diet. Glucokinase and pyruvate kinase activity were lower in the livers of trout fed the plant-based diet which the proportion of starch was lower than in the control diet. Glutamate dehydrogenase was induced by the plant-based diet, suggesting an imbalance of amino acids and a possible link with the lower protein retention observed. Gene expression of delta 6 desaturase was higher in fish fed the plant-based diet, probably linked to a high dietary level of linolenic acid and the absence of long-chain polyunsaturated fatty acids in vegetable oils. Hydroxymethylglutaryl-CoA synthase expression was also induced by plant-based diet because of the low rate of cholesterol in the diet. Changes in regulation mechanisms already identified through short-term nutritional experiments (<12 weeks) suggest that metabolic responses are implemented at short term and remain in the long term. PMID:26746847

  1. What are the effects of varenicline compared with nicotine replacement therapy on long-term smoking cessation and clinically important outcomes? Protocol for a prospective cohort study

    PubMed Central

    Davies, Neil M; Taylor, Gemma; Taylor, Amy E; Thomas, Kyla H; Windmeijer, Frank; Martin, Richard M; Munafò, Marcus R

    2015-01-01

    Introduction Smoking is a major avoidable cause of ill-health and premature death. Treatments that help patients successfully quit smoking have an important effect on health and life expectancy. Varenicline is a medication that can help smokers successfully quit smoking. However, there are concerns that it may cause adverse effects, such as increase in the occurrence of depression, self-harm and suicide and cardiovascular disease. In this study we aim to examine the effects of varenicline versus other smoking cessation pharmacotherapies on smoking cessation, health service use, all-cause and cause-specific mortality and physical and mental health conditions. Methods In this project we will investigate the effects of varenicline compared to nicotine replacement therapies on: (1) long-term smoking cessation and whether these effects differ by area level deprivation; and (2) the following clinically-important outcomes: rate of general practice and hospital attendance; all-cause mortality and death due to diseases of the respiratory system and cardiovascular disease; and a primary care diagnosis of respiratory illness, myocardial infarction or depression and anxiety. The study is based on a cohort of patients prescribed these smoking cessation medications from the Clinical Practice Research Datalink (CPRD). We will use three methods to overcome confounding: multivariable adjusted Cox regression, propensity score matched Cox regression, and instrumental variable regression. The total expected sample size for analysis will be at least 180 000. Follow-up will end with the earliest of either an ‘event’ or censoring due to the end of registration or death. Ethics and dissemination Ethics approval was not required for this study. This project has been approved by the CPRD's Independent Scientific Advisory Committee (ISAC). We will disseminate our findings via publications in international peer-reviewed journals and presentations at international conferences. PMID

  2. [Effects of different long-term fertilization on the activities of enzymes related to carbon, nitrogen, and phosphorus cycles in a red soil].

    PubMed

    Fan, Miao-zhen; Yin, Chang; Fan, Fen-liang; Song, A-lin; Wang, Bo-ren; Li, Dong-chu; Liang, Yong-chao

    2015-03-01

    Using a microplate fluorimetric assay method, five fertilization treatments, i.e. no-fertilizer control (CK) , sole application of nitrogen (N), balanced application of nitrogen, phosphorus, and potassium fertilizer (NPK), application of pig manure (M), and combination of pig manure with balanced chemical fertilizer (MNPK) were selected to investigate the effects of different long-term fertilization regimes on the activity of five enzymes (β-1, 4-glucosidase, βG; cellobiohydrolase, CBH; β-1, 4-xylosidase, βX; β-1, 4-N-acetylglucosaminidase, NAG; acid phosphatase, AP) in a red soil sampled from Qiyang, Hunnan Province. The results showed that compared with CK treatment, N treatment had no impact on βG, βX, CBH, and NAG activities but reduced AP activity, while NPK, M and MNPK treatments increased the activities of all the five enzymes. Correlation analysis indicated that all the five enzyme activities were positively correlated with the content of nitrate (r=0.465-0.733) , the content of available phosphorus (r=0.612-0.947) , soil respiration (r=0.781-0.949) and crop yield (r=0.735-0.960), while βG, CBH and AP were positively correlated with pH (r= 0.707-0.809), only AP was significantly correlated with dissolvable organic carbon (r = -0.480). These results suggested that the activities of the measured enzymes could be used as indicators of red soil fertility under different fertilization regimes, but the five enzymes tested provided limited information on the degree of acidification induced by application of mineral nitrogen. PMID:26211066

  3. Maintenance of oestradiol production and expression of cytochrome P450 aromatase enzyme mRNA in long-term serum-free cultures of pig granulosa cells.

    PubMed

    Picton, H M; Campbell, B K; Hunter, M G

    1999-01-01

    Studies were carried out to investigate the conditions required for maintenance of aromatase activity and expression in long-term cultures of pig granulosa cells. Cells from large (> 2 mm) and small (< or = 2 mm) follicles were cultured at 37 degrees C with 5% CO2 in McCoys 5a medium supplemented with 0.1% (w/v) BSA, testosterone (100 micrograms l-1), insulin (10 micrograms l-1) and long R3 insulin-like growth factor I (IGF-I) (100 micrograms l-1). Cells were cultured with five concentrations of USDA pFSH-I-2 (0-100 micrograms l-1) for 48, 96 or 144 h with or without fetal calf serum (FCS). The number of cells and oestradiol, progesterone and inhibin production were measured. In marked contrast to oestradiol production from cells cultured in plates precoated with FCS, 1 microgram FSH l-1 was optimal for the maintenance of high oestradiol production by granulosa cells from large follicles after 144 h of serum-free culture. Culture with FCS promoted cell proliferation, reduced oestradiol production, and supported FSH-dependent (P < 0.01) increased progesterone and inhibin production indicating cellular luteinization. Northern blot analysis of total RNA from cells cultured with 1 microgram FSH l-1 detected 2.5 and 1.8 kb transcripts encoding aromatase cytochrome P450 (P450arom) and cholesterol side-chain cleavage cytochrome P450 (P450scc), respectively. Transcript expression was hormone sensitive, irrespective of the presence of FCS. High concentrations of FSH (100 micrograms l-1) stimulated expression of P450scc, but inhibited P450arom expression as the cells luteinized after 144 h of culture. This serum-free system, which maintains the aromatase enzyme complex, is fundamental if physiologically relevant observations are to be made of the mechanisms regulating follicle hierarchy development from long-term cultures of pig cells. PMID:10341724

  4. Hydrogen peroxide generation and antioxidant enzyme activities in the leaves and roots of wheat cultivars subjected to long-term soil drought stress.

    PubMed

    Huseynova, Irada M; Aliyeva, Durna R; Mammadov, Alamdar Ch; Aliyev, Jalal A

    2015-08-01

    The dynamics of the activity of catalase, ascorbate peroxidase, guaiacol peroxidase, and benzidine peroxidase, as well as the level of hydrogen peroxide in the vegetative organs of durum wheat (Triticum durum Desf.) cultivars was studied under long-term soil drought conditions. It was established that hydrogen peroxide generation occurred at early stages of stress in the tolerant variety Barakatli-95, whereas in the susceptible variety Garagylchyg-2 its significant amounts were accumulated only at later stages. Garagylchyg-2 shows a larger reduction of photochemical activity of PS II in both genotypes at all stages of ontogenesis under drought stress than Barakatli-95. The highest activity of catalase which plays a leading role in the neutralization of hydrogen peroxide was observed in the leaves and roots of the drought-tolerant variety Barakatli-95. Despite the fact that the protection system also includes peroxidases, the activity of these enzymes even after synthesis of their new portions is substantially lower compared with catalase. Native PAGE electrophoresis revealed the presence of one isoform of CAT, seven isoforms of APX, three isoforms of GPO, and three isoforms of BPO in the leaves, and also three isoforms of CAT, four isoforms of APX, two isoforms of GPO, and six isoforms of BPO in the roots of wheat. One isoform of CAT was found in the roots when water supply was normal and three isoforms were observed under drought conditions. Stress associated with long-term soil drought in the roots of wheat has led to an increase in the heterogeneity due to the formation of two new sedentary forms of catalase: CAT2 and CAT3. PMID:26008794

  5. Aggression in Replacement Grower and Finisher Gilts fed a High-Tryptophan Diet and the Effect of Long-term Human-Animal Interaction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aggression is a major problem for swine production as it negatively impacts the pigs’ health and welfare. Dietary approaches such as increasing tryptophan (TRP) ingestion to raise cerebral serotonin (5-HT) – a key neurotransmitter for aggression control, and long-term positive social handling have b...

  6. Asfotase alfa: enzyme replacement for the treatment of bone disease in hypophosphatasia.

    PubMed

    Hofmann, C; Seefried, L; Jakob, F

    2016-05-01

    Hypophosphatasia (HPP) is a rare disease caused by loss-of-function mutations in the tissue-nonspecific alkaline phosphatase (TNAP, TNSALP) gene. HPP causes a multisystemic syndrome with a predominant bone phenotype. The clinical spectrum ranges from high lethality in early onset (<6 months) HPP to mild late-onset syndromes. HPP management so far has been only supportive. Subcutaneous asfotase alfa, a first-in-class bone-targeted human TNAP enzyme replacement therapy, is the first compound to be approved for long-term treatment of bone manifestations in pediatric-onset HPP. In noncomparative clinical trials (treatment up to 7 years), this treatment was associated with skeletal, respiratory and functional improvement in perinatal, infantile and childhood-onset HPP. Compared with age-matched historical controls, patients with life-threatening perinatal and infantile HPP treated with asfotase alfa had substantially improved bone mineralization, survival and ventilation-free survival. In childhood HPP, asfotase alfa improved growth, gross motor function, strength and agility and decreased pain. The compound was well tolerated and most adverse events were of mild to moderate intensity. To date, data and experience concerning its efficacy and safety in long-term treatment are not yet available. Further studies to evaluate risks and benefits of enzyme replacement therapy with asfotase alfa in adults are in progress and are also strongly needed. PMID:27376160

  7. Long-term effects of oral tea polyphenols and Lactobacillus brevis M8 on biochemical parameters, digestive enzymes, and cytokines expression in broilers

    PubMed Central

    Li, Hua-li; Li, Zong-jun; Wei, Zhong-shan; Liu, Ting; Zou, Xiao-zuo; Liao, Yong; Luo, Yu

    2015-01-01

    This study investigates the long-term effects of oral tea polyphenols (TPs) and Lactobacillus brevis M8 (LB) on biochemical parameters, digestive enzymes, and cytokines expression in broilers. In experiment 1, 240 broiler chickens were selected to investigate the effects of 0.06 g/kg body weight (BW) TP and 1.0 ml/kg BW LB on broilers; in experiment 2, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of TP (0.03, 0.06, and 0.09 g/kg BW) combined with 1.0 ml/kg BW LB on broilers; in experiment 3, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of LB (0.5, 1.0, and 1.5 ml/kg BW) combined with 0.06 g/kg BW TP on broilers. The results showed that TP and LB affected serum biochemical parameters, and TP reduced serum cholesterol (CHO) and low-density lipoprotein cholesterol (LDL-C) abundances in a dosage-dependent manner (P<0.05) on Day 84. Meanwhile, broilers fed a diet supplemented with TP or LB had a lower intestinal lipase activity on Day 84 compared with the control group (P<0.05). Middle and high dosages of TP increased pancreatic lipase and proventriculus pepsin activities (P<0.05). Also middle and high dosages of LB significantly enhanced pancreatic lipase activity (P<0.05), while high LB supplementation inhibited intestinal trypsase (P<0.05) on Day 84. Furthermore, both TP and LB reduced intestinal cytokine expression and nuclear factor-κ B (NF-κB) mRNA level on Days 56 and 84. In conclusion, long-term treatment of TP and LB improved lipid metabolism and digestive enzymes activities, and affected intestinal inflammatory status, which may be associated with the NF-κB signal. PMID:26642185

  8. Neuronal lysosomal enzyme replacement using fragment C of tetanus toxin.

    PubMed

    Dobrenis, K; Joseph, A; Rattazzi, M C

    1992-03-15

    Development of a strategy for efficient delivery of exogenous enzyme to neuronal lysosomes is essential to achieve enzyme replacement in neurodegenerative lysosomal storage diseases. We tested whether effective lysosomal targeting of the human enzyme beta-N-acetylhexosaminidase A (Hex A; beta-N-acetyl-D-hexosaminide N-acetylhexosaminohydrolase, EC 3.2.1.52) can be obtained by coupling it via disulfide linkage to the atoxic fragment C of tetanus toxin (TTC) that is bound avidly by neuronal membrane. TTC-Hex A conjugation resulted in neuronal surface binding and enhanced endocytosis of enzyme as observed in immunofluorescence studies with rat brain cultures. In immunoelectrophoretic quantitative uptake studies, rat neuronal cell cultures contained 16- and 40-fold greater amounts of enzyme after incubation with TTC-Hex A than with nonderivatized Hex A. In cerebral cortex cell cultures from a feline model of human GM2 gangliosidosis (Tay-Sachs and Sandhoff diseases), binding and uptake patterns of the enzymes were similar to those in the rat brain cell cultures. After exposure to extracellular concentrations of enzyme attainable in vivo, lysosomal storage of immunodetectable GM2 ganglioside was virtually eliminated in neurons exposed to TTC-Hex A, whereas a minimal effect was observed with Hex A. These findings demonstrate the usefulness of TTC adducts for effective neuronal lysosomal enzyme replacement. PMID:1532255

  9. Enzyme replacement therapy for Gaucher's disease: the early Canadian experience

    PubMed Central

    MacKenzie, J J; Amato, D; Clarke, J T

    1998-01-01

    BACKGROUND: The management of severe Gaucher's disease was dramatically improved by the development of enzyme replacement therapy. However, this treatment is very costly (currently about $21,000 per infusion for adults at the starting dose recommended by the manufacturer). The goal of this study was to determine how enzyme replacement therapy was being prescribed and financially supported in various parts of Canada. In addition, demographic and outcome information was elicited. METHODS: Prescribing physicians were identified through professional associations and with the help of the manufacturer of the enzyme preparations used for the treatment of Gaucher's disease. The physicians were surveyed by questionnaire in July 1995. The study included all patients in Canada who had received enzyme replacement therapy for Gaucher's disease before July 1, 1995. RESULTS: A total of 25 patients (15 children and 10 adults) with type 1 Gaucher's disease, the common nonneuronopathic variant of the disease, were receiving enzyme replacement therapy by the end of 1995. The indications for treatment included massive splenomegaly, growth failure, and severe bony, hematologic and pulmonary complications of the disease; no patients with mild disease were receiving treatment. Treatment regimens varied markedly (from 12 to 160 units of enzyme/kg per month). All the patients were reported to have responded well to therapy, based on serial measurements of hematologic indices, liver and spleen volumes, and numbers of bony crises as well as patients' subjective impressions. Financial support for therapy varied markedly from one province to another. None of the reporting physicians was aware of any patients with severe Gaucher's disease who were denied therapy as a result of inability to pay for the medication. Various agencies provided financial support for therapy, including both federal and provincial governments, private insurance carriers and the commercial supplier of the enzyme. In

  10. Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency

    PubMed Central

    Nilsson, A G; Marelli, C; Fitts, D; Bergthorsdottir, R; Burman, P; Dahlqvist, P; Ekman, B; Edén Engström, B; Olsson, T; Ragnarsson, O; Ryberg, M; Wahlberg, J; Lennernäs, H; Skrtic, S; Johannsson, G

    2014-01-01

    Objective The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20–40 mg once daily and hydrocortisone 20–40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results In stage 1, patients had a median 1.5 (range, 1–9) intercurrent illness events with DR-HC and 1.0 (1–8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1–3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy. PMID:24944332

  11. Long-term replacement of a mutated nonfunctional CNS gene: reversal of hypothalamic diabetes insipidus using an EIAV-based lentiviral vector expressing arginine vasopressin.

    PubMed

    Bienemann, Alison S; Martin-Rendon, Enca; Cosgrave, Anna S; Glover, Colin P J; Wong, Liang-Fong; Kingsman, Susan M; Mitrophanous, Kyriacos A; Mazarakis, Nicholas D; Uney, James B

    2003-05-01

    Due to the complexity of brain function and the difficulty in monitoring alterations in neuronal gene expression, the potential of lentiviral gene therapy vectors to treat disorders of the CNS has been difficult to fully assess. In this study, we have assessed the utility of a third-generation equine infectious anemia virus (EIAV) in the Brattleboro rat model of diabetes insipidus, in which a mutation in the arginine vasopressin (AVP) gene results in the production of nonfunctional mutant AVP precursor protein. Importantly, by using this model it is possible to monitor the success of the gene therapy treatment by noninvasive assays. Injection of an EIAV-CMV-AVP vector into the supraoptic nuclei of the hypothalamus resulted in expression of functional AVP peptide in magnocellular neurons. This was accompanied by a 100% recovery in water homeostasis as assessed by daily water intake, urine production, and urine osmolality lasting for a 1-year measurement period. These data show that a single gene defect leading to a neurological disorder can be corrected with a lentiviral-based strategy. This study highlights the potential of using viral gene therapy for the long-term treatment of disorders of the CNS. PMID:12718901

  12. Enzyme replacement therapy for pancreatic insufficiency: present and future

    PubMed Central

    Fieker, Aaron; Philpott, Jessica; Armand, Martine

    2011-01-01

    Pancreatic enzyme replacement therapy is currently the mainstay of treatment for nutrient malabsorption secondary to pancreatic insufficiency. This treatment is safe and has few side effects. Data demonstrate efficacy in reducing steatorrhea and fat malabsorption. Effective therapy has been limited by the ability to replicate the physiologic process of enzyme delivery to the appropriate site, in general the duodenum, at the appropriate time. The challenges include enzyme destruction in the stomach, lack of adequate mixing with the chyme in the duodenum, and failing to deliver and activate at the appropriate time. Treatment is begun when clinically significant malabsorption occurs resulting in steatorrhea and weight loss. Treatment failure is addressed in a sequential fashion. Current research is aimed at studying new enzymes and delivery systems to improve the efficiency of action in the duodenum along with developing better means to monitor therapy. PMID:21753892

  13. Successful noninvasive ventilation and enzyme replacement therapy in an adult patient with morbus hunter.

    PubMed

    Westhoff, M; Litterst, P

    2012-01-01

    M. Hunter is characterized by an accumulation of mucopolysaccharides in cells, blood, and connective tissue as a consequence of a deficiency of the enzyme iduronate-2-sulfatase. Unlike enzyme replacement therapy with idursulfase in children, there is limited long-term experience in adult patients with Morbus Hunter.The case presented here describes the development of a man born in 1971 who was admitted to Hemer Lung Clinic in 2005 with severe obstructive sleep apnea, pulmonary functional impairment, and ventilatory failure (FEV 1: 0.8 L, VC: 1.0 L; pO(2): 52 mmHg; pCO(2): 81 mmHg, 6 MWT: 100 m). Initially, the patient received symptomatic treatment with noninvasive ventilation, which achieved a considerable improvement in pulmonary function and a normalization of blood gasses. Since February 2008, the patient received additional enzyme replacement therapy with idursulfase, which resulted in a further significant functional improvement (FEV1: 1.6; VC: 2.3 L; VO(2)max: 1,350 mL or 28.1 mL/kg body weight), in a normalization of prior elevated pulmonary artery pressures and also in impressive changes in the physiognomy and joint mobility. In November 2010, the polysomnography and nocturnal blood gas analysis without NIV showed only a mild obstructive sleep-related breathing disorder with no sign of hypoventilation. Therapy was changed to nocturnal CPAP therapy with a constant pressure of 6 cm H(2)O. Additional administration of oxygen was not required. With this therapy, the patient has been asymptomatic up to September 2011.Adult Hunter patients also benefit from enzyme replacement therapy and, in restrictive ventilatory defects with hypoventilation, from symptomatic therapy with noninvasive ventilation. PMID:23430920

  14. Long-term soil microbial community and enzyme activity responses to an integrated cropping-livestock system in a semi-arid region

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study is part of a larger long-term project to develop and evaluate integrated crop and livestock systems in order to reduce dependence on underground water sources by optimizing cotton (Gossypium hirsutum) production in the Texas High Plains of U.S. Microbial communities and activities were e...

  15. Long Term Effect of Curcumin in Restoration of Tumour Suppressor p53 and Phase-II Antioxidant Enzymes via Activation of Nrf2 Signalling and Modulation of Inflammation in Prevention of Cancer

    PubMed Central

    Das, Laxmidhar; Vinayak, Manjula

    2015-01-01

    Inhibition of carcinogenesis may be a consequence of attenuation of oxidative stress via activation of antioxidant defence system, restoration and stabilization of tumour suppressor proteins along with modulation of inflammatory mediators. Previously we have delineated significant role of curcumin during its long term effect in regulation of glycolytic pathway and angiogenesis, which in turn results in prevention of cancer via modulation of stress activated genes. Present study was designed to investigate long term effect of curcumin in regulation of Nrf2 mediated phase-II antioxidant enzymes, tumour suppressor p53 and inflammation under oxidative tumour microenvironment in liver of T-cell lymphoma bearing mice. Inhibition of Nrf2 signalling observed during lymphoma progression, resulted in down regulation of phase II antioxidant enzymes, p53 as well as activation of inflammatory signals. Curcumin potentiated significant increase in Nrf2 activation. It restored activity of phase-II antioxidant enzymes like GST, GR, NQO1, and tumour suppressor p53 level. In addition, curcumin modulated inflammation via upregulation of TGF-β and reciprocal regulation of iNOS and COX2. The study suggests that during long term effect, curcumin leads to prevention of cancer by inducing phase-II antioxidant enzymes via activation of Nrf2 signalling, restoration of tumour suppressor p53 and modulation of inflammatory mediators like iNOS and COX2 in liver of lymphoma bearing mice. PMID:25860911

  16. JCL Roundtable: enzyme replacement therapy for lipid storage disorders.

    PubMed

    Brown, W Virgil; Desnick, Robert J; Grabowski, Gregory A

    2014-01-01

    There are several inherited disorders that involve abnormal storage of lipids in tissues leading to severe compromise of organs. Sadly, these are often accompanied by lifelong morbidity and early mortality. Disorders such as Gaucher, Fabry, and lysosomal acid lipase deficiencies (Wolman and cholesteryl ester storage diseases) have been known for many years, and provide a difficult and frustrating set of problems for patients, their families, and their physicians. With recombinant methods of protein synthesis, it is now possible to literally replace the defective enzymes that underlie the basic pathophysiology of many such disorders. The delivery of these enzymes into the affected cells is possible because of their location in the lysosomes where the natural degradation of their lipid substrates occurs. I have asked 2 well-known investigators to join us for this Roundtable. These are professors who have been involved with the research that has made this type of therapy possible and who have participated in the clinical trials that demonstrated the value of enzyme replacement therapy. They are Dr. Robert Desnick, dean of Genetic and Genomic Medicine and professor and chairman emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and Dr. Gregory Grabowski, professor of Microbiology, Biochemistry, and Pediatrics, at the University of Cincinnati College of Medicine. Dr. Grabowski recently retired from that school to become the chief science officer of Synageva, a company involved in producing enzymes for this type of therapy. PMID:25234559

  17. Usefulness of plasma renin activity in predicting haemodynamic and clinical responses and survival during long term converting enzyme inhibition in severe chronic heart failure. Experience in 100 consecutive patients.

    PubMed Central

    Packer, M; Medina, N; Yushak, M; Lee, W H

    1985-01-01

    The relation between plasma renin activity before treatment and the haemodynamic and clinical responses to converting enzyme inhibition was determined in 100 consecutive patients with severe chronic heart failure who were treated with captopril or enalapril. Initial doses of captopril produced significant increases in cardiac index and decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure, heart rate, and systemic vascular resistance that varied linearly with the pretreatment value for plasma renin activity. In contrast, there was no relation between the pretreatment activity and the magnitude of haemodynamic improvement after 1-3 months of treatment with the converting enzyme inhibitors, and, consequently, a similar proportion of patients with a high (greater than 6 ng/ml/h; greater than 4.62 mmol/l/h), intermediate (2-6 ng/ml/h; 1.54-4.62 mmol/l/h), and low (less than 2 ng/ml/h; less than 1.54 mmol/l/h) pretreatment value improved clinically during long term treatment (64%, 60%, and 64% respectively). Long term survival after one, two, and three years was similar in the three groups. Estimating the degree of activation of the renin-angiotensin system by measuring pretreatment plasma renin activity fails to predict the long term haemodynamic or clinical responses to converting enzyme inhibitors in patients with severe chronic heart failure, and thus appears to be of limited value in selecting those patients likely to benefit from treatment with these drugs. PMID:2994697

  18. Comparison of the characteristics of long-term users of electronic cigarettes versus nicotine replacement therapy: A cross-sectional survey of English ex-smokers and current smokers

    PubMed Central

    Nelson, Victoria A.; Goniewicz, Maciej L.; Beard, Emma; Brown, Jamie; Sheals, Kate; West, Robert; Shahab, Lion

    2015-01-01

    Background Electronic cigarettes (ECs) and nicotine replacement therapy (NRT) are non-combustible nicotine delivery devices being widely used as a partial or a complete long-term substitute for smoking. Little is known about the characteristics of long-term users, their smoking behaviour, attachment to smoking, experience of nicotine withdrawal symptoms, or their views on these devices. This study aimed to provide preliminary evidence on this and compare users of the different products. Methods UK participants were recruited from four naturally occurring groups of long-term (≥6 months) users of either EC or NRT who had stopped or continued to smoke (N = 36 per group, total N = 144). Participants completed a questionnaire assessing socio-demographic and smoking characteristics, nicotine withdrawal symptoms, smoker identity and attitudes towards the products they were using. Results Adjusting for relevant confounders, EC use was associated with a stronger smoker identity (Wald X2(1) = 3.9, p = 0.048) and greater product endorsement (Wald X2(1) = 4.6, p = 0.024) than NRT use, irrespective of smoking status. Among ex-smokers, EC users reported less severe mood and physical symptoms (Wald X2(1) = 6.1, p = 0.014) and cravings (Wald X2(1) = 8.5, p = 0.003), higher perceived helpfulness of the product (Wald X2(1) = 4.8, p = 0.028) and lower intentions to stop using the product (Wald X2(1) = 17.6, p < 0.001) than NRT users. Conclusions Compared with people who use NRT for at least 6 months, those who use EC over that time period appear to have a stronger smoker identity and like their products more. Among long-term users who have stopped smoking, ECs are perceived as more helpful than NRT, appear more effective in controlling withdrawal symptoms and continued use may be more likely. PMID:26026493

  19. The Effects of Long-Term Feeding of Rodent Food Bars on Lipid Peroxidation And Antioxidant Enzyme Levels In Fisher Rats

    NASA Technical Reports Server (NTRS)

    Ramirez, Joel; Zirkle-Yoshida, M.; Piert, S.; Barrett, J.; Yul, D.; Dalton, B.; Girten, B.

    2001-01-01

    A specialized rodent food bar diet has been developed and utilized successfully for short-duration shuttle missions. Recent tests conducted in preparation for experiments aboard the International Space Station (ISS) indicated that long-term food bar feeding for three months induced hyperlipidemia in rats. This study examined oxidative stress status in livers of these same animals. Spectrophotometric analysis of 79 Fischer rat livers (40 female and 39 male) for lipid peroxidation (LPO) and superoxide dismutase (SOD) was conducted using Bioxytech LPO-587(TM) assay kit and SOD-525(Tm) assay kit, respectively. The treatment groups consisted of 20 male CHOW and 19 male FOOD BAR rats and 20 female CHOW and 20 female FOOD BAR rats. Statistical analysis to compare differences between groups was performed by standard analysis of variance procedures. The male FOOD BAR group LPO mean (3.6 +/- 0.2 mmol/g) was significantly (p less than or equal to 0.05) greater than that of the male CHOW group (2.1 +/-0.1 mmol/g). Moreover the female FOOD BAR group LPO mean (2.9 +/-0.1 mmol/g) was also significantly greater than the female CHOW group mean (2.2 +/-0.1 mmol/g). The mean values for SOD in both male and female groups showed no significant differences between CHOW and FOOD BAR groups. These results show that LPO levels were significantly higher in both the male and female FOOD BAR groups compared to CHOW groups and that there was no concomitant increase in SOD levels across the group. In addition, males showed a greater difference than females in terms of LPO levels. These findings suggest a need for further investigation into the use of the current food bar formulation for long-term experiments such as those planned for the ISS.

  20. A Newly Defined and Xeno-Free Culture Medium Supports Every-Other-Day Medium Replacement in the Generation and Long-Term Cultivation of Human Pluripotent Stem Cells.

    PubMed

    Ahmadian Baghbaderani, Behnam; Tian, Xinghui; Scotty Cadet, Jean; Shah, Kevan; Walde, Amy; Tran, Huan; Kovarcik, Don Paul; Clarke, Diana; Fellner, Thomas

    2016-01-01

    Human pluripotent stem cells (hPSCs) present an unprecedented opportunity to advance human health by offering an alternative and renewable cell resource for cellular therapeutics and regenerative medicine. The present demand for high quality hPSCs for use in both research and clinical studies underscores the need to develop technologies that will simplify the cultivation process and control variability. Here we describe the development of a robust, defined and xeno-free hPSC medium that supports reliable propagation of hPSCs and generation of human induced pluripotent stem cells (hiPSCs) from multiple somatic cell types; long-term serial subculturing of hPSCs with every-other-day (EOD) medium replacement; and banking fully characterized hPSCs. The hPSCs cultured in this medium for over 40 passages are genetically stable, retain high expression levels of the pluripotency markers TRA-1-60, TRA-1-81, Oct-3/4 and SSEA-4, and readily differentiate into ectoderm, mesoderm and endoderm. Importantly, the medium plays an integral role in establishing a cGMP-compliant process for the manufacturing of hiPSCs that can be used for generation of clinically relevant cell types for cell replacement therapy applications. PMID:27606941

  1. Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter randomized controlled trial in Japan (EARTH Study).

    PubMed

    Konaka, Hiroyuki; Sugimoto, Kazuhiro; Orikasa, Hideki; Iwamoto, Teruaki; Takamura, Toshinari; Takeda, Yoshiyu; Shigehara, Kazuyoshi; Iijima, Masashi; Koh, Eitetsu; Namiki, Mikio

    2016-01-01

    Androgen replacement therapy (ART) efficacy on late-onset hypogonadism (LOH) has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores (IPSS), International Index of Erectile Function-5 (IIEF-5) scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients > 40 years with LOH were randomly assigned to either the ART (n = 169) or control groups (n = 165). Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey (SF-36) scale (P = 0.0318). ART was also associated with significant decreases in waist circumstance (P = 0.002) and serum triglyceride (TG) (P = 0.013) and with significant increases in whole-body and leg muscle mass volumes (P = 0.071 and 0.0108, respectively), serum hemoglobin (P < 0.001), IPSS voiding subscore (P = 0.0418), and the second question on IIEF-5 (P = 0.0049). There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area. PMID:25761833

  2. Effects of long-term androgen replacement therapy on the physical and mental statuses of aging males with late-onset hypogonadism: a multicenter, randomized controlled trial in Japan (EARTH Study)

    PubMed Central

    Konaka, Hiroyuki; Sugimoto, Kazuhiro; Orikasa, Hideki; Iwamoto, Teruaki; Takamura, Toshinari; Takeda, Yoshiyu; Shigehara, Kazuyoshi; Iijima, Masashi; Koh, Eitetsu; Namiki, Mikio

    2016-01-01

    Androgen replacement therapy (ART) efficacy on late-onset hypogonadism (LOH) has been widely investigated in Western countries; however, it remains controversial whether ART can improve health and prolong active lifestyles. We prospectively assessed long-term ART effects on the physical and mental statuses of aging men with LOH in Japan. The primary endpoint was health-related quality of life assessed by questionnaires. Secondary endpoints included glycemic control, lipid parameters, blood pressure, waist circumference, body composition, muscular strength, International Prostate Symptom Scores (IPSS), International Index of Erectile Function-5 (IIEF-5) scores, and serum prostate-specific antigen levels. Of the 1637 eligible volunteers, 334 patients > 40 years with LOH were randomly assigned to either the ART (n = 169) or control groups (n = 165). Fifty-two weeks after the initial treatment, ART significantly affected the role physical subdomain of the short form-36 health survey (SF-36) scale (P = 0.0318). ART was also associated with significant decreases in waist circumstance (P = 0.002) and serum triglyceride (TG) (P = 0.013) and with significant increases in whole-body and leg muscle mass volumes (P = 0.071 and 0.0108, respectively), serum hemoglobin (P < 0.001), IPSS voiding subscore (P = 0.0418), and the second question on IIEF-5 (P = 0.0049). There was no significant difference between the groups in terms of severe adverse events. In conclusion, in patients with LOH, long-term ART exerted beneficial effects on Role Physical subdomain of the SF-36 scale, serum TG, waist circumstance, muscle mass volume, voiding subscore of IPSS, and the second question of IIEF-5. We hope our study will contribute to the future development of this area. PMID:25761833

  3. High-dose enzyme replacement therapy in murine Hurler syndrome.

    PubMed

    Ou, Li; Herzog, Tyler; Koniar, Brenda L; Gunther, Roland; Whitley, Chester B

    2014-02-01

    Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from deficiency of α-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease (e.g., hepatomegaly, splenomegaly, glycosaminoglycanuria) and ameliorates others (e.g., pulmonary function, cardiac disease, arthropathy, exercise tolerance). However, neurologic benefits are thought to be negligible because the blood-brain barrier (BBB) blocks enzyme from reaching the central nervous system (CNS). We considered the possibility that a very high dose of intravenous laronidase might be able to traverse the BBB in small quantities, and provide some metabolic correction in the brain. To address this question, high-dose laronidase was administered (11.6 mg/kg, once per week, 4 weeks) to adult MPS I mice. IDUA enzyme activity in the cortex of treated mice increased to 97% of that in wild type mice (p<0.01). GAG levels in cortex were reduced by 63% of that from untreated MPS I mice (p<0.05). Further, immunohistochemical analysis showed that treatment reduced secondary GM3-ganglioside accumulation in treated MPS I mice. Water T-maze tests showed that the learning abnormality in MPS I mice was reduced (p<0.0001). In summary, repeated, high-dose ERT facilitated laronidase transit across the BBB, reduced GAG accumulation within the CNS, and rescued cognitive impairment. PMID:24100243

  4. Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: early treatment rescues bone lesions?

    PubMed Central

    Tomatsu, Shunji; Montaño, Adriana M.; Oikawa, Hirotaka; Dung, Vu Chi; Hashimoto, Amiko; Oguma, Toshihiro; Takahashi, Tatsuo; Shimada, Tsutomu; Orii, Tadao; Sly, William S.

    2014-01-01

    We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology (1). To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250 units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in liver and spleen, with detectable activity in bone and brain. Second, newborn ERT was conducted after tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th week were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in liver, spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than adult mice treated with ERT; however, hyaline and fibrous cartilage cells in femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mouse. PMID:24953405

  5. Long-term testing

    NASA Astrophysics Data System (ADS)

    Ferber, M.; Graves, G. A., Jr.

    Land-based gas turbines are significantly different from automotive gas turbines in that they are designed to operate for 50,000 h or greater (compared to 5,000-10,000 h). The primary goal of this research is to determine the long-term survivability of ceramic materials for industrial gas turbine applications. Research activities in this program focus on the evaluation of the static tensile creep and stress rupture (SR) behavior of three commercially available structural ceramics which have been identified by the gas turbine manufacturers as leading candidates for use in industrial gas turbines. For each material investigated, a minimum of three temperatures and four stresses will be used to establish the stress and temperature sensitivities of the creep and SR behavior. Because existing data for many candidate structural ceramics are limited to testing times less than 2,000 h, this program will focus on extending these data to times on the order of 10,000 h, which represents the lower limit of operating time anticipated for ceramic blades and vanes in gas turbine engines. A secondary goal of the program will be to investigate the possibility of enhancing life prediction estimates by combining interrupted tensile SR tests and tensile dynamic fatigue tests in which tensile strength is measured as a function of stressing rate. The third goal of this program will be to investigate the effects of water vapor upon the SR behavior of the three structural ceramics chosen for the static tensile studies by measuring the flexural strength as a function of stressing rate at three temperatures.

  6. Long-term testing

    SciTech Connect

    Ferber, M.; Graves, G.A. Jr.

    1994-12-31

    Land-based gas turbines are significantly different from automotive gas turbines in that they are designed to operate for 50,000 h or greater (compared to 5,000--10,000 h). The primary goal of this research is to determine the long-term survivability of ceramic materials for industrial gas turbine applications. Research activities in this program focus on the evaluation of the static tensile creep and stress rupture (SR) behavior of three commercially available structural ceramics which have been identified by the gas turbine manufacturers as leading candidates for use in industrial gas turbines. For each material investigated, a minimum of three temperatures and four stresses will be used to establish the stress and temperature sensitivities of the creep and SR behavior. Because existing data for many candidate structural ceramics are limited to testing times less than 2,000 h, this program will focus on extending these data to times on the order of 10,000 h, which represents the lower limit of operating time anticipated for ceramic blades and vanes in gas turbine engines. A secondary goal of the program will be to investigate the possibility of enhancing life prediction estimates by combining interrupted tensile SR tests and tensile dynamic fatigue tests in which tensile strength is measured as a function of stressing rate. The third goal of this program will be to investigate the effects of water vapor upon the SR behavior of the three structural ceramics chosen for the static tensile studies by measuring the flexural strength as a function of stressing rate at three temperatures.

  7. Brush border enzyme activities in the small intestine after long-term gliadin feeding in animal models of human coeliac disease.

    PubMed

    Kozáková, H; Stĕpánková, R; Kolínská, J; Farré, M A; Funda, D P; Tucková, L; Tlaskalová-Hogenová, H

    1998-01-01

    Coeliac disease is a human, genetically linked, disorder which develops in gluten-sensitive persons. The aim of this study was to investigate the effect of prolonged feeding of gliadin, a major fraction of gluten, on enzyme activities of enterocyte brush border membrane enzymes in rats, mice and pigs. Brush-border membranes were isolated from mucosal scrapings of the small intestine of 21-d-old rat pups hand-fed with formula milk diet, two-month-old nu/nu and +/+ BALB/c mice and two-month-old piglets fed three times a week starting at birth with high doses of gliadin. Activities of lactase, sucrase and dipeptidyl peptidase IV (DPP IV) were determined. Individual animal models differed in their response to gliadin feeding. In comparison with albumin fed controls the activities of DPP IV and lactase were decreased in rat pups, nu/nu BALB/c mice and piglets. DPP IV activity was mostly affected in the ileum of rats and piglets fed with gliadin starting at birth. On the other hand, lactase and sucrase activities of nu/nu BALB/c mice and piglets decreased to the largest extent in jejunum. PMID:9821309

  8. Enzyme replacement prevents enamel defects in hypophosphatasia mice.

    PubMed

    Yadav, Manisha C; de Oliveira, Rodrigo Cardoso; Foster, Brian L; Fong, Hanson; Cory, Esther; Narisawa, Sonoko; Sah, Robert L; Somerman, Martha; Whyte, Michael P; Millán, José Luis

    2012-08-01

    Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity, leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl(-/-), aka Akp2(-/-)) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl(-/-) mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl(-/-) mice, histological, µCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. PMID:22461224

  9. [Enzyme replacement therapy in a patient with Pompe disease].

    PubMed

    Fujikawa, Yoshinao; Kinoshita, Satoru; Miyamoto, Yusaku; Nakayama, Tojo; Endo, Yusaku; Sasaki, Masayuki

    2007-09-01

    Pompe disease is a rare autosomal recessive disease caused by the deficiency of acid alpha-glucosidase (GAA), which is required for the degradation of lysosomal glycogen. Glycogen accumulation in heart, muscle and liver eventually leads to muscle weakness, hepatomegaly and cardiomegaly. Although an approved therapy does not exist, the efficacy of enzyme replacement therapy (ERT) has recently been reported in multinational trials in Europe and the US. Here, we present data on the efficacy of recombinant human acid alpha-glucosidase (rhGAA) (provided by Genzyme Corporation) in a patient with Pompe disease. At 5 months of age, motor delay (could not raise his head) and cardiomegaly were observed. A definite diagnosis of Pompe disease was made at 8 months of age after the accumulation of glycogen in a muscle biopsy specimen was observed. This was confirmed by low GAA activity. Since then, motor delay predominated and he was unable to sit independently by age 2.5 years. Every 2 weeks, 20 mg/kg of rhGAA was infused intravenously. To assess the effectiveness, chest X-ray, echocardiography and auditory brain response were recorded. The patient was administered rhGAA for 26 months from 2 years and 8 months of age. Following the initiation of ERT, hepatomegaly and cardiac function (ejection fraction) were rapidly improved and motor function was gradually improved. At 4 years and 10 months, the patient could walk with support. No adverse event has been observed. It can be concluded that ERT with rhGAA is an effective and safe regimen for this case. PMID:17879614

  10. Long-term environmental stewardship.

    SciTech Connect

    Nagy, Michael David

    2010-08-01

    The purpose of this Supplemental Information Source Document is to effectively describe Long-Term Environmental Stewardship (LTES) at Sandia National Laboratories/New Mexico (SNL/NM). More specifically, this document describes the LTES and Long-Term Stewardship (LTS) Programs, distinguishes between the LTES and LTS Programs, and summarizes the current status of the Environmental Restoration (ER) Project.

  11. Presynaptic long-term plasticity

    PubMed Central

    Yang, Ying; Calakos, Nicole

    2013-01-01

    Long-term synaptic plasticity is a major cellular substrate for learning, memory, and behavioral adaptation. Although early examples of long-term synaptic plasticity described a mechanism by which postsynaptic signal transduction was potentiated, it is now apparent that there is a vast array of mechanisms for long-term synaptic plasticity that involve modifications to either or both the presynaptic terminal and postsynaptic site. In this article, we discuss current and evolving approaches to identify presynaptic mechanisms as well as discuss their limitations. We next provide examples of the diverse circuits in which presynaptic forms of long-term synaptic plasticity have been described and discuss the potential contribution this form of plasticity might add to circuit function. Finally, we examine the present evidence for the molecular pathways and cellular events underlying presynaptic long-term synaptic plasticity. PMID:24146648

  12. Management of chronic pancreatitis. Focus on enzyme replacement therapy.

    PubMed

    Dobrilla, G

    1989-01-01

    The goals of treatment with pancreatic extracts in patients with chronic relapsing pancreatitis are twofold: pain relief and control of maldigestion caused by exocrine pancreatic insufficiency. Experience with the use of pancreatic enzymes for analgesic purposes suggests that the less severe the pain, the greater the analgesic effect of these enzymes. However, the number of trials, as well as the number of patients treated, is fairly small and more studies in larger patient populations are needed. The use of pancreatic enzymes for maldigestion owing to exocrine pancreatic insufficiency which is secondary to chronic pancreatitis, pancreatectomy, cystic fibrosis, or GI bypass surgery incurs several problems. These problems are primarily caused by gastric inactivation of the enzymes, low enzyme activity of many commercial preparations and/or poor patient compliance. Treatment with conventional enzyme products (powdered extracts, enteric-coated tablets or capsules) has been disappointing. At best, results were inconsistent, showing a high degree of individual variation. The introduction of enzyme preparations in the form of pH-sensitive enteric-coated microspheres in hard gelatin capsules represents a significant advance. These microspheres are superior to conventional enzyme preparations in improving the symptoms of pancreatic insufficiency, particularly steatorrhea, where low doses of microspheres are as effective as large doses of conventional enzyme preparations. Steatorrhea, however, is rarely completely resolved. In cases refractory to therapy, treatment with the combination of pH-sensitive enteric-coated microspheres and H2-antagonists or prostaglandins has met with some success. PMID:2702247

  13. Long term complications of diabetes

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000327.htm Long term complications of diabetes To use the sharing ... sores and infections. If it goes on too long, your toes, foot, or leg may need to ...

  14. Abdominal Pain, Long-Term

    MedlinePlus

    MENU Return to Web version Abdominal Pain, Long-term See complete list of charts. Ongoing or recurrent abdominal pain, also called chronic pain, may be difficult to diagnose, causing frustration for ...

  15. Short-term effects on antioxidant enzymes and long-term genotoxic and carcinogenic potential of CuO nanoparticles compared to bulk CuO and ionic copper in mussels Mytilus galloprovincialis.

    PubMed

    Ruiz, Pamela; Katsumiti, Alberto; Nieto, Jose A; Bori, Jaume; Jimeno-Romero, Alba; Reip, Paul; Arostegui, Inmaculada; Orbea, Amaia; Cajaraville, Miren P

    2015-10-01

    The aim of this work was to study short-term effects on antioxidant enzyme activities and long-term genotoxic and carcinogenic potential of CuO nanoparticles (NPs) in comparison to bulk CuO and ionic copper in mussels Mytilus galloprovincialis after 21 days exposure to 10 μg Cu L(-1). Then, mussels were kept for up to 122 days in clean water. Cu accumulation depended on the form of the metal and on the exposure time. CuO NPs were localized in lysosomes of digestive cells, as confirmed by TEM and X ray microanalysis. CuO NPs, bulk CuO and ionic copper produced different effects on antioxidant enzyme activities in digestive glands, overall increasing antioxidant activities. CuO NPs significantly induced catalase and superoxide dismutase activities. Fewer effects were observed in gills. Micronuclei frequency increased significantly in mussels exposed to CuO NPs and one organism treated with CuO NPs showed disseminated neoplasia. However, transcription levels of cancer-related genes did not vary significantly. Thus, short-term exposure to CuO NPs provoked oxidative stress and genotoxicity, but further studies are needed to determine whether these early events can lead to cancer development in mussels. PMID:26297043

  16. Enzyme replacement improves ataxic gait and central nervous system histopathology in a mouse model of metachromatic leukodystrophy.

    PubMed

    Matzner, Ulrich; Lüllmann-Rauch, Renate; Stroobants, Stijn; Andersson, Claes; Weigelt, Cecilia; Eistrup, Carl; Fogh, Jens; D'Hooge, Rudi; Gieselmann, Volkmar

    2009-04-01

    Inherited deficiencies of lysosomal hydrolases cause lysosomal storage diseases (LSDs) that are characterized by a progressive multisystemic pathology and premature death. Repeated intravenous injection of the active counterpart of the deficient enzyme, a treatment strategy called enzyme replacement therapy (ERT), evolved as a clinical option for several LSDs without central nervous system (CNS) involvement. To assess the efficacy of long-term ERT in metachromatic leukodystrophy (MLD), an LSD with prevailing nervous system disease, we treated immunotolerant arylsulfatase A (ASA) knockout mice with 52 doses of either 4 or 50 mg/kg recombinant human ASA (rhASA). ERT was tolerated without side effects and improved disease manifestations in a dose-dependent manner. Dosing of 4 mg/kg diminished sulfatide storage in kidney and peripheral nervous system (PNS) but not the CNS, whereas treatment with 50 mg/kg was also effective in the CNS in reducing storage in brain and spinal cord by 34 and 45%, respectively. Histological analyses revealed regional differences in sulfatide clearance. While 70% less storage profiles were detectable, for example, in the hippocampal fimbria, the histopathology of the brain stem was unchanged. Both enzyme doses normalized the ataxic gait of ASA knockout mice, demonstrating prevention of nervous system dysfunctions that dominate early stages of MLD. PMID:19174759

  17. Enzyme Replacement Improves Ataxic Gait and Central Nervous System Histopathology in a Mouse Model of Metachromatic Leukodystrophy

    PubMed Central

    Matzner, Ulrich; Lüllmann-Rauch, Renate; Stroobants, Stijn; Andersson, Claes; Weigelt, Cecilia; Eistrup, Carl; Fogh, Jens; D'Hooge, Rudi; Gieselmann, Volkmar

    2009-01-01

    Inherited deficiencies of lysosomal hydrolases cause lysosomal storage diseases (LSDs) that are characterized by a progressive multisystemic pathology and premature death. Repeated intravenous injection of the active counterpart of the deficient enzyme, a treatment strategy called enzyme replacement therapy (ERT), evolved as a clinical option for several LSDs without central nervous system (CNS) involvement. To assess the efficacy of long-term ERT in metachromatic leukodystrophy (MLD), an LSD with prevailing nervous system disease, we treated immunotolerant arylsulfatase A (ASA) knockout mice with 52 doses of either 4 or 50 mg/kg recombinant human ASA (rhASA). ERT was tolerated without side effects and improved disease manifestations in a dose-dependent manner. Dosing of 4 mg/kg diminished sulfatide storage in kidney and peripheral nervous system (PNS) but not the CNS, whereas treatment with 50 mg/kg was also effective in the CNS in reducing storage in brain and spinal cord by 34 and 45%, respectively. Histological analyses revealed regional differences in sulfatide clearance. While 70% less storage profiles were detectable, for example, in the hippocampal fimbria, the histopathology of the brain stem was unchanged. Both enzyme doses normalized the ataxic gait of ASA knockout mice, demonstrating prevention of nervous system dysfunctions that dominate early stages of MLD. PMID:19174759

  18. Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome

    PubMed Central

    Tomatsu, Shunji; Sawamoto, Kazuki; Alméciga-Díaz, Carlos J; Shimada, Tsutomu; Bober, Michael B; Chinen, Yasutsugu; Yabe, Hiromasa; Montaño, Adriana M; Giugliani, Roberto; Kubaski, Francyne; Yasuda, Eriko; Rodríguez-López, Alexander; Espejo-Mojica, Angela J; Sánchez, Oscar F; Mason, Robert W; Barrera, Luis A; Mackenzie, William G; Orii, Tadao

    2015-01-01

    Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS

  19. Long Term Illness and Wages

    ERIC Educational Resources Information Center

    Sandy, Robert; Elliott, Robert R.

    2005-01-01

    Long-term illness (LTI) is a more prevalent workplace risk than fatal accidents but there is virtually no evidence for compensating differentials for a broad measure of LTI. In 1990 almost 3.4 percent of the U.K. adult population suffered from a LTI caused solely by their working conditions. This paper provides the first estimates of compensating…

  20. Long-term data archiving

    SciTech Connect

    Moore, David Steven

    2009-01-01

    Long term data archiving has much value for chemists, not only to retain access to research and product development records, but also to enable new developments and new discoveries. There are some recent regulatory requirements (e.g., FDA 21 CFR Part 11), but good science and good business both benefit regardless. A particular example of the benefits of and need for long term data archiving is the management of data from spectroscopic laboratory instruments. The sheer amount of spectroscopic data is increasing at a scary rate, and the pressures to archive come from the expense to create the data (or recreate it if it is lost) as well as its high information content. The goal of long-term data archiving is to save and organize instrument data files as well as any needed meta data (such as sample ID, LIMS information, operator, date, time, instrument conditions, sample type, excitation details, environmental parameters, etc.). This editorial explores the issues involved in long-term data archiving using the example of Raman spectral databases. There are at present several such databases, including common data format libraries and proprietary libraries. However, such databases and libraries should ultimately satisfy stringent criteria for long term data archiving, including readability for long times into the future, robustness to changes in computer hardware and operating systems, and use of public domain data formats. The latter criterion implies the data format should be platform independent and the tools to create the data format should be easily and publicly obtainable or developable. Several examples of attempts at spectral libraries exist, such as the ASTM ANDI format, and the JCAMP-DX format. On the other hand, proprietary library spectra can be exchanged and manipulated using proprietary tools. As the above examples have deficiencies according to the three long term data archiving criteria, Extensible Markup Language (XML; a product of the World Wide Web

  1. Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

    PubMed

    Kishnani, Priya S; Dickson, Patricia I; Muldowney, Laurie; Lee, Jessica J; Rosenberg, Amy; Abichandani, Rekha; Bluestone, Jeffrey A; Burton, Barbara K; Dewey, Maureen; Freitas, Alexandra; Gavin, Derek; Griebel, Donna; Hogan, Melissa; Holland, Stephen; Tanpaiboon, Pranoot; Turka, Laurence A; Utz, Jeanine J; Wang, Yow-Ming; Whitley, Chester B; Kazi, Zoheb B; Pariser, Anne R

    2016-02-01

    The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes. PMID:26597321

  2. [DELAYED RESULTS OF ENZYME REPLACEMENT THERAPY, PRESCRIBED BY RESULTS OF 13C-TRIGLYCERIDE BREATH TEST].

    PubMed

    Chernyavskiy, V V; Gvozdetska, L S

    2015-01-01

    Maldigestion persists in most patients with chronic pancreatitis (CP). The objective lipase and amylase insufficiency diagnosis is needed to achieve an adequate clinical response to oral pancreatic enzyme substitution therapy. The novel data is presented in the article about the role of 13C-mixed triglyceride breath test as a tool for exocrine pancreatic insufficiency diagnosis, for evaluating fat malabsorbtion in CP patients. 135 patients were included in the investigation. Delayed results of enzyme replacement therapy were estimated after 1 and 2 year of surveillance. It has been shown, that partial recovery of exocrine pancreatic function is possible, and replacement therapy leads to patients nutritional status improving. Thus 13C-triglyceride breath test could be useful tool in clinical practice for CP diagnosis. The test make it possible to choose the initial pancreatic enzyme dosage and are beneficial during the treatment for pancreatic enzyme dose correction. PMID:26827447

  3. Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

    PubMed

    Cox-Brinkman, J; van Breemen, M J; van Maldegem, B T; Bour, L; Donker, W E; Hollak, C E M; Wijburg, F A; Aerts, J M F G

    2008-12-01

    We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects. PMID:18850301

  4. The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders.

    PubMed

    Broomfield, A; Jones, S A; Hughes, S M; Bigger, B W

    2016-07-01

    In the light of clinical experience in infantile onset Pompe patients, the immunological impact on the tolerability and long-term efficacy of enzyme replacement therapy (ERT) for lysosomal storage disorders has come under renewed scrutiny. This article details the currently proposed immunological mechanisms involved in the development of anti-drug antibodies and the current therapies used in their treatment. Given the current understanding of the adaptive immune response, it focuses particularly on T cell dependent mechanisms and the paradigm of using lymphocytic negative selection as a predictor of antibody formation. This concept originally postulated in the 1970s, stipulated that the genotypically determined lack of production or production of a variant protein determines an individual's lymphocytic repertoire. This in turn is the key factor in determining the potential severity of an individual's immunological response to ERT. It also highlights the need for immunological assay standardization particularly those looking at describing the degree of functional impact, robust biochemical or clinical endpoints and detailed patient subgroup identification if the true evaluations of impact are to be realised. PMID:26883220

  5. Modified beta-D-N-acetylhexosaminidase isozymes for enzyme replacement in GM2 gangliosidosis.

    PubMed

    Rattazzi, M C; Dobrenis, K; Joseph, A; Schwartz, P

    1987-01-01

    The therapeutic potential of enzyme replacement in lysosomal storage disorders has remained largely unfulfilled, perhaps because of negative reactions to the initial disappointing results. Despite the existence of several animal models that can be utilized to explore solutions to the problems of exogenous enzyme targeting, the interest in ERT prevalent during the 1970's seems to have subsided to be replaced by active interest in bone marrow transplantation (BMT, Krivit and Paul [1986]). This is a logical approach to enzyme replacement in storage disorders of the RE system, and indeed some encouraging results have been obtained. However, in addition to having high morbidity and mortality, in the ultimate analysis BMT presents the same targeting problems as conventional ERT. In our opinion, these problems can be solved more easily in the case of ERT by exploiting the existing cellular uptake mechanisms and infusing enzymes whose structure has been suitably modified by simple biochemical manipulations. Accordingly, we have explored a methodology that takes advantage of negative charges on the cell surface to obtain nonspecific but effective membrane binding of beta-hex coupled to the highly positively charged PLL, followed by internalization and routing to the lysosomes. This system increases uptake of exogenous enzyme by some neurons in vitro and possibly in vivo, but its efficiency depends on the cells' endocytic activity that, in the case of neuronal soma, apparently is low. Thus, we have chosen as recognition marker for specific neuronal uptake a nontoxic fragment of TTx that is efficiently taken up by these cells. The initial results are encouraging; they support our contention that effective enzyme replacement methodologies can be devised, and encourage us to continue our work in this direction. Finally, recombinant DNA techniques are now being applied to a number of LSD, and the genes for several of the pertinent enzymes have been or are being isolated. In

  6. Scheie syndrome: enzyme replacement therapy does not prevent progression of cervical myelopathy due to spinal cord compression.

    PubMed

    Illsinger, S; Lücke, T; Hartmann, H; Mengel, E; Müller-Forell, W; Donnerstag, F; Das, A M

    2009-12-01

    Hurler-Scheie syndrome is caused by alpha-l-iduronidase deficiency. Enzyme replacement therapy (ERT) can improve physical capacity and reduces organomegaly. However, the effect on bradytrophic connective tissue is limited. As intravenously administered enzyme cannot cross the blood-brain barrier, the therapy of choice for the more severe Hurler syndrome is haematopoietic stem cell transplantation (HCT). In the more attenuated Scheie syndrome, neurological impairment is less severe; therefore, ERT may be appropriate to treat these patients. Information on long-term outcome in Scheie patients undergoing ERT is scarce. We report a 38-year-old female Scheie patient who has been on ERT for 8 years. While non-neurological symptoms improved, she developed paresthesias in her hands and feet and progressive pain in her legs. Somatosensory evoked potentials were abnormal, suggesting dysfunction of the dorsal funiculus and lemniscus medialis. After 6 years of ERT, a spinal MRI showed dural thickening at the upper cervical spine. These soft-tissue deposits are presumably due to the accumulation of mucopolysaccharides. Intramedullary hyperintensities at the level of C1/2 revealed cervical myelopathy. An MRI before the start of ERT had shown milder spinal lesions. Cystic lesions in the white matter of the centrum semiovale due to dilated Virchow-Robin spaces were essentially unchanged compared with the MRI scan before ERT. Decompression of the spinal cord resulted in clinical improvement. In an adult patient with Scheie syndrome, ERT failed to prevent progression of cervical myelopathy. Clinical significance of cerebral changes is unclear. Whether early HCT or intrathecal ERT could have prevented these lesions remains speculative. PMID:19894140

  7. Stapedectomy - long-term report.

    PubMed

    Shea, J J

    1982-01-01

    The long-term results with large fenestra stapedectomy with vein graft and Teflon piston are compared with results with the small fenestra stapedectomy with teflon piston directly into the vestibule. There were 1,943 operations in the former group and 2,155 in the latter when compared in 1970. One hundred consecutive patients from the beginning of each group with follow-up to present were compared. Results were generally the same with no great change in 15 and 20 years as compared to those at 5 years. The complication of perilymph fistula was caused by creating an opening in the footplate much larger than the prosthesis and was eliminated by interposing a living oval window seal if the opening was much larger than the prosthesis and a flap of lining membrane from the promontory when it was not. Other factors that influence a good result are discussed, including the type and the diameter of the piston used, the type of living oval window seal and the method of attachment to the incus. The small fenestra operation was found to be superior to the large, not only for the hearing gain achieved, but the case of performance and the freedom from complications due to migration of the prosthesis and/or the oval window seal. At present we have done about all that can be done for the conductive components. What remains is the sensorineural component which our studies indicate may be due to an autoimmune response. PMID:6897157

  8. Long Term Surface Salinity Measurements

    NASA Technical Reports Server (NTRS)

    Schmitt, Raymond W.; Brown, Neil L.

    2005-01-01

    Our long-term goal is to establish a reliable system for monitoring surface salinity around the global ocean. Salinity is a strong indicator of the freshwater cycle and has a great influence on upper ocean stratification. Global salinity measurements have potential to improve climate forecasts if an observation system can be developed. This project is developing a new internal field conductivity cell that can be protected from biological fouling for two years. Combined with a temperature sensor, this foul-proof cell can be deployed widely on surface drifters. A reliable in-situ network of surface salinity sensors will be an important adjunct to the salinity sensing satellite AQUARIUS to be deployed by NASA in 2009. A new internal-field conductivity cell has been developed by N Brown, along with new electronics. This sensor system has been combined with a temperature sensor to make a conductivity - temperature (UT) sensor suitable for deployment on drifters. The basic sensor concepts have been proven on a high resolution CTD. A simpler (lower cost) circuit has been built for this application. A protection mechanism for the conductivity cell that includes antifouling protection has also been designed and built. Mr. A.Walsh of our commercial partner E-Paint has designed and delivered time-release formulations of antifoulants for our application. Mr. G. Williams of partner Clearwater Instrumentation advised on power and communication issues and supplied surface drifters for testing.

  9. The Role of Mannosylated Enzyme and the Mannose Receptor in Enzyme Replacement Therapy

    PubMed Central

    Du, Hong; Levine, Mark; Ganesa, Chandrashekar; Witte, David P.; Cole, Edward S.; Grabowski, Gregory A.

    2005-01-01

    Lysosomal acid lipase (LAL) is the critical enzyme for the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) in lysosomes. LAL defects cause Wolman disease (WD) and CE storage disease (CESD). An LAL null (lal−/−) mouse model closely mimics human WD/CESD, with hepatocellular, Kupffer cell and other macrophage, and adrenal cortical storage of CEs and TGs. The effect on the cellular targeting of high-mannose and complex oligosaccharide–type oligosaccharide chains was tested with human LAL expressed in Pichia pastoris (phLAL) and CHO cells (chLAL), respectively. Only chLAL was internalized by cultured fibroblasts, whereas both chLAL and phLAL were taken up by macrophage mannose receptor (MMR)–positive J774E cells. After intraperitoneal injection into lal−/− mice, phLAL and chLAL distributed to macrophages and macrophage-derived cells of various organs. chLAL was also detected in hepatocytes. Ten injections of either enzyme over 30 d into 2- and 2.5-mo-old lal−/− mice produced normalization of hepatic color, decreased liver weight (50%–58%), and diminished hepatic cholesterol and TG storage. Lipid accumulations in macrophages were diminished with either enzyme. Only chLAL cleared lipids in hepatocytes. Mice double homozygous for the LAL and MMR deficiences (lal−/−;MMR−/−) showed phLAL uptake into Kupffer cells and hepatocytes, reversal of macrophage histopathology and lipid storage in all tissues, and clearance of hepatocytes. These results implicate MMR-independent and mannose 6-phosphate receptor–independent pathways in phLAL uptake and delivery to lysosomes in vivo. In addition, these studies show specific cellular targeting and physiologic effects of differentially oligosaccharide-modified human LALs mediated by MMR and that lysosomal targeting of mannose-terminated glycoproteins occurs and storage can be eliminated effectively without MMR. PMID:16380916

  10. Does single-amino-acid replacement work in favor of or against improvement of the thermostability of immobilized enzyme?

    PubMed Central

    Koizumi, J; Zhang, M; Imanaka, T; Aiba, S

    1990-01-01

    Thermostabilities of kanamycin nucleotidyltransferase and of its mutants that became thermostable, in the free state, because of single-amino-acid replacements were studied after immobilization of the enzymes on cyanogen bromide-activated Sephadex G-200 particles. Lys in place of Gln at position 102 decreased the thermostability of the immobilized enzyme, whereas replacement with other amino acids enhanced it. PMID:2176451

  11. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy.

    PubMed

    Matzner, Ulrich; Herbst, Eva; Hedayati, Kerstin Khalaj; Lüllmann-Rauch, Renate; Wessig, Carsten; Schröder, Stephan; Eistrup, Carl; Möller, Christer; Fogh, Jens; Gieselmann, Volkmar

    2005-05-01

    A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide). Sphingolipid storage results in progressive demyelination and severe neurologic symptoms. The disease is lethal, and curative therapy is not available. To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA. Plasma levels of ASA declined with a half-time of approximately 40 min, and enzyme was detectable in tissues within minutes after injection. The uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney and very low into brain. The apparent half-life of endocytosed enzyme was approximately 4 days. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also were surprisingly effective in reducing sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential demonstrate the benefits of ERT on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease. PMID:15772092

  12. Role of Nanotechnology for Enzyme Replacement Therapy in Lysosomal Diseases. A Focus on Gaucher's Disease.

    PubMed

    Martín-Banderas, L; Holgado, M A; Durán-Lobato, M; Infante, J J; Álvarez-Fuentes, J; Fernández-Arévalo, M

    2016-01-01

    Lysosomal storage diseases (LSDs) comprise a group of rare inherited chronic syndromes that cause deficiency of specific native enzymes within the lysosomes. The macromolecular compounds that are usually catabolized by lysosomal enzymes are accumulated within these organelles, causing progressive damage to tissues, skeleton and organs and, in several cases, the central nervous system (CNS). The damage caused by substrate accumulation finally results in physical deterioration, functional impairment and potential death. Up to date, the most promising therapy for most LSDs is enzyme-replacement therapy (ERT), which provides patients with the corresponding active enzyme. However, these enzymes do not have enough stability in blood, the treatment must be therefore periodically administrated by i.v. infusion under medical supervision, and immunogenicity issues are frequent. In addition, affected areas within the CNS, where the blood-brain barrier (BBB) is a major obstacle, cannot be reached by the enzymes. Nanotechnology can provide useful carriers to successfully protect and preserve enzymes, and transport them through the BBB towards brain locations. Several strategies based on targeting specific receptors on the BBB have led to nanoparticles that successfully carry sensitive molecules to the brain. Then, the main LSDs are described and a thorough review of nanotechnology strategies for brain delivery studied up to date is presented. PMID:26860997

  13. Effect of Cross-Sex Hormonal Replacement on Antioxidant Enzymes in Rat Retroperitoneal Fat Adipocytes

    PubMed Central

    Velázquez Espejel, Rodrigo; Cabrera-Orefice, Alfredo; Uribe-Carvajal, Salvador; Pavón, Natalia

    2016-01-01

    We report the effect of cross-sex hormonal replacement on antioxidant enzymes from rat retroperitoneal fat adipocytes. Eight rats of each gender were assigned to each of the following groups: control groups were intact female or male (F and M, resp.). Experimental groups were ovariectomized F (OvxF), castrated M (CasM), OvxF plus testosterone (OvxF + T), and CasM plus estradiol (CasM + E2) groups. After sacrifice, retroperitoneal fat was dissected and processed for histology. Adipocytes were isolated and the following enzymatic activities were determined: Cu-Zn superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). Also, glutathione (GSH) and lipid peroxidation (LPO) were measured. In OvxF, retroperitoneal fat increased and adipocytes were enlarged, while in CasM rats a decrease in retroperitoneal fat and small adipocytes are observed. The cross-sex hormonal replacement in F rats was associated with larger adipocytes and a further decreased activity of Cu-Zn SOD, CAT, GPx, GST, GR, and GSH, in addition to an increase in LPO. CasM + E2 exhibited the opposite effects showing further activation antioxidant enzymes and decreases in LPO. In conclusion, E2 deficiency favors an increase in retroperitoneal fat and large adipocytes. Cross-sex hormonal replacement in F rats aggravates the condition by inhibiting antioxidant enzymes.

  14. Long-term solar-terrestrial observations

    NASA Technical Reports Server (NTRS)

    1988-01-01

    The results of an 18-month study of the requirements for long-term monitoring and archiving of solar-terrestrial data is presented. The value of long-term solar-terrestrial observations is discussed together with parameters, associated measurements, and observational problem areas in each of the solar-terrestrial links (the sun, the interplanetary medium, the magnetosphere, and the thermosphere-ionosphere). Some recommendations are offered for coordinated planning for long-term solar-terrestrial observations.

  15. Reconstructing the Phylogenetic History of Long-Term Effective Population Size and Life-History Traits Using Patterns of Amino Acid Replacement in Mitochondrial Genomes of Mammals and Birds

    PubMed Central

    Nabholz, Benoit; Lartillot, Nicolas

    2013-01-01

    The nearly neutral theory, which proposes that most mutations are deleterious or close to neutral, predicts that the ratio of nonsynonymous over synonymous substitution rates (dN/dS), and potentially also the ratio of radical over conservative amino acid replacement rates (Kr/Kc), are negatively correlated with effective population size. Previous empirical tests, using life-history traits (LHT) such as body-size or generation-time as proxies for population size, have been consistent with these predictions. This suggests that large-scale phylogenetic reconstructions of dN/dS or Kr/Kc might reveal interesting macroevolutionary patterns in the variation in effective population size among lineages. In this work, we further develop an integrative probabilistic framework for phylogenetic covariance analysis introduced previously, so as to estimate the correlation patterns between dN/dS, Kr/Kc, and three LHT, in mitochondrial genomes of birds and mammals. Kr/Kc displays stronger and more stable correlations with LHT than does dN/dS, which we interpret as a greater robustness of Kr/Kc, compared with dN/dS, the latter being confounded by the high saturation of the synonymous substitution rate in mitochondrial genomes. The correlation of Kr/Kc with LHT was robust when controlling for the potentially confounding effects of nucleotide compositional variation between taxa. The positive correlation of the mitochondrial Kr/Kc with LHT is compatible with previous reports, and with a nearly neutral interpretation, although alternative explanations are also possible. The Kr/Kc model was finally used for reconstructing life-history evolution in birds and mammals. This analysis suggests a fairly large-bodied ancestor in both groups. In birds, life-history evolution seems to have occurred mainly through size reduction in Neoavian birds, whereas in placental mammals, body mass evolution shows disparate trends across subclades. Altogether, our work represents a further step toward a more

  16. RTB Lectin: a novel receptor-independent delivery system for lysosomal enzyme replacement therapies

    PubMed Central

    Acosta, Walter; Ayala, Jorge; Dolan, Maureen C.; Cramer, Carole L.

    2015-01-01

    Enzyme replacement therapies have revolutionized patient treatment for multiple rare lysosomal storage diseases but show limited effectiveness for addressing pathologies in “hard-to-treat” organs and tissues including brain and bone. Here we investigate the plant lectin RTB as a novel carrier for human lysosomal enzymes. RTB enters mammalian cells by multiple mechanisms including both adsorptive-mediated and receptor-mediated endocytosis, and thus provides access to a broader array of organs and cells. Fusion proteins comprised of RTB and human α-L-iduronidase, the corrective enzyme for Mucopolysaccharidosis type I, were produced using a tobacco-based expression system. Fusion products retained both lectin selectivity and enzyme activity, were efficiently endocytosed into human fibroblasts, and corrected the disease phenotype of mucopolysaccharidosis patient fibroblasts in vitro. RTB-mediated delivery was independent of high-mannose and mannose-6-phosphate receptors, which are exploited for delivery of currently approved lysosomal enzyme therapeutics. Thus, the RTB carrier may support distinct in vivo pharmacodynamics with potential to address hard-to-treat tissues. PMID:26382970

  17. A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient.

    PubMed

    Tartibi, Hana M; Hershfield, Michael S; Bahna, Sami L

    2016-01-01

    Severe combined immunodeficiency (SCID) is a fatal childhood disease unless immune reconstitution is performed early in life, with either hematopoietic stem cell transplantation or gene therapy. One of its subtypes is caused by adenosine deaminase (ADA) enzyme deficiency, which leads to the accumulation of toxic metabolites that impair lymphocyte development and function. With the development of polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) enzyme replacement therapy, many ADA-deficient children with SCID who could not receive a hematopoietic stem cell transplantation or gene therapy survived and had longer and healthier lives. We report a 24-year course of treatment in a patient who was diagnosed with ADA deficiency at 4 months of age. The patient was treated with PEG-ADA, which was the only therapy available for him. The patient's plasma ADA level was regularly monitored and the PEG-ADA dose adjusted accordingly. This treatment has resulted in near-normalization of lymphocyte counts, and his clinical course has been associated with only minor to moderate infections. Thus far, he has had no manifestations of autoimmune or lymphoproliferative disorders. This patient is among the longest to be maintained on PEG-ADA enzyme replacement therapy. PMID:26684479

  18. LONG-TERM MONITORING SENSOR NETWORK

    SciTech Connect

    Stephen P. Farrington; John W. Haas; Neal Van Wyck

    2003-10-16

    Long-term monitoring (LTM) associated with subsurface contamination sites is a key element of Long Term Stewardship and Legacy Management across the Department of Energy (DOE) complex. However, both within the DOE and elsewhere, LTM is an expensive endeavor, often exceeding the costs of the remediation phase of a clean-up project. The primary contributors to LTM costs are associated with labor. Sample collection, storage, preparation, analysis, and reporting can add a significant financial burden to project expense when extended over many years. Development of unattended, in situ monitoring networks capable of providing quantitative data satisfactory to regulatory concerns has the potential to significantly reduce LTM costs. But survival and dependable operation in a difficult environment is a common obstacle to widespread use across the DOE complex or elsewhere. Deploying almost any sensor in the subsurface for extended periods of time will expose it to chemical and microbial degradation. Over the time-scales required for in situ LTM, even the most advanced sensor systems may be rendered useless. Frequent replacement or servicing (cleaning) of sensors is expensive and labor intensive, offsetting most, if not all, of the cost savings realized with unattended, in situ sensors. To enable facile, remote monitoring of contaminants and other subsurface parameters over prolonged periods, Applied Research Associates, Inc has been working to develop an advanced LTM sensor network consisting of three key elements: (1) an anti-fouling sensor chamber that can accommodate a variety of chemical and physical measurement devices based on electrochemical, optical and other techniques; (2) two rapid, cost effective, and gentle means of emplacing sensor packages either at precise locations directly in the subsurface or in pre-existing monitoring wells; and (3) a web browser-based data acquisition and control system (WebDACS) utilizing field-networked microprocessor-controlled smart

  19. Long-term Effects of Shrub Encroachment and Grazing on Soil Microbial Composition and Function

    NASA Astrophysics Data System (ADS)

    Gallery, R. E.; O'Shea, C.; Kwiecien, A.; Predick, K.; Archer, S. R.

    2014-12-01

    Drylands account for ca. 35% of terrestrial net primary productivity and thus play a significant role in global water and biogeochemical cycles. Replacement of grasses by shrubs has been widespread in these systems and has altered rates of erosion and native plant biodiversity and productivity. The net effect of these changes on biogeochemical cycling is not well understood. Projected warmer and drier conditions may further alter the function and stability of these ecosystems and soil resources through direct effects on soil microbiota and plant-microbe interactions. We quantified microbial community responses to long-term livestock grazing and shrub encroachment in a Sonoran Desert grassland. We sought to characterize tipping points where biotic controls over ecosystem processes shift from being 'grass-driven' to 'shrub-driven.' We asked: How do livestock grazing (the predominant land use in dryland ecosystems) and shrub invasion (a predominant land cover change) interact to influence microbial biomass and the relative abundance of bacteria, archaea, and fungi and their extracellular enzyme activities? Surface soil from bare-ground patches, native and invasive grass rhizospheres, and bole and canopy dripline locations in patches of mature mesquite trees in long-term grazed and long-term (70+ y) protected pastures were collected and analyzed for microbial community composition, biomass, potential exoenzyme activities, and a suite of biogeochemical characteristics. We found no differences in microbial communities or the soils associated with native vs. exotic grasses. Overall, mesquite bole patches differed from other patches in all soil characteristics except potential enzyme activity: soil temperature was significantly lower, and total carbon (C) and soil moisture were significantly higher. Potential activities were lowest for bare ground and highest at shrub dripline patches for all seven exoenzymes tested. Mean potential activities for C and phosphorous (P

  20. Long-term preservation of Anammox bacteria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Deposit of useful microorganisms in culture collections requires long-term preservation and successful reactivation techniques. The goal of this study was to develop a simple preservation protocol for the long-term storage and reactivation of the anammox biomass. To achieve this, anammox biomass w...

  1. Long Term Preservation of Digital Information.

    ERIC Educational Resources Information Center

    Lorie, Raymond A.

    The preservation of digital data for the long term presents a variety of challenges from technical to social and organizational. The technical challenge is to ensure that the information, generated today, can survive long term changes in storage media, devices, and data formats. This paper presents a novel approach to the problem. It distinguishes…

  2. Virtual Models of Long-Term Care

    ERIC Educational Resources Information Center

    Phenice, Lillian A.; Griffore, Robert J.

    2012-01-01

    Nursing homes, assisted living facilities and home-care organizations, use web sites to describe their services to potential consumers. This virtual ethnographic study developed models representing how potential consumers may understand this information using data from web sites of 69 long-term-care providers. The content of long-term-care web…

  3. Paying for long-term care.

    PubMed Central

    Estes, C L; Bodenheimer, T

    1994-01-01

    Everyone agrees that insurance for long-term care is inadequate in the United States. Disagreement exists, however, on whether such insurance should be provided through the private or public sector. Private insurance generally uses the experience-rating principle that persons with higher risk of illness are charged higher premiums. For private insurance for long-term care, this principle creates a dilemma. Most policies will be purchased by the elderly; yet, because the elderly have a high risk of needing long-term care, only about 20% of them can afford the cost of premiums. A public-private partnership by which the government partially subsidizes private long-term-care insurance is unlikely to resolve this dilemma. Only a social insurance program for long-term care can provide universal, affordable, and equitable coverage. PMID:8128712

  4. Enzyme replacement therapy in Hurler syndrome after failure of hematopoietic transplant

    PubMed Central

    Arranz, Leonor; Aldamiz-Echevarria, Luis

    2015-01-01

    The most severe form of Mucopolysaccharosidosis type I (MPS-I), Hurler syndrome, presents with progressive respiratory, cardiac and musculoskeletal symptoms and cognitive deterioration. Treatment includes enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). We describe the case of an 8-year old boy with MPS-I, homozygous for W402X, treated at 10 months of age with HSCT and after failure of the transplant, with ERT during 2 years showing good results, including a positive neuropsychological development. PMID:26937401

  5. [Hurler syndrome. Early diagnosis and successful enzyme replacement therapy: a new therapeutic approach. Case report].

    PubMed

    Dupont, C; El Hachem, C; Harchaoui, S; Ribault, V; Amiour, M; Guillot, M; Maire, I; Froissart, R; Guffon-Fouilhoux, N

    2008-01-01

    Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder due to alpha-L-iduronidase deficiency. Its severe prognosis has been significantly improved by enzyme replacement therapy using recombinant human alpha-L-iduronidase (laronidase). We report the case of a boy who was diagnosed at 19 months of age with Hurler's disease, the most severe form of MPS I, and received thereafter a treatment by laronidase, resulting in clinical and biological improvement. The aim of this case report is to draw physicians' attention on the presenting signs of Hurler's disease, in order to enable an earlier diagnosis, increasing the treatment's benefits. PMID:18162380

  6. Enzyme replacement therapy in Hurler syndrome after failure of hematopoietic transplant.

    PubMed

    Arranz, Leonor; Aldamiz-Echevarria, Luis

    2015-06-01

    The most severe form of Mucopolysaccharosidosis type I (MPS-I), Hurler syndrome, presents with progressive respiratory, cardiac and musculoskeletal symptoms and cognitive deterioration. Treatment includes enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). We describe the case of an 8-year old boy with MPS-I, homozygous for W402X, treated at 10 months of age with HSCT and after failure of the transplant, with ERT during 2 years showing good results, including a positive neuropsychological development. PMID:26937401

  7. AB126. Enzyme replacement therapy in patient with mucopolysaccharidosis type I: a case report

    PubMed Central

    Can, Ngoc Thi Bich; Vu, Dung Chi; Le, Hang Thi Thuy; Nguyen, Khanh Ngoc; Bui, Huong Thi

    2015-01-01

    Background and objective Mucopolysaccharidosis I (MPS I) is a rare, recessively inherited, lysosomal storage disorder caused by deficiency on the enzyme α-L-iduronidase. This defect results in accumulation of heparan and dermatan sulfate in different tissues and organs due to a deficiency in the catabolism of glycosaminoglycans. The overall incidence of MPS I is 0.99-1.99/100,000 live births. Enzyme replacement therapy (ERT) with recombinant α-L-iduronidase (laronidase) has shown to significantl improve the quality of life in children. To describe clinical characteristics, enzyme activity and genetic finding in the first Vietnamese patient with MPS type I with aldurazyme replacement therapy. Methods Clinical features, biochemical finding, enzyme activity, mutation analysis and management in a 4 years 6-month-old girl was study. Based on analysis of a patient’s clinical symptoms associated with enzyme α-L-iduronidase activity measurement in leukocyte, the diagnosis of MPS type I was therefore made. Genomic DNAs were extracted from peripheral blood leukocytes from the patient and identify mutation of IDUA gene, 14 exons and their intronic boundaries of the IDUA gene were sequenced using genomic DNA from the patient. The patient has been treated with aldurazyme infusion every week with the dose of 0.58 mg/kg/week. Results A 4 years 6-month-old girl was presented with joint stiffness at 2 years old. She was admitted with the features of short status, coarse facial, corneal clouding, carpel tunnel syndrome and joint stiffness, kyphosis, abdominal distension, palpable liver at 3 cm below the costal margin, sleep disturbances/snoring. Laboratory showed: hearing lost at right ear in acoumetry, hepatosplenomegaly in ultrasound with right liver length of 117 mm, spleen length of 89 mm, a 6-minute walk test distance of 158.6 m, α-I-duronidase 0.43 nmoL/mg Prot/hrs (normal: 41.8±15.9), urine glycosaminoglycan (GAG) of 508.83 mg/g creatinine (normal: 10.74-112.02). PCR

  8. AB127. Enzyme replacement therapy in patient with mucopolysaccharidosis type II: a case report

    PubMed Central

    Can, Ngoc Thi Bich; Vu, Dung Chi; Le, Hang Thi Thuy; Nguyen, Khanh Ngoc; Bui, Huong Thi

    2015-01-01

    Background and objective Mucopolysaccharidosis (MPS) type II (Hunter syndrome) is an X-linked lysosomal storage disorder due to the deficit of iduronate 2-sulfatase, an enzyme catalysing the degradation of the glycosaminoglycans (GAG) dermatan- and heparan-sulfate. Treatment of the disease is mainly performed by enzyme replacement therapy (ERT) with idursulfase. This article aims to describe clinical characteristics, enzyme activity and genetic finding in the first Vietnamese patient with MPS type II treated with idursulfase (Elaprase) replacement therapy. Methods Clinical features, biochemical finding, enzyme activity, mutation analysis and management in a 4 years 6-month-old girl was study. Based on analysis of a patient’s clinical symptoms associated with enzyme iduronate-2-sulphate sulphatase activity measurement in plasma, the diagnosis of MPS type II was therefore made. Genomic DNAs were extracted from peripheral blood leukocytes from the patient and identify mutation of IDS gene, nine exons and their intronic boundaries of the IDS gene were sequenced using genomic DNA from the patient. The patient has been treated with Elaprase infusion every week with the dose of 0.05 mg/kg/week. Results A 34-month-old boy was presented with coarse facial at 24 months of age. He was admitted with the features of coarse facial, with frontal bossing, prominent supraorbital ridge, large nose and flat nasal bridge, widely spaced teeth, thickened gingival mucosa, and macroglossia, broadly built of the body habitus with a short neck, broad chest, and protuberant abdomen and Mongolian spots at the back and breech, joint finger stiffness, abdominal distension, palpable liver at 3 cm below the costal margin, sleep disturbances/snoring, mental development delay. Laboratory showed: hepatosplenomegaly in ultrasound with right liver length of 127 mm, spleen length of 93 mm, a 6-minute walk test distance of 240 m, DQ 55%, α iduronate sulphate: 0 nmoL/4 h/mL plasma (normal: 600

  9. Early administration of enzyme replacement therapy for Pompe disease: short-term follow-up results.

    PubMed

    Hamdan, M A; Almalik, M H; Mirghani, H M

    2008-12-01

    Pompe disease (glycogen storage disease II, OMIM # 232300), is a hereditary lysosomal disorder. It is characterized by deficiency of acid alpha-glucosidase enzyme (acid maltase, GAA, OMIM *606800, EC 3.1.26.2), secondary to mutations in the GAA gene (HGNC:4065) on chromosome 17q25.2-q25.3. Absent enzyme activity in the infantile form of Pompe disease results in abnormal glycogen deposition in the skeletal, cardiac, and smooth muscles, leading to hypertrophic cardiomyopathy, feeding abnormalities, hypotonia, weakness, respiratory insufficiency, and ultimately death. Prenatal diagnosis is accomplished by enzyme assay, mutation analysis or electron microscopy of amniotic fluid cells or chorionic villus sample. However, these techniques may not always be available, and can result in perinatal morbidity and fetal loss. Early diagnosis of Pompe disease results in early institution of enzyme replacement therapy (ERT), which minimizes morbidity and prolongs survival. We report the case of a 35-week part-of-twin neonate, whose older sibling died earlier because of infantile Pompe disease. At 32 weeks of gestation, fetal echocardiography showed hypertrophic cardiomyopathy in twin 1, which persisted until birth at 35 weeks of gestation. Diagnosis was confirmed after birth by enzyme assay, and mutation analysis showing homozygosity for the sequence change 1327-2A>G (GAA intr 8). Administration of ERT at 18 h of age, resulted in normalization of cardiac abnormalities within 21 weeks of therapy, and normal neurodevelopmental assessment at 46 weeks, using Griffiths Mental Development Scales. To our knowledge, this is the youngest patient reported to receive ERT for Pompe disease, and the first report of prenatal diagnosis of Pompe disease by fetal echocardiography. PMID:19067231

  10. Business Students' Choice of Short-Term or Long-Term Study Abroad Opportunities

    ERIC Educational Resources Information Center

    Fitzsimmons, Stacey R.; Flanagan, David J.; Wang, Xiaodan

    2013-01-01

    Recent years have seen a proliferation of short-term study abroad opportunities. Although they are both supplementing and replacing semester-long study abroad programs, research has focused primarily on semester (long-term) programs. We draw on the theory of planned behavior (TPB) to explore factors that predict why students choose long-term and…

  11. Towards the development of an enzyme replacement therapy for the metabolic disorder propionic acidemia.

    PubMed

    Darvish-Damavandi, Mahnaz; Ho, Han Kiat; Kang, Tse Siang

    2016-09-01

    Propionic acidemia (PA) is a life-threatening disease caused by the deficiency of a mitochondrial biotin-dependent enzyme known as propionyl coenzyme-A carboxylase (PCC). This enzyme is responsible for degrading the metabolic intermediate, propionyl coenzyme-A (PP-CoA), derived from multiple metabolic pathways. Currently, except for drastic surgical and dietary intervention that can only provide partial symptomatic relief, no other form of therapeutic option is available for this genetic disorder. Here, we examine a novel approach in protein delivery by specifically targeting and localizing our protein candidate of interest into the mitochondrial matrix of the cells. In order to test this concept of delivery, we have utilized cell penetrating peptides (CPPs) and mitochondria targeting sequences (MTS) to form specific fusion PCC protein, capable of translocating and localizing across cell membranes. In vitro delivery of our candidate fusion proteins, evaluated by confocal images and enzymatic activity assay, indicated effectiveness of this strategy. Therefore, it holds immense potential in creating a new paradigm in site-specific protein delivery and enzyme replacement therapeutic for PA. PMID:27504265

  12. Long Term Effects of Food Poisoning

    MedlinePlus

    ... develop chronic arthritis. Brain and nerve damage A Listeria infection can lead to meningitis, an inflammation of ... brain. If a newborn infant is infected with Listeria , long-term consequences may include mental retardation, seizures, ...

  13. Mental Health in Long Term Care Settings.

    ERIC Educational Resources Information Center

    Shore, Herbert

    1978-01-01

    There are many ways in which long-term care facilities attempt to cope with the mental health problems of the elderly. The author reviews five factors crucial to effective care for the aged in these facilities. (Author/RK)

  14. Asthma Medicines: Long-Term Control

    MedlinePlus

    ... Español Text Size Email Print Share Asthma Medicines: Long-term Control Page Content Article Body Corticosteroids Synthetic ... and sprinkle forms are available for young children. Long-Acting Beta2-Agonists Medications in the beta 2 - ...

  15. Outcome after three years of laronidase enzyme replacement therapy in a patient with Hurler syndrome.

    PubMed

    Thomas, J A; Jacobs, S; Kierstein, J; Van Hove, J

    2006-12-01

    Enzyme replacement therapy (ERT) with laronidase, recombinant alpha-L-iduronidase, for mucopolysaccharidosis type I (MPS I) has been clinically available since April 2003. Pre-approval studies were performed on patients with the more attenuated forms of MPS I, Hurler-Scheie and Scheie syndromes. The clinical efficacy of laronidase on the severe form of MPS I, Hurler syndrome, is not well known. We present a patient with Hurler syndrome who has been treated with laronidase for 3 years. Clinically, the patient demonstrated improvement in urinary glycosaminoglycan (GAG) levels and hepatomegaly, but continued to experience decline in respiratory status, musculoskeletal and spinal involvement, and developmental skills. Overall, the benefit of ERT with laronidase in advanced Hurler syndrome appeared to be minimal in this patient. PMID:17089217

  16. Cardiomyopathy and response to enzyme replacement therapy in a male mouse model for Fabry disease.

    PubMed

    Nguyen Dinh Cat, Aurelie; Escoubet, Brigitte; Agrapart, Vincent; Griol-Charhbili, Violaine; Schoeb, Trenton; Feng, Wenguang; Jaimes, Edgar; Warnock, David G; Jaisser, Frederic

    2012-01-01

    Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, (predominately globotriaosylceramide; GL-3) in lysosomes, as well as other cellular compartments and the extracellular space. Our aim was to characterize the cardiac phenotype of male knock-out mice that are deficient in alpha-galactosidase A activity, as a model for Fabry disease and test the efficacy of Enzyme Replacement Therapy with agalsidase-beta. Male mice (3-4 months of age) were characterized with awake blood pressure and heart rate measurements, cardiac echocardiography and electrocardiography measurements under light anesthesia, histological studies and molecular studies with real-time polymerase chain reaction. The Fabry knock-out mouse has bradycardia and lower blood pressure than control wild type (CB7BL/6J) mice. In Fabry knock-out mice, the cardiomyopathy associated mild hypertrophy at echography with normal systolic LV function and mild diastolic dysfunction. Premature atrial contractions were more frequent in without conduction defect. Heart weight normalized to tibial length was increased in Fabry knock-out mice. Ascending aorta dilatation was observed. Molecular studies were consistent with early stages of cardiac remodeling. A single dose of agalsidase-beta (3 mg/kg) did not affect the LV hypertrophy, function or heart rate, but did improve the mRNA signals of early cardiac remodeling. In conclusion, the alpha-galactosidase A deficient mice at 3 to 4 months of age have cardiac and vascular alterations similar to that described in early clinical stage of Fabry disease in children and adolescents. Enzyme replacement therapy affects cardiac molecular remodeling after a single dose. PMID:22574107

  17. Structural Phylogenomics Reveals Gradual Evolutionary Replacement of Abiotic Chemistries by Protein Enzymes in Purine Metabolism

    PubMed Central

    Caetano-Anollés, Kelsey; Caetano-Anollés, Gustavo

    2013-01-01

    The origin of metabolism has been linked to abiotic chemistries that existed in our planet at the beginning of life. While plausible chemical pathways have been proposed, including the synthesis of nucleobases, ribose and ribonucleotides, the cooption of these reactions by modern enzymes remains shrouded in mystery. Here we study the emergence of purine metabolism. The ages of protein domains derived from a census of fold family structure in hundreds of genomes were mapped onto enzymes in metabolic diagrams. We find that the origin of the nucleotide interconversion pathway benefited most parsimoniously from the prebiotic formation of adenine nucleosides. In turn, pathways of nucleotide biosynthesis, catabolism and salvage originated ∼300 million years later by concerted enzymatic recruitments and gradual replacement of abiotic chemistries. Remarkably, this process led to the emergence of the fully enzymatic biosynthetic pathway ∼3 billion years ago, concurrently with the appearance of a functional ribosome. The simultaneous appearance of purine biosynthesis and the ribosome probably fulfilled the expanding matter-energy and processing needs of genomic information. PMID:23516625

  18. β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.

    PubMed

    Koeberl, Dwight D; Li, Songtao; Dai, Jian; Thurberg, Beth L; Bali, Deeksha; Kishnani, Priya S

    2012-02-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  19. β2 Agonists Enhance the Efficacy of Simultaneous Enzyme Replacement Therapy in Murine Pompe Disease

    PubMed Central

    Koeberl, Dwight D.; Li, Songtao; Dai, Jian; Thurberg, Beth L.; Bali, Deeksha; Kishnani, Priya S.

    2011-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes. PMID:22154081

  20. Enzyme replacement with PEGylated cystathionine β-synthase ameliorates homocystinuria in murine model

    PubMed Central

    Bublil, Erez M.; Majtan, Tomas; Park, Insun; Carrillo, Richard S.; Hůlková, Helena; Krijt, Jakub; Kožich, Viktor

    2016-01-01

    Homocystinuria, which typically results from cystathionine β-synthase (CBS) deficiency, is the most common defect of sulfur amino acid metabolism. CBS condenses homocysteine and serine to cystathionine that is then converted to cysteine. Individuals with homocystinuria have markedly elevated plasma levels of homocysteine and methionine and reduced concentrations of cystathionine and cysteine. Clinical disease manifestations include thromboembolism and neuropsychiatric, ocular, and skeletal complications. Here, we have shown that administration of PEGylated CBS into the circulation of homocystinuria model mice alters the extra- and intracellular equilibrium of sulfur amino acids, resulting in a decrease of approximately 75% in plasma total homocysteine (tHcy) and normalization of cysteine concentrations. Moreover, the decrease in homocysteine and the normalization of cysteine in PEGylated CBS–treated model mice were accompanied by improvement of histopathological liver symptoms and increased survival. Together, these data suggest that CBS enzyme replacement therapy (ERT) is a promising approach for the treatment of homocystinuria and that ERT for metabolic diseases may not necessitate introduction of the deficient enzyme into its natural intracellular compartment. PMID:27183385

  1. Long-term Multiwavelength Observations of Polars

    NASA Astrophysics Data System (ADS)

    Santana, Joshua; Mason, Paul A.

    2016-06-01

    Polars are cataclysmic variables with the highest magnetic field strengths (10-250 MG). Matter is accreted after being funneled by the strong magnetic field of the white dwarf. We perform a meta-study of multi-wavelength data of polars. Many polars have been observed in surveys, such as SDSS, 2MASS, ROSAT, just to name a few. Some polars have now been detected by the JVLA, part of an expanding class of radio CVs. A large subset of polars have long-term optical light curves from CRTS and AAVSO. We suggest that the long term light curves of polars display a variety of signature behaviors and may be grouped accordingly. Additional characteristics such a binary period, magnetic field strengths, X-ray properties, and distance estimates are examined in context with long-term observations.

  2. Assessment of stability, toxicity and immunogenicity of new polymeric nanoreactors for use in enzyme replacement therapy of MNGIE.

    PubMed

    De Vocht, Caroline; Ranquin, An; Willaert, Ronnie; Van Ginderachter, Jo A; Vanhaecke, Tamara; Rogiers, Vera; Versées, Wim; Van Gelder, Patrick; Steyaert, Jan

    2009-08-01

    The lack of a crucial metabolic enzyme can lead to accumulating substrate concentrations in the bloodstream and severe human enzyme deficiency diseases. Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is such a fatal genetic disorder, caused by a thymidine phosphorylase deficiency. Enzyme replacement therapy is a strategy where the deficient enzyme is administered intravenously in order to decrease the toxic substrate concentrations. Such a therapy is however not very efficient due to the fast elimination of the native enzyme from the circulation. In this study we evaluate the potential of using polymeric enzyme-loaded nanoparticles to improve the delivery of therapeutic enzymes. We constructed new 200-nanometer PMOXA-PDMS-PMOXA polymeric nanoparticles that encapsulate the enzyme thymidine phosphorylase. These particles are permeabilised for substrates and products by the reconstitution of the nucleoside-specific porin Tsx in their polymeric wall. We show that the obtained 'nanoreactors' are enzymatically active and stable in blood serum at 37 degrees C. Moreover, they do not provoke cytotoxicity when incubated with hepatocytes for 4 days, nor do they induce a macrophage-mediated inflammatory response ex vivo and in vivo. All data highlight the potential of such nanoreactors for their application in enzyme replacement therapy of MNGIE. PMID:19371766

  3. Scenarios for long-term analysis

    SciTech Connect

    Wolbers, Stephen; /Fermilab

    2009-01-01

    Data Preservation and Long-Term Analysis of High Energy Physics (HEP) Experiments data is described and summarized in this talk. The summary covers information presented at the First Workshop on Data Preservation and Long-Term Analysis. Experiments representing e{sup +}e{sup -} collisions (LEP, B Factories and CLEO), ep collisions (H1 and ZEUS), p{bar p} collisions (CDF and D0) and others presented interesting information related to utilizing the large datasets collected over many years at these HEP facilities. Many questions and issues remain to be explored.

  4. Long-Term Use of Benzodiazepines

    PubMed Central

    Potts, Nicholas L.S.; Krishnan, K. Ranga R.

    1992-01-01

    Problems associated with physical dependence and abuse of benzodiazepines by a small percentage of patients have reduced their popularity from the most commonly prescribed psychoactive drug in the 1970s to being prescribed for mainly short periods. Patients who benefit from long-term benzodiazepine use are nearly ignored by the medical community as a whole. This article details what patient population can improve from long-term benzodiazepine therapy, the risks and benefits of treatment, and how to select appropriate candidates. PMID:21229127

  5. Long-term Outcomes after Severe Shock

    PubMed Central

    Pratt, Cristina M.; Hirshberg, Eliotte L.; Jones, Jason P.; Kuttler, Kathryn G.; Lanspa, Michael J.; Wilson, Emily L.; Hopkins, Ramona O.; Brown, Samuel M.

    2014-01-01

    Background Severe shock is a life-threatening condition with very high short-term mortality. Whether the long-term outcomes among survivors of severe shock are similar to long-term outcomes of other critical illness survivors is unknown. We therefore sought to assess long-term survival and functional outcomes among 90-day survivors of severe shock and determine whether clinical predictors were associated with outcomes. Methods Seventy-six patients who were alive 90 days after severe shock (received ≥1 mcg/kg/min of norepinephrine equivalent) were eligible for the study. We measured three-year survival and long-term functional outcomes using the Medical Outcomes Study 36-Item Short-Form Health Survey, the EuroQOL 5-D-3L, the Hospital Anxiety and Depression Scale, the Impact of Event Scale-Revised and an employment instrument. We also assessed the relationship between in-hospital predictors and long-term outcomes. Results The mean long-term survival was 5.1 years: 82% (62/76) of patients survived, of whom 49 were eligible for follow-up. Patients who died were older than patients who survived. Thirty-six patients completed a telephone interview a mean of five years after hospital admission. The patients’ Physical Functioning scores were below US population norms (p<0.001), whereas mental health scores were similar to population norms. Nineteen percent of the patients had symptoms of depression, 39% had symptoms of anxiety and 8% had symptoms of posttraumatic stress disorder. Thirty-six percent were disabled, and 17% were working full time. Conclusions Early survivors of severe shock had a high three-year survival rate. Patients’ long term physical and psychological outcomes were similar to those reported for cohorts of less severely ill ICU survivors. Anxiety and depression were relatively common, but only a few patients had symptoms of posttraumatic stress disorder. This study supports the observation that acute illness severity does not determine long-term

  6. An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with Fabry disease who are naïve to enzyme replacement therapy

    PubMed Central

    Goker-Alpan, Ozlem; Longo, Nicola; McDonald, Marie; Shankar, Suma P; Schiffmann, Raphael; Chang, Peter; Shen, Yinghua; Pano, Arian

    2016-01-01

    Background Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease. Methods In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ≥7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. Results Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=−0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (−3.3, 3.7) g/m2.7; midwall fractional shortening, −0.62% (−2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (−11.4, 11.7) mL/min/1.73 m2; urine protein, −1.8 (−6.0, 2.4) mg/dL; urine microalbumin, 0.6 (−0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), −5.71 (−10.8, −0.6) nmol/mL; urinary Gb3, −1,403.3 (−3,714.0, 907.4) nmol/g creatinine

  7. LONG TERM HYDROLOGICAL IMPACT ASSESSMENT (LTHIA)

    EPA Science Inventory

    LTHIA is a universal Urban Sprawl analysis tool that is available to all at no charge through the Internet. It estimates impacts on runoff, recharge and nonpoint source pollution resulting from past or proposed land use changes. It gives long-term average annual runoff for a lan...

  8. Long Term Care Aide. Course Outline.

    ERIC Educational Resources Information Center

    Wilbee, Judy

    This course outline is intended to assist the instructor in the development of a curriculum for a long-term care aide program by specifying one component of the curriculum--the objectives. These objectives, or competencies expected as outcomes for student performance on completion of the program, describe the capabilities an individual must…

  9. Who Recommends Long-Term Care Matters

    ERIC Educational Resources Information Center

    Kane, Robert L.; Bershadsky, Boris; Bershadsky, Julie

    2006-01-01

    Purpose: Making good consumer decisions requires having good information. This study compared long-term-care recommendations among various types of health professionals. Design and Methods: We gave randomly varied scenarios to a convenience national sample of 211 professionals from varying disciplines and work locations. For each scenario, we…

  10. Long-term fixed income market structure

    NASA Astrophysics Data System (ADS)

    Grilli, Luca

    2004-02-01

    Long-term fixed income market securities present a strong positive correlation in daily returns. By using a metrical approach and considering “modified” time series, I show how it is possible to show a more complex structure which depends strictly on the maturity date.

  11. Professionalism in Long-Term Care Settings

    ERIC Educational Resources Information Center

    Lubinski, Rosemary

    2006-01-01

    Speech-language pathologists who serve elders in a variety of long-term care settings have a variety of professional skills and responsibilities. Fundamental to quality service is knowledge of aging and communication changes and disorders associated with this process, institutional alternatives, and the changing nature of today's elders in…

  12. NATIONAL LONG TERM CARE SURVEY (NLTCS)

    EPA Science Inventory

    National Long Term Care Surveys (NLTCS) are surveys of the entire aged population with a particular emphasis on the functionally impaired. Longitudinal study of the health and well-being of elderly Americans. Information about the population of chronically disabled elderly person...

  13. Long-Term Memory and Learning

    ERIC Educational Resources Information Center

    Crossland, John

    2011-01-01

    The English National Curriculum Programmes of Study emphasise the importance of knowledge, understanding and skills, and teachers are well versed in structuring learning in those terms. Research outcomes into how long-term memory is stored and retrieved provide support for structuring learning in this way. Four further messages are added to the…

  14. Long-Term Stability of Social Participation

    ERIC Educational Resources Information Center

    Hyyppa, Markku T.; Maki, Juhani; Alanen, Erkki; Impivaara, Olli; Aromaa, Arpo

    2008-01-01

    The long-term stability of social participation was investigated in a representative urban population of 415 men and 579 women who had taken part in the nationwide Mini-Finland Health Survey in the years 1978-1980 and were re-examined 20 years later. Stability was assessed by means of the following tracking coefficients: kappa, proportion of…

  15. Aortic and Mitral Valve Involvement in Maroteaux-Lamy Syndrome VI: Surgical Implications in the Enzyme Replacement Therapy Era.

    PubMed

    Torre, Salvatore; Scarpelli, Mauro; Salviati, Alessandro; Buffone, Ebba; Faggian, Giuseppe; Luciani, Giovanni Battista

    2016-07-01

    Open-heart operations in patients with mucopolysaccharidoses are exceedingly rare and pose distinct clinical challenges. Few reports exist of valve replacement in type VI mucopolysaccharidosis, mostly entailing combined mitral and aortic valve replacement. Here reported is the case of a young woman with mitral and aortic valve disease, in whom the surgical procedure was confined to the aortic valve. The rationale behind this strategy, particularly in light of the benefits offered by specific enzyme replacement therapy of type VI mucopolysaccharidosis, is discussed. PMID:27343522

  16. Enhanced response to enzyme replacement therapy in Pompe disease after the induction of immune tolerance.

    PubMed

    Sun, Baodong; Bird, Andrew; Young, Sarah P; Kishnani, Priya S; Chen, Y-T; Koeberl, Dwight D

    2007-11-01

    Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid alpha -glucosidase (GAA) (also called "acid maltase"), causes death in early childhood related to glycogen accumulation in striated muscle and an accompanying infantile-onset cardiomyopathy. The efficacy of enzyme replacement therapy (ERT) with recombinant human GAA was demonstrated during clinical trials that prolonged subjects' overall survival, prolonged ventilator-free survival, and also improved cardiomyopathy, which led to broad-label approval by the U.S. Food and Drug Administration. Patients who lack any residual GAA expression and are deemed negative for cross-reacting immunologic material (CRIM) have a poor response to ERT. We previously showed that gene therapy with an adeno-associated virus (AAV) vector containing a liver-specific promoter elevated the GAA activity in plasma and prevented anti-GAA antibody formation in immunocompetent GAA-knockout mice for 18 wk, predicting that liver-specific expression of human GAA with the AAV vector would induce immune tolerance and enhance the efficacy of ERT. In this study, a very low number of AAV vector particles was administered before initiation of ERT, to prevent the antibody response in GAA-knockout mice. A robust antibody response was provoked in naive GAA-knockout mice by 6 wk after a challenge with human GAA and Freund's adjuvant; in contrast, administration of the AAV vector before the GAA challenge prevented the antibody response. Most compellingly, the antibody response was prevented by AAV vector administration during the 12 wk of ERT, and the efficacy of ERT was thereby enhanced. Thus, AAV vector-mediated gene therapy induced a tolerance to introduced GAA, and this strategy could enhance the efficacy of ERT in CRIM-negative patients with Pompe disease and in patients with other lysosomal storage diseases. PMID:17924344

  17. Enhanced Response to Enzyme Replacement Therapy in Pompe Disease after the Induction of Immune Tolerance

    PubMed Central

    Sun, Baodong ; Bird, Andrew ; Young, Sarah P. ; Kishnani, Priya S. ; Chen, Y.-T. ; Koeberl, Dwight D. 

    2007-01-01

    Pompe disease, which results from mutations in the gene encoding the glycogen-degrading lysosomal enzyme acid α-glucosidase (GAA) (also called “acid maltase”), causes death in early childhood related to glycogen accumulation in striated muscle and an accompanying infantile-onset cardiomyopathy. The efficacy of enzyme replacement therapy (ERT) with recombinant human GAA was demonstrated during clinical trials that prolonged subjects’ overall survival, prolonged ventilator-free survival, and also improved cardiomyopathy, which led to broad-label approval by the U.S. Food and Drug Administration. Patients who lack any residual GAA expression and are deemed negative for cross-reacting immunologic material (CRIM) have a poor response to ERT. We previously showed that gene therapy with an adeno-associated virus (AAV) vector containing a liver-specific promoter elevated the GAA activity in plasma and prevented anti-GAA antibody formation in immunocompetent GAA-knockout mice for 18 wk, predicting that liver-specific expression of human GAA with the AAV vector would induce immune tolerance and enhance the efficacy of ERT. In this study, a very low number of AAV vector particles was administered before initiation of ERT, to prevent the antibody response in GAA-knockout mice. A robust antibody response was provoked in naive GAA-knockout mice by 6 wk after a challenge with human GAA and Freund’s adjuvant; in contrast, administration of the AAV vector before the GAA challenge prevented the antibody response. Most compellingly, the antibody response was prevented by AAV vector administration during the 12 wk of ERT, and the efficacy of ERT was thereby enhanced. Thus, AAV vector–mediated gene therapy induced a tolerance to introduced GAA, and this strategy could enhance the efficacy of ERT in CRIM-negative patients with Pompe disease and in patients with other lysosomal storage diseases. PMID:17924344

  18. Enzyme replacement therapy of a novel humanized mouse model of globoid cell leukodystrophy.

    PubMed

    Matthes, Frank; Andersson, Claes; Stein, Axel; Eistrup, Carl; Fogh, Jens; Gieselmann, Volkmar; Wenger, David A; Matzner, Ulrich

    2015-09-01

    An inherited deficiency of β-galactosylceramidase (GALC) causes the lysosomal storage disease globoid cell leukodystrophy (GLD). The disease is characterized by the accumulation of the cytotoxic metabolite psychosine (galactosylsphingosine), causing rapid degeneration of myelinating cells. Most patients suffer from the infantile form of GLD with onset of disease between 3 and 6 months after birth and death by 2 years of age. The most widely used animal model of GLD, the twitcher mouse, presents with an even more rapid course of disease and death around 40 days of age. We have generated a novel "humanized" mouse model of GLD by inserting a human GALC cDNA containing an adult-onset patient mutation into the murine GALC gene. Humanized GALC mice exhibit pathological hallmarks of GLD including psychosine accumulation, neuroinflammation, CNS infiltration of macrophages, astrogliosis and demyelination. Residual GALC activities in mouse tissues are low and the mice display a median lifespan of 46 days. Due to the expression of the human transgene, the mice do not develop an immune response against rhGALC, rendering the animal model suitable for therapies based on human enzyme. Intravenously injected rhGALC was able to surmount the blood-brain barrier and was targeted to lysosomes of brain macrophages, astrocytes and neurons. High-dose enzyme replacement therapy started at postnatal day 21 reduced the elevated psychosine levels in the peripheral and central nervous system by 14-16%, but did not ameliorate neuroinflammation, demyelination and lifespan. These results may indicate that treatment must be started earlier before pathology occurs. PMID:25956830

  19. Long-Term Monitoring Research Needs: A DOE Perspective

    NASA Astrophysics Data System (ADS)

    Moore, B.; Davis, C. B.

    2002-05-01

    The U.S. Department of Energy's Office of Environmental Management is responsible for dealing with the nation's legacy of Cold War radioactive and hazardous waste and contamination. Major efforts are underway to deal with this legacy; these are expected to last up to decades and cost up to billions of dollars at some sites. At all sites, however, active remediation must eventually cease; if hazards then remain, the site must enter into a long-term stewardship mode. In this talk we discuss aspects of long-term monitoring pertinent to DOE sites, focusing on challenges to be faced, specific goals or targets to be met, and research needs to be addressed in order to enable DOE to meet its long-term stewardship obligations. DOE LTM research needs fall into three major categories: doing what we can do now much more efficiently; doing things we cannot do now; and proving the validity of our monitoring programs. Given the enormity of the DOE obligations, it will be highly desirable to develop much more efficient monitoring paradigms. Doing so will demand developing autonomous, remote monitoring networks of in situ sensors capable of replacing (or at least supplementing to a large extent) conventional groundwater and soil gas sampling and analysis programs. The challenges involved range from basic science (e.g., inventing in situ sensors for TCE that do not demand routine maintenance) to engineering (attaining superior reliability in data reporting in remote networks) to ergonomics (developing decent ways of selecting and presenting the "right" information from the monitoring network) to regulatory affairs (presenting convincing evidence that the more efficient systems actually provide superior monitoring). We explore these challenges in some detail, focusing on the "long" in long-term monitoring as it applies to DOE sites. Monitoring system performance validation and, ultimately, regulator and stakeholder acceptance of site closure and long-term stewardship plans depend

  20. Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): effect and limitations

    PubMed Central

    Tomatsu, Shunji; Sawamoto, Kazuki; Shimada, Tsutomu; Bober, Michael B.; Kubaski, Francyne; Yasuda, Eriko; Mason, Robert W.; Khan, Shaukat; Alméciga-Díaz, Carlos J.; Barrera, Luis A.; Mackenzie, William G.

    2015-01-01

    Introduction Following a Phase III, randomized, double-blind, placebo (PBO)-controlled, multinational study in subjects with mucopolysaccharidosis IVA (MPS IVA), enzyme replacement therapy (ERT) of elosulfase alfa has been approved in several countries. The study was designed to evaluate safety and efficacy of elosulfase alfa in patients with MPS IVA aged 5 years and older. Areas covered Outcomes of clinical trials for MPS IVA have been described. Subjects received either 2.0 mg/kg/week, 2.0 mg/kg/every other week, or PBO, for 24 weeks. The primary endpoint was the change from baseline 6-min walk test (6MWT) distance compared to PBO. The 6MWT results improved in patients receiving 2 mg/kg weekly compared to PBO. The every other week regimen resulted in walk distances comparable to PBO. There was no change from baseline in the 3 Min Stair Climb Test in both treatment groups. Following completion of the initial study, patients, who continued to receive elosulfase alfa 2 mg/kg weekly (QW) for another 48 weeks (for a total of up to 72-week exposure), did not show additional improvement on 6MWT. Expert opinion We suggest that ERT is a therapeutic option for MPS IVA, providing a modest effect and the majority of the effects are seen in the soft tissues. PMID:26973801

  1. Respiratory mechanics in an infant with perinatal lethal hypophosphatasia treated with human recombinant enzyme replacement therapy.

    PubMed

    Rodriguez, Elena; Bober, Michael B; Davey, Lauren; Zamora, Arlene; Li Puma, Annelise B; Chidekel, Aaron; Shaffer, Thomas H

    2012-09-01

    Hypophosphatasia is a rare autosomal recessive disorder caused by deficient activity of tissue nonspecific alkaline phosphatase (TNSALP) and characterized by defective bone mineralization. In the perinatal lethal form, respiratory complications due to rachitic deformities of the thoracic cage and associated hypoplastic lungs are present. ENB-0040 is a bone-targeted human recombinant TNSALP fusion protein that aims to restore skeletal mineralization. The goal of this study was to characterize pulmonary and thoracic cage mechanics in an infant with the perinatal lethal form of hypophosphatasia under enzyme replacement therapy. Pulmonary function testing was performed on a preterm, 8-week-old patient with hypophosphatasia who was mechanically ventilated since birth because of severe chest wall insufficiency. The measurements consisted of respiratory impulse oscillation measurements (resistance and reactance), ventilatory mechanics (compliance and resistance), and thoracoabdominal motion (TAM) analysis. At baseline, chest wall compliance was 50% of normal, and the TAM indicated predominantly abdominal displacement. After 12 weeks of treatment, a consistent decrease in ventilator requirements and improvement in lung function and chest wall mechanics were observed and correlated with thoracic cage radiologic findings. Measurable changes in chest wall dynamics and respiratory mechanics using noninvasive technology were useful for respiratory management and therapeutic guidance of ENB-0040 treatment in this patient. PMID:22328548

  2. Progress in Enzyme Replacement Therapy in Glycogen Storage Disease Type II.

    PubMed

    Angelini, Corrado; Semplicini, Claudio; Tonin, Paola; Filosto, Massimiliano; Pegoraro, Elena; Sorarù, Gianni; Fanin, Marina

    2009-05-01

    Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adultonset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT, since not all late-onset patients respond similarly to ERT. PMID:21179524

  3. Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age.

    PubMed

    Matthes, Frank; Stroobants, Stijn; Gerlach, Debora; Wohlenberg, Claudia; Wessig, Carsten; Fogh, Jens; Gieselmann, Volkmar; Eckhardt, Matthias; D'Hooge, Rudi; Matzner, Ulrich

    2012-06-01

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of arylsulfatase A (ASA). Previous studies in ASA-knockout mice suggested enzyme replacement therapy (ERT) to be a promising treatment option. The mild phenotype of ASA-knockout mice did, however, not allow to examine therapeutic responses of the severe neurological symptoms that dominate MLD. We, therefore, generated an aggravated MLD mouse model displaying progressive demyelination and reduced nerve conduction velocity (NCV) and treated it by weekly intravenous injections of 20 mg/kg recombinant human ASA for 16 weeks. To analyze the stage-dependent therapeutic effects, ERT was initiated in a presymptomatic, early and progressed disease stage, at age 4, 8 and 12 months, respectively. Brain sulfatide storage, NCV and behavioral alterations were improved only in early, but not in late, treated mice showing a clear age-dependent efficacy of treatment. Hematopoietic stem cell transplantation (HSCT) for late-onset variants is the only therapeutic option for MLD to date. ERT resembles a part of the HSCT rationale, which is based on ASA supply by donor cells. Beyond ERT, our results, therefore, corroborate the clinical observation that HSCT is only effective when performed in early stages of disease. PMID:22388935

  4. Myocardial protection during aortic valve replacement. Cardiac metabolism and enzyme release following hypothermic cardioplegia.

    PubMed

    Bomfim, V; Kaijser, L; Bendz, R; Sylvén, C; Olin, C

    1980-01-01

    Cardiac metabolism following hypothermic potassium cardioplegia was studied in 23 patients undergoing isolated aortic valve replacement. All had normal coronary arteries. Cardioplegia was induced by infusing 700-1 000 ml of cold Ringer's acetate containing 20 mekv K+ selectively into the left coronary artery. Simultaneous blood samples were taken from the radial artery, a central vein and from the coronary sinus before and after cardioplegia. The PO2, O2-saturation and content, PCO2, pH, lactate, glucose, potassium, myoglobin, total creatine kinase (CK), its isoenzyme CK-MB, aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) were assessed. Before bypass lactate was extracted by the heart. During the initial 10 to 20 min after cardioplegia there was a marked release of lactate in the coronary sinus. Myoglobin concentration and CK-MB serum activity peaked during the first 4 hours after the release of the aortic cross-clamping. In order to determine the best indicator of myocardial damage after cardioplegia, duration of extracorporeal circulation (ECC-time), aortic occlusion time (AOT), mean myocardial temperature (MMT) and the product of AOT and MMT, referred to as time-temperature area (TTA), were related to possible indicators of myocardial injury, such as enzyme and myoglobin release. The TTA was the best way of expressing the degree of exposure of the heart to ischaemia. The CK-MB to peak area (CK-MB max area) was the best indicator of the degree of ischaemic injury sustained by the heart during operation. PMID:7375890

  5. Enzyme replacement therapy prevents dental defects in a model of hypophosphatasia.

    PubMed

    McKee, M D; Nakano, Y; Masica, D L; Gray, J J; Lemire, I; Heft, R; Whyte, M P; Crine, P; Millán, J L

    2011-04-01

    Hypophosphatasia (HPP) occurs from loss-of-function mutation in the tissue-non-specific alkaline phosphatase (TNALP) gene, resulting in extracellular pyrophosphate accumulation that inhibits skeletal and dental mineralization. TNALP-null mice (Akp2(-/-)) phenocopy human infantile hypophosphatasia; they develop rickets at 1 week of age, and die before being weaned, having severe skeletal and dental hypomineralization and episodes of apnea and vitamin B(6)-responsive seizures. Delay and defects in dentin mineralization, together with a deficiency in acellular cementum, are characteristic. We report the prevention of these dental abnormalities in Akp2(-/-) mice receiving treatment from birth with daily injections of a mineral-targeting, human TNALP (sALP-FcD(10)). sALP-FcD(10) prevented hypomineralization of alveolar bone, dentin, and cementum as assessed by micro-computed tomography and histology. Osteopontin--a marker of acellular cementum--was immuno-localized along root surfaces, confirming that acellular cementum, typically missing or reduced in Akp2(-/-) mice, formed normally. Our findings provide insight concerning how acellular cementum is formed on tooth surfaces to effect periodontal ligament attachment to retain teeth in their osseous alveolar sockets. Furthermore, they provide evidence that this enzyme-replacement therapy, applied early in post-natal life--where the majority of tooth root development occurs, including acellular cementum formation--could prevent the accelerated tooth loss seen in individuals with HPP. PMID:21212313

  6. Health reform: setting the agenda for long term care.

    PubMed

    Hatch, O G; Wofford, H; Willging, P R; Pomeroy, E

    1993-06-01

    The White House Task Force on National Health Care Reform, headed by First Lady Hillary Rodham Clinton, is expected to release its prescription for health care reform this month. From the outset, Clinton's mandate was clear: to provide universal coverage while reining in costs for delivering quality health care. Before President Clinton was even sworn into office, he had outlined the major principles that would shape the health reform debate. Global budgeting would establish limits on all health care expenditures, thereby containing health costs. Under a system of managed competition, employers would form health alliances for consumers to negotiate for cost-effective health care at the community level. So far, a basic approach to health care reform has emerged. A key element is universal coverage--with an emphasis on acute, preventive, and mental health care. Other likely pieces are employer-employee contributions to health care plans, laws that guarantee continued coverage if an individual changes jobs or becomes ill, and health insurance alliances that would help assure individual access to low-cost health care. What still is not clear is the extent to which long term care will be included in the basic benefits package. A confidential report circulated by the task force last month includes four options for long term care: incremental Medicaid reform; a new federal/state program to replace Medicaid; a social insurance program for home and community-based services; or full social insurance for long term care. Some work group members have identified an additional option: prefunded long term care insurance.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:10126659

  7. Long term mortality in burned children

    PubMed Central

    Stamboulian, Daniel; Lede, Roberto

    2015-01-01

    Studies about risk factors for mortality in burn children are scarce and are even less in the follow up of this population across time. Usually, after complete event attendance, children are not follow-up as risk patients, burn injury affects all facets of life. Integration of professionals from different disciplines has enabled burn centers to develop collaborative methods of assessing the quality of care delivered to patients with burns. In this editorial we comment the paper of Duke et al. The authors highlight the importance of maintaining a long-term monitoring of children who suffered burns. The importance of this original study is to promote the reconsideration of clinical guides of long-term follow-up of burn patients. PMID:26835375

  8. Long term mortality in burned children.

    PubMed

    Rosanova, María Teresa; Stamboulian, Daniel; Lede, Roberto

    2015-07-01

    Studies about risk factors for mortality in burn children are scarce and are even less in the follow up of this population across time. Usually, after complete event attendance, children are not follow-up as risk patients, burn injury affects all facets of life. Integration of professionals from different disciplines has enabled burn centers to develop collaborative methods of assessing the quality of care delivered to patients with burns. In this editorial we comment the paper of Duke et al. The authors highlight the importance of maintaining a long-term monitoring of children who suffered burns. The importance of this original study is to promote the reconsideration of clinical guides of long-term follow-up of burn patients. PMID:26835375

  9. Long-term safety of retinoid therapy.

    PubMed

    Vahlquist, A

    1992-12-01

    The concern about long-term toxicity of oral synthetic retinoids has developed because many patients, especially those with genodermatoses, require lifelong therapy. Several organ systems are at risk, especially the hepatic, skeletal, and cardiovascular systems. Although acute hepatotoxicity is a rare side effect of etretinate and acitretin therapy, prospective studies have not demonstrated chronic liver toxicity. The frequency of bone changes induced by retinoids is difficult to estimate, because this adverse effect is usually asymptomatic and requires x-ray or scintigraphic examination for detection. Atherosclerosis develops in many patients who receive long-term retinoid therapy, but the extent to which the process is aggravated by drug-induced hyperlipidemia is not known. Many patients have now been treated with either etretinate or isotretinoin continuously for as many as 15 years and have not developed any signs of severe chronic toxicity. However, continued intense surveillance is recommended for patients expected to require lifelong therapy. PMID:1460122

  10. [Taiwan long-term care insurance and the evolution of long-term care in Japan].

    PubMed

    Huang, Hui-Wen; Liu, Shu-Hui; Pai, Yu-Chu

    2010-08-01

    The proportion of elderly (65 years of age and older) in Taiwan has exceeded 10% since 2008. With more elderly, the number of patients suffering from dementia and disabilities has also been rapidly increasing. Japan also has been facing increasing demand for long-term care due to an aging society. Prior to 2000, social welfare programs in Japan, working to cope with changing needs, typically provided insufficient services, and geriatric patients were hospitalized unnecessarily, wasting medical resources and causing undue patient hardship. In response, Japan launched its long-term care insurance program in April 2000. Under the program, city, town and village-based organizations should take responsibility for providing care to the elderly in their place of residence. The program significantly improved previous financial shortfalls and long-term care supply and demand has been met by existing social welfare organization resources. In Taiwan, the provision of long-term care by county / city authorities has proven inconsistent, with performance deemed poor after its first decade of long-term care operations. Service was found to be affected by differences in available resources and insufficient long-term care administration. The cultures of Taiwan and Japan are similar. The authors visited the Japan Long-Term Care Insurance Institute in August 2009. Main issues involved in the implementation and evolution of the Japan long-term Care Insurance are reported on in this paper. We hope such may be useful information to those working to develop long-term care programs in Taiwan. PMID:20661859

  11. Long-term orbital lifetime predictions

    NASA Astrophysics Data System (ADS)

    Dreher, P. E.; Lyons, A. T.

    1990-10-01

    Long-term orbital lifetime predictions are analyzed. Predictions were made for three satellites: the Solar Max Mission (SMM), the Long Duration Exposure Facility (LDEF), and the Pegasus Boiler Plate (BP). A technique is discussed for determining an appropriate ballistic coefficient to use in the lifetime prediction. The orbital decay rate should be monitored regularly. Ballistic coefficient updates should be done whenever there is a significant change in the actual decay rate or in the solar activity prediction.

  12. Long-term sequelae of electrical injury

    PubMed Central

    Wesner, Marni L.; Hickie, John

    2013-01-01

    Abstract Objective To summarize the current evidence-based knowledge about the long-term sequelae of injuries from electrical current. Quality of evidence MEDLINE was searched for English-language articles published in the past 20 years using the following search terms: electrical, injuries, wound, trauma, accident, sequelae, long-term, follow-up, and aftereffects. For obvious reasons, it is unethical to randomly study electrical injury in controlled clinical trials. By necessity, this topic is addressed in less-rigorous observational and retrospective work and case studies. Therefore, the strength of the literature pertaining to the long-term sequelae of electrical injury is impaired by the necessity of retrospective methods and case studies that typically describe small cohorts. Main message There are 2 possible consequences of electrical injury: the person either survives or dies. For those who survive electrical injury, the immediate consequences are usually obvious and often require extensive medical intervention. The long-term sequelae of the electrical injury might be more subtle, pervasive, and less well defined, but can include neurologic, psychological, and physical symptoms. In the field of compensation medicine, determining causation and attributing outcome to an injury that might not result in objective clinical findings becomes a considerable challenge. Conclusion The appearance of these consequences of electrical injury might be substantially delayed, with onset 1 to 5 or more years after the electrical injury. This poses a problem for patients and health care workers, making it hard to ascribe symptoms to a remote injury when they might not arise until well after the incident event. PMID:24029506

  13. Long-term home hemodialysis in children

    PubMed Central

    Borra, Sonia; Kaye, Michael

    1971-01-01

    Experience with chronic hemodialysis as a definitive form of therapy is described for six children aged 11 to 15 years at the onset. Duration on dialysis in the home has been between one and 4½ years. All patients are alive and rehabilitated without serious complications. It is concluded that although transplantation is the most desirable form of treatment for children, long-term hemodialysis is an alternative acceptable second choice. ImagesFIG. 2 PMID:5150193

  14. Long-term Variation of AGNs

    NASA Astrophysics Data System (ADS)

    Fan, J. H.; Xie, G. Z.; Adam, G.; Copin, Y.; Lin, R. G.; Bai, J. M.; Quin, Y. P.

    In this paper we will present the long-term variation in the optical and the infrared bands for some selected AGNs. 1. Some new optical data observed by us have been presented for BL Lacertae (1995-1996) and OJ 287 (1994-1995), and new infrared data are presented for OJ 287 (Nov=2E 1995), which corresponds to the second optical peak (Sillanpaa et al. 1996; Takalo et al. 1996) and during last outburst. 2. For objects with long term observations, the Jurkevich's method has been used to analyses the long-term variation period. It is interesting that the reported periods of AGNs are of the similar value of about 10 years: 3C 345 11.4 years (Webb et al. 1988), 3C 120 15 years (Belokon et al. 1987; Hagen-Thorn et al. 1997), ON 231 13.6 years (Liu et al. 1995), OJ 287 12 years (Sillanpaa et al. 1988; Kidger et al. 1992), PKS 0735+178 14 years (Fan et al. 1997), NGC 4151 15 years (Fan et al. 1998a), BL Lacertae 14.0 years (Fan et al. 1998b). Is the mechanism for the long-term variation the same for different AGNs? 3. The DCF method has been adopted to analysis the variation correlation in the optical and infrared bands for BL Lac object OJ 287, the results show that these two bands are strongly correlated, which suggest that the emission mechanism in the two bands is the same. 4. For the optical and infrared bands, the maximum variations are correlated.

  15. Long-term consequences of anorexia nervosa.

    PubMed

    Meczekalski, Blazej; Podfigurna-Stopa, Agnieszka; Katulski, Krzysztof

    2013-07-01

    Anorexia nervosa (AN) is a psychiatric disorder that occurs mainly in female adolescents and young women. The obsessive fear of weight gain, critically limited food intake and neuroendocrine aberrations characteristic of AN have both short- and long-term consequences for the reproductive, cardiovascular, gastrointestinal and skeletal systems. Neuroendocrine changes include impairment of gonadotropin releasing-hormone (GnRH) pulsatile secretion and changes in neuropeptide activity at the hypothalamic level, which cause profound hypoestrogenism. AN is related to a decrease in bone mass density, which can lead to osteopenia and osteoporosis and a significant increase in fracture risk in later life. Rates of birth complications and low birth weight may be higher in women with previous AN. The condition is associated with fertility problems, unplanned pregnancies and generally negative attitudes to pregnancy. During pregnancy, women with the condition have higher rates of hyperemesis gravidarum, anaemia and obstetric complications, as well as impaired weight gain and compromised intrauterine foetal growth. It is reported that 80% of AN patients are affected by a cardiac complications such as sinus bradycardia, a prolonged QT interval on electrocardiography, arrythmias, myocardial mass modification and hypotension. A decrease in bone mineral density (BMD) is one of the most important medical consequences of AN. Reduced BMD may subsequently lead to a three- to seven-fold increased risk of spontaneous fractures. Untreated AN is associated with a significant increase in the risk of death. Better detection and sophisticated therapy should prevent the long-term consequences of this disorder. The aims of treatment are not only recovery but also prophylaxis and relief of the long-term effects of this disorder. Further investigations of the long-term disease risk are needed. PMID:23706279

  16. Titanium for long-term tritium storage

    SciTech Connect

    Heung, L.K.

    1994-12-01

    Due to the reduction of nuclear weapon stockpile, there will be an excess of tritium returned from the field. The excess tritium needs to be stored for future use, which might be several years away. A safe and cost effective means for long term storage of tritium is needed. Storing tritium in a solid metal tritide is preferred to storing tritium as a gas, because a metal tritide can store tritium in a compact form and the stored tritium will not be released until heat is applied to increase its temperature to several hundred degrees centigrade. Storing tritium as a tritide is safer and more cost effective than as a gas. Several candidate metal hydride materials have been evaluated for long term tritium storage. They include uranium, La-Ni-Al alloys, zirconium and titanium. The criteria used include material cost, radioactivity, stability to air, storage capacity, storage pressure, loading and unloading conditions, and helium retention. Titanium has the best combination of properties and is recommended for long term tritium storage.

  17. [Long-term survival after severe trauma].

    PubMed

    Mutschler, W; Mutschler, M; Graw, M; Lefering, R

    2016-07-01

    Long-term survival after severe trauma is rarely addressed in German trauma journals although knowledge of life expectancy and identification of factors contributing to increased mortality are important for lifetime care management, development of service models, and targeting health promotion and prevention interventions. As reliable data in Germany are lacking, we compiled data mainly from the USA and Australia to describe life expectancy, risk factors, and predictors of outcome in patients experiencing traumatic spinal cord injury, traumatic brain injury, and polytrauma. Two years after trauma, life expectancy in all three categories was significantly lower than that of the general population. It depends strongly on severity of disability, age, and gender and is quantifiable. Whereas improvements in medical care have led to a marked decline in short-term mortality, surprisingly long-term survival in severe trauma has not changed over the past 30 years. Therefore, there is need to intensify long-term trauma patient care and to find new strategies to limit primary damage. PMID:27342106

  18. Enzyme Replacement Therapy in Mucopolysaccharidosis II Patients Under 1 Year of Age.

    PubMed

    Lampe, Christina; Atherton, Andrea; Burton, Barbara K; Descartes, Maria; Giugliani, Roberto; Horovitz, Dafne D G; Kyosen, Sandra O; Magalhães, Tatiana S P C; Martins, Ana Maria; Mendelsohn, Nancy J; Muenzer, Joseph; Smith, Laurie D

    2014-01-01

    Mucopolysaccharidosis (MPS) II, or Hunter syndrome, is a lysosomal storage disease characterized by multi-systemic involvement and a progressive clinical course. Enzyme replacement therapy with idursulfase has been approved in more than 50 countries worldwide; however, safety and efficacy data from clinical studies are currently only available for patients 1.4 years of age and older. Sibling case studies of infants with MPS I, II, and VI who initiated ERT in the first weeks or months of life have reported no new safety concerns and a more favorable clinical course for the sibling treated in infancy than for the later-treated sibling. Here we describe our experiences with a case series of eight MPS II patients for whom idursulfase treatment was initiated at under 1 year of age. The majority of the patients were diagnosed because of a family history of disease. All of the infants displayed abnormalities consistent with MPS II at diagnosis. The youngest age at treatment start was 10 days and the oldest was 6.5 months, with duration of treatment varying between 6 weeks and 5.5 years. No new safety concerns were observed, and none of the patients experienced an infusion-related reaction. All of the patients treated for more than 6 weeks showed improvements and/or stabilization of some somatic manifestations while on treatment. In some cases, caregivers made comparisons with other affected family members and reported that the early-treated patients experienced a less severe clinical course, although a lack of medical records for many family members precluded a rigorous comparison. PMID:24515576

  19. Adjunctive albuterol enhances the response to enzyme replacement therapy in late-onset Pompe disease.

    PubMed

    Koeberl, Dwight D; Austin, Stephanie; Case, Laura E; Smith, Edward C; Buckley, Anne F; Young, Sarah P; Bali, Deeksha; Kishnani, Priya S

    2014-05-01

    Effective dosages for enzyme replacement therapy (ERT) in Pompe disease are much higher than for other lysosomal storage disorders, which has been attributed to low cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle. We have previously demonstrated the benefit of increased CI-MPR-mediated uptake of recombinant human acid-α-glucosidase during ERT in mice with Pompe disease following addition of albuterol therapy. Currently we have completed a pilot study of albuterol in patients with late-onset Pompe disease already on ERT for >2 yr, who were not improving further. The 6-min walk test (6MWT) distance increased in all 7 subjects at wk 6 (30±13 m; P=0.002), wk 12 (34±14 m; P=0.004), and wk 24 (42±37 m; P=0.02), in comparison with baseline. Grip strength was improved significantly for both hands at wk 12. Furthermore, individual subjects reported benefits; e.g., a female patient could stand up from sitting on the floor much more easily (time for supine to standing position decreased from 30 to 11 s), and a male patient could readily swing his legs out of his van seat (hip abduction increased from 1 to 2+ on manual muscle testing). Finally, analysis of the quadriceps biopsies suggested increased CI-MPR at wk 12 (P=0.08), compared with baseline. With the exception of 1 patient who succumbed to respiratory complications of Pompe disease in the first week, only mild adverse events have been reported, including tremor, transient difficulty falling asleep, and mild urinary retention (requiring early morning voiding). Therefore, this pilot study revealed initial safety and efficacy in an open label study of adjunctive albuterol therapy in patients with late-onset Pompe disease who had been stable on ERT with no improvements noted over the previous several years. PMID:24443373

  20. Effects of Enzyme Replacement Therapy Started Late in a Murine Model of Mucopolysaccharidosis Type I

    PubMed Central

    Pasqualim, Gabriela; Baldo, Guilherme; de Carvalho, Talita Giacomet; Tavares, Angela Maria Vicente; Giugliani, Roberto; Matte, Ursula

    2015-01-01

    Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don’t receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6–8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible. PMID:25646802

  1. Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network

    PubMed Central

    Dornelles, Alícia Dorneles; de Camargo Pinto, Louise Lapagesse; de Paula, Ana Carolina; Steiner, Carlos Eduardo; Lourenço, Charles Marques; Kim, Chong Ae; Horovitz, Dafne Dain Gandelman; Ribeiro, Erlane Marques; Valadares, Eugênia Ribeiro; Goulart, Isabela; Neves de Souza, Isabel C.; da Costa Neri, João Ivanildo; Santana-da-Silva, Luiz Carlos; Silva, Luiz Roberto; Ribeiro, Márcia; de Oliveira Sobrinho, Ruy Pires; Giugliani, Roberto; Schwartz, Ida Vanessa Doederlein

    2014-01-01

    Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed. PMID:24688287

  2. [Long-term treatment with amiodarone].

    PubMed

    Baedeker, W; Goedel-Meinen, L; Schmidt, G; Hofmann, M; Barthel, P; Blömer, H

    1991-02-01

    The aim of this study was to investigate the efficacy and the side effects of a long-term treatment with amiodarone. We analyzed the data of 41 patients in whom amiodarone therapy had been initiated between 1974 and 1984. Twenty-one patients had dilative cardiomyopathy, 14 patients had chronic myocardial infarction, four patients suffered from WPW syndrome with intermittent atrial fibrillation, one patient had aortic valve surgery, whereas in one patient there was no clinical evidence of a heart disease. All patients had salvos of ventricular extrasystoles, ventricular tachycardia or documented intermittent ventricular fibrillation. There have been seven drop-outs up to the present time. In each patient, the lowest antiarrhythmically effective dose was applied, which was generally higher in patients with low ejection fraction. Effective treatment of the ventricular tachycardia was achieved in 55-92% of patients and did not depend on the duration of treatment. In 10 patients in whom amiodarone therapy had to be stopped for various reasons. Sudden cardiac death was slightly more frequent than in the 24 patients treated with amiodarone, though the difference was not significant. In cases with a history of syncope the prognosis was poor, even with amiodarone therapy. Due to side effects, a dosage reduction or discontinuation of amiodarone treatment became necessary in 14 patients. Amiodarone proved to be an effective drug also for the long-term treatment of ventricular tachycardia, and possibly for the prevention of sudden cardiac death. With the exception of blue skin color, there was no accumulation of side effects, even during long-term treatment of several years. PMID:1711739

  3. Long-term EARLINET dust observations

    NASA Astrophysics Data System (ADS)

    Mona, Lucia; Amiridis, Vassilis; Amodeo, Aldo; Binietoglou, Ioannis; D'Amico, Giuseppe; Schwarz, Anja; Papagiannopoulos, Nikolaos; Papayannis, Alexandros; Sicard, Michael; Comeron, Adolfo; Pappalardo, Gelsomina

    2015-04-01

    Systematic observations of Saharan dust events over Europe are performed from May 2000 by EARLINET, the European Aerosol Research LIdar NETwork. EARLINET is a coordinated network of stations that make use of advanced lidar methods for the vertical profiling of aerosols. The backbone of EARLINET network is a common schedule for performing the measurements and the quality assurance of instruments/data. Particular attention is paid to monitoring the Saharan dust intrusions over the European continent. The geographical distribution of the EARLINET stations is particularly appealing for the dust observation, with stations located all around the Mediterranean and in the center of the Mediterranean (Italian stations) where dust intrusions are frequent, and with several stations in the central Europe where dust penetrates occasionally. All aerosol backscatter and extinction profiles related to observations collected during these alerts are grouped in the devoted "Saharan dust" category of the EARLINET database. This category consists of about 4700 files (as of December 2013). Case studies involving several stations around Europe selected from this long-term database have been provided the opportunity to investigate dust modification processes during transport over the continent. More important, the long term EARLINET dust monitoring allows the investigation of the horizontal and vertical extent of dust outbreaks over Europe and the climatological analysis of dust optical intensive and extensive properties at continental scale. This long-term database is also a unique tool for a systematic comparison with dust model outputs and satellite-derived dust products. Because of the relevance for both dust modeling and satellite retrievals improvement, results about desert dust layers extensive properties as a function of season and source regions are investigated and will be presented at the conference. First comparisons with models outputs and CALIPSO dust products will be

  4. Timber beams subjected to long - term loading

    NASA Astrophysics Data System (ADS)

    Sógel, K.

    2010-09-01

    Wood is a significant structural material, which is often used for timber bearing structures. Elements of timber structures must especially satisfy safety requirements, which are expressed by the ultimate limit states in the established standards. The structure must also satisfy the serviceability limit states. Local and global deformations make it impossible for the structure to serve the purpose it was designed for. It is important to take the deflections and their possible increase into account in the design to provide a structure which can be used during the whole period of service. Based on earlier examinations, it is known that a timber element over the course of long-term loading shows creep behavior. The structure of wood is able to adapt to the conditions of the surrounding environment. The properties of wood are especially affected by the relative humidity of the air and then by the type, intensity and duration of the loading. The most important factors affecting the serviceability of timber structures are volume changes caused by humidity and additional deflections caused by the effects of long-term loading. These phenomena emphasize the importance of serviceability limit states for timber structures. The paper deals with a long-term experimental investigation of timber girders that are currently often used. The aim was to obtain the deflection curves and mark the time dependence and the final deflections. The paper will also define the approximations for simulating the time-dependent deflections and obtain the creep coefficients for calculating the final deflections of the girders investigated.

  5. Long-Term Wind Power Variability

    SciTech Connect

    Wan, Y. H.

    2012-01-01

    The National Renewable Energy Laboratory started collecting wind power data from large commercial wind power plants (WPPs) in southwest Minnesota with dedicated dataloggers and communication links in the spring of 2000. Over the years, additional WPPs in other areas were added to and removed from the data collection effort. The longest data stream of actual wind plant output is more than 10 years. The resulting data have been used to analyze wind power fluctuations, frequency distribution of changes, the effects of spatial diversity, and wind power ancillary services. This report uses the multi-year wind power data to examine long-term wind power variability.

  6. Long-term outcomes in multiple gestations.

    PubMed

    Rand, Larry; Eddleman, Keith A; Stone, Joanne

    2005-06-01

    Children born from a multiple gestation are at increased risk for cerebral palsy, learning disability, and language and neurobehavioral deficits. With the increased incidence of multiple pregnancies and use of assisted reproductive technology (ART), these issues are more commonly affecting parents. Long-term outcomes are a critical part of preconceptual and early pregnancy counseling for parents faced with a multiple gestation or considering ART, and the provider should be well versed on issues surrounding zygosity, gestational age, higher-order multiples, and the effects of options such as multifetal pregnancy reduction. PMID:15922795

  7. Long-Term Solar Irradiance Variability

    NASA Technical Reports Server (NTRS)

    Pap, J. M.

    1996-01-01

    Measurements of the solar energy throughout the solar spectrum and understanding its variability provide important information about the physical processes and structural changes in the solar interior and in the solar atmosphere...The aim of this paper is to discuss the solar-cycle-related long-term changes in solar total and UV irradiances. The spaceborne irradiance observations are compared to ground-based indices of solar magnetic activity, such as the Photometric Sunspot Index, full disk magnetic flux, and the Mt. Wilson Magnetic Plage Strength Index.

  8. Long Term Archiving and CCSDS Standards

    NASA Astrophysics Data System (ADS)

    Boucon, Danièle

    This article presents some conceptual and implementation CCSDS -Consultative Committee for Space Data Systemsstandards for long term archiving. It focuses on the most recent one, the Producer Archive Interface Specification (PAIS) standard. This standard, currently available as a draft on the CCSDS web site, will be published by the beginning of 2014. It will enable the Producer to share with the Archive a sufficiently precise and unambiguous formal definition of the Digital Objects to be produced and transferred, by means of a model. It will also enable a precise definition of the packaging of these objects in the form of Submission Information Packages (SIPs), including the order in which they should be transferred.

  9. Human Behaviour in Long-Term Missions

    NASA Technical Reports Server (NTRS)

    1997-01-01

    In this session, Session WP1, the discussion focuses on the following topics: Psychological Support for International Space Station Mission; Psycho-social Training for Man in Space; Study of the Physiological Adaptation of the Crew During A 135-Day Space Simulation; Interpersonal Relationships in Space Simulation, The Long-Term Bed Rest in Head-Down Tilt Position; Psychological Adaptation in Groups of Varying Sizes and Environments; Deviance Among Expeditioners, Defining the Off-Nominal Act in Space and Polar Field Analogs; Getting Effective Sleep in the Space-Station Environment; Human Sleep and Circadian Rhythms are Altered During Spaceflight; and Methodological Approach to Study of Cosmonauts Errors and Its Instrumental Support.

  10. Performance considerations in long-term spaceflight

    NASA Technical Reports Server (NTRS)

    Akins, F. R.

    1979-01-01

    Maintenance of skilled performance during extended space flight is of critical importance to both the health and safety of crew members and to the overall success of mission goals. An examination of long term effects and performance requirements is therefore a factor of immense importance to the planning of future missions. Factors that were investigated include: definition of performance categories to be investigated; methods for assessing and predicting performance levels; in-flight factors which can affect performance; and factors pertinent to the maintenance of skilled performance.

  11. 47 CFR 54.303 - Long term support.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 3 2010-10-01 2010-10-01 false Long term support. 54.303 Section 54.303... SERVICE Universal Service Support for High Cost Areas § 54.303 Long term support. (a) Beginning January 1... shall receive Long Term Support. Beginning July 1, 2004, no carrier shall receive Long Term Support....

  12. 47 CFR 54.303 - Long term support.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 3 2011-10-01 2011-10-01 false Long term support. 54.303 Section 54.303... SERVICE Universal Service Support for High Cost Areas § 54.303 Long term support. (a) Beginning January 1... shall receive Long Term Support. Beginning July 1, 2004, no carrier shall receive Long Term Support....

  13. Non-inhibitory antibodies impede lysosomal storage reduction during enzyme replacement therapy of a lysosomal storage disease.

    PubMed

    Matzner, Ulrich; Matthes, Frank; Weigelt, Cecilia; Andersson, Claes; Eistrup, Carl; Fogh, Jens; Gieselmann, Volkmar

    2008-04-01

    Enzyme replacement therapy is a treatment option for several lysosomal storage disorders. We reported previously that treatment of a knockout mouse model of the sphingolipid storage disease metachromatic leukodystrophy (MLD) by intravenous injection of recombinant human arylsulfatase A (rhASA) reduces sulfatide storage and improves nervous system pathology and function. Here, we show that treated mice can develop anti-rhASA antibodies, which impede sulfatide clearance without inhibiting enzyme activity. The neutralizing effect of antibodies was reproduced in cell culture models of MLD by demonstrating that mouse immune serum reduces the ability of rhASA to clear sulfatide from cultured ASA-deficient Schwann and kidney cells. We show that reduced clearance is due to an antibody-mediated blockade of mannose 6-phosphate receptor-dependent enzyme uptake, retargeting of rhASA from sulfatide-storing cells to macrophages, intracellular misrouting of rhASA, and reduction of enzyme stability. Induction of immunotolerance to rhASA by transgenic expression of an active site mutant of human ASA restores sulfatide clearance in mice. The data indicate that the influence of non-inhibitory antibodies must be more intensively considered in evaluating the therapeutic efficacy of enzyme replacement in lysosomal storage disorders in general and in patients without cross-reacting material specifically. PMID:18360747

  14. Long term perfusion system supporting adipogenesis

    PubMed Central

    Abbott, Rosalyn D.; Raja, Waseem K.; Wang, Rebecca Y.; Stinson, Jordan A.; Glettig, Dean L.; Burke, Kelly A.; Kaplan, David L.

    2015-01-01

    Adipose tissue engineered models are needed to enhance our understanding of disease mechanisms and for soft tissue regenerative strategies. Perfusion systems generate more physiologically relevant and sustainable adipose tissue models, however adipocytes have unique properties that make culturing them in a perfusion environment challenging. In this paper we describe the methods involved in the development of two perfusion culture systems (2D and 3D) to test their applicability for long term in vitro adipogenic cultures. It was hypothesized that a silk protein biomaterial scaffold would provide a 3D framework, in combination with perfusion flow, to generate a more physiologically relevant sustainable adipose tissue engineered model than 2D cell culture. Consistent with other studies evaluating 2D and 3D culture systems for adipogenesis we found that both systems successfully model adipogensis, however 3D culture systems were more robust, providing the mechanical structure required to contain the large, fragile adipocytes that were lost in 2D perfused culture systems. 3D perfusion also stimulated greater lipogenesis and lipolysis and resulted in decreased secretion of LDH compared to 2D perfusion. Regardless of culture configuration (2D or 3D) greater glycerol was secreted with the increased nutritional supply provided by perfusion of fresh media. These results are promising for adipose tissue engineering applications including long term cultures for studying disease mechanisms and regenerative approaches, where both acute (days to weeks) and chronic (weeks to months) cultivation are critical for useful insight. PMID:25843606

  15. Sleep facilitates long-term face adaptation.

    PubMed

    Ditye, Thomas; Javadi, Amir Homayoun; Carbon, Claus-Christian; Walsh, Vincent

    2013-10-22

    Adaptation is an automatic neural mechanism supporting the optimization of visual processing on the basis of previous experiences. While the short-term effects of adaptation on behaviour and physiology have been studied extensively, perceptual long-term changes associated with adaptation are still poorly understood. Here, we show that the integration of adaptation-dependent long-term shifts in neural function is facilitated by sleep. Perceptual shifts induced by adaptation to a distorted image of a famous person were larger in a group of participants who had slept (experiment 1) or merely napped for 90 min (experiment 2) during the interval between adaptation and test compared with controls who stayed awake. Participants' individual rapid eye movement sleep duration predicted the size of post-sleep behavioural adaptation effects. Our data suggest that sleep prevented decay of adaptation in a way that is qualitatively different from the effects of reduced visual interference known as 'storage'. In the light of the well-established link between sleep and memory consolidation, our findings link the perceptual mechanisms of sensory adaptation--which are usually not considered to play a relevant role in mnemonic processes--with learning and memory, and at the same time reveal a new function of sleep in cognition. PMID:23986109

  16. Long-term intracranial pressure monitoring.

    PubMed

    de Jong, D A; Maas, A I; den Ouden, A H; de Lange, S A

    Continuous or intermittent measurement of intracranial pressure (ICP) is important in patients at risk for raised ICP. Indications exist for short- and long-term measurements. The various methods used for short-term monitoring are discussed with their relative advantages and disadvantages. For long-term measurements of ICP use of a completely implantable telemetric epidural pressure transducer is indicated. No such device is commercially available. We have developed an inexpensive passive telemetric transducer for this purpose. Results obtained up till now have demonstrated its reliability for measurements of two to three months duration. The life span of the device is limited by degrading of the epoxy utilized for sealing of the titanium pressure sensing part to the radiolucent ceramic cap of the transducer, causing leakage of water into the transducer and false low measurements. Because of these problems new hermetic sealing techniques were tested. Both active metal brazing and glass bonding yielded good results and hermetic sealing could be obtained. The metal to ceramic bonding presented is generally applicable within the design of implants. Besides the technical progress reported, the experience with clinical use in 12 patients is presented. PMID:6674738

  17. Long-Term Care Policy: Singapore's Experience.

    PubMed

    Chin, Chee Wei Winston; Phua, Kai-Hong

    2016-01-01

    Singapore, like many developed countries, is facing the challenge of a rapidly aging population and the increasing need to provide long-term care (LTC) services for elderly in the community. The Singapore government's philosophy on care for the elderly is that the family should be the first line of support, and it has relied on voluntary welfare organizations (VWOs) or charities for the bulk of LTC service provision. For LTC financing, it has emphasized the principles of co-payment and targeting of state support to the low-income population through means-tested government subsidies. It has also instituted ElderShield, a national severe disability insurance scheme. This paper discusses some of the challenges facing LTC policy in Singapore, particularly the presence of perverse financial incentives for hospitalization, the pitfalls of over-reliance on VWOs, and the challenges facing informal family caregivers. It discusses the role of private LTC insurance in LTC financing, bearing in mind demand- and supply-side failures that have plagued the private LTC insurance market. It suggests the need for more standardized needs assessment and portable LTC benefits, with reference to the Japanese Long-Term Care Insurance program, and also discusses the need to provide more support to informal family caregivers. PMID:26808468

  18. Long Term Changes in the Polar Vortices

    NASA Astrophysics Data System (ADS)

    Braathen, Geir O.

    2016-04-01

    As the amount of halogens in the stratosphere is slowly declining and the ozone layer slowly recovers it is of interest to see how the meteorological conditions in the vortex develop over the long term since such changes might alter the foreseen ozone recovery. In conjunction with the publication of the WMO Antarctic and Arctic Ozone Bulletins, WMO has acquired the ERA Interim global reanalysis data set for several meteorological parameters. This data set goes from 1979 - present. These long time series of data can be used for several useful studies of the long term development of the polar vortices. Several "environmental indicators" for vortex change have been calculated, and a climatology, as well as trends, for these parameters will be presented. These indicators can act as yardsticks and will be useful for understanding past and future changes in the polar vortices and how these changes affect polar ozone depletion. Examples of indicators are: vortex mean temperature, vortex minimum temperature, vortex mean PV, vortex "importance" (PV*area), vortex break-up time, mean and maximum wind speed. Data for both the north and south polar vortices have been analysed at several isentropic levels from 350 to 850 K. A possible link between changes in PV and sudden stratospheric warmings will be investigated, and the results presented. The unusual meteorological conditions of the 2015 south polar vortex and the 2010/11 and 2015/16 north polar vortices will be compared to other recent years.

  19. Long term changes in the polar vortices

    NASA Astrophysics Data System (ADS)

    Braathen, Geir O.

    2015-04-01

    As the amount of halogens in the stratosphere is slowly declining and the ozone layer slowly recovers it is of interest to see how the meteorological conditions in the vortex develop over the long term since such changes might alter the foreseen ozone recovery. In conjunction with the publication of the WMO Antarctic and Arctic Ozone Bulletins, WMO has acquired the ERA Interim global reanalysis data set for several meteorological parameters. This data set goes from 1979 - present. These long time series of data can be used for several useful studies of the long term development of the polar vortices. Several "environmental indicators" for vortex change have been calculated, and a climatology, as well as trends, for these parameters will be presented. These indicators can act as yardsticks and will be useful for understanding past and future changes in the polar vortices and how these changes affect polar ozone depletion. Examples of indicators are: vortex mean temperature, vortex minimum temperature, vortex mean PV, vortex "importance" (PV*area), vortex break-up time, mean and maximum wind speed. Data for both the north and south polar vortices have been analysed at several isentropic levels from 350 to 850 K. A possible link between changes in PV and sudden stratospheric warmings will be investigated, and the results presented.

  20. The long-term performance of DXA bone densitometers.

    PubMed

    Wells, J; Ryan, P J

    2000-07-01

    Long-term performance of a bone mass measuring device is an important criterion when considering the purchase of such equipment and has been regarded as an important feature of dual X-ray absorptiometry (DXA). The performance of a 6-year-old bone densitometer, the Lunar DPX alpha, which has undertaken 1500 scans annually over this period, was assessed. The short-term coefficient of variation calculated from 15 measurements with repositioning on a single day, using the Lunar aluminium phantom, was 0.242%. Long-term precision, also calculated by the coefficient of variation, was 0.548%. The manufacturer's quality control (QC) procedure was performed daily and allowed the machine to be used except on 15 occasions when bone density measurements could be acquired after rebooting. However, a 2.2% shift in phantom values occurred in July 1996 owing to a photomultiplier tube failure, but this did not produce a failure in the Lunar QC. The optical disc drive was replaced in July 1997. The machine failed to back up on six occasions over the last 2 years owing to software corruption and the acquired femur data were not saved on seven occasions owing to overloading of the memory buffer. In conclusion, expected hardware failure and minor software problems have occurred. We were concerned that the manufacturer's QC failed to detect a 2% shift in the phantom bone mineral density values and recommend regular measurements of the Lunar aluminum phantom in addition to the daily QC measurement of the tissue-equivalent block. We were nevertheless impressed by the long-term stability and reproducibility of the Lunar DPX alpha. PMID:11089465

  1. Enhanced efficacy of enzyme replacement therapy in Pompe disease through mannose-6-phosphate receptor expression in skeletal muscle.

    PubMed

    Koeberl, Dwight D; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G; Chen, Y-T; Bali, Deeksha S

    2011-06-01

    Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with the administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β(2)-agonist, enhanced the CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA. PMID:21397538

  2. Enhanced Efficacy of Enzyme Replacement Therapy in Pompe Disease Through Mannose-6-Phosphate Receptor Expression in Skeletal Muscle

    PubMed Central

    Koeberl, Dwight D.; Luo, Xiaoyan; Sun, Baodong; McVie-Wylie, Alison; Dai, Jian; Li, Songtao; Banugaria, Suhrad G.; Chen, Y-T; Bali, Deeksha S.

    2011-01-01

    Enzyme replacement therapy (ERT) with acid α-glucosidase has become available for Pompe disease; however, the response of skeletal muscle, as opposed to the heart, has been attenuated. The poor response of skeletal muscle has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle compared to heart. To further understand the role of CI-MPR in Pompe disease, muscle-specific CI-MPR conditional knockout (KO) mice were crossed with GAA-KO (Pompe disease) mice. We evaluated the impact of CI-MPR-mediated uptake of GAA by evaluating ERT in CI-MPR-KO/GAA-KO (double KO) mice. The essential role of CI-MPR was emphasized by the lack of efficacy of ERT as demonstrated by markedly reduced biochemical correction of GAA deficiency and of glycogen accumulations in double KO mice, in comparison with administration of the same therapeutic doses in GAA-KO mice. Clenbuterol, a selective β2-agonist, enhanced CI-MPR expression in skeletal tissue and also increased efficacy from GAA therapy, thereby confirming the key role of CI-MPR with regard to enzyme replacement therapy in Pompe disease. Biochemical correction improved in both muscle and non-muscle tissues, indicating that therapy could be similarly enhanced in other lysosomal storage disorders. In summary, enhanced CI-MPR expression might improve the efficacy of enzyme replacement therapy in Pompe disease through enhancing receptor-mediated uptake of GAA. PMID:21397538

  3. Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10year combined experience of 2 centres.

    PubMed

    Ghosh, Arunabha; Miller, Weston; Orchard, Paul J; Jones, Simon A; Mercer, Jean; Church, Heather J; Tylee, Karen; Lund, Troy; Bigger, Brian W; Tolar, Jakub; Wynn, Robert F

    2016-03-01

    Haematopoietic stem cell transplantation is the treatment of choice for the severe form of Mucopolysaccharidosis Type I, or Hurler syndrome. In many centres standard practice is to deliver enzyme replacement therapy alongside haematopoietic stem cell transplantation to improve the condition of the patient prior to transplant. We report the combined 10year experience of this approach in two paediatric metabolic and transplant centres. Of 81 patients who underwent a first transplant procedure for Hurler, 88% (71/81) survived and 81% (66/81) were alive and engrafted at a median follow-up of 46months (range 3-124months). The incidence of grade II-IV acute and any chronic graft versus host disease was 17% and 11% respectively. Urinary glycosaminoglycans were significantly reduced after a period of enzyme replacement therapy, and further reductions were seen at 13-24months and 25+months after transplantation. In several individuals with decreased cardiac contractility, an improvement of their condition during enzyme replacement therapy enabled them to undergo transplantation, with one individual receiving full intensity conditioning. PMID:26832957

  4. Managing soils for long-term productivity

    PubMed Central

    Syers, J. K.

    1997-01-01

    Meeting the goal of long-term agricultural productivity requires that soil degradation be halted and reversed. Soil fertility decline is a key factor in soil degradation and is probably the major cause of declining crop yields. There is evidence that the contribution of declining soil fertility to soil degradation has been underestimated.
    Sensitivity to soil degradation is implicit in the assessment of the sustainability of land management practices, with wide recognition of the fact that soils vary in their ability to resist change and recover subsequent to stress. The concept of resilience in relation to sustainability requires further elaboration and evaluation.
    In the context of soil degradation, a decline in soil fertility is primarily interpreted as the depletion of organic matter and plant nutrients. Despite a higher turnover rate of organic matter in the tropics there is no intrinsic difference between the organic matter content of soils from tropical and temperate regions. The level of organic matter in a soil is closely related to the above and below ground inputs. In the absence of adequate organic material inputs and where cultivation is continuous, soil organic matter declines progressively. Maintaining the quantity and quality of soil organic matter should be a guiding principle in developing management practices.
    Soil microbial biomass serves as an important reservoir of nitrogen (N), phosphorus (P) and sulphur (S), and regulates the cycling of organic matter and nutrients. Because of its high turnover rate, microbial biomass reacts quickly to changes in management and is a sensitive indicator for monitoring and predicting changes in soil organic matter. Modelling techniques have been reasonably successful in predicting changes in soil organic matter with different organic material inputs, but there is little information from the tropics.
    Nutrient depletion through harvested crop components and residue removal, and by leaching and soil

  5. Enzyme replacement therapy for mucopolysaccharidosis VI: Growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase

    PubMed Central

    Decker, Celeste; Yu, Zi-Fan; Giugliani, Roberto; Schwartz, Ida Vanessa D.; Guffon, Nathalie; Teles, Elisa Leão; Miranda, M. Clara Sá; Wraith, J. Edmond; Beck, Michael; Arash, Laila; Scarpa, Maurizio; Ketteridge, David; Hopwood, John J.; Plecko, Barbara; Steiner, Robert; Whitley, Chester B.; Kaplan, Paige; Swiedler, Stuart J.; Conrad, Susan; Harmatz, Paul

    2010-01-01

    Background and Methods Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling. Results Mean height increased by 2.9 cm after 48 weeks and 4.3 cm after 96 weeks on enzyme replacement therapy (ERT). Growth on ERT was not correlated with baseline urinary GAG. Patients under 16 years of age showed greatest increases in height on treatment. Model results based on pooled data showed significant improvement in growth rate during 96 weeks of ERT when compared to the equivalent pretreatment time period. Delayed pubertal onset or progression was noted in 10 patients entering the clinical trials; all of whom showed progression of at least one Tanner stage during 2 years on ERT, and 6 of whom (60%) completed puberty. Conclusion Analysis of mean height by treatment week and longitudinal modeling demonstrate significant increase in height and growth rate in MPS VI patients receiving long-term ERT. This impact was greatest in patients aged below 16 years. Height increase may result from bone growth and/or reduction in joint contractures. Bone growth and resolution of delayed puberty may be related to improvements in general health, bone cell health, nutrition, endocrine gland function and reduced inflammation. PMID:20634905

  6. Enzyme replacement therapy for mucopolysaccharidosis VI: Growth and pubertal development in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase.

    PubMed

    Decker, Celeste; Yu, Zi-Fan; Giugliani, Roberto; Schwartz, Ida Vanessa D; Guffon, Nathalie; Teles, Elisa Leão; Miranda, M Clara Sá; Wraith, J Edmond; Beck, Michael; Arash, Laila; Scarpa, Maurizio; Ketteridge, David; Hopwood, John J; Plecko, Barbara; Steiner, Robert; Whitley, Chester B; Kaplan, Paige; Swiedler, Stuart J; Conrad, Susan; Harmatz, Paul

    2010-01-01

    BACKGROUND AND METHODS: Growth failure is characteristic of untreated mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome). Growth was studied in fifty-six MPS VI patients (5 to 29 years old) prior to and for up to 240 weeks of weekly infusions of recombinant human arylsulfatase B (rhASB) at 1 mg/kg during Phase 1/2, Phase 2, Phase 3 or Phase 3 Extension clinical trials. Height, weight, and Tanner stage data were collected. Pooled data were analyzed to determine mean height increase by treatment week, growth impacts of pubertal status, baseline urinary GAG, and age at treatment initiation. Growth rate for approximately 2 years prior to and following treatment initiation was analyzed using longitudinal modeling. RESULTS: Mean height increased by 2.9 cm after 48 weeks and 4.3 cm after 96 weeks on enzyme replacement therapy (ERT). Growth on ERT was not correlated with baseline urinary GAG. Patients under 16 years of age showed greatest increases in height on treatment. Model results based on pooled data showed significant improvement in growth rate during 96 weeks of ERT when compared to the equivalent pretreatment time period. Delayed pubertal onset or progression was noted in 10 patients entering the clinical trials; all of whom showed progression of at least one Tanner stage during 2 years on ERT, and 6 of whom (60%) completed puberty. CONCLUSION: Analysis of mean height by treatment week and longitudinal modeling demonstrate significant increase in height and growth rate in MPS VI patients receiving long-term ERT. This impact was greatest in patients aged below 16 years. Height increase may result from bone growth and/or reduction in joint contractures. Bone growth and resolution of delayed puberty may be related to improvements in general health, bone cell health, nutrition, endocrine gland function and reduced inflammation. PMID:20634905

  7. Long-term results of the Wagner cone prosthesis

    PubMed Central

    Schraml, Annemarie; Hohenberger, Gerd

    2007-01-01

    The Wagner cone prosthesis is indicated in uncemented total hip replacement of cases with cylinder-shaped femurs, deformed femurs, femurs with increased antetorsion, and in conditions of intramedullary bony scar tissue after previous osteotomies. The objective of this study is to present long-term results. From January 1, 1993 to December 31, 1995, 132 implantations were made with the Wagner cone prosthesis. We report the clinical and radiographic results of 94 cone prostheses with a mean observation period of 11.5 years. The Merle d’Aubigné score improved from a preoperative mean value of 8.8 to a postoperative mean of 16.3. The radiographic evaluation revealed 32 cases with cortical hypertrophy, 73 cases with atrophy of the proximal femur, and 18 cases with complete pedestal formation. Radiolucencies over Gruen zones 1 and 7 occurred in 42 cases; only zone 1 was affected in 24 cases. Complications included three deep infections, three acetabular revisions, five total joint revisions, one recurrent luxation, and three heterotopic ossifications. In spite of the fact that the examined cohort often included patients who had undergone multiple previous operations (a maximum of six) of the proximal femur or the acetabulum, the long-term results of the Wagner cone prostheses were very promising. PMID:17932669

  8. Advanced long term cryogenic storage systems

    NASA Technical Reports Server (NTRS)

    Brown, Norman S.

    1987-01-01

    Long term, cryogenic fluid storage facilities will be required to support future space programs such as the space-based Orbital Transfer Vehicle (OTV), Telescopes, and Laser Systems. An orbital liquid oxygen/liquid hydrogen storage system with an initial capacity of approximately 200,000 lb will be required. The storage facility tank design must have the capability of fluid acquisition in microgravity and limit cryogen boiloff due to environmental heating. Cryogenic boiloff management features, minimizing Earth-to-orbit transportation costs, will include advanced thick multilayer insulation/integrated vapor cooled shield concepts, low conductance support structures, and refrigeration/reliquefaction systems. Contracted study efforts are under way to develop storage system designs, technology plans, test article hardware designs, and develop plans for ground/flight testing.

  9. Long term performance of radon mitigation systems

    SciTech Connect

    Prill, R.; Fisk, W.J.

    2002-03-01

    Researchers installed radon mitigation systems in 12 houses in Spokane, Washington and Coeur d'Alene, Idaho during the heating season 1985--1986 and continued to monitor indoor radon quarterly and annually for ten years. The mitigation systems included active sub-slab ventilation, basement over-pressurization, and crawlspace isolation and ventilation. The occupants reported various operational problems with these early mitigation systems. The long-term radon measurements were essential to track the effectiveness of the mitigation systems over time. All 12 homes were visited during the second year of the study, while a second set 5 homes was visited during the fifth year to determine the cause(s) of increased radon in the homes. During these visits, the mitigation systems were inspected and measurements of system performance were made. Maintenance and modifications were performed to improve system performance in these homes.

  10. Long-term U. S. energy outlook

    SciTech Connect

    Friesen, G.

    1984-01-01

    Each year Chase Econometrics offers its clients a brief summary of the assumptions underlying the long-term energy forecast for the U.S. To illustrate the uncertainty involved in forecasting for the period to the year 2000, they choose to compare forecasts with some recent projections prepared by the Department of Energy's Office of Policy, Planning and Analysis for the annual National Energy Policy Plan supplement. Particular emphasis is placed on Scenario B, which is the mid-range reference case. As the introduction to the supplement emphasizes, the NEPP projections should not be considered a statement of the policy goals of the Reagan Administration. They represent an analysis of the possible evolution of U.S. energy markets, given current information and existing policies. The purpose of providing Scenario B as a reference case as well as Scenarios A and C as alternate cases is to show the sensitivity of oil price projections to small swings in energy demand.

  11. Long-term control of root growth

    DOEpatents

    Burton, Frederick G.; Cataldo, Dominic A.; Cline, John F.; Skiens, W. Eugene

    1992-05-26

    A method and system for long-term control of root growth without killing the plants bearing those roots involves incorporating a 2,6-dinitroaniline in a polymer and disposing the polymer in an area in which root control is desired. This results in controlled release of the substituted aniline herbicide over a period of many years. Herbicides of this class have the property of preventing root elongation without translocating into other parts of the plant. The herbicide may be encapsulated in the polymer or mixed with it. The polymer-herbicide mixture may be formed into pellets, sheets, pipe gaskets, pipes for carrying water, or various other forms. The invention may be applied to other protection of buried hazardous wastes, protection of underground pipes, prevention of root intrusion beneath slabs, the dwarfing of trees or shrubs and other applications. The preferred herbicide is 4-difluoromethyl-N,N-dipropyl-2,6-dinitro-aniline, commonly known as trifluralin.

  12. Long-term control of root growth

    SciTech Connect

    Burton, F.G.; Cataldo, D.A.; Cline, J.F.; Skiens, W.E.

    1992-05-26

    A method and system for long-term control of root growth without killing the plants bearing those roots involves incorporating a 2,6-dinitroaniline in a polymer and disposing the polymer in an area in which root control is desired. This results in controlled release of the substituted aniline herbicide over a period of many years. Herbicides of this class have the property of preventing root elongation without translocating into other parts of the plant. The herbicide may be encapsulated in the polymer or mixed with it. The polymer-herbicide mixture may be formed into pellets, sheets, pipe gaskets, pipes for carrying water, or various other forms. The invention may be applied to other protection of buried hazardous wastes, protection of underground pipes, prevention of root intrusion beneath slabs, the dwarfing of trees or shrubs and other applications. The preferred herbicide is 4-difluoromethyl-N,N-dipropyl-2,6-dinitro-aniline, commonly known as trifluralin. 7 figs.

  13. Withdrawal from long-term benzodiazepine treatment.

    PubMed Central

    Petursson, H; Lader, M H

    1981-01-01

    Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety. PMID:6114776

  14. Long term thermoelectric module testing system.

    PubMed

    D'Angelo, Jonathan; Hogan, Timothy

    2009-10-01

    Thermoelectric generators can be used for converting waste heat into electric power. Significant interest in developing new materials in recent years has led to the discovery of several promising thermoelectrics, however, there can be considerable challenges in developing the materials into working devices. Testing and feedback is needed at each step to gain valuable information for identification of difficulties, quality of the materials and modules, repeatability in fabrication, and longevity of the devices. This paper describes a long-term module testing system for monitoring the output power of a module over extended testing times. To evaluate the system, we have tested commercially available thermoelectric modules over a one month time period. PMID:19895086

  15. Feasibility of using an isolated intestinal segment as an artificial organ for enzyme replacement therapy.

    PubMed

    Shelt, D; Walton, D; Sato, P

    1982-01-01

    Guinea pigs fed an ascorbic acid-deficient diet develop scurvy because of the absence of the enzyme L-gulonolactone oxidase. In theory if this enzyme is provided and its substrate L-gulonolactone is present at adequate concentrations ascorbic acid will be synthesized and the development of scurvy prevented. Using this model we tested whether a viable segment of intestine could be used to contain the administered enzyme and act as an artificial organ for the production of ascorbic acid. A surgical procedure was developed to prepare an externalized pouch of intestine with its circulation left intact. When enzyme is inserted in this intestinal bag it is not toxic and not antigenic in some animals, whereas, enzyme injected intraperitoneally is clearly antigenic. Synthesis of ascorbic acid by this artificial organ could not, however, be detected by elevation of plasma concentrations of the vitamin. PMID:7104431

  16. Managing Records for the Long Term - 12363

    SciTech Connect

    Montgomery, John V.; Gueretta, Jeanie

    2012-07-01

    The U.S. Department of Energy (DOE) is responsible for managing vast amounts of information documenting historical and current operations. This information is critical to the operations of the DOE Office of Legacy Management. Managing legacy records and information is challenging in terms of accessibility and changing technology. The Office of Legacy Management is meeting these challenges by making records and information management an organizational priority. The Office of Legacy Management mission is to manage DOE post-closure responsibilities at former Cold War weapons sites to ensure the future protection of human health and the environment. These responsibilities include environmental stewardship and long-term preservation and management of operational and environmental cleanup records associated with each site. A primary organizational goal for the Office of Legacy Management is to 'Preserve, Protect, and Share Records and Information'. Managing records for long-term preservation is an important responsibility. Adequate and dedicated resources and management support are required to perform this responsibility successfully. Records tell the story of an organization and may be required to defend an organization in court, provide historical information, identify lessons learned, or provide valuable information for researchers. Loss of records or the inability to retrieve records because of poor records management processes can have serious consequences and even lead to an organisation's downfall. Organizations must invest time and resources to establish a good records management program because of its significance to the organization as a whole. The Office of Legacy Management will continue to research and apply innovative ways of doing business to ensure that the organization stays at the forefront of effective records and information management. DOE is committed to preserving records that document our nation's Cold War legacy, and the Office of Legacy

  17. Long-term dynamics of Typha populations

    USGS Publications Warehouse

    Grace, J.B.; Wetzel, R.G.

    1998-01-01

    The zonation of Typha populations in an experimental pond in Michigan was re-examined 15 years after the original sampling to gain insight into the long-term dynamics. Current distributions of Typha populations were also examined in additional experimental ponds at the site that have been maintained for 23 years. The zonation between T. latifolia and T. angustifolia in the previously studied pond 15 years after the initial sampling revealed that the density and distribution of shoots had not changed significantly. Thus, it appears that previously reported results (based on 7- year old populations) have remained consistent over time. Additional insight into the interaction between these two taxa was sought by comparing mixed and monoculture stands in five experimental ponds that have remained undisturbed for their 23-year history. The maximum depth of T. latifolia, the shallow- water species, was not significantly reduced when growing in the presence of the more flood tolerant T. angustifolia. In contrast, the minimum depth of T. angustifolia was reduced from 0 to 37 cm when in the presence of T. latifolia. When total populations were compared between monoculture and mixed stands, the average density of T. angustifolia shoots was 59.4 percent lower in mixed stands while the density of T. latifolia was 32 percent lower, with T. angustifolia most affected at shallow depths (reduced by 92 percent) and T. latifolia most affected at the deepest depths (reduced by 60 percent). These long-term observations indicate that competitive displacement between Typha taxa has remained stable over time.

  18. Pancreatic enzyme replacement therapy for pancreatic exocrine insufficiency in the 21st century

    PubMed Central

    Trang, Tony; Chan, Johanna; Graham, David Y

    2014-01-01

    Restitution of normal fat absorption in exocrine pancreatic insufficiency remains an elusive goal. Although many patients achieve satisfactory clinical results with enzyme therapy, few experience normalization of fat absorption, and many, if not most, will require individualized therapy. Increasing the quantity of lipase administered rarely eliminates steatorrhea but increases the cost of therapy. Enteric coated enzyme microbead formulations tend to separate from nutrients in the stomach precluding coordinated emptying of enzymes and nutrients. Unprotected enzymes mix well and empty with nutrients but are inactivated at pH 4 or below. We describe approaches for improving the results of enzyme therapy including changing to, or adding, a different product, adding non-enteric coated enzymes, (e.g., giving unprotected enzymes at the start of the meal and acid-protected formulations later), use of antisecretory drugs and/or antacids, and changing the timing of enzyme administration. Because considerable lipid is emptied in the first postprandial hour, it is prudent to start therapy with enteric coated microbead prior to the meal so that some enzymes are available during that first hour. Patients with hyperacidity may benefit from adjuvant antisecretory therapy to reduce the duodenal acid load and possibly also sodium bicarbonate to prevent duodenal acidity. Comparative studies of clinical effectiveness of different formulations as well as the characteristics of dispersion, emptying, and dissolution of enteric-coated microspheres of different diameter and density are needed; many such studies have been completed but not yet made public. We discuss the history of pancreatic enzyme therapy and describe current use of modern preparations, approaches to overcoming unsatisfactory clinical responses, as well as studies needed to be able to provide reliably effective therapy. PMID:25206255

  19. Preeclampsia: long-term consequences for vascular health.

    PubMed

    Amaral, Lorena M; Cunningham, Mark W; Cornelius, Denise C; LaMarca, Babbette

    2015-01-01

    Preeclampsia (PE) is a pregnancy-specific syndrome and one of the leading causes of preterm birth, neonatal and maternal morbidity and mortality. This disease is characterized by new onset hypertension usually in the third trimester of pregnancy and is sometimes associated with proteinuria, although proteinuria is not a requirement for the diagnosis of PE. In developing countries, women have a higher risk of death due to PE than more affluent countries and one of the most frequent causes of death is high blood pressure and stroke. Although PE only affects approximately 2%-8% of pregnancies worldwide it is associated with severe complications such as eclampsia, hemorrhagic stroke, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and pulmonary edema. Importantly, there is no "cure" for the disease except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms. In addition, PE is linked to the development of cardiovascular disease and stroke in women after reproductive age, leaving PE a risk factor for long-term health in women. This review will highlight factors implicated in the pathophysiology of PE that may contribute to long-term effects in women with preeclamptic pregnancies. PMID:26203257

  20. Preeclampsia: long-term consequences for vascular health

    PubMed Central

    Amaral, Lorena M; Cunningham, Mark W; Cornelius, Denise C; LaMarca, Babbette

    2015-01-01

    Preeclampsia (PE) is a pregnancy-specific syndrome and one of the leading causes of preterm birth, neonatal and maternal morbidity and mortality. This disease is characterized by new onset hypertension usually in the third trimester of pregnancy and is sometimes associated with proteinuria, although proteinuria is not a requirement for the diagnosis of PE. In developing countries, women have a higher risk of death due to PE than more affluent countries and one of the most frequent causes of death is high blood pressure and stroke. Although PE only affects approximately 2%–8% of pregnancies worldwide it is associated with severe complications such as eclampsia, hemorrhagic stroke, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), renal failure and pulmonary edema. Importantly, there is no “cure” for the disease except for early delivery of the baby and placenta, leaving PE a health care risk for babies born from PE moms. In addition, PE is linked to the development of cardiovascular disease and stroke in women after reproductive age, leaving PE a risk factor for long-term health in women. This review will highlight factors implicated in the pathophysiology of PE that may contribute to long-term effects in women with preeclamptic pregnancies. PMID:26203257

  1. Long-term potentiation and long-term depression: a clinical perspective

    PubMed Central

    Bliss, Timothy V.P.; Cooke, Sam F

    2011-01-01

    Long-term potentiation and long-term depression are enduring changes in synaptic strength, induced by specific patterns of synaptic activity, that have received much attention as cellular models of information storage in the central nervous system. Work in a number of brain regions, from the spinal cord to the cerebral cortex, and in many animal species, ranging from invertebrates to humans, has demonstrated a reliable capacity for chemical synapses to undergo lasting changes in efficacy in response to a variety of induction protocols. In addition to their physiological relevance, long-term potentiation and depression may have important clinical applications. A growing insight into the molecular mechanisms underlying these processes, and technological advances in non-invasive manipulation of brain activity, now puts us at the threshold of harnessing long-term potentiation and depression and other forms of synaptic, cellular and circuit plasticity to manipulate synaptic strength in the human nervous system. Drugs may be used to erase or treat pathological synaptic states and non-invasive stimulation devices may be used to artificially induce synaptic plasticity to ameliorate conditions arising from disrupted synaptic drive. These approaches hold promise for the treatment of a variety of neurological conditions, including neuropathic pain, epilepsy, depression, amblyopia, tinnitus and stroke. PMID:21779718

  2. Acid ceramidase and the treatment of ceramide diseases: The expanding role of enzyme replacement therapy.

    PubMed

    Schuchman, Edward H

    2016-09-01

    Ceramides are a diverse group of sphingolipids that play important roles in many biological processes. Acid ceramidase (AC) is one key enzyme that regulates ceramide metabolism. Early research on AC focused on the fact that it is the enzyme deficient in the rare genetic disorder, Farber Lipogranulomatosis. Recent research has revealed that deficiency of the same enzyme is responsible for a rare form of spinal muscular atrophy associated with myoclonic epilepsy (SMA-PME). Due to their diverse role in biology, accumulation of ceramides also has been implicated in the pathobiology of many other common diseases, including infectious lung diseases, diabetes, cancers and others. This has revealed the potential of AC as a therapy for many of these diseases. This review will focus on the biology of AC and the potential role of this enzyme in the treatment of human disease. PMID:27155573

  3. Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease.

    PubMed

    Tajima, Youichi; Kawashima, Ikuo; Tsukimura, Takahiro; Sugawara, Kanako; Kuroda, Mayuko; Suzuki, Toshihiro; Togawa, Tadayasu; Chiba, Yasunori; Jigami, Yoshifumi; Ohno, Kazuki; Fukushige, Tomoko; Kanekura, Takuro; Itoh, Kohji; Ohashi, Toya; Sakuraba, Hitoshi

    2009-11-01

    A modified alpha-N-acetylgalactosaminidase (NAGA) with alpha-galactosidase A (GLA)-like substrate specificity was designed on the basis of structural studies and was produced in Chinese hamster ovary cells. The enzyme acquired the ability to catalyze the degradation of 4-methylumbelliferyl-alpha-D-galactopyranoside. It retained the original NAGA's stability in plasma and N-glycans containing many mannose 6-phosphate (M6P) residues, which are advantageous for uptake by cells via M6P receptors. There was no immunological cross-reactivity between the modified NAGA and GLA, and the modified NAGA did not react to serum from a patient with Fabry disease recurrently treated with a recombinant GLA. The enzyme cleaved globotriaosylceramide (Gb3) accumulated in cultured fibroblasts from a patient with Fabry disease. Furthermore, like recombinant GLA proteins presently used for enzyme replacement therapy (ERT) for Fabry disease, the enzyme intravenously injected into Fabry model mice prevented Gb3 storage in the liver, kidneys, and heart and improved the pathological changes in these organs. Because this modified NAGA is hardly expected to cause an allergic reaction in Fabry disease patients, it is highly promising as a new and safe enzyme for ERT for Fabry disease. PMID:19853240

  4. Robotics for Long-Term Monitoring

    SciTech Connect

    Shahin, Sarkis; Duran, Celso

    2002-07-01

    While long-term monitoring and stewardship means many things to many people, DOE has defined it as The physical controls, institutions, information, and other mechanisms needed to ensure protection of people and the environment at sites where DOE has completed or plans to complete cleanup (e.g., landfill closures, remedial actions, and facility stabilization). Across the United States, there are thousands of contaminated sites with multiple contaminants released from multiple sources where contaminants have transported and commingled. The U.S. government and U.S. industry are responsible for most of the contamination and are landowners of many of these contaminated properties. These sites must be surveyed periodically for various criteria including structural deterioration, water intrusion, integrity of storage containers, atmospheric conditions, and hazardous substance release. The surveys, however, are intrusive, time-consuming, and expensive and expose survey personnel to radioactive contamination. In long-term monitoring, there's a need for an automated system that will gather and report data from sensors without costly human labor. In most cases, a SCADA (Supervisory Control and Data Acquisition) unit is used to collect and report data from a remote location. A SCADA unit consists of an embedded computer with data acquisition capabilities. The unit can be configured with various sensors placed in different areas of the site to be monitored. A system of this type is static, i.e., the sensors, once placed, cannot be moved to other locations within the site. For those applications where the number of sampling locations would require too many sensors, or where exact location of future problems is unknown, a mobile sensing platform is an ideal solution. In many facilities that undergo regular inspections, the number of video cameras and air monitors required to eliminate the need for human inspections is very large and far too costly. HCET's remote harsh

  5. Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA.

    PubMed

    King, Barbara; Hassiotis, Sofia; Rozaklis, Tina; Beard, Helen; Trim, Paul J; Snel, Marten F; Hopwood, John J; Hemsley, Kim M

    2016-05-01

    Repeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained-release (osmotic pump-delivered) enzyme replacement therapy in murine MPS IIIA as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six-week-old MPS IIIA and unaffected mice were implanted with subcutaneous mini-osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7 weeks, with pumps replaced part-way through the experimental period. We observed near-normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the MPS IIIA brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored GM 3 ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump-like conditions for at least 1 month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of MPS IIIA and other lysosomal storage disorders that affect the brain. Clinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre-clinical study, we examined an alternative approach - slow, continual infusion

  6. Treatment for childhood cancer -- long-term risks

    MedlinePlus

    ... ency/patientinstructions/000849.htm Treatment for childhood cancer - long-term risks To use the sharing features on ... has. Being aware of your child's risk of long-term health problems can help you follow-up ...

  7. Long-term adequacy of metal resources

    USGS Publications Warehouse

    Singer, D.A.

    1977-01-01

    Although the earth's crust contains vast quantities of metals, extraction technologies and associated costs are inextricably bound to three fundamental geological factors - the amount of metal available in the earth's crust in each range of grades, the mineralogical form and chemical state of the metal, and the spatial distribution of the metal. The energy required to recover a given amount of metal increases substantially as grade declines. Most metal is produced from sulphide or oxide minerals, whereas most metal in the crust may be locked in the structures of the more refractory silicates. Recovery from silicate minerals could require orders of magnitude more energy than that used at present as also could exploitation of small, widely scattered or thin, deeply buried deposits. Although specific information on the fundamental factors is not available, each factor must in turn tend to further restrict exploitation. Independence of average grade and tonnage for many deposit types further reduces the availability of rock as a source of metal. In the long term, effects of these factors will be large increases in price for many metals. ?? 1977.

  8. Long-term outcome in aqueductal stenosis.

    PubMed

    Villani, R; Tomei, G; Gaini, S M; Grimoldi, N; Spagnoli, D; Bello, L

    1995-03-01

    In this study, 78 patients with aqueductal stenosis were submitted to detailed neurodevelopmental assessment with a follow-up of 5-25 years. Sixty-eight percent of patients were categorized as normal; they either attended normal school courses or had regular jobs. Among these, 34% had some motor abnormalities (ataxia, mild hemiparesis, visual disturbances). Twenty-four percent (19 cases) were moderately disabled (trainable retardation) and 8% (6 cases) were severely handicapped. Epilepsy was observed in 13% of the cases. Incidence of recurrent and generalized seizures paralleled neurodevelopmental outcome (5% in normal, 16% in moderately disabled and 50% in severely disabled patients). Endocrine dysfunctions were evident in 28% of the cases and were characterized by precocious or delayed puberty, amenorrhea and somatic underdevelopment. No patient with ventricular enlargement and a cortical mantle width below 20 mm showed a good outcome. Large ventricles were compatible with normal mental development when compensated with a corresponding cranial vault enlargement. In patients with normal mental status and motor abnormalities, long-term CT scan findings revealed the presence of focal brain abnormalities (poroencephaly, brain atrophy, calcifications, extracerebral collections). PMID:7773981

  9. Alpine Soils as long-term Bioindicators

    NASA Astrophysics Data System (ADS)

    Nestroy, O.

    2009-04-01

    Alpine soils as long-term bioindicators The introductory words concern the definitions and peculiarities of alpine soils and their position in the Austrian Soil Classification 2000 in comparison with the World Reference Base for Soil Resources 2006. The important parameters for genesis and threats for these soils in steep and high positions are discussed. It must be emphasized that the main threats are the very different kinds of erosion e.g. by water, wind and snow, and also by skiing (end of season) as well as and mountain-biking (mainly summer-sport). Due the very slow regeneration and - in this connection - due to the very slow changes of the soil entities, these soils give an utmost importance as a long-time bioindicator. With regard to the climate change one can assume an increase in the content of organic matter on site, but also an increase of erosion and mass movement on the other site, e. g. in kind of "plaiken" (soil slide) as result of an increasing intensity of rainfall. It lies partly in our hands to diminish the number and the intensity of the threats, we can influence the soil development, but the result to reach a new ecological equilibrium is very long - in case of alpine soil more than two generations.

  10. Neurological long term consequences of deep diving.

    PubMed Central

    Todnem, K; Nyland, H; Skeidsvoll, H; Svihus, R; Rinck, P; Kambestad, B K; Riise, T; Aarli, J A

    1991-01-01

    Forty commercial saturation divers, mean age 34.9 (range 24-49) years, were examined one to seven years after their last deep dive (190-500 metres of seawater). Four had by then lost their divers' licence because of neurological problems. Twenty seven (68%) had been selected by neurological examination and electroencephalography before the deep dives. The control group consisted of 100 men, mean age 34.0 (range 22-48) years. The divers reported significantly more symptoms from the nervous system. Concentration difficulties and paraesthesia in feet and hands were common. They had more abnormal neurological findings by neurological examination compatible with dysfunction in the lumbar spinal cord or roots. They also had a larger proportion of abnormal electroencephalograms than the controls. The neurological symptoms and findings were highly significantly correlated with exposure to deep diving (depth included), but even more significantly correlated to air and saturation diving and prevalence of decompression sickness. Visual evoked potentials, brainstem auditory evoked potentials, and magnetic resonance imaging of the brain did not show more abnormal findings in the divers. Four (10%) divers had had episodes of cerebral dysfunction during or after the dives; two had had seizures, one had had transitory cerebral ischaemia and one had had transitory global amnesia. It is concluded that deep diving may have a long term effect on the nervous system of the divers. PMID:2025592

  11. Long term prediction of flood occurrence

    NASA Astrophysics Data System (ADS)

    Aguilar, Cristina; Montanari, Alberto; José Polo, María

    2016-05-01

    How long a river remembers its past is still an open question. Perturbations occurring in large catchments may impact the flow regime for several weeks and months, therefore providing a physical explanation for the occasional tendency of floods to occur in clusters. The research question explored in this paper may be stated as follows: can higher than usual river discharges in the low flow season be associated to a higher probability of floods in the subsequent high flow season? The physical explanation for such association may be related to the presence of higher soil moisture storage at the beginning of the high flow season, which may induce lower infiltration rates and therefore higher river runoff. Another possible explanation is persistence of climate, due to presence of long-term properties in atmospheric circulation. We focus on the Po River at Pontelagoscuro, whose catchment area amounts to 71 000 km2. We look at the stochastic connection between average river flows in the pre-flood season and the peak flows in the flood season by using a bivariate probability distribution. We found that the shape of the flood frequency distribution is significantly impacted by the river flow regime in the low flow season. The proposed technique, which can be classified as a data assimilation approach, may allow one to reduce the uncertainty associated to the estimation of the flood probability.

  12. Long-term corrosion testing pan.

    SciTech Connect

    Wall, Frederick Douglas; Brown, Neil R.

    2008-08-01

    This document describes the testing and facility requirements to support the Yucca Mountain Project long-term corrosion testing needs. The purpose of this document is to describe a corrosion testing program that will (a) reduce model uncertainty and variability, (b) reduce the reliance upon overly conservative assumptions, and (c) improve model defensibility. Test matrices were developed for 17 topical areas (tasks): each matrix corresponds to a specific test activity that is a subset of the total work performed in a task. A future document will identify which of these activities are considered to be performance confirmation activities. Detailed matrices are provided for FY08, FY09 and FY10 and rough order estimates are provided for FY11-17. Criteria for the selection of appropriate test facilities were developed through a meeting of Lead Lab and DOE personnel on October 16-17, 2007. These criteria were applied to the testing activities and recommendations were made for the facility types appropriate to carry out each activity. The facility requirements for each activity were assessed and activities were identified that can not be performed with currently available facilities. Based on this assessment, a total of approximately 10,000 square feet of facility space is recommended to meet all future testing needs, given that all testing is consolidated to a single location. This report is a revision to SAND2007-7027 to address DOE comments and add a series of tests to address NWTRB recommendations.

  13. Long-term corrosion testing plan.

    SciTech Connect

    Wall, Frederick Douglas; Brown, Neil R.

    2009-02-01

    This document describes the testing and facility requirements to support the Yucca Mountain Project long-term corrosion testing program. The purpose of this document is to describe a corrosion testing program that will (a) reduce model uncertainty and variability, (b) reduce the reliance upon overly conservative assumptions, and (c) improve model defensibility. Test matrices were developed for 17 topical areas (tasks): each matrix corresponds to a specific test activity that is a subset of the total work performed in a task. A future document will identify which of these activities are considered to be performance confirmation activities. Detailed matrices are provided for FY08, FY09 and FY10 and rough order estimates are provided for FY11-17. Criteria for the selection of appropriate test facilities were developed through a meeting of Lead Lab and DOE personnel on October 16-17, 2007. These criteria were applied to the testing activities and recommendations were made for the facility types appropriate to carry out each activity. The facility requirements for each activity were assessed and activities were identified that can not be performed with currently available facilities. Based on this assessment, a total of approximately 10,000 square feet of facility space is recommended to accommodate all future testing, given that all testing is consolidated to a single location. This report is a revision to SAND2008-4922 to address DOE comments.

  14. Transuranic waste: long-term planning

    SciTech Connect

    Young, K.C.

    1985-07-01

    Societal concerns for the safe handling and disposal of toxic waste are behind many of the regulations and the control measures in effect today. Transuranic waste, a specific category of toxic (radioactive) waste, serves as a good example of how regulations and controls impact changes in waste processing - and vice versa. As problems would arise with waste processing, changes would be instituted. These changes improved techniques for handling and disposal of transuranic waste, reduced the risk of breached containment, and were usually linked with regulatory changes. Today, however, we face a greater public awareness of and concern for toxic waste control; thus, we must anticipate potential problems and work on resolving them before they can become real problems. System safety analyses are valuable aids in long-term planning for operations involving transuranic as well as other toxic materials. Examples of specific system safety analytical methods demonstrate how problems can be anticipated and resolution initiated in a timely manner having minimal impacts upon allocation of resource and operational goals. 7 refs., 1 fig.

  15. Long-term predictions using natural analogues

    SciTech Connect

    Ewing, R.C.

    1995-09-01

    One of the unique and scientifically most challenging aspects of nuclear waste isolation is the extrapolation of short-term laboratory data (hours to years) to the long time periods (10{sup 3}-10{sup 5} years) required by regulatory agencies for performance assessment. The direct validation of these extrapolations is not possible, but methods must be developed to demonstrate compliance with government regulations and to satisfy the lay public that there is a demonstrable and reasonable basis for accepting the long-term extrapolations. Natural systems (e.g., {open_quotes}natural analogues{close_quotes}) provide perhaps the only means of partial {open_quotes}validation,{close_quotes} as well as data that may be used directly in the models that are used in the extrapolation. Natural systems provide data on very large spatial (nm to km) and temporal (10{sup 3}-10{sup 8} years) scales and in highly complex terranes in which unknown synergisms may affect radionuclide migration. This paper reviews the application (and most importantly, the limitations) of data from natural analogue systems to the {open_quotes}validation{close_quotes} of performance assessments.

  16. [Long term adherence to HAART in Senegal].

    PubMed

    Bastard, M; Fall, M Basty Koita

    2014-10-01

    Adherence is one of the main predictors of antiretroviral treatment success. A governmental initiative was launched in 1998 for HIV-infected patients in Senegal to provide access to highly active antiretroviral therapy (HAART). Adherence measurements, defined as pills taken/pills prescribed, were assessed between November 1999 and June 2010 using a pill count along with a questionnaire for 330 patients. Predictors of adherence and identification of adherence trajectories were explored through latent class mixed model. We also performed a survival analysis using Cox proportional hazard model. Three adherence behaviours were revealed as well as a better adherence for women. A third of patients had a high adherence trajectory over time and a third had an intermediate one. Male gender and low adherence behaviour over time were independently associated with a higher mortality rate. This study shows that an overall good adherence can be obtained in the long term in Senegal, suggests a better adherence for women and points out a large subsample of patients with intermediate level of adherence behaviour who are at risk for developing resistance to antiretroviral drugs. PMID:24615434

  17. Intermediate- and long-term earthquake prediction.

    PubMed

    Sykes, L R

    1996-04-30

    Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study. PMID:11607658

  18. Intermediate- and long-term earthquake prediction.

    PubMed Central

    Sykes, L R

    1996-01-01

    Progress in long- and intermediate-term earthquake prediction is reviewed emphasizing results from California. Earthquake prediction as a scientific discipline is still in its infancy. Probabilistic estimates that segments of several faults in California will be the sites of large shocks in the next 30 years are now generally accepted and widely used. Several examples are presented of changes in rates of moderate-size earthquakes and seismic moment release on time scales of a few to 30 years that occurred prior to large shocks. A distinction is made between large earthquakes that rupture the entire downdip width of the outer brittle part of the earth's crust and small shocks that do not. Large events occur quasi-periodically in time along a fault segment and happen much more often than predicted from the rates of small shocks along that segment. I am moderately optimistic about improving predictions of large events for time scales of a few to 30 years although little work of that type is currently underway in the United States. Precursory effects, like the changes in stress they reflect, should be examined from a tensorial rather than a scalar perspective. A broad pattern of increased numbers of moderate-size shocks in southern California since 1986 resembles the pattern in the 25 years before the great 1906 earthquake. Since it may be a long-term precursor to a great event on the southern San Andreas fault, that area deserves detailed intensified study. Images Fig. 1 PMID:11607658

  19. Long Term Storage of Lyophilized Liposomal Formulations

    PubMed Central

    Payton, N.M.; Wempe, M.F.; Xu, Y.; Anchordoquy, T.J.

    2014-01-01

    Because aqueous liposomal formulations containing multiply unsaturated lipids are susceptible to chemical degradation, these formulations are often lyophilized. Despite their limited chemical stability, interest in the use of multiply unsaturated lipids to promote intracellular delivery has increased considerably in recent years. The goal of the current study was to examine the long term storage stability of lyophilized formulations containing lipids with increasing levels of unsaturation, and various strategies which can be employed to improve stability. Aqueous lipid-trehalose formulations containing 1,2-dilinolenoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLinPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were lyophilized and stored at temperatures ranging from 4°C to 60°C. We observed that the lipid degradation rate increased as the storage temperature and unsaturation level were increased. Even the cleanest sugars which are available commercially contain iron contaminants, and it was observed that the chelation of these iron contaminants significantly improved the stability of DLPC during storage. However, the glass transition temperature of the sugar which was included in the formulation, the reduction of the oxygen in the aqueous sample prior to lyophilization, the inclusion of helper lipids (i.e., cholesterol), and the rate of freezing did not significantly improve stability. PMID:25308534

  20. Long-term intraperitoneal insulin delivery.

    PubMed Central

    Pitt, H A; Saudek, C D; Zacur, H A

    1992-01-01

    Over the past 5 years, 21 patients with insulin-dependent diabetes mellitus have been managed at the Johns Hopkins Medical Institutions with variable rate, remotely controlled implanted insulin pumps. To date, nearly 70 patient-years of experience has been gained with intraperitoneal delivery of a new U-400 insulin with a surfactant. All 21 patients are alive after a mean of 39.3 months (range, 10 to 65 months) after insulin pump implantation. Nineteen of the 21 patients remain on intraperitoneal insulin, for a 5-year actuarial system survival of 90%. Glucose control was improved, especially during the first 16 months after pump implantation, without an increased incidence of severe hypoglycemia. Catheter blockage has been a significant problem, occurring in nine of the 21 patients (43%). Catheter occlusion has been successfully managed, however, with laparoscopic repair in seven of 10 attempts or with catheter change in four of five patients. Nevertheless, quality of life and patient acceptance remain excellent. Moreover, pre-existing nephropathy, neuropathy, and retinopathy have been surprisingly stable. With an aggressive policy of catheter change or laparoscopic clearance of catheter blockage, long-term intraperitoneal insulin delivery is now a safe and effective treatment for type I diabetics. PMID:1417197

  1. The long-term variability of Vega

    NASA Astrophysics Data System (ADS)

    Butkovskaya, V.; Plachinda, S.; Valyavin, G.; Baklanova, D.; Lee, B.-C.

    2011-12-01

    Over the time of 60 years Vega (α Lyrae = HD 172167, A0V) has been generally accepted as a standard star in the near-infrared, optical, and ultraviolet regions. But is the spectrophotometric standard Vega really non-variable star? Researchers give very different answers to this question. We aim to search a periodicity in our results of spectropolarimetric study of Vega, namely periodic variations in equivalent width of the spectral lines and longitudinal magnetic field measurements. High-accuracy spectropolarimetric observations of Vega have been performed during 26 nights from 1997 to 2010 using the Coudé spectrograph of the 2.6-m Shain reflector at the Crimean Astrophysical Observatory (CrAO, Ukraine) and during 4 nights in 2007 and 2008 using the echelle spectrograph BOES at the Bohyunsan Optical Astronomy Observatory (BOAO, South Korea). The long-term (year-to-year) variability of Vega was confirmed. It was concluded that this variability does not have magnetic nature. The paper is dedicated to the memory of V.P. Merezhin.

  2. 22 CFR 228.12 - Long-term leases.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Long-term leases. 228.12 Section 228.12 Foreign... Transactions for USAID Financing § 228.12 Long-term leases. Any commodity obtained under a long-term lease..., a long-term lease is defined as a single lease of more than 180 days, or repetitive or...

  3. 22 CFR 228.12 - Long-term leases.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Long-term leases. 228.12 Section 228.12 Foreign... Transactions for USAID Financing § 228.12 Long-term leases. Any commodity obtained under a long-term lease..., a long-term lease is defined as a single lease of more than 180 days, or repetitive or...

  4. 26 CFR 1.460-1 - Long-term contracts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 6 2011-04-01 2011-04-01 false Long-term contracts. 1.460-1 Section 1.460-1...) INCOME TAXES (CONTINUED) Taxable Year for Which Items of Gross Income Included § 1.460-1 Long-term... the manufacture, building, installation, or construction of property is a long-term contract...

  5. 22 CFR 228.18 - Long-term leases.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Long-term leases. 228.18 Section 228.18 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT RULES FOR PROCUREMENT OF COMMODITIES AND SERVICES FINANCED BY... USAID Financing § 228.18 Long-term leases. Any commodity obtained under a long-term lease agreement...

  6. 26 CFR 1.460-1 - Long-term contracts.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 26 Internal Revenue 6 2014-04-01 2014-04-01 false Long-term contracts. 1.460-1 Section 1.460-1...) INCOME TAXES (CONTINUED) Taxable Year for Which Items of Gross Income Included § 1.460-1 Long-term... the manufacture, building, installation, or construction of property is a long-term contract...

  7. 22 CFR 228.18 - Long-term leases.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Long-term leases. 228.18 Section 228.18 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT RULES FOR PROCUREMENT OF COMMODITIES AND SERVICES FINANCED BY... USAID Financing § 228.18 Long-term leases. Any commodity obtained under a long-term lease agreement...

  8. 26 CFR 1.460-1 - Long-term contracts.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 6 2013-04-01 2013-04-01 false Long-term contracts. 1.460-1 Section 1.460-1...) INCOME TAXES (CONTINUED) Taxable Year for Which Items of Gross Income Included § 1.460-1 Long-term... the manufacture, building, installation, or construction of property is a long-term contract...

  9. 17 CFR 256.224 - Other long-term debt.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Other long-term debt. 256.224 Section 256.224 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) UNIFORM... COMPANY ACT OF 1935 6. Long-Term Debt § 256.224 Other long-term debt. This account shall include all...

  10. 17 CFR 256.224 - Other long-term debt.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Other long-term debt. 256.224 Section 256.224 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) UNIFORM... COMPANY ACT OF 1935 6. Long-Term Debt § 256.224 Other long-term debt. This account shall include all...