Cumulative Dose (cumulative + dose)

Distribution by Scientific Domains
Distribution within Medical Sciences


Selected Abstracts


Fluence Rate or Cumulative Dose?

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2007
Vulnerability of Larval Northern Pike (Esox lucius) to Ultraviolet Radiation
Newly hatched larvae of northern pike were exposed in the laboratory to four fluence rates of ultraviolet radiation (UVR; 290,400 nm) over three different time periods, resulting in total doses ranging from 3.0 0.2 to 63.0 4.4 kJm,2. Mortality and behavior of the larvae were followed for 8,12 days, and growth measured at the end of the experiment. Also, the principle of reciprocity,that the UVR-induced mortality depends on the cumulative dose, independent of fluence rate,was tested. Fluence rates higher than 1480 150 mWm,2 caused mortality and growth retardation. The highest fluence rate (3040 210 mWm,2) caused 100% mortality in 5 days. All fluence rates caused behavioral disorders, which led to death at fluence rates higher than 1480 mWm,2. Reciprocity failure occurred with the lowest and highest dose (550 45 and 3040 210 mWm,2, respectively). The results show that fluence rate is of primary importance when assessing the UVR-related risk. [source]


Cumulative Dose of Hypertension Predicts Outcome in Intracranial Hemorrhage Better Than American Heart Association Guidelines

ACADEMIC EMERGENCY MEDICINE, Issue 8 2007
Christopher W. Barton MD
BackgroundHypertension is common after intracranial hemorrhage (ICH) and may be associated with higher mortality and adverse neurologic outcome. The American Heart Association recommends that blood pressure be maintained at a mean arterial pressure (MAP) less than 130 mm Hg to prevent secondary brain injury. ObjectivesTo prospectively evaluate whether a new method of assessing hypertension in ICH more accurately identifies patients at risk for adverse outcomes. MethodsThe authors prospectively studied all patients presenting to two University of California, San Francisco hospitals with acute ICH from June 1, 2001, to May 31, 2004. Factors related to acute hospitalization were recorded in a database, including all charted vital signs for the first 15 days. Patients were followed up for one year, with their modified Rankin Scale (mRS) score at 12 months as primary outcome. Hypertension dose was determined as the area under the curve between patient MAP and a cut point of 110 mm Hg while in the emergency department (ED). The dose was adjusted for time spent in the ED (dose/timeed [d/ted]). Hypertension dose was divided into four categories (none, and progressive tertiles). Multivariate logistic regression was used to calculate the odds ratio for adverse mRS by tertiles of d/ted. ResultsA total of 237 subjects with an ED average (SD) length of stay of 3.42 (3.7) hours were enrolled. In a multivariate logistic regression model controlling for the effects of age, volume of hemorrhage, presence of intraventricular hemorrhage, race, and preexisting hypertension, there was a 4.7- and 6.1-fold greater likelihood of an adverse neurologic outcome (by mRS) at one and 12 months, respectively, in the highest d/ted tertile relative to the referent group without hypertension. ConclusionsHypertension after acute ICH is associated with adverse neurologic outcome. The dose of hypertension may more accurately identify patients at risk for adverse outcomes than the American Heart Association guidelines and may lead to better outcomes if treated when identified in this manner. [source]


Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal,arterial pCO2 gradient in abdominal aortic aneurysm surgery

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2008
H. LEPPIKANGAS
Background: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Methods: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double-blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG-PDR) was used to estimate the total splanchnic blood flow. Results: The immediate post-operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8,4.7) l/min/m2 vs. 2.6(2.3,3.6) l/min/m2; P<0.05] and the gastric mucosal,arterial pCO2 gradient was lower in levosimendan-treated patients [0.9(0.6,1.2) kPa vs. 1.7(1.2,2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG-PDR, was comparable [29(21,29)% vs. 20(19,25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post-operative day. Conclusion: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation. [source]


Impact of hemoglobin level on survival in definitive chemoradiotherapy for T4/M1 lymph node esophageal cancer

DISEASES OF THE ESOPHAGUS, Issue 3 2008
S. Zenda
SUMMARY., We retrospectively investigated the impact of the pre-chemoradiotherapy hemoglobin level (pre-CRT Hb level) for T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus. Chemotherapy consisted of protracted infusion with 5-fluorouracil (5-FU) at 400 mg/m2/day on days 1,5 and 8,12, combined with cisplatin at 40 mg/m2/day on days 1 and 8, repeated twice at a 5-week interval. Concurrent radiation therapy was started on day 1 and delivered at 2 Gy/day for five days a week for a total radiation dose of 60 Gy, with a two-week break after a cumulative dose of 30 Gy. Several factors considered to be related with treatment outcome were evaluated by univariate and multivariate analysis. A total of 48 patients with T4/M1 LYM (lymphocyte) esophageal cancer treated with chemoradiotherapy (CRT) between September 2002 and April 2005 were enrolled. The complete response rate to this regimen was 44% and median survival time was 13.6 months, with a median follow-up period of 26.8 months. Median pre-CRT Hb level was 13.5 (10.4,15.3) g/dL. The CR rate in patients with a pre-CRT Hb level of 13 g/dL or less was only 24% but it was 60% in those with a level that was more than 13 g/dL (P=0.01). As for survival, anovarevealed that a pre-CRT Hb of 13 g/dL or less was a significant prognostic factor with a hazard ratio of 0.45 (95% confidence interval [CI]); 0.21,0.97, P=0.04), while on manova, including performance status, tumor size, TNM stage and pre-CRT Hb level, a pre-CRT Hb level of 13 g/dL or less was the only significant prognostic factor, with a hazard ratio of 0.35 (95% CI; 0.13,0.90, P=0.03). In conclusion, the pre-CRT Hb level may be an important determinant of outcome in patients with T4/M1 LYM squamous cell carcinoma of the esophagus. [source]


Mutagenicity of zidovudine, lamivudine, and abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure of CD-1 mice to single agents or drug combinations,,

ENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 3-4 2007
Salina M. Torres
Abstract Experiments were performed to investigate the impact of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) on cell survival and mutagenicity in two reporter genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK), using cell cloning assays for assessing the effects of individual drugs/drug combinations in (1) TK6 human lymphoblastoid cells exposed in vitro and (2) splenic lymphocytes from male CD-1 mice exposed transplacentally on days 12,18 of gestation. In TK6 cells, dose-related increases in HPRT and TK mutant frequencies were found following 3 days of exposure to AZT or 3TC alone (33, 100, or 300 ,M), or to equimolar amounts of AZT-3TC. Compared with single drug exposures, AZT-3TC coexposures generally yielded enhanced elevations in HPRT and TK mutant frequencies. Mutagenicity experiments with ABC alone, or in combination with AZT-3TC, were complicated by the extreme cytotoxicity of ABC. Exposure of cells either to relatively high levels of AZT-3TC short-term (100 ,M, 3 days), or to peak plasma-equivalent levels of AZT-3TC for an extended period (10 ,M, 30 days), resulted in similar drug-induced mutagenic responses. Among sets of mice necropsied on days 13, 15, or 21 postpartum, Hprt mutant frequencies in T-cells were significantly elevated in the AZT-only (200 mg/kg bw/day) and AZT-3TC (200 mg AZT + 100 mg 3TC/kg bw/day) groups at 13 days of age. These results suggest that the mutagenicity by these nucleoside analogs is driven by cumulative dose, and raises the question of whether AZT-3TC has greater mutagenic effects than AZT alone in perinatally exposed children. Environ. Mol. Mutagen. 2007 Wiley-Liss, Inc. [source]


Epileptic Seizures after Treatment with Thiocolchicoside

EPILEPSIA, Issue 8 2001
Pier Luigi De Riu
Summary: ,Purpose: To report the occurrence of epileptic seizures in humans, closely related to the use of the centrally acting muscle relaxant thiocolchicoside. Methods: Description of three case histories. Results: Two patients, affected with complex-partial seizures, sometimes secondarily generalized, receiving antiepileptic therapy, were seizure free for 7 and 9 years, respectively. They had the reappearance of tonic,clonic seizures few days after the continued use of thiocolchicoside, at a cumulative dose of the drug of 52 mg and 76 mg, respectively. The third patient was brain damaged and without a history of seizures. He had a sudden, convulsive seizure a few minutes after 4 mg intramuscular thiocolchicoside. Conclusions: Our case histories indicate that thiocolchicoside has a powerful epileptogenic activity. This drug should be avoided in patients with epilepsy or acute brain injury and possible disruption of the blood,brain barrier. [source]


Intravenous cocaine induced-activity and behavioural sensitization in norepinephrine-, but not dopamine-transporter knockout mice

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2002
Andy N. Mead
Abstract Previously, it was reported that both norepinephrine transporter (NET) and dopamine transporter (DAT) knockout (KO) mice were sensitive to the reinforcing effects of cocaine. However, assessing the locomotor-stimulant effects of cocaine in these subjects has proven difficult due to significant differences in their baseline activity compared to wild-type controls. The present studies were designed to clarify the role of NET and DAT in the stimulant effects of acute and repeated cocaine utilizing these knockout mice, and thereby assess the role of these substrates in the locomotor stimulant effects of cocaine. Mice were habituated to the test environment for sufficient time to ensure equal baselines at the time of cocaine administration. Mice then received cocaine (3,25 mg/kg) intravenously according to a within-session cumulative dose,response design. Cocaine dosing was repeated at 48-h intervals for four sessions to assess behavioural sensitization. NET-KO mice exhibited a reduced response to acute cocaine administration compared to wild-type (WT) controls. However, comparable sensitization developed in NET-KO and WT mice. The DAT-KO and DAT-heterozygote (HT) mice displayed no locomotor activation following either acute or repeated cocaine administration. These data suggest a role for the NET in the acute response to cocaine, but no involvement in sensitization to cocaine. In contrast, DAT appears to be necessary for both the acute locomotor response to cocaine and the subsequent development of sensitization. In addition to existing data concerning the reinforcing effects of cocaine in DAT-KO mice, these data suggest a dissociation between the reinforcing and locomotor stimulant effects of cocaine. [source]


FEIBA in treatment of acute bleeding episodes in patients with haemophilia A and factor VIII inhibitors: a retrospective survey in regional haemophilia centre

HAEMOPHILIA, Issue 3 2009
P. SMEJKAL
Summary., FEIBA (factor eight inhibitor by-passing activity) is used to achieve haemostasis in haemophiliacs with inhibitor. The aim of this study was to evaluate efficacy and consumption of the product in treatment of haemorrhages in haemophiliacs with factor VIII inhibitor, and determine factors that can influence the results of treatment. We used data from our haemophilia centre from years 2000,2008. Six haemophiliacs with factor VIII inhibitor were treated on demand with FEIBA for 61 bleeding episodes (45 haemarthroses, six muscle bleeds, six other sites bleeds and four multiple sites bleeds). The median cumulative dose of FEIBA per bleeding episode was 205 U kg,1. Bleeding was stopped in 96.7% (59 of 61) of events but re-bleeding occurred in 3 events (4.9%) within 48 h after cessation of bleeding. In home treatment (20 of 61) bleeding stopped in 90% (18 of 20) without recurrence and the median consumption per event was reduced to 153 U kg,1. Without the use of home treatment the median consumption was 250 U kg,1 per event and bleeding ceased definitely in 92.7% (38 of 41) of cases. The cumulative dose of FEIBA was lower for three episodes with re-bleeding: median 96 U kg,1 but not in the two cases of ineffective treatment: 361 U kg,1. FEIBA in management of bleeding episodes completely resolved the haemorrhage in 91.8% of events and in a further 4.9% if treatment was restarted. Using home treatment saved expenditure due to the lower cumulative dose needed for treatment of haemorrhage. [source]


Muscle performance in patients with Crohn's disease in clinical remission

INFLAMMATORY BOWEL DISEASES, Issue 3 2005
Jean-Baptiste Wiroth PhD
Abstract Background: Because patients with Crohn's disease (CD) often show increased energy expenditure, nutritional deficiencies, and general fatigue, all which may persist after a flare, we hypothesized that CD could alter muscle mass and function. This study aimed to assess muscle strength and endurance in CD patients in clinical remission and the influencing factors. Methods: Forty-one outpatients (17 men and 24 women; age, 37 10 yr), in remission (CD Activity Index < 150) for >3 months, and 25 age-matched healthy controls (10 men and 15 women; age, 37 13 yr) were evaluated. Evaluation included a sit-up test, hand-grip strength test, hand-grip endurance test, lower limb strength test, and lower limb endurance test (LE), as well as a measure of physical activity. Results: No significant difference was found between CD and control groups regarding weight, height, body mass index, fat mass, and fat-free mass. Strength performance was lower in CD subjects compared with controls, particularly for lower limb indexes: lower limb strength test (,24.6%, P < 0.001), LE (,25.8%, P < 0.001), and sit-up test (,25.1%, P < 0.001). Previous disease severity, disease duration, the cumulative dose of glucocorticosteroids, current inflammation, and global habitual physical activity did not affect muscle performance. A recent use of steroids improved LE. Conclusions: CD patients in clinical remission have decreased muscle function that may affect their quality of life. This pattern is reflected by reduced strength and endurance indexes, particularly for lower limbs. The reasons for these changes need further study. Strength training should be assessed in these patients. [source]


Bone mineral density and bone turnover markers in patients receiving a single course of isotretinoin for nodulocystic acne

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 6 2008
Nilgun Solak Tekin Associate Professor
Background, High-dose isotretinoin has been reported to have adverse effects on bone mineral density (BMD); however, studies evaluating changes in BMD with isotretinoin therapy at different dosages and with varying treatment durations have produced conflicting results. Objective, To investigate the effect of a standard, single course of isotretinoin therapy on BMD and bone turnover markers in patients with nodulocystic acne. Methods, Thirty-six patients (15 male, 21 female) with severe, recalcitrant, nodulocystic acne and 36 healthy controls (16 male, 20 female) were enrolled in the study. Patients received isotretinoin treatment for 4,6 months until a cumulative dose of 120 mg/kg had been achieved. BMD in the lumbar spine and femur was measured at baseline and at the end of therapy by dual-energy X-ray absorptiometry. Serum calcium, phosphate, parathormone, total alkaline phosphatase, osteocalcin, free deoxypyridinoline, and urinary calcium were also measured before and at the end of treatment. Results, No significant differences were found in lumbar spine and femoral BMD between the patient and control groups at the beginning of the study (P > 0.05), and no statistically significant difference was observed between the BMD values in patients at the beginning vs. the end of treatment (P > 0.05). No statistically significant difference in bone turnover markers was found between patients and controls at the beginning of the study (P > 0.05), and no statistically significant changes in bone turnover markers were observed in patients at the beginning vs. the end of treatment (P > 0.05). Conclusion, A single course of isotretinoin therapy has no clinically significant effect on bone metabolism. [source]


The frequency of low bone mineral density and its associated risk factors in patients with inflammatory bowel diseases

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 3 2010
Yasser EZZAT
Abstract Objective:, To detect the frequency and the predictive factors of low bone mineral density in inflammatory bowel disease (IBD) patients, so as to optimize bone mineral density (BMD) monitoring and treatment for those at risk. Subjects and methods:, Thirty Asian patients were included in this study and were divided into 18 patients with ulcerative colitis (UC), and 12 patients with Crohn's disease (CD). All patients were diagnosed by colonoscopy and histopathological biopsy and were subjected to routine laboratory investigations in addition to 25 hydroxy vitamin D levels as well as serum calcium, phosphorus and alkaline phosphatise. BMD was measured by using dual-energy X-ray absorptiometry (DEXA) scan at lumbar spine and femoral neck; predictive factors for BMD were analyzed by group comparison and step-wise regression analysis. Results:, There was increased frequency of osteoporosis and osteopenia involving the lumbar spine in patients with IBD being more common among CD patients than in the UC group. Positive correlations were found between low BMD measurements and vitamin D levels, body mass index (BMI) (P < 0.001) as well as steroid cumulative dose and duration of therapy (P < 0.001); stepwise regression analysis showed that CD and vitamin D deficiency are predictive factors for both osteoporosis and osteopenia (P = 0.024, P = 0.027, respectively). Conclusion:, Low BMD was found to be more frequent among patients with CD than UC; in addition CD and vitamin D deficiency act as predictive factors for low BMD. We recommend that calcium and vitamin D should be given to all IBD patients; in addition, bisphosphonate administration should be put into consideration. [source]


Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration

JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2004
Sherif Y. Saad
Abstract The higher incidence of cardiotoxicity of doxorubicin (DOX)/paclitaxel (PTX) combination compared with DOX alone remains to be a major obstacle against effective chemotherapeutic treatment. We investigated the effect of sequence and time interval between administration of both drugs on the severity of cardiotoxicity of the combination. Male Wistar rats were divided into seven groups. DOX was administeded intraperitoneally (ip) at a single dose of 5 mg kg,1 every other 2 days, 2 doses per week for a total cumulative dose of 20 mg kg,1. PTX was administered by an ip route at a dose of 20 mg kg,1 every other 2 days. Both drugs were injected either alone or sequentially in combination. In one case, DOX preceded PTX by 30 min and 24 h and in the other case, PTX preceded DOX by 30 min and 24 h. Cardiotoxicity was evaluated by both biochemical and histopathological examination, 48 h after the last DOX dose. DOX-induced cardiotoxicity was manifested by abnormal biochemical changes including marked increases in serum creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and aspartate aminotransferase (AST) activity levels. Myocardial tissue from DOX-treated rats showed significant increases in malondialdehyde (MDA) production and total nitrate/nitrite (NOx) levels, parallel with depletion of "endogenous antioxidant reserve," including GSH contents and GSH-Px activity level. PTX treatment produced significant changes in the biochemical parameters measured by a lower magnitude than those changes produced by DOX alone. Combination of both drugs resulted in aggravation of DOX-induced cardiotoxicity regardless the sequence and time interval between administration of either drug. Administration of PTX 30 min and 24 h after DOX treatment showed exaggeration of combination-induced cardiotoxicity compared with the reverse sequence. This exacerbation was manifested by much more pronounced changes in serum and cardiac tissue parameters measured. Histopathological examination of ventricles of rat's heart revealed that DOX treatment produced myo-cytolysis and myocardial necrosis. Administration of PTX following DOX treatment showed extensive myocardial necrosis compared with those rats treated with either DOX alone or the reverse sequence of administration. Moreover, rats treated with PTX 24 h after DOX treatment showed exaggeration of the combination-induced cardiotoxicity. In conclusion, PTX might synergistically aggravate DOX-induced cardiotoxicity. The effect might be much more pronounced with those rats treated with PTX 24 h after DOX treatment. 2004 Wiley Periodicals, Inc. J Biochem Mol Toxicol 18:78,86, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20012 [source]


An Ovine Model of Chronic Heart Failure: Echocardiographic and Tissue Doppler Imaging Characterization

JOURNAL OF CARDIAC SURGERY, Issue 1 2006
M.Sc., Nicolas Borenstein D.V.M.
In order to validate novel surgical or pharmacological treatments, reproducible animal models of left ventricular dysfunction are necessary. In the current study, we report our data and experience with a model of toxin-induced heart failure in the sheep. Methods: Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until standard echocardiographic and tissue Doppler imaging detection of myocardial systolic dysfunction. The animals were assessed 1 month later and harvested. Indices of cardiac function from baseline to last day of protocol were recorded and their differences were evaluated by a Wilcoxon rank test for paired data. Results: Ten sheep received 2.5 0.7 intracoronary injections of a cumulative dose of 88.8 25 mg/m2 doxorubicin. All available parameters demonstrated signs of severe cardiac dysfunction with statistical significance. All hearts demonstrated severe histological lesions, some of which were consistent with doxorubicin-induced toxicity. Conclusions: The present study shows that this ovine model is reproducible and stable. It can therefore be relevant to the study of chronic heart failure. It will be incorporated in our future studies concerning novel treatments (such as cell therapy) of nonischemic dilated cardiomyopathy. [source]


Comparison of closed loop vs. manual administration of propofol using the Bispectral index in cardiac surgery

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2009
J. AGARWAL
Background: In recent years, electroencephalographic indices of anaesthetic depth have facilitated automated anaesthesia delivery systems. Such closed-loop control of anaesthesia has been described in various surgical settings in ASA I,II patients (1,4), but not in open heart surgery characterized by haemodynamic instability and higher risk of intra-operative awareness. Therefore, a newly developed closed-loop anaesthesia delivery system (CLADS) to regulate propofol infusion by the Bispectral index (BIS) was compared with manual control during open heart surgery. Methods: Forty-four adult ASA II,III patients undergoing elective cardiac surgery under cardiopulmonary bypass were enrolled. The study participants were randomized to two groups: the CLADS group received propofol delivered by the CLADS, while in the manual group, propofol delivery was adjusted manually. The depth of anaesthesia was titrated to a target BIS of 50 in both the groups. Results: During induction, the CLADS group required lower doses of propofol (P<0.001), resulting in lesser overshoots of BIS (P<0.001) and mean arterial blood pressure (P=0.004). Subsequently, BIS was maintained within 10 of the target for a significantly longer time in the CLADS group (P=0.01). The parameters of performance assessment, median absolute performance error (P=0.01), wobble (P=0.04) and divergence (P<0.001), were all significantly better in the CLADS group. Haemodynamic stability was better in the CLADS group and the requirement of phenylephrine in the pre-cardiopulmonary bypass period as well as the cumulative dose of phenylephrine used were significantly higher in the manual group. Conclusion: The automated delivery of propofol using CLADS was safe, efficient and performed better than manual administration in open heart surgery. [source]


Melatonin attenuates kainic acid-induced hippocampal neurodegeneration and oxidative stress through microglial inhibition

JOURNAL OF PINEAL RESEARCH, Issue 2 2003
Seung-Yun Chung
Abstract:,The antioxidant and anti-inflammatory effects of melatonin on kainic acid (KA)-induced neurodegeneration in the hippocampus were evaluated in vivo. It has been suggested that the pineal secretory product, melatonin, protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors, and from oxidative stress-induced DNA damage and apoptosis. In this study, we injected 10 mg/kg kainate intraperitoneally (i.p.) into adult male Sprague-Dawley rats. This results in selective neuronal degeneration accompanied by intense microglial activation and triggers DNA damage in the hippocampus. We tested the in vivo efficacy of melatonin in preventing KA-induced neurodegeneration, oxidative stress and neuroinflammation in the hippocampus. Melatonin (2.5 mg/kg, i.p.) was given 20 min before, immediately after, and 1 and 2 hr after KA administration. Rats were killed 72 hr later and their hippocampi were examined for evidence of DNA damage (in situ dUTP end-labeling, i.e. TUNEL staining), cell viability (hematoxylin and eosin staining), and microglial (isolectin-B4 histochemistry) and astroglial responses (glial fibrillary acidic protein immunohistochemistry), as well as lipid peroxidation (4-hydroxynonenal immunohistochemistry). A cumulative dose of 10 mg/kg melatonin attenuates KA-induced neuronal death, lipid peroxidation, and microglial activation, and reduces the number of DNA breaks. A possible mechanism for melatonin-mediated neuroprotection involves its antioxidant and anti-inflammatory actions. The present data suggest that melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress-induced neuronal damage such as epilepsy, stroke, and traumatic brain injury. [source]


Melatonin protects against cardiac toxicity of doxorubicin in rat

JOURNAL OF PINEAL RESEARCH, Issue 4 2001
Mei Feng Xu
Doxorubicin (DOX) is commonly used for the treatment of hematological and solid tumors. However, there are serious toxic effects on the cardiovascular system, which limits the application of the drug. Recently, melatonin has been reported to have immunomodulatory effect in addition to lowering cholesterol levels as well as inhibiting malignant tumors. In this study, the effect of melatonin against the toxicity of doxorubicin was investigated in rats. Hemodynamic function, pathological and biochemical changes were determined in different treated hearts. Our findings showed that a significant protection by melatonin (6 mg kg,1 for 15 days, cumulative dose of 90 mg kg,1) against the DOX-induced toxicity was observed. Cardiac function was improved and lipid peroxidation decreased after melatonin treatment. It is concluded that melatonin provides protection against doxorubicin toxicity via an attenuation of lipid peroxidation. [source]


Effects of levosimendan on indocyanine green plasma disappearance rate and the gastric mucosal,arterial pCO2 gradient in abdominal aortic aneurysm surgery

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2008
H. LEPPIKANGAS
Background: Levosimendan has a dual mechanism of action: it improves myocardial contractility and causes vasodilatation without increasing myocardial oxygen demand. In a laboratory setting, it selectively increases gastric mucosal oxygenation in particular and splanchnic perfusion in general. The aim of our study was to describe the effects of levosimendan on systemic and splanchnic circulation during and after abdominal aortic surgery. Methods: Twenty abdominal aortic aneurysm surgery patients were randomized to receive either levosimendan (n=10) or placebo (n=10) in a double-blinded manner. Both the mode of anaesthesia and the surgical procedures were performed according to the local guidelines. Automatic gas tonometry was used to measure the gastric mucosal partial pressure of carbon dioxide. Systemic indocyanine green clearance plasma disappearance rate (ICG-PDR) was used to estimate the total splanchnic blood flow. Results: The immediate post-operative recovery was uneventful in the two groups with a comparable, overnight length of stay in the intensive care unit. Cumulative doses of additional vasoactive drugs were comparable between the groups, with a tendency towards a higher cumulative dose of noradrenaline in the levosimendan group. After aortic clamping, the cardiac index was higher [4(3.8,4.7) l/min/m2 vs. 2.6(2.3,3.6) l/min/m2; P<0.05] and the gastric mucosal,arterial pCO2 gradient was lower in levosimendan-treated patients [0.9(0.6,1.2) kPa vs. 1.7(1.2,2.1) kPa; (P<0.05)]. However, the total splanchnic blood flow, estimated by ICG-PDR, was comparable [29(21,29)% vs. 20(19,25)%; NS]. Organ dysfunction scores (sequential organ dysfunction assessment) were similar between the groups on the fifth post-operative day. Conclusion: Levosimendan favours gastric perfusion but appears not to have a major effect on total splanchnic perfusion in patients undergoing an elective aortic aneurysm operation. [source]


Intrauterine exposure to polycyclic aromatic hydrocarbons, fine particulate matter and early wheeze.

PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 4p2 2010
Prospective birth cohort study in 4-year olds
Jedrychowski WA, Perera FP, Maugeri U, Mrozek-Budzyn D, Mroz E, Klimaszewska-Rembiasz M, Flak E, Edwards S, Spengler J, Jacek R, Sowa A. Intrauterine exposure to polycyclic aromatic hydrocarbons, fine particulate matter and early wheeze. Prospective birth cohort study in 4-year olds. Pediatr Allergy Immunol 2010: 21: e723,e732. 2010 John Wiley & Sons A/S The main goal of the study was to determine the relationship between prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) measured by PAH-DNA adducts in umbilical cord blood and early wheeze. The level of PAH-DNA adducts in the cord blood is assumed to reflect the cumulative dose of PAHs absorbed by the foetus over the prenatal period. The effect of prenatal PAH exposure on respiratory health measured by the incidence rate ratio (IRR) for the number of wheezing days in the subsequent 4 yr follow-up was adjusted for potential confounding factors such as personal prenatal exposure to fine particulate matter (PM2.5), environmental tobacco smoke (ETS), gender of child, maternal characteristics (age, education and atopy), parity and mould/dampness in the home. The study sample includes 339 newborns of non-smoking mothers 18,35 yr of age and free from chronic diseases, who were recruited from ambulatory prenatal clinics in the first or second trimester of pregnancy. The number of wheezing days during the first 2 yr of life was positively associated with prenatal level of PAH-DNA adducts (IRR = 1.69, 95%CI = 1.52,1.88), prenatal particulate matter (PM2.5) level dichotomized by the median (IRR = 1.38; 95%CI: 1.25,1.51), maternal atopy (IRR = 1.43; 95%CI: 1.29,1.58), mouldy/damp house (IRR = 1.43; 95%CI: 1.27,1.61). The level of maternal education and maternal age at delivery was inversely associated with the IRRs for wheeze. The significant association between frequency of wheeze and the level of prenatal environmental hazards (PAHs and PM2.5) was not observed at ages 3 or 4 yrs. Although the frequency of wheezing at ages 3 or 4 was no longer associated with prenatal exposure to PAHs and PM2.5, its occurrence depended on the presence of wheezing in the first 2 yr of life, which nearly tripled the risk of wheezing in later life. In conclusion, the findings may suggest that driving force for early wheezing (<24 months of age) is different to those leading to later onset of wheeze. As we reported no synergistic effects between prenatal PAH (measured by PAH-DNA adducts) and PM2.5 exposures on early wheeze, this suggests the two exposures may exert independent effects via different biological mechanism on wheeze. [source]


Glomerular toxicity persists 10 years after ifosfamide treatment in childhood and is not predictable by age or dose,

PEDIATRIC BLOOD & CANCER, Issue 7 2010
FRCPCH, Roderick Skinner PhD
Abstract Background This prospective longitudinal single institution cohort study evaluated the natural history of and risk factors for chronic nephrotoxicity 10 years after ifosfamide treatment in childhood. Procedure Twenty-five patients (16 males) treated with ifosfamide were investigated at end of treatment (End), 1 and 10 years later. Glomerular filtration rate (GFR), serum phosphate (PO4) and bicarbonate (HCO3) and renal tubular threshold for phosphate (Tmp/GFR) were measured, and total nephrotoxicity score (Ns) graded. Results More patients had a low GFR at 1 (72%) and 10 (50%) years than at End (26%) (P,=,0.006 for End vs. 1 year). Electrolyte supplementation requirements for tubular toxicity resolved by 10 years (0% vs. 32% at End and 24% at 1 year; both P,<,0.05). At 10 years, 17% of patients had moderate overall nephrotoxicity and 13% clinically significant reduction of GFR (<60,ml/min/1.73,m2). Neither dose nor age at treatment predicted any measure of toxicity at 10 years or reduced GFR at any timepoint. Higher cumulative ifosfamide dose correlated with greater tubular and overall nephrotoxicity at End and/or 1 year (P,<,0.05 for each of PO4, HCO3, Tmp/GFR, Ns), but age at treatment did not differ between patients with normal or abnormal results. Conclusions Although clinically significant tubular toxicity had resolved by 10 years, GFR was <60,ml/min/1.73,m2 in 13% of patients, raising concerns about very long-term glomerular function. Higher cumulative dose was associated with greater tubular and overall toxicity at End and 1 year, but not at 10 years. Age at treatment did not predict nephrotoxicity at any timepoint. Pediatr Blood Cancer 2010;54:983,989 2010 Wiley-Liss, Inc. [source]


Echocardiographic evaluation of patients cured of childhood cancer: A single center study of 117 subjects who received anthracyclines

PEDIATRIC BLOOD & CANCER, Issue 6 2001
Grazia Bossi MD
Abstract Background The risk of cardiomyopathy following exposure to anthracycline in asymptomatic long-term survivors of childhood cancer is still hard to predict and precisely quantify. To identify the impact of different cumulative doses, even within a non-high dose range, and the echocardiographic parameters suitable for evaluating cardiac function, we studied diastolic and systolic echocardiographic parameters in a cohort of patients followed in a single center. Procedure A total of 117 subjects were studied at a median time of 7 years after treatment completion. A complete M-mode, two-dimensional and Doppler echocardiographic study was obtained at rest in all patients according to the standard recommendations of the American Society of Echocardiography. Results Ninety-nine patients (85%) had completely normal cardiac function, while 18 had abnormal echocardiographic findings: 12 had one abnormal value, 5 had two, and 1 had three abnormal values. All the changes were in left ventricular dimensions, wall thickness or indices of systolic function; no alterations in left ventricular diastolic function parameters were found. None of the echocardiographic parameters correlated significantly with the cumulative dose of anthracyclines administered either at univariate analysis or after adjusting for sex, body surface area or considered risk factors. Conclusions Subjects exposed to a median cumulative dose of 214,mg/m2 had no echographic abnormalities a median of 7 years later. We did not find any correlation between cumulative anthracycline dose and the echocardiographic parameters tested. We now offer echocardiographic follow-up to patients with mildly reduced fractional shortening and/or ejection fraction to rule out late onset dysfunction. Med. Pediatr. Oncol. 36:593,600, 2001. 2001 Wiley-Liss, Inc. [source]


No association between inhaled corticosteroids and whole body DXA in postmenopausal women,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2006
Slve Elmsthl MD
Abstract Purpose Postmenopausal women treated with corticosteroids are regarded as a high-risk group due to the effect of both natural bone loss and possible adverse effects of treatment with inhaled corticosteroids (IC). Objective To compare bone mineral density (BMD) in postmenopausal women exposed only to IC (IC group, n,=,106) with that of BMD in women not exposed to corticosteroids (n,=,124) and women exposed to oral and/or intra-articular injections in addition to inhaled corticosteroids (OC group, n,=,31). The women were recruited from a population-based prospective cohort study. Methods Dual X-ray absorptiometry (DXA) technique was used to measure BMD in whole body, spine, pelvis and lower extremities. A health questionnaire and an interview about past and present medication use were used. Results The mean duration and dose of IC were 9.5,,4.5 years and 615,g daily. Whole body BMD did not significantly differ between the IC group (1.103,g/cm2) and the unexposed group (1.087,g/cm2). Within the IC group, BMD stratified for cumulative dose of IC, duration or current dose above or below 800,g did not differ. Z -score BMD for tertiles did not differ when comparing the IC and OC groups. Conclusion No difference in BMD was noted between postmenopausal women exposed to inhaled corticosteroids and unexposed controls nor was there any dose response relationship between inhaled corticosteroid therapy and BMD. Copyright 2006 John Wiley & Sons, Ltd. [source]


Oral anticoagulants and the risk of osteoporotic fractures among elderly,,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 5 2004
Danielle Pilon MD
Abstract Purpose Coumadin-based oral anticoagulants are associated with a decrease in bone mass density, but their role in fracture risk is equivocal. Because the use of oral anticoagulants is prevalent among the elderly, as is the risk and morbidity of osteoporotic fractures, the association between osteoporotic fractures and oral anticoagulants needs to be clarified. Method We conducted a case-control study on a 10% random sample of subjects aged 70 years and older enrolled in the Quebec universal health insurance plan between 1992 and 1994. Incident cases of a first osteoporotic fracture were identified by International Classification of Diseases, Ninth Revision codes. Exposure was defined as one or more prescriptions of oral anticoagulants dispensed before the osteoporotic fracture. Ten controls for each case, matched by age and date of osteoporotic fracture, were identified. Results Among 1523 cases, 48 (3.2%) were ever exposed to oral anticoagulants; among 15,205 controls, 461 (3.0%) were ever exposed (crude odds ratio: 1.0: 95% confidence interval: 0.7,1.5). These negative results persisted after adjusting for potential confounding variables and stratifying exposure into cumulative dose and treatment duration. Conclusions Coumadin-based oral anticoagulants are not significantly associated with osteoporotic fractures among the elderly, providing reassurance for elderly patients on long-term oral anticoagulants. Copyright 2003 John Wiley & Sons, Ltd. [source]


Fluence Rate or Cumulative Dose?

PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2007
Vulnerability of Larval Northern Pike (Esox lucius) to Ultraviolet Radiation
Newly hatched larvae of northern pike were exposed in the laboratory to four fluence rates of ultraviolet radiation (UVR; 290,400 nm) over three different time periods, resulting in total doses ranging from 3.0 0.2 to 63.0 4.4 kJm,2. Mortality and behavior of the larvae were followed for 8,12 days, and growth measured at the end of the experiment. Also, the principle of reciprocity,that the UVR-induced mortality depends on the cumulative dose, independent of fluence rate,was tested. Fluence rates higher than 1480 150 mWm,2 caused mortality and growth retardation. The highest fluence rate (3040 210 mWm,2) caused 100% mortality in 5 days. All fluence rates caused behavioral disorders, which led to death at fluence rates higher than 1480 mWm,2. Reciprocity failure occurred with the lowest and highest dose (550 45 and 3040 210 mWm,2, respectively). The results show that fluence rate is of primary importance when assessing the UVR-related risk. [source]


Efficacy of topical PUVA soaks for palmoplantar dermatoses: an audit

PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 6 2008
Donal O'Kane
Background: With a lack of evidence base for individual topical PUVA protocols, treatment is presently based on the consensus of current practice. This audit was designed to investigate the effectiveness of topical PUVA for palmoplantar dermatoses. Methods: Phototherapy notes were reviewed on all patients who received hand and/or foot PUVA 2002,2007 in the Northern Health and Social Care Trust (NHSCT), Northern Ireland. Results: Thirty patients met the inclusion criteria for the study. The mean number of treatments, maximum single UVA dose, and cumulative dose, were 18.4, 4.2 J/cm2, and 48.3 J/cm2, respectively. A positive response to treatment occurred in 51.3% of patients, which fell short of the 70% standard set. In a multivariate logistic regression analysis, number of treatments (P=0.04) and maximum single UVA dose (P=0.03) were the only variables associated with positive treatment outcome. The response was not influenced significantly by skin type, concurrent topical treatments, or cumulative UVA dose. Limitations to the study: Small patient numbers may have prevented the statistical significance of individual variables. Conclusions: UV dose increments should be clearly defined to avoid excess caution at the expense of an adequate patient response, and a minimum of 20 treatments administered to all patients, if tolerated. [source]


Reduction of the UV burden to indoor tanners through new exposure schedules: a pilot study

PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 2 2006
Sharon A. Miller
Background: The development of new pigmentation (tan) in human skin after UV exposure requires several days. Once it is developed, the tan can last for weeks. Current recommendations for tanning exposure schedules in the USA (FDA Letter to Manufacturers: Policy on maximum timer interval and exposure schedule for sunlamps, August 21, 1986) allow exposures three times per week for the development of a tan, and one to two times per week for maintenance exposures. However, this policy is often interpreted in the indoor tanning industry as allowing three exposures per week on a continuous basis. We believe that the reduction of the recommended cumulative dose to indoor tanners should be explored. Two approaches for achieving this are (1) decreasing the number of exposures and (2) increasing the time interval between exposures. To explore such changes, we conducted a pilot study. Methods: The pilot study involved three exposure schedules (evaluated on each of six subjects) that evolved throughout the course of the study. Digital photography, visual assessment and diffuse reflectance spectrometry were used to assess skin color changes. The six pilot subjects were studied for 8,18 weeks. The changes in skin color obtained through the use of the different exposure schedules were compared with changes reported by Caswell (Caswell M, The kinetics of the tanning response to tanning bed exposures, Photodermatol Photoimmunol Photomed 2000: 16: 10,14) who used schedules based on current recommendations. Results: Two out of the three experimental schedules produced tans comparable with those reported by Caswell. In these two schedules, cumulative doses were a factor of 2,3 below doses from current schedules. Conclusion: The UV burden to indoor tanners can be substantially reduced without compromising the cosmetic effect. These results need to be confirmed in a larger study. [source]


Panax ginseng reduces adriamycin-induced heart failure in rats

PHYTOTHERAPY RESEARCH, Issue 12 2005
Jyh-Sheng You
Abstract The purpose of this study was to investigate the protective effects of Panax ginseng on adriamycin-induced heart failure. Wistar rats were divided into four groups: control, adriamycin, ginseng and adriamycin with ginseng. Adriamycin (cumulative dose, 15 mg/kg) was administered to rats in six equal intraperitoneal injections over a period of 2 weeks. Ginseng was administered via an oral feeding tube once a day for 30 days (cumulative dose, 150 g/kg). At the end of the 5 week post-treatment period, the hearts of the rats were used to study the synthesis rates of DNA, RNA and protein, myocardial antioxidants and lipid peroxidation. At the end of 3 weeks treatment, heart failure was characterized by ascites, congested liver and depressed cardiac function. Nucleic acid as well as protein synthesis was inhibited, lipid peroxidation was increased and myocardial glutathione peroxidase activity was decreased indicating adriamycin-induced heart failure. In contrast, the administration of ginseng, before and concurrent with adriamycin, significantly attenuated the myocardial effects, lowered the mortality as well as the amount of ascites, increased in myocardial glutathione peroxidase, macromolecular biosynthesis and superoxide dismutase activities, with a concomitant decrease in lipid peroxidation. These findings indicated that ginseng may be partially protective against adriamycin-induced heart failure. Copyright 2005 John Wiley & Sons, Ltd. [source]


Interstitial pulmonary fibrosis after severe exposure to welding fumes

AMERICAN JOURNAL OF INDUSTRIAL MEDICINE, Issue 4 2002
U. Buerke MD
Abstract Background Interstitial pulmonary fibrosis (IPF) is reported after long term, severe exposure to welding fumes in poorly ventilated workplaces. Methods Fifteen welders with IPF were examined,13 in our outpatient clinic,from 1990 to 1997. Occupational histories and examinations, lung function analyses, symptoms and clinical findings, histological analyses in 13 patients partly including SEM/EDX-analyses, chest X-rays, chest computed tomographies were conducted. Results Duration of work as welders was 28 years and the cumulative dose of welding fumes 221 mg/m3,,years (median). Lung function studies found pattern of restriction or combined restriction-obstruction, lower diffusion capacity, and reduced blood oxygen tension at exercise. Histologicallly, patchy interstitial fibrosis was noted. Accumulations of particulate matter typically for welding fume were detected. EDX showed increase of iron load and close topographical relationship to welding fume particles embedded in areas of scattered fibrosis. Conclusion While epidemiological data are limited, it is reasonable to conclude that a causal relationship exists between IPF in welders with long term exposure to high concentrations of welding fumes. Am. J. Ind. Med. 41:259,268, 2002. 2002 Wiley-Liss, Inc. [source]


Narrow-band ultraviolet B phototherapy in patients with recalcitrant nodular prurigo

THE JOURNAL OF DERMATOLOGY, Issue 10 2007
Risa TAMAGAWA-MINEOKA
ABSTRACT Management of nodular prurigo has been less than satisfactory. Conventional therapies such as systemic antihistamines and topical steroids have not been particularly successful. The effects of narrow-band ultraviolet B (NB-UVB) phototherapy in the treatment of various inflammatory dermatoses have been proven, however, no data exist on the efficacy and the duration of remission in NB-UVB monotherapy for nodular prurigo. The aim of this study was to evaluate the effect of NB-UVB phototherapy on recalcitrant nodular prurigo. NB-UVB phototherapy was performed once a week on 10 patients with recalcitrant nodular prurigo. The initial dose was 0.4 J/cm2, and the dose was increased by 0.1 J/cm2 for each treatment. The treatment was performed until the eruption was almost clear. In each patient, a mean cumulative dose of 23.88 J/cm2 was applied over a mean of 24.3 irradiations. The mean maximum daily dose of ultraviolet B was 1.2 0.4 J/cm2. NB-UVB phototherapy notably improved the eruption of nodular prurigo in all patients. Follow up at 1 year revealed that only one patient had relapsed. The remaining nine patients continued to derive long-term benefits. NB-UVB phototherapy appears to be an effective treatment for recalcitrant nodular prurigo, offering long-term benefits in the majority of those treated. [source]


Investigation of Lymphocyte Depletion and Repopulation Using Alemtuzumab (Campath-1H) in Cynomolgus Monkeys

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
D. J. Van Der Windt
As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20+B cells and CD8+T cells was complete within 2 and 3 months, respectively, and repopulation of CD4+T cells was 67% after 1 year. MMF significantly delayed CD4+T-cell repopulation. Among repopulating CD4+ and CD8+ T cells, a phenotypic shift was observed from CD45RAhiCD62Lhi nave cells toward CD45RAloCD62Llo effector memory cells. In lymph nodes, the depletion of nave cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models. [source]


Diffraction data analysis in the presence of radiation damage

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 4 2010
Dominika Borek
In macromolecular crystallography, the acquisition of a complete set of diffraction intensities typically involves a high cumulative dose of X-ray radiation. In the process of data acquisition, the irradiated crystal lattice undergoes a broad range of chemical and physical changes. These result in the gradual decay of diffraction intensities, accompanied by changes in the macroscopic organization of crystal lattice order and by localized changes in electron density that, owing to complex radiation chemistry, are specific for a particular macromolecule. The decay of diffraction intensities is a well defined physical process that is fully correctable during scaling and merging analysis and therefore, while limiting the amount of diffraction, it has no other impact on phasing procedures. Specific chemical changes, which are variable even between different crystal forms of the same macromolecule, are more difficult to predict, describe and correct in data. Appearing during the process of data collection, they result in gradual changes in structure factors and therefore have profound consequences in phasing procedures. Examples of various combinations of radiation-induced changes are presented and various considerations pertinent to the determination of the best strategies for handling diffraction data analysis in representative situations are discussed. [source]