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Lower Doses (lower + dose)
Selected AbstractsCombining etanercept with traditional agents in the treatment of psoriasis: a review of the clinical evidenceJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 10 2010PA Foley Abstract Psoriasis is a chronic, systemic inflammatory disorder manifesting primarily in skin and potentially in joints, frequently necessitating treatment with conventional systemic therapies, phototherapy or biological agents. Patients with moderate to severe disease suffer a diminished quality of life, experience significant comorbidities and have a higher mortality. Although traditional treatments are effective in the short-term, their use is often limited by concerns over long-term toxicity, including end-organ damage and risk of malignancy. Combination therapy is a commonly used approach and is often more effective than any single agent. Lower doses of two treatments in combination can also minimize potential side effects from a single agent at higher doses. Etanercept is a recombinant human tumour necrosis factor (TNF), receptor (p75) protein fused with the Fc portion of IgG1 that binds to TNF,. This article reviews the evidence on the efficacy and safety of etanercept in combination with methotrexate, acitretin, narrowband UVB and cyclosporin. The largest body of evidence assesses the combination with methotrexate, although evidence is available for the other combinations. Data suggest that although highly effective as monotherapy, etanercept in combination with a conventional systemic agent can enhance efficacy and allow drug sparing. Potentially, the combination may also result in faster treatment responses and permit safe transitioning from one systemic agent to another. Evidence to date suggests that these benefits can be achieved without significant additional toxicity, although long-term data on the efficacy and safety of the combination in psoriatic populations is limited and further evaluation is warranted. [source] Randomized trial comparing primidone initiation schedules for treating essential tremorMOVEMENT DISORDERS, Issue 2 2002Padraig O'Suilleabhain MB Abstract Early side effects are common when primidone is used to treat essential tremor, with as many as one-third of patients failing to tolerate the tablets. Lower doses can be prescribed initially using a suspension formulation. We suspected suspension initiation would result in fewer early side effects, allow better acclimatization, and improve compliance. Forty patients with essential tremor were randomized to begin primidone treatment using either 2.5 mg doses in the suspension form or 25 mg doses in the tablet form. Doses gradually increased over 3 weeks to 150 mg/day. This was a double-blind, double-dummy trial. Medication cessation due to side effects was designated the primary end-point. Four patients in the suspension group and two in the tablet group dropped out due to early side effects, resulting in a relative risk of 1.9 (95% confidence interval 0.4 to 9.2). Side effects in the first 48 hours of treatment were equally common, affecting seven subjects in each group. Treatment benefits were the same in both groups. We concluded that use of a very low initial dose and a graduated titration schedule in suspension formulation did not appear to improve primidone tolerability. If anything, compliance tended to be worse when compared with the tablet formulation, though the study was under-powered to reject the null hypothesis of equivalence. © 2002 Movement Disorder Society. [source] Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intoleranceCANCER, Issue 11 2010Hagop Kantarjian MD Abstract BACKGROUND: INNO-406, a dual v-abl Abelson murine leukemia viral oncogene homolog (Abl)/v-yes-1 Yamaguchi sarcoma viral-related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including mutations that involve a phenylalanine-to-leucine or phenylalanine-to-valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO-406 in patients with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance. METHODS: A dose-escalation study was conducted at a starting dose of oral INNO-406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months. RESULTS: INNO-406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine-to-histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine-to-glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine-to-isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO-406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph-positive ALL. The dose-limiting toxicities (DLTs) at an INNO-406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia. CONCLUSIONS: INNO-406 had anti-CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO-406 was 240 mg twice daily. Lower doses of INNO-406 may be equally effective and should be explored. Cancer 2010. © 2010 American Cancer Society. [source] Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male ratsDEVELOPMENTAL NEUROBIOLOGY, Issue 10 2007Mark D. Spritzer Abstract Past research suggested that androgens may play a role in the regulation of adult neurogenesis within the dentate gyrus. We tested this hypothesis by manipulating androgen levels in male rats. Castrated or sham castrated male rats were injected with 5-Bromo-2,deoxyuridine (BrdU). BrdU-labeled cells in the dentate gryus were visualized and phenotyped (neural or glial) using immunohistochemistry. Castrated males showed a significant decrease in 30-day cell survival within the dentate gyrus but there was no significant change in cell proliferation relative to control males, indicating that androgens positively affect cell survival, but not cell proliferation. To examine the role of testosterone on hippocampal cell survival, males were injected with testosterone s.c. for 30 days starting the day after BrdU injection. Higher doses (0.5 and 1.0 mg/kg) but not a lower dose (0.25 mg/kg) of testosterone resulted in a significant increase in neurogenesis relative to controls. We next tested the role of testosterone's two major metabolites, dihydrotestosterone (DHT), and estradiol, upon neurogenesis. Thirty days of injections of DHT (0.25 and 0.50 mg/kg) but not estradiol (0.010 and 0.020 mg/kg) resulted in a significant increase in hippocampal neurogenesis. These results suggest that testosterone enhances hippocampal neurogenesis via increased cell survival in the dentate gyrus through an androgen-dependent mechanism. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007. [source] Neonatal alcohol exposure impairs acquisition of eyeblink conditioned responses during discrimination learning and reversal in weanling ratsDEVELOPMENTAL PSYCHOBIOLOGY, Issue 3 2007Kevin L. Brown Abstract Discrimination and reversal of the classically conditioned eyeblink response depends on cerebellar,brainstem interactions with the hippocampus. Neonatal "binge" exposure to alcohol at doses of 5 g/kg/day or more has been shown to impair single-cue eyeblink conditioning in both weanling and adult rats. The present study exposed neonatal rats to acute alcohol intubations across different developmental periods (postnatal day [PND] 4-9 or PND7-9) and tested them from PND26-31 on discriminative classical eyeblink conditioning and reversal. A high dose of alcohol (5 g/kg/day) dramatically impaired conditioning relative to controls when exposure occurred over PND4-9, but produced mild or no impairments when delivered over PND7-9. These findings support previous claims that developmental exposure period plays a critical role in determining the deleterious effects of alcohol on the developing brain. A lower dose of alcohol (4 g/kg/day) delivered from PND4-9,lower than has previously been shown to affect single-cue eyeblink conditioning,also produced deficits on the discrimination task, suggesting that discrimination learning and acquisition of responding to CS+ during reversal may be especially sensitive behavioral indicators of alcohol-induced brain damage in this rat model. © 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 243,257, 2007. [source] The effects of dexamethasone and prednisolone on pituitary and ovarian function in the mareEQUINE VETERINARY JOURNAL, Issue 5 2010R. A. FERRIS Summary Reasons for performing study: Persistent mating induced endometritis is among the most common causes of infertility in the mare. Recently, improved pregnancy rates have been reported when corticosteroids were administered to ,problem mares' specifically, to modulate the post mating inflammatory response; however, the effect of treatment on pituitary and ovarian function requires further study. Objectives: To evaluate the effects of prolonged treatment with glucocorticoids on pituitary and ovarian function. Methods: Eighteen cycling Quarter Horse mares in early oestrus were assigned randomly to one of 3 treatment groups: dexamethasone 0.05 mg/kg bwt i.v. twice a day, prednisolone 0.5 mg/kg per os twice a day, or placebo for 5 days. Mares were examined by ultrasound daily to evaluate reproductive function. Blood samples were collected daily to measure luteinising hormone (LH), progesterone and cortisol levels. Results: Dexamethasone treatment caused greater (P<0.05) suppression of endogenous cortisol concentration (9.4 ± 1.1 ng/ml) compared to prednisolone- (41.9 ± 4.0 ng/ml) or placebo-treated mares (32.4 ± 3.8 ng/ml). After 24 h, mares treated with dexamethasone exhibited lower uterine oedema scores than prednisolone- or placebo-treated mares. An ovulation rate of 40% was observed in dexamethasone-treated mares (2/5) compared to 83% for prednisolone (5/6) and 100% for placebo-treated (6/6) mares. An absence of a LH surge was noted in 3 of 5 dexamethasone-treated mares and one of 6 prednisolone-treated mares. Conclusions: Repeated administration of dexamethasone to mares in oestrus is associated with decreased uterine oedema, suppression of LH and a high rate of ovulation failure. It is recommended that dexamethasone treatment is limited to only 1 or 2 days and that a lower dose is considered in the management of persistent mating induced endometritis to avoid potential adverse affects on reproductive function. [source] Cyclosporin A can achieve immune tolerance in a patient with severe haemophilia B and refractory inhibitorsHAEMOPHILIA, Issue 1 2007D. C. A. CROSS Summary., Immune tolerance induction (ITI) is described in a patient with severe haemophilia B complicated by the presence of an inhibitor. A number of ITI regimes were attempted without success and the patient suffered from frequent relapses and bleeding episodes. Successful ITI was achieved with the additional use of cyclosporin A. The patient developed nephrotic syndrome although had a negative Bethesda titre at this time. When cyclosporin A therapy was ceased, the inhibitor titre rose and the patient suffered again from bleeding episodes. Cyclosporin A was reintroduced at a lower dose. The patient has now received cyclosporin A for 10 years, during which time he has relapsed three times for short periods (2 weeks). He is also on prophylaxis with factor IX three times a week with preinfusion levels >1% and without bleeding. [source] Interactions between N,acetylcysteine and sodium selenite in modulating the clastogenicity of urethane and 2,acetylaminofluorene in miceINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Roumen M. Balansky Abstract Combined treatment with different agents represents a promising approach in cancer chemoprevention. Therefore, it is useful to assess in preclinical models the efficacy of combinations that are selected by taking into account mechanistic considerations. We designed 2 studies evaluating the interaction between N,acetylcysteine (NAC) and sodium selenite (Se), both given with the drinking water to Balb/c mice, in modulating clastogenic effects in bone marrow polychromatic erythrocytes. In a first study, a single i.p. injection of urethane considerably enhanced the frequency of micronucleated cells. While NAC produced a significant inhibition, Se further enhanced urethane clastogenicity. When given in combination at the same doses, NAC prevented the adverse effect of Se. In a second study, a single i.p. injection of 2,acetylaminofluorene enhanced the frequency of micronucleated cells. Se did not reduce this effect to a significant extent, while NAC produced a dose,dependent inhibition. When tested at the lower dose in combination with Se, the protective effect of NAC was unchanged. Especially in association with Se, NAC also prevented the toxicity of 2,acetylaminofluorene by normalizing the ratio of polychromatic to normochromatic erythrocytes. In conclusion, NAC attenuated the clastogenicity of both urethane and 2,acetylaminofluorene and the toxicity of this aromatic amine. In addition, NAC prevented the clastogenic and toxic effects resulting from the interaction of Se with urethane. Together with the findings of previous studies, it appears that, besides its intrinsic protective properties in carcinogenesis, NAC is capable of attenuating the adverse effects of several cytotoxic drugs and chemopreventive agents. © 2003 Wiley-Liss, Inc. [source] Grazing incidence small-angle X-ray scattering studies of the synthesis and growth of CdS quantum dots from constituent atoms in SiO2 matrixJOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3-1 2003U.V. Desnica Grazing incidence small angle X-ray scattering was applied to study the synthesis and growth of CdS quantum dots (QDs) from Cd and S atoms implanted in SiO2. For a dose of 1017/cm2, the partial synthesis of CdS QDs occurred already during implantation, with only moderate size increase upon subsequent annealing up to Ta=1073 K. The dynamics of QD synthesis and growth were considerably different for just two times lower dose, where synthesis started only if the implanted samples were annealed at Ta = 773 K or higher, with a strong increase of the size of QDs upon annealing at higher Ta. The results suggest that high-dose implantation followed by low-temperature annealing could lead to better defined sizes and narrower size distributions of QDs. [source] Dichloroacetate- and trichloroacetate-induced oxidative stress in the hepatic tissues of mice after long-term exposureJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2010Ezdihar A. Hassoun Abstract Dichoroacetate (DCA) and trichloroacetate (TCA) were found to be hepatotoxic and hepatocarcinogenic in rodents. To investigate the role of oxidative stress in the long-term hepatotoxicity of the compounds, groups of mice were administered 7.7, 77, 154 and 410,mg,kg,1 per day, of either DCA or TCA, by gavage, for 4 weeks (4-W) and 13 weeks (13-W), and superoxide anion (SA), lipid peroxidation (LP) and DNA-single strand breaks (SSBs) were determined in the hepatic tissues. Significant increases in all of the biomarkers were observed in response to the tested doses of both compounds in the two test periods, with significantly greater increases observed in the 13-W, as compared with the 4-W, period. Hepatomegaly was only observed with a DCA dose of 410,mg,kg,1 per day in the 13-W treatment period, and that was associated with significant declines in the biomarkers, when compared with the immediately lower dose. With the exception of LP production in the 13-W treatment period that was similarly induced by the two compounds, the DCA-induced increases in all of the biomarkers were significantly greater than those of TCA. Since those biomarkers were significantly induced by the compounds' doses that were shown to be carcinogenic but at earlier periods than those demonstrating hepatotoxicity/haptocarcinogencity, they can be considered as initial events that may lead to later production of those long-term effects. The results also suggest LP to be a more significant contributing mechanism than SA and DNA damage to the long-term hepatotoxicity of TCA. Copyright © 2010 John Wiley & Sons, Ltd. [source] Protection against acetaminophen hepatotoxicity by clofibrate pretreatment: Role of catalase induction,JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 5 2002Chuan Chen Abstract Mice pretreated with the peroxisome proliferator clofibrate (CFB) are highly resistant to acetaminophen (APAP)-induced hepatotoxicity. The objective of the present study was to investigate whether the increase in hepatic catalase activity following CFB pretreatment plays a role in this hepatoprotection. An irreversible inhibitor, 3-amino-1,2,4-triazole (3-AT), was used to modulate catalase activity. Hepatic catalase activity in mice pretreated with CFB (500 mg/kg, i.p., for 10 days) was significantly inhibited by 3-AT (100 or 500 mg/kg, i.p.). In addition, the lower dose of 3-AT (100 mg/kg) had minimal effect on biliary and urinary excretion of APAP metabolites generated from a nontoxic dose, suggesting that APAP metabolism was not modulated by this dose of 3-AT. The mortality rate of corn-oil-pretreated mice challenged with APAP (800 mg/kg, p.o.) was significantly increased by 3-AT (100 mg/kg, i.p.) given 1 h before APAP. As expected, CFB pretreatment conferred full protection against APAP-induced hepatotoxicity. The same 3-AT treatment, however, did not abolish hepatoprotection in CFB-pretreated mice, despite the marked inhibition of hepatic catalase activity. In conclusion, these results indicate that elevated catalase activity in mice exposed to CFB does not appear to mediate the hepatoprotection, suggesting that other cellular defense mechanisms are involved. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:227,234, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10043 [source] A comparison of 60, 70, and 90 kDa stress protein expression in normal rat NRK-52 and human HK-2 kidney cell lines following in vitro exposure to arsenite and cadmium alone or in combinationJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 1 2002Emily F. Madden Abstract Arsenite and cadmium are two potent nephrotoxicants and common Superfund site elements. These elements are included among the stress protein inducers, but information regarding relationships between toxicity produced by combinations of these agents to the stress protein response is lacking. In this study, the immortalized cell lines normal rat kidney NRK-52E and human kidney HK-2 were exposed in vitro to arsenite (As3+), cadmium (Cd2+), or to equimolar As3+ plus Cd2+ mixture combinations for 3 and 5 h over a concentration range of 0.1,100 ,M. After a 12-h recovery period, cultured cells were then evaluated for expression of the 60, 70, and 90 kDa major stress protein families. Results indicated that expression of stress proteins varied depending on the species of kidney cells exposed, the exposure concentrations, and the length of exposure to each element on an individual basis and for combined mixtures. For the HK-2 kidney cell line, increased levels of the 70 kDa stress protein was observed for single and combined element exposures whereas there was no change or a decrease of stress proteins 60 and 90 kDa. Increased 70 kDa expression was observed for 10-,M doses of single elements and for a lower dose of 1 ,M of the As plus Cd mixture at 3- and 5-h exposures. NRK-52 kidney cells exposed to equivalent doses of As3+ and Cd2+ alone or in combination showed increased levels of all stress proteins 60, 70, and 90 kDa. This increase was seen for 10 ,M of the As plus Cd mixture at 3 h whereas for single element exposures, increased stress protein levels were generally observed for the 100-,M doses. At 5 h- exposure, 60 and 90 kDa levels increased for 10 ,M of Cd2+ and 60 kDa levels increased for 1 ,M of As3+. However, exposures to 10 ,M of the As plus Cd mixture decreased 60 kDa protein expression to control levels at 5 h. For both kidney cell lines, there was a decrease in the stress protein expression levels for all three stress protein families for 100-,M doses of the mixture combination for 3- and 5-h exposures. These data indicate a dose- and combination-related correlation between depression of the stress protein response and the onset of overt cellular toxicity and/or cell death. The threshold for these changes was cell line specific. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:24,32, 2002; DOI 10.1002/jbt.10015 [source] Assessing the accuracy of a computerized decision support system for digoxin dosing in primary care: an observational studyJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005W. L. G. Kroese Drs Summary Background:, This study was carried out as part of a European Union funded project (PharmDIS-e+), to develop and evaluate software aimed at assisting physicians with drug dosing. A drug that causes particular problems with drug dosing in primary care is digoxin because of its narrow therapeutic range and low therapeutic index. Objectives:, To determine (i) accuracy of the PharmDIS-e+ software for predicting serum digoxin levels in patients who are taking this drug regularly; (ii) whether there are statistically significant differences between predicted digoxin levels and those measured by a laboratory and (iii) whether there are differences between doses prescribed by general practitioners and those suggested by the program. Methods:, We needed 45 patients to have 95% Power to reject the null hypothesis that the mean serum digoxin concentration was within 10% of the mean predicted digoxin concentration. Patients were recruited from two general practices and had been taking digoxin for at least 4 months. Exclusion criteria were dementia, low adherence to digoxin and use of other medications known to interact to a clinically important extent with digoxin. Results:, Forty-five patients were recruited. There was a correlation of 0·65 between measured and predicted digoxin concentrations (P < 0·001). The mean difference was 0·12 ,g/L (SD 0·26; 95% CI 0·04, 0·19, P = 0·005). Forty-seven per cent of the patients were prescribed the same dose as recommended by the software, 44% were prescribed a higher dose and 9% a lower dose than recommended. Conclusion:, PharmDIS-e+ software was able to predict serum digoxin levels with acceptable accuracy in most patients. [source] Differential sensitivity to the effects of nicotine and bupropion in adolescent and adult male OF1 mice during social interaction testsAGGRESSIVE BEHAVIOR, Issue 4 2008M.C. Gómez Abstract Few studies have compared the action of both nicotine (NIC) and bupropion (BUP), an antidepressant used to treat NIC dependence, on social and aggressive behavior at different ages. This study aims to determine whether these drugs produce differential effects in adolescent (postnatal day: 36,37) and adult (postnatal day: 65,66) mice that have been housed individually for 2 weeks in order to induce aggressive behavior. Mice received BUP (40, 20, or 10,mg/kg), NIC (1, 0.5, and 0.25,mg/kg as base), or vehicle earlier to a social interaction test. BUP (40,mg/kg) decreased social investigation and increased nonsocial exploration in both adolescent and adult mice. The same effects were also observed in adult mice administered with a lower dose of the same drug (20,mg/kg). In adolescents, NIC (1,mg/kg) decreased social investigation, but this effect did not reach statistical significance in adults. In conclusion, a differential sensitivity to the effects of NIC or BUP emerged in some of the behavioral categories when the two age groups were compared. Aggr. Behav. 34:369,379, 2008. © 2008 Wiley-Liss, Inc. [source] Experimental Cryptobia salmositica (Kinetoplastida) infections in Atlantic salmon, Salmo salar L.: cell-mediated and humoral immune responses against the pathogenic and vaccine strains of the parasiteJOURNAL OF FISH DISEASES, Issue 5 2002B F Ardelli Hatchery-reared Atlantic salmon, Salmo salar L., were vaccinated intraperitoneally (i.p.) with a live attenuated Cryptobia salmositica vaccine (either 100 000 or 5000 parasites fish,1) and 4 weeks later were challenged with the parasite (either 100 000 or 5000 parasites fish,1). Unvaccinated, infected salmon had high parasitaemias and were anaemic. Fish given a high dose (100 000 parasites fish,1) had higher parasitaemias than fish given the lower dose. Vaccinated fish had low parasitaemias and a mild anaemia, but recovered quickly after challenge. Complement-fixing antibody increased in vaccinated fish after challenge and was highest at 2 weeks post-challenge. The cell-mediated response (both T cells and B cells) was depressed in infected fish until 4 weeks after infection. In vaccinated fish, the humoral response (i.e. B-lymphocytes) was greater than the cell-mediated response (i.e. T-lymphocytes). In contrast, infected fish had a greater cell-mediated than humoral immune response. [source] Body Mass Index and Effectiveness of Reperfusion Strategies: Implications for the Management of Patients with ST-Elevation Myocardial InfarctionJOURNAL OF INTERVENTIONAL CARDIOLOGY, Issue 1 2008M.S., RAJENDRA H. MEHTA M.D. Background:Fibrinolytic therapy has maximum dose limit in patients with ST-elevation myocardial infarction (STEMI). Consequently, obese patients receive lower dose of fibrinolytic per kg body weight compared to lower weight patients. Whether the relatively lower dose results in lower effectiveness of fibrinolytic agents versus primary percutaneous coronary interventions (PCI) in patients with higher body mass index (BMI) is not known. Methods:We analyzed 7,630 STEMI patients receiving primary PCI (46%) or fibrinolysis (54%) <24 hours of symptom onset from the MITRA PLUS registry. The relative effectiveness of the 2 reperfusion strategies on in-hospital death (adjusted with propensity scores) and bleeding were studied in 3 BMI groups: I-BMI 20,24.9 kg/m2 (n = 2,277), II-BMI 25,29.9 kg/m2 (n = 3,763), and III-BMI ,30 kg/m2 (n = 1,590). Results:BMI was inversely related to death, shock, stroke, and bleeding in patients treated with either reperfusion strategy. However, compared with primary PCI, fibrinolysis was associated with higher adjusted death with similar relative adjusted difference in all 3 groups (group I OR 1.69, 95% CI 1.19,2.44; group II OR 1.89, 95% CI 1.39,2.56; group III OR 1.85, 95% CI 1.08,3.22). Conclusions:Compared with primary PCI, fibrinolysis was associated with relatively similar higher risk of death in all 3 BMI groups. Whether the differences in death between fibrinolysis and primary PCI in the high-BMI categories can be reduced by higher fibrinolytic doses without increasing bleeding risks needs evaluation in future studies. [source] Thyroid Hormone Acts Centrally to Programme Photostimulated Male American Tree Sparrows (Spizella arborea) for Vernal and Autumnal Components of Seasonality1JOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2000Wilson Thyroid hormone and long days interact to programme American tree sparrows (Spizella arborea) for seasonality (i.e. thyroid hormone-dependent photoperiodic gonadal growth, photorefractoriness, and postnuptial moult). This study explored in radiothyroidectomized (THX) males given thyroid hormone replacement therapy whether thyroid hormone acts within the brain and, additionally, the identity of the putative tissue-active thyroid hormone. The minimum dose (30 ng) of l -thyroxine (T4) that restored all components of seasonality when given i.c.v. daily during the first 21 days of photostimulation restored no component of seasonality when given s.c. The same dose of l -triiodothyronine (T3) also was ineffective when administered s.c., but restored photoperiodic testicular growth (though neither photorefractoriness nor postnuptial moult) when admiministered i.c.v. Three of seven birds given a 10-fold lower dose of T4 (3 ng) exhibited thyroid hormone-dependent photoperiodic testicular growth, albeit damped. The other four birds given 3 ng T4 and all birds given 3 ng T3 responded like THX controls, exhibiting only slight thyroid hormone-independent photoperiodic testicular growth. The highest dose (300 ng) of T3 restored all components of seasonality only when administered i.c.v. daily during the first 49 days of photostimulation. This demonstration in American tree sparrows is the first in any species that the thyroid-dependent transition from the breeding season to the non-breeding season can be effected by T3. The same dose of reverse T3 administered daily over the same 49 days restored photoperiodic testicular growth in only half of 10 subjects and photorefractoriness and moult in none. Collectively, the data support the hypothesis that thyroid hormone acts centrally to programme photostimulated male American tree sparrows for all components of seasonality. The most parsimonious interpretation of the data, including the threshold-like effect of 3 ng T4, favours T4 as the tissue-active thyroid hormone for vernal as well as autumnal events, but does not entirely exclude T3. [source] Differential Effects of Acute and Chronic Ethanol Exposure on Orexin Expression in the Perifornical Lateral HypothalamusALCOHOLISM, Issue 5 2010Irene Morganstern Background:, Recent reports support the involvement of hypothalamic orexigenic peptides in stimulating ethanol intake. Our previous studies have examined the effects of ethanol on hypothalamic peptide systems of the paraventricular nucleus (PVN) and identified a positive feedback loop in which PVN peptides, such as enkephalin and galanin, stimulate ethanol intake and ethanol, in turn, stimulates the expression of these peptides. Recently, orexin (OX), a peptide produced mainly by cells in the perifornical lateral hypothalamus (PFLH), has been shown to play an important role in mediating the rewarding aspects of ethanol intake. However, there is little evidence showing the effects that ethanol itself may have on the OX peptide system. In order to understand the feedback relationship between ethanol and the OX system, the current investigation was designed to measure OX gene expression in the PFLH following acute as well as chronic ethanol intake. Methods:, In the first experiment, Sprague,Dawley rats were trained to voluntarily consume a 2 or 9% concentration of ethanol, and the expression of OX mRNA in the PFLH was measured using quantitative real-time polymerase chain reaction (qRT-PCR). The second set of experiments tested the impact of acute oral gavage of 0.75 and 2.5 g/kg ethanol solution on OX expression in the PFLH using qRT-PCR, as well as radiolabeled in situ hybridization. Further tests using digoxigenin-labeled in situ hybridization and immunofluorescence histochemistry allowed us to more clearly distinguish the effects of acute ethanol on OX cells in the lateral hypothalamic (LH) versus perifornical (PF) regions. Results:, The results showed chronic consumption of ethanol versus water to dose-dependently reduce OX mRNA in the PFLH, with a larger effect observed in rats consuming 2.5 g/kg/d (,70%) or 1.0 g/kg/d (,50%) compared to animals consuming 0.75 g/kg/d (,40%). In contrast to chronic intake, acute oral ethanol compared to water significantly enhanced OX expression in the PFLH, and this effect occurred at the lower (0.75 g/kg) but not higher (2.5 g/kg) dose of ethanol. Additional analyses of the OX cells in the LH versus PF regions identified the former as the primary site of ethanol's stimulatory effect on the OX system. In the LH but not the PF, acute ethanol increased the density of OX-expressing and OX-immunoreactive neurons. The increase in gene expression was detected only at the lower dose of ethanol (0.75 g/kg), whereas the increase in OX peptide was seen only at the higher dose of ethanol (2.5 g/kg). Conclusion:, These results lead us to propose that OX neurons, while responsive to negative feedback signals from chronic ethanol consumption, are stimulated by acute ethanol administration, most potently in the LH where OX may trigger central reward mechanisms that promote further ethanol consumption. [source] Projected Alcohol Dose Influences on the Activation of Alcohol Expectancies in College DrinkersALCOHOLISM, Issue 7 2009Jennifer P. Read Background:, Alcohol expectancies have been linked to drinking behavior in college students, and vary according to a number of factors, including projected dose of alcohol. Research using Multidimensional Scaling (MDS) suggests that drinking may be influenced by activation of differing expectancy dimensions in memory, yet studies have not examined expectancy activation according to projected alcohol doses. Methods:, The present study used Individual Differences Scaling (INDSCAL) to map expectancy networks of college students (n = 334) who imagined varied drinking at high and low alcohol doses. Expectancy activation was modeled by dose, as well as by gender and by drinking patterns (typical quantity, blood alcohol content, heavy episodic drinking, and alcohol consequences). Expectancies were organized along positive,negative and arousal,sedation dimensions. Anticipation of a high dose of alcohol was associated with greater emphasis on the arousal,sedation dimension, whereas anticipation of a lower dose was associated with greater emphasis on the positive,negative dimension. Results:, Across heavy, medium, and light drinkers, expectancy dimensions were most distinguishable at higher doses; activation patterns were more similar across drinking groups at lighter doses. Modest evidence for the influence of gender on activation patterns was observed. Findings were consistent across alcohol involvement indices. Conclusions:, These data suggest that both dimensionality and context should be considered in the refinement of interventions designed to alter expectancies in order to decrease hazardous drinking. [source] Cortisol response to two different doses of intravenous synthetic ACTH (tetracosactrin) in overweight catsJOURNAL OF SMALL ANIMAL PRACTICE, Issue 12 2000J. P. Schoeman Fifteen middle-aged to older, overweight cats attending a first-opinion clinic were investigated to rule out hyperadrenocorticism as a cause of their weight problem, using two different protocols for the adrenocortlcotropic hormone (ACTH) stimulation test. The cats received intravenous synthetic ACTH (tetracosactrin) at an initial dose of 125 ,g; a second test was performed between two and three weeks later, using a dose of 250 vg intravenously. The mean basal serum cortisol concentration was 203 nmol/litre (range 81 to 354 nmol/litre). The highest mean serum cortisol concentration occurred at 60 minutes following the 125 ,g dose and at 120 minutes following the 250 ,g dose. There was, however, no statistically significant difference between these peak cortisol concentrations attained using either dose of tetracosactrin. A significantly higher mean serum cortisol concentration was attained after the higher dose at the 180 minutes time point, indicating a more prolonged response when compared with the lower dose. The cats were followed up for one year after the initial investigations and none were found to develop hyperadrenocorticism during this time. [source] A hierarchical modelling approach to analysing longitudinal data with drop-out and non-compliance, with application to an equivalence trial in paediatric acquired immune deficiency syndromeJOURNAL OF THE ROYAL STATISTICAL SOCIETY: SERIES C (APPLIED STATISTICS), Issue 1 2002Joseph W Hogan Longitudinal clinical trials with long follow-up periods almost invariably suffer from a loss to follow-up and non-compliance with the assigned therapy. An example is protocol 128 of the AIDS Clinical Trials Group, a 5-year equivalency trial comparing reduced dose zidovudine with the standard dose for treatment of paediatric acquired immune deficiency syndrome patients. This study compared responses to treatment by using both clinical and cognitive outcomes. The cognitive outcomes are of particular interest because the effects of human immunodeficiency virus infection of the central nervous system can be more acute in children than in adults. We formulate and apply a Bayesian hierarchical model to estimate both the intent-to-treat effect and the average causal effect of reducing the prescribed dose of zidovudine by 50%. The intent-to-treat effect quantifies the causal effect of assigning the lower dose, whereas the average causal effect represents the causal effect of actually taking the lower dose. We adopt a potential outcomes framework where, for each individual, we assume the existence of a different potential outcomes process at each level of time spent on treatment. The joint distribution of the potential outcomes and the time spent on assigned treatment is formulated using a hierarchical model: the potential outcomes distribution is given at the first level, and dependence between the outcomes and time on treatment is specified at the second level by linking the time on treatment to subject-specific effects that characterize the potential outcomes processes. Several distributional and structural assumptions are used to identify the model from observed data, and these are described in detail. A detailed analysis of AIDS Clinical Trials Group protocol 128 is given; inference about both the intent-to-treat effect and average causal effect indicate a high probability of dose equivalence with respect to cognitive functioning. [source] Consumption of raw brown onions variably modulate plasma lipid profile and lipoprotein oxidation in pigs fed a high-fat dietJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 1 2005Nicholas K Gabler Abstract This study was undertaken to determine the effects of two commercially available brown onion varieties, ,Cavalier' and ,Destiny', supplemented at two different levels, on blood lipid and oxidative status using the pig as a model. Twenty-five female cross-bred pigs were allocated to one of five dietary treatments that consisted of a high-fat control diet with no onion added, a low onion dose of 10 g onion MJ,1 DE and a high dose of 25 g onion MJ,1 DE for each variety of onion. Supplementation with ,Destiny' onion resulted in a 21% (p < 0.05) reduction in the averaged fasted and postprandial plasma triacylglyceride (TG) measurements taken over the six-week period in comparison with the control pigs. The average fasting and postprandial plasma cholesterol concentrations were significantly reduced by 5.5 and 12.4% in pigs that consumed the low and high dose of ,Destiny' onion, respectively (p < 0.010), while ,Cavalier' was only effective at lowering cholesterol levels by 10% at the lower dose of supplementation. Inhibition in the rate of serum lipoprotein oxidation, measured as lag time, was increased by 23% (p < 0.05) in plasma obtained from pigs that consumed ,Cavalier' compared with the control and ,Destiny' onion diets. These data indicate that onion consumption level may provide a dietary means of manipulating some of the risk indices associated with coronary heart disease, but the responses varied with type and dose of onion. Copyright © 2004 Society of Chemical Industry [source] Comparison of 2 Doses of Recombinant Human Thyrotropin for Thyroid Function Testing in Healthy and Suspected Hypothyroid DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2009F.S. Boretti Background: Various protocols using different doses of recombinant human thyrotropin (rhTSH) in TSH stimulation testing have been described. However, the influence of TSH dosage on thyroxine (T4) concentration has not yet been evaluated in suspected hypothyroid dogs. Objective: To evaluate the effectiveness of 2 doses of rhTSH. Animals: Fifteen dogs with clinical signs consistent with hypothyroidism and abnormal stimulation results with 75 ,g rhTSH and 18 clinically healthy dogs. Methods: All dogs were stimulated with 75 and 150 ,g rhTSH IV in a 1st and 2nd stimulation test, respectively. Blood samples were taken before and 6 hours after rhTSH administration for determination of total T4 concentration. Results: Using the higher dose led to a normal test interpretation in 9 of the 15 dogs, in which stimulation had been abnormal using the lower dose. Based on follow-up information, hypothyroidism was excluded in 7 of these 9 dogs. In all 6 dogs with a blunted response to the higher dose, hypothyroidism could be confirmed. Healthy dogs showed significantly higher post-TSH T4 concentrations with the higher compared with the lower dose. Post-TSH T4 concentrations after TSH stimulation were not related to dogs' body weight in either healthy or diseased dogs. Conclusions and Clinical Relevance: TSH dose significantly influenced test interpretation in suspected hypothyroid dogs. Differentiation between primary hypothyroidism and nonthyroidal disease was improved with 150 ,g rhTSH. Because this effect was independent of the dogs' body weight, the higher dose is recommended in dogs that have concurrent disease or are receiving medication. [source] Treatment of Immune-Mediated Hemolytic Anemia in Dogs with CyclophosphamideJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2000Kristine Burgess A review of 60 cases of immune-mediated hemolytic anemia (IMHA) in the dog was performed in order to characterize the disease and to identify potential prognostic indicators. Dogs ranged in age from 1 to 13 years, with a mean age of 6.5 years. The 2 most commonly affected breeds were Cocker Spaniels and Labrador Retrievers. Fifty-two of the 60 dogs tested (87%) were autoagglu-tination positive and spherocytes were present in 45 (75%). Forty-one (89%) of 46 patients tested positive for the presence of immunoglobulin on the red blood cell surface (Coombs assay). The most common clinical signs at presentation were lethargy, weakness, pale mucous membranes, icterus, hemoglobinuria, and anorexia. PCV less than 25% was present in 59 (98%) dogs. At the time of presentation, 35 dogs (58%) had a nonregenerative anemia, whereas 25 patients (42%) had a regenerative response. Thrombocytopenia was seen in 41 (68%) dogs. Nine of 34 dogs (26%) had a prolonged prothrombin time, 19 of 34 (56%) had a prolonged activated partial thromboplastin clotting time, and 12 of 34 (35%) had abnormal fibrinogen concentrations. All dogs received prednisone at immunosuppressive doses (2.2,4.4 mg/kg PO as a single or divided dose every 24 hours) and cyclophosphamide as primary therapy. Forty-one dogs (63%) received cyclophosphamide at 50 mg/m2 q24h for 4 days, whereas 9 dogs (15%) received an initial high dose (200 mg/m2) followed by 3 days of a lower dose (50 mg/m2 q24h). No statistical difference in survival times was found for either protocol. Thirteen dogs were treated with azathioprine in addition to cyclophosphamide and prednisone. The median survival time of dogs that received all 3 drugs was 370 days as compared to 9 days for those dogs that were treated with cyclophosphamide and prednisone alone. Thirty-one (52%) dogs died from the disease, 13 (22%) dogs were alive, and 15 (25%) dogs were lost to follow-up. The median length of survival for all dogs was 21 days. Eight dogs that were discharged from the hospital suffered a relapse (PCV < 25%). [source] Comparative pharmacokinetics of amikacin in Greyhound and Beagle dogsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008B. KUKANICH The purpose of the study was to compare the pharmacokinetics of amikacin administered i.v., to Greyhound and Beagle dogs and determine amikacin pharmacokinetics administered subcutaneously to Greyhounds. Amikacin was administered i.v. at 10 mg/kg to six healthy Greyhounds and six healthy Beagles. The Greyhounds also received amikacin, 10 mg/kg s.c. Plasma was sampled at predetermined time points and amikacin concentrations determined by a fluorescence polarization immunoassay (FPIA). The volume of distribution was significantly smaller in Greyhounds (mean = 176.5 mL/kg) compared to Beagles (234.0 mL/kg). The C0 and AUC were significantly larger in Greyhounds (86.03 ,g/mL and 79.97 h·,g/mL) compared to Beagles (69.97 ,g/mL and 50.04 h·,g/mL). The plasma clearance was significantly lower in Greyhounds (2.08 mL/min/kg) compared to Beagles (3.33 mL/min/kg). The fraction of the dose absorbed after s.c. administration to Greyhounds was 0.91, the mean absorption time was 0.87 h, and the mean maximum plasma concentration was 27.40 ,g/mL at 0.64 h. Significant differences in the pharmacokinetics of amikacin in Greyhounds indicate it should be administered at a lower dose compared to Beagles. The dose in Greyhounds to achieve a Cmax:AUC , 8 for bacteria (with an MIC , 4 ,g/mL) is 12 mg/kg q24 h compared to 22 mg/kg q24 in Beagles. [source] Residue depletion of thiamphenicol in the sea-bassJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002L. INTORRE The residue depletion of thiamphenicol (TAP) was investigated in the sea-bass (Dicentrarchus labrax) after 5 days' treatment with medicated food at a dose of 15 or 30 mg/kg bw/day. Fish were sampled for blood and muscle + skin from 3 h until 14 days after treatment. Thiamphenicol concentrations were assayed by high performance liquid chromatography. Thiamphenicol concentrations measured 3 h after stopping treatment were 0.77 ,g/mL and 0.91 (15 mg/kg dose) or 1.32 ,g/mL and 1.47 ,g/g (30 mg/kg dose), in plasma and muscle + skin, respectively. After a withdrawal of 3 days, plasma and tissue concentrations were: 0.08 ,g/mL and 0.03 ,g/g (lower dose) or 0.12 ,g/mL and 0.06 ,g/g (higher dose), respectively. Thiamphenicol was not detectable either in plasma or in tissues on days 7, 10 and 14 following withdrawal of the medicated food. Based on maximum residue levels (MRL) for TAP in fin fish, established at 50 ,g/kg for muscle and skin in natural proportions, a withdrawal period of 5 and 6 days is proposed, after treatment at 15 or 30 mg/kg of TAP with medicated feed pellets, respectively, to avoid the presence of violative residues in the edible tissues of the sea-bass. [source] Enhanced antiviral effect in cell culture of type 1 interferon and ribozymes targeting HCV RNAJOURNAL OF VIRAL HEPATITIS, Issue 6 2001D. G. Macejak We have recently shown that the replication of an HCV-poliovirus (PV) chimera that is dependent upon the hepatitis C virus (HCV) 5, untranslated region (UTR) can be inhibited by treatment with ribozymes targeting HCV RNA. To determine the antiviral effects of anti-HCV ribozyme treatment in combination with type 1 interferon (IFN), we analysed the replication of this HCV-PV chimera in HeLa cells treated with anti-HCV ribozyme and/or IFN-,2a, IFN-,2b, or consensus IFN. The anti-HCV ribozyme, or any of the IFNs alone have significant inhibitory effects on HCV-PV replication compared to control treatment (, 85%, P < 0.01). The maximal inhibition due to IFN treatment (94%, P < 0.01) was achieved with , 50 U/ml for either IFN-,2a or IFN-,2b compared to control treatment. A similar level of inhibition in viral replication could be achieved with a 5-fold lower dose of IFN if ribozyme targeting the HCV 5, UTR was given in combination. For consensus IFN, the dose could be reduced by > 12.5-fold if ribozyme targeting the HCV 5, UTR was given in combination. Conversely, the dose of ribozyme could be reduced 3-fold if given in combination with any of the IFN preparations. Moreover, treatment with low doses (1,25 U/mL) of IFN-,2a, IFN-,2b, or consensus IFN in combination with anti-HCV ribozyme resulted in > 98% inhibition of HCV-PV replication compared to control treatment (P < 0.01). These results demonstrate that IFN and ribozyme each have a beneficial antiviral effect that is augmented when given in combination. [source] Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in ratsNEUROGASTROENTEROLOGY & MOTILITY, Issue 10 2006M. Sanson Abstract, Activation of cannabinoid CB1 and CB2 receptors is known to attenuate nociception and hyperalgesia in somatic inflammatory conditions. The aim of this study was to determine whether cannabinoids modulate colonic sensitivity in basal and inflammatory conditions. The effects of CB1 and CB2 receptor agonists and antagonists on the abdominal contractile response to colorectal distension (CRD) in basal conditions and after 2,4,6-trinitrobenzenesulphonic acid-induced colitis were investigated. As previously described, colitis triggered a hypersensitivity to CRD. In basal conditions, both CB1 (WIN 55212-2) and CB2 (JWH 015) agonists reduced the abdominal response to CRD at a dose of 1 mg kg,1, i.p. Both compounds were active at a lower dose (0.1 mg kg,1) abolishing the hypersensitivity induced by colitis. Administered alone, CB1 (Rimonabant) and CB2 (SR 144528) receptor antagonists (10 mg kg,1) had no effect on basal sensitivity. In contrast, the CB1, but not the CB2, receptor antagonist enhanced colitis-induced hyperalgesia. It is concluded that colonic inflammation enhances the antinociceptive action of CB1 and CB2 receptor agonists, and activates an endogenous, CB1 receptor mediated, antinociceptive pathway. [source] Synergistic Interactions Between a KCNQ Channel Opener and an Opioid: Flupirtine and Morphine in Rat Pain Models Including Neuropathic PainPAIN MEDICINE, Issue 7 2007C Goodchild Purpose of the study:, Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ 2,3 potassium channel opener. These experiments were performed to see if this property could be useful in treating more severe pain states characterised by central sensitisation with the drug either given alone or in combination with morphine. Methods:, Experiments were performed in rats in an observer blinded fashion with vehicle controls. Non sedating doses of flupirtine, morphine and combinations containing both drugs were defined using the rotarod technique. Dose response relationships were determined for non sedating doses of both drugs given alone and together in combination in causing antinociception in three nociception paradigms: electrical pain; carrageenan paw inflammation; streptozotocin-induced diabetic neuropathy. Results:, Flupirtine and morphine when given alone caused slight to moderate antinociception in all three paradigms. Flupirtine also caused significant increases in morphine antinociception in all three models. In carrageenan paw inflammation complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model (see figure) morphine 3.2 mg/kg given alone caused significant antinociception but the size of that response was significantly less than that caused by a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg (p < 0.001; one way ANOVA). Conclusions:, Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with severe pain states involving central sensitization. [source] The impact of CD34+ cell dose on platelet engraftment in pediatric patients following unmanipulated haploidentical blood and marrow transplantation,PEDIATRIC BLOOD & CANCER, Issue 6 2009Ying-Jun Chang PhD Abstract Objective Unmanipulated haploidentical blood and marrow transplantation has been developed as an alternative transplant strategy for pediatric patients with hematological diseases. The aim of this study was to investigate the effects of donor and recipient characteristics on hematopoietic recovery in pediatric patients following unmanipulated haploidentical transplantation. Methods Factors correlating with hematopoietic recovery in 133 pediatric patients after unmanipulated haploidentical transplantation were analyzed retrospectively. Results All patients reached an absolute neutrophil count of 500/µl in a median of 12 days (range, 9,49 days). One hundred thirty-three patients reached an untransfused platelet count of more than 20,000/µl in a median of 15 days (range, 7,180 days). Univariate analysis showed five factors associated with platelet engraftment. These were time to transplantation after diagnosis (P,=,0.072), infused nuclear cells/kg of recipient weight (P,=,0.028), CD3+ cells/kg of recipient weight (P,=,0.082), CD4+ cells/kg of recipient weight (P,=,0.083), and CD34+ cells/kg of recipient weight (P,=,0.012). Multivariate analysis showed that infused CD34+ cells/kg of recipient weight (CD34+ cells more than 2.42,×,106/kg vs. less than or equal to 2.42,×,106/kg, HR,=,1.733; 95% CI 1.222,2.549; P,=,0.002) were significantly associated with an increased risk of platelet engraftment. Patients receiving a CD34+ cell dose more than 2.42,×,106/kg had a short time [12 days (range, 7,176 days)] to achieve an untransfused platelet engraftment, compared to 18 days (range, 7,180 days) in patients receiving a lower dose (P,<,0.001). Conclusions Our results suggest that low number of CD34+ cells in allografts is a critical factor associated with delayed platelet engraftment after unmanipulated haploidentical transplantation in pediatric patients. Pediatr Blood Cancer 2009;53:1100,1106. © 2009 Wiley-Liss, Inc. [source] | ||||||||||||||||||||||||||||||||||||||||||||||