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1.
J. M. McGree J. A. Eccleston S. B. Duffull 《Journal of pharmacokinetics and pharmacodynamics》2009,36(2):101-123
We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional
nature of such models, differences in predicted responses are a consequence of different assumptions about how the models
interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques
have been explored in the literature where it was found that the sequential and FO approaches can produce biased results.
It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal
design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected
Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into
our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical
and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates
formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed
and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature.
We consider design for situations where all responses are continuous and extend this methodology to the case where a response
may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such
responses will offer little information about all parameters and hence a sequential optimization, in the form of product design
optimality, may yield near optimal designs. 相似文献
2.
M. Naranjo-Gómez M.A. Fernández M. Bofill R. Singh C.V. Navarrete R. Pujol-Borrell F.E. Borràs 《American journal of transplantation》2005,5(12):2838-2848
The role played by dendritic cell (DC) subsets in the immune response to alloantigens is not well defined. In vitro experiments have extensively shown that freshly isolated myeloid (M)DCs induce a strong T lymphocyte proliferation whereas plasmacytoid (P)DCs do not, unless activated by CD40 ligation. The aim of these studies was to explore whether the interplay among PDCs, MDCs and T cells modulates alloresponse. Freshly isolated MDCs and PDCs were merged in different proportions and used as antigen presenting cells (APCs) in mixed lymphocyte cultures (MLC). As described, isolated PDCs only induced a mild alloresponse, while MDCs were potent inducers of alloproliferation. Unexpectedly, when PDCs were merged with even low numbers of MDCs (down to 100 cells) and used as APCs, a potent Th1 cell proliferation was detected. Survival and maturation of PDCs was increased in these MLC conditions, which could partially explain the magnitude of the T-cell response. Interestingly, the proportion of IFNgamma-producing cells generated in such cultures was higher compared to MDC-stimulated cultures. These data suggest that the interaction between both DC subsets is determinant to generate a potent Th1 response, at least in an allogeneic situation, and may be relevant to the outcome of allogeneic stem cell transplantation. 相似文献
3.
Metabolism is one of the major determinants for age-related changes in susceptibility to chemicals. Aldehydes are highly reactive molecules present in the environment that also can be produced during biotransformation of xenobiotics and endogenous metabolism. Although the lung is a major target for aldehyde toxicity, early development of aldehyde dehydrogenases (ALDHs) in lung has been poorly studied. The expression of ALDH in liver and lung across ages (postnatal day 1, 8, 22, and 60) was investigated in Wistar-Han rats. In adult, the majority of hepatic ALDH activity was found in mitochondria, while cytosolic ALDH activity was the highest contributor in lung. Total aldehyde oxidation capability in liver increases with age, but stays constant in lung. These overall developmental profiles of ALDH expression in a tissue appear to be determined by the different composition of ALDH isoforms within the tissue and their independent temporal and tissue-specific development. ALDH2 showed the most notable tissue-specific development. Hepatic ALDH2 was increased with age, while the pulmonary form did not. ALDH1 was at its maximum value at postnatal day 1 (PND1) and decreased thereafter both in liver and lung. ALDH3 increased with age in liver and lung, although ALDH3A1 was only detectible in lung. Collectively, the present study indicates that, in the case of aldehyde exposure, the in vivo responses would be tissue and age dependent. 相似文献
4.
Masaru Kato Rie Kobayashi Ikuo Watanabe 《Documenta ophthalmologica. Advances in ophthalmology》1993,84(1):71-81
An unusual form of scotopic electroretinogram with a bright white stimulus, which consisted of a rectangular a-wave of normal amplitude and a b-wave of supernormal amplitude, was recorded in three patients with cone dysfunction. In addition to poor visual acuity, abnormal color vision and reduced amplitude of the photopic electroretinogram, these patients showed a 2-log unit elevation of the dark-adaptation threshold. Funduscopic examination and fluorescein angiography revealed fine granular pigment disturbances at the mascula. The relationship between the response of the dark-adapted electroretinogram versus stimulus intensity was unique to these patients. The b-wave thresholds were elevated by 1 log unit. The b-waves were reduced in amplitude and markedly delayed in implicit time to dim stimuli, but supernormal in amplitude and normal in implicit time to bright stimuli.Abbreviations GMP
guanosine monophosphate 相似文献
5.
目的观察罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征患者的内分泌改善及生殖功能的临床疗效。方法50例肥胖型PCOS患者分别给予罗格列酮4mg/d和二甲双胍1500mg/d联合氯米芬100mg/d,治疗3个月,比较治疗前后体重指数、内分泌参数、腰臀比和Hom a IR的变化。结果用罗格列酮治疗后排卵率为88%,周期排卵率为64.29%,优势卵泡平均个数为1.8±0.8个,妊娠率为56%,而用二甲双胍治疗后分别为72%、54.84%、1.1±0.6个、48%。两者治疗后能使LH、LH/FSH、T的血清浓度明显下降,SHBG的浓度明显上升,Hom a IR明显改善。结论罗格列酮和二甲双胍联合氯米芬治疗肥胖型多囊卵巢综合征疗效可靠。二甲双胍有降低体重作用、价格便宜,适用于肥胖型P-COS伴胰岛素抵抗不严重者;罗格列酮在胰岛素增敏作用优于二甲双胍,适用于胰岛素抵抗较严重的PCOS患者。 相似文献
6.
F. Njaa T. Baekken D. Bjaamer J. I. Holme F. Korsrud O. Woxen A. K. Olsen 《Pediatric allergy and immunology》1992,3(1):39-42
Fifty–five children 6–16 years old with allergic rhinoconjunctivitis due to both birch and grass pollinosis were randomized into 2 parallel groups, treated in double–blind fashion with either levocabastinc (LEV) eye–drops twice daily plus placebo eyedrops twice daily or sodium cromoglycate (SCG) eyedrops 4 times daily for 3 months. Spersallerg® (antazolini chloride + tetryzolini chloride) eyedrops were allowed as rescue medicine. All children received basic treatment with an antihistamine (terfenadine) during the complete trial period, and a local nasal corticosteroid if needed. Eye symptoms were recorded daily by the patients and at 4 visits by the investigator, at start and after 4, 10 and 13 weeks. Pollen counts were performed and a blood sample was collected at start and end of the treatment. The global evaluation of treatment was similar for the 2 groups, and there was no significant difference in any effect parameter except for the symptom, itchy eyes, which had lower score in the SCG group as evaluated by the investigator after 4 weeks. On days with low pollen counts the patients in the SCG group had fewer days with moderate or severe eye symptoms. It is concluded that even though LEV and SCG eyedrops were given in addition to systemic treatment with an antihistamine, no consistently significant differences in clinical effect were found between the 2 treatment groups, but the SCG group experienced slightly less eye symptoms throughout the trial. LEV eye–drops appear safe in long–term treatment in children, and no signs of tachyphylaxis were recorded. 相似文献
7.
Chelyabinsk Medical Institute. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 113, No. 3, pp. 299–301, March, 1992. 相似文献
8.
N. J. Friedman S. E. Shiff F. E. Ward R. I. Schiff R. H. Buckley 《Pediatric allergy and immunology》1991,2(3):111-116
We describe a patient with severe combined immunodeficiency and transplacental transfer of maternal T cells who received an unfractionated HLA-identical sibling bone marrow transplant without prior conditioning. He presented prior to transplantation with a dermatitis later diagnosed as mild graft versus host disease. He had a normal absolute lymphocyte count, but proliferative responses to mitogens were very low. Antigens of the noninherited maternal HLA haplotype were detected on his blood lymphocytes. After transplantation, he developed a severe reaction including fever, cutaneous erythema and hepatosplenomegaly. Lymphocytes carrying the noninherited maternal HLA haplotype disappeared from his circulation, and his unprimed mononuclear cells became spontaneously cytotoxic to maternal lymphoblasts. He subsequently developed a lymphocytosis of 69,000/mm3 , diarrhea, elevated transaminases and a worsening rash, necessitating treatment with immunosuppressive agents. Full T-cell engraftment and evidence of B-cell function later ensued and spontaneously cytotoxic lymphocytes against maternal cells disappeared by 47 days post-transplantation. We postulate that the patient's constellation of signs and symptoms after transplantation represented a combination of severe graft versus graft and mild graft versus host reactions. 相似文献
9.
Twenty-six bone marrow transplant recipients, 14 of whom had evidence of acute graft versus host disease at autopsy, were studied. The pancreas in four of these patients exhibited changes thought to be due to acute graft versus host disease. Pathognomonic findings were in exocrine ducts which showed marked epithelial cellular atypia associated with a mild lymphocytic infiltrate. This was accompanied by ulceration and intraluminal haemorrhage in severe cases. In three of these four cases ductal epithelium showed marked hyperexpression of class I and class II major histocompatibility complex molecules. By contrast islets were not inflamed, showed no evidence of endocrine cell damage and no abnormalities of major histocompatibility complex expression were seen. 相似文献
10.
The present study was designed to investigate the effects of combined treatment with a serotonin (5-HT)1A receptor agonist, 8-hydroxy-2-(dipropylamino)-tetralin (8-OH-DPAT), and a muscarinic acetylcholine receptor antagonist, scopolamine, on water maze (WM) navigation. Treatment with either 8-OH-DPAT or scopolamine before daily behavioral training disrupted spatial navigation at medium doses and cue navigation at high doses. Pretraining treatment with a combination of subthreshold doses of 8-OH-DPAT and scopolamine impaired WM spatial and cue navigation, but did not impair the WM performance if the drugs were injected post-training. In trained rats, combined injections of subthreshold doses of 8-OH-DPAT and scopolamine given pretraining did not impair the rats' ability to find the platform in a familiar or in a novel position. The combination of 8-OH-DPAT and scopolamine also disrupted WM navigation in rats with central 5-HT depletion. A combination of a peripheral muscarinic acetylcholine receptor antagonist and 8-OH-DPAT had no effect on WM navigation. These data suggest that combined treatment with drugs blocking muscarinic acetylcholine receptors and activating 5-HT1A receptors greatly impairs WM learning/performance, but does not impair spatial memory per se. 相似文献