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The CD20-specific monoclonal antibody rituximab (MabThera(®), Rituxan(®)) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab.

The CD20-specific monoclonal antibody rituximab (MabThera registered , Rituxan registered ) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation.

The effects of small-molecule p38 inhibitors in numerous models of different disease states have been published, including those of SD-282, an indole-5-carboxamide inhibitor. The aim of the present study was to evaluate the pharmacological activity of SD-282 on cytokine production in vitro as well as in 2 in vivo models of inflammation in order to illuminate the role of this particular inhibitor in diverse disease states. The results presented here provide further characterization of SD-282 and provide a context in which to interpret the activity of this p38 inhibitor in models of arthritis, pain, myocardial injury, sepsis and asthma; all of which have an inflammatory component. SD-282 represents a valuable tool to elucidate the role of p38 MAP kinase in multiple models of inflammation. Copyright © 2008 S. Karger AG, Basel [PUBLICATION ABSTRACT]

A growing body of evidence suggests that α-synuclein accumulation may play an important role in the pathogenesis of Parkinson＇s disease. The aim of this study was to investigate the roles of the proteasome and autophagy pathways in the clearance of wild-type and mutant α-synuclein in PC12 cells. Methods： PC12 cells overexpressing either wild-type or A30P mutant α-synuclein were treated with the proteasome inhibitor epoxomi- cin, the macroautophagy inhibitor 3-MA and the macroautophagy activator rapamycin alone or in combination. The cell viability was assessed using MTF assay. Immunofluorescence and Western blot analysis were used to detect the level of α-synuclein, LAMP-2A, E1 activase, and E2 ligase in the cells. Chymotrypsin-like proteasomal activity was measured using a commercial kit. Results： When the proteasome and macroautophagy in the wild-type and mutant cells were inhibited with epoxomicin and 3-MA, respectively, the cell viability was significantly decreased, and the a-synuclein level was increased. Both epoxomicin and 3-MA activated the chaperone-mediated autophagy （CMA） by increasing the level of the CMA-limiting enzyme LAMP-2A. Furthermore, 3-MA or epoxo- micin significantly decreased chymotrypsin-like proteasomal activity. 3-MA or epoxomicin did not change E1 activase expression in either mutant or wild-type cells, but increased E2 ligase expression, especially when used together. Macroautophagy inducer rapamy- cin increased the cell viability and reduced epoxomicin-induced α-synuclein accumulation. Interestingly, CMA was also activated by rapamycin. Conclusion： Our results demonstrate the existence of complex crosstalk between different forms of autophagy and between autophagy and the proteasome pathway in the clearance of a-synuclein in PC12 cells.

Background： Parkinson＇s disease （PD） patients with long-term levodopa （L-DOPA） treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. Methods： The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine （6-OHDA）, followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus （SCN）, liver, and plasma were collected at 6：00, 12：00, 18：00, and 24：00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. Results： L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test （P 〈 0.01, P 〈 0.001, respectively）. After L-DOPA treatment, Bmall decreased in the SCN compared with 6-OHDA group at 12：00 （P 〈 0.01） and 24：00 （P 〈 0.001 ）. In the striatum, the expression ofBmall, Rorα was lower than that in the 6-OHDA group at 18：00 （P 〈 0.05） and L-DOPA seemed to delay the peak of Per2 to 24：00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes （P 〉 0.05）. In addition, the cortisol secretion was increased （P 〉 0.05）, but melatonin was further inhibited after L-DOPA treatment at 6：00 （P 〈 0.01）. Conclusions： In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.

Background：Few studies have addressed whether abnormalities in the lenticular nucleus （LN） are characteristic transcranial sonography （TCS） echo features in patients with primary dystonia.This study aimed to explore alterations in the basal ganglia in different forms of primary focal dystonia.Methods：A cross-sectional observational study was performed between December 2013 and December 20 1 4 in 80 patients with different forms of primary focal dystonia and 55 neurologically normal control subjects.TCS was performed in patients and control subjects.Multiple comparisons of multiple rates were used to compare LN hyperechogenicity ratios between control and patient groups.Results：Thirteen individuals were excluded due to poor temporal bone windows,and two subjects were excluded due to disagreement in evaluation by sonologists.Totally,70 patients （cervical dystonia,n =30;blepharospasm,n =30;oromandibular dystonia,n =10） and 50 normal controls were included in the final analysis.LN hyperechogenicity was observed in 51% （36/70） of patients with primary focal dystonia,compared with 12% （6/50） of controls （P 〈 0.001）.Substantia nigra hyperechogenicity did not differ between the two groups.LN hyperechogenicity was observed in 73% （22/30） of patients with cervical dystonia,a greater prevalence than in patients withblepharospasm （33%,10/30,P =0.002） and oromandibular dystonia （40%,4/10,P =0.126）.LN hyperechogenicity was more frequently observed in patients with cervical dystonia compared with controls （73% vs.12%,P 〈 0.001）;however,no significant difference was detected in patients with blepharospasm （33% vs.12%,P =0.021） or oromandibular dystonia （40% vs.12%,P =0.088）.Conclusions：LN hyperechogenicity is more frequently observed in patients with primary focal dystonia than in controls.It does not appear to be a characteristic TCS echo feature in patients with blepharospasm or oromandibular dystonia.

$\\beta$-Glucans have been shown to have immunopotentiating effects in a variety of animal species. The ability of $\\beta$-glucan derived from Schizophyllum commune to enhance immune responses of channel catfish was determined by antibody to the bacterial pathogen Edwardsiella ictaluri after immersion challenge, accumulation of phagocytic cells in the peritoneal exudate, accumulation of intraepithelial leucocytes in the gut wall, and mortality in challenge trials. Intraperitoneal (IP) injection of $\\beta$-glucan resulted in an initial accumulation of neutrophils in the peritoneal exudate that declined over a four day period. However, macrophage numbers increased over the four day period and were more abundant in the exudate on day four post-injection. Fish fed rations supplemented with 0.1% $\\beta$-glucan had significantly higher antibody titers to E. ictaluri than fish fed control or 1.0% $\\beta$-glucan supplemented rations. This response was found to be related to the weight of the fish. In immersion challenge trials using E. ictaluri, $\\beta$-glucan-supplemented rations did not significantly alter mortality of fish weighing 18 $\\pm$ 2 g when compared to catfish fed control rations. $\\beta$-Glucan may be useful when used in conjunction with vaccines to enhance their effectiveness.

Background： Both Parkinson＇s disease （PD） and multiple system atrophy （MSA） have associated sleep disorders related to the underlying neurodegenerative pathology. Clinically, MSA with predominant parkinsonism （MSA-P） resembles PD in the manifestation of prominent parkinsonism, Whether the amount of rapid eye movement （REM） sleep without atonia could be a potential marker for differentiating MSA-P from PD has not been thoroughly investigated. This study aimed to examine whether sleep parameters could provide a method for differentiating MSA-P from PD. Methods： This study comprised 24 MSA-P patients and 30 PD patients, and they were of similar age, gender, and REM sleep behavior disorder （RBD） prevalence. All patients underwent clinical evaluation and one night of video-polysomnography recording. The tonic and phasic chin electromyogram （EMG） activity was manually quantified during REM sleep of each patient. We divided both groups in terms of whether they had RBD to make subgroup analysis. Results： No significant difference between MSA-P group and PD group had been tbund in clinical characteristics and sleep architecture. However, MSA-P patients had higher apnea-hypopnea index （AHI; 1.15 [0.00, 8.73]/h vs. 0.00 [0.00, 0.55]/h, P = 0.024） and higher tonic chin EMG density （34.02 [ 18.48, 57.18]% vs. 8.40 [3.11, 13.061%, P 〈 0.001 ） as compared to PD patients. Subgroup analysis found that tonic EMG density in MSA ＋ RBD subgroup was higher than that in PD ＋ RBD subgroup （55.04 [26.81,69.62]% vs. 11.40 [8.51,20.411%, P 〈 0.001 ）. Furthermore, no evidence of any difference in tonic EMG density emerged between PD ＋ RBD and MSA - RBD subgroups （P 〉 0.05）. Both disease duration （P = 0.056） and AHI （P = 0.051） showed no significant differences during subgroup analysis although there was a trend toward longer disease duration in PD ＋ RBD subgroup and higher AHI in MSA - RBD subgroup. Stepwise multiple linear regression analysis identified the presence of MSA-P （[3 0.552, P 〈 0.001 ） and RBD （[3 = 0.433, P 〈 0.001 ） as predictors of higher tonic EMG density. Conclusion： Tonic chin EMG density could be a potential marker for differentiating MSA-P from PD.