Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy

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Polyclonal antibody responses against Listeria monocytogenes 4b surface proteins in asymptomatic human carriers

Listeria monocytogenes 4b surface protein extract was used in an immunoblot assay to analyze the antibody profile in sera from 40 healthy urban workers (U group), 40 healthy slaughterhouse workers (W group) and four healthy carriers with positive L. monocytogenes 4b feces culture (positive controls). In addition, pooled rabbit sera, before and after immunization with L. monocytogenes 4b whole‐cell suspension, were analyzed against L. monocytogenes 4b surface protein extract in order to determine the specific L. monocytogenes 4b antibody pattern. The degree of similarity (S) between such a pattern and each of those obtained with serum samples from the three subject groups was assessed. For U and W group sera, mean S values were 24.3 ± 13.5 and 32.8 ± 14.3, respectively. An S value greater than 65, corresponding to mean S_U value ± 3 standard deviation, was considered as an indicator of a healthy carrier. Thus, the estimated healthy carrier percentages found in U and W groups were 2.5 and 5%, respectively. The proposed immunoblot assay may prove a useful tool for epidemiological surveys to determine whether a healthy person is a L. monocytogenes 4b carrier.     

CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis

Background

Myositis is a heterogeneous group of muscular auto-immune diseases with clinical and pathological criteria that allow the classification of patients into different sub-groups. Inclusion body myositis is the most frequent myositis above fifty years of age. Diagnosing inclusion body myositis requires expertise and is challenging. Little is known concerning the pathogenic mechanisms of this disease in which conventional suppressive-immune therapies are inefficacious.

Plaque-forming cell capability in the senescent

The number of plaque-forming cells (PFC) developed in pokeweed mitogen (PWM)-activated unfractionated or T/B separated, 4:1 reconstituted cultures of peripheral blood lymphocytes (PBL) with well-characterized subpopulations obtained from healthy, aged subjects was compared to that of young blood donors. The absolute number of PBL in the aged was reduced by 36%, and the percentage of sheep erythrocyte-rosette-forming cells (E-RFC) by 27%, compared to the percentage obtained in young donors. The IgM-, IgG- and IgA-immunoglobulin (Ig) secretion was monitored with a protein A PFC assay. The number of PFC in PBL cultures of the aged was 58% of the number found in cultures of the young controls. The number of PFC generated in cultures of autologous irradiated T and untreated B cells showed a 104% increase in the aged whereas a 63% increase was obtained using cells from young individuals. Co-cultures of young B cells with untreated or irradiated young or aged T cells showed a significant rise in the PFC response in cultures with irradiated aged T cells, while an equal number of PFC was generated in cultures of young B cells with young or aged untreated T cells. Our results demonstrate a decreased number of PBL, especially T cells, an impaired B cell function and a pronounced enhancement of the PFC response in cultures of irradiated aged T cells and young or aged B cells, whereas the T helper function of untreated cells was found to be normal. The influence of monocytes on the PFC response did not differ in the two groups.     

T cell receptor (TCR) V gene segment use in HLA-typed Japanese healthy subjects

The expression of 13 different α and β V gene segments of the T cell receptor for antigen (TCR) was examined, using V gene-specific MoAbs, on human peripheral blood T lymphocytes from 32 healthy Japanese subjects. In addition, to examine associations between TCR V gene products and HLA alleles, the HLA class I and class II types of all subjects were serologically determined. The reactivities of the anti-TCR V-specific MoAbs were, with some significant exceptions, similar to those previously described in healthy Caucasian subjects. We found a non-random V gene usage as well as a statistically significant bias of the expression of eight Vβ gene products towards the CD4⁺ subpopulation, and a significant skewness in the usage of Vα12 towards the CD8⁺ population. Some subjects showed increased reactivities (above 10%) of certain MoAbs, mainly in the CD8⁺ subpopulation. We found no distinct correlation between any certain HLA class I or II allele and TCR V gene usage in the CD8⁺ or CD4⁺ subpopulations, respectively. In conclusion, the pattern of anti-TCR V-specific MoAb reactivities found in CD4⁺ and CD8⁺ subsets of peripheral blood lymphocytes of healthy Japanese subjects was in general found to match that previously described in healthy Caucasian subjects.     

The effects of nifedipine on platelet aggregation and plasma 6-keto-PGF1α, and its interaction with indomethacin

Summary Pre-incubation of human platelets with nifedipine in vitro or treatment of normal volunteers with nifedipine, 30 mg daily for one week, did not alter ADP induced aggregation measured by whole blood aggregometry. 6-oxo-Prostaglandin F₁ remained undetectable in plasma following oral administration of nifedipine to normal volunteers. The hypotensive response to intravenous nifedipine administration was similar in spontaneously hypertensive rats pretreated with indomethacin or placebo. These results conflict with previous reports that nifedipine alters platelet aggregation and prostaglandin metabolism.     

Prevalence and prognostic significance of cardiac arrhythmias detected by ambulatory electrocardiography in subjects 85 years of age

24 hour ambulatory electrocardiography was performed in a representativegroup of people born in 1897. Out of 73 people included in thestudy, 22 were without known heart disease, 15 had definiteischaemic heart disease (IHD) and 36 symptoms of possible cardiacorigin. An R-R interval in excess of 2000 ms was seen in only3 subjects and Wenckebach A-V block in only one. One subjectwithout a history of syncope had a nocturnal episode of completeA-V block with an escape interval of 8000 ms. The most strikingdifference between healthy subjects and patients with IHD wasthe higher number of patients with more than 1000 ventricularpremature beats (VPBs) per 24 hour and ventricular coupletscompared with the number of healthy subjects with such findings.At follow-up two years later 11% had died, with the highestmortality in patients with IHD (33%), and out of 8 patientswith IHD who had more than 1000 VPBs per 24 hour, 4 (50%) haddied compared with only one (14%) of those with less than 1000VPBs. Our results seem to indicate that more than 1000 VPBsper 24 hour is a very unusual finding in healthy 85 year oldindividuals. When it occurs in very old people, it is usuallyin connection with IHD, and in this setting it signifies a poorprognosis.     

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment

Summary Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30–63 ml/min) and 7 patients with severe renal impairment (CRI II, creatinine clearance 9–29 ml/min). All except one of the patients with renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t_1/2) was 0.94 h. In CRI the mean plasma t_1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6–8 h after dosing, with the maximal decrease at 2–3 h (healthy subjects 118/71107/56, CRI 159/95136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2–6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled.The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.     

Effects of fenflumizole on aggregation ex vivo of human platelets and formation of thromboxane B2 and 6-keto-prostaglandin-F_{1\alpha }

Summary Fenflumizole (2-(2,4-difluorophenyl)-4,5-bis(4-methoxyphenyl)imidazole), a new non-steroidal anti-inflammatory drug, was given to healthy subjects in single oral doses of 0.1, 1 and 2 mg/kg. The effect of the drug was followed for up to 8 h by repeated tests of arachidonic acid-induced platelet aggregation and was related to its concomitant plasma concentration. Fenflumizole reversibly inhibited platelet aggregation and the degree of inhibition was found to be linearly correlated with the log plasma concentration. There was depression of the formation of thromboxane B₂ and 6-keto-prostaglandin F₁ (the stable metabolites of thromboxane A₂ and prostacyclin) in clotted whole blood measured by radioimmunoassay after fenflumizole 1 mg/kg. This effect was directly related to the concentration of the drug in plasma, the maximum effect being reached at fenflumizole concentrations >200 ng/ml. EC₅₀-values for inhibition of the formation of thromboxane B₂ and 6-keto-prostaglandin were approximately 20 and 40 ng/ml, respectively. The results suggest that orally administered fenflumizole is a potent inhibitor of platelet aggregation and prostanoid formation.     

基于“正虚邪滞”理论探讨肺癌自噬机制及中药干预进展

自噬是一种细胞自我保护和自我更新机制,与肺癌的发生发展密切相关,有利自噬可以减缓肺癌进展,而不利自噬能够促进肺癌进展,故调节自噬水平在肺癌治疗中具有重要意义。“正虚邪滞”是王永炎院士“虚气留滞”理论的延伸,是指因肺脾肾气亏虚,引发津液代谢异常,导致痰瘀阻滞的病理过程,以肺脾肾气亏虚为本、痰瘀阻滞为标,是肺癌的关键病机。肺癌的自噬机制与“正虚邪滞”有着相互贯通之处,肺脾肾气亏虚是肺癌有利自噬减弱的关键因素,进而抑制了肿瘤细胞凋亡,并导致有害物质蓄积;痰瘀阻滞是肺癌不利自噬增强的直接因素,进而促进了正常细胞自噬性死亡,削弱了免疫细胞对肿瘤细胞的免疫抑制作用,导致肿瘤细胞增殖和迁移。正虚与邪滞相合,致使自噬状态向着不利的方向不断发展,最终导致肺癌持续进展。因此,中医干预肺癌自噬机制需以扶正抗邪为原则,补益正气以治其本,祛痰化瘀以治其标,增强有利自噬的同时抑制不利自噬,将自噬水平调节到最佳状态,从而抑制肿瘤细胞增殖和迁移,促进肺癌的缓解。通过分析现有文献可知,目前通过自噬途径治疗肺癌的中医药以中药单体为主,中医药干预肺癌自噬的作用主要集中在促进自噬激活层面,这可能是因为藉由肺脾肾气亏虚引发的有利自噬减弱是肺癌发展的根本原因。