Rituximab-Based Chemoimmunotherapy Prolongs Survival of Patients With Chronic Lymphocytic Leukemia Independently of the Time of Administration

BackgroundThe combination of purine analogues (PA) and rituximab (chemoimmunotherapy) is considered the treatment of choice for CLL. The aim of this study was to determine whether chemoimmunotherapy prolonged the overall survival in patients with CLL from a single center.Patients and MethodsFrom 1980 to 2010, 273 patients with CLL received: (1) PA (n = 159); and (2) PA plus rituximab (PA+R) (n = 114). All treated patients were included in the analysis, regardless of time at which treatment was administered, duration of therapy, and response.ResultsPatients from the PA and PA+R groups were well balanced for demographic, clinical, and biologic features. At 8 years, the survival from diagnosis of the PA+R group was 88% (95% confidence interval [CI], 82-94%) compared with 68% (95% CI, 60-76%) for the PA group (P < .001). When survival of patients treated with PA+R was analyzed according to the time of treatment administration (first- [n = 55] vs. second or more lines [n = 59]), no significant differences were observed (8-year overall survival 89% vs. 87%, respectively; P = .8).ConclusionChemoimmunotherapy prolonged the survival of patients with CLL and this effect was independent of the phase of the disease at which treatment was given.     

针灸与中西药合用治疗痛风研究简况

现代中医药治疗痛风方法众多,针药合用治疗痛风不仅提高疗效,而且降低毒副作用,较单一给药或单一针灸疗效确切,针刺与药物配合,相辅相成,相得益彰,有独特优势,疗效在临床上得到了证实,主要有针灸结合中药(针灸-中药复方、针灸结合中药洗剂、针刺结合中药离子导入、针刺-中药灌肠、针刺-中药外敷);针灸结合西药以秋水仙碱、别嘌醇为主;其它(穴位注射、穴位敷贴)。由于痛风的基础研究相对薄弱,作用机制未完全明确;各种治疗方法的横向可比性差;也没有复制出更符合该病特点的动物模型。今后应进一步将动物实验与临床研究相结合,这样更有助于提高针药合用的核心价值。痛风发病与高嘌呤的食物摄入有关,并出现低龄化,应增强对痛风疾病防范意识,调整饮食,避免过度劳累、湿冷等诱因,并根据患者痛风症的不同表现采用个体化的治疗方案。     

The effect of endurance training on changes in purine metabolism: a longitudinal study of competitive long-distance runners

The purpose of the study was to characterize the changes in purine metabolism in long-distance runners in the main phases of their 1-year training cycle. Nine male athletes competing in distances 5 and 10 km at national/regional level, mean age 22.9 ± 0.6 years, practising sport for 8.6 ± 0.3 years, participated in the study. The changes in plasma concentrations of hypoxanthine (Hx), xanthine (X) and uric acid (UA) and the activity of the enzyme HGPRT in red blood cells haemolysate were followed in four characteristic points of the annual training cycle: preparatory phase (specific subphase), competition period, transition period and preparatory phase (intermediate subphase). Resting and postexercise plasma concentrations of X and, Hx and HGPRT activity changed significantly during 1-year training cycle. Significant changes in postexercise Hx values between training phases were found, from 9.3 μmol l⁻¹ in competition period to 22.9 μmol l⁻¹ in transition period (Friedmann’s ANOVA, P < 0.01). Postexercise UA values ranged from 371 to 399 μmol l⁻¹ and did not change significantly between training phases. An increase in resting (from 52.0 to 58.4 IMP mg⁻¹ Hb min⁻¹, P < 0.05) and postexercise (from 70.7 to 76.2 IMP mg⁻¹ Hb min⁻¹, not significant) HGPRT activity between the specific preparation and competition period was observed. In the transition period, Hx postexercise concentration increased (22.9 μmol l⁻¹, P < 0.01) and HGPRT postexercise activity decreased (58.8 IMP mg⁻¹ Hb min⁻¹, P < 0.01) significantly. The results indicate that the level of plasma Hx at rest and after standard exercise may be a useful tool for monitoring the adaptation of energetic processes in different training phases and support the overload/overtraining diagnosis.     

Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency

Adenylosuccinate lyase (ADSL) catalyzes two steps in purine nucleotide metabolism—the 8th step in the de novo pathway: conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR), and conversion of adenylosuccinate (S-AMP) to adenylate (AMP) in the purine nucleotide cycle. To date, over 50 patients have been reported suffering from ADSL deficiency. We report all seven so far diagnosed Polish patients with this defect. Most of our patients shared intractable seizures and psychomotor retardation since the neonatal period and had biochemical evidence of severe (type I) deficiency. Two patients with type II suffered only from mild/moderate psychomotor retardation and showed a transientvisual contact disturbance. One patient had a fatal neonatal form of ADSL deficiency with lack of spontaneous movement, respiratory failure, severe encephalopathy and intractable seizures. Analysis of the ADSL gene showed that four apparently unrelated patients carried a R426H mutation (two homozygous and two compound heterozygous). With the exception of the latter mutation, a Y114H mutation that had been reported previously, and a novel mutation T242I, all other mutations (including D268H and three novel S23R, D215H and I351T mutations) were found only in single families in single alleles. A search for this disorder should be included in the screening program of all infants with unexplained neonatal seizures, severe infantile epileptic encephalopathy, developmental delay, hypotonia, and/or autistic features.     

Genetic evidence for the essential role of PfNT1 in the transport and utilization of xanthine, guanine, guanosine and adenine by Plasmodium falciparum

The malaria parasite, Plasmodium falciparum, is unable to synthesize the purine ring de novo and is therefore wholly dependent upon purine salvage from the host for survival. Previous studies have indicated that a P. falciparum strain in which the purine transporter PfNT1 had been disrupted was unable to grow on physiological concentrations of adenosine, inosine and hypoxanthine. We have now used an episomally complemented pfnt1Delta knockout parasite strain to confirm genetically the functional role of PfNT1 in P. falciparum purine uptake and utilization. Episomal complementation by PfNT1 restored the ability of pfnt1Delta parasites to transport and utilize adenosine, inosine and hypoxanthine as purine sources. The ability of wild-type and pfnt1Delta knockout parasites to transport and utilize the other physiologically relevant purines adenine, guanine, guanosine and xanthine was also examined. Unlike wild-type and complemented P. falciparum parasites, pfnt1Delta parasites could not proliferate on guanine, guanosine or xanthine as purine sources, and no significant transport of these substrates could be detected in isolated parasites. Interestingly, whereas isolated pfnt1Delta parasites were still capable of adenine transport, these parasites grew only when adenine was provided at high, non-physiological concentrations. Taken together these results demonstrate that, in addition to hypoxanthine, inosine and adenosine, PfNT1 is essential for the transport and utilization of xanthine, guanine and guanosine.     

Antagonism by methylxanthines of purine nucleotide- and dipyridamole-induced inhibition of peristaltic activity of the guinea pig ileum

The effect of the methylxanthines (aminophylline, AMI and theophylline, THEO) on the responses to the purine pig ileum has been studied. ATP, ADP and adenosine produced concentration-dependent inhibition of peristaltic activity in non-treated, reserpine- or 6-hydroxydopamine-pretreated preparations; the relative potencies in descending order were ATP ? ADP > adenosine. This inhibition of peristaltic activity by the purine nucleotides was antagonized by low concentrations of the methylxanthines and this effect was reversible at all concentrations tested. The antagonism by THEO (5.0 μM) appeared competitive in nature. In contrast, peristaltic acdtivity inhibited by noradrenaline, isoprenaline, periarterial nerve stimulation (PNS) or papaverine was unaffected by the presence of the methylxanthines. Dipyridamole (5–10 μM) produced and inhibition in the late phase of the peristaltic activity, while lower concentrations (0.5–1.3 μM) potentiated the inhibitory response to ATP, ADP and adenosine without influencing the responses to noradrenaline, isoprenaline, PNS or papaverine. The methylxanthines selectively antagonized the inhivitory effects of dipyridamole alone or in combination with the purine nucleotides.It is proposed, that AMI and THEO exert a selective action on a specific ATP-receptor and that THEO may be a competitive antagonist of the purine nucleotides on peristaltic activity of the guinea pig ileum. Since 100-fold greater concentrations of AMI ot THEO are required to inhibit this preparation by inhibition of phosphodiesterase, it is highly unlikely that the inhibition of peristalsis by dipyridamole and the subsequent blockade by low concentrations of the methylxanthines involves the 3′, 5′-cyclic AMP pathway. Furthermore, the parallelism observed, between the effect of the methylxanthines on the inhibitory responses obtained with dipyridamole nad the effect of ATP, ADP and adenosine, supports the hypothesis that non-adrenergic, non-cholinergic inhibitory neurons releasing a purine nucleaotide as the neurotransmitter contribute to the descending inhibition observed during peristalsis.     

Effects of adrenalectomy on AGRP,POMC, NPY and CART gene expression in the basal hypothalamus of fed and fasted rats

In a first series of experiments, the morphological changes of corticoencephalic cells by ischaemia were determined by staining with celestine blue-acid fuchsin in order to classify cells as intact, dark basophilic (supposedly reversibly injured) and preacidophilic or acidophilic (profoundly injured). Hypoxia and glucose-deprivation (in vitro ischaemia) markedly decreased the number of intact cells and correspondingly increased the number of both reversibly and profoundly damaged cells. The morphological characteristics indicated a partial recovery during reoxygenation either in the absence or presence of glucose and irrespective of whether normobaric or hyperbaric oxygen was used. In a second series of experiments, nucleoside triphosphate and diphosphate levels were determined in corticoencephalic cultures by high-performance liquid chromatography. Hypoxia in combination with glucose-deficiency markedly decreased the ATP:ADP, GTP:GDP and UTP:UDP ratios. A still larger fall of these ratios was observed both after normobaric and hyperbaric reoxygenation. In contrast, both normobaric and hyperbaric reoxygenation in the presence of glucose led to an almost complete recovery near the control normoxic values. In conclusion, the histological changes were not adequately reflected by changes in the nucleoside triphosphate:diphosphate ratios and, in addition, hyperbaric oxygen had neither favourable nor unfavourable effects on the early morphological and functional restitution of ischaemically damaged cells under the conditions of the present study.     

Effect of adenosine on sinoatrial and ventricular automaticity of the guinea pig

Summary In isolated spontaneously beating right ventricular strips and right atrial preparations of guinea pigs adenosine was found to exert a concentration-dependent suppressing effect on the pacemaker activity. Responsiveness to adenosine was approximately 30-fold higher in ventricular than in atrial preparations. A decrease in the rate of slow diastolic (phase 4) depolarization of Purkinje and sinoatrial nodal fibers proved to be a major determinant of the adenosine-induced alteration in pacemaker activity. It is suggested that adenosine might exert its depressant effect on ventricular automaticity via direct excitation of purine receptors located in the specialized pacemaker fibres of the ventricular tissue.This work was supported by the Scientific Research Council, Ministry of Public Health, Hungary, Grant No. 2-06-0101-02-2/SzPreliminary report of this work was presented at the 7th International Congress of Pharmacology, Paris, 1978     

Expression of key enzymes of purine and pyrimidine metabolism in a hepatocyte-derived cell line at different phases of the growth cycle

Summary The effect of growth phase on enzymatic activities of the de novo and salvage pathways for purine and pyrimidine nucleotide synthesis was studied in a hepatocyte-derived cell line from the rat. The cells were in lag phase after plating for 36 h; log phase started at 48 h and persisted up to 120 h of culture. Then the cells stopped growing and entered into plateau phase (144 h). In non-proliferating cells (144 h of culture) the basal activities of the enzymes of purine de novo biosynthesis were 1.7- to 6.8-fold higher than in normal rat liver, those of pyrimidine de novo synthesis showed 0.6- to 30-fold increase in activity. The purine salvage enzymes were unchanged, and the pyrimidine salvage enzymes were 3.1- to 7.4-fold higher compared to normal liver. During the growth cycle all enzymes except the purine salvage enzymes, which did not change, showed a peak in activity at 72 h of culture (log phase). The increase in activity in log phase compared to plateau phase was 1.3- to 2.4-fold for purine de novo synthetic enzymes, 1.1- to 2.4-fold for pyrimidine de novo enzymes, and 1.4- to 4.7-fold for pyrimidine salvage enzymes. The specific activities of the enzymes in exponentially growing cells were comparable either to that in 24-h regenerating liver, or to that in hepatomas of low or medium growth rate. It was concluded that the enzymatic pattern and metabolic state of the cells shared some features with regenerating liver, others with tumors, although they were not tumorigenic after transplantation into athymic nude mice.     

心肌缺血预处理对嘌呤释放和嘌呤核苷磷酸化酶活性的影响

【目的】研究心肌缺血预处理对离体大鼠心脏嘌呤代谢与嘌呤核苷磷酸化酶的影响。【方法】将24只大鼠随机分为2组,采用Langendorff离体心脏灌注模型。缺血预处理组心脏经每次3 min缺血 3 min再灌注,循环3次,而后保持持续工作状态10 min;对照组心脏保持持续工作状态10 min。使用高效液相色谱技术测定嘌呤代谢产物(尿酸、黄嘌呤、次黄嘌呤、次黄苷)及嘌呤核苷磷酸化酶的活性。比较对照组与缺血预处理组嘌呤碱基的释放速率与嘌呤核苷磷酸化酶的活性。【结果】心肌缺血预处理组嘌呤碱基的释放降低(P<0.05),并且尿酸为嘌呤释放的主要成分;与总嘌呤释放减少相反,次黄苷的释放有所增加(P<0.05);遭受缺血处理后嘌呤核苷磷酸化酶的活性降低(P<0.05)。【结论】实验结果表明心肌缺血预处理调节离体心脏嘌呤代谢速率,修饰嘌呤核苷磷酸化酶成为导致次黄苷间接生成增加的原因。