Emerging therapies for patients with advanced chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia is a common lymphoid malignancy with a variable clinical course. While some patients never require treatment or can be managed effectively with palliative chemotherapy, others experience early disease progression and death. The development of new prognostic markers has helped in the identification of patients with high risk disease, even among those diagnosed at early stage. Recent prospective trials have established chemo-immunotherapy combinations as the new standard of care for CLL patients requiring therapy. Unfortunately, patients whose tumour cells have certain genomic aberrations, such as a chromosome 17 deletion, have a disease that is frequently refractory to conventional therapy and should have their treatment tailored accordingly. Younger patients with high risk disease should be referred for allogeneic haematopoietic cell transplantation if they have an appropriate donor. For the remaining high risk patients, a number of new compounds are emerging, which could lead to further improvement in their outcome.     

Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia

Murine spinal cord primary mixed cultures were treated with the respiratory inhibitor, rotenone, to mimic hypoxic conditions. Under these conditions neurons rapidly underwent oncosis (necrosis) with a complete loss in viability occurring within 260 min; however, astrocytes, which accounted for most of the cell population, died more slowly with 50% viability occurring at 565 min. Inosine preserved both total cell and neuronal viability in a concentration-dependent manner. The time of inosine addition relative to hypoxic insult was critical with the most effective protection occurring when inosine was added just prior to or within 5 min after insult. Inosine was ineffective when added 30 min after hypoxic insult. The effect of guanosine was similar to that of inosine. Treatment of cultures with BCX-34, a purine nucleoside phosphorylase inhibitor, prevented protection by inosine or guanosine, suggesting involvement of a purine nucleoside phosphorylase in the nucleoside protective effect.     

Elevated UTP and CTP content in cultured neurons from HPRT-deficient transgenic mice

Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8.; HPRT) catalyzes the salvage synthesis of inosine-5′-monophosphate (IMP) and guanosine-5′-monophosphate (GMP) from the purine bases hypoxanthine and guanine, respectively. Complete deficiency of HPRT activity is associated with the Lesch-Nyhan syndrome (LNS), characterized by excessive purine production and severe neurological manifestations. The etiology of the metabolic consequences of HPRT deficiency is clarified, but that of the neurological manifestations is not yet understood. HPRT-deficient mice represent an experimental animal model of LNS. In search for a possible metabolic abnormality in LNS brains, connecting the neurological deficit to HPRT deficiency, the purine and pyrimidine nucleotide content of cultured neurons, prepared from HPRT-deficient transgenic mice, was now determined. The HPRT-deficient neuronal cultures exhibited a significantly elevated content of the pyrimidine nucleotides UTP (1.33-fold the normal level, p=0.0002) and CTP (1.28-fold the normal level, p=0.02), but normal content of the purine nucleotides ATP and GTP. This abnormality in neuronal pyrimidine nucleotide content may be associated with the pathophysiology of the neurological deficit in LNS.     

Purine metabolism in Trypanosoma cruzi

Culture forms of Trypanosoma cruzi are incapable of synthesizing purines de novo from formate, glycine, or serine and require an exogenous purine for growth. Adenine, hypoxanthine, guanine, xanthine and their respective ribonucleosides are equal in their abilities to support growth. Radiolabeled purine bases, with the exception of guanine, are stable and are converted to their respective ribonucleotides directly by phosphoribosyltransferase activity. Guanine is both converted to its ribonucleotide and deaminated to xanthine. Purine nucleosides are not hydrolysed to any extent but are converted to their respective ribonucleotides. This conversion may involve a rate-limiting ribonucleoside cleaving activity or a purine nucleoside kinase or phosphotransferase activity. The apparent order of salvage efficiency for the bases and their respective ribonucleosides is adenine > hypoxanthine > guanine > xanthine.     

Purine and pyrimidine metabolizing activities in Trichomonas vaginalis extracts

Sixty-one purine and pyrimidine metabolizing activities were assayed in extracts of Trichomonas vaginalis. Of these, 43 were detected and quantitated. The only phosphoribosyltransfer activity observed was with uracil. No such activity was observed with adenine, guanine, hypoxanthine, xanthine or orotic acid. The rate of nucleoside cleavage was increased dramatically by the addition of inorganic phosphate. In addition, the extracts could catalyze the synthesis of ribonucleosides from the bases adenine, hypoxanthine, guanine and uracil but not cytosine, thymine or orotic acid, in the presence of ribose 1-phosphate. These data suggest that T. vaginalis contains primarily nucleoside phosphorylases instead of nucleoside hydrolases. Adenosine, deoxyadenosine, guanosine, deoxyguanosine, inosine, uridine, thymidine and GMP were phosphorylated in the presence of ATP. No nucleoside phosphotransferase activity was detected. Deamination of guanine, adenosine, deoxyadenosine, cytidine and deoxycytidine but not adenine was observed. These data suggest that salvage of adenine and guanine for ribonucleotide synthesis in T. vaginalis occurs via a phosphorylase/kinase pathway instead of through a phosphoribosyltransferase pathway which predominates in mammalian cells. In contrast, the pyrimidine base uracil can be converted to UMP via both a phosphoribosyltransferase or a phosphorylase/kinase pathway, analogous to that in mammals.     

The influence of dietary manipulation on plasma ammonia accumulation during incremental exercise in man

Summary The influence of a pattern of exercise and dietary manipulation, intended to alter carbohydrate (CHO) availability, on pre-exercise acid-base status and plasma ammonia and blood lactate accumulation during incremental exercise was investigated. On three separate occasions, five healthy male subjects underwent a pre-determined incremental exercise test (IET) on an electrically braked cycle ergometer. Each IET involved subjects exercising for 5 min at 30%, 50%, 70% and 95% of their maximal oxygen uptake ( ) and workloads were separated by 5 min rest. The first IET took place after 3 days of normal dietary CHO intake. The second and third tests followed 3 days of low or high CHO intake, which was preceded by prolonged exercise to exhaustion in an attempt to deplete muscle and liver glycogen stores. Acid-base status and plasma ammonia and blood lactate levels were measured on arterialised venous blood samples immediately prior to and during the final 15 s of exercise at each workload and for 40 min following the completion of each IET. Three days of low CHO intake resulted in the development of a mild metabolic acidosis in all subjects. Plasma ammonia (NH₃) accumulation on the low-CHO diet tended to be greater than normal at each exercise workload. Values returned towards resting levels during each recovery period. After the normal and high-CHO diets plasma NH₃ levels did not markedly increase above resting values until after exercise at 95% . Plasma NH₃ levels after the high-CHO diet were similar to those after the normal CHO diet. Blood lactate levels did not markedly increase with each treatment until after exercise at 70% . There was a trend for blood lactate accumulation after the low-CHO diet to be lower than that after the normal and high-CHO diets during the IET and for the majority of the recovery period. Levels after the high-CHO diet tended to be similar to those after the normal diet. The present experiment demonstrates that an alteration in pre-exercise substrate availability will influence the accumulation of plasma NH₃ during exercise. In this situation, the use of plasma NH₃ as an index of exercise intensity and the onset of fatigue should be viewed with some caution.     

Purine and pyrimidine metabolism in the Trypanosomatidae

The pathways leading to purine and pyrimidine nucleotide production in members of the family Trypanosomatidae are discussed with special emphasis on data relating to pathogenic species published from 1974 to 1983 inclusive. Trypanosomes and leishmania in general lack a de novo purine biosynthetic pathway, but have a multiplicity of possible routes for purine salvage. In contrast, pyrimidine nucleotides can be produced by either de novo or salvage pathways. The properties of these pathways in trypanosomatids are compared and contrasted with those of their hosts.     

Synthesis and antiviral properties of carbocyclic 3′-oxa-2′,3′-dideoxyguanosine and its 7-deazaguanosine analogue

To evaluate analogues of the antiviral agent (R)-9-(3,4-dihydroxybutyl)guanine in which the side-chain C-3 hydroxyl oxygen is part of a five-membered ring, carbocyclic 3′-oxa-2′,3′-dideoxyguanosine (4) and carbocyclic 3′-oxa-2′,3′-dideoxy-7-deazaguanosine (5) have been synthesized in 17 and 14 steps, respectively, from

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. Compounds 4 and 5 and their 6-chloro precursors were evaluated against a wide variety of DNA and RNA viruses. Only 4 showed any marginal activity and this was limited to HSV-1 and HSV-2. Even though 4 was less potent towards these latter two viruses than acyclovir, its mechanism and target of action is proposed to resemble that of acyclovir. The only toxicity observed for these compounds was observed in the cell growth assay with human embryonic lung cells.     

高海拔登山运动对人体血清尿酸的影响

目的探究高海拔登山运动对人体尿酸的影响，以及不同有氧适应，体脂肪含量和性别在登山过程中对尿酸浓度的影响。方法30名自愿受试者，从事3d高海拔的登山运动，测身高、体重、体脂能代谢，进行尿酸浓度分析。结果（1）高海拔登山运动，使血清尿酸浓度显著降低（P〈0．05）。（2）体脂肪含量的高低不影响高海拔登山运动过程中血清尿酸浓度。（3）高海拔登山运动过程血清尿酸浓度女性显著低于男性（P〈0．05）。（4）有氧适应的好坏对高海拔登山运动血清尿酸浓度差异无统计学意义。结论高海拔登山血清尿酸浓度显著降低。