Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.

Methotrexate (MTX) is one of the most widely used drugs for the treatment of childhood acute lymphoblastic leukemia (ALL) and is commonly given in high doses. However, the rationale for high-dose MTX (HDMTX) has been challenged recently. To determine whether higher MTX polyglutamate (MTXPG) concentrations in ALL blasts translate into greater antileukemic effects, 150 children with newly diagnosed ALL were randomized to initial treatment with either HDMTX (1,000 mg/m2 intravenously over 24 h) or lower-dose MTX (30 mg/m2 by mouth every 6 h x 6). ALL blasts accumulated higher concentrations of MTXPG and long-chain MTXPG (MTXPGLC) after HDMTX (P < 0.00001). Of 101 patients evaluable for peripheral blast cytoreduction, MTXPG concentrations were higher in patients whose blast count decreased within 24 h (P = 0.005) and in those who had no detectable circulating blasts within 4 days (P = 0.004). The extent of inhibition of de novo purine synthesis in ALL blasts was significantly related to the blast concentration of MTXPGLC (IC95% = 483 pmol/10(9) blasts). The percentage of patients with 44-h MTXPGLC exceeding the IC95% was greater after HDMTX (81%) than LDMTX (46%, P < 0.0001). These data indicate that higher blast concentrations of MTXPG are associated with greater antileukemic effects, establishing a strong rationale for HD-MTX in the treatment of childhood ALL.     

Hyperdiploid (47-50) acute lymphoblastic leukemia in children.

Among ploidy groups in childhood acute lymphoblastic leukemia (ALL), hyperdiploidy 47 to 50 is perhaps the least well known. From December 1979 to December 1990, we successfully studied banded karyotypes in 598 cases of newly diagnosed ALL, of which 86 (14.4%) had modal chromosome numbers of 47 to 50. In this group, the most frequently acquired numerical abnormalities were +21 (n = 34), +X (18), +8 (8), and +10 (7). The chromosomal regions most often affected by structural abnormalities were 1q (n = 13), 6q (12), 12p (18), and 19p (9). Analysis of event-free survival (EFS) for Studies X and XI among patients with hyperdiploid (47 to 50) ALL showed no significant differences in outcome according to the presence (n = 36) or absence (n = 35) of chromosomal translocations (P = .81) or the gain of specific chromosomes (P = .40). Patients with hyperdiploid (47 to 50) ALL treated in a contemporary program of multiagent chemotherapy had a significantly better outcome than did those in an earlier study using less intensive therapy (4-year EFS = 75% [95% confidence interval, 55% to 86%] v 41% [22% to 59%]; P = .006 by the logrank test). Our findings indicate that the adverse prognosis previously attributed to hyperdiploidy 47 to 50 improves significantly with more effective chemotherapy.     

Outcome of childhood acute lymphoblastic leukaemia in resource-poor countries

The causes of treatment failure in childhood acute lymphoblastic leukaemia are thought to differ between resource-rich and resource-poor countries. We assessed the records of 168 patients treated for this disease in Honduras. Abandonment of treatment (n=38), the main cause of failure, was associated with prolonged travel time to the treatment facility (2-5 h: hazard ratio 3.1, 95% CI 1.2-8.1 vs >5 h: 3.7, 1.3-10.9) and age younger than 4.5 years (2.6, 1.1-6.3). 35 patients died of treatment-related effects. Outcome could be substantially improved by interventions that help to prevent abandonment of therapy (such as funding for transport, satellite clinics, and support groups), and by prompt treatment of infection.     

The hemodynamic and pain impact of peripheral nerve block versus spinal anesthesia in diabetic patients undergoing diabetic foot surgery

Clinical Autonomic Research - Comparison of hemodynamic profiles and pain scores in diabetic patients undergoing diabetic foot surgery receiving peripheral nerve block (PNB) or spinal anesthesia...     

金银花药材中抗呼吸道病毒感染的咖啡酰奎宁酸类成分的定量研究

目的:寻找金银花中的抗呼吸道病毒感染的成分,并进行定量研究。方法:采用各种柱层析和制备薄层层析等方法分离、细胞病变法进行抗病毒作用的研究,采用RP-HPLC方法进行定量方法的研究。结果:分离得到了13种咖啡酰奎宁酸类化合物和咖啡酸、咖啡酸甲酯,确认咖啡酰奎宁酸类成分具有较强的抗呼吸道病毒作用,并采用HPLC方法测定了金银花中的 6种咖啡酰奎宁酸类成分和咖啡酸的含量。结论:咖啡酰奎宁酸类成分为金银花中的有效成分,定量方法准确、重复性好。     

Controlled‐release oral melatonin supplementation for hypertension and nocturnal hypertension: A systematic review and meta‐analysis

Oral melatonin is a potential alternative treatment for hypertension and nocturnal hypertension. However, high‐quality and relevant meta‐analyses are lacking. This meta‐analysis aimed to investigate whether oral melatonin supplementation reduces daytime/asleep blood pressure and cardiovascular risk, improves sleep quality, and is well‐tolerated compared with placebo. Relevant articles were searched in multiple databases, including MEDLINE, EMBASE, CINAHL Complete, and the Cochrane Library, from their inception to June 2021. The included studies were randomized controlled trials recruiting patients with hypertension, using oral melatonin as the sole intervention, and investigating its effect on blood pressure. The mean out‐of‐office (including 24‐h, daytime, and asleep) systolic and diastolic blood pressures, sleep quality, and side effects were compared between the melatonin and placebo arms using pairwise random‐effect meta‐analyses. A risk of bias assessment was performed using the Cochrane risk‐of‐bias tool. Four studies were included in the analysis and only one study was considered to have a low risk of bias. No study reported on cardiovascular risk or outcomes. Only controlled‐release melatonin (not an immediate‐release preparation) reduced asleep systolic blood pressure by 3.57 mm Hg (95% confidence interval: –7.88 to .73; I² = 0%). It also reduced asleep and awake diastolic blood pressure, but these differences were not statistically significant. Melatonin improves sleep efficacy and total sleep time and is safe and well‐tolerated. Due to the limited number of high‐quality trials, the quality of evidence was low to very low. Therefore, adequately powered randomized controlled trials on melatonin are warranted.