Efficacy of botulinum toxin A in children with cerebral palsy in Gross Motor Function Classification System levels IV and V: a systematic review

Aim Previous studies have shown the efficacy of botulinum toxin type A (BoNT‐A) in the management of ambulant individuals with cerebral palsy (CP). There is little evidence on its use in non‐ambulant children with CP. This review aimed to investigate indications and efficacy for BoNT‐A use in managing pain, care, and comfort, and improving function in children with CP in Gross Motor Function Classification System (GMFCS) levels IV and V. Method Electronic databases were searched from the earliest available date to June 2012 using a combination of subject headings and free text. Inclusion criteria consisted of studies with (1) participants aged 18 or under, (2) participants with CP in GMFCS levels IV and V, (3) participants receiving BoNT‐A treatment, and (4) studies published in English‐language peer‐reviewed journals. Results The search resulted in a total of 814 studies, of which 19 met the inclusion criteria. Eighteen studies provided level IV or V evidence and one level I evidence according to the American Academy for Cerebral Palsy and Developmental Medicine guidelines for the development of systematic reviews. Most of the studies were of weak to moderate methodological quality. Interpretation The evidence that BoNT‐A is effective in reducing postoperative pain in children with CP in GMCFS levels IV and V is limited, with only one level I study identified. Remaining indications were general pain reduction, maintaining hip integrity, achieving functional changes, and goal attainment. A high percentage of participants in the studies showed positive changes in these areas. With the poor level of evidence of the included studies, no definite conclusion could be drawn on the indications for BoNT‐A use in children with CP in GMCFS levels IV and V. Further investigation by rigorous studies is required.     

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.     

Antiarrhythmic and Electrophysiologic Effects of Intravenous Ibutilide and Sotaloi in the Canine Sterile Pericarditis Model

Ibutilide, Sotalol, and Atrial Flutter. Introduction: Atrial arrhythmias are a frequent clinical complication following open heart surgery. We compared the Class III agents d,I-sotalol and ibutilide fumarate in an intravenous cross-over study using the canine atrial sterile pericarditis model. Methods and Results: We studied pacing-induced sustained atrial flutter over a 7-day post-surgical period in conscious dogs, alternating analysis of ibutilide (1.0 to 30.0 μg/kg) and d,I-sotalol (0.1 to 3.0 mg/kg). Ibutilide significantly increased atrial flutter cycle length (AFL CL) II ± 2 msec and atrial effective refractory period (AERP) 13 ± 2 msec, and terminated atrial flutter in all cases (n = 12) following a mean dose of 6 ± 2 μg/kg. Plasma concentrations of ibutilide were 53 ± 13 ng/mL. Ventricular effective refractory period (VERP) was not signiflcantly affected (4 ± 2 msec). Following termination with ibutilide, atrial flutter could he reinitiated in 1 of 12 trials, and was nonsustained (40-sec duration). Sotalol significantly increased AFL CL 23 ± 3 msec and terminated atrial flutter in 8 of 12 trials following a mean dose of 1.5 ± 0.4 mg/kg. AERP and VERP were significantly increased 20 ± 6 and 12 ± 2 msec, respectively. The incidence of reinduced atrial flutter was 9 of 12 trials (P ≥ 0.05 vs ibutilide) (7 nonsustained 57 ± 7 sec duration, and 2 sustained). Sotalol failed to terminate atrial flutter in two dogs on days 1 and 5, despite increases in AFL CL (21 ± 8 msec) and AERP (16 ± 9 msec), whereas on day 3, ibutilide (20 ± 7 μg/kg) terminated atrial flutter in those two dogs while increasing AFL CL and AERP 18 ± 6 and 15 ± 0 msec, respectively. Conclusion: Both sotalol and ibutilide terminate atrial flutter in this model. Ibutilide converted atrial flutter in dogs in which sotalol was not successful. Following atrial flutter termination, ibutilide had a lower incidence of reinduced arrhythmias compared to sotalol. Ibutilide produced atrial antiarrhythmic effects while having no significant electrophysiologic effects on the ventricle.     

Respiratory-Dependent Pacing: A Dual Response From A Single Sensor

Five patients with respiratory dependent rate responsive pacemakers (Biorate HDP3, Biotec) were studied using ambulatory telemetry to evaluate the sensitivity of this pacing system to nonrespiratory signals. In each case the pacemaker was implanted in the left infraclavicular position with an impedance sensing electrode inserted into the subcutaneous tissues of the anterior chest wall. The pacing rate was 73 ± 2 beats per minute at rest and rose by 42 ± 5 beats per minute when the patients were walking with both arms swinging (mean ± SEMJ. Three of the five patients had sensing electrodes that extended across the midline. In this subgoup, pacing rate rose by 26 ±4 beats per minute when walking with arms held immobile and by 36 ± 2 beats per minute during sustained voluntary hyperventilation. These same activities did not elicit any appreciable changes in pacing rate in the remaining two patients whose sensing electrodes were confined to the left hemithorax. Recordings taken from all jive patients while they were standing upright and regularly swinging one upper limb showed an increase in pacing rate of 15 + 6 beats per minute with movement of the right arm and 46 + 8 with movement of the left. These observations establish that the Biorate RDP3 pacemaker is capable of responding both to changes in respiratory rate and to movement of the upper limbs. The sensitivity to limb movement is greatest when the chest wall impedance sensor does not extend across the midline and is most evident when the arm ipsilateral to the pacemaker is swung. This anomalous response may have a profound effect on pacing rate during certain forms of exercise and must be taken into account when programming the pacemaker to meet the heart rate requirements of individual patients.     

Familial apolipoprotein CII deficiency: plasma lipoproteins and apolipoproteins in heterozygous and homozygous subjects and the effects of plasma infusion

Abstract. Plasma lipoproteins and apolipoproteins have been studied in a kindred with familial apolipoprotein CII (apo CII) deficiency. As in two other recently documented pedigrees, apo CII deficiency appeared to be transmitted as an autosomal recessive trait. The homozygous state was characterized by gross fasting hypertriglyceridaemia, complete absence of apo CII from plasma and failure of plasma to activate lipoprotein lipase. Post-heparin plasma hepatic triglyceride lipase activity was normal. Hypertriglyceridaemia reflected chylomicronaemia and elevated Sf 100–400 and Sf 20–100 lipoprotein concentrations; lipoproteins of Sf 12–20 (LDL₁), Sf 0–12 (LDL₂), F_1.23.5–9 (HDL₂) and F_1.20–3.5 (HDL₃) were greatly reduced in concentration. Low density lipoproteins (1.006–1.063 g/ml), isolated by preparative ultracentrifugation, and high density lipoproteins, isolated by heparin/Mn⁺⁺, were triglyceride-enriched. Electroimmunoassays revealed additionally low plasma concentrations of apolipoproteins AI, AII and B and very high concentrations of apolipoproteins CIII and E in the homozygote. The parents of the proband (heterozygotes) were normotriglyceridaemic, and had normal lipoprotein lipid concentrations and normal apolipoprotein AI, AII, B, CIII and E concentrations, in spite of having low apo CII concentrations. Activation of lipoprotein lipase in the homozygote by intravenous infusion of 200 ml fresh-frozen plasma rapidly reduced the plasma concentrations of chylomicrons and very low density lipoproteins (VLDL). Within VLDL, the decrease in concentration occurred sequentially in the Sf 100–400 and Sf 20–100 subclasses. These changes were associated during a 4-day study period with reciprocal increases in LDL₁, LDL₂, HDL₂ and HDL₃. The plasma concentrations of apo AI and apo B also increased, associated with a less marked fall in that of apo CIII; the apo AII and apo E concentrations were unchanged. These observations support other evidence that apo CII is a cofactor for the catabolism of chylomicrons and both major subfractions of VLDL by lipoprotein lipase in man, and that human LDL₁ and LDL₂ are derived, at least in part, from triglyceride-rich lipoprotein catabolism. They also suggest that both major subfractions of HDL acquire additional components during triglyceride-rich lipoprotein catabolism. In normal subjects the plasma apo CII concentration appears to be greatly in excess of that required for adequate activation of lipoprotein lipase.     

Adverse change in low-density lipoprotein subfractions profile with oestrogen-only hormone replacement therapy

In a prospective longitudinal study in 17 women, we investigated the effects of surgical menopause and subsequent oestrogen-only hormone replacement therapy (HRT) on plasma concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride and LDL subfractions profile. Plasma LDL is a heterogeneous population of particles of varying size, density and chemical composition. The predominance of small LDL particles is a newly-recognized risk factor for coronary artery disease. The LDL score is used to describe LDL subfractions profile and the greater the score, the higher the proportion of small LDL particles. Six weeks after hysterectomy and bilateral oopherectomy, total cholesterol and triglyceride concentrations were significantly increased (p < 0.01) as well as the LDL score (p < 0.05). After 6 weeks of oestrogen-only HRT, total cholesterol concentration was significantly lower and HDL cholesterol concentration significantly higher than before the treatment (p < 0.05). At the same time, mean LDL score significantly increased and in none of the women did LDL subfractions profile change favourably.      

腹主动脉部分缩窄大鼠模型体外心脏的电生理特点

目的:观察腹主动脉部分缩窄模型大鼠体外心脏的电生理特点。方法:实验于2005-04/08在北京中医药大学东直门医院重点实验室完成。①取雄性SD大鼠30只,单纯随机分为3组,正常组6只,假手术组和模型组各12只,后2组又分为造模后4,8周2个时间点,每个时间点6只。②造模后4周、8周采用飞利浦HDI5000超声诊断仪、15MHz高频线阵探头,经胸骨旁左室长轴切面检测大鼠心脏左室室壁厚度及左室腔内径。③超声检测完毕后剪取大鼠心脏,称量左室质量,计算左室心肌质量指数(实测左室质量/体表面积)。④造模后第8周时取下心脏进行体外灌流,吸附电极记录单相动作电位,测量动作电位复极20%,50%,90%的时间(APD20,APD50,APD90),有效不应期,动作电位最大幅度,零相上升的最大速度。结果:经补充后29只大鼠进入结果分析。①心脏超声指标比较:造模后第4周模型组室间隔舒张末期厚度大于假手术组[(2.57±0.35),(1.86±0.15)mm,P<0.01];造模后第8周模型组室间隔舒张末期厚度、左室后壁舒张末期厚度和左室舒张末期内径均大于假手术组[(2.52±0.32),(1.94±0.07)mm,P<0.01;(2.54±0.30),(2.06±0.11)mm,P<0.01;(6.27±0.54),(5.65±0.34)mm,P<0.05];模型组左室舒张末期内径第8周较第4周显著增加(P<0.01)。②左室心肌质量指数:造模后第4,8周,模型组均高于假手术组[(28.88±2.57),(15.10±1.49)g/m2;(31.09±2.85),(28.88±2.57)g/m2;P均<0.01]。③体外心脏电生理参数:模型组左心房APD90长于假手术组(P<0.05),有效不应期/APD90比值小于假手术组(P<0.05);左心室APD20,APD50,APD90和有效不应期长于假手术组(P<0.01,0.05),有效不应期/APD90比值小于假手术组(P<0.05);右心室各参数比较无差异;模型组APD90离散度(左心室-右心室)显著高于假手术组[(56.8±4.7),(18.7±4.0)ms,P<0.01];模型组有效不应期离散度(左心室-右心室)也显著高于假手术组[(25.4±1.1),(5.2±0.8)ms,P<0.01]。结论:部分缩窄大鼠腹主动脉模型的早期(4周)是由压力负荷致心脏左室向心性肥厚的模型,随着压力负荷的持续和容量负荷的增加,左室逐渐演变为向心性肥厚和离心性肥厚的混和型肥厚(8周)。混合型肥厚心脏左心室、左心房单相动作电位的复极时间均显著延长,心脏不同部位离散度增加,这些电生理特点是促进折返形成,造成心律失常的主要原因。     

Changes in screening behaviors and attitudes toward screening from pre‐test genetic counseling to post‐disclosure in Lynch syndrome families

The purpose of this study was to examine colonoscopy adherence and attitudes toward colorectal cancer (CRC) screening in individuals who underwent Lynch syndrome genetic counseling and testing. We evaluated changes in colonoscopy adherence and CRC screening attitudes in 78 cancer‐unaffected relatives of Lynch syndrome mutation carriers before pre‐test genetic counseling (baseline) and at 6 and 12 months post‐disclosure of test results (52 mutation negative and 26 mutation positive). While both groups were similar at baseline, at 12 months post‐disclosure, a greater number of mutation‐positive individuals had had a colonoscopy compared with mutation‐negative individuals. From baseline to 12 months post‐disclosure, the mutation‐positive group demonstrated an increase in mean scores on measures of colonoscopy commitment, self‐efficacy, and perceived benefits of CRC screening, and a decrease in mean scores for perceived barriers to CRC screening. Mean scores on colonoscopy commitment decreased from baseline to 6 months in the mutation‐negative group. To conclude, adherence to risk‐appropriate guidelines for CRC surveillance improved after genetic counseling and testing for Lynch syndrome. Mutation‐positive individuals reported increasingly positive attitudes toward CRC screening after receiving genetic test results, potentially reinforcing longer term colonoscopy adherence.