心梗后患者12周康复锻炼后一次递增负荷运动中VO2、HR、%HRmax、RPP、ST、RPE变化及其相互关系

目的:探讨12周运动心脏康复锻炼对心梗后患者(PMI患者)心脏机能的影响。方法:112名男性PMI患者(均进行了12周运动心脏康复锻炼)进行一次递增负荷运动实验(Ⅰ、Ⅱ、Ⅲ、Ⅳ、Ⅴ级负荷跑速分别为1.7、1.7、1.7、2.5、3.5mph;坡度分别为0.5 %、10 %、12 %、14 %,每一级负荷运动3分钟) ,其间记录每级负荷时的VO2、HR、血压和自我用力感觉(RPE) ,计算心率血压乘积(RPP) ,并持续监测12导联心电图(ECG) ,然后对上述指标进行相关分析并建立了用HR和RPE推测VO2和RPP的回归方程。结果:(1)相邻两级负荷间的VO2、HR、RPP、RPE具有显著差异(P<0.01) ;(2)VO2、HR、最大心率百分数( %HRmax)、RPP、ST段水平(ST)和RPE的峰值分别为26.4±7.1ml·kg-1·min-1、126.8±20.3beats·min-1、80.4±12.9 %、209.0±46.3beats·mmHg·100-1、-1.0±0.7mm和14.9±2.1;(3)运动中VO2、HR、%HRmax、RPP、RPE呈高度正相关,它们与ST呈高度负相关(P<0.01或P<0.05) ,建立了用HR和RPE推测VO2和RPP的回归方程。结论:(1)康复锻炼后利用改良Bruce跑台方案进行机能测试有效;(2)12周康复锻炼后,PMI患者进行运动时其强度不宜超过80 %HRmax或RPE不超过15 ;(3)利用本研究建立的预测方程,可在PMI患者康复活动中,根据其心率或RPE变化间接得知其呼吸循环机能的反应和心肌的耗氧状况。     

Randomized phase II – study evaluating EGFR targeting therapy with Cetuximab in combination with radiotherapy and chemotherapy for patients with locally advanced pancreatic cancer – PARC: study protocol [ISRCTN56652283]

Background

Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR.

Methods/design

The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrolment.

Discussion

The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.     

Lead exposure and children's intelligence: Do low levels of lead in blood cause mental deficit?

It has come to be generally accepted that low levels of lead exposure may result in mental deficit. This causal inference is based on claimed time precedence of the lead exposure and on biological plausibility. The objective of this study is to argue that mental deficit causes pica which causes lead exposure (i.e. to support the theory of reverse causation).

Methodology:

The literature since the 1930s has been interpreted in the light of our own long experience in the investigation of lead exposure in children and adults to support the arguments in favour of reverse causation.

Results:

The arguments for reverse causation are based on: (i) analogy with mental retardation which causes increased lead exposure; (ii) the results of published prospective studies that show a special relationship between blood lead levels at 24 months and intelligence tested later, exactly what would be predicted by the reverse causation theory; and (iii) on an alternative explanation for mental retardation following lead encephalopathy (i.e. that mental retardation following encephalopathy is due to anoxia and not due to a direct destructive effect on the brain neurones). The arguments, which have been proposed for the conventional view, are rejected for the following reasons: (i) none of the prospective studies have found a relationship between cord blood lead levels and intelligence tested later, undermining the argument based on time precedence of lead exposure; and (ii) there is no convincing evidence that lead poisoning, short of encephalopathy, causes mental retardation.

Conclusion:

We believe that the reverse causation hypothesis is a more plausible explanation of the facts.     

The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non- SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.      

Direct immunofluorescence microscopy for rapid screening of Campylobacter enteritis.

Diagnostic use of a direct fluorescent-antibody test for detection of Campylobacter jejuni and C. coli in human fecal specimens (n = 497) was compared with detection by culturing (specificity, 99.7%; sensitivity, 40%). Conjugates were prepared from immunoglobulin G antibody against 22 Lior C. jejuni and C. coli reference strains (H. Lior, D. L. Woodward, J. A. Edgar, L. J. Laroche, and P. Gill, J. Clin. Microbiol. 15:761-768, 1982). Interestingly, the serotypes of cultures tested by the direct fluorescent antibody test were different from those of cultures tested by Lior slide agglutination, although the antisera used were common to both test systems.     

Linkage disequilibrium mapping of the Nova Scotia variant of Niemann–Pick disease

Niemann-Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13-cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232-235) recently demonstrated that one of these ESTs is the Niemann-Pick type C (NPCI) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097-->T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1-cM (1.3-1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5-cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.     

Mediastinal tumors: evaluation with suprasternal sonography

Twelve patients with mediastinal masses evaluated by computed tomography (CT) and histologically verified were evaluated sonographically by means of the suprasternal approach. Eleven of 12 mediastinal tumors could be visualized sonographically, mainly as hypoechoic and perivascularly situated masses, and could be located topographically with a fair degree of certainty. Suprasternal sonography is particularly useful in the detection of small, perivascular lymphomas of the supraaortic branches. In patients with problematic CT findings, particularly children and patients with allergies to contrast media, suprasternal sonography can provide important additional information. Moreover, suprasternal sonography can be used to determine the consistency and to monitor the treatment of mediastinal tumors. Finally, the suprasternal approach is suitable for sonographically guided biopsies of mediastinal tumors.     

Biochemical and electrophysiological properties of SR 57746A, a new, potent 5-HT1A receptor agonist

Summary— SR 57746A (1-[2-(naphth-2-yl) ethyl]-4-(3-trifluoromethylphenyl)-1, 2, 5, 6 tetra-hydropyridine hydrochloride) binds competitively, and with high affinity (K_i = 2.0 ± 0.7 nM) to 5-HT_1A receptors from rat hippocampus in vitro , but has much less affinity for other 5-HT receptor subtypes (IC₅₀ > 650 nM). SR 57746A produces a concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal homogenates, with a maximal effect identical to that of 8-OH-DPAT, suggesting that SR 57746A behaves as a full agonist in tthis experimental model. SR 57746A potently displaces [³H]8-OH-DPAT binding to rat hippocampal membranes ex vivo , with an ID₅₀ of 11.1 mg/kg po, 30 min after administration, and 2.8 mg/kg po, 2 h after administration. This effect of SR 57746A is long-lasting (at least 24 hours at 10 mg/kg po). SR 57746A does not modify the levels of 5-HT or DA in various brain areas, but decreases the concentrations of 5-HIAA, and increases those of DOPAC, HVA and 3-MT. Following iv administration, SR 57746A (0.095 to 0.25 mg/kg) inhibits the spontaneous firing of dorsal raphe neurones, but does not modify the activity of DA neurones in the substantia nigra or ventral tegmental area. Thus, SR 57746A is a potent, selective and full agonist at 5-HT_1A receptors in vitro and vivo.