In vitro 1H-magnetic resonance spectroscopy of Barrett's esophageal mucosa using magic angle spinning techniques

OBJECTIVES: In vitro proton magnetic resonance spectroscopy (MRS) allows changes in cell membrane lipid structure associated with dysplasia and malignant transformation to be investigated. Magic angle spinning (MAS) MRS allows small esophageal tissue specimens to be studied directly without the need to extract the tissue, but it is not known how intact the tissue architecture remains after MAS. We report the first prospective MAS MRS study of Barrett's esophagus using endoscopic biopsies with direct histological correlation. METHODS: Biopsies were obtained during surveillance esophagoscopy from Barrett's epithelium and adjacent normal squamous epithelium in 16 patients (34 samples). High-resolution MAS MRS was performed at 500 MHz. Following MRS, the histology was evaluated. A further, separate group of 14 biopsies were examined histologically to assess architectural damage caused by tissue preservation alone. RESULTS: For squamous and Barrett's epithelium, respectively, metabolite ratios of choline-containing compounds to creatine plus phosphocreatine (Cho/Cr) were 1.99 and 5.65 (P < 10) and methyl lipid to creatine plus phosphocreatine ratios (lipid-CH3/Cr) were 4.07 and 7.4 (P < 10). There was no significant difference in histological preservation between the squamous and Barrett's mucosa without MRS (z = 0.67, P = 0.61), but significant differences were found post-MAS MRS (z = 4.06, P < 0.0001). CONCLUSIONS: Squamous and Barrett's epithelium can be distinguished metabolically, based on Cho/Cr and lipid-CH3/Cr ratios. Although MAS does affect the histological architecture in Barrett's epithelium, compared with squamous epithelium, direct histological assessment was possible in the majority of samples.     

Corticostriatal plasticity: life after the depression

Experience-dependent changes in corticostriatal transmission efficacy are likely to support the role of the striatum in reinforcement-based motor learning. Whereas long-term depression at glutamatergic corticostriatal synapses has long been regarded as the normal form of striatal plasticity, recent work provides evidence that use-dependent potentiation can naturally occur at these connections through an increase in both synaptic efficacy and postsynaptic intrinsic excitability. By decreasing the weight of cortical inputs required to fire striatal output neurons, short-term and long-term potentiation at corticostriatal connections can jointly participate in the formation of sensorimotor links by which specific context-dependent patterns of cortical activity can engage selected motor programs.     

Humor and health in early adolescents: perceived field motion as a mediating variable

The purpose of this study was to test a mediational model, developed within the science of unitary human beings, by examining the relationship between humor and eudaimonistic health conception in early adolescents and by examining the extent to which perceived field motion mediated this relationship. The sample consisted of 136 adolescents, aged 12 to 14, who responded to instruments measuring humor, perceived field motion, and eudaimonistic health conception in classroom settings. Correlational analysis supported the three hypothesized relationships. Regression analyses indicated that perceived field motion was one mediator of the relationship between humor and eudaimonistic health conception.     

Is the Health Utilities Index responsive in total hip arthroplasty patients?

OBJECTIVE: The purpose is to examine the responsiveness of the Health Utilities Index Mark 2 (HUI2), Mark 3 (HUI3), and other generic and disease-specific measures in osteoarthritis patients undergoing total hip arthroplasty (THA). METHODS: Ninety patients (mean age=68.13; SD=8.15) on a waiting list for THA completed measures that included the standard gamble, HUI2, HUI3, SF-36, Harris Hip Scale, WOMAC, and MACTAR. before and after THA. Responsiveness statistics (effect size, standardized response mean, Guyatt's responsiveness statistic, paired-sample t-tests, and relative efficiency statistic) were calculated. RESULTS: The disease-specific measures were more responsive than the generic measures. Rankings of the degree of responsiveness varied depending on the responsiveness statistic used. CONCLUSIONS: Disease-specific measures are the most responsive in THA patients. However, the SF-36, HUI2, and HUI3 had summary scores and domain/attributes scores that were also responsive and provided additional information. Among the generic measures, HUI3 was the most responsive.     

Relationship between elevated levels of the alpha 1 acid glycoprotein in chronic myelogenous leukemia in blast crisis and pharmacological resistance to imatinib (Gleevec) in vitro and in vivo

The Abl tyrosine kinase inhibitor imatinb is becoming a standard for the treatment of chronic myelogenous leukemia (CML). However, Bcr-Abl gene mutations have been reported mainly in relapsing or resistant patients. In primary resistant patients, only few mutations have been documented so far, suggesting alternative mechanisms. We aimed to investigate if alpha 1 acid glycoprotein (AGP), an acute phase drug binding protein, could be a biological marker for pharmacological resistance to imatinib in nine patients in acute phase CML. All patients (3/3) with high AGP dosages (2.31+/-0.17 mg/mL; normal values, 0.5-1.3mg/mL) were primary resistant to imatinib whereas an early clinical response was observed for the six patients with normal AGP levels (1.13+/-0.2mg/mL). No mutation in the adenosine triphosphate domain of Abl were detected before the initiation of imatinib therapy. By using in vitro tests combining various imatinib concentrations (1-10 microM) with purified human AGP (1 and 3 mg/mL), we demonstrate that imatinib-induced apoptosis of K562 or fresh leukemic CML cells is abrogated or reduced. The same effect was observed using sera from donors with high AGP levels (1.9-3.28 mg/mL). In patients with CML in blastic phase, AGP levels could reflect pharmacological resistance to imatinib, suggesting that increased dosage of imatinib or the use of a competitor to drug binding should be recommended to optimize the therapeutic effect of the drug.     

Measuring the success of primary care organizations: is it possible?

Primary care in the UK has been the subject of numerous changes and reorganizations since 1990. Each innovation in organization, with the exception of fundholding, has been the subject of evaluation. However, the complexities of some innovations make the evaluation process problematic and this is further complicated by the trend towards central policy decision making being subject to local interpretation and implementation, by means of simultaneous devolution and centralization. This paper discusses the challenges and problems posed by attempting to evaluate these new organizations, particularly with regard to whether or not they can be considered to be "successful". It draws specifically on the national evaluation of the total purchasing pilots and indicates how the findings can be applied to primary care groups.