DNA methylation and developmental genes in lymphomagenesis--more questions than answers?

There is now considerable evidence suggesting that alterations in the DNA methylating machinery play an important role in tumorigenesis and tumour progression. For example, focal hypermethylation and generalised genomic demethylation are features of many different types of neoplasms. It is thought that tumorigenesis and tumour progression may be caused by hypermethylation induced mutational events and silencing of genes which control cellular proliferation and/or demethylation induced reactivation of genes which may only be required during embryological development. Consequently, we have begun to investigate the role of DNA methylation and developmental genes in malignant lymphoproliferative diseases. Previously, in all cases of non-Hodgkins lymphoma and leukemia studied, we have shown that the myogenic developmental gene Myf-3 is abnormally hypermethylated. In this review we discuss the possible significance of these findings since in vitro studies suggest that Myf-3 may play an important role in control of the cell cycle and therefore lymphomagenesis. In vitro and in vivo evidence suggests that PAX genes may also have oncogenic potential. The PAX family of developmental genes are involved in cellular differentiation, proliferation and cell migration. Expression of PAX3 in particular is associated with cellular mobility. Our previous studies have indicated that alternate regional expression of PAX genes may be controlled by DNA methylation. Therefore, we have proposed that abnormal methylation profiles of PAX3 may be associated with neoplastic transformation and/or metastatic potential. Results thus far reveal that the paired box of PAX3 is abnormally hypermethylated and the homeobox abnormally hypomethylated in lymphomas and leukemias. These new findings are consistent with our postulate and support the idea that inappropriate methylation induced activation or inactivation of developmental genes such as Myf-3 and PAX3 play an important role in lymphomagenesis and disease progression and that inspection of the methylation status of other developmental genes is warranted.     

On-line H NMR spectroscopic investigation of hydrogen bonding in supercritical and near critical CO2–methanol up to 35 MPa and 403 K

On-line NMR spectroscopy can beneficially be applied to studies of supercritical and near-critical fluids as an alternative to optical spectroscopy. Up to now high pressure NMR experiments are predominantly accomplished using custom made NMR batch reactors. The authors present a novel high pressure cell with displacement plunger for on-line NMR experiments on compressible fluids which can be used in conjunction with commercially available SCF NMR flow probes. The on-line technique offers advantages compared to stopped flow techniques such as enhanced control of mixture composition and reaction parameters as well as the facility of engagement into the reaction. The new apparatus is used for NMR studies on hydrogen bonding of methanol in near critical and supercritical carbon dioxide up to 403 K and 35 MPa for which data on the chemical shift of the hydroxyl group and methyl group are reported and interpreted.     

Iterative interference cancellation for high spectral efficiencysatellite communications

The problem of efficient utilization of the frequency spectrum for satellite systems is investigated; one which results as a consequence of highly crowding adjacent channels. An analytical characterization of the resulting interference channel is introduced and then exploited for interference cancellation. Two classes of cancelers are investigated. The first approach does not benefit from the forward error control (FEC) coding information which limits the performance gain. This motivates the second approach where a joint implementation of interference cancellation and decoding is developed using soft-input-soft-output (SISO) modules along with the iterative structure. It is shown that iterative interference cancellation techniques can achieve significant gains compared with the single-user matched filter receiver     

Associated ulcerative colitis, sclerosing cholangitis, and insulin-dependent diabetes mellitus

We report two young men with clinical and laboratory evidence of macroscopic ulcerative colitis, sclerosing cholangitis, and insulin-dependent diabetes mellitus. The first patient presented at age 15 with vomiting, abdominal pain, weight loss, and abnormal liver function test results. Liver biopsy and endoscopic retrograde cholangiopancreatography (ERCP) demonstrated sclerosing cholangitis. Colonoscopy with biopsy revealed ulcerative colitis which responded to sulfasalazine. Diabetes occurred at age 18 and insulin therapy was begun. The second patient was 19 at presentation with diarrhea, hematochezia, and weight loss. Proctosigmoidoscopy revealed ulcerative colitis, and sulfasalazine led to clinical remission. Three months later he developed diabetes requiring insulin therapy. At age 28, he developed elevated alkaline phosphatase, and ERCP revealed sclerosing cholangitis. At age 37 he expired from adenocarcinoma that metastasized to the liver. Literature review revealed only one possible case report of this association with microscopic asymptomatic ulcerative colitis in that patient. Statistical analysis suggests that this association is real rather than a chance occurrence. An autoimmune process may be involved and a specific histocompatibility locus antigen (HLA) type may exert a regulatory influence.     

The Microbiological Quality of Private Water Supplies

This paper provides a detailed assessment of the microbiological quality of a selection of private water supplies. Samples were taken from 91 supplies and analyzed for total coliforms, faecal coliforms and faecal streptococci. The microbiological quality of the samples was generally poor, with almost 50% of the supplies failing to meet the required standards on at least one occasion. Given the high level of sanitary microbiological failures, there is the possibility that harmful microorganisms could be present and a significant risk to health cannot be discounted.     

Autoxidation of Hydrocarbons: From Chemistry to Catalysis

This contribution summarizes our recent efforts to unravel the radical chemistry of autoxidations. Abstraction of the weakly bonded αH-atom of the primary hydroperoxide product by chain carrying peroxyl radicals is identified as the source of major end products such as alcohol and ketone/aldehyde. In the case of cyclohexane autoxidation, this reaction is even responsible for the majority of ring-opened by-products. In a second part, different approaches to autoxidation catalysis are discussed, ranging from transition metal ion catalysis to organocatalysis with immobilized N-hydroxyphthalimide.     

Global folds of highly deuterated, methyl-protonated proteins by multidimensional NMR

The development of 15N, 13C, 2H multidimensional NMR spectroscopy has facilitated the assignment of backbone and side chain resonances of proteins and protein complexes with molecular masses of over 30 kDa. The success of these methods has been achieved through the production of highly deuterated proteins; replacing carbon-bound protons with deuterons significantly improves the sensitivity of many of the experiments used in chemical shift assignment. Unfortunately, uniform deuteration also radically depletes the number of interproton distance restraints available for structure determination, degrading the quality of the resulting structures. Here we describe an approach for improving the precision and accuracy of global folds determined from highly deuterated proteins through the use of deuterated, selectively methyl-protonated samples. This labeling profile maintains the efficiency of triple-resonance NMR experiments while retaining a sufficient number of protons at locations where they can be used to establish NOE-based contacts between different elements of secondary structure. We evaluate how this deuteration scheme affects the sensitivity and resolution of experiments used to assign 15N, 13C, and 1H chemical shifts and interproton NOEs. This approach is tested experimentally on a 14 kDa SH2/phosphopeptide complex, and a global protein fold is obtained from a set of methyl-methyl, methyl-NH, and NH-NH distance restraints. We demonstrate that the inclusion of methyl-NH and methyl-methyl distance restraints greatly improves the precision and accuracy of structures relative to those generated with only NH-NH distance restraints. Finally, we examine the general applicability of this approach by determining the structures of several proteins with molecular masses of up to 40 kDa from simulated distance and dihedral angle restraint tables.     

Medical records and other stories: a narratological framework

A new model of the medical record is introduced which can incorporate context, structure, process and use of the medical record within a single narratological framework. It is claimed that the analysis of narrative and, in particular, the study of the story metaphor can provide a theoretical model which provides coherence within the broad discipline of Medical Informatics. It is argued that this framework maintains different levels of abstraction, is useful for teaching and clinical practice, and that its concepts can be readily understood by those in both lay and technical healthcare professions.