Somatic mutation analysis of <Emphasis Type="Italic">MYH11</Emphasis>in breast and prostate cancer

Background  

MYH11 (also known as SMMHC) encodes the smooth-muscle myosin heavy chain, which has a key role in smooth muscle contraction. Inversion at the MYH11 locus is one of the most frequent chromosomal aberrations found in acute myeloid leukemia. We have previously shown that MYH11 mutations occur in human colorectal cancer, and may also be associated with Peutz-Jeghers syndrome. The mutations found in human intestinal neoplasia result in unregulated proteins with constitutive motor activity, similar to the mutant myh11 underlying the zebrafish meltdown phenotype characterized by disrupted intestinal architecture. Recently, MYH1 and MYH9 have been identified as candidate breast cancer genes in a systematic analysis of the breast cancer genome.     

Operant behavioral treatment of fibromyalgia: a controlled study

OBJECTIVE: To evaluate the efficacy of operant pain treatment for fibromyalgia syndrome (FMS) in an inpatient setting. METHODS: Sixty-one patients who fulfilled the American College of Rheumatology criteria for FMS were randomly assigned to the operant pain treatment group (OTG; n = 40) or a standardized medical program with an emphasis on physical therapy (PTG; n = 21). Pain assessments were performed before, immediately after, 6 months after, and 15 months after treatment. RESULTS: The OTG patients reported a significant and stable reduction in pain intensity, interference, solicitous behavior of the spouse, medication, pain behaviors, number of doctor visits, and days at a hospital as well as an increase in sleeping time. Sixty-five percent of the OTG compared with none of the patients in the PTG showed clinically significant improvement. CONCLUSION: These results suggest that operant pain treatment provided in an inpatient setting is an effective treatment for FMS, whereas a purely somatically oriented program may lead to a deterioration of the pain problem.     

Evaluation of cocktail approach to standardise Caco-2 permeability experiments.

The purpose of this study was to investigate the suitability and reliability of n-in-one approach using FDA suggested compounds for standardising Caco-2 permeability experiments. Special attention was paid to the evaluation of rank order correlation and mechanistic insights of compound permeability. Transport studies with antipyrine, metoprolol, ketoprofen, verapamil, hydrochlorothiazide, ranitidine, mannitol and fluorescein were performed in 12- and 24-well formats, as single compounds and in cocktails under iso-pH 7.4 and pH-gradient (pH 5.5 vs. 7.4) conditions. Compounds were quantified using n-in-one LC/MS/MS analysis. The cocktail-dosing proved to be a feasible method to determine the permeability of the Caco-2 cell line and to introduce external standards for permeability tests. Even though sink conditions were lost in cocktail experiments for highly permeable compounds, the rank order of compound permeability and the classification to low and high permeability compounds remained unchanged between single and cocktail studies and permeability values of 12- and 24-well formats were directly comparable. Under pH-gradient conditions the margin between high and low permeability compounds was narrower due to the lower permeability (higher fraction of ionisation) of basic molecules. Of the compounds studied, antipyrine, metoprolol, hydrochlorothiazide and mannitol are suitable for evaluation and standardisation purposes of passive permeability, while fluorescein would function as paracellular marker under iso-pH 7.4. As efflux activity may vary between cell batches, verapamil is a useful marker for P-glycoprotein.     

Brain abscess drainage by use of MR fluoroscopic guidance

We describe herein the use of MR fluoroscopic guidance in the drainage of abscess cavities. We percutaneously drained 12 brain abscesses in 11 patients. A 0.3T open MR imaging system was used. Sixteen drainages were performed in 12 abscesses. Repeat drainage was needed in three recurrences and one residual lesion. No serious complications were seen. MR fluoroscopy-guided percutaneous brain abscess drainage in an open MR imaging system is feasible.     

Influence of different promoters on the expression pattern of mutated human alpha-synuclein in transgenic mice

Two missense mutations (A53T and A30P) in the gene encoding the presynaptic protein alpha-synuclein (asyn) are associated with rare, dominantly inherited forms of Parkinson's disease (PD) and its accumulation in Lewy bodies and Lewy neurites. As an initial step in investigating the role of asyn in the pathogenesis of PD, we have generated C57BL/6 transgenic mice overexpressing the doubly mutated human asyn under the control of three different promoters; the chicken beta-actin (chbetaactin), the mouse tyrosine hydroxylase 9.6 kb (msTH) and the mouse prion protein (msprp). In this study we compared the regional and cellular expression pattern of the transgenic protein in the brain and peripheral organs of various transgenic mouse lines. Western blot analysis and immunohistochemistry consistently showed that all three promoters successfully drive the expression of the transgene. The msprp promoter was found to give the highest level of transgene expression. All promoters directed the expression into the brain and specific neuron types. However, the promoters differed with respect to (i) the expression pattern in peripheral organs, (ii) the number and (iii) the regional distribution of expressing cells in the brain. Furthermore, remarkable line-to-line variation of expression patterns was observed in mouse lines carrying the same construct. Future studies will analyze how the variations in transgene expression affect the pathogenesis in the animals.     

Histopathologic and immunocytochemical changes in the liver in patients with chronic hepatitis C

BACKGROUND: The presence of lymphocytes within the liver parenchyma is related to immunologically mediated liver damage in chronic hepatitis C. The aim of the study was to make histological, histochemical, and immunocytochemical assessment of liver biopsy specimens in patients with chronic hepatitis C virus (HCV) infection. METHODS: Biopsy specimens of 20 patients with chronic HCV disease were analyzed, using standard staining procedures to verify histologic liver lesions, as well as immunoenzymatic staining with monoclonal antibodies to detect CD4+ T-lymphocytes, B-lymphocytes, and macrophages. RESULTS: Micromorphologic characteristics of chronic active viral hepatitis C were present in all the patients, differing, however, by the level of their activity. Dominant changes were found within the portal space, consisting of mononuclear lympho-plasmocytic infiltration and macrophages. Immunocytochemical investigation of mononuclear and macrophageal infiltration showed the correlation between micromorphological findings and the degree of the activity. CONCLUSION: The presence of lymphocytic and macrophageal infiltration within the hepatic tissue directly correlated with the intensity of the liver damage. Analysis of the population of cellular infiltrate in the liver together with the monitoring of viremia level and the level of hepatocyte necrosis, could be useful tools for elucidation of the pathogenesis of chronic hepatitis C.