Citations

Thiopurine S -methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs. TPMT genetic polymorphisms represent a striking example of the potential clinical value of pharmacogenetics. Subjects homozygous for TPMT * 3A , the most common variant allele for low activity, an allele that encodes a protein with two changes in amino acid sequence, are at greatly increased risk for life-threatening toxicity when treated with standard doses of thiopurines. These subjects have virtually undetectable levels of TPMT protein. In this study, we tested the hypothesis that TPMT * 3A might result in protein misfolding and aggregation. We observed that TPMT * 3A forms aggresomes in cultured cells and that it aggregates in vitro , functional mechanisms not previously described in pharmacogenetics. Furthermore, there was a correlation among TPMT half-life values in rabbit reticulocyte lysate, aggresome formation in COS-1 cells, and protein aggregation in vitro for the three variant allozymes encoded by alleles that include the two TPMT * 3A single-nucleotide polymorphisms. These observations were compatible with a common structural explanation for all of these effects, a conclusion supported by size-exclusion chromatography and CD spectroscopy. The results of these experiments provide insight into a unique pharmacogenetic mechanism by which common polymorphisms affect TPMT protein function and, as a result, therapeutic response to thiopurine drugs.

AbstractIncreased attention to surgical indications and technique can minimize the risks of recurrent rectal cancer. In addition, the use of adjuvant chemoradiation therapy has been shown to further decrease the risks of recurrent rectal cancer. In the event a recurrence develops, surgical therapy, combined with radiation therapy, can result in local control in as many as 75% of patients and long term survival in 25% to 40% of patients.

AbstractResults from epidemiologic studies have provided insights into the etiology of large bowel cancer. Markedly diverse incidences of colorectal cancer exist in various parts of the world and within different regions of a given country. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk. Sedentary lifestyle, cholecystectomy, and ureterosigmoidostomy may also increase the risk of developing large bowel cancer.

During the past 3 decades implant arthroplasty of the destroyed wrist has become a reliable and satisfying procedure. However, the first total wrist replacement was performed in Berlin as early as 1890. This paper describes the history of resection and interposition arthroplasty of the wrist leading to the first total wrist implant arthroplasty performed by Themistocles Gluck. An overview of recent designs is given, and the relevant historical cases are reported.

We reviewed retrospectively a series of 128 consecutive patients who had wrist arthroscopy at our institution between January 1988 and July 1991. The aim of the procedure was to establish a diagnosis in 27 patients, to challenge a pre-operative diagnosis in 95 patients and to evaluate joint surfaces in six patients. For the 27 patients with a previously unknown diagnosis, the diagnostic sensitivity was 67% and the specificity 100%. Arthrotomy or other intervention was avoided in 18. For the 95 patients with an established pre-operative diagnosis, arthrotomy was avoided in 45: in 26 the desired procedure could be done arthroscopically, and in 19 the diagnosis, as improved by arthroscopy, was felt not to require further treatment. Procedures performed arthroscopically included débridement of triangular fibrocartilage and inter-carpal ligament tears; lysis of adhesions, and synovectomy. In six patients, arthroscopy was performed to evaluate joint surfaces after fracture reduction or before ulnar shortening osteotomy. In none of the six was arthrotomy felt necessary after arthroscopy. Wrist arthroscopy avoided the need for further surgery in 66 (52%) of our patients; arthrotomy was avoided in 69 (54%). In cases with significant carpal instability evident pre-operatively, arthroscopy was unlikely to avoid the need for open treatment.