Citations

AbstractThe experience at the Mayo Clinic, Rochester, Minnesota, U.S.A., with abdominal colectomy, mucosal proctectomy, and ileo‐anal anastomosis is now approaching 600 patients. The procedure is safe and, with careful timing and selection of patients, can be performed with minimal mortality. Postoperative morbidity, however, is still considerable, even in the most experienced hands. Increasing experience with the procedure has been shown to be associated with a continuing decline in the incidence of postoperative complications, and a defunctioning ileostomy is still a necessity in the majority of patients.Long‐term functional results of the procedure are satisfactory and have been shown to improve both with the experience of the operator and with the passage of time after surgery. Patient acceptance remains the ultimate sanction, and it appears that the majority of patients are satisfied with their outcome after ileo‐anal anastomosis, with only very few being prepared to consider an alternative. The operation appears to provide a superior quality of life relative to that expected after proctocolectomy and Brooke ileostomy.Not all patients with chronic ulcerative colitis or adenomatosis coli are potential candidates for this procedure, however. The problems of age, obesity, indeterminate colitis and Crohn's disease, co‐existing colorectal neoplasia, technical difficulties at the time of the operation, and the wishes of the patient all must be taken into consideration when assessing the optimal operation in a particular situation. Proctocolectomy with Brooke ileostomy or continent ileostomy and total abdominal colectomy with ileo‐rectal anastomosis both still have roles in the management of diseases such as chronic ulcerative colitis and adenomatosis coli. For a patient who is young, relatively fit, and well motivated and in whom there is little or no doubt about the diagnosis, ileo‐anal anastomosis must be considered as the possible treatment of choice. Increasing experience with the procedure and improvements in functional results seem to be confirming this position.

AbstractMultiple myeloma (MM) is a B-lineage malignancy characterized by diverse genetic subtypes and clinical outcomes. The recurrent immunoglobulin heavy chain (IgH) switch translocation, t(4;14)(p16;q32), is associated with poor outcome, though the mechanism is unclear. Quantitative reverse-transcription–polymerase chain reaction (RT-PCR) for proposed target genes on a panel of myeloma cell lines and purified plasma cells showed that only transcripts originating from the WHSC1/MMSET/NSD2 gene are uniformly dysregulated in all t(4;14)POS patients. The different transcripts detected, multiple myeloma SET domain containing protein (MMSET I), MMSET II, Exon 4a/MMSET III, and response element II binding protein (RE-IIBP), are produced by alternative splicing and alternative transcription initiation events. Translation of the various transcripts, including those from major breakpoint region 4-2 (MB4-2) and MB4-3 breakpoint variants, was confirmed by transient transfection and immunoblotting. Green fluorescent protein (GFP)–tagged MMSET I and II, corresponding to proteins expressed in MB4-1 patients, localized to the nucleus but not nucleoli, whereas the MB4-2 and MB4-3 proteins concentrate in nucleoli. Cloning and localization of the Exon 4a/MMSET III splice variant, which contains the protein segment lost in the MB4-2 variant, identified a novel protein domain that prevents nucleolar localization. Kinetic studies using photobleaching suggest that the breakpoint variants are functionally distinct from wild-type proteins. In contrast, RE-IIBP is universally dysregulated and also potentially functional in all t(4;14)POS patients irrespective of fibroblast growth factor receptor 3 (FGFR3) expression or breakpoint type.

Abstract Background: Measurements of serum or urine concentrations of synthetic glucocorticoids are useful for assessing suspected iatrogenic hypothalamic-pituitary-adrenal axis suppression and Cushing syndrome. We have developed a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantitative analysis of beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, fludrocortisone, flunisolide, fluorometholone, fluticasone propionate, megestrol acetate, methylprednisolone, prednisolone, prednisone, triamcinolone, and triamcinolone acetonide. Methods: Stable isotopes of cortisol-9,11,12,12-d4 and triamcinolone-d1 acetonide-d6 were added as internal standards to calibrators, controls, and unknown samples. After acetonitrile precipitation, these samples were extracted with methylene chloride, and the extracts were washed and dried. Reconstituted extract (15 μL) was injected on a reversed-phase column and analyzed by LC-MS/MS in positive-ion mode. Assay precision, accuracy, linearity, and sample stability were determined by use of enriched samples. Clinical validation included analysis of 8 serum and 20 urine samples from patients with undetectable cortisol concentrations and analysis of different types of tablets. Results: Functional assay sensitivity was as low as 0.6–1.6 nmol/L for all compounds except for triamcinolone (7.6 nmol/L). Interassay CVs were 3.0–20% for concentrations of 0.6–364 nmol/L for all analytes. Recoveries of all analytes (except triamcinolone in serum) were 82–138% at 19.2–693 nmol/L. All but one of the serum and urine samples from patients who were tested because of suppressed cortisol concentrations contained at least one synthetic steroid. Tablet analysis recovered 75% of the synthetic steroids in suspected drugs. Conclusions: LC-MS/MS allows simultaneous quantitative detection of various synthetic steroids in serum, plasma, urine, and tablets. This provides a valuable tool for evaluating the clinical effects of topical and systemic synthetic corticosteroids.

The mechanisms underlying CD4+ T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4+ and CD8+ T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4+ T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5+ CD4+ T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4+ T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5+ CD4+ T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation.

Wheelchair propulsion is a man-machine interaction in which chair design and fit affect the relative positions and orientations of the upper extremity relative to the handrim and wheel axle. To understand these relationships better, experimental data were collected in five hand positions from five subjects exerting maximal effort to propel an instrumented wheelchair with its wheel in a locked position. The results of experiments revealed that the progression moment was greater at both initial and terminal propulsion positions and smaller in the mid-propulsion position. The vertical and horizontal force components were directed radially away from the wheel axle posterior to the dead centre position and radially towards the wheel axle anterior to top dead centre. Subsequently, a subject-specific quasi-static model of the upper extremity which maximized wheel progression moment was developed to augment our understanding of experimental measures. Model-predicted trends in progression moments and hand force direction were similar to experiment. Model predictions revealed that the optimal progression moment generation could potentially be affected by an individual's anthropometric parameters, joint strengths and also the direction of force applied by the hand on the handrim. Through wheelchair fitting and training of wheelchair users, it may be possible to improve propulsion technique.