Citations

▪ Abstract The potent immunosuppressive drugs FK506 and rapamycin interfere with signal transduction pathways required for T cell activation and growth. The distinct inhibitory effects of these drugs on the T cell activation program are mediated through the formation of pharmacologically active complexes with members of a family of intracellular receptors termed the FK506 binding proteins (FKBPs). The FKBP12 · FK506 complex specifically binds to and inhibits calcineurin, a signaling protein required for transcriptional activation of the interleukin (IL)-2 gene in response to T cell antigen receptor engagement. The FKBP12 · rapamycin complex interacts with a recently defined target protein termed the mammalian target of rapamycin (mTOR). Accumulating data suggest that mTOR functions in a previously unrecognized signal transduction pathway required for the progression of IL-2-stimulated T cells from G1into the S phase of the cell cycle. Here we review the immunopharmacology of rapamycin, with particular emphasis on the characterization of mTOR.

▪ Abstract Genetic disorders of mitochondrial fatty acid β-oxidation have been recognized within the last 20 years as important causes of morbidity and mortality, highlighting the physiological significance of fatty acids as an energy source. Although the mammalian mitochondrial fatty acid-oxidizing system was recognized at the beginning of the last century, our understanding of its exact nature remains incomplete, and new components are being identified frequently. Originally described as a four-step enzymatic process located exclusively in the mitochondrial matrix, we now recognize that long-chain-specific enzymes are bound to the inner mitochondrial membrane, and some enzymes are expressed in a tissue-specific manner. Much of our new knowledge of fatty acid metabolism has come from the study of patients who were diagnosed with single-gene autosomal recessive defects, a situation that seems to be further evolving with the emergence of phenotypes determined by combinations of multiple genetic and environmental factors. This review addresses the normal process of mitochondrial fatty acid β-oxidation and discusses the clinical, metabolic, and molecular aspects of more than 20 known inherited diseases of this pathway that have been described to date.

▪ Abstract In vitro studies of adipocytes taken from different body fat regions suggest substantial differences in lipolysis between intra-abdominal, lower-body subcutaneous, and abdominal subcutaneous regions. Gender and obesity appear to influence these regional differences. In situ measurements of glycerol release from adipose tissue provided further evidence that regional heterogeneity of lipolysis occurs in humans. In vivo studies of regional free fatty acid (FFA) release have confirmed that adipose tissue lipolysis varies between upper- and lower-body fat. Release of FFA from lower-body adipose tissue is less than that from upper-body adipose tissue in both obese and non-obese men and women. In non-obese men and women, meal ingestion suppresses FFA release from all adipose tissue regions, and adrenergic stimulation activated FFA release from different sites in a gender-specific fashion. Significant regional and gender differences in adipose tissue lipolysis occur in humans, and this could contribute to differences in the health effects of adipose tissue and could theoretically influence body fat distribution.

Renal insufficiency, which is present initially in almost half of patients with multiple myeloma, usually results from myeloma kidney or hypercalcemia. Neither the class of light chain nor the isoelectric point plays an important role in kidney failure. Acute renal failure must be treated with appropriate fluids and with electrolytes and hemodialysis if necessary. Plasma exchange may be helpful, but has not been proven as such. The presence of a nephrotic syndrome and a monoclonal κ or λ light chain in the urine almost always indicates primary amyloidosis (AL) or light-chain deposition disease. Amyloid fibrils must be distinguished from the fibrils of immunotactoid glomerulopathy.

A unified model for text categorization and text retrieval is introduced. We use a training set of manually categorized documents to learn word-category associations, and use these associations to predict the categories of arbitrary documents. Similarly, we use a training set of queries and their related documents to obtain empirical associations between query words and indexing terms of documents, and use these associations to predict the related documents of arbitrary queries. A Linear Least Squares Fit (LLSF) technique is employed to estimate the likelihood of these associations. Document collections from the MEDLINE database and Mayo patient records are used for studies on the effectiveness of our approach, and on how much the effectiveness depends on the choices of training data, indexing language, word-weighting scheme, and morphological canonicalization. Alternative methods are also tested on these data collections for comparison. It is evident that the LLSF approach uses the relevance information effectively within human decisions of categorization and retrieval, and achieves a semantic mapping of free texts to their representations in an indexing language. Such a semantic mapping lead to a significant improvement in categorization and retrieval, compared to alternative approaches.

Six cases of greater arc injury, defined as a perilunate dislocation of the carpus with a fracture of at least both the scaphoid and the capitate, were treated by open reposition and both internal and external fixation. Revascularisation of the capitate by implantation of the first dorsal intermetacarpal artery was attempted in three cases. At a mean follow-up of six years and four months, all patients complained of residual pain in the wrist. Carpal mobility and grip strength were reduced, and all patients showed mild or moderate arthritic changes. Progressive cartilage damage over the proximal pole of the capitate seems to be a determining factor in the outcome. Open reposition and both internal and external fixation are recommended in order to possibly diminish the incidence of arthritis and minimise secondary carpal instability.

ABSTRACT A 300-bp plasmid fragment of the hemagglutinin gene was used as target DNA to develop a rapid real-time LightCycler (Roche Applied Science, Indianapolis, Ind.) PCR assay for laboratory detection of smallpox virus. PCR primers and probes were designed specifically for detection of smallpox virus DNA, but all viruses of the genus Orthopoxvirus tested could be detected by use of the hemagglutinin gene target sequence. Base pair mismatches in the 204-bp amplicon allowed discrimination of cowpox virus (melting temperature [ T m ], 56.40°C), monkeypox virus ( T m , 56.24°C), and vaccinia virus ( T m , 56.72°C), including the Dryvax vaccine strain, from smallpox virus ( T m , 62.45°C) by melting curve analysis. The analytical sensitivity was 5 to 10 copies of target DNA per sample. The assay was specific for members of the genus Orthopoxvirus ; the DNAs of herpes simplex virus and varicella-zoster virus were not detected by the smallpox virus LightCycler PCR.

ABSTRACT The performance of the Amplified Mycobacterium Tuberculosis Direct (AMTD) test (Gen-Probe Inc., San Diego, Calif.) was assessed in a large tertiary care mycobacteriology laboratory. Both acid-fast smear-positive and smear-negative respiratory and nonrespiratory clinical specimens were analyzed. From February 1998 to 4 October 2001, AMTD assays were performed on 391 respiratory specimens and 164 nonrespiratory specimens. The AMTD assay was compared to the “gold standard” of combined culture and clinical diagnosis. The overall sensitivity for all specimens, including those for which no smear result was available, was 91.2%. The overall sensitivities of the assay, including acid-fast smear-positive and -negative specimens, were 97.8 and 77.3% for respiratory and nonrespiratory specimens, respectively. The corresponding specificities for respiratory and nonrespiratory specimens were 99.1 and 98.5%, respectively. The overall specificity for all specimens was 98.9%. Positive and negative predictive values were 93.9 and 99.7% and 91.7 and 96.4% for respiratory and nonrespiratory specimens, respectively. The time saved by using the AMTD test for making a diagnosis of tuberculosis instead of using culture was 8.99 days. Inhibitors to the AMTD assay were found in 3.1% of respiratory specimens and 3.1% of nonrespiratory specimens. The assay, used in a general mycobacteriology laboratory setting, represents an important advance in improving the speed and accuracy of diagnosis in the management of patients with tuberculosis.