No evidence for linkage of a novel CA repeat polymorphism for apoptosis antigen 1 (APO-1 or fas) with type I diabetes in a Caucasian population

Abstract DNA typing of four tetrameric repeat loci (HUMVWA, HUMTH0I, D21SII and HPRT) was carried out in a Chinese Han population from Shanghai (East China) and one from Guangzhou (South-East China) using a quadruplex PCR amplification and detection of the fluorescent-labeled alleles on the ALF DNA sequencer. All loci were in accordance with Hardy-Weinberg equilibrium except for D21S11 in the Guangzhou population. A test for population differentiation showed no statistical difference in the allele frequency distribution between the two populations. Comparison of the allele frequency data with other Chinese Han populations from North and South-West China for the STR loci HUMVWA and HUMTH01 revealed heterogeneity between Northern Chinese Han and Southern Chinese Han, which is in accordance with previous studies on the basis of protein markers.     

Histopathology of coronary lesions with early loss of minimal luminal diameter after successful percutaneous transluminal coronary angioplasty: is thrombus a significant contributor?

BACKGROUND: Early loss of minimal luminal diameter of >0.3 mm after successful percutaneous transluminal coronary angioplasty (PTCA) is associated with a higher incidence of restenosis. The underlying mechanism of this early loss is unknown and thrombus may be a contributing factor. METHODS: We performed a prospective study using quantitative computerized planimetry on coronary tissue specimens obtained by directional coronary atherectomy of 24 lesions in which early loss occurred 22+/-9 minutes after successful PTCA. RESULTS: Thrombus was present in 9 (37%) of 24 coronary specimens. Segmental areas (mm2) and percentage of total area were distributed as follows: sclerotic tissue, 4.07+/-0.7 mm2 (63%+/-6%); fibrocellular tissue, 0.97+/-0.27 mm2 (16%+/-4%); hypercellular tissue, 0.99+/-0.29 mm2 (12%+/-3%); atheromatous gruel, 0.18+/-0.07 mm2 (3%+/-0.1%); and thrombus, 0.24+/-0.15 mm2 (6%+/-0.4%). There was no difference in the relative early loss index between lesions with or without thrombus (35%+/-7% vs 26%+/-2%, respectively; P= .87). Multiple stepwise regression analysis did not identify any histologic predictors of relative early loss index. CONCLUSION: Histopathologic analysis of coronary lesions with early loss after successful PTCA suggests that thrombus may not play a significant role in this angiographic phenomenon.     

Association of glutathione S-transferase GSTM1 and GSTT1 null genotypes with clinical outcome in epithelial ovarian cancer

Epithelial ovarian cancer is generally associated with a poor outcome, although the mechanisms that determine survival and progression-free interval (PFI) are unclear. Data from ovarian tumors showing associations between (a) null genotypes at the glutathione S-transferase GSTM1 and GSTT1 loci and expression of p53 protein and (b) outcome and expression of p53 suggest that polymorphism at these loci is a factor determining outcome. Accordingly, we have studied the association between the GSTM1 null and GSTT1 null genotypes and survival and PFI in 148 women with epithelial ovarian cancer. Although we did not find an association between individual genotypes and outcome, women with both GSTM1 null and GSTT1 null genotypes demonstrated poorer survival (P = 0.001) and reduced PFI (P = 0.003). Thus, no cases with both these genotypes survived past 42 months postdiagnosis. In contrast, 43% of the women without this combination survived beyond this time. Because response to chemotherapy is a major factor determining outcome in ovarian cancer, we also examined the data for associations between the glutathione S-transferase genotypes and response to such treatment. Thus, in 78 patients treated with chemotherapy, the combination of GSTM1 null and GSTT1 null was associated with unresponsiveness to primary chemotherapy (P = 0.004); none of the eight patients with both these genotypes responded, compared with 38 of 70 (54%) of patients with other genotype combinations. The effect of the combination of genotypes on survival and PFI was lost in a multivariate model that included response to chemotherapy as a confounding factor. This suggests that the combination of GSTM1 null/GSTT1 null is associated with outcome because of its influence on response to chemotherapy. These preliminary findings may provide a basis for the selection of patients for treatment with chemotherapeutic agents.     

Structural features of thyroid hormone response elements that increase susceptibility to inhibition by an RTH mutant thyroid hormone receptor

The chicken lysozyme silencer F2 (F2) thyroid hormone response element (TRE) contains an unusual everted palindromic arrangement, has a high affinity for thyroid hormone receptor (TR) homodimers, and is especially sensitive to dominant negative inhibition by, the T3 resistance (RTH) mutant TR beta P453H. We used various TREs and TR mutations to determine the mechanisms for this sensitivity. Changing the F2 orientation from an everted palindrome to a direct repeat with a 4-bp gap (DR+4) (F2-DR) decreased the sensitivity to inhibition at high T3 concentrations, while a loss of this sensitivity occurred with a palindromic arrangement of these same half-sites. F2 contains the dinucleotide TG 5' to each consensus half-site conforming to the optimal TR-binding octamer, YRRGGTCA. A T to A change in position 1 of both F2 half-sites markedly reduced T3-induction, yet only slightly reduced TR homodimer or TR-retinoid X receptor (RXR) heterodimer binding. The TR beta ninth heptad mutation, L428R, prevents TR heterodimerization with RXR and eliminates the inhibitory effect of the P453H mutant TR on the F2-DR, but not the F2 element. Structural features of a TRE that favor strong TR binding of both TR homodimers and TR-RXR heterodimers containing the mutant TR, such as the everted palindromic conformation or the optimal TR-binding consensus octamer, enhance the sensitivity of a TRE to inhibition by the mutant TR. Thus, both half-site orientation and sequence contribute to the sensitivity of a given TRE to dominant negative inhibition by a mutant TR.     

The Society of Gastrointestinal Radiologists: its future and relevance

The authors present a case of tremor isolated to the lower extremity that was treated with stereotactically guided thalamotomy in a patient with Parkinson's disease. The technology that makes this procedure effective for this particular manifestation of parkinsonism is discussed.     

Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA

Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus-type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen-peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.     

Effects of the PIPC model on outcome measures of productivity and costs

The purpose of this experimental research was to determine the effects of the Partners in Care Practice Model (PIPC) on the outcomes of productivity and costs. Over an 18-month study period, no significant differences were found in costs per patient day between the pilot and control units; however, significant differences were found in actual salaries, amount of time spent in documentation, and supply costs. Differences in costs and productivity reflected increased training costs and costs for additional supplies on the pilot unit.     

Bacterial lipopolysaccharide can enter monocytes via two CD14-dependent pathways

Host recognition and disposal of LPS, an important Gram-negative bacterial signal molecule, may involve intracellular processes. We have therefore analyzed the initial pathways by which LPS, a natural ligand of glycosylphosphatidylinositol (GPI)-anchored CD14 (CD14-GPI), enters CD14-expressing THP-1 cells and normal human monocytes. Exposure of the cells to hypertonic medium obliterated coated pits and blocked 125I-labeled transferrin internalization, but failed to inhibit CD14-mediated internalization of [3H]LPS monomers or aggregates. Immunogold electron microscope analysis found that CD14-bound LPS moved principally into noncoated structures (mostly tubular invaginations, intracellular tubules, and vacuoles), whereas relatively little moved into coated pits and vesicles. When studied using two-color laser confocal microscopy, internalized Texas Red-LPS and BODIPY-transferrin were found in different locations and failed to overlap completely even after extended incubation. In contrast, in THP-1 cells that expressed CD14 fused to the transmembrane and cytosolic domains of the low-density lipoprotein receptor, a much larger fraction of the cell-associated LPS moved into coated pits and colocalized with intracellular transferrin. These results suggest that CD14 (GPI)-dependent internalization of LPS occurs predominantly via noncoated plasma membrane invaginations that direct LPS into vesicles that are distinct from transferrin-containing early endosomes. A smaller fraction of the LPS enters via coated pits. Aggregation, which greatly increases LPS internalization, accelerates its entry into the nonclathrin-mediated pathway.