ATI welcomes new dietitian.
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Community Health Services↗
Biomedical subjects
K Williams
Publications and source records attributed to K Williams.
Myocardial glucose utilization and optimization of (18)F-FDG PET imaging in patients with non-insulin-dependent diabetes mellitus, coronary artery disease, and left ventricular dysfunction.
UNLABELLED: In patients with non-insulin-dependent diabetes mellitus (NIDDM), FDG PET imaging is often problematic because of poor uptake of FDG. Different protocols have been used; however, these have not been directly compared in patients with NIDDM who have both coronary artery disease (CAD) and severe left ventricular (LV) dysfunction, for which defining viability is most relevant. The aim of this study was to better define the optimal means of FDG PET imaging, assessed by image quality and myocardial glucose utilization rate (rMGU), among 3 imaging protocols in patients with NIDDM, CAD, and severe LV dysfunction. METHODS: Ten patients with NIDDM, CAD, and severe LV dysfunction (mean ejection fraction, 29.8% +/- 7.1%) underwent dynamic FDG PET scanning using 3 different protocols: the standard protocol, consisting of oral glucose loading or a supplemental insulin bolus based on fasting glucose; the niacin protocol, consisting of pretreatment with niacin to lower free fatty acids; and the insulin clamp protocol, consisting of hyperinsulinemic euglycemic clamp. Image quality was satisfactory with at least 1 approach in 8 patients, who formed the primary analysis group. RESULTS: Myocardium-to-blood-pool ratios were significantly higher with the insulin clamp (standard, 1.7 +/- 1.2; niacin, 1.6 +/- 1.0; insulin clamp, 3.4 +/- 2.5 [P < 0.05 vs. standard and niacin]). Values for rMGU were higher with the insulin clamp (standard, 0.11 +/- 0.07 micromol/g/min; niacin, 0.12 +/- 0.11 micromol/g/min; insulin clamping, 0.22 +/- 0.12 micromol/g/min [P = 0.004 vs. standard and 0.07 vs. niacin]). CONCLUSION: The hyperinsulinemic euglycemic clamp yielded the highest FDG PET image quality and the highest rMGU in a comparison with the standard and niacin protocols in this difficult group of patients with NIDDM, CAD, and severe LV dysfunction. The hyperinsulinemic euglycemic clamp may be the preferred method for FDG PET viability imaging in this population. Larger clinical trials are needed to assess whether accuracy is greater with this approach.
Coronary Artery Disease↗
Identification, cloning, expression, and biochemical characterization of the testis-specific RNA polymerase II elongation factor ELL3.
The human ELL gene, which is a frequent target for translocation in acute myeloid leukemia, was initially isolated from rat liver nuclei and found to be an RNA polymerase II elongation factor. Based on homology to ELL, we later cloned ELL2 and demonstrated that it can also increase the catalytic rate of transcription elongation by RNA polymerase II. To better understand the role of ELL proteins in the regulation of transcription by RNA polymerase II, we have initiated a search for proteins related to ELLs. In this report, we describe the molecular cloning, expression, and characterization of ELL3, a novel RNA polymerase II elongation factor approximately 50% similar to both ELL and ELL2. Our transcriptional studies have demonstrated that ELL3 can also increase the catalytic rate of transcription elongation by RNA polymerase II. The C-terminal domain of ELL, which we recently demonstrated to be required and sufficient for the immortalization of myeloid progenitor cells, shares strong similarities to the C-terminal domain of ELL3. ELL3 was localized by immunofluorescence to the nucleus of cells, and Northern analysis indicated that ELL3 is a testis-specific RNA polymerase II elongation factor.
Amino Acid Sequence↗
Good practice guidance for continence services.
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Adult↗
Dobutamine stress echocardiography in patients undergoing liver transplantation evaluation.
BACKGROUND: Coronary artery disease has an important impact on perioperative morbidity and mortality in patients undergoing liver transplantation. To assess the role of dobutamine stress echocardiography (DSE) in these patients, DSE was included in the preoperative evaluation. METHODS: Patients under consideration for liver transplantation underwent detailed clinical history, electrocardiography, and echocardiography. Patients with documented coronary disease or symptoms of myocardial ischemia underwent angiography. The remaining patients with cardiac risk factors, atypical chest pain, or age > or = 60 years underwent DSE. RESULTS: These 121 patients (77 men and 44 women) ranged in age from 34 to 73 years (mean 53). Among the 61 patients who underwent liver transplantation, DSE was normal in 25, nondiagnostic in 34 because of inadequate heart rate response, and abnormal in two patients. Major perioperative events occurred in eight patients, all with normal or nondiagnostic DSE studies (negative predictive value 86%). CONCLUSIONS: In patients with low to moderate risk of cardiac disease, DSE performed as part of an evaluation for liver transplantation is a poor predictor of major perioperative events.
Adult↗
Identification of mismatch repair protein complexes in HeLa nuclear extracts and their interaction with heteroduplex DNA.
Deficiencies in DNA mismatch repair (MMR) have been found in hereditary colon cancers (hereditary non-polyposis colon cancer, HNPCC) as well as in sporadic cancers, illustrating the importance of MMR in maintaining genomic integrity. We have examined the interactions of specific mismatch repair proteins in human nuclear extracts. Western blot and co-immunoprecipitation studies indicate two complexes as follows: one consisting of hMSH2, hMSH6, hMLH1, and hPMS2 and the other consisting of hMSH2, hMSH6, hMLH1, and hPMS1. These interactions occur without the addition of ATP. Furthermore, the protein complexes specifically bind to mismatched DNA and not to a similar homoduplex oligonucleotide. The protein complex-DNA interactions occur primarily through hMSH6, although hMSH2 can also become cross-linked to the mismatched substrate when not participating in the MMR protein complex. In the presence of ATP the binding of hMSH6 to mismatched DNA is decreased. In addition, hMLH1, hPMS2, and hPMS1 no longer interact with each other or with the hMutSalpha complex (hMSH2 and hMSH6). However, the ability of hMLH1 to co-immunoprecipitate mismatched DNA increases in the presence of ATP. This interaction is dependent on the presence of the mismatch and does not appear to involve a direct binding of hMLH1 to the DNA.
Adaptor Proteins, Signal Transducing↗
Three-dimensional conformal therapy or standard irradiation in localized carcinoma of prostate: preliminary results of a nonrandomized comparison.
PURPOSE: We present preliminary results of a nonrandomized comparison of three-dimensional conformal radiation therapy (3D CRT) and standard radiation therapy (SRT) in localized carcinoma of the prostate in two groups of patients with comparable prognostic factors treated during the same period. METHODS AND MATERIALS: Between January 1992 and December 1997, 146 patients were treated with 3D CRT and 131 with SRT alone for clinical stage T1c or T2 histologically confirmed carcinoma of the prostate. None of these patients received hormonal therapy. Mean follow-up for all patients is 3 years (range, 1-6 years). For 3D CRT, 7 intersecting fields were used (Cerrobend blocking or multileaf collimation) to deliver 68-73.8 Gy to the prostate; 3D dose distributions and dose-volume histograms (DVHs) of the planning target volume, bladder, and rectum were obtained. SRT consisted of bilateral 120 degrees rotational arcs, with portals with 2-cm margins around the prostate to deliver 68-70 Gy to the prostate. The criterion for chemical disease-free survival was a postirradiation prostate-specific antigen (PSA) (Tandem-R, Hybritech) value following the American Society for Therapeutic Radiology and Oncology guidelines. Symptoms during treatment were quantitated weekly, and late effects were assessed every 4-6 months. RESULTS: DVHs showed a two-thirds reduction in normal bladder or rectum receiving 70 Gy or more with 3D CRT. Higher 5-year chemical disease-free survival was observed with 3D CRT (91% for T1c and 96% for T2 tumors) compared with SRT (53% and 58%, respectively). There was no statistically significant difference in chemical disease-free survival in patients with Gleason score of 4 or less (p = 0.83), but with Gleason score of 5-7, the 5-year survival rates were 96% with 3D CRT and 53% with SRT (p < or = 0.01). In 111 patients with pretreatment PSA of 10 ng/mL or less, treated with 3D CRT, the chemical disease-free rate was 96% vs. 65% in 94 patients treated with SRT (p < or = 0.01). In patients with PSA of 10. 1-20 ng/mL, the chemical disease-free survival rate for 26 patients treated with 3D CRT was 88% compared with 40% for 20 patients treated with SRT (p = 0.05). The corresponding values were 71% and 26%, respectively, for patients with PSA levels of greater than 20 ng/mL (p = 0.30). On multivariate analysis, the most important prognostic factors for chemical failure were pretreatment PSA (p = 0. 023), nadir PSA (p = 0.001), and 3D CRT technique (p = 0.033). Moderate dysuria and difficulty in urinating were reported by 2-5% of patients treated with 3D CRT in contrast to 6-9% of patients treated with SRT; moderate urinary frequency and nocturia were reported by 18-24% treated with 3D CRT and 18-27% of patients in the SRT group. The incidence of moderate loose stools/diarrhea, usually after the 4th week of treatment, was 3-5% in the 3D CRT patients and 8-19% in the SRT group. Late intestinal morbidity (proctitis, rectal bleeding) was very low (1.7%) in the 3D CRT group in contrast to the SRT patients (8%). CONCLUSION: Three-dimensional CRT spares more normal tissues, yields higher chemical disease-free survival, and results in less treatment morbidity than SRT in treatment of Stage T1-T2 prostate cancer. Longer follow-up is needed to confirm these preliminary observations.
Disease-Free Survival↗
Investigation into the role of the serine protease HtrA in Yersinia pestis pathogenesis.
The HtrA stress response protein has been shown to play a role in the virulence of a number of pathogens. For some organisms, htrA mutants are attenuated in the animal model and can be used as live vaccines. A Yersinia pestis htrA orthologue was identified, cloned and sequenced, showing 86% and 87% similarity to Escherichia coli and Salmonella typhimurium HtrAs. An isogenic Y. pestis htrA mutant was constructed using a reverse genetics approach. In contrast to the wild-type strain, the mutant failed to grow at an elevated temperature of 39 degrees C, but showed only a small increase in sensitivity to oxidative stress and was only partially attenuated in the animal model. However, the mutant exhibited a different protein expression profile to that of the wild-type strain when grown at 28 degrees C to simulate growth in the flea.
Animals↗
Differential vulnerability of primary cultured cholinergic neurons to nitric oxide excess.
Many neuronal nitric oxide synthase (nNOS)-expressing brain neurons, including some cholinergic populations, are resistant to disease or to certain forms of excitotoxicity. Vulnerability to NO excess of forebrain (medial septal/diagonal band; MS-ACh) and brainstem (pedunculopontine/laterodorsal tegmental nuclei; BS-ACh) cholinergic neurons was compared in E16-E18 primary rat brain cultures. MS-ACh cells were approximately 300-fold more sensitive to the NO donor S-nitro-N-acetyl-D,L-penicillamine (SNAP) than were BS-ACh cells. Most (69%) MS-ACh cells contained nuclear DNA fragments by 2 h after addition of SNAP, while only 21% BS-ACh cells were TUNEL-positive after NO excess. Depletion of glutathione content did not potentiate the effect of SNAP on MS-ACh cells, but sensitized BS-ACh cells to the NO donor. Caffeic acid, a putative NF-kappa B inhibitor, enhanced the toxicity of SNAP to cholinergic neurons in both preparations. Our experiments show that cholinergic neurons in mixed primary cultures from different brain regions possess biochemical differences with respect to their vulnerability to NO excess.
Acetylcholine↗
Serotonergic modulation of the P13 midlatency auditory evoked potential in the rat.
The vertex-recorded, sleep state-dependent P13 midlatency auditory evoked potential in the rat may be generated, in part, by pedunculopontine nucleus (PPN) projections. Injections into the PPN of the 5-HT(1A) serotonin receptor agonist, 8-hydroxy-2-di-n-propylaminotetralin hydrobromide (DPAT), were found to reduce the amplitude of the P13 potential in a dose- and time-dependent manner. The suppressive effect of DPAT was blocked or reduced by pretreatment with the 5-HT(1A) serotonin receptor antagonist, Pindobind. These results show that the P13 potential can be modulated by known inhibitory serotonergic inputs to the PPN.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Soluble antigen and CD40 triggering are sufficient to induce primary and memory cytotoxic T cells.
The signals directing induction of tolerance rather than immunity are largely unknown. The CD8 T cell response to soluble Ags generally results in deletional tolerance following transient, costimulation-dependent activation. We demonstrated that CD40 signaling reversed the outcome of this response. Adoptive transfer of OVA-specific CD8 T cells followed by soluble OVA immunization resulted in induction of lytic activity and optimal clonal expansion only when CD40 was triggered via an agonistic mAb. Activation of CD8 T cells by CD40 signaling was indirect, because CD40 expression by host cells was required. CD40 signaling along with soluble Ag immunization also induced expansion of secondary lymphoid and intestinal mucosal endogenous OVA-specific CD8 T cells as detected by MHC tetramer reactivity. When CD40 activation was included, long-lived secondary lymphoid and mucosal memory CD8 cells were generated from adoptively transferred and endogenous CD8 T cells. Mucosal and peripheral CD8 memory cells exhibited constitutive Ag-specific lytic activity, with mucosal memory cells being 10-fold more lytic than splenic or lymph node memory cells. These results demonstrated that CD40 signaling during a response to a poorly immunogenic soluble Ag was necessary and sufficient for CTL and memory T cell induction.
Adoptive Transfer↗
Bladder training for urinary incontinence in adults.
BACKGROUND: Bladder training is widely used for the treatment of urinary incontinence. It is generally used for the treatment of people with urge incontinence or detrusor instability, although it is also thought that it might be of use for people with mixed incontinence or stress incontinence. OBJECTIVES: To assess the effects of bladder training for the treatment of urinary incontinence. SEARCH STRATEGY: We searched the Cochrane Incontinence Group trials register up to July 1999. Date of the most recent search: July 1999. SELECTION CRITERIA: Randomised or quasi-randomised trials of bladder training for the treatment of incontinence. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data that were then cross-checked by the third reviewer. All three reviewers assessed trial quality. MAIN RESULTS: We found seven eligible trials with a total of 259 predominantly female patients with urinary urge incontinence. The quality of trials was variable. Three trials involving 92 women compared bladder training with no bladder training. These tended to favour bladder training but data were available for only a limited number of pre-specified outcomes that varied across the three trials. No data describing long term follow up are available. One trial compared bladder training with drug therapy, but was inconclusive. Another trial compared bladder training with an electronic prompt device. The trial was small and included only 20 women. Data were not presented in a form suitable for quantitative analysis. Two further trials compared bladder training supplemented by drug therapy with bladder training alone. Again, the limited data provided insufficient evidence on which to draw conclusions. REVIEWER'S CONCLUSIONS: Bladder training may be helpful for the treatment of urinary urge incontinence, but this conclusion can only be tentative, based on the evidence available. There was not enough evidence to show whether drug therapy was better than bladder training or useful as a supplement to it.
Adult↗
Myeloma proteins that bind Hsp65 (GroEL) are polyreactive and are found in high incidence in pristine induced plasmacytomas.
The myeloma proteins produced by 44 plasmacytomas (PCTs) recently induced by pristane in BALB/cAnPt and closely related PCT susceptible congenic strains of mice were isolated chromatographically and screened against a panel of 10 protein, nucleic acid and lipid antigens. This sample was highly unusual because 82% of the proteins had IgG isotopes. Nine of the proteins bound to Hsp65 (GroEL), and all of these were polyreactative. Twenty-one of the myeloma proteins were polyreactive and bound two or more antigens in the panel, and five were monoreactive. Thus, an antigen binding activity was determined for 59% of these myeloma proteins.
Animals↗
All trans retinoic acid induces apoptosis in acute promyelocytic NB4 cells when combined with isoquinolinediol, a poly(ADP-ribose) polymerase inhibitor.
NB4 cells, a model of acute promyelocytic leukemia have been shown to undergo granulocytic differentiation in response to all trans retinoic acid (ATRA), or monocytic differentiation in response to 1alpha,25 dihydroxyvitamin D(3) (1,25 D(3)) and phorbol ester. We have shown previously that the expression of poly(ADP-ribose) polymerase (PARP) is dramatically increased during monocytic differentiation and completely down-regulated during neutrophilic differentiation. Here we show that NB4 cells simultaneously treated with ATRA and isoquinolinediol (Iso-Q), a specific PARP inhibitor, fail to differentiate into neutrophils. Nitroblue tetrazolium (NBT) dye reduction was inhibited by 48% and neutrophil formation was reduced by 75%. NB4 cells treated with ATRA and Iso-Q instead showed features of apoptosis including nuclear condensation, DNA fragmentation, and PARP cleavage yielding a 85 kDa fragment. NB4 cells treated with ATRA in combination with 1,25 D(3), a monocytic differentiation inducer, while continuing to reduce NBT also failed to mature into neutrophils or monocytes and again showed features of apoptosis. Down-regulation of Bcl-2 protein expression was evident in NB4 cells treated with ATRA and ATRA in combination with Iso-Q or 1,25 D(3), but not in cells treated with a classic chemotherapeutic agent, arabinosycytosine, suggesting that Bcl-2 down-regulation is neither necessary, nor specific for apoptosis in this model.
Apoptosis↗
Induction of progesterone receptor immunoexpression in stromal tissue throughout the male reproductive tract after neonatal oestrogen treatment of rats.
Oestrogen exposure of the male during fetal/neonatal life can fundamentally alter the structure and function of the reproductive system, though how is unknown. This study examined whether such treatment was able to induce a 'female' characteristic, namely immunoexpression of progesterone receptor (PR), in the reproductive system of the male. Rats were treated on postnatal days 2, 4, 6, 8, 10 and 12 with either 10, 1 or 0.1 microg diethystilbestrol (DES) or with the vehicle (20 microl corn oil). Groups of control and treated rats were killed on days 18, 25, 35 and 90 (= adults) and tissues fixed in Bouins for immunolocalisation studies using antisera to PR (recognises A and B forms) and oestrogen receptor-beta (ER beta). PR immunoexpression was absent from all tissues studied in control rats at all ages with the exception of the parasympathetic ganglia of the prostate. In rats treated with 10 microg DES, intense immunoexpression of PR was detected in the nuclei of stromal, but not epithelial, cells of the caput and cauda epididymis, the vas deferens, seminal vesicles and at the base of the dorsolateral prostatic complex (DLPC) at day 18, but was absent from the ventral prostate and from the testis. DES induction of PR immunoexpression was evident after a single injection (on day 3) and at 18-35 days the intensity of immunoexpression was DES dose-dependent; rats treated neonatally with 0.1 microg DES showed no detectable PR immunoexpression at any age. These findings were confirmed by Western analysis which indicated that most of the PR induced was probably the B form. Co-localisation studies, using confocal microscopy, demonstrated that PR and ER beta frequently co-localised to the same stromal cells in the DLPC, epididymis and seminal vesicles of DES-treated rats at day 18, whereas epithelial cells, which also expressed ER beta, did not express PR. In the tissues studied, only occasional stromal cells expressed ER alpha in comparison to the more widespread expression of ER beta, although epithelial cell expression of ER alpha was also detected in the epididymis on day 18 (but not on day 10). In DES-treated rats, immunoexpression of PR in the reproductive tract decreased progressively in intensity from days 18-35 and was non-detectable in adulthood. In conclusion, these findings are interpreted as evidence that neonatal oestrogen treatment exerts pervasive 'reprogramming' effects throughout the reproductive system of the developing male as indicated by the induction of PR immunoexpression. This induction was restricted to stromal tissue even though both stromal and epithelial cells at most sites expressed ER beta and/or ER alpha.
Aging↗
Inducible expression of a p56Lck transgene reveals a central role for Lck in the differentiation of CD4 SP thymocytes.
The T lymphocyte-specific protein tyrosine kinase p56lck (Lck) is an essential component of the TCR-mediated signal transduction complex. Lck knockout mice have reduced numbers of double-positive thymocytes and very few mature single-positive cells, particularly of the CD4 lineage. Here we demonstrate the ability of a tetracycline-based tissue-specific inducible Lck transgene to restore expansion of early thymocytes and maturation of single-positive cells in Lckneg mice upon induction with doxycycline. Restoration of Lck expression is particularly important for positive selection to the CD4+ lineage but has a lesser impact on selection to the CD8+ lineage, suggesting activation of Lck is an important component of the signals involved in lineage choice during thymic differentiation.
Animals↗
Patient satisfaction with urodynamics: a qualitative study.
This qualitative study was undertaken to assess patients' views of the urodynamic investigation. The aim was to identify the dimensions important to patients in evaluating satisfaction with this type of procedure and ways in which care could be improved. Unstructured interviews were carried out by four trained interviewers with 21 people (17 female and 4 male) who had undergone the urodynamic investigation at various gynaecology, urology and continence outpatient clinics. The interviews were audio-taped and transcribed verbatim. The data was then coded and a thematic analysis carried out. The main theme to emerge was focused on patients' feelings about the procedure. This consisted of a combination of anxiety and embarrassment. Anxiety was because of fear of the unknown and embarrassment at the intimate nature of the procedure and lack of privacy. The interpersonal and communication skills of the health care professional were central in alleviating these negative feelings. The establishment of a friendly relationship based on equality and mutual respect and trust was important in preventing anxiety and embarrassment. A number of practical issues were identified that would contribute to improving the service for patients. It was found that nurses possessed all the attributes required to provide an effective service and recommendations were made that nurses specializing in continence care should take a more active role in urodynamic investigations.
Adult↗
FrzB-2: a human secreted frizzled-related protein with a potential role in chondrocyte apoptosis.
OBJECTIVE: To characterize a novel secreted frizzled-related protein (SFRP) and determine its tissue distribution at the mRNA and protein level. METHODS: The FrzB-2 gene was identified by expressed sequence tag (EST) analysis of human tissue-derived libraries. Tissue distribution of FrzB-2 mRNA was determined by Northern blot analysis and in situ hybridization. FrzB-2 protein reactivity was localized in human OA articular cartilage by immunocytochemistry, using a polyclonal antibody against a peptide sequence unique to FrzB-2. Apoptosis was detected in articular cartilage sections using Tunel staining. RESULTS: ESTs corresponding to FrzB-2 were found in osteoblast, chondrosarcoma, osteosarcoma, osteoclastoma and synovial fibroblast libraries. FrzB-2 mRNA is expressed in a number of tissues and cell types including bone-related cells and tissues such as primary human osteoblasts and osteoclastoma. In situ hybridization studies showed strong FrzB-2 mRNA expression in human chondrocytes in human osteoarthritic (OA) cartilage but negligible levels in normal cartilage chondrocytes. The FrzB-2 cDNA encodes a secreted 40 kDa protein consisting of 346 amino acids. FrzB-2 is 92. 5% identical to the rat orthologue, DDC-4, which has been shown to be associated with physiological apoptosis. FrzB-2 protein was selectively detected in human OA articular cartilage by immunocytochemistry, using a polyclonal antibody. Consistent with its potential role in apoptosis, positive FrzB-2 staining and Tunel positive nuclei staining were detected in chondrocyte clones in sections of human OA cartilage. CONCLUSION: These data suggest that FrzB-2 may play a role in apoptosis and that the expression of this protein may be important in the pathogenesis of human OA.
Amino Acid Sequence↗