Biomedical subjects
Publications and source records attributed to J C Walsh.
A 26-year-old man presented with left leg pain and progressive paraparesis. Imaging revealed a large intradural tumour compressing the cauda equina. The lesion was radically resected and histological analysis revealed it to be a paraganglioma. The clinical features of this rare tumour are described with a review of the literature.
This study was designed to examine the effects of preparatory information and behavioural training on patients about to undergo an endoscopy procedure. Forty-five first-time endoscopy patients (aged 20-70 years), were randomly assigned to one of three groups (cognitive, cognitive/behavioural and control group). The cognitive group received a 12 min preparation with sensory and procedural information relating to the sensations and sequence of events associated with the endoscopy procedure. The cognitive/behavioural group received, in addition, instruction in deep breathing exercises, tongue depressor task and swallowing technique. Results indicated that patients in the two experimental conditions experienced significantly fewer signs of behavioural distress during endoscopy. The cognitive group required a significantly shorter time to induce the scope. There were no statistical differences between the groups however, for mood, physiological and anxiety measures, although a positive trend was evident for the two intervention groups.
The aim of this study was to examine current approaches to supporting adherence to antiretroviral therapy in UK HIV clinics. One hundred HIV/AIDS/GUM physicians were interviewed: 97% were personally involved in discussing adherence, spending 22% of consultation time on this issue and assessing adherence most commonly by patient self-report (88%). Other personnel involved included nurses (74%), other doctors (56%), health advisers (54%) and pharmacists (48%). Among criteria for achieving treatment success, adherence support ranked fourth after 'treatment fitting well into patient's lifestyle', regular viral load monitoring and the 'experience of the clinician/healthcare team'. A variety of tools were used to support adherence including dosette boxes (53%), written information (44%) and verbal communication (42%). Only 20% of physicians followed adherence protocols or formal guidelines. Three-quarters of physicians had received no training on adherence issues. The most common ways physicians kept informed about adherence matters were by attending conferences (87%), reading literature (71%) and learning from colleagues (51%). Eighty-seven per cent of physicians believed national adherence guidelines would be valuable. In conclusion, there is a need for training and direction within current adherence support services. National guidelines could provide a valuable framework for health care professionals.
Chromium tricarbonyl complexed aryl aldeyhydes and ketones underwent Sm(II)-promoted radical lactone formation in the presence of alpha,beta-unsaturated esters to produce diastereomerically pure lactones in good yields. The completely diastereoselective lactone formation involves capture of the benzylic ketyl radical by the ester anti to the chromium tricarbonyl moiety. The relative stereochemistry of the lactone and chromium tricarbonyl moieties was proven by X-ray crystallography and supports the proposed mechanism. Enantiopure chromium tricarbonyl complexed arenes afforded single enantiomers when subjected to Sm(II)-promoted radical lactone formation condiditions. The enantio- and diastereomerically pure chromium tricarbonyl complexed lactones were subsequently treated with BF3.OEt2 to generate a mixture of diastereomers via Lewis acid promoted chromium tricabonyl directed cationic rearrangement. The diastereomers were separated and individually decomplexed with I2 to afford both of the corresponding chromium-free enantiomerically pure lactones starting from a single enantiomerically pure chromium tricarbonyl complex.
The objective of the study was to define common reasons for non-adherence (NA) to highly active antiretroviral therapy (HAART) and the number of reasons reported by non-adherent individuals. A confidential questionnaire was administered to HIV-seropositive patients taking proteinase inhibitor based HAART. Median self-reported adherence was 95% (n = 178, range = 60-100%). The most frequent reasons for at least 'sometimes' missing a dose were eating a meal at the wrong time (38.2%), oversleeping (36.3%), forgetting (35.0%) and being in a social situation (30.5%). The mean number of reasons occurring at least 'sometimes' was 3.2; 20% of patients gave six or more reasons; those reporting the lowest adherence reported a significantly greater numbers of reasons (rho = - 0.59; p < 0.001). Three factors were derived from the data by principal component analysis reflecting 'negative experiences of HAART', 'having a low priority for taking medication' and 'unintentionally missing doses', accounting for 53.8% of the variance. On multivariate analysis only the latter two factors were significantly related to NA (odds ratios 0.845 and 0.849, respectively). There was a wide spectrum of reasons for NA in our population. The number of reasons in an individual increased as adherence became less. A variety of modalities individualized for each patient are required to support patients with the lowest adherence.
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The degree of patient adherence is increasingly recognized to be a key factor in the success of highly active antiretroviral therapy (HAART). HAART regimens are also among the most complex ever prescribed and low adherence is directly related to treatment complexity. Physicians prescribing HAART need to make adherence a priority both in clinical practice and in the design and interpretation of clinical trials if HAART really is to succeed in the long term.
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PU.1 is a unique regulatory protein required for the generation of both the innate and the adaptive immune system. It functions exclusively in a cell-intrinsic manner to control the development of granulocytes, macrophages, and B and T lymphocytes. We demonstrate that mutation of the PU.1 gene causes a severe reduction in myeloid (granulocyte/macrophage) progenitors. PU.1 -/- myeloid progenitors can proliferate in vitro in response to the multilineage cytokines interleukin-3 (IL-3), IL-6 and stem cell factor but are unresponsive to the myeloid-specific cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and M-CSF. The failure of PU.1 -/- progenitors to respond to G-CSF is bypassed by transient signaling with IL-3. In the presence of IL-3 and G-CSF, PU.1 -/- progenitors can differentiate into granulocytic precursors containing myeloperoxidase-positive granules. Thus PU.1 is not essential for specification of granulocytic precursors, but is required for their further differentiation. The failure of PU.1 -/- progenitors to respond to M-CSF is due to lack of c-fms gene transcription. Transduction of c-fms into PU.1 -/- myeloid progenitors bypasses the block to M-CSF-dependent proliferation but does not induce detectable macrophage differentiation. Therefore, PU. 1 appears to be essential for specification of monocytic precursors. Importantly, retroviral transduction of PU.1 into mutant progenitors restores responsiveness to myeloid-specific cytokines and development of mature granulocytes and macrophages. Thus PU.1 controls myelopoiesis by regulating both proliferation and differentiation pathways.
OBJECTIVE: To assess the effect of combination antiretroviral therapy including HIV protease inhibitors on the survival of patients with cytomegalovirus retinitis (CMVR). DESIGN AND PARTICIPANTS: A longitudinal study of patients with CMVR diagnosed between October 1992 and May 1996 and followed to May 1997. SETTING: UK National Health Service specialist HIV medicine department. OUTCOME MEASURE: Time to death from first diagnosis of CMVR. Data were censored on 31 May 1997. RESULTS: Data were available on 147 patients with CMVR. Median survival of CMVR patients before December 1995 was 256 days [95% confidence interval (CI), 197-315]. Following the introduction of protease inhibitors in December 1995 this rose to 555 days (95% CI, 351-759). By 31 May 1996 median survival for the entire group of patients alive with CMVR had risen to 720 days (95% CI, 551-889). The mean survival after CMVR diagnosis was 224 days (n=89; 95% CI, 186-261; 1-year survival, 16%) in those who took no further antiretroviral therapy, 353 days in those who took nucleoside reverse transcriptase inhibitors but no protease inhibitors (n=34; 95% CI, 289-418; 1 -year survival, 50%), and 914 days in those who took a protease inhibitor (n=24; 95% CI, 768-1059; 1-year survival, 83%; P < 0.0001). Multivariate analysis showed that the strongest independent predictor of improved survival was having ever received a protease inhibitor after CMVR (relative risk of death, 0.063; 95% CI, 0.027-0.149; P < 0.0001). CONCLUSIONS: The use of HIV protease inhibitors in combination antiretroviral therapy has been associated with a marked increase in the survival of patients with CMVR.
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PURPOSE: Low-dose-rate radiation therapy has been widely used in the treatment of urogenital malignancies. When continuously exposed to low-dose-rate ionizing radiation, target cancer cells typically exhibit abnormalities in replicative cell-cycle progression. Cancer cells that arrest in the G2 phase of the cell cycle when irradiated may become exquisitely sensitive to killing by further low-dose-rate radiation treatment. Oncogenic human papillomaviruses (HPVs), which play a major role in the pathogenesis of uterine cervix cancers and other urogenital cancers, encode E6 and E7 transforming proteins known to abrogate a p53-dependent G1 cell-cycle checkpoint activated by conventional acute-dose radiation exposure. This study examined whether expression of HPV E6 and E7 oncoproteins by cancer cells alters the cell-cycle redistribution patterns accompanying low-dose-rate radiation treatment, and whether such alterations in cell-cycle redistribution affect cancer cell killing. METHODS AND MATERIALS: RKO carcinoma cells, which contain wild-type P53 alleles, and RKO cell sublines genetically engineered to express HPV E6 and E7 oncoproteins, were treated with low-dose-rate (0.25-Gy/h) radiation and then assessed for p53 and p21WAF1/CIP1 polypeptide induction by immunoblot analysis, for cell-cycle redistribution by flow cytometry, and for cytotoxicity by clonogenic survival assay. RESULTS: Low-dose-rate radiation of RKO carcinoma cells triggered p53 polypeptide elevations, p21WAF1/CIP1 induction, and arrest in the G1 and G2 phases of the cell cycle. In contrast, RKO cells expressing E6 and E7 transforming proteins from high-risk oncogenic HPVs (HPV 16) arrested in G2, but failed to arrest in G1, when treated with low-dose-rate ionizing radiation. Abrogation of the G1 cell-cycle checkpoint activated by low-dose-rate radiation exposure appeared to be a characteristic feature of transforming proteins from high-risk oncogenic HPVs: RKO cells expressing E6 from a low-risk nononcogenic HPV (HPV 11) exposed to low-dose-rate radiation arrested in both G1 and G2. Surprisingly, despite differences in cell-cycle redistribution accompanying low-dose-rate radiation treatment associated with high-risk HPV transforming protein expression, no consistent differences in clonogenic survival following low-dose-rate radiation treatment were found for RKO cell sublines expressing high-risk HPV oncoproteins and arresting only in G2 during low-dose-rate radiation exposure vs. RKO cell sublines exhibiting both G1 and G2 cell-cycle arrest when irradiated. CONCLUSION: The results of this study demonstrate that neither HPV oncoprotein expression nor loss of the radiation-activated G1 cell-cycle checkpoint alter the sensitivity of RKO carcinoma cell lines to low-dose-rate radiation exposure in vitro. Perhaps for urogenital malignancies associated with oncogenic HPVs in vivo, HPV oncoprotein-mediated abrogation of the G1 cell-cycle checkpoint may not limit the potential efficacy of low-dose-rate radiation therapy.
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BACKGROUND: Gene-modified tumor cell vaccines have shown efficacy in animal models of malignancy, including prostate cancer. Class I major histocompatibility complex (MHC) assembly and function in the cellular targets of such therapies is pivotal in determining the efficacy of specific cytokine-secreting tumor vaccines. PURPOSE: To help guide development of genetically engineered vaccine therapy for human prostate cancer, potential immune resistance pathways were evaluated by analysis of class I MHC assembly in prostate cancer cells. METHOD: Class I MHC assembly in metastasis-derived human prostate cancer cell lines (LNCaP, PPC-1, DU-145, PC-3, and TSU) and a normal prostate-derived cell line (TP-2) were characterized by phenotypic, molecular, and functional assays. Assembled class I MHC and antigen was measured by flow cytometry; mRNA levels of assembly components (class I MHC heavy chain, beta 2-microglobulin, and the antigen transporter gene product TAP-2) were determined; and antigen processing was measured with a chimeric reconstituted system using vaccinia vectors. Restoration of antigen processing was attempted by interferon gamma stimulation and by transfection with mouse class I MHC heavy-chain cDNA. RESULTS: Assembled class I MHC was underexpressed in two (LNCaP and PPC-1) of five prostate cancer cell lines compared with normal prostate-derived controls. PPC-1 cells underexpressed TAP-2 mRNA despite abundant class I MHC and beta 2-microglobulin message. Induction of TAP-2 by interferon gamma indicated that coding sequences for TAP-2 message were present in PPC-1. Resistance to cytotoxic T lymphocytes (CTL) lysis showed a functional defect in antigen transport by PPC-1 cells; reversal of the molecular defect with interferon gamma led to restoration of functional antigen processing. In contrast, LNCaP cells had competent antigen transport but deficient class I MHC heavy-chain function despite abundant class I MHC RNA; though refractory to stimulation by interferon gamma, this defect responded to transfection of class I MHC heavy-chain cDNA. CONCLUSIONS: Metastatic prostate cancer cells can escape T-cell recognition via divergent mechanisms of defective class I MHC assembly. The specific underexpression of TAP-2 gene product in PPC-1 cells contrasts with prior studies of TAP gene underexpression in lung cancer (which concurrently underexpressed class I MHC heavy chain) and provides evidence for a regulatory pathway controlling TAP-2 gene expression in human cancers that may not affect class I MHC heavy-chain expression. IMPLICATIONS: In clinical application of gene therapy for prostate cancer, these findings provide a rationale for focusing on strategies that can circumvent sole reliance on class I MHC-mediated tumor cell recognition by CTL.
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Proliferating cells characteristically undergo programmed (i.e. apoptotic) death if their progression through the cell cycle is sufficiently perturbed. To determine whether androgen ablation-induced programmed death of prostatic glandular cells involves apoptosis triggered by recruitment of nonproliferating cells into a perturbed cell cycle, rat ventral prostates were assessed temporally after castration for several stereotypical molecular stigmata of entry into the proliferative cell cycle. Northern blot analysis was used to assess levels of transcripts from genes characteristically activated 1) during the transition from quiescence (G(0)) into G1 of the proliferative cell cycle (cyclin-D1 and cyclin-C), 2) during the transition from G1 to S (cyclin-E, cdk2, thymidine kinase, and H4-histone), and 3) during progression through S (cyclin-A). Although levels of each of these transcripts increased as expected in prostatic glandular epithelial cells stimulated to proliferate by the administration of exogenous androgen to previously castrated rats, levels of the same transcripts decreased in prostatic glandular cells induced to undergo apoptosis after androgen withdrawal. Northern and Western blot analyses also demonstrated that there was no increase in prostatic p53 messenger RNA or protein content per cell after androgen ablation. Likewise, after castration, there was no enhanced prostatic expression of the WAF1/CIP1 gene, a gene whose expression is known to be induced in both a p53-dependent and -independent manner during recruitment from G0 into G1. In addition, androgen ablation-induced apoptosis of prostatic glandular cells was not accompanied by retinoblastoma protein phosphorylation, which is characteristic of progression into late G1. Nuclear run-on assays demonstrated that there was no increase in the prostatic rate of transcription of the c-myc and c-fos genes after castration. These results demonstrate that prostatic glandular cells undergo programmed death in G(0) without recruitment into the G1 phase of a defective cell cycle, and that an increase in p53 protein or its function is not involved in this death process.
Preoperative venous duplex scanning has revealed unexpected deep venous incompetence in patients with apparently only varicose veins. Acting on the hypothesis that the deep vein reflux was secondary to deep vein dilation caused by reflux volume, the following was done. Between July 1990 and April 1993, 29 limbs in 21 patients (16 females) were examined by color-flow duplex imaging to determine valve closure by the method of van Bemmelen. Instrumentation included high-resolution ATL-9 venous interrogation using a pneumatic cuff deflation stimulus of reflux in the standing, nonweight-bearing limb. All limbs showed greater saphenous vein reflux. Twenty-nine showed superficial femoral vein reflux and of these three showed popliteal vein reflux. Duplex testing was performed by a certified vascular technologist whose interpretation was blinded as to the results of clinical examination and grading of the severity of venous insufficiency. Surgery was performed on an outpatient basis under general anesthesia using groin-to-knee removal of the greater saphenous vein by the vein inversion technique of Van Der Strict. Stab avulsion of varicose tributary veins was accomplished during the same period of anesthesia. In 27 of 29 limbs with preoperative femoral reflux, that reflux was abolished by greater saphenous stripping. In patients with popliteal reflux both femoral and popliteal reflux was abolished. Improvement of deep venous hemodynamics by ablation of superficial reflux supports the reflux circuit theory of venous overload. Furthermore, preoperative evaluation of venous hemodynamics by duplex scanning appears to provide useful pre- and postoperative information regarding venous insufficiency in individual patients.