Risk factors for adult acquired subglottic stenosis.

OBJECTIVE: The aetiology and outcomes for patients with acquired subglottic stenosis are highly variable. This study aimed to identify risk factors for subglottic stenosis and patient characteristics that predict long-term clinical outcomes. METHODS: A retrospective review was performed on 63 patients with subglottic stenosis and 63 age-matched controls. Patient demographics and clinical characteristics were compared. Subglottic stenosis patients were further grouped according to tracheostomy status (i.e. tracheostomy never required, tracheostomy initially required but patient eventually decannulated, and tracheostomy-dependent). Patient factors from these three groups were then compared to evaluate risk factors for long-term tracheostomy dependence. RESULTS: Compared to controls, patients with subglottic stenosis had a significantly higher body mass index (30.8 vs 26.0 kg/m2; p < 0.001) and were more likely to have diabetes (23.8 per cent vs 7.94 per cent; p = 0.01). Comparing tracheostomy outcomes within the subglottic stenosis group, body mass index trended towards significance (p = 0.08). Age, gender, socio-economic status, subglottic stenosis aetiology and other co-morbidities did not correlate with outcome. CONCLUSION: Obesity and diabetes are significant risk factors for acquiring subglottic stenosis. Further investigations are required to determine if obesity is also a predictor for failed tracheostomy decannulation in subglottic stenosis.

Anticholinergic medication use is associated with globus pharyngeus.

BACKGROUND: Globus pharyngeus has been linked to salivary hypofunction. We hypothesise that a considerable portion of the globus experienced by patients is due to a drying effect secondary to anticholinergic medication use; this study aimed to determine their association. METHODS: A cross-sectional study was conducted of 270 patients who presented to a laryngology practice over 6 months. Participants rated globus sensation on a 5-point severity scale, with those scoring 0 considered as controls (non-globus). Participants were excluded if they had a likely cause of globus. Scores were compared with participants' medication lists, co-morbidities, age and gender, and evaluated using multivariate analysis, with significance set at p < 0.05. RESULTS: Any participant taking at least 2 anticholinergic medications had a 3.52 increased odds (p = 0.02) of experiencing globus. A previous diagnosis of gastroesophageal reflux disease was also significantly associated with globus (p = 0.004), with an odds ratio of 3.75. CONCLUSION: A substantial portion of idiopathic globus may be due to anticholinergic use or reflux. The findings implicate medication use as a risk factor for globus. An awareness of these associations is invaluable for identifying cause and treating globus.

MRP- and BCL-2-mediated drug resistance in human SCLC: effects of apoptotic sphingolipids in vitro.

Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive to treatment with exogenous ceramide (Cer), sphingosine (Sp) or dimethyl-sphingosine (DMSP) as the parental line. Next, we observed that high BCL-2-expressing human H69 SCLC cells, that were approximately 160-fold more sensitive to Dox than their combined BCL-2 and MRP-over-expressing (H69AR) counterparts, were only approximately 5-fold more resistant to DMSP. Time-lapse fluorescence microscopy of either UMCC cell line treated with DMSP-Coumarin revealed comparable extents and kinetics of SL uptake, further ruling out MRP-mediated effects on drug uptake. DMSP potentiated the cytotoxic activity of VP-16 and Taxol, but not Dox, in drug-resistant UMCC-1/VP cells. However, this sensitization did not appear to involve DMSP-mediated effects on the function of MRP in drug export; nor did DMSP strongly shift the balance of pro-apoptotic Sps and anti-apoptotic Sp-1-Ps in these cells. We conclude that SL-induced apoptosis markedly overcomes or bypasses MRP-mediated drug resistance relevant to SCLC and may suggest a novel therapeutic approach to chemotherapy for these tumors.

Sphingolipids and the sphingosine kinase inhibitor, SKI II, induce BCL-2-independent apoptosis in human prostatic adenocarcinoma cells.

BACKGROUND: Elevated BCL-2 is one mechanism of therapeutic resistance in prostate cancer (PC), and new approaches are needed to overcome such resistance. METHODS: We evaluated the effects of BCL-2 over-expression in human prostatic adenocarcinoma cells on their susceptibility to sphingolipids (SLs) and to the sphingosine kinase (SpK) inhibitor, SKI II. RESULTS: In survival assays, no significant differences were observed in the responses to sphingosine or ceramide among parental PC-3 cells lacking detectable BCL-2 and BCL-2 over-expressing PC-3 transfectants; similarly, the responses to dimethyl-sphingosine (DMSP) of parental LNCaP cells and a BCL-2 over-expressing LNCaP transfectant were equivalent. SKI II induced protracted, BCL-2-independent survival loss in both PC-3 and LNCaP parental/transfectant pairs; in contrast, DMSP induced rapid cell shrinkage, caspase activation and caspase-dependent DNA fragmentation. DMSP-induced DNA fragmentation and loss of mitochondrial membrane potential were equivalent in BCL-2 transfectants and parental PC-3 cells and were not associated with BCL-2 downregulation. DMSP-mediated cytotoxicity was not associated with the enhanced production of reactive oxygen intermediates. SL analyses of parental and transfectant PC-3 cells did not reveal increased levels of sphingosine-1-phosphate in the BCL-2 transfectants; further, there only a modest early shift, corresponding to apoptotic onset, in pro- versus anti-apoptotic SLs in response to DMSP treatment. CONCLUSIONS: Thus, in contrast to the inhibitory effects of BCL-2 on apoptosis induced by various agents in tumor cells, SKI II and selected pro-apoptotic SLs appear atypical in their independence from such inhibition, and may have merits as new candidates for treatment of AI PC.

Magnetic resonance imaging-based prospective detection of intraperitoneal human ovarian carcinoma xenografts treatment response.

The feasibility of applying magnetic resonance imaging (MRI) for conducting prospective studies of intraperitoneal (i.p.) tumor treatment response to chemotherapy and resultant effects on survival in human ovarian carcinoma/nude mouse orthotopic xenograft models was evaluated. Female nude mice were implanted i.p. with either NMP-1 or SKOV-3ip. human ovarian carcinoma cells on day 0. Initial T2-weighted magnetic resonance (MR) images of the abdomens of NMP-1-implanted mice were obtained on day 7 to confirm the presence of nascent tumors; similar confirmations were made on day 14 with mice bearing SKOV-3ip. xenografts. On the initial imaging days, a multiple-dose regimen of cisplatin (CDDP; qd7 x3) was commenced, using 4 or 6 mg/kg treatments with the NMP-1 model and using 6 mg/kg treatments with the SKOV-3ip. model. Mice were reimaged multiple times, 2 days following each CDDP injection and at later times as well, depending on host survival. The images for each mouse from the last imaging day (day 30 for NMP-1, day 44 for SKOV-3ip.) were used in a blinded fashion to attempt to visually distinguish control from treated mice and to determine whether MRI could predict a survival benefit. For SKOV-3ip. mice, ten out of ten mice were correctly segregated into the control or the CDDP treatment group based solely on these blinded, nonquantified MR results. In this model, the 6 mg/kg multiple-dose regimen achieved a modest response, improving life span by approximately 24%. However, for the NMP-1 mice, only six out of nine evaluable mice were correctly segregated into the control or one of the treatment groups by similar MRI criteria, a virtually random distribution; further, neither CDDP treatment regimen achieved a significant improvement in survival in this model. In another study, NMP-1-implanted mice were treated on day 7 after tumor implantation with a single injection of a hyaluronic acid-paclitaxel copolymer. Control and treated mice were MR imaged on day 28, which revealed marked reductions in tumor burden in treated mice, correlating well with a subsequently observed improved survival of approximately 40%. Our results suggest that MRI can be used to serially and noninvasively monitor treatment response and predict ongoing treatment effects on survival.

The rational clinical examination. Does this patient have clubbing?

CONTEXT: The association between digital clubbing and a host of diseases has been recognized since the time of Hippocrates. Although the features of advanced clubbing are familiar to most clinicians, the presence of early clubbing is often a source of debate. OBJECTIVE: To perform a systematic review of the literature for information on the precision and accuracy of clinical examination for clubbing. DATA SOURCES: The MEDLINE database from January 1966 to April 1999 was searched for English-language articles related to clubbing. Bibliographies of all retrieved articles and of standard textbooks of physical diagnosis were also searched. STUDY SELECTION: Studies selected for data extraction were those in which quantitative or qualitative assessment for clubbing was described in a series of patients. Sixteen studies met these criteria and were included in the final analysis. DATA EXTRACTION: Data were extracted by both authors, who independently reviewed and appraised the quality of each article. Data extracted included quantitative indices for distinguishing clubbed from normal digits, precision of clinical examination for clubbing, and accuracy of clubbing as a marker of selected diseases. DATA SYNTHESIS: The profile angle, hyponychial angle, and phalangeal depth ratio can be used as quantitative indices to assist in identifying clubbing. In individuals without clubbing, values for these indices do not exceed 176 degrees, 192 degrees, and 1.0, respectively. When clinicians make a global assessment of clubbing at the bedside, interobserver agreement is variable, with kappa values ranging between 0.39 and 0.90. Because of the lack of an objective diagnostic criterion standard, accuracy of physical examination for clubbing is difficult to determine. The accuracy of clubbing as a marker of specific underlying disease has been determined for lung cancer (likelihood ratio, 3.9 with phalangeal depth ratio in excess of 1.0) and for inflammatory bowel disease (likelihood ratio, 2.8 and 3.7 for active Crohn disease and ulcerative colitis, respectively, if clubbing is present). CONCLUSIONS: We recommend use of the profile angle and phalangeal depth ratio as quantitative indices in identifying clubbing. Clinical judgment must be exercised in determining the extent of further evaluation for underlying disease when these values exceed 180 degrees and 1.0, respectively.

Impact of a nurse led multidisciplinary team on an acute medical admissions unit.

OBJECTIVE: To determine the impact of a nurse-led multi-disciplinary team on management of elderly patients with functional problems admitted to an acute medical admission unit. DESIGN: Data collection from the first 16 months of the team's operation. SETTING: A district general hospital, Scotland. SUBJECTS: All elderly patients with functional problems who were considered fit for immediate multi-disciplinary assessment. RESULTS: Over 1000 patients were assessed during the first 16 months. Twenty four per cent of these frail individuals were discharged directly home, of whom, almost half had some form of ongoing support. The remaining 76% were transferred for ongoing care to other wards in the Medical Directorate. Of this group, 49% moved to general medicine, 43% to geriatric assessment and 8% to the Stroke Unit. The team were perceived to improve the appropriateness of these transfers by enabling staff to review both the medical and functional needs of elderly patients when deciding on the best setting for ongoing care. CONCLUSIONS: Immediate multi-disciplinary assessment of elderly patients admitted to a medical admissions unit enables the early supported discharge of a proportion of elderly and enhances the ability of the hospital to place appropriately those patients requiring a longer stay.