Edoxaban for treatment of venous thromboembolism in patient groups with different types of cancer: Results from the Hokusai VTE Cancer study.

BACKGROUND: The safety and efficacy of edoxaban and dalteparin is unclear for several cancer groups. METHODS: We evaluated the occurrence of the primary outcome in large cancer groups. The primary outcome was the composite of recurrent VTE or major bleeding over 12 months. RESULTS: In patients with gastrointestinal cancer, the primary outcome occurred in 19.4% patients given edoxaban and in 15.0% given dalteparin (risk difference [RD], 4.4%; 95%-CI, -4.1% to 12.8%). The corresponding rates for edoxaban and dalteparin were 10.4% and 10.7% for lung cancer (RD, -0.3%; 95%-CI, -10.0% to 9.5%), 13.6% and 12.5% for urogenital cancer (RD, 1.1; 95%-CI, -10.1-12.4), 3.1% and 11.7% for breast cancer (RD, -8.6; 95%-CI, -19.3-2.2), 8.9% and 10.9% for hematological malignancies (RD, -2.0; 95%-CI, -13.1-9.1), and 10.4% and 17.4% for gynecological cancer (RD, -7.0; 95%-CI, -19.8-5.7). In the subgroup of gastrointestinal cancer, edoxaban was associated with a 3.5% lower absolute risk of recurrent VTE and a 7.9% higher risk of major bleeding. CONCLUSION: Edoxaban has a similar risk-benefit ratio to dalteparin in most cancer groups. In those with gastrointestinal cancer, the lower risk of recurrent VTE and the advantages of oral therapy need to be balanced against the increased risk of major bleeding.

Pharmacological treatments for acute respiratory distress syndrome: systematic review.

BACKGROUND: Our objective was to systematically review the effect of pharmacological therapies on mortality in patients with acute respiratory distress syndrome (ARDS), focusing on randomized controlled trials (RCTs) published since a previous review in 2004. METHODS: We updated previous searches and searched OVID versions of MEDLINE, EMBASE and CENTRAL (to January 2013) and proceedings from conferences and bibliographies of included studies. We included RCTs of pharmacologic therapies compared with placebo or no therapy for adult patients with ARDS, using authors' definitions, which reported on mortality (≤ 3 months after randomization). We excluded subgroups of patients with ARDS reported in RCTs enrolling other populations and RCTs of therapies to prevent ARDS, nutritional or fluid interventions, inhaled nitric oxide, therapies coupled to a mechanical ventilation strategy, or oxygen. Two reviewers independently screened citations, selected articles for inclusion, and abstracted clinical and methodological data from included studies with disagreements resolved by a third reviewer. Mortality data were pooled using random-effects models. RESULTS: From 13461 citations, 58 trials (6635 patients) of 21 classes of medications met selection criteria; 26 trials (3880 patients) were published after 2003. Meta-analyses showed reduced 28-day mortality with a 48-hour infusion of cis-atracurium in early ARDS (relative risk 0.66, 95% confidence interval 0.50 to 0.87; 431 patients, 138 deaths). There was no effect on mortality with granulocyte-macrophage colony stimulating factor, late low-dose methylprednisolone, neutrophil elastase inhibitors, intravenous salbutamol, surfactant, or N-acetylcysteine; each meta-analysis included ≥ 1 trial published after 2003. Seven single trials of other treatments published after 2003 showed no effect. Meta-analysis of older trials of prostaglandin E1 also showed no effect. CONCLUSION: Effective pharmacotherapy for ARDS remains extremely limited. Cis-atracurium is a promising treatment for early moderate-severe ARDS (using Berlin definition nomenclature) and merits further investigation in a large RCT.

TRPA1 and TRPV4 activation in human odontoblasts stimulates ATP release.

The mechanism of pain in dentine hypersensitivity is poorly understood but proposed to result from the activation of dental sensory neurons in response to dentinal fluid movements. Odontoblasts have been suggested to contribute to thermal and mechanosensation in the tooth via expression of transient receptor potential (TRP) channels. However, a mechanism by which odontoblasts could modulate neuronal activity has not been demonstrated. In this study, we investigated functional TRP channel expression in human odontoblast-like cells and measured ATP release in response to TRP channel activation. Human immortalized dental pulp cells were driven toward an odontoblast phenotype by culture in conditioned media. Functional expression of TRP channels was determined with reverse transcription polymerase chain reaction and ratiometric calcium imaging with Fura-2. ATP release was measured using a luciferin-luciferase assay. Expression of mRNA for TRPA1, TRPV1, and TRPV4 but not TRPM8 was detected in odontoblasts by reverse transcription polymerase chain reaction. Expression of TRPV4 protein was detected by Western blotting and immunocytochemistry. The TRPA1 agonists allyl isothiocyanate and cinnamaldehyde and the TRPV4 agonist GSK1016790A caused a concentration-dependent increase in intracellular Ca(2+) concentration that was inhibited by the selective antagonists HC030031, AP18, and HC067047, respectively. In contrast, exposure to the TRPV1 agonist capsaicin or the TRPM8 agonist icilin had no effect on intracellular Ca(2+) concentration. Treatment with allyl isothiocyanate, cinnamaldehyde, or GSK1016790A caused an increase in ATP concentration in culture medium that was abolished by preincubation with TRP channel antagonists. These data demonstrate that activation of TRPA1 and TRPV4 channels in human odontoblast-like cells can stimulate ATP release. We were unable to confirm the presence of thermosensitive TRPV1 and TRPM8 that has previously been reported in odontoblasts.

Comparison of one- and three-dimensional soil vapour extraction experiments.

Soil vapour extraction (SVE) is a common remediation technology used to clean soil contaminated with gasoline. Even though many studies have been completed on SVE, the majority of them have been at the one-dimensional level, while SVE occurs at a three dimensional level. Accordingly, one-dimensional and radial column laboratory experiments were completed to determine if the experimental configuration made a difference with the results. Two soil types were tested at a variety of flow rates. The contaminant used was toluene. The results were analysed both qualitatively and quantitatively. Analysis of both systems showed them to provide good mass closures. On a qualitative basis, the one-dimensional experiments showed that an increase in flow rates did not result in significant mass transfer limitations for the air flow rates tested. The radial columns revealed mass transfer limitations that were not seen in the one-dimensional column. Quantitative comparison through back-calculated mass transfer coefficients confirmed the trends seen in the qualitative analysis. It is unclear if this is a result of geometry of the radial column or the higher velocities within the radial column. The results indicate that further work with the radial column is necessary to better understand field SVE systems, making it possible to better predict field performance.

Compression of the deep palmar branch of the ulnar nerve by a ganglion : a case report.

A ganglion originating from the pisotriquetral joint is the most common cause of distal ulnar nerve compression. Midpalmar ganglions causing ulnar nerve compression are rare. This case describes a ganglion arising from the third carpometacarpal joint causing compression of the deep motor branch of the ulnar nerve.

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for 5 days every 3 weeks to patients with advanced ovarian, tubal or peritoneal cancer resistant to platinum, taxane and topotecan.

BACKGROUND: DX-8951f is a water-soluble camptothecin derivative with greater in vivo and in vitro activity than topotecan or irinotecan. The objectives of this phase II study were to determine the antitumor activity, safety and pharmacokinetic profile of DX-8951f administered intravenously for five consecutive days, every 3 weeks in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. METHODS: Enrolled in the study at The University of Texas M. D. Anderson Cancer Center were 16 patients with measurable cancer resistant to platinum, taxane and topotecan. All 16 patients were assessable for safety and 15 for efficacy analyses. Treatment consisted of a daily infusion of DX-8951f at 0.3 mg/m(2) per day (except for one minimally pretreated patient who started at 0.5 mg/m(2) per day) over 30 min for five consecutive days every 3 weeks. The pharmacokinetic and excretory profiles of DX-8951, the anhydrous form of DX-8951f, were also characterized. RESULTS: Disease was stable in 7 of 16 patients (44%) (4 minor response and 3 stable disease). The median time to tumor progression was 43 days (95% CI 37-92 days). The median overall survival was 117 days (95% CI 90-279 days). The main toxic effect was neutropenia and leukopenia with 50% of patients experiencing grade 3 or 4 neutropenia and leukopenia. One episode of neutropenic fever was observed. Grade 3 or more anemia and thrombocytopenia were seen in 25% and 13% of patients, respectively. Grade 3 nonhematologic side effects included nausea (25% of patients) and fatigue (19%). Other side effects were not more than grade 2, and included gastrointestinal dysfunction, stomatitis, dermatitis, alopecia, liver dysfunction and drug fever. DX-8951 displayed linear pharmacokinetic characteristics at the doses administered. The average plasma clearance, total volume of distribution, and terminal elimination half-life were 2.1 l/h per m(2), 20 l/m(2) and 9.5 h, respectively. CONCLUSIONS: DX-8951f administered parenterally as a single agent daily at a dose of either 0.5 or 0.3 mg/m(2) per day for 5 days is feasible in patients with advanced ovarian, tubal and peritoneal cancer resistant to platinum, taxane and topotecan. Although no responses were observed, a significant number of patients had stable disease with a decrease in CA-125 levels. In this heavily pretreated population, DX-8951f has clinically relevant hematologic and gastrointestinal toxicities in about 25% of patients. DX-8951 appeared to have linear pharmacokinetic characteristics on the basis of multiple administrations.

Reconstructing tumour defects: lyophilised, irradiated bone allografts.

Tumour excision leaves behind large defects. Allografts provide an excellent alternative to autografts without donor site morbidity and are especially useful in large defects or in children where the quantity of available autograft is limited. In this paper we discuss our experience with indigenously procured and processed lyophilised, irradiated bone allografts. Bone allografts were used in 41 patients. They were used morsellised and used in 32 cases. Of these, 25 cases were available for follow-up. These included 21 patients in whom the allograft was used in contained cavities. Complete incorporation of the graft was seen between 6 and 9 months in all these 21 patients. In 4 patients the allograft was layered onto autograft. In only one of these the allograft incorporated with the host bone. Struts were used in 9 cases (3 cases complete intercalary segmental defect, 3 cases of hemicortical defects, 2 cases of allograft-prosthesis composite around the hip, in 1 case an iliac-crest block was used to stop bleeding from an anterior sacral defect). Of these, 2 full segment struts showed no incorporation. Both these patients were on chemotherapy and radiotherapy. There was no follow-up in sacral defect case. All the other struts incorporated with the host bone within 6-9 months.In 5 cases there was sterile postoperative drainage. All these cases went on to uneventful. Deep infection was observed in 4 patients (10%). In one, the graft was removed, another settled uneventfully with subsequent incorporation of graft, and two have a persisting sinus but good incorporation.To restore part of the strength of the struts it was necessary to hydrate them for 30 min prior to use. Autogenous marrow or autograft was used to provide osteoinductive properties.Conclusion. In selected cases the lyophilised, irradiated bone allografts proved to be very useful in reconstruction of large tumour defects.

The use of irradiated allografts in reconstruction of tumor defects - the tata memorial hospital experience.

A Tissue Bank is a valuable adjunct to tumour management. In bone tumours, the defects produced by ablative surgery can be reconstructed using banked tissue, thereby obviating the donor site morbidity associated with autografts. Allografts are especially useful in large defects or in children where the quantity of available autograft is limited. The use of bone allografts in India has been limited by the availability of good quality, affordable grafts. In this article we share our experience with the use of indigenously produced allografts in limb salvage, as bone graft expanders and as struts. Lyophilised, irradiated bone allografts were morcellised and used in 32 patients. In 21 of these patients the allograft was used in contained cavities. Complete incorporation of the graft was seen between 6-9 months in all the 25 cases available for follow-up. In 4 patients the allograft was layered onto autograft. The allograft incorporated with the host bone in only one of these patients.Struts were used in 9 cases (3 cases complete intercalary segmental defect, 3 cases of hemicortical defects, 2 cases of allograft-prosthesis composite around the hip, 1 case an iliac-crest block was used to stop bleeding from an anterior sacral defect). Of these, no incorporation of the full segment struts was observed in 2 patients who were on chemotherapy and radiotherapy. The sacral defect case was lost to follow-up. All the other struts incorporated with the host bone within 6-9 months. In 5 cases there was sterile postoperative drainage. Overall infection was observed in 4 patients (10%). In one the graft was removed, another settled uneventfully with subsequent incorporation of graft, and two have a persisting sinus but good incorporation. Since radiation and lyophilisation are known to affect the material properties of bone, the grafts were rehydrated in saline for 30 minutes prior to transplantation. Autogenous marrow or autograft was used to provide osteoinductive properties. In selected cases the lyophilised, irradiated bone allografts proved to be clinically useful in the reconstruction of large tumour defects.

Aspects of food refusal in the elderly: the "hunger strike".

OBJECTIVE: To present food refusal in old age as a means of attempting to control the outcome of intergenerational family conflicts. METHOD: Two cases are described. RESULTS: Food refusal does not necessarily arise in the context of a classical eating disorder but may represent a form of protest, or hunger strike. DISCUSSION: Food refusal is seen as distinct from a pure anorectic pattern of behavior. It may be a separate psychobehavioral entity in old age. Behavioral methods may help to encourage a resolution by setting clear limits and encouraging patients to share responsibility in decision making.

Clinicopathological correlation in biopsy-proven atherosclerotic nephropathy: implications for renal functional outcome in atherosclerotic renovascular disease.

BACKGROUND: Atherosclerotic renovascular disease (ARVD) is commonly associated with renal failure. It is now recognized that intrarenal damage, (ischaemic or atherosclerotic nephropathy) is a major contributor to the renal impairment in these patients. In this study the impact of histological changes upon renal functional outcome was investigated in patients with atherosclerotic nephropathy. METHODS: The Hope Hospital renal biopsy database (1985-1998) was interrogated for patients with histology compatible with atherosclerotic nephropathy. Case-note review enabled the assessment of several clinical parameters and outcomes, including change in creatinine clearance per year (DeltaCrCl (ml/min/year)), blood pressure control, dialysis need, and death. Renal parenchymal damage was analysed by morphometric analysis (of interstitial fibrosis and glomerulosclerosis) and a semi-quantitative chronic damage score (score 0-3 (normal-severe) for each of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriolar hyalinosis; maximum=12). Patients were stratified into two groups who had either deteriorating (group 1) or stable (group 2) renal function during follow-up. RESULTS: Twenty-five patients (age 64.7+/-10.5, range 43-83 years; 17 male, eight female) were identified. Sixteen patients had undergone angiography; two had significant (>50%) renal artery stenosis. Mean follow-up was 25.6+/-14.8 (range 5-50) months. Group 1 patients had DeltaCrCl -7.4+/-6.8 ml/min/year, n=14 and group 2 patients had DeltaCrCl 4.8+/-7.0 ml/min/year, n=11. Four patients in group 1 developed end-stage renal disease and five patients died (three in group 1 and two in group 2). At study entry, group 1 patients had worse renal function (CrCl 27.6+/-17.6 vs 36.0+/-33.9, NS), greater proteinuria (1.2 vs 0.5 g/24 h, NS), and higher systolic blood pressure (167.1+/-30.8 mmHg vs 150.6+/-37.8, NS) compared with group 2 patients. Group 1 patients showed more glomerulosclerosis (51.6 vs 24.9%, P:<0.01), greater proportional interstitial volume (44.9 vs 33.9%, P:<0.02), and higher overall chronic damage score (P:<0.05) than those in group 2. There was a significant correlation between renal functional outcome and chronic damage score, glomerulosclerosis and proportional interstitial volume for the entire patient cohort. CONCLUSION: In patients with atherosclerotic nephropathy the severity of histopathological damage is an important determinant and predictor of renal functional outcome.

Ribosomal variation in six species of Fusarium.

Eighteen isolates representing six Fusarium species from diverse hosts and geographical origins were evaluated to determine ribosomal DNA variation using polymerase chain reaction and restriction fragment length polymorphisms. No length variation was observed for amplified 18S and 28S regions. However, amplification of the ITS region showed one isolate, a F. oxysporum, to be about 120 bp larger than the remaining 17. Restriction digestions in the 18S region revealed polymorphisms within species of F. oxysporum and F. solani. An amplified variable stretch of the 28S gene showed restriction site differences between F. avenecum, F. sambucinum and F. sporotrichioides. A large degree of polymorphism was observed both between and within species in the ITS region. Therefore, entire sequences of the ITS and the 5.8S subunit were obtained for 17 of the 18 isolates. These sequences, along with those from eight additional isolates, were analysed using PAUP to assess the occurrence of DNA sequence divergence within the ITS region. The lack of correlation between molecular-based relationships and species affinities inferred from morphology for some isolates indicates that species designation can be unreliable using morphological data alone. Possible reasons for the discordance of the sequence and morphological data are discussed.

Inflammatory bowel disease in individuals seropositive for the human immunodeficiency virus.

OBJECTIVE: CD4 lymphocytes mediate disease expression in both human immunodeficiency virus (HIV) infection and inflammatory bowel disease (IBD). Analysis of the clinical course of IBD in HIV-seropositive individuals may elucidate aspects of the role of CD4 lymphocytes in the pathogenesis of these conditions. DESIGN: A retrospective case series study. PATIENTS: Diagnostic coding for IBD and pharmacy records for 5-aminosalicylic acid compounds and rectal steroid preparations were examined for all HIV-seropositive subjects attending the Chelsea and Westminster Hospitals between January 1988 and December 1993. Eight HIV-seropositive individuals with a confirmed diagnosis of IBD were identified. SETTING: HIV/Genitourinary medicine (GUM) units. MAIN OUTCOME MEASURES: Change in CD4 count. RESULTS: Four subjects with an intact colon had a decline in CD4 count of 85 cells/mm3/year, four patients undergoing colectomy had a subsequent rise of four cells/mm3/year and eight case matched controls had a decline of 47 cells/mm3/year. Acute exacerbations of IBD did not cause a significant change in CD4 count. There were no exacerbations of IBD in patients with a CD4 count below 200 cells/mm3. CONCLUSION: HIV infection may influence the pathogenesis of IBD. A chronically inflamed colon may accelerate CD4 cell depletion which is reversed by colectomy.

Optical detection of ultrasound with a microchip laser.

A novel optical ultrasonic detector that relies on frequency modulation of a microchip laser is proposed and demonstrated. When the laser is placed in a time-varying acoustic field, the microchip laser cavity length is periodically modulated, creating a frequency-modulated optical output in which the frequency shift is linearly proportional to the acoustic-wave amplitude. With a confocal Fabry-Perot slope filter and a Nd:YAG microchip laser operating at 1.06 microm, a detector response of 7.5 MHz/kPa was measured at an acoustic frequency of 7.75 MHz. A one-dimensional acoustic model is developed to explain the observed detector performance.