A biomarker panel predicts progression of Barrett's esophagus to esophageal adenocarcinoma.

Progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is uncommon but the consequences are serious. Predictors of progression are essential to optimize resource utilization. This study assessed the utility of a promising panel of biomarkers applicable to routine paraffin embedded biopsies (FFPE) to predict progression of BE to EAC in a large population-based, nested case-control study.We utilized the Amsterdam-based ReBus nested case-control cohort. BE patients who progressed to high-grade dysplasia (HGD)/EAC (n = 130) and BE patients who never progressed (n = 130) were matched on age, sex, length of the BE segment, and duration of endoscopic surveillance. All progressors had minimum 2 years of endoscopic surveillance without HGD/EAC to exclude prevalent neoplasia. We assessed abnormal DNA content, p53, Cyclin A, and Aspergillus oryzae lectin (AOL) in FFPE sections. We performed conditional logistic regression analysis to estimate odds ratio (OR) of progression based on biomarker status.Expert LGD (OR, 8.3; 95% CI, 1.7-41.0), AOL (3 vs. 0 epithelial compartments abnormal; OR, 3.6; 95% CI, 1.2-10.6) and p53 (OR, 2.3; 95% CI, 1.2-4.6) were independently associated with neoplastic progression. Cyclin A did not predict progression and DNA ploidy analysis by image cytometry was unsuccessful in the majority of cases, both were excluded from the multivariate analysis. The multivariable biomarker model had an area under the receiver operating characteristic curve of 0.73.Expert LGD, AOL, and p53 independently predict neoplastic progression in BE patients and are applicable to routine practice. These biomarkers can aid in selecting patients for endoscopic ablation or more intensive surveillance.

Peri-operative management of the obese surgical patient 2015: Association of Anaesthetists of Great Britain and Ireland Society for Obesity and Bariatric Anaesthesia.

Guidelines are presented for the organisational and clinical peri-operative management of anaesthesia and surgery for patients who are obese, along with a summary of the problems that obesity may cause peri-operatively. The advice presented is based on previously published advice, clinical studies and expert opinion.

Complex visual hallucinations and attentional performance in eye disease and dementia: a test of the Perception and Attention Deficit model.

OBJECTIVE: This study aimed to test the prediction from the Perception and Attention Deficit model of complex visual hallucinations (CVH) that impairments in visual attention and perception are key risk factors for complex hallucinations in eye disease and dementia. METHODS: Two studies ran concurrently to investigate the relationship between CVH and impairments in perception (picture naming using the Graded Naming Test) and attention (Stroop task plus a novel Imagery task). The studies were in two populations-older patients with dementia (n = 28) and older people with eye disease (n = 50) with a shared control group (n = 37). The same methodology was used in both studies, and the North East Visual Hallucinations Inventory was used to identify CVH. RESULTS: A reliable relationship was found for older patients with dementia between impaired perceptual and attentional performance and CVH. A reliable relationship was not found in the population of people with eye disease. CONCLUSIONS: The results add to previous research that object perception and attentional deficits are associated with CVH in dementia, but that risk factors for CVH in eye disease are inconsistent, suggesting that dynamic rather than static impairments in attentional processes may be key in this population.

Accelerated resolution therapy and a thematic approach to military experiences in US Special Operations Veterans.

Accelerated Resolution Therapy (ART) is an emerging therapeutic intervention that has demonstrated effectiveness in treating post-traumatic stress, anxiety and depression. The ART protocol aligns with first-line trauma-focused psychotherapies and clinical guides in the USA and UK. This review addresses previous ART research that includes members of US Special Operations Forces. Observations from that research has led to a thematic conceptualisation of trauma through ART interventions. These include three clusters of traumatic memories and several themes relevant to individual distress but not necessarily symptoms that meet diagnostic criteria for PTSD. ART represents a movement in treatment away from the symptoms, to the individuals' story. Not only the story of an event, but how that experience becomes incorporated into one's sense of identity. The themes identified (and treated with ART) appear to have broader application to the entirety of one's military experience, not just PTSD. These themes may be helpful in directing treatment and may help to focus on significant aspects of service not traditionally associated with PTSD. Theoretically, some of these areas may have protective implications in suicide.

Strychnine poisoning: gone but not forgotten.

Strychnine was used as a pesticide until 1968 and a rodenticide until 2006 when its sale was banned throughout the EU and all supplies recalled. A case of strychnine poisoning seen in a UK emergency department in 2009 is reported to remind clinicians of the features and management of this increasingly rare presentation. Prompt recognition and early intensive supportive therapy can result in a favourable outcome.

Impaired functional capacity is associated with all-cause mortality after major elective intra-abdominal surgery.

BACKGROUND: Studies of preoperative cardiopulmonary exercise testing (CPET) have shown that a reduced oxygen uptake at anaerobic threshold (AT) and elevated ventilatory equivalent for carbon dioxide (VE/VCO(2)) were associated with reduced short- and medium-term survival after major surgery. The aim of this study was to determine the relative values of these, and also clinical risk factors, in identifying patients at risk of death after major intra-abdominal, non-vascular surgery. METHODS: Patients aged >55 yr, undergoing elective colorectal resection, radical nephrectomy, or cystectomy between June 2004 and May 2009 had CPET during their routine pre-assessment clinic visit. We performed a retrospective analysis of known clinical risk factors and data from CPET to assess their relationship to all-cause mortality after surgery. RESULTS: Eight hundred and forty-seven patients underwent surgery, of whom 18 (2.1%) died. A clinical history of ischaemic heart disease (RR 3.1, 95% CI 1.3-7.7), a VE/VCO(2) >34 (RR 4.6, 95% CI 1.4-14.8), and an AT < or =10.9 ml kg(-1) min(-1) (RR 6.8, 95% CI 1.6-29.5) were all significant predictors of all-cause hospital and 90 day mortality. The effect of reduced AT was most pronounced in patients with no history of cardiac risk factors (RR 10.0, 95% CI 1.7-61.0). CONCLUSIONS: The routine measurement of AT and VE/VCO(2) using CPET for patients undergoing high-risk surgery can accurately identify the majority of high-risk patients, while the use of clinical risk factors alone will only identify a relatively small proportion of at-risk patients.

Free-running activity rhythms in the rat: entrainment by melatonin.

The pineal gland hormone melatonin may play a role in synchronization of rat circadian rhythms. Free-running activity rhythms of the rat were entrained by a daily melatonin injection, with entrainment occurring when the onset of activity coincided with the time of daily injections. When injections were stopped, activity rhythms became free-running again. Thus in pharmacological experiments, the time of day of melatonin administration is crucial.

Neuroendocrine and subjective responses to pharmacological challenge with citalopram: a controlled study in male and female ecstasy/MDMA users.

Despite evidence that +/-3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') causes persistent alterations to the serotonergic system of animals, evidence for long-term neurological effects of ecstasy/MDMA in humans remains equivocal. The current study assessed serotonin functioning of nine male and 11 female recreational ecstasy polydrug users by measuring neuroendocrine (prolactin, cortisol) responses to pharmacological challenge with the selective serotonin reuptake inhibitor citalopram, compared with nine male and five female cannabis polydrug users and 11 male and 11 female non-drug using controls. A single-blind, randomised, placebo-controlled design was used. Subjective responses, other substance use, mood, personality traits and demographic variables were measured to control for potentially confounding variables. There were no significant differences between ecstasy polydrug users, cannabis polydrug users and non-drug using controls in neuroendocrine or subjective responses to serotonergic challenge, and there were no sex by drug group interactions. There was no relationship between extent of ecstasy use and neuroendocrine functioning, alone or in combination with potential confounding variables. Subjective responses to the pharmacological challenge (nausea, tremor, dry mouth), novelty seeking and lifetime dose of alcohol were the only variables that contributed to one or more of the neuroendocrine outcome variables. These data do not support the premise that recreational ecstasy/MDMA use results in measurable impairment of serotonergic control of endocrine activity.

Metamemory in recreational ecstasy polydrug users: what do self-reports of memory failures mean?

Previous research has found relationships between self-rated memory and ecstasy use, such that heavier users report worse function. These findings have been interpreted in terms of objective memory capacity. However, research on metamemory suggests that self-reported memory may be only weakly related to objective function, with demographics, mood, and memory-related beliefs and feelings also contributing to ratings. This study examined relationships between ecstasy/other drug use and self-reported memory, controlling for effects of demographic factors and mood. Associations between self-reported memory, memory-related beliefs and feelings, and objectively-measured cognitive function were also examined. Forty-five ecstasy polydrug, 48 cannabis polydrug, and 40 legal drug users completed a battery of neuropsychological tests and questionnaire measures of metamemory, including memory-related control beliefs, memory-related anxiety, and self-reported prospective and general/retrospective memory. The combined polydrug groups reported more general/retrospective memory failures. Covariance analysis, however, suggested that this finding was confounded by general anxiety levels. A combination of objective cognitive measures contributed to prediction of self-rated prospective memory, with demographics, mood, and memory-related anxiety also contributing to variability. However, associations between objective and self-reported memory were not strong. Self-report may not be a specific methodology with which to assess objective memory capacities in ecstasy and other drug users.

Understanding the potential for selective natural organic matter removal by ion exchange.

Dissolved organic carbon (DOC) removal from a river water source was investigated using ion exchange (IEX), coagulation and membrane filtration. This research linked the variable charge characteristics of the organic compounds present in the source water with removal by IEX and coagulation. The raw water charge density fluctuated considerably (between 5.4 and 10.7 meq mgDOC-1) and controlled removal of the charge loading. Importantly, charge density was not correlated with the organic carbon concentration. The combined IEX and coagulation process reduced the specific DBP-FP (sDBP-FP) of the final water, with values as low as 18 µg mgDOC-1 for both haloacetic acids and trihalomethanes. IEX removed a particular fraction of NOM that 1) enhanced coagulation efficiency, providing increased removal of overall DOC; and 2) enabled coagulation to subsequently remove higher levels of specific components of NOM that have a high DBP-FP. The component of NOM removed by IEX that had a positive impact on coagulation was identified to be charged low molecular weight organic compounds of all hydrophobicity levels, resulting in a reduced specific DBP-FP compared to coagulation alone.

Binding and metabolism of platelet-activating factor by human neutrophils.

Human polymorphonuclear neutrophils rapidly incorporated radiolabeled platelet-activating factor, 1-O-[hexadecyl-9, 10-3H2]-2-acetyl-sn-glycero-3-phosphocholine ([3H]PAF), and then metabolized it into its sn-2-fatty acyl derivative. Fractionation of radiolabel-pretreated cells over Percoll gradients revealed that virtually all of the intact [3H]PAF was located in nongranule membranes that were enriched with alkaline phosphatase and cell surface glycoproteins. While still membrane associated, the ligand was rapidly converted to its acyl derivative and then more slowly transferred to specific granules and, to a lesser extent, azurophilic granules. In contrast, neutrophils did not metabolize [3H]PAF at 4 degrees C but rather gradually accumulated it in their alkaline phosphatase-enriched membrane subfractions. These same subfractions contained receptors for the ligand, as determined by their capacity to bind [3H]PAF specifically. Binding was readily saturated, partially reversible, and fit a two receptor model; dissociation constant (Kd) values for high and low affinity sites were 0.2 and 500 nM, respectively. Receptors with similar affinities were detected in whole cells. Furthermore, the potencies of several structural analogues in inhibiting binding of [3H]PAF to membranes correlated closely with their respective potencies in stimulating degranulation responses. Finally, quantitative studies suggested all or most of the cell's receptors were membrane associated. We conclude that PAF rapidly enters cellular membranes to bind with specific receptors that trigger function. The intramembranous ligand is also deacetylated, acylated, and then transferred to granules. This metabolism may be sufficiently rapid to limit ligand-receptor binding and distort quantitative analyses of receptors.

Is celecoxib a useful adjunct in the treatment of post-tonsillectomy pain in the adult population? A randomised, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of celecoxib for pain management in post-tonsillectomy adult patients. DESIGN: A randomised, double-blind, placebo-controlled, phase 3 clinical trial was conducted in an adult population (aged 18-55 years), with a parallel group design using an allocation ratio of 1:1. METHODS: Eighty patients underwent elective tonsillectomy or adenotonsillectomy, operated on by one surgeon. They were discharged home with randomly assigned celecoxib or placebo, together with regular post-tonsillectomy medications (paracetamol and Endone). Pain scores were measured from post-operative days 1 to 10. All patients were assessed on post-operative days 5, 12 and 28. RESULTS: There were no statistically significant differences in the daily or overall pain scores, the total intake of Endone, or the time taken to achieve freedom from pain after tonsillectomy between the study arms (n = 40 each arm). The celecoxib-treated group experienced significantly more vomiting (celecoxib vs placebo p < 0.001 (Mann-Whitney test), confidence interval = 0.57 to 0.76). CONCLUSION: Celecoxib usage was associated with significantly more vomiting and did not reduce narcotic analgesia requirement post-tonsillectomy.

Chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin for parenchymal brain lymphoma.

Ten patients with parenchymal CNS lymphoma received combination chemotherapy with dexamethasone, high-dose cytarabine, and cisplatin (DHAP), and additional therapy according to clinical circumstances. Two of four patients with primary CNS lymphoma achieved and remain in complete remission (CR). Four of six patients with CNS lymphoma at relapse also achieved CR. DHAP is active against CNS lymphoma. Further trials with DHAP, particularly in conjunction with other treatment modalities, are warranted.

Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms.

Several cytokines including gamma-interferon, tumor necrosis factor alpha, interleukin 1 beta (IL-1 beta), and interleukin 6 (IL-6) are pyrogenic and can inhibit lipogenic processes. Because patients with lymphoma often suffer from fever, weight loss, and night sweats (B symptoms), the etiology of which is unknown, the authors investigated serum levels of these cytokines in normal volunteers and in patients with Hodgkin's and non-Hodgkin's lymphoma. Sixty serum samples from patients with Hodgkin's disease (28 patients) or non-Hodgkin's lymphoma (32 patients), as well as 20 samples from normal volunteers, were collected. The majority of patients had advanced (Stage III or IV) or relapsed disease. The assay for gamma-interferon was a specific and sensitive radioimmunoassay (lower limit of detection = 0.1 unit/ml); the assays for tumor necrosis factor alpha, IL-1 beta, and IL-6 were enzyme-linked immunoassays with lower limits of sensitivity of 10 pg/ml, 20 pg/ml, and 22 pg/ml, respectively. There were no statistically significant differences in gamma-interferon, tumor necrosis factor alpha, or IL-1 beta levels between lymphoma patients and normal subjects. In contrast, 20 of 57 patients (35%) with lymphoma as compared with 0 of 19 normal volunteers (0%) had detectable serum IL-6 levels (P < 0.005, chi 2 test). Interestingly, 17 of 29 lymphoma patients with B symptoms (59%) as opposed to 3 of 28 lymphoma patients without B symptoms (11%) had detectable serum IL-6 levels (P < 0.001, chi 2 test); the median IL-6 level was 28.9 pg/ml (B symptoms present) versus undetectable (no B symptoms) (P < 0.005, Mann-Whitney U test). Analyzing Hodgkin's and non-Hodgkin's lymphoma groups separately revealed similar results. IL-6 levels showed no significant correlation with time from diagnosis, beta 2-microglobulin, or lactate dehydrogenase levels. However, analysis by the method of Kaplan and Meir demonstrated that the median survival of Hodgkin's disease patients with detectable IL-6 levels (> or = 22 pg/ml) was 10 mo, whereas the median survival has not been reached at a median follow-up time of 37.5 mo in those patients with lower values (Wilcoxon P value = 0.0012). There were too few patients in each subset of non-Hodgkin's lymphoma to determine the correlation between IL-6 and survival but, considered as a single group, a statistically significant correlation was not found.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family.

Four naturally occurring platelet-activating factor (PAF) analogs, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, 1-octadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine, stimulated human neutrophils (PMN) to mobilize Ca2+, degranulate, and produce superoxide anion. They were, respectively, 5-, 300-, 500-, and 4000-fold weaker than PAF in each assay; inhibited PMN-binding of [3H]PAF at concentrations paralleling their biological potencies; and showed sensitivity to the inhibitory effects of PAF antagonists. PAF and the analogs, moreover, desensitized PMN responses to each other but not to leukotriene B4 and actually increased (or primed) PMN responses to N-formyl-MET-LEU-PHE. Finally, 5-hydroxyeicosatetraenoate-enhanced PMN responses to PAF and the analogs without enhancing the actions of other stimuli. It stereospecifically raised each analog's potency by as much as 100-fold and converted a fifth natural analog, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine from inactive to a weak stimulator of PMN. PAF and its analogs thus represent a structurally diverse family of cell-derived phospholipids which can activate, prime, and desensitize neutrophils by using a common, apparently PAF receptor-dependent mechanism.

Prognostic factors in advanced ovarian carcinoma.

Nineteen factors were analyzed for prognostic significance in a series of 89 women with advanced (stage III or IV) ovarian carcinoma treated with chemotherapy after initial debulking surgery. Seventy-eight of these women received cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, Ohio), and cisplatin (CAP) treatment, and 11 received cyclophosphamide initially with Adriamycin and cisplatin administered at the time of recurrence. Median survival and remission duration were 25 and 19 months, respectively. Using survival as an end point, significant prognostic factors in univariate analyses included the total residual mass after debulking (P = .0007), largest residual mass after debulking (P = .0008), and stage (P = .0098). Using remission duration as an end point, significant prognostic factors in univariate analyses included total residual mass after debulking (P = .007) and the largest residual mass after debulking (P = .0020). The prognostic variables were then considered as possible predictors of survival in a multivariate analysis using the Cox proportional hazards model resulting in the following expression: lambda i(t)/lambda o(t) = exp(0.5928 (log TRM - 1.8117) + 0.6450 (stage - 0.3827) + 0.6673 (C4 - 0.4198) - 0.8596 (CAP - 0.8642)), where lambda i(t)/lambda o(t) is the risk of dying for a particular patient compared with the average risk of the entire group; log TRM is the log of the volume of the total residual mass in cm3 plus 1.0; stage = 0 if stage III, 1 if stage IV; C4 = 0 if cytologic grade is 1, 2, or 3 and 1 if grade 4; CAP = 0 if treatment is cyclophosphamide and 1 if CAP. Median survival times of patients with relative risk greater than 1 and less than 1 are 43 and 19 months respectively. If this model is confirmed in a prospective study, then it could be used to assign risk and assess treatment options for similar patients at diagnosis.

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

PURPOSE: Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS: Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS: The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION: FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

Phase II trial of fludarabine phosphate in lymphoma: an effective new agent in low-grade lymphoma.

PURPOSE: In a phase II trial we investigated fludarabine phosphate (FAMP) as therapy for patients with relapsed lymphoma to determine its effectiveness and toxicity in this disease. PATIENTS AND METHODS: The 67 assessable patients had a median age of 56 years and had received a median of three chemotherapy regimens before treatment with FAMP. The starting dose was 25 mg/m2 administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks. RESULTS: High response rates were observed for follicular small cleaved-cell lymphoma (FSCCL) (62%), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (FLCL) (100%). Responses also occurred in small lymphocytic lymphoma (SLL) (33%), transformed lymphoma (33%), mycosis fungoides (40%), and Hodgkin's disease (25%). No responses were observed in other intermediate- or high-grade lymphomas (N = 20). Overall, there were five patients with a complete response, 23 patients with a partial response, and an overall response rate of 37%. Toxicity was primarily hematologic and infectious. No significant gastrointestinal, hepatic, renal, or neurologic toxicity occurred. CONCLUSIONS: We conclude that FAMP has major activity in follicular lymphoma. Fundamental research is needed to understand this differential efficacy in low-grade lymphoma yet lack of efficacy in intermediate- and high-grade lymphoma. Clinical investigations should be done using FAMP in varying dose schedules and in combination regimens.

A new serologic staging system for large-cell lymphomas based on initial beta 2-microglobulin and lactate dehydrogenase levels.

We report results of our investigation of prognostic factors for patients with large-cell lymphoma who were entered on the same treatment protocol and who had known pretreatment serum beta 2-microglobulin (beta 2M) and lactate dehydrogenase (LDH) levels. beta 2M and LDH levels were the most significant and independent variables for predicting time to treatment failure (TTF) and survival. The serum level of beta 2M correlated with tumor burden. These two serum markers defined three significantly different prognostic groups. All 27 patients in the low-risk group remain alive and in remission; in contrast, 22 of the 27 patients (81%) in the high-risk group have failed treatment, and only seven (26%) remain alive. In comparison with the Ann Arbor staging system, serum levels of beta 2M and LDH may provide a more precise system for defining risk groups and thereby allow a more rational approach to the development and analysis of treatment strategies.

Small noncleaved cell lymphoma in adults: superior results for stages I-III disease.

Small noncleaved cell lymphoma (SNCCL), a rare lymphoma in adults, is associated with not only a rapid complete response (CR) to chemotherapy but also with the potential to rapidly relapse both systemically and in the CNS. We treated 44 assessable adults with two similar protocols, consisting of three sequential chemotherapy combinations and intrathecal prophylaxis with methotrexate and cytarabine. The overall CR rate was 80%; it was 100% in patients with Ann Arbor (AA) stages I-III disease and 57% in those with stage IV disease. The overall survival (OS) rate at 5 years was 52%. The overall 5-year freedom from tumor mortality (FTM) rate was 63%; it was 95% for patients with AA stages I-III disease, and 29% for those with stage IV disease. Stepwise multivariate analysis of factors associated with remission duration and survival indicated that advanced-disease stage and age of 40 years or over were predictors of poor prognosis. Twelve patients with positive human immunodeficiency virus (HIV) serology were also included in this series. They had an 83% CR rate and an 83% 5-year FTM, but only a 36% 5-year OS; most deaths were secondary to opportunistic infection. Histologic subtype (Burkitt's lymphoma [BL] or non-Burkitt's lymphoma [NBL]) did not correlate with patient age, site of tumor presentation, response to therapy, or survival. Both protocols achieved comparable results. The approach used in these protocols is highly effective for patients with early staged disease, regardless of their HIV status; however, better therapy is necessary for those with SNCCL presenting in an advanced stage.