Extensive retreat and re-advance of the West Antarctic Ice Sheet during the Holocene.

To predict the future contributions of the Antarctic ice sheets to sea-level rise, numerical models use reconstructions of past ice-sheet retreat after the Last Glacial Maximum to tune model parameters 1 . Reconstructions of the West Antarctic Ice Sheet have assumed that it retreated progressively throughout the Holocene epoch (the past 11,500 years or so)2-4. Here we show, however, that over this period the grounding line of the West Antarctic Ice Sheet (which marks the point at which it is no longer in contact with the ground and becomes a floating ice shelf) retreated several hundred kilometres inland of today's grounding line, before isostatic rebound caused it to re-advance to its present position. Our evidence includes, first, radiocarbon dating of sediment cores recovered from beneath the ice streams of the Ross Sea sector, indicating widespread Holocene marine exposure; and second, ice-penetrating radar observations of englacial structure in the Weddell Sea sector, indicating ice-shelf grounding. We explore the implications of these findings with an ice-sheet model. Modelled re-advance of the grounding line in the Holocene requires ice-shelf grounding caused by isostatic rebound. Our findings overturn the assumption of progressive retreat of the grounding line during the Holocene in West Antarctica, and corroborate previous suggestions of ice-sheet re-advance 5 . Rebound-driven stabilizing processes were apparently able to halt and reverse climate-initiated ice loss. Whether these processes can reverse present-day ice loss 6 on millennial timescales will depend on bedrock topography and mantle viscosity-parameters that are difficult to measure and to incorporate into ice-sheet models.

Systematic review of the use of topical diltiazem compared with glyceryltrinitrate for the nonoperative management of chronic anal fissure.

AIM: The study analyzed clinical trials investigating the effectiveness of diltiazem (DTZ) and glyceryltrinitrate (GTN) for the nonsurgical management of chronic anal fissure (CAF). METHOD: Randomized trials on the effectiveness of DTZ and GTN were analyzed systematically using RevMan(®) where combined outcome was expressed as risk ratio (RR). RESULTS: Seven randomized controlled trials that included 481 patients were analyzed. Two-hundred and thirty-eight patients were treated with DTZ and 243 patients were treated with GTN. There was significant heterogeneity [Tau(2) = 0.24, χ2 = 13.16, d.f. = 6 (P < 0.05); I(2) = 54%] among the included trials. In the random-effects model, DTZ was associated with a lower incidence of side effects (RR = 0.48; 95% CI = 0.27, 0.86; z = 2.46; P < 0.01), headache (RR = 0.39; 95% CI = 0.24, 0.66; z = 3.54; P < 0.004) and recurrence (RR = 0.68; 95% CI = 0.52, 0.89; z = 2.77; P < 0.006) of CAF. Both GTN and DTZ were equally effective (RR = 1.10; 95% CI = 0.90, 1.34; z = 0.92; P = 0.36) in the nonsurgical management of CAF. CONCLUSION: This systematic review of seven trials validates and strengthens the finding of a previously published meta-analysis of two randomized trials. Both DTZ and GTN are equally effective in the management of CAF. However, DTZ is associated with a lower incidence of headache and recurrent fissure. Therefore DTZ should be the preferred first line of treatment for CAF.

A systematic review comparing transanal haemorrhoidal de-arterialisation to stapled haemorrhoidopexy in the management of haemorrhoidal disease.

BACKGROUND: The aim of this study was to systematically analyse the clinical trials on the effectiveness of transanal haemorrhoidal de-arterialisation (THD) and stapled haemorrhoidopexy (SH) in the management of haemorrhoidal disease (HD). METHODS: Clinical trials on the effectiveness of THD and SH in the management of HD were analysed systematically using RevMan(®), and combined outcomes were expressed as risk ratio (RR) and mean difference (MD). RESULTS: Three randomised, controlled trials encompassing 150 patients were analysed systematically. There were 80 THD patients and 70 SH patients. There was no significant heterogeneity (P = 0.40) among included trials. Therefore, in the fixed effects model, THD and SH were statistically equivalent in terms of treatment success rate (P = 0.19), operation time (P = 0.55), postoperative complications (P = 0.11) and recurrence (P = 0.46) of HD. THD was associated with significantly less postoperative pain (MD, -2.00; 95% CI, -2.06, -1.94; z = 63.59; P < 0.00001) compared to SH. CONCLUSIONS: Both THD and SH are equally effective and can be attempted for the management of HD. However, THD is associated with significantly lesser postoperative pain and therefore may be considered a preferred procedure. This conclusion is based only on treating 150 patients by THD or SH in three moderate-quality randomised trials. A major, multicenter, randomised trial is required to validate this conclusion and investigate other variables like hospital stay, cost-effectiveness and health-related quality of life measurement.

Unexpected findings at diagnostic laparoscopy: caecal incarceration with concurrent appendicitis in a patient with bilateral broad ligament defects.

Internal herniations through broad ligament defects are very rare. We present the first report of the triad of broad ligament defect, internal herniation of the caecum and appendicitis. A 36-year-old woman with phocomelia presented with right iliac fossa pain and vomiting. The patient had no previous history of trauma or surgery. Abdominal ultrasound showed a small amount of free fluid. At laparoscopy, bilateral broad ligament defects were found, with herniation of the caecum and an inflamed appendix through the right-sided defect. A laparoscopic salpingo-oophorectomy was required for reduction of the herniated bowel, and an appendicectomy was performed. Broad ligament defects may be congenital or acquired. In this case, in light of the limb abnormality and absence of previous surgery, a congenital aetiology is more likely. Ultrasound scan is not reliable and, although computed tomography may be of help, a diagnostic laparoscopy is the best investigation.

A multi-criteria weight of evidence approach for deriving ecological benchmarks for radioactive substances.

Dose rate benchmarks are required in the tiered approaches used to screen out benign exposure scenarios in radiological ecological risk assessment. Such screening benchmarks, namely the predicted no-effect dose rates (PNEDR), have been derived by applying, as far as possible, the European guidance developed for chemicals. To derive the ecosystem level (or generic) PNEDR, radiotoxicity EDR(10) data (dose rates giving a 10% effect in comparison with the control) were used to fit a species sensitivity distribution (SSD) and estimate the HDR(5) (the hazardous dose rate affecting 5% of species with a 10% effect). Then, a multi-criteria approach was developed to justify using an assessment factor (AF) to apply to the HDR(5) for estimating a PNEDR value. Several different statistical data treatments were considered which all gave reasonably similar results. The suggested generic screening value of 10 microGy h(-1) (incremental dose rate) was derived using the lowest available EDR(10) value per species, an unweighted SSD, and an AF of 2 applied to the estimated HDR(5). Consideration was also given to deriving screening benchmark values for organism groups but this was not thought to be currently appropriate due to few relevant data being currently available.

Protection of the environment from ionising radiation in a regulatory context--an overview of the PROTECT coordinated action project.

The outcome of the PROTECT project (Protection of the Environment from Ionising Radiation in a Regulatory Context) is summarised, focusing on the protection goal and derivation of dose rates which may detrimentally affect wildlife populations. To carry out an impact assessment for radioactive substances, the estimated dose rates produced by assessment tools need to be compared with some form of criteria to judge the level of risk. To do this, appropriate protection goals need to be defined and associated predefined dose rate values, or benchmarks, derived and agreed upon. Previous approaches used to estimate dose rates at which there may be observable changes in populations or individuals are described and discussed, as are more recent derivations of screening benchmarks for use in regulatory frameworks. We have adopted guidance and procedures used for assessment and regulation of other chemical stressors to derive benchmarks. On the basis of consultation with many relevant experts, PROTECT has derived a benchmark screening dose rate, using data on largely reproductive effects to derive species sensitivity distributions, of 10 microGy h(-1) which can be used to identify situations which are below regulatory concern with a high degree of confidence.

The role of nutrients in the prevention and treatment of Alzheimer's disease: methodology for a systematic review.

There is a large body of existing data on nutrition in Alzheimer's disease (AD). We are conducting a systematic review of published scientific literature to determine the role of specific nutrients, both individually and in combination, in the prevention and treatment of AD. This will contribute towards a structured evidence base to help inform the clinical management of AD. The objective of the systematic review is to evaluate the strength of evidence from both observational cohort studies and randomized controlled trials on the role of fats, vitamins, antioxidants and other nutrients in the prevention and treatment of AD. We present here the methodology of our systematic review.

Towards the establishment of an environmental quality standard for aluminium in surface waters.

Steps taken to establish an environmental quality standard (EQS) for aluminium are described. The range of water types in England and Wales and the concentrations of low molecular weight (active) forms of aluminium have been assessed in order to evaluate the risk posed by aluminium in surface waters. Levels of low molecular weight forms of aluminium are mainly in the range 0-25 microg l(-1). Data suggest that dissolved aluminium might form the basis of a reasonably useful prediction of active aluminium leading to a simplified approach to compliance monitoring of an EQS set in terms of active aluminium.

Transanal endoscopic microsurgery: local recurrence rate following resection of rectal cancer.

OBJECTIVE: Transanal endoscopic microsurgery (TEM) is a safe and effective treatment for the excision of benign rectal adenomas. In recent years it has been used for the excision of malignant lesions, although its use in this context remains controversial. The aim of this study was to investigate the local recurrence of rectal cancers following local excision by TEM. METHOD: Forty-two patients with rectal cancer were treated by TEM between 1998 and 2005. However, six patients went on to have immediate radical surgery and are excluded from the study. Of the remaining 36 the treatment intention was for cure in 16 (38.1%), compromise in 17 patients unfit for radical surgery (40.5%), and palliation in three (7.1%). RESULTS: The mean age of patients was 75 years (range 41-90). The mean lesion area was 15 cm(2) (range 0.8-42) and mean distance from the dentate line was 6.6 cm (range 0-11). The mean follow up was 34 months (range 4-94). During the follow-up period there have been eight local recurrences (22%). The recurrence rates were 26% (6/23) for pT1, 22% (2/9) for pT2 and 0% (0/4) for pT3 lesions. The mean time to recurrence was 18.3 months (range 5-42). CONCLUSION: Transanal endoscopic microsurgery is a safe procedure with obvious advantages over radical procedures. However, in this study the local recurrence rate is high. The recurrence rate may be an acceptable compromise in elderly or medically unfit patients but is hard to justify for curative intent.

Transanal endoscopic microsurgery: risk factors for local recurrence of benign rectal adenomas.

OBJECTIVE: Transanal endoscopic microsurgery (TEM) is a minimally invasive technique for excision of selected benign and malignant rectal neoplasms. It is considered a safe and effective treatment but recurrence rates of 1-13% are reported for benign lesions. The aim of this study was to assess risk factors for local recurrence of benign rectal lesions and to evaluate mortality and morbidity following TEM. METHOD: Data were prospectively collected from all patients undergoing TEM for benign adenomas from January 1998 to March 2005. The procedure was performed by a single surgeon and patients were regularly followed up. RESULTS: One hundred and forty-six procedures were included, with a median patient age of 74 years (range 22-92 years). The mean lesion area was 16 cm(2) (range 0.3-150 cm(2)) and the median distance from the dentate line was 9 cm (range 0-17 cm). Immediate complications included bleeding (six) and acute urinary retention (six). There has been one (0.68%) procedure-related death. After a median follow up of 39 months (range 4-89 months) there have been seven recurrences (4.8%), recurring at a mean time of 23.3 months (range 5-48 months). Only microscopic involvement of the circumferential resection margin was found to be significantly associated with recurrence (P = 0.0059). Recurrence was not associated with age, size of lesion, previous treatment, severity of dysplasia or use of the harmonic scalpel. CONCLUSION: TEM is a safe and effective treatment for benign rectal adenomas. Circumferential resection margin involvement is associated with recurrence, which tends to occur late. Therefore extended follow up is recommended.

Speaking of research advance directives: planning for future research participation.

OBJECTIVE: To examine one model of research advance directive as a possible way to reduce the mismatch between patient and proxy choices and also to learn more about how patients with mild to moderate dementia may want to keep decision making or cede it to their proxies in the future. METHODS: Separate interviews were conducted with 149 dyads of dementia patients and family proxies about future enrollment in five types of research. Subsequent joint interviews were conducted with 69 of those dyads to discuss their separately articulated decisions and ask whether the patient prefers future enrollment decisions to be made as he or she directs today or as the proxy deems best in the future. RESULTS: Patients chose to cede future decision making to their proxies in 82.9% of the trials. Patients ceded decisions to their proxies in 80.7% of those trials about which the dyad had given opposite answers (n = 74, 49.7%). Patients who had expressed discomfort about the prospect of the proxy making an enrollment decision in a trial (n = 49, 32.9%) ceded decision making to their proxies in 45.7% of those trials. CONCLUSIONS: Both patients and proxies were willing to discuss future research enrollment in the context of an advance directive for research. Such a document may be helpful to proxies and researchers in the future to judge the types of research and associated risks patients are willing to enroll in. Although most patients willingly cede future decisions to their proxies, a sizeable minority do not wish to do so.

Twenty-four-hour rhythms of sleep-wake cycle and temperature in Alzheimer's disease.

The authors aimed to examine the difference in 24-hour rhythms of sleep-wake cycle and temperature between Alzheimer's disease (AD) patients and elderly comparison subjects. The continuous measuring of wrist activity and skin temperature was conducted for 96 hours in seven AD patients (age: 77.0 +/- 4.3) and 11 normal comparison subjects (age: 74.2 +/-5.2). The mean acrophases and amplitudes of the two rhythms in the AD group were not different from those in the comparison group. The mean phase difference between the two rhythms, however, was significantly lower in the AD group than in the comparison group.

Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C.

Advanced or metastatic disease is common in both oesophagogastric and colorectal cancers, with poor 5-year survival despite palliative chemotherapy. We have investigated the sensitivity of gastrointestinal tumours to gemcitabine in combination with mitomycin C (GeM), using a modified ex vivo ATP-based tumour chemosensitivity assay (ATP-TCA). Tumour material from 41 colorectal and 22 oesophagogastric cancers were assessed. The GeM combination showed variable but definite activity in most of the samples tested. The results show that GeM achieves >95% inhibition at concentrations within the range achievable clinically in 60% of colorectal tumours (21 out of 35) and 38% of oesophagogastric tumours (five out of 13) tested. We did not identify any significant difference in sensitivity using concurrent or sequential exposure of tumour-derived cells to these two drugs. The results from this study suggest that GeM may be a useful combination in the treatment of advanced gastrointestinal malignancy.

Synergistic activity of gamma-linolenic acid and cytotoxic drugs against pancreatic adenocarcinoma cell lines.

BACKGROUND: Gamma-linolenic acid (GLA) is growth inhibitory both in vitro and in vivo, at doses non-toxic to non-cancer cells. Chemotherapeutic agents have limited activity in pancreatic cancer. Interactions between GLA and cytotoxic drugs have not previously been investigated; any synergy might improve the therapeutic effect of these agents. AIM: To investigate possible interactions between GLA and 5-fluorouracil (5-FU) or gemcitabine against pancreatic cancer cell lines in vitro. METHODS: Two pancreatic cancer cell lines were exposed to GLA alone and in combination with 5-FU or gemcitabine. Residual viable biomass was measured using the MTT assay and the results analysed by the median effect method of Chou and Talalay [Adv Enzyme Regul 1984;22:27-55]. RESULTS: GLA concentrations of 3.9- 125 microg/ml had a synergistic or additive growth inhibitory effect on all tested concentrations of gemcitabine. Synergism was demonstrated between GLA and 5-FU only at concentrations of 62.5-125 microg/ml of 5-FU. CONCLUSION: GLA has a synergistic effect with gemcitabine at concentrations that correspond to in vivo therapeutic doses. GLA with 5-FU is synergistic only at a tight range of high concentrations of 5-FU. GLA lacks toxic side effects and may be useful in combination with gemcitabine.

Incorporation of in situ and biomarker assays in higher-tier assessment of the aquatic toxicity of insecticides.

This study was designed to test the feasibility of integrating in situ, single species exposures and biomarker analysis into microcosm studies. Experimental ponds were dosed with pirimiphos methyl (PM) and lindane. C. riparius fourth instar larvae were deployed for 48h on nine separate occasions during the study period before and after treatment. Surviving larvae were analysed for acetylcholinesterase activity (AChE). Survival and biomarker data were compared to chironomid assemblage analysis by monitoring insects emerging from the microcosms. Survival of chironomids within the in situ systems commenced on day +16 after treatment with 31.6% and 53.3% survival in the lindane and PM treated ponds, respectively. In contrast, the first emergence from the microcosms occurred on days +27, in respect to lindane, and +59 for the PM treated ponds. Thus the in situ bioassay was able to demonstrate gradual reduction in toxicity within the sediment before this was evident from macroinvertebrate monitoring. Significant AChE inhibition was only detected on exposure to PM. Levels decreased from 75% on day +16 to 26% by day +29. The biomarker analysis confirmed that, by the end of the study, the insecticide was no longer exerting an effect. We discuss how the use of in situ bioassays could also aid comparison of microcosm studies by adding a standardized dimension.

Vinpocetine for cognitive impairment and dementia.

BACKGROUND: Vinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear. OBJECTIVES: To assess the efficacy and safety of vinpocetine in the treatment of patients with cognitive impairment due to vascular disease, Alzheimer's disease, mixed (vascular and Alzheimer's disease) and other dementias. SEARCH STRATEGY: The Cochrane Dementia & Cognitive Improvement Group's Specialized Register was searched using the terms vinpocetin*, cavinton, kavinton, Rgh-4405, Tcv-3B, "ethyl apovincaminate", vinRx, periwinkle, "myrtle vincapervinc" and cezayirmeneksesi. The manufacturers of vinpocetine were asked for information on trials of vinpocetine for dementia. In addition we tried to collect articles not listed in MEDLINE or other sources on the Internet (e.g. articles in Hungarian and Romanian). SELECTION CRITERIA: All human, unconfounded, double-blind, randomized trials in which treatment with vinpocetine was administered for more than a day and compared to control in patients with vascular dementia, Alzheimer's dementia or mixed Alzheimer's and vascular dementia and other dementias. Non-randomized trials were excluded. DATA COLLECTION AND ANALYSIS: Data were independently extracted by the two reviewers (SzSz and PW) and cross-checked. Data from "washout" periods were not used for the analysis. For continuous or ordinal variables, such as cognitive test results, the main outcomes of interest were the change in score from baseline. The categorical outcome of global impression was transformed to binary data (improved or not improved) as was the occurrence of adverse effects; here the endpoint itself was of interest the Peto method of the "typical odds ratio" was used. A test for heterogeneity of treatment effects between the trials was made if appropriate. Data synthesis and analysis were performed using the Cochrane Review Manager software (RevMan version 4.1). MAIN RESULTS: All identified studies were performed before the 1990s and used various terms and criteria for cognitive decline and dementia. The three studies included in the review involved a total of 583 people with dementia treated with vinpocetine or placebo. The reports of these studies did not make possible any differentiation of effects for degenerative or vascular dementia. The results show benefit associated with treatment with vinpocetine 30mg/day and 60 mg/day compared with placebo, but the number of patients treated for 6 months or more was small. Only one study extended treatment to one year. Adverse effects were inconsistently reported and without regard for relationship to dose. The available data do not demonstrate many problems of adverse effects but intention-to-treat data were not available for any of the trials. REVIEWER'S CONCLUSIONS: Although the basic science is interesting, the evidence for beneficial effect of vinpocetine on patients with dementia is inconclusive and does not support clinical use. The drug seems to have few adverse effects at the doses used in the studies. Large studies evaluating the use of vinpocetine for people suffering from well defined types of cognitive impairment are needed to explore possible efficacy of this treatment.