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.

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.

Cholinergic innervation in neuritic plaques.

Although several studies of Alzheimer's disease suggest that the frequency of neuritic plaques in the cerebral cortex is correlated with the severity of dementia and with reduction in presynaptic cholinergic markers in the cortex, the relationship between cholinergic cortical innervation and the pathogenesis of plaques is unknown. The hypothesis was tested that the neurites in the plaque consist, in part, of presynaptic cholinergic axons, many of which arise from neurons in the basal forebrain. This hypothesis was tested by analyzing the character and distribution of plaques in monkeys, aged 4 to 31 years, with staining for acetylcholin-esterase and also with Congo red and silver stains. Immature and mature plaques were rich in acetylcholinesterase. As the plaques matured, the amount of amyloid increased, and the number of neurites and the activity of acetylcholinesterase decreased. End-stage amyloid-rich plaques lacked acetylcholinesterase. These observations indicate that changes in cortical cholinergic innervation are an important feature in the pathogenesis and evolution of the neuritic plaque.

Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.

Recent evidence indicates that the nucleus basalis of Meynert, a distinct population of basal forebrain neurons, is a major source of cholinergic innervation of the cerebral cortex. Postmortem studies have previously demonstrated profound reduction in the presynaptic markers for cholinergic neurons in the cortex of patients with Alzheimer's disease and senile dementia of the Alzheimer's type. The results of this study show that neurons of the nucleus basalis of Meynert undergo a profound (greater than 75 percent) and selective degeneration in these patients and provide a pathological substrate of the cholinergic deficiency in their brains. Demonstration of selective degeneration of such neurons represents the first documentation of a loss of a transmitter-specific neuronal population in a major disorder of higher cortical function and, as such, points to a critical subcortical lesion in Alzheimer's patients.

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.

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.

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.

Topography of the magnocellular basal forebrain system in human brain.

In primates, the large neurons in the nucleus basalis of Meynert (nbM), nucleus of the diagonal band of Broca (dbB), and medial septum are part of a cholinergic system with direct projections to amygdala, hippocampus, and cortex. Recent evidence indicates that neurons of this system selectively degenerate in individuals with Alzheimer's disease (AD) and suggests that degeneration of these cells contributes to the loss of presynaptic cortical cholinergic markers which occurs in these patients. The present report describes the topographical distribution of these large intensely basophilic, basal forebrain neurons in human brain. Rostrally, neurons of this magnocellular system are present in the medial septum and the dorsal and ventral parts of the nucleus of the dbB. The largest number occur in the nbM, which is situated in the substantia innominata below the globus pallidus. Caudally, large nbM-type neurons are found along the ventral and lateral edges of the globus pallidus. Neurons of this type are also encountered in the white matter below the putamen and nucleus accumbens, at the edges of the anterio commissure, in the white matter laminae of the globus pallidus and within and at the medial edge of the genu of the interal capsule. Directions for dissection of this system in human brain are given in an Appendix.

Cholinergic therapy in dementia.

After reviewing the evidence for cholinergic pathology in Alzheimer's disease and related disorders, this paper reviews strategies for treating dementia using cholinomimetic drugs. Special attention is paid to cholinesterase inhibitors, particularly tacrine, the drug recently approved by the FDA. New studies suggesting that muscarinic and nicotinic cholinergic receptor active drugs may be more effective will be reviewed. Brief mention will be made of strategies to slow the progression of Alzheimer's disease.

Future prospects for Alzheimer's disease therapy: ethical and policy issues for the international community.

In addition to being driven by basic scientific research and the preclinical and clinical evaluation of promising new compounds, the development of drugs for patients with Alzheimer's disease (AD) must also be guided by public policy and ethical considerations. More carefully coordinated efforts should be devoted to reducing caregiver burden and providing community-based health care services for patients with chronic as opposed to acute diseases. Important ethical issues include the appropriate duration of double-blind, placebo-controlled clinical trials, the determination of the meaning of "informed consent" when dealing with patients with dementia, the establishment of outcome goals for various stages of the disease process, and the provision of appropriate hospice-type care. The establishment of the International Working Group on Harmonization of Dementia Drug Guidelines is an important step in the process of achieving an international approach toward the development and evaluation of drugs for patients with AD.

Specific neurochemical systems and memory.

This commentary addresses issues raised in common by the various authors of papers in this section: the role of different chemical systems in memory, new approaches for assessing the effects of drugs, and issues for the future in evaluating animal models of human disorders of memory.

New approaches to quantitative neuropathology: multivariate analysis of morphologic and neurochemical measures.

The excellent review by Coleman and Flood on neuropathological changes in normal aging and Alzheimer's disease highlights the need for development and application of computer-assisted image analysis to the study of neurons in these conditions. The morphological and neurochemical changes in normal and pathological aging require quantitation and statistical analysis that can be best performed with the assistance of the image and data processing capabilities of the computer. Advanced image processing systems are being developed to identify and classify neurons according to several intelligently chosen visual features, apply discriminant analysis and population statistics to this data, and correlate this information to other neurochemical measurements as well as the clinical history of the patient. Techniques such as immunocytochemistry, receptor autoradiography and in situ hybridization produce information-rich images of the distribution of proteins and nucleic acids in tissue slices that can be analyzed by this approach.

Intracellular membranes are more fluid in platelets of Alzheimer's disease patients.

We studied 12 patients with probable Alzheimer's disease versus age- and sex-matched healthy control subjects. Platelets were subfractionated into intracellular membranes and plasma membranes, and steady-state anisotropy of diphenylhexatriene was measured on the preparations as an index of membrane fluidity. Fluidity was higher in intracellular membranes from platelets of Alzheimer's patients compared to controls (P = 0.016). However, no difference was observed in purified plasma membrane's fluidity from the same patients versus controls. Neither the platelet counts, platelet volumes, percent of larger platelets, nor the amount of internal membrane protein per platelet were different between groups. There was no correlation between intracellular membrane anisotropy and severity of dementia as measured on the Mini-Mental State Exam. The results extend previous studies suggesting that there is an intracellular membrane alteration in platelets in Alzheimer's disease.

Is the placebo control obsolete in a world after donepezil and vitamin E?

Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research community is now in a gray zone between the absence of accepted therapies and the presence of completely effective therapies. How should these therapies guide the choice of the proper control for future AD clinical trials? The community equipoise principle can guide a process to answer this question. The principle is that a clinical trial should answer clinical questions that are valued by the community who will use the results of that trial. This means that the choice of the proper control for future AD clinical trials ought to be guided by the values of a community who will experience the results of those trials: physicians and patients or their representatives such as caregivers. The values of patients can be included by giving them a voice in the design and review of clinical trials. Community dialogue should be the norm for the design and review of AD clinical trials. We conclude with suggestions to foster this dialogue and issues that should be addressed.

Personality changes in Alzheimer's disease.

How personality changes in Alzheimer's disease is not well understood. Accentuations of premorbid personality, systematic shifts in personality traits, and specific personality changes affecting subtypes of patients have been postulated. To investigate which of these alternatives occurs in Alzheimer's disease, caregivers were given a comprehensive personality inventory standardized for use by informants. Caregivers observed more neurotic, less extroverted, and less conscientious behavior. To a smaller extent, patients with Alzheimer's disease were reported as becoming less agreeable and less open. The changes in reports of neuroticism, extroversion, agreeableness, and openness suggested consistent systematic shifts across all patients. Patients with depressive features were reported to have been more neurotic; those with paranoid delusions were reported as having been more hostile. Premorbid personality traits may predispose to subsequent psychiatric symptoms in Alzheimer's disease.

Memory evaluation in Alzheimer's disease. Caregivers' appraisals and objective testing.

OBJECTIVES: To evaluate if caregivers are reliable informants concerning memory deficits in patients with Alzheimer's disease (AD). DESIGN: Responses of caregivers of patients with probable AD and responses of healthy control subjects on a standardized memory questionnaire were compared with objective measures of cognition (Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery) and with clinical estimates of activities of daily living, depression, and psychopathology (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] clinical assessment battery) using the Self-report Memory Questionnaire. SETTING: A federally funded AD research center. SUBJECTS: The referred sample included 117 patients with probable AD, their informants, and 41 healthy control subjects age-matched to the patients. Patients and control subjects were between the ages of 58 and 85 years, had between 9 and 19 years of education, and were in good health. EXCLUSIONS: Patients who did not meet NINCDS-ADRDA criteria of probable AD. MAIN OUTCOME MEASURE: The optimal number of questionnaire items yielding the best combination of sensitivity and specificity. RESULTS: An abbreviated version of the scale, renamed the Short-Memory Questionnaire, had excellent specificity and sensitivity for identifying dementia. Positive and negative predictive values were 63.5% and near 100%, respectively. The Short-Memory Questionnaire showed good reliability, internal consistency, and external validity. Caregiver appraisals of memory deficits significantly correlated with objective measures of memory and also with generalized cognitive dysfunction. CONCLUSIONS: Caregivers of patients with AD are reliable informants of their relatives' deficits. The Short-Memory Questionnaire is an easily administered, informant-based scale that may be useful in clinical settings or epidemiologic studies to screen out persons with memory difficulties.

Reductions in acetylcholine and nicotine binding in several degenerative diseases.

Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are all characterized by loss of neurons in the basal forebrain cholinergic system and by associated reductions in cortical presynaptic cholinergic markers, such as choline acetyltransferase. In this report, we identify that a major cortical receptor alteration in these disorders is a reduction in nicotinic receptors measured using both tritiated acetylcholine and levorotatory tritiated nicotine binding.