Robust but weak winter atmospheric circulation response to future Arctic sea ice loss.

The possibility that Arctic sea ice loss weakens mid-latitude westerlies, promoting more severe cold winters, has sparked more than a decade of scientific debate, with apparent support from observations but inconclusive modelling evidence. Here we show that sixteen models contributing to the Polar Amplification Model Intercomparison Project simulate a weakening of mid-latitude westerlies in response to projected Arctic sea ice loss. We develop an emergent constraint based on eddy feedback, which is 1.2 to 3 times too weak in the models, suggesting that the real-world weakening lies towards the higher end of the model simulations. Still, the modelled response to Arctic sea ice loss is weak: the North Atlantic Oscillation response is similar in magnitude and offsets the projected response to increased greenhouse gases, but would only account for around 10% of variations in individual years. We further find that relationships between Arctic sea ice and atmospheric circulation have weakened recently in observations and are no longer inconsistent with those in models.

Possible impacts of a future grand solar minimum on climate: Stratospheric and global circulation changes.

A future decline in solar activity would not offset projected global warmingA future decline in solar activity could have larger regional effects in winterTop-down mechanism contributes to Northern Hemisphere regional response.

Health effects of exposure to cyanobacteria (blue-green algae) during recreational water-related activities.

The aim of this study was to investigate effects on health of exposure to cyanobacteria as a result of recreational water activities. Participants, who were aged six years and over, were interviewed at water recreation sites in South Australia, New South Wales and Victoria on selected Sundays during January and February 1995. Telephone follow-up was conducted two and seven days later to record any subsequent diarrhoea, vomiting, flu-like symptoms, skin rashes, mouth ulcers, fevers and eye or ear irritations. On the Sundays of interview, water samples from the sites were collected for cyanobacterial cell counts and toxin analysis. There were 852 participants, of whom 75 did not have water contact on the day of interview and were considered unexposed. The 777 who had water contact were considered exposed. No significant differences in overall symptoms were found between the unexposed and exposed after two days. At seven days, there was a significant trend to increasing symptom occurrence with duration of exposure (P = 0.03). There was a significant trend to increasing symptom occurrence with increase in cell count (P = 0.04). Participants exposed to more than 5000 cells per mL for more than one hour had a significantly higher symptom occurrence rate than the unexposed. Symptoms were not correlated with the presence of hepatotoxins. These results suggest symptom occurrence was associated with duration of contact with water containing cyanobacteria, and with cyanobacterial cell density. The findings suggest that the current safety threshold for exposure of 20,000 cells per mL may be too high.

Clinical trials with velnacrine: (PROPP) the physician reference of predicted probabilities--a statistical model for the estimation of hepatotoxicity risk with velnacrine maleate.

Safety observations during the clinical development of Mentane (velnacrine maleate) have included the occurrence of generally asymptomatic liver enzyme elevations confined to patients with Alzheimer's disease (AD). The clinical presentation of this reversible hepatocellular injury is analogous to that reported for tetrahydroaminoacridine (THA). Direct liver injury, possibly associated with the production of a toxic metabolite, would be consistent with reports of aberrant xenobiotic metabolism in Alzheimer's disease patients. Since a patient related aberration in drug metabolism was suspected, a biostatistical strategy was developed with the objective of predicting hepatotoxicity in individual patients prior to exposure to velnacrine maleate. The method used logistic regression techniques with variable selection restricted to those items which could be routinely and inexpensively accessed at screen evaluation for potential candidates for treatment. The model was to be predictive (a marker for eventual hepatotoxicity) rather than a causative model, and techniques employed "goodness of fit", percentage correct, and positive and negative predictive values. On the basis of demographic and baseline laboratory data from 942 patients, the PROPP statistic was developed (the Physician Reference Of Predicted Probabilities). Main effect variables included age, gender, and nine hematological and serum chemistry variables. The sensitivity of the current model is approximately 49%, specificity approximately 88%. Using prior probability estimates, however, in which the patient's likelihood of liver toxicity is presumed to be at least 30%, the positive predictive value ranged between 64-77%. Although the clinical utility of this statistic will require refinements and additional prospective confirmation, its potential existence speaks to the possibility of markers for idiosyncratic drug metabolism in patients with Alzheimer's disease.

Pentoxifylline in cerebrovascular dementia.

OBJECTIVE: To test the effect of pentoxifylline, a hemorheologic agent used to treat intermittent claudication, on the course of vascular dementia. DESIGN: Randomized, double-blind, placebo-controlled, parallel group trial. SETTING: Outpatient tertiary care center. PATIENTS: 64 patients meeting DSM-III criteria for multi-infarct dementia with modified Hachinski ischemic scores greater than or equal to 6, 38 of whom completed the trial. INTERVENTION: Pentoxifylline (Trental) 400 milligram tablets three times daily vs placebo for 36 weeks. MAIN OUTCOME MEASURE: Alzheimer's Disease Assessment Scale (ADAS). RESULTS: Baseline demographic values and psychometric variables were similar in the placebo and control groups; endpoint statistical analysis was used to allow the use of data from all patients in this clinically high-risk group. For the total group, the slowing of deterioration did not reach statistical significance (by 2-tailed t test), as measured by scores on the total ADAS (P = 0.058) or on the cognitive (ADAS items 1-11; P = 0.064) or non-cognitive subscales (ADAS items 12-21; P = 0.234), although it was significant on the cognitive subscales excluding memory (ADAS items 2-6, 8-10; P = 0.036). For the subgroup of 40 patients who had CT and/or MRI evidence of stroke as well as meeting the other inclusion criteria, treatment with pentoxifylline was associated with significantly slower deterioration, as measured by the total ADAS (P = 0.023) and cognitive subscores (P = 0.020) but not non-cognitive subscores (P = 0.118). For the subgroup of 37 patients who had at least one discrete clinical stroke, treatment with pentoxifylline was associated with significantly less deterioration on the total ADAS (P = 0.002) and both the cognitive (P = 0.001) and non-cognitive (P = 0.017) subscores. CONCLUSION: Treatment with pentoxifylline may slow the progression of dementia in patients who meet DSM-III criteria for "multi-infarct dementia" and who also have clinical and neuroradiological evidence of cerebrovascular disease.

Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Body scale and the development of prehension.

This study examined whether common dimensionless ratios define the critical point in the shifts in the grip coordination pattern of preschoolers and adults engaged in a displacement grasping activity with cubes that varied in object size. The findings indicated that there was an interaction between task constraints and organismic constraints in determining the grasping pattern utilized. However, when the object size is scaled to hand size there are common dimensionless ratios that correspond to the grasping patterns and the limb orientations employed across the age range utilized. Furthermore, 5 grip configurations accounted for the majority of grip variance in both age groups. The findings suggest a strong role for the impact of body scale on the development of coordination and provide preliminary evidence for the view that the development of prehension is a reflection of the constraints imposed on action.

Pooling 12 nomifensine studies for efficacy generalizability.

Twelve parallel group, randomized, double-blind studies of nomifensine's safety and efficacy in the treatment of depressed patients were combined into three pools according to common protocols. This approach permitted evaluation of 1) efficacy results for studies with moderate-sized pools of patients, 2) the degree to which efficacy was generalizable to depressed patients in the general population, and 3) the conditions under which pooled active vs. active (imipramine vs. nomifensine) studies could be regarded as pivotal in support of efficacy. Results showed that nomifensine's superiority over placebo was generalizable to patients with a wide range of characteristics, including age 60 years or older. An appropriate statistical profile of more pronounced nomifensine responders would include patients with a duration of present episode less than 4 months who are acutely depressed, exhibit more severe symptoms, and have been previously hospitalized or treated with other psychotropic medications. A comprehensive assessment and power analysis of the pooled active vs. active studies provided strong evidence for comparability of nomifensine and imipramine.

An overview of side effects and long-term experience with nomifensine from United States clinical trials.

During the clinical development of nomifensine maleate (Merital), 1319 depressed patients received nomifensine (average doses of 150 mg/day) in 4-6 week trials; treatment was continued for at least 2 months in 170 patients and at least 6 months in 53. Comparison data were provided by 593 patients who received placebo and 612 given the tricyclic antidepressant imipramine HCl (average doses of 150 mg/day). The relationship of therapeutic gain to interfering side effects (the therapeutic index) was rated by the investigators and nomifensine received a more favorable therapeutic index rating than did imipramine. Side effect information was collected at each visit. Nomifensine produced less sedating, anticholinergic, and other discomforting side effects than imipramine and was able to sustain clinical benefit with minimal side effects in patients treated up to 6 months.

Primes, contingent attention, and training: effects on a child's motor behavior.

The use of primes, contingent attention, and training sessions to assess a child's engagement and skill in six large motor activities was examined using a combination reversal and multiple-baseline design. Assessment was based on four levels: proximity to equipment, touching equipment, unskilled participation, and skilled participation. Before training, priming (suggestion to the child) was more effective than contingent attention for increasing the subject's engagement (but not skill) in five activities and for increasing skilled participation in one activity. Training of four activities in the natural environment effectively increased the subject's skill level in five activities. Thus, training appeared to generalize to one of these five activities in this setting and also to skillfully executed stair climbing in an adjoining setting. After training, primes and contingent attention were sufficient to maintain both the subject's skill level and engagement in all activities. Postchecks in the same setting the following semester with different teachers revealed only slight increases in participation, as compared to previous baselines, but all participation was at the skilled level. Social interaction, which was not experimentally manipulated, did not systematically vary in relation to changes in experimental conditions.