Altered deactivation in individuals with genetic risk for Alzheimer's disease.

Regions that show task-induced deactivations may be part of a default-mode network related to processes that are more engaged during passive than active task conditions. Alteration of task-induced deactivations with age and dementia is indicated by atypical engagement of default-mode network regions. Genetic studies show a relation between the apolipoprotein E4 (APOE4) allele and the common form of Alzheimer's disease (AD), and altered functional brain activation has been observed in non-demented APOE4 carriers compared to non-carriers. Here we investigate the hypothesis of altered default-mode network brain responses in individuals with genetic risk for AD. Functional MRI was used to assess task-induced deactivation in 60 subjects of which 30 carried at least one copy of the APOE4 allele, and 30 non-carriers. Subjects were scanned while performing a semantic categorization task shown to promote episodic memory encoding. The results show patterns of deactivation consistent with the default-mode network. We also found reduced deactivation in non-demented APOE4 carriers compared to non-carriers, suggesting alterations in the default-mode network in the absence of dementia. These results implicate possibilities for investigating altered properties of task-induced deactivations in individuals with genetic risk for AD, and may prove useful for pre-clinical identification of individuals susceptible to memory problems and AD.

Optimized convective transport with automated pressure control in on-line postdilution hemodiafiltration.

PURPOSE: In a stable patient population we evaluated on-line postdilution hemodiafiltration (HDF) on the incremental improvement in blood purification versus high-flux HD, using the same dialyzer and blood flow rate. For HDF we used a new way of controlling HDF treatments based on the concept of constant pressure control where the trans-membrane pressure is automatically set by the machine using a feedback loop on the achieved filtration (HDF UC). METHODS: We enrolled 20 patients on on-line HDF treatment and during a 4-week study period recorded key treatment parameters in HDF UC. For one mid-week study treatment performed in HD and one midweek HDF UC treatment we sampled blood and spent dialysate to evaluate the removal of small- and middle-sized solutes. RESULTS: We achieved 18+/-3 liters of ultrafiltration in four-hour HDF UC treatments, corresponding to 27+/-3% of the treated blood volume. That percentage varied by patient hematocrit level. The ultrafiltration amounted to 49+/-4% of the estimated plasma water volume treated. We noted few machine alarms. For beta2m and factor D the effective reduction in plasma level by HDF (76+/-6% and 43+/-9%, respectively) was significantly greater than in HD, and a similar relation was seen in mass recovered in spent dialysate. Small solute removal was similar in HDF and HD. Albumin loss was low. CONCLUSION: The additional convective transport provided by on-line HDF significantly improved the removal of middle molecules when all other treatment settings were equal. Using the automated pressure control mode in HDF, the convective volume depended on the blood volume processed and the patient hematocrit level.

Evaluation of the Polyflux 6H dialyzer in pediatric patients receiving maintenance hemodialysis.

Hemodialysis remains the only life sustaining maintenance renal replacement therapy option for children who cannot undergo expeditious renal transplantation or who are not medical candidates for peritoneal dialysis. Provision of maintenance hemodialysis to small children entails many challenges, which arise from the limited choices for appropriately sized disposable dialysis treatment components. The dialysis extracorporeal circuit volume, comprised of the blood tubing and dialyzer, should be low enough to prevent hypotension and prevent the need for repeated blood transfusions. We performed a market acceptance evaluation of the Polyflux 6H dialyzer (0.6 m2 membrane surface area; Gambro Renal Products, Lakewood, Colorado) in six pediatric patients (3 male, 3 female, mean weight 24.4+6.5 kg, mean age 10.3+3.8 yrs). We found that the Polyflux 6H Dialyzer provided a trend for improved clearance compared to Fresenius F3 and F4 dialyzers. We found that the Polyflux 6H Dialyzer provided adequate clearance for children up to 24 kg in size and is a suitable dialyzer choice for patients 13 to 26 kg in size.

Association of cyclin-dependent kinase 5 and neuronal activators p35 and p39 complex in early-onset Alzheimer's disease.

Malfunctioning of cyclin-dependent kinase 5 (CDK5) through aberrant proteolytic cleavage of its neuronal activators p35 and p39 is involved in neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative brain diseases. By extensive genetic analysis of the genes encoding CDK5 (CDK5), p35 (CDK5R1) and p39 (CDK5R2), we excluded causal mutations in 70 familial early-onset AD patients. We performed an association study with five informative SNPs in CDK5 in two independent samples of early-onset AD patients and matched control individuals from The Netherlands and northern Sweden. Association was observed with g.149800G>C in intron 5 of CDK5, and a two times increased risk was observed in both patient samples for carriers of the C-allele. Our data are indicative for a role of the CDK5 molecular complex in the genetic etiology of early-onset AD, and suggest that a yet unknown functional variant in CDK5 or in a nearby gene might lead to increased susceptibility for early-onset AD.

The accuracy of the dichotic, the visual half-field, and the intracarotid sodium amytal memory tests in preoperative neuropsychological investigation of epileptic patients.

Three methods for determining the lateralization of memory functions in patients with pharmacologically resistant intractable partial epilepsy were compared and evaluated. The three methods studied were a dichotic memory test, a visual half-field memory test, and an intracarotid Sodium Amytal memory test. A total of 35 epileptic patients considered for surgical therapy and a group of 20 non-epileptic control subjects took part in the study. The results show that the three tests tap different memory functions and that each of the test pick up a memory dysfunction in the hemisphere indicated by EEG recordings. In combination with an extensive neuropsychological test battery, the three methods produce data that concur with the evaluation made of EEG recordings.

Preoperative and postoperative memory testing of epileptic patients.

The present paper has four main objectives. First, it proposes a general theoretical orientation of memory functions as a basis for the research to be discussed. This framework is functionalistic/interactionistic in nature, in that memory is seen as an interaction between available cognitive capabilities of the individual and specific demands of the situation in which the individual is to remember a certain set of materials. Secondly, on the basis of this framework certain methodological requirements are discussed. These considerations take into account the need for a proper analysis of the to-be-remembered (TBR) information and those cognitive functions involved in remembering the TBR information presented. Thirdly, a preoperative and postoperative memory test is presented. This was designed on the basis of the theoretical and methodological considerations mentioned. Data from one such ongoing study is presented, taking into account various measures of memory functions; immediate free recall, final free recall, final cued recall, serial recall, final final free recall, short-term memory and long-term memory capacity as measured by the Tulving & Colotla [1] lag measure, primacy, asymptote and recency effects, and semantic memory. Finally, on the basis of the experience from this memory test a few aspects of memory testing in epileptic patients are suggested for future research.

Pre- and postoperative memory of dichotically presented words in patients with complex partial seizures.

Dichotic listening tests were used to determine cerebral hemisphere memory functions in patients with complex partial seizures before, 10 days after, and 1-3 yr after right (RTE) or left (LTE) temporal-lobe excisions. Control subjects were also tested on two occasions. The tests consisted of presenting a series of 12-word lists and 7-word lists alternately to the two ears while backward speech was presented to the other ear. Measures of immediate free recall, final free recall, final cued recall, and serial recall were employed. The results revealed: (a) that both groups of patients were inferior the control group in tests tapping long-term memory functions rather than short-term memory functions, (b) a right-ear advantage for RTE patients at postoperative testing, (c) that the LTE group was more affected by surgery than the RTE group, and (d) a general improvement in recall performance from early to late postoperative testing. Taken together, these results indicate that the present dichotic test can be used as a non-invasive hemisphere memory test to complement invasive techniques for diagnosis of patients considered for epilepsy surgery.

Memory improvement at different stages of Alzheimer's disease.

Three groups of patients with dementia of the Alzheimer type (mildly, moderately and severely demented) and two groups of healthy older adults (73 and 82 yr old) were examined on free and cued recall of subject-performed tasks (SPTs) or verbally presented sentences depicting the same verbal information as the SPTs. Results indicated that all groups examined performed better on SPTs than on the verbal task. In addition, for all groups cuing effects were greater in the SPT task than in the verbal task.

Quality of life rapidly improves with budesonide therapy for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group.

Our aims were to assess the impact on health-related quality of life (HRQOL) of a controlled ileal release (CIR) formulation of budesonide in active Crohn's disease (CD) and further define the role of HRQOL, using the Inflammatory Bowel Disease Questionnaire (IBDQ), in assessing outcome in CD. A randomized trial was conducted in 258 patients with active ileal or ileocecal CD. Budesonide CIR 1.5 mg, 4.5 mg, 7.5 mg, or placebo was given b.i.d. for 8 weeks. IBDQ score changes were compared among groups. Correlations for IBDQ and Crohn's Disease Activity Index (CDAI) scores were calculated. Mean IBDQ scores improved significantly over placebo by 2 weeks in budesonide 15 mg (155+/-38; p = 0.006) and 9 mg groups (157+/-33; p = 0.0002). Bowel, systemic, social, and emotional subscores were also significantly better (p < 0.002) at 2 and 8 weeks in the 9 mg group. Improved HRQOL scores correlated well with decreased CDAI (-0.8 < r < -0.4). Average per item change in IBDQ at remission was 1.17 to 1.48. Prior surgery (p < 0.005) or current smoker (p < 0.05) status predicted poorer initial HRQOL but not response. Budesonide CIR 9 or 15 mg/day rapidly and significantly improved HRQOL in active CD.

The impact of regular multidisciplinary team interventions on psychotropic prescribing in Swedish nursing homes.

OBJECTIVE: To evaluate the impact of regular multidisciplinary team interventions on the quantity and quality of psychotropic drug prescribing in Swedish nursing homes. DESIGN: A randomized controlled trial. SETTING: A sample of 33 nursing homes: 15 experimental homes and 18 control homes representing 5% of all Swedish nursing homes. PARTICIPANTS: The sample consisted of 1854 long-term care residents with an average age of 83 years. Seventy percent of the residents were women, and 42% had a documented diagnosis of dementia. An additional 5% had a psychotic disorder, and 7% had a diagnosis of depression. INTERVENTION: Experimental homes participated in an outreach program that was designed to influence drug use through improved teamwork among physicians, pharmacists, nurses, and nurses' assistants. Multidisciplinary team meetings were held on a regular basis throughout the 12-month study period. MEASUREMENTS: Lists of each resident's prescriptions were collected 1 month before and 1 month after the 12-month intervention. Measures included the proportion of residents with any psychotropic drug, polymedicine, and therapeutic duplication and proportion of residents with nonrecommended and acceptable drugs in each psychotropic drug class, as defined by current Swedish guidelines. RESULTS: Baseline results show extensive psychotropic drug prescribing, with the most commonly prescribed drugs being hypnotics (40%), anxiolytics (40%), and antipsychotics (38%). After 12 months of team meetings in the experimental homes, there was a significant decrease in the prescribing of psychotics (-19%), benzodiazepine hypnotics (-37%), and antidepressants (-59%). Orders for more acceptable antidepressants also increased in the experimental homes. In the control homes there was increased use of acceptable antidepressants, but there were no significant reductions in other drug classes. CONCLUSIONS: There is excessive prescription of psychotropic drugs in Swedish nursing homes. Improved teamwork among caregivers can improve prescribing as defined by clinical guidelines.

Memory function and brain biochemistry in normal aging and in senile dementia.

One might argue that the decrease in the number of brain cells as a function of age could be the source of the functional age deficits in memory performance. However, this possibility seems less likely since the actual loss of neurons up to advanced age is relatively small. There are no good estimates of the loss of synapses. Golgi staining of cortical neurons would indicate that there is a loss with higher age. So far, however, the most convincing data of marked loss with age appear at the biochemical level. Most human data fail to demonstrate a decrease in cholinergic and serotonergic activity as a function of normal aging, although there is a loss of corresponding receptors. In AD/SDAT, however, there is a marked damage to these systems. Conceivably, acetylcholine may be providing informational rather than tone setting or balancing influence on memory function. This may explain the failure of cholinomimetic drugs to improve memory in AD/SDAT due to their inability to supply the informational properties of normal neuronal transmission. The catecholamines, noradrenaline and dopamine are both lost in normal aging and to a much higher degree in AD/SDAT. Animal data show that noradrenaline deficiency results in scattered attention. Such a pattern might also exist in the intact aged and through guidance by means of instructions, contextual cues, and a richer TBR information, the elderly are being forced to attend. This may promote and supersede the normal functions of the noradrenaline system by directions from external rather than internal influences, conceivably by potentiating the remaining noradrenaline neurons. The cortical motor areas are relatively spared from neuro-degenerative changes in normal aging and in AD/SDAT and this might provide a neuroanatomical basis for the elderly's and mildly to moderately demented patients' success in memory performance when motor action is involved. The role of dopamine in motor function and its stability with age in hippocampus may also provide a neurochemical basis for the preservation of memory when the subjects are allowed to act physically during encoding.

Activity in motor areas while remembering action events.

Episodic memory for simple commands is better following enacted than verbal encoding. This has been proposed to be due to the possibility to base retrieval on motor information. Here we used PET to test the hypothesis that motor brain areas show increased retrieval-related activity following enacted compared to verbal encoding. Brain activity was also monitored during retrieval after imaginary enactment during encoding. It was found that activity in the right motor cortex was maximal following encoding enactment, intermediate following imaginary encoding enactment, and lowest following verbal encoding. These findings provide support that one basis for the facilitating effect on memory performance of overt, and to a lesser degree covert, encoding enactment is the possibility to base retrieval on motor information.

Functional brain maps of retrieval mode and recovery of episodic information.

Positron emission tomography (PET) was used to identify brain regions associated with two component processes of episodic retrieval; those related to thinking back in subjective time (retrieval mode) and those related to actual recovery of stored information (ecphory). Healthy young subjects recognized words that had been encoded with respect to meaning or the speaker's voice. Regardless of how the information had been encoded, recognition was associated with increased activation in regions in right prefrontal cortex, left anterior cingulate, and cerebellum. These activations reflect retrieval mode. Recognition following meaning encoding was specifically associated with increased activation in left temporal cortex, and recognition following voice encoding involved regions in right orbital frontal and parahippocampal cortex. These activations reflect ecphory of differentially encoded information.

Hemisphere memory of concrete and abstract information determined with the intracarotid Sodium Amytal test.

An extended version of the bilateral intracarotid Sodium Amytal test was administered pre-operatively to 13 patients with intractable complex partial epileptic seizures, to determine cerebral hemisphere speech and memory. There were 6 patients with left temporal lobe lesions and 7 patients with right temporal lobe lesions. Amobarbital (175 mg, 10%), injected on 2 occasions, determined the left hemisphere to be speech dominant in all cases. Memory assessed with recall, cued recall, and recognition of concrete/abstract words and pictures, was studied on 3 occasions: in a baseline test considered to indicate the degree of patient cooperation and the bilateral hemisphere memory; in a right hemisphere Amytal test; and in a left hemisphere Amytal test. The specific data pattern obtained, that abstract pictorial information is most efficiently processed by an intact right hemisphere and that verbal information is processed best by an intact left hemisphere, demonstrates the reliability of the approach taken here to present abstract and concrete to be remembered information.

Subjective gastrointestinal tolerability of acetylsalicylic acid and paracetamol after single dose treatment.

UNLABELLED: A prospective, randomised, double-blind, parallel group, two center, single-dose study was conducted to evaluate and compare the incidence of upper gastrointestinal complaints of acetylsalicylic acid and paracetamol. 600 healthy volunteers received acetylsalicylic acid (2 effervescent tablets of 400 mg), paracetamol (2 effervescent tablets of 500 mg) or placebo (2 effervescent tablets) in three treatment groups. Subjects filled in a questionnaire at 0.5, 1, 2, 3 and 4 h after dosing to evaluate eight upper gastrointestinal symptoms, which were stomach pain, burning sensation, nausea, heartburn, gas, burping, indigestion and upset stomach. The primary study objective was to show equivalence between acetylsalicylic acid and paracetamol. RESULTS: The absolute number of subjects reporting gastrointestinal intolerance were 50 of 200 in the placebo group, 46 of 200 in the paracetamol group and 56 of 201 in the acetylsalicylic acid group. The statistical test showed equivalence between both active substances. CONCLUSION: The rate of gastrointestinal intolerance following a single dose of two effervescent tablets of acetylsalicylic acid is equivalent to that of paracetamol and not different from gastrointestinal intolerance of placebo.

Adult age differences in source recall: a population-based study.

Age differences in source recall were investigated in a population-based sample of healthy adults aged 35 to 80 years (N = 1000). Participants, who were screened on a variety of demographic, psychological, and biological variables, studied facts about well-known and unknown persons that were presented in four different ways, depicting four different sources of item information. An age-related deterioration of both item and source recall was observed, with source recall being more impaired than item recall. Source error analyses revealed an increase of source amnesia in subjects aged 75-80 years. Individual differences in background variables, age, gender, and word comprehension were related to source recall of well-known items, whereas age and years of formal education were related to source recall of unknown items. Source amnesia was accentuated in the two oldest cohorts and related to word comprehension. The age-related tendency to forget the source even when the fact is retained is suggested to be a specific feature of cognitive aging.

Age differences in episodic memory, semantic memory, and priming: relationships to demographic, intellectual, and biological factors.

This study examined age differences in episodic memory, semantic memory, and priming using a random sample of 1,000 men and women from 10 age groups (35, 40, 45, . . . 80 years). The main purpose was to determine whether an age effect existed after differences on various demographic, intellectual, and biological factors had been controlled for. The simple correlations of age with episodic and semantic memory performance were found to be significant, whereas no relationship was found between age and levels of priming. After controlling for differences on the background factors, age predicted episodic but not semantic memory performance. It is proposed that the failure to account for the age effect on episodic memory is because it is caused by age-related neuronal changes.

What church examination records can tell us about the inheritance of reading disability.

Long before the establishment of a general school system in Sweden (1842), a vast majority of the adult population had reached some reasonable level of reading literacy. The level of reading skill among the members of a household was assessed by the parish priest at annual catechetical examinations, and the results of these examinations were recorded in church registers. Eventually (in the 18th century) a 5-point grading scale was developed. In the present investigation, these unique records were used to study the transmission of low reading marks over successive generations in 17 families. For comparison, a set of 17 family trees originating from good readers was traced. The average scores of the descendants of poor readers were significantly lower than corresponding scores for descendants of good readers. However, the transmission patterns in the family trees of poor readers did not indicate any simple genetic mechanism. In another study, two dyslexic cases living today were traced backward to ancestors born around 1750. In one of the cases, a massive familial pattern of reading disability down to the eighth generation was observed, while most ancestors of the other case had average or above average reading skill as judged by the priests. The reasons for the absence of a simple hereditary pattern were critically discussed.

Quality decision making in dialysis.

A patient approaching the final stage of his renal disease is faced with many difficult questions. Should he opt for a transplant or start on dialysis? In the case of dialysis, can he manage his treatment at home or will he need to be cared for in a clinic? Should be choose peritoneal dialysis or haemodialysis? Is the freedom of being independent from a machine, given by CAPD, as valuable as the freedom of having days without treatment, given by HD? The issues are complex and do not have a given answer. To make the proper decisions about his treatment the patient needs extensive information and support from the caregivers. Likewise, the caregivers need to know the patient well in order to give appropriate advice. In this exchange of information, the renal nurse has a very important role. Some patients may need to be dialysed in a hospital but most can get an equally good or even better dialysis treatment in a less stressful environment. A high degree of self-care is preferred by people who value independence and freedom of movement. Self-care also improves the self-confidence and increases the chances of maintaining employment and a rich social life. Self-care could mean both PD and HD, sometimes with the assistance of a spouse or a nurse. But a certain degree of self-care can also be maintained in limited-care centres and satellites, where the presence of nursing staff gives the feeling of security. For everybody involved, not least the purchasers of health care, it is desirable to keep the patients out of the costly hospital environment for as long as possible.

An improved optical eye movement detector for visual half-field studies of cerebral hemisphere memory.

An instrument for the evaluation of cerebral hemisphere memory using the visual half-field (VHF) technique is described. The object was to improve the existing VHF-techniques by means of an infra-red eye movement detector to control visual fixation, and to automatically control the presentation of visual stimuli. The instrument consists of four functional parts; visual presentation; optical eye movement control; electronic programming; and reaction time measuring. The instrument has been used on normal controls and in neuropsychological pre- and post-operative investigations on patients with drug resistant partial epilepsy. It has proved easy to use and reveals valuable information about hemisphere memory function. The use of an optical eye movement detector together with electronic logic has improved the accuracy and reliability of the VHF-test. A schematic outline of the instrument and a brief description of electronic circuitry are given.