New approaches to antibiotic discovery.

New antibiotics are urgently required by human medicine as pathogens emerge with developed resistance to almost all antibiotic classes. Pioneering approaches, methodologies and technologies have facilitated a new era in antimicrobial discovery. Innovative culturing techniques such as iChip and co-culturing methods which use 'helper' strains to produce bioactive molecules have had notable success. Exploiting antibiotic resistance to identify antibacterial producers performed in tandem with diagnostic PCR based identification approaches has identified novel candidates. Employing powerful metagenomic mining and metabolomic tools has identified the antibiotic'ome, highlighting new antibiotics from underexplored environments and silent gene clusters enabling researchers to mine for scaffolds with both a novel mechanism of action and also few clinically established resistance determinants. Modern biotechnological approaches are delivering but will require support from government initiatives together with changes in regulation to pave the way for valuable, efficacious, highly targeted, pathogen specific antimicrobial therapies.

Stroke risk predicts verbal fluency decline in healthy older men: evidence from the normative aging study.

Risk factors for stroke cause ischemic changes in the cerebral white matter that may affect frontal lobe functions more than other brain functions. Therefore, stroke risk could specifically affect performance on behavioral indexes traditionally associated with frontal lobe function such as verbal fluency. The authors examined this hypothesis in 235 healthy older men (mean age = 66.41 years) who received concurrent medical and neuropsychological examinations twice at a 3-year interval. Relations between stroke risk and decline in verbal fluency, memory, and visuospatial performance were analyzed through regression, controlling for age and education. Age was associated with decline in all cognitive functions; stroke risk was associated with decline only on verbal fluency. The relation between stroke risk and fluency decline was 80% as large as that between age and fluency decline. These results suggest that stroke risk rivals the effects of aging on verbal fluency performance.

Phasic and tonic alertness in Alzheimer's disease.

Phasic alertness (the rapid mobilization of resources to process an expected stimulus) was examined in Alzheimer patients and normals by a choice RT task in which the stimulus was usually preceded by a warning signal. The time subjects needed to attain maximal phasic alertness was determined by varying the Stimulus Onset Asynchrony (SOA) between the warning and the stimulus. In comparison to trials without any warning, presentation of a warning signal reduced the RT of Alzheimer patients as much as it did that of normals. Similarly, the SOA necessary for maximal alertness was the same in Alzheimer patients and in normals. Maintenance of tonic alertness was investigated by examining how RT changed across a long period of continuous testing. Alzheimer patients and normals showed a similar rise in RT with increasing time on task. These results suggest that phasic and tonic alertness are relatively unimpaired by Alzheimer's disease.

Cognitive slowing in Alzheimer's disease and geriatric depression.

Response slowing on psychological tasks is found both in Alzheimer's disease and depression. However, the underlying cause for this slowing may be different in the two disorders. This research examined whether the behavioral slowing found in Alzheimer patients results from a reduction in their rate of cognitive processing, whereas the slowing in depressed geriatric patients reflects a purely motor retardation. This hypothesis was tested using a task in which subjects had simply to determine the number of dots present in an array (i.e., enumeration). In all four subject groups (Alzheimer patients, depressed geriatric patients, healthy old controls, and healthy young controls), response time increased linearly with array size. The slope of this linear function (reflecting rate of enumeration) was the same in the normal and depressed patients, but was significantly greater in the Alzheimer patients, suggesting the presence of a cognitive slowing in Alzheimer's disease, but not in depression.

Generalized cognitive slowing and severity of dementia in Alzheimer's disease: implications for the interpretation of response-time data.

A meta-analysis was performed on the response times (RTs) of Alzheimer patients and normal subjects for 61 experimental conditions. Regression of the RTs of Alzheimer patients against those of young normals yielded a linear function: Alzheimer (time) = A+B Young (time), where B was a constant proportion of 2.3. As dementia severity increased, so too did the magnitude of this RT slowing, B rising from 2.0 to 2.9. The linearity of this function suggests that Alzheimer's disease produces a generalized slowing of cognitive processing. Since Alzheimer patients are proportionally slower than normals, the size of the absolute difference in RT between Alzheimer patients and normals increases as task complexity rises, irrespective of the exact cognitive operations being tested. It will be necessary to take this generalized slowing into account when interpreting differences in the effect that various experimental conditions have on the RTs of normals and Alzheimer patients.

The effect of contextual constraint on semantic judgments by Alzheimer patients.

Subjects (Alzheimer patients, normal young and elderly individuals) heard a sentence the last word of which was missing. A visual word then appeared and the subjects decided whether it made a sensible ending to the sentence. Sentences varied in the degree to which their semantic context constrained possible endings to the sentence. The degree of contextual constraint greatly influenced response time--the greater the constraint, the faster subjects made their decisions. While Alzheimer patients were slower than normals, their decision time was affected by contextual constraint to the same degree as that of normals. Thus, the performance of Alzheimer patients was sensitive to the amount of semantic context present in sentences, and this context facilitated their ability to make conscious semantic judgements. These findings suggest that Alzheimer patients are capable of using semantic information in a task requiring attention-dependent processes.

Preserved organization of semantic attributes in Alzheimer's disease.

This study investigated whether Alzheimer's disease (AD) disrupts the basic organization of the semantic attributes of concepts. Young and normal older subjects and AD patients were presented with a target concept followed by a stimulus word and were to decide whether the stimulus was related to the target. On those trials where it was, the stimulus was either a high-, medium-, or low-dominance attribute of the target. The higher the normative dominance, the more important the attribute to concept meaning. In all 3 subject groups, decision time varied as a function of dominance. The higher the dominance, the faster the decision. Attribute dominance affected the performance of AD patients more than that of normal subjects. These results suggest that AD patients retain their knowledge of the relative importance that the different attributes of a concept have for concept meaning.

Focused and divided attention in Alzheimer's disease.

Visual search tasks were used to examine two aspects of selective attention (focused and divided attention) in normal young and older persons and in Alzheimer patients. Normal and demented subjects were equally efficient in using a color cue to selectively search only the relevant items in an array. Thus, focused attention abilities appear to be relatively unimpaired by Alzheimer's disease. By contrast, in comparison to normals, the search time of demented patients rose disproportionately as the number of items over which they had to distribute their attention was increased. This suggests that Alzheimer patients are less efficient than normals in dividing their attention.

Automatic and attentional mechanisms of semantic priming in Alzheimer's disease.

Previous studies using a word-naming task have suggested that in demented patients, semantic priming results only from automatic spreading activation and not from attention-dependent processes. If this is true, then on a lexical-decision task where attention-dependent processes are a major source of the semantic-priming effect, demented patients should show little or no priming. To test this prediction, three groups of 16 subjects (young and normal-old individuals and patients with Alzheimer's disease) were given a Word-Naming and a Lexical-Decision task. In both tasks, the amount of semantic priming (the difference in response time to a word preceded by a semantically unassociated vs. a semantically associated word) was determined. Demented patients showed significantly greater semantic priming than either normal group on both tasks. This result argues against the hypothesis that the semantic priming found in demented patients is due solely to automatic processes.

The effect of semantic and syntactic structure on verbal memory in Alzheimer's disease.

This study examined the ability of 17 patients with Alzheimer's disease and 17 normal-old subjects to recall short sentences that were normal, or had a disruption in either their semantic structure, their syntactic structure, or both their semantic and syntactic structure. Results showed that sentence recall performance was affected similarly in the demented and normal-old subjects by both the syntactic and semantic structure of the sentences. The presence of either type of language structure appeared to allow both normal and demented subjects to organize strings of words into multiword chunks for more efficient memory encoding.

Integrity of semantic fields in Alzheimer's disease.

It has been suggested that Alzheimer patients retain general semantic knowledge about concrete objects (e.g., category membership) but lose information about objects' distinctive features and functions. To test this hypothesis, normal young and old subjects and Alzheimer patients were given a concrete concept. They were then shown a series of words and for each had to say whether it was related to the concept. Of the words that were related to a given concept, one was a physical feature, another a function, another the object's superordinate category, and another a generally associated concept. In comparison to the normals, Alzheimer patients were not disproportionately worse at making decisions about features and actions than they were about categories and general associates. Also, while Alzheimer patients were less accurate in generating features, actions and associates to a given concept than were normals, they were not differentially more impaired on any one type.