Nanoscale magnetic field detection using a spin torque oscillator.

Magnetic field detection with extremely high spatial resolution is crucial to applications in magnetic storage, biosensing, and magnetic imaging. Here, we present the concept of using a spin torque oscillator (STO) to detect magnetic fields by measuring the frequency of the oscillator. This sensor's performance relies predominantly on STO properties such as spectral linewidth and frequency dispersion with magnetic field, rather than signal amplitude as in conventional magnetoresistive sensors, and is shown in measured devices to achieve large signal to noise ratios. Using macrospin simulations, we describe oscillator designs for maximizing performance, making spin torque oscillators an attractive candidate to replace more commonly used sensors in nanoscale magnetic field sensing and future magnetic recording applications.

Compensatory strategies for acquired disorders of memory and planning: differential effects of a paging system for patients with brain injury of traumatic versus cerebrovascular aetiology.

BACKGROUND: Previous studies have demonstrated the effectiveness of paging systems in compensating for everyday memory and planning problems after brain injury, including in individuals with traumatic brain injury (TBI). METHODS: Here, in addition to further analyses of the TBI data from a previous randomised control crossover trial, results are reported from a sub-group of 36 participants with brain injury from cerebrovascular accident (CVA). RESULTS: Results indicate that, as with the TBI group, the pager was effective. However, the pattern of results following cessation of treatment differed. At a group level, TBI participants demonstrated maintenance of pager-related benefits, whereas CVA participants' performance returned to baseline levels. Comparisons of demographic and neuropsychological characteristics of the groups showed that the CVA group was older, had a shorter interval post-injury, and had poorer executive function than the TBI group. Furthermore, within the TBI group, maintenance was associated with executive functioning, such that executive dysfunction impeded maintenance. This correlation remained after controlling for demographic differences between groups. CONCLUSIONS: Together, these findings suggest that executive dysfunction may affect treatment-for example, whether or not temporary use of the pager is sufficient to establish a subsequently self-sustaining routine.

Pasteurella multocida toxin as a tool for studying Gq signal transduction.

Pasteurella multocida toxin (PMT) stimulates and subsequently uncouples phospholipase C (PLC) signal transduction through its selective action on the Galphaq subunit. This review summarizes what is currently known about the molecular action of PMT on Gq and the resulting cellular effects. Examples are presented illustrating the use of PMT as a powerful tool for dissecting the molecular mechanisms involving pertussis toxin (PT)-insensitive heterotrimeric G proteins.

Recovery of cognitive functions following nonprogressive brain injury.

It has recently become clear that the adult human brain is capable of more plasticity than previously thought. Investigations into the natural history of change following brain injury demonstrate that partial recovery of function can and does occur. Furthermore, there is increasing evidence that intervention through re-training or provision of compensatory memory aids can result in improved cognitive functioning.

Coupling function of endogenous alpha(1)- and beta-adrenergic receptors in mouse cardiomyocytes.

Genetically altered mouse models constitute unique systems to delineate the role of adrenergic receptor (AR) signaling mechanisms as modulators of cardiomyocyte function. The interpretation of results from these models depends on knowledge of the signaling properties of endogenous ARs in mouse cardiomyocytes. In the present study, we identify for the first time several defects in AR signaling in cardiomyocytes cultured from mouse ventricles. beta(1)-ARs induce robust increases in cAMP accumulation and the amplitude of the calcium and cell motion transients in mouse cardiomyocytes. Selective beta(2)-AR stimulation increases the amplitude of calcium and motion transients, with only a trivial rise in cAMP accumulation in comparison. beta(2)-AR responses are not influenced by pertussis toxin in cultured mouse cardiomyocytes. alpha(1)-ARs fail to activate phospholipase C, the extracellular signal-regulated protein kinase, p38-MAPK, or stimulate hypertrophy in mouse cardiomyocytes. Control experiments establish that this is not due to a lesion in distal elements in the signaling machinery, because these responses are induced by protease-activated receptor-1 agonists and phospholipase C is activated by Pasteurella multocida toxin (a G(q) alpha-subunit agonist). Surprisingly, norepinephrine activates p38-MAPK via beta-ARs in mouse cardiomyocytes, but beta-AR activation of p38-MAPK alone is not sufficient to induce cardiomyocyte hypertrophy. Collectively, these results identify a generalized defect in alpha(1)-AR signaling and a defect in beta(2)-AR linkage to cAMP (although not to an inotropic response) in cultured mouse cardiomyocytes. These naturally occurring vagaries in AR signaling in mouse cardiomyocytes provide informative insights into the requirements for hypertrophic signaling and impact on the value of mouse cardiomyocytes as a reconstitution system to investigate AR signaling in the heart.

E1A oncogene expression level in sarcoma cells: an independent determinant of cytolytic susceptibility and tumor rejection.

Ad2/5 E1A oncogene expression induces cytolytic susceptibility of rodent cells to natural killer lymphocytes. To determine whether the requisite thresholds of E1A oncoprotein expression differ for induction of cytolytic susceptibility as compared with other E1A-related activities, sarcoma cells expressing low or normal levels of E1A oncoproteins were compared for differences in morphological transformation, transactivation of viral genes, cytolytic susceptibility and tumorigenicity. Low-level E1A expression transformed sarcoma cells and transactivated the Ad5 E2A gene but did not induce the increased cytolytic susceptibility observed with normal levels of E1A expression. Furthermore, low-level E1A expressers retained the tumorigenicity of parental cells, whereas normal-level expressers were non-tumorigenic in hosts with intact natural killer (NK)-cell responses. In contrast to E1A, E1B oncogene expression caused no changes in morphological, cytolytic or tumorigenic phenotypes in these sarcoma cells. These data define an expression threshold for E1A-induced cytolytic susceptibility and associated NK-cell-dependent tumor rejection. The results suggest that the cellular mechanisms involved in E1A induction of cytolytic susceptibility differ from those involved in E1A-mediated cellular transformation and viral gene transactivation.

New activated RAS2 mutations identified in Saccharomyces cerevisiae.

Activating mutations in RAS proto-oncogenes encode proteins with greater GTP binding. Such mutant proteins are responsible for many human cancers. Six new amino acids were discovered that can yield an activated Saccharomyces cerevisiae RAS2 protein when they are altered. These new RAS2 alleles were found among a collection of 35 random mutations that exhibit a dominant reduction of glycogen accumulation. The RAS2-P41S and RAS2-E99K alleles encode proteins that have lost responsiveness to GTPase activating proteins. They affect amino acids in loop 2 and helix 3 respectively and illustrate that GTPase activating proteins recognize a larger portion of the RAS structure than previously realized. RAS2 mutations E130K, S153F, A154T, and A157S alter amino acids proximal to the guanine binding site and probably influence nucleotide binding either directly or indirectly.

A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.

ATP-sensitive potassium (K[ATP]) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate. Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), which also encompasses a locus for HI, we screened the Kir6.2 gene for the presence of mutations in 78 HI probands by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mutation, Tyr-->Stop at codon 12 (designated Y12X) was observed in the homozygous state in a single proband. 86Rb+ efflux measurements and single-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that K(ATP) channel activity was abolished by this nonsense mutation. The identification of an HI patient homozygous for the Kir6.2/Y12X allele affords an opportunity to observe clinical features associated with mutations resulting in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 subunit of the islet beta-cell K(ATP) channel are associated with the HI phenotype and also suggest that the majority of HI cases are not attributable to mutations in the coding region of the Kir6.2 gene.

When implicit learning fails: amnesia and the problem of error elimination.

We propose that one of the major functions of explicit memory is the elimination of learning errors. The hypothesis is explored by means of a stem completion task in which subjects are presented with stems having many potential completions, and in the initial phase are either encouraged to guess, the "errorful" procedure, or are provided with the correct completion, the "errorless" condition. Learning is then tested over a sequence of nine trials. The performance of amnesic subjects who are assumed to have good implicit but bad explicit learning is compared with that of normal elderly subjects, who are assumed to have an intermediate level of explicit learning skill, and young controls who are expected to be high in both implicit and explicit learning capacity. As predicted, errorless learning is beneficial, with the effect being particularly marked for the amnesic group. A detailed analysis of the intrusion errors supports an interpretation of the results in terms of the relative contribution to the three groups of implicit learning, which is assumed to be particularly vulnerable to interference. Implications for the analysis of normal learning, and for the rehabilitation of brain damaged patients are discussed.

Interaction of hand use and spatial selective attention in children.

It has been argued that concurrent motor action can modulate visual spatial attention. The visual spatial biases of adult patients with unilateral neglect, for example, can be ameliorated by simultaneous use of the contralesional hand. Such improvements are most dramatic when the contralesional hand is moved within contralesional space. To date, evidence of such an interaction in neurologically healthy individuals has not been presented. Line bisection is a simple task that is sensitive to attentional spatial bias. When young children are asked to bisect horizontal lines using their right hands, they show a reliable, if small, bias that is consistent with the pattern seen in adult neglect. This bias is reversed when the left hand is used. Here, we show that these effects are significantly modulated by the location of the movements relative to the body mid-line - specifically that the conjunction of hand movements within ipsilateral space is necessary for the previously reported pattern to be observed. We further demonstrate that these effects are not present in the bisections of neurologically healthy adults. In a final study, we examined whether the hand movement effects seen in children's line bisections would persist in a purely visual task (that is when the movements were made irrelevant to the response). Again, significant modulation of children's perception by concurrent hand movements - and the relative location of those movements - was observed. The theoretical and clinical implications of the results are discussed.

Skeletal muscle lactate release and glycolytic intermediates during hypercapnia.

The effects of respiratory acidosis on glycolysis in the autoperfused canine gastrocnemius-plantaris were studied using anesthetized dogs that were ventilated either with air (n = 30) or with 4% CO2-21% O2-75% N2 (n = 30). The left muscle group was stimulated at 3 Hz for up to 20 min, after which the active and the contralateral resting muscles were removed and frozen in liquid N2. Blood flow, VO2, Vco2, and tension development were unaffected by CO2. Glycogen catabolism was not affected, but lactate release (La) was lower (P less than 0.05) during activity with CO2; and greater fructose 6-phosphate, fructose 6-phosphate/fructose 1,6-diphosphate, and alpha-glycerophosphate/dihydroxyacetone phosphate ratios resulted (P less than 0.05). With respiratory acidosis, muscle lactate tended to accumulate early in contractions, but a net lactate uptake occurred during the last 10 min of contractions. Thus, respiratory acidosis reduced lactate efflux and there was a net uptake late in the contraction period. Glycogen phosphorylase did not appear to be affected by the respiratory acidosis, but there was evidence of inhibition at the phosphofructokinase step as well as a tendency for lactate to accumulate within the muscle. La often occurred in a direction contrary to the muscle-venous lactate concentration difference with either air or CO2 and La also decreased far more rapidly over time than did the arterial-venous H+.

Effects of centrally administered naloxone on phrenic nerve activity.

The present study examined the effect on respiration of naloxone administered centrally. Experiments were performed on anesthetized, paralyzed cats whose vagi and carotid sinus nerves had been cut. The animals' end-tidal pCO2 and body temperature were kept constant with servocontrollers. Naloxone administered into the third cerebral ventricle in doses of 40 micrograms/kg and 400 micrograms/kg resulted in significant (P less than 0.05) increases in phrenic neural activity. The response to the 400 micrograms/kg dose was significantly greater (P less than 0.05) than the response to the 40 micrograms/kg dose. A dose of 40 micrograms/kg naltrexone administered to each of two animals produced similar increases in respiratory activity. These data indicate that in the preparation studied endogenous opiates exert a tonic inhibitory effect on respiration through their action on central opiate receptors.

Partial recovery from visual object agnosia: a 10 year follow-up study.

We describe a young woman, J.R., who sustained a very severe head injury in 1981 at the age of 17 years. She was assessed in 1982 and found to have visual agnosia. Since then J.R. has been assessed on several occasions over a period of ten years. Her agnosia for real objects has resolved and she has improved on the identification of other classes of stimuli. However, she still has some problems with the identification of line drawings, photographs and model animals. Her drawing from memory remains particularly poor and she has difficulty with visual imagery. We consider her residual deficits in the light of Farah's (1990) theoretical framework; this proposes that associative agnosia could be due to a disconnection syndrome, a loss of stored visual representations or to the loss of knowledge of how to perceive objects. J.R.'s residual impairments appear to be mainly due to a loss of access to visual representations in the absence of visual input.

A case of word deafness with preserved span: implications for the structure and function of short-term memory.

Case IJ shows impaired capacity to repeat individual words despite normal hearing as measured by audiometry and tympanometry. She also has difficulty in identifying other environmental sounds. Her phonological memory span for visually-presented material is normal, and her memory span for spoken digits is only slightly impaired. It is suggested that she has a pre-phonological auditory processing deficit; the implications of this for discussion of the role of phonological short-term memory in language processing are discussed.

Spontaneous recovery of impaired memory span: does comprehension recover?

We have previously described a patient, T.B., who had a memory span of two digits and a sentence span of three words. He showed no evidence of effects of either phonological similarity or word length on span and his deficit was interpreted as reflecting the impaired functioning of the phonological loop component of working memory. Analysis of his language comprehension indicated normal processing of short sentences, together with a marked deficit in understanding long sentences, whether these were presented visually or auditorily (Baddeley and Wilson, 1988). When re-tested after several years, T.B.'s memory span had increased to nine digits, and showed clear effects of phonological similarity and word length. His performance on a series of language comprehension tests indicated a complete recovery, although he continued to show impairment on two tests of phonological awareness. These results are consistent with the proposed link between phonological working memory and language comprehension. In addition, they indicate a dissociation between short-term phonological memory and phonological awareness.

Myotonic dystrophy and progressive cognitive decline: a common condition or two separate problems?

We report the case of NG, a 43-year old woman with myotonic dystrophy (MYD) who has shown a slow decline in both motor and cognitive abilities since her referral to us at age 32. MYD is an autosomal dominant disorder characterised by weakening and wasting of the muscles together with impaired muscle relaxation. Cognitive abilities are usually little affected in the adult onset form, although there is a high risk of cognitive impairment in those with childhood onset. Cognitive decline is also typically associated with maternal inheritance. NG, who was diagnosed with MYD at the age of 18, inherited it from her father. We report the decline in NG's cognitive abilities over 11 years of longitudinal assessment, and consider whether she is an atypical MYD patient or whether the MYD and cognitive decline are attributable to two separate pathological processes.

Knowing where and knowing what: a double dissociation.

We report a double dissociation between visuo-spatial abilities and semantic knowledge (knowledge of the names and attributes of objects and people), in two brain-injured people with longstanding stable impairments, using a wide range of tests to explore the extent of the dissociation, MU, who has bilateral lesions of occipito-parietal cortex, shows severe spatial disorientation with relatively well-preserved semantic knowledge. He is contrasted with JBR, who has bilateral temporal lobe damage and shows severe semantic problems and no impairment on visuo-spatial tasks. Our findings thus demonstrate a double dissociation between the performance of semantic and spatial tasks by MU and JBR. This pattern is consistent with Ungerleider and Mishkin's (1982) neurophysiological hypothesis of separable cortical visual pathways; one which is specialised for spatial perception and follows a dorsal route from occipital to parietal lobes, and the other following a more ventral route from occipital to temporal lobes, whose target is semantic information needed in specifying what an object is.

How do old dogs learn new tricks: teaching a technological skill to brain injured people.

Little is known about the way people learn technological skills. This investigation was carried out to see how 100 brain injured, 50 controls and two amnesic patients performed on a task requiring them to learn a six-step programme for an electronic memory aid. Performance was correlated with other measures of memory to determine whether the technological skill was similar to a procedural learning task, a spatial memory task, a visual task, a verbal task or an amalgam of these. All controls but only 59 percent of the patients learned the task within three trials. The two amnesic patients also failed to learn the new skill. There was a high correlation between overall performance on a standardized test of everyday memory (the Rivermead Behavioural Memory Test) but little evidence that the technological skill was similar to a procedural learning task; nor was it specifically related to visual, verbal or spatial memory. It is concluded that a combination of skills is required to learn the technological task. Implications for the concept of procedural learning are discussed.

Right neglect following right hemisphere damage?

From a sample of 90 stroke cases showing visual inattention following right hemisphere brain damage, 17 cases were identified who showed more inattention on the right than the left side on some tests. Eight of these subjects had CT scan-confirmed unilateral right hemisphere damage and one of these eight had MRI scan-confirmed unilateral right brain damage. A number of hypotheses are examined to explain this "paradoxical" right inattention. The most parsimonious proposes that right inattention is produced by an interaction of a compensatory left sided scanning strategy in association with a non-lateralised attentional loss.