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Evaluation of functional capacity after stroke with special emphasis on motor function and activities of daily living.

In a multidisciplinary study comprising 280 patients with acute cerebrovascular disease (median age 76, range 30-96 years), instruments for functional assessment in stroke care were developed. The improvements of motor function and activities of daily living were investigated during a period of up to one year after a stroke. A new chart for motor capacity assessment, which includes both the paretic and the non-paretic side, modified after that of Fugl-Meyer et al, was tested for its reliability and validity. At the same time the Activity Index of Hamrin & Wohlin was further tested. The internal consistency reliability measured with the standardized item alpha method confirmed that the two instruments have high homogeneity. Construct validity was investigated by factor analysis and showed a logical structure. The predictive validity of the scores on admission was significant and the two tools had a satisfactory predictive capacity for survival and later functional outcome. The improvements in different motor functions were followed up for up to one year after the stroke among the 183 one-year survivors. In patients with minor impairment, the improvement occurred mostly during the first week. Patients with moderate or moderately severe impairment improved more continuously for up to three months, while the few surviving patients with very severe impairment continued to recover to some extent even after three months. Older patients with severe functional loss seemed to improve more slowly and not as well as younger patients with equivalent impairment. The patterns of instrumental activities of daily living (I-ADL), such as household work, locomotion, psychosocial functions and intellectual activities, were investigated in the 207 three-month survivors and the 183 one-year survivors. At both the three-month and the one-year follow-ups the scores had decreased considerably, compared with before the stroke, for all activities except locomotion, and many patients were dependent on somebody else for help. The same group of patients was also examined by a Standardized Practical Equipment (SPE) test constructed by Tömquist three months and one year after the stroke. The construct validity of the SPE test was estimated through factor analysis. Three factors emerged, one concerning mainly cognitive factors and co-ordination, one concerning hand function and one concerning mainly mobility and balance. The instruments developed in the course of this study have proved to be reliable and valid, and useful in assessing functional losses and following progress. The tools are well suited for any clinical settings and for home care examinations as well as research.

Activities of Daily Living↗

Nine-year outcome of the Vermont intervention program for low birth weight infants.

Twenty-four low birth weight children who had received an experimental intervention (LBWE) during the neonatal period, 31 control children who had received no treatment (LBWC), and 36 normal birth weight children were compared. The intervention involved seven hospital sessions and four home sessions in which a nurse helped mothers adapt to their LBW babies. At age 9, LBWE children scored significantly higher than LBWC children on the Kaufman Mental Processing Composite, Sequential, Simultaneous, Achievement, Arithmetic, and Riddles scales, after statistical adjustments for socioeconomic status. The LBWE children had also advanced more rapidly in school than had LBWC children. Parent (Child Behavior Checklist) and teacher (Teacher's Report Form) ratings of school functioning were more favorable for LBWE than LBWC children, with especially strong effects on Teacher's Report Form scores for academic performance and the attention problems syndrome. At age 9, LBWE children were not significantly inferior to normal birth weight children on any measure. These results bear out a progressive divergence between the LBWE and LBWC children that first became statistically significant in cognitive scores at age 3. The findings suggest that the intervention prevented cognitive lags among LBW children and that this eventually had a favorable effect on academic achievement, behavior, and advancement in school. The progression from no significant differences between LBWE and LBWC children on early cognitive and achievement scores to significant and pervasive differences in later functioning argues for long-term follow-up periods to evaluate properly the power of behavioral interventions to compensate for biological risks.

Adaptation, Psychological↗

A new animal model to assess angiogenesis and endocrine function of parathyroid heterografts in vivo.

BACKGROUND: It is still a matter of investigation how angiogenesis and restoration of gland perfusion determine graft function after free parathyroid autotransplantation. We provide a new animal model allowing simultaneous and repetitive in vivo assessment of angiogenesis and endocrine function of parathyroid transplants. METHODS: Fresh human parathyroid tissue from patients with secondary hyperparathyroidism was grafted into dorsal skinfold chamber preparations of athymic nude mice (CD1-nu; n=8). Equivalent pieces of the same human donor specimens were heat-inactivated and served as control grafts (n=7). RESULTS: In all animals receiving parathyroid transplants, intact human parathyroid hormone levels were detectable by species-specific enzyme-linked immunosorbent assay analysis of plasma samples on day 5 after transplantation and increased by 2.5-fold over the observation period (19 days) in contrast with controls. Plasma Ca levels revealed no differences between the groups. On day 5 after transplantation, intravital fluorescence microscopy revealed murine angiogenic microvessels sprouting along nonperfused human donor vessels, and 1 week later functional microvasculature was established in all parathyroid transplants. Histologic analysis revealed well-vascularized endocrine tissue. In contrast, control grafts were necrotic and partly resorbed; they exhibited no angiogenic activity or well-vascularized fat cells indicating fatty degeneration. In addition, species-specific Western blot analysis revealed vascular endothelial growth factor expression of parathyroid transplants rather than functional vessel density as the functional parameter of angiogenesis determining transplant function in vivo. CONCLUSION: This model may serve to understand mechanisms associated with specific parathyroid transplant angiogenesis and its significance for transplant function to optimize clinical success of autotransplantation in therapy-resistant patients.

Animals↗

Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus.

It is well accepted that events that interfere with the normal program of neuronal differentiation and brain maturation may be relevant for the etiology of psychiatric disorders, setting the stage for synaptic disorganization that becomes functional later in life. In order to investigate molecular determinants for these events, we examined the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) and the glutamate NMDA receptor following 24 h maternal separation (MD) on postnatal day 9. We found that in adulthood the expression of BDNF as well as of NR-2A and NR-2B, two NMDA receptor forming subunits, were significantly reduced in the hippocampus of MD rats whereas, among other structures, a slight reduction of NR-2A and 2B was detected only in prefrontal cortex. These changes were not observed acutely, nor in pre-weaning animals. Furthermore we found that in MD rats the modulation of hippocampal BDNF in response to an acute stress was altered, indicating a persistent functional impairment in its regulation, which may subserve a specific role for coping with challenging situations. We propose that adverse events taking place during brain maturation can modulate the expression of molecular players of cellular plasticity within selected brain regions, thus contributing to permanent alterations in brain function, which might ultimately lead to an increased vulnerability for psychiatric diseases.

Animals↗

[Laterality of musical functions in partial epilepsy].

Fourteen right handed patients with partial epilepsy (Epileptic Group) and with a median age of 31 years were divided into two groups (Right and Left), according the laterality of paroxystic activity in the electroencaphalogram. Of the 14 patients, 42.8% (6/14) presented a focus at the right side while the others 57.2% (8/14) presented a focus at the left. The Control Group consisted of 31 right handed individuals with a median age of 30 years and with no previous history of neurological disease or epileptic seizures. All the individuals had no musical skills. They carried out Music Abilities Tests including Spontaneous Rhythm, Elemental Music Functions Perception (tone color, duration, pitch, intensity and rhythm) and Complex Strutures Tests (recognition and reproduction of corporal rhythmic movements). We concluded that the focus at the right and the left cerebral hemisphere affect the development of the melodic recognition functions while in cases with focus at the left cerebral hemisphere, rhythmic reproduction and organization are more impaired when compared to the Control Group.

Adult↗

her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis.

Somite formation is thought to be regulated by an unknown oscillator mechanism that causes the cells of the presomitic mesoderm to activate and then repress the transcription of specific genes in a cyclical fashion. These oscillations create stripes/waves of gene expression that repeatedly pass through the presomitic mesoderm in a posterior-to-anterior direction. In both the mouse and the zebrafish, it has been shown that the notch pathway is required to create the stripes/waves of gene expression. However, it is not clear if the notch pathway comprises part of the oscillator mechanism or if the notch pathway simply coordinates the activity of the oscillator among neighboring cells. In the zebrafish, oscillations in the expression of a hairy-related transcription factor, her1 and the notch ligand deltaC precede somite formation. Our study focuses on how the oscillations in the expression of these two genes is affected in the mutants aei/deltaD and des/notch1, in 'morpholino knockdowns' of deltaC and her1 and in double 'mutant' combinations. This analysis indicates that these oscillations in gene expression are created by a genetic circuit comprised of the notch pathway and the notch target gene her1. We also show that a later function of the notch pathway can create a segmental pattern even in the absence of prior oscillations in her1 and deltaC expression.

Animals↗

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous subtype of non-insulin-dependent diabetes mellitus (NIDDM) characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. Recent studies have shown that mutations in the two functionally related transcription factors, hepatocyte nuclear factor 4 alpha (HNF-4alpha) and hepatocyte nuclear factor 1 alpha (HNF-1alpha) are associated with the MODY1 and MODY3 forms of diabetes respectively, whereas mutations in the enzyme glucokinase are the cause of the MODY2 form. We have examined 10 unrelated Caucasian families in which MODY/NIDDM co-segregated with markers for MODY3 for mutations in the HNF-1alpha gene (TCF1). Ten different mutations were observed in these families, all of which co-segregated with diabetes. There were no obvious relationships between the nature of the mutations observed (i.e. frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in these families. The mechanisms by which mutations in the HNF-1alpha gene cause diabetes mellitus are unclear but might include abnormal pancreatic islet development during foetal life thereby limiting their later function, as well as impaired transcriptional regulation of genes that play a key role in normal pancreatic beta cell function.

DNA-Binding Proteins↗

Visual input and lateralization of brain function in learning in the chick.

Several lines of evidence (biochemical, neuroanatomical, electrophysiological, and behavioural) have indicated a critical role for the intermediate medial hyperstriatum ventrale of the chick forebrain in the acquisition of a passive avoidance response. Previous lesion studies indicated that bilateral or left, but not right, pretraining intermediate medial hyperstriatum ventrale lesions interfere with the acquisition of this task. We have further analysed this asymmetrical involvement of the intermediate medial hyperstriatum ventrale by use of a monocular learning protocol and intermediate medial hyperstriatum ventrale lesions (sham, bilateral, or unilateral). The results indicated that there is interocular transfer of information of passive avoidance learning between the two eye systems, with a tendency to be more successful from the right eye system to the left than in the opposite direction. As in binocular conditions, bilateral pretraining intermediate medial hyperstriatum ventrale lesions impair learning in monocularly trained animals. Unilateral lesions to either left or right monocularly trained experimental animals resulted in amnesia when they were made to the right intermediate medial hyperstriatum ventrale and the chicks were trained/tested with the left eye open. These results indicate that, although right intermediate medial hyperstriatum ventrale lesions do not result in amnesia in binocular animals, this region is capable of participating in memory acquisition processes. They also suggest a connection between lateralization of intermediate medial hyperstriatum ventrale function in passive avoidance learning and the behavioural and structural visual asymmetries known to occur in chicks.

Animals↗

Acquisition of Hox codes during gastrulation and axial elongation in the mouse embryo.

Early sequential expression of mouse Hox genes is essential for their later function. Analysis of the relationship between early Hox gene expression and the laying down of anterior to posterior structures during and after gastrulation is therefore crucial for understanding the ontogenesis of Hox-mediated axial patterning. Using explants from gastrulation stage embryos, we show that the ability to express 3' and 5' Hox genes develops sequentially in the primitive streak region, from posterior to anterior as the streak extends, about 12 hours earlier than overt Hox expression. The ability to express autonomously the earliest Hox gene, Hoxb1, is present in the posterior streak region at the onset of gastrulation, but not in the anterior region at this stage. However, the posterior region can induce Hoxb1 expression in these anterior region cells. We conclude that tissues are primed to express Hox genes early in gastrulation, concomitant with primitive streak formation and extension, and that Hox gene inducibility is transferred by cell to cell signalling. Axial structures that will later express Hox genes are generated in the node region in the period that Hox expression domains arrive there and continue to spread rostrally. However, lineage analysis showed that definitive Hox codes are not fixed at the node, but must be acquired later and anterior to the node in the neurectoderm, and independently in the mesoderm. We conclude that the rostral progression of Hox gene expression must be modulated by gene regulatory influences from early on in the posterior streak, until the time cells have acquired their stable positions along the axis well anterior to the node.

Animals↗

Is donepezil therapy associated with reduced mortality in nursing home residents with dementia?

BACKGROUND: Since cholinesterase inhibitors (CEIs) were approved for use in mild to moderate Alzheimer's disease, the therapeutic efficacy of this class of medications has largely centered on demonstration of short-term improvement in cognition and global function. Later evidence suggested that the beneficial effects of CEIs might be sustainable for at least 3 years and that CEIs may have a disease-modifying effect on Alzheimer's disease. These broad-ranging, long-term effects may explain the recent finding that the use of a CEI among nursing home residents with dementia was associated with lower mortality. OBJECTIVE: The goal of this study was to investigate whether donepezil treatment is associated with reduced mortality in nursing home residents who have dementia. METHODS: We performed a retrospective matched cohort study using the Systematic Assessment of Geriatric Drug Use via Epidemiology database, which contains data collected with the Minimum Data Set on a cross section of 915,469 nursing home residents aged > 65 years between 1998 and 2000 in 6 US states. We identified users of donepezil (5 and 10 mg) and an equal number of matched nonusers in the same facility, date of donepezil use, level of cognitive function, and dementia diagnosis. Comparisons of the 2 groups were made for sociodemographic variables, dementia severity, number of medications, and major comorbid illnesses (heart disease, cancer, diabetes mellitus, chronic obstructive pulmonary disease, and malnutrition), as well as survival over the 2-year study period. RESULTS: A total of 5423 users and 5423 nonusers of donepezil were identified. Based on Cox proportional hazards models, donepezil users showed a lower mortality rate than nonusers. The hazard rate ratio was 0.89 (95% CI, 0.83-0.95). After adjusting for the confounding variables, sociodemographic factors, other psychotropic drugs, and comorbid conditions, this survival advantage remained (hazard rate ratio, 0.90; 95% CI, 0.84-0.96). CONCLUSIONS: A relationship was observed between treatment of nursing home residents with donepezil and lower mortality. If the relationship was due to a direct effect of donepezil use, then this observation has implications for the socioeconomic impact of CEI therapy in those with advanced dementia in the nursing home. These implications deserve future investigation.

Aged↗

Evaluation of ankle instability using the Biodex Stability System.

Ten patients with chronic unilateral functional lateral instability of the ankle were evaluated using the Biodex Stability System. This system uses a multiaxial testing platform which can be set at variable degrees of instability. Patients are then tested for their ability to "balance" the platform during single-limb stance, and a stability index is electronically generated. This stability index is believed to be an objective measurement that correlates with proprioceptive status of the ankle. Instability of the ankle was confirmed in all 10 patients, using stress radiographs. Two levels of platform stability were tested. With the platform in its most stable configuration, there was minimal difference between the previously injured and the uninjured ankle. With the platform set to permit up to 20 degrees of tilt in any plane, 6 of 10 patients had more difficulty balancing the platform with their injured ankle (higher stability index). This preliminary study suggests that the Biodex Stability System may be a useful tool in trying to objectively measure proprioceptive function.

Adult↗

Prematurity-associated nephrocalcinosis and kidney function in early childhood.

To assess the impact of prematurity-associated nephrocalcinosis on kidney function later in life, 20 premature children with neonatal nephrocalcinosis and 20 controls, matched for birth weight and postnatal age but without nephrocalcinosis, were examined (birth weight 905+/-209 vs. 957+/-226 g; study age 4.7+/-1.1 vs. 4.6+/-0.9 years). Distal tubular acidification capacity was measured with the oral acetazolamide test, in which the response was abnormal in 1 out of the 20 children with a history of nephrocalcinosis, but in none of the controls. Urinary calcium and beta(2)-microglobulin excretion were higher in the children with nephrocalcinosis, but no differences were found in fractional excretion of sodium and potassium or tubular reabsorption of phosphate. Estimated creatinine clearance was not different between the groups. Of the 6 children with nephrocalcinosis lasting beyond 2 years of age, 5 had had chronic lung disease neonatally and exhibited a tendency for compensated respiratory acidosis at the time of the examination. Neonatal nephrocalcinosis seems to lead to some signs of renal tubular dysfunction in early childhood of preterm infants. Glomerular function, however, appears not to be specifically disturbed by nephrocalcinosis.

Calcium↗

New routes for lignin biosynthesis defined by biochemical characterization of recombinant ferulate 5-hydroxylase, a multifunctional cytochrome P450-dependent monooxygenase.

The enzymes and genes of the lignin biosynthetic pathway have been studied for several decades, but the gene encoding ferulate 5-hydroxylase (F5H) was cloned only 3 years ago by T-DNA tagging in Arabidopsis. To characterize the enzyme in detail, we have expressed F5H in yeast. According to current models of the phenylpropanoid pathway, F5H catalyzes the hydroxylation of ferulate to 5-hydroxyferulate; however, our studies indicate that the enzyme also uses coniferaldehyde and coniferyl alcohol as substrates. Unexpectedly, the K(m) values measured for the latter two substrates are three orders of magnitude lower than that measured for ferulic acid, suggesting that in lignifying tissues, syringyl monomers may be derived from their guaiacyl counterparts by hydroxylation and subsequent methylation. Thus, F5H may function later in the lignin biosynthetic pathway than was originally proposed. To further test this model, recombinant F5H was incubated together with ferulic acid, coniferaldehyde, or coniferyl alcohol in the presence of native or recombinant Arabidopsis caffeic acid/5-hydroxyferulic acid O-methyltransferase and [(14)C]S-adenosylmethionine. In all cases, the corresponding radiolabeled sinapyl derivatives were synthesized, indicating that the necessary enzymes required for this pathway are present in Arabidopsis. Taken together, these data suggest that the previously accepted pathway for lignin biosynthesis is likely to be incorrect.

Arabidopsis↗

Functional specificity of lateral geniculate nucleus laminae of the rhesus monkey.

1. This study investigated the functional specificity of the lateral geniculate mucleus (LGN) of the rhesus monkey using microelectrode-recording techniques. 2. The parvocellular laminae of the LGN receive input predominantly from medium-conduction-velocity optic tract fibers, while the magnocellular laminae receive fast-conducting axons from the retina. 3. Cells projecting from the parvocellular layers to area 17 have medium-conduction velocities, while those from the magnocellular layers are fast conducting. 4. The majority of cells in the parvocellular layers have a concentric color-opponent receptive-field organization. The receptive fields of magnocellular layers cells are also concentrically organized, but their center-surround organization is independent of wavelength. 5. Responses in the parvocellular layers are more sustained than in the magnocellular layers. 6. Cells in the dorsal pair of parvocellular layers are predominantly on-center. In the ventral pair of parvocellular layers, most cells are off-center. 7. Blue-selective cells are found predominantly in the ventral pair of parvocellular layers. All of these found gave on-responses to blue stimuli.

Animals↗

The Cognitive Bias Task and lateralized frontal lobe functions in males.

The Cognitive Bias Task (CBT) is a multiple-choice response selection paradigm characterized by inherent ambiguity. All items offer a range from extremely context-dependent to extremely context-invariant responses. Lateralized prefrontal lesions produce extreme, and opposite, response biases on CBT in right-handed males. Healthy control subjects perform in the middle range. Findings suggest a dynamic balance between two synergistic decision-making systems in the frontal lobes: context-dependent in the left hemisphere and context-invariant in the right. The robust lateralized effects, which are dependent on task ambiguity, are sensitive and specific to frontal dysfunction. CBT is discussed in comparison with the Wisconsin Card Sorting Test as a potential cognitive activation task for functional neuroimaging of the frontal lobes.

Adult↗

In utero exposure to coumarins and cognition at 8 to 14 years old.

OBJECTIVE: To assess the cognitive abilities in school-aged children who have been exposed to coumarins in utero. BACKGROUND: Coumarin derivatives are an effective option for anticoagulant therapy in pregnant women. However, case reports describe anomalies of the fetal central nervous system after in utero exposure to coumarins. It is unclear whether prenatal exposure has an effect on cognitive functioning later in childhood. METHODS: The exposed cohort consisted of 291 children from mothers who were prospectively registered because of coumarin treatment during pregnancy. The nonexposed cohort included 253 age-matched peers. An IQ was estimated using subtests of the Weschler Intelligence Scale for Children-Revised. Educational achievement was examined with tests for reading, spelling, and arithmetic. In addition, schoolteachers were asked to judge performance on language and arithmetic. The observers were not aware of the exposure status of the child. RESULTS: No differences in mean IQ were found between the exposed and nonexposed cohort (mean difference: -1.1; 95% confidence interval [CI]: -3.2-1.1), but an IQ score below 80 was found in 11 children in the exposed compared with 3 children in the nonexposed cohort (odds ratio [OR] = 3.1; CI: 0.8-11.6). Regarding the tests for educational achievement, exposed children as a group performed as well as nonexposed controls. Exposed boys, in comparison with nonexposed boys, showed a higher frequency of poor performance on reading (OR = 2.9; CI: 1.1-7.4) and spelling (OR = 2.5; CI: 1.0-6.0). CONCLUSION: Cognitive functioning in coumarin-exposed children does not differ from nonexposed controls, but a minority of children seem to be prone to the potential negative effects of coumarins during pregnancy.

Adolescent↗

Cerebral lateralization and cognitive functioning in patients with congenital adrenal hyperplasia.

A battery of tests was administered to 17 patients with congenital adrenal hyperplasia (CAH) and 17 normal controls to investigate the effect of prenatal androgen exposure on cerebral lateralization and cognitive performance. Individuals were compared on measures of hand preference, verbal and performance IQ, and temporal processing asymmetry. A higher incidence of left-handedness was found among CAH participants. CAH individuals exhibited higher performance IQs as opposed to verbal IQs. Temporal processing asymmetries were investigated using an auditory gap detection task. Measures of reaction time and response error revealed a right-ear, therefore left-hemisphere, advantage for gap detection. This right-ear advantage did not differ between CAH individuals and controls. Results partially support the hypothesis that prenatal androgen exposure causes a shift in cerebral lateralization toward right-hemisphere dominance.

Adolescent↗

Are there critical periods for brain growth in children born preterm?

BACKGROUND: Children born very preterm who attend mainstream schools have a high prevalence of minor motor, behavioural, and learning disorders. These appear to be associated with reduced postnatal growth, particularly of the head. It is unclear when this poor growth occurs and whether growth restriction during different periods has different effects on later function. OBJECTIVE: To identify periods during early development, in children born preterm, when impaired head growth may influence minor motor and cognitive function. POPULATION: A geographically defined cohort of 194 infants born in Merseyside during 1980-81 and weighing less than 1500 g. METHODS: Measurements of head circumference (occipitofrontal circumference (OFC)) were available at birth, hospital discharge, 4 years, and 15 years of age. Assessments of intelligence (intelligence quotient (IQ)) and minor motor impairment (test of motor impairment (TOMI)) were made at 8 years of age. Clinical, social, and demographic variables were obtained from the clinical record and maternal interviews. RESULTS: IQ correlated significantly with OFC at 4 and 15 years of age after correction for growth restriction at birth (intrauterine growth restriction (IUGR)) and social class. TOMI scores correlated significantly with OFC at all four times, but especially with OFC at discharge and with change in OFC between birth and discharge. They were not affected by correction for social class or IUGR. CONCLUSION: Although both IQ and minor motor impairments correlate strongly with each other at school age in very low birthweight children, the factors determining them and their timing of operation are different. Interventions designed to improve IQ in this population would need to reduce IUGR and improve later childhood growth. Those aimed to improve motor ability need to be targeted more at brain protection during the neonatal period.

Brain↗