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A combined neuropsychological and neuroimaging study of topographical and non-verbal memory in semantic dementia.

A combined neuropsychological and neuroimaging investigation was carried out on a patient (O.I.) with semantic dementia who had asymmetrical temporal lobe atrophy, greater on the left. His performance on tests of verbal memory was gravely impaired. Similarly, his visual memory as indexed by recognition of unfamiliar faces was impaired. By contrast, his recognition memory for topographical memoranda (e.g. buildings, landscapes) and ability to find his way around was preserved. In order to identify the neural substrates supporting the preserved recognition of static topographical memoranda, O.I. was scanned using positron emission tomography (PET) during the encoding and recognition of building and landscape stimuli. In common with control subjects, during encoding O.I. activated parahippocampal cortex bilaterally, along with bilateral temporo-parietal, retrosplenial and left frontal cortices. During recognition, both patient and controls activated right parahippocampal, right superior parietal and right frontal cortices. Notably, control subjects, but not O.I., also activated at encoding the precuneus and at recognition the retrosplenial cortex. This allows the conclusion that these two areas while involved may not be necessary for topographical memory. Interestingly, the patient also activated regions that were not evident in control subjects both during encoding and recognition. These additional areas of activation may be necessary in a compensatory role. Overall, these data represent the first reported assessment of the functional integrity of degenerating brain tissue and its contribution to preserved topographical memory. The combination of the neuropsychological and neuroimaging approaches may provide insights into the functional-anatomy of memory while having clinical utility for the assessment of residual brain tissue.

Aged↗

Thymosin beta 4 interactions.

Thymosin beta 4 is a small, 5-kDa protein with a diverse range of activities, including its function as an actin monomer sequestering protein, an antiinflammatory agent, and an inhibitor of bone marrow stem cell proliferation. Only the effects of thymosin beta 4 on the actin cytoskeleton have an explanation based on identified molecular interactions. Thymosin beta 4 is largely unfolded or perhaps completely unfolded in solution. Based on the paradigm introduced by Wright and Dyson (1999) that unfolded proteins may have multiple functions based on their ability to recognize numerous ligands, the flexible structure of thymosin beta 4 may facilitate the recognition of a variety of molecular targets, thus explaining the plethora of functions attributed to thymosin beta 4. Furthermore, if multiple ligands bind to thymosin beta 4, then it is possible that thymosin beta 4 has a unique integrative function that links the actin cytoskeleton to important immune and cell growth-signaling cascades.

Actins↗

Hand injuries and disorders. Principles of management for the family physician.

Hand injuries and disorders constitute a major cause of disability and time lost from work. Viewed as relatively minor, they are often neglected until permanent disability and restriction of function occur. The first physician to evaluate and treat an injured hand often determines the ultimate outcome of the patient's hand function. Skillful diagnosis and appropriate treatment are necessary. Neglected or mistreated injury may result in significant impairment in a person whose livelihood depends on the skillful, integrated function of both hands.

Burns↗

Progress on development of the live BCG recombinant vaccine vehicle for combined vaccine delivery.

BCG, the current vaccine for tuberculosis, has been administered to approximately three billion people. This live vaccine has a low incidence of serious side effects and can be given at birth. Within the past six years, systems for the manipulation and expression of foreign genes in mycobacteria have been developed, allowing the evaluation of rBCG as a vaccine delivery vehicle for heterologous antigens. Recent studies from our group have shown that rBCG expressing outer surface protein A of Borrelia burgdorferi can completely protect mice from an intradermal challenge with this organism. Immune responses protective against Streptococcus pneumoniae challenge have also been achieved by immunization of mice with rBCG expressing PspA. The simplest means of administering multiple vaccine antigens in a rBCG vehicle would be to coexpress these simultaneously in the same BCG recombinant. Currently two general classes of vectors exist for the expression of foreign proteins in BCG: shuttle plasmid vectors, which replicate extrachromosomally in mycobacteria, and shuttle "phasmid" vectors, which integrate as a single copy into the mycobacterial chromosome by means of vector-encoded integration functions of the lysogenic mycobacteriophage L5. The genetic capacity of the multicopy plasmid vectors may be 20 kb or more, while the potential exists for stable integration of much larger amounts of DNA into the mycobacterial genome (L5 itself is 52 kb). Additionally, these two expression systems can have the compatibility to coexist in a single BCG cell. Otitis media is caused by infections of the middle ear chiefly with either S. pneumoniae or H. influenzae. Thus, an effective vaccine would necessarily include antigens from both these pathogens. Our initial attempt at construction of a BCG multivaccine vehicle was to express proteins from each of these pathogens from the same multicopy plasmid. We have recently succeeded in coexpressing the S. pneumoniae PspA and H. influenzae PAL proteins in BCG. Future work will address how the biochemical characterization of and immune responses to the recombinant antigens of the "bivalent" rBCG:PspA/PAL vaccine compare to those of the respective "monovalent" rBCG vaccines.

Antigens, Bacterial↗

Structural and functional studies of the tryptic core of the human chorionic gonadotropin beta-subunit.

The beta-subunit of hCG was digested with trypsin to produce a modified form of the subunit for structure-function and immunological studies. After digestion of hCG beta with trypsin, the residual disulfide-linked core was isolated and found to be lacking the carboxy-terminal peptide (residues 115-145) and to contain bond cleavages between residues 2-3, 43-44, 74-75, and 95-96. The locations of these bond cleavages within the disulfide-bridged core were identified by isolation of the following peptides after reduction and S-carboxymethylation of the trypsin beta-core: beta 1-43, beta 3-43, beta 44-74, beta 44-95, beta 75-95, and beta 96-114. The circular dichroic spectrum of the tryptic beta-core over the wavelength region of about 200-320 nm was similar to that of the native subunit. In addition, the tryptic beta-core retained nearly full immunopotency in both polyclonal and monoclonal competitive RIAs and could combine with complementary native alpha-subunit. The hybrid, composed of the tryptic beta-core and native alpha, was purified and displayed a molar potency of about 0.1% relative to intact hCG in both a radioreceptor assay and an adenylate cyclase assay. Thus, the hybrid retained little biological activity. Although the extensive bond cleavages in the tryptic beta-core did not appear to change its secondary and tertiary structure sufficiently to significantly alter the circular dichroic spectrum, the immunoreactivity, or the capability to combine with its alpha-subunit complement, the biological functional integrity of the tryptic beta-core-containing hybrid was essentially abolished. Hence, the tryptic beta-core provides a useful derivative for detailed structure-function studies aimed at defining the necessary determinants for subunit association, receptor binding, and subsequent biological actions.

Adenylyl Cyclases↗

Evolution and mammalian dental morphology.

Evidence for the action of natural selection on the mammalian dentition is reviewed. Dental variation largely reflects genetical differences, but environmental factors have a significant effect, especially on the later developing teeth. Reduction of dental variance with age provides direct evidence of selection, but most evidence consists of demonstrations of adaptiveness. Dental adaptation is partly external, mainly to the food, and partly internal, resulting in the functional integration of teeth with each other, as in occlusal relations, and with the neuromuscular system responsible for jaw movements. Ontogeny is also adapted to produce a functional end-product. Most interspecific differences have not yet been explained in terms of function, and many of them may be due to drift.

Adaptation, Physiological↗

[Evaluation of hearing loss by means of inner ear acoustic emission in neonates treated with aminoglycoside].

Despite their ototoxic and other side effects, aminoglycosides are still widely used in the treatment of neonatal infections. A novel method for evaluation of hearing loss is distortion product otoacoustic emission (DPOAE). Physiologic acoustic energy-emission produced by sound stimulus in the inner ear is detected by DPOAE. Existing acoustic emission indicates the functional integrity of the inner ear. DPOAE was performed in 19 newborns treated with netilmicin for different infections. Serum netilmicin levels did not exceed 12 mg/l; renal functions were normal. Existence of emission was detected in 15 newborns. There was no emission found in 4 newborns unilaterally, which was fully restored in 2 months. In conclusion, aminoglycosides have no considerable ototoxic side effects. DPOAE is thought to be an objective, fast, and non-invasive method for hearing screening in the newborn period.

Anti-Bacterial Agents↗

Accessory oculomotor nuclei of man. II. The interstitial nucleus of Cajal: a Nissl and Golgi study.

The interstitial nucleus of Cajal (INC) is an important premotor centre related to the control of eye and head movements. The aim of the present research was to draw a detailed picture of the cytoarchitecture of the human INC, in particular taking into consideration the morphological features of the neurons and their functional implications. Within the neuronal population, two groups of cells were identified: one group (the most substantial) was made up of small and medium-sized neurons showing different soma shapes and both light and moderate basophilia. The second group consisted of a limited number (about 25%) of large cells dispersed throughout the whole INC, showing polygonal soma and intense basophilia. The hypothesis that these large cells represent a different cellular population inside the INC is advanced. On the basis of the dendritic emergence pattern, two types of cells were identified: multipolar and fusiform cells. The multipolar cells (59%) had small to large nerve cell bodies giving off 2-3 dendrites radiating in all directions. Dendrites and axons were often seen spreading outside the INC. The fusiform cells were small or medium sized and two dendrites emerged from the opposite poles of their elongated perikaryon. Their dendrites and axons always lay inside the INC. The fusiform cells were interpreted as neurons carrying out a mainly local integrative function, while the multipolar cells could also probably carry out an important projective role. The structural data reported are in agreement with the functional studies indicating the INC as both an integrative and a projective center.

Adult↗

A transient osmotic permeabilization method for the introduction of impermeant molecules into functional brain membrane vesicles.

Mouse brain membrane vesicles (microsacs) were transiently permeabilized by hypo-osmotic shock. This permeabilization method resulted in the encapsulation of both [14C]sucrose and exogenous alkaline phosphatase. The efficiency of this method was estimated by [14C]sucrose encapsulation experiments to be approximately 81%. External membrane binding experiments with the lectin [3H]concanavalin A demonstrate that the microsacs were not inverted by permeabilization. Following permeabilization, the functional integrity of a ligand-gated ion channel, the GABAA receptor complex, was investigated. Muscimol-stimulated 36Cl-uptake experiments show that this receptor retains its functional properties including blockade by the receptor antagonist bicuculline and potentiation by the allosteric modulators flunitrazepam and pentobarbital. The osmotic permeabilization technique described here provides several advantages over other permeabilization methods. These advantages include a high trapping efficiency, the encapsulation of not only small solutes but large membrane impermeant compounds such as enzymes and the functional preservation of at least one transmembrane protein. Furthermore, this method does not require specialized equipment and does not result in large, permanent holes in the plasma membrane.

Alkaline Phosphatase↗

Task-specific authoring functions for end-users in a hospital information system.

Authoring functions--integrated in a Hospital Information System (HIS)--provide a means for physicians and nurses to adapt partly their man/machine interface. We successfully implemented task-specific authoring functions that enable end-users to comprehend and structure a large body of multimedia documents, to focus attention during medical decision making, to speed up medical tasks and to standardise the drafting of documents.

Decision Making, Computer-Assisted↗

Integrative neuroscience: linking levels of analyses.

If we are to understand how the brain performs different integrated functions in cellular terms, we need both to understand all relevant levels of analysis from the molecular to the behavioural and cognitive levels and to realize an integration of such levels. This is currently a major challenge for neuroscience. Most research, whether dealing with perception, action or learning, focuses on a few levels of organization, for instance the molecular level and brain imaging, and leaves other crucial areas practically untouched. To reach the level of understanding that we desire, a multi-level approach is required in which the different levels link into each other. It is possible to bridge across the different levels for one system, and this has been demonstrated, for example, in the lamprey in generation of goal-directed locomotion. It can be argued that an integrated analysis of any neural system cannot be performed without the aid of a close interaction between experiments and modelling. The dynamic processing within any neural system is such that an intuitive interpretation is rarely sufficient.

Animals↗

Sildenafil extends survival and graft function in a large animal lung transplantation model.

OBJECTIVE: Restoring intracellular cGMP and inducing NO-synthesis attenuates ischemia-associated early pulmonary allograft dysfunction. Phosphodiesterase-5 (PDE), predominantly expressed in lung tissue, plays a pivotal role in modulating the cGMP/NO-synthase pathway in endothelial and epithelial cells. In this study, we evaluate the effect of employing sildenafil (Viagra), a specific inhibitor of PDE-5, to counteract ischemia/reperfusion (I/R) injury in a single lung transplantation model of extended ischemia. METHODS: Donor animals (weight matched outbred pigs, 28-35 kg) in the treatment group (I) (n=5) were injected with 0.7 mg sildenafil/kg into the pulmonary artery (PA) prior to inflow occlusion. For perfusion, Perfadex, containing 0.7 mg sildenafil/l was used, and the graft stored at 1 degrees C in the perfusion solution. After 24h ischemia, unilateral left lung transplantation was performed. Starting at reperfusion, group I received continuous sildenafil (0.7 mg sildenafil/kg), over 6h. Except for the sildenafil application, the control group (II) (n=4) was treated identically (PGE1 was injected into the PA). One hour after reperfusion, the right main bronchus (MB) and right PA were occluded. Over the next 5h, cardiopulmonary parameters (systemic atrial, PA, central venous, left atrial pressure, pCO(2), pO(2)) were measured, including extravascular lung water (EVLW). Thiobarbituric acid-reactive substance assay (TBARS) and myeloperoxidase (MPO) analysis from lung tissue were run. RESULTS: All recipients of group I survived the 6-h reperfusion period; in contrast, all control animals died within 1-2h after occlusion of the right side. In comparison to a marked rise in pulmonary vascular resistance (PVR) in group II (>1000 dynescm(-5)), PVR in group I remained stable, moderately elevated from baseline (baseline: 150-180 dynescm(-5) vs endpoint: 1000 dynescm(-5)). EVLW in group I did not increase during reperfusion (baseline: 6.75+/-1.4 mg/kg vs endpoint: 6.7+/-1.0mg/kg), in contrast to group II, where pulmonary edema at 2-h reperfusion preceded terminal graft failure (group I: 9.7+/-0.1mg/kg vs group II: 6.48+/-1.8 mg/kg). Tissue reactive free radicals at endpoint measurement in group I did not differ significantly from native tissue. Yet, when compared to specimen taken from group II at time of terminal graft failure, a significant increase in free radicals was noted (group I: 13.8+/-1.6 pmol/g vs group II: 18.5+/-3.0 pmol/g, p<0.05). CONCLUSION: Sildenafil treatment prevents terminal early graft failure, allowing lung transplantation after 24-h ischemia time. Reperfusion edema was strikingly diminished, preserving pulmonary structural and functional integrity while prolonging graft ischemia time. Employing the established PDE-5 inhibitor sildenafil during lung perfusion, storage, and implantation, ischemic tolerance may be extended and early graft function improved.

3',5'-Cyclic-GMP Phosphodiesterases↗

Prospective function of placental leptin at maternal-fetal interface.

Leptin is an endocrine and a growth factor which is important for regulation of body fat, feeding, and energy homeostasis. The anti-obesity function of leptin has been recently extended to reproduction, puberty and pregnancy as an endocrine signal to the hypothalamus. Leptin controls the functional integrity of the feto-placental unit thereby maintaining pregnancy by virtue of its immunomodulatory property via T lymphocytes or other proto-oncogenes. Dysregulation of autocrine/paracrine function of leptin at feto-placento-maternal interface may be implicated in the pathogenesis of recurrent miscarriage gestational diabetes, pre-eclampsia and intra-uterine fetal growth retardation including disturbance of fetal bone turnover. This review will focus on the role of leptin in normal and abnormal pregnancy and fetal growth.

Adult↗

The Black-Scholes pricing formula in the quantum context.

A natural explanation for extreme irregularities in the evolution of prices in financial markets is provided by quantum effects. The lack of simultaneous observability of relevant variables and the interference of attempted observation with the values of these variables represent such effects. These characteristics have been noted by traders and economists and appear intrinsic to market dynamics. This explanation is explored here in terms of a corresponding generalization of the Wiener process and its role in the Black-Scholes-Merton theory. The differentiability of the Wiener process as a sesquilinear form on a dense domain in the Hilbert space of square-integrable functions over Wiener space is shown and is extended to the quantum context. This provides a basis for a corresponding generalization of the Ito theory of stochastic integration. An extension of the Black-Scholes option pricing formula to the quantum context is deduced.

Journal Article↗

Chromosome integrity in Saccharomyces cerevisiae: the interplay of DNA replication initiation factors, elongation factors, and origins.

The integrity of chromosomes during cell division is ensured by both trans-acting factors and cis-acting chromosomal sites. Failure of either these chromosome integrity determinants (CIDs) can cause chromosomes to be broken and subsequently misrepaired to form gross chromosomal rearrangements (GCRs). We developed a simple and rapid assay for GCRs, exploiting yeast artificial chromosomes (YACs) in Saccharomyces cerevisiae. We used this assay to screen a genome-wide pool of mutants for elevated rates of GCR. The analyses of these mutants define new CIDs (Orc3p, Orc5p, and Ycs4p) and new pathways required for chromosome integrity in DNA replication elongation (Dpb11p), DNA replication initiation (Orc3p and Orc5p), and mitotic condensation (Ycs4p). We show that the chromosome integrity function of Orc5p is associated with its ATP-binding motif and is distinct from its function in controlling the efficiency of initiation of DNA replication. Finally, we used our YAC assay to assess the interplay of trans and cis factors in chromosome integrity. Increasing the number of origins on a YAC suppresses GCR formation in our dpb11 mutant but enhances it in our orc mutants. This result provides potential insights into the counterbalancing selective pressures necessary for the evolution of origin density on chromosomes.

Cell Cycle Proteins↗

Two key strategies in the nutritional management of the extremely low birth weight infant.

Two relatively new strategies in the nutritional management of the extremely low birthweight infant include early administration of amino acids and the integration with minimal enteral nutrition within the first days of life. These strategies will promote early positive energy balance and nitrogen retention as well as stimulate the functional integrity of the gastrointestinal tract. Clinical outcomes that should be improved include decreasing post-natal weight loss and earlier return to birthweight.

Enteral Nutrition↗

Effect of cardiolipin on functional properties of isolated rat liver mitochondria.

The specific involvement of cardiolipin in modulating and/or controlling the activity of a number of mitochondrial carriers, enzymes and receptors is well documented; however, comparatively less understood is its role for the integrated functions of intact mitochondria. The aim of the present research was to get a better insight into this problem by investigating the effect of in vitro addition of cardiolipin on the properties of isolated liver mitochondria. The results obtained show that cardiolipin induces extensive structural and functional perturbations at the level of the inner mitochondrial membrane. In fact, addition of cardiolipin to intact mitochondria causes a significant increase of proton leak associated with a parallel increase of respiratory rate in State 4. Concomitantly, a slight uncoupling of phosphorylation associated with a moderate increase in ATPase activity is observed. Furthermore, the pore-mediated membrane permeability to calcium is drastically modified, an effect that can be reversed by addition of cyclosporin.

Adenosine Triphosphatases↗

An architectural perspective of cell-cycle control at the G1/S phase cell-cycle transition.

A prominent role for the execution of cell cycle and growth regulatory mechanisms within the three-dimensional context of nuclear architecture is becoming increasingly evident. Signaling pathways and regulatory networks that govern activation and suppression of genes controlling proliferation are functionally integrated for the organization and assembly of transcriptional machinery in nuclear microenvironments. The transcriptional activation of histone genes at the G1/S phase transition (S-point) is temporarily, functionally, and spatially distinct from transcriptional mechanisms at the restriction point (R-point). The spatial distinction in R-point versus S-point control is the localization of clustered histone gene loci at cajal bodies, which is modulated during the cell cycle. Histone nuclear factor P (HiNF-P), the principal factor mediating H4 histone gene transcription, is the final link in the signaling cascade that is initiated with growth factor dependent induction of cyclin E/CDK2 kinase activity at the R-point and culminates in the NPAT-mediated activation of histone H4 genes through HiNF-P at the G1/S phase cell-cycle transition.

Cell Cycle↗