In most people the left hemisphere of the brain is dominant for language. Because of the increased incidence of atypical right-hemispheric language in left-handed neurological patients, a systematic association between handedness and dominance has long been suspected. To clarify the relationship between handedness and language dominance in healthy subjects, we measured lateralization directly by functional transcranial Doppler sonography in 326 healthy individuals using a word-generation task. The incidence of right-hemisphere language dominance was found to increase linearly with the degree of left-handedness, from 4% in strong right-handers (handedness = 100) to 15% in ambidextrous individuals and 27% in strong left-handers (handedness = -100). The relationship could be approximated by the formula: f1.gif" BORDER="0">. These results clearly demonstrate that the relationship between handedness and language dominance is not an artefact of cerebral pathology but a natural phenomenon.

We have purified and characterized the growth inhibitory factor (GIF) that is abundant in the normal human brain, but greatly reduced in the Alzheimer's disease (AD) brain. GIF inhibited survival and neurite formation of cortical neurons in vitro. Purified GIF is a 68 amino acid small protein, and its amino acid sequence is 70% identical to that of human metallothionein II with a 1 amino acid insert and a unique 6 amino acid insert in the NH2-terminal and the COOH-terminal portions, respectively. The antibodies to the unique sequence of GIF revealed a distinct subset of astrocytes in the gray matter that appears to be closely associated with neuronal perikarya and dendrites. In the AD cortex, the number of GIF-positive astrocytes was drastically reduced, suggesting that GIF is down-regulated in the subset of astrocytes during AD.

OBJECTIVE

To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which has been known to cluster in families, but the heritability of the common form has not been well defined.

RESULTS

The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF = average KC x 100,000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI = 13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI = 13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI = 12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI = 11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI = 10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population.

CONCLUSIONS

AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF.

The regulatory circuits that control nitrogen metabolism are relatively well known in several bacterial model groups. However, much less is understood about how the nitrogen status of the cell is perceived in vivo. In cyanobacteria, the transcription factor NtcA is required for regulation (activation or repression) of an extensive number of genes involved in nitrogen metabolism. In contrast, how NtcA activity is regulated is largely unknown. Assimilation of ammonium by most microorganisms occurs through the sequential action of two enzymes: glutamine synthetase (GS) and glutamate synthase. Interestingly, regulation of the expression of NtcA-dependent genes in the cyanobacterium Synechocystis sp. PCC 6803 is altered in mutants with modified levels of GS activity. Two types of mutants were analyzed: glnA null mutants that lack GS type I and gif mutants unable to inactivate GS in the presence of ammonium. Changes in the intracellular pools of 19 different amino acids and the keto acid 2-oxoglutarate were recorded in wild-type and mutant strains under different nitrogen conditions. Our data strongly indicate that the nitrogen status in cyanobacteria is perceived as changes in the intracellular 2-oxoglutarate pool.

Previously, we described the AtGRF [Arabidopsis thaliana growth-regulating factor (GRF)] gene family, which encodes putative transcription factors that play a regulatory role in growth and development of leaves and cotyledons. We demonstrate here that the C-terminal region of GRF proteins has transactivation activity. In search of partner proteins for GRF1, we identified another gene family, GRF-interacting factor (<em>GIF</em>), which comprises three members. Sequence and molecular analysis showed that <em>GIF</em>1 is a functional homolog of the human SYT transcription coactivator. We found that the N-terminal region of <em>GIF</em>1 protein was involved in the interaction with GRF1. To understand the biological function of <em>GIF</em>1, we isolated a loss-of-function mutant of <em>GIF</em>1 and prepared transgenic plants subject to <em>GIF</em>1-specific RNA interference. Like grf mutants, the gif1 mutant and transgenic plants developed narrower leaves and petals than did wild-type plants, and combinations of gif1 and grf mutations showed a cooperative effect. The narrow leaf phenotype of gif1, as well as that of the grf triple mutant, was caused by a reduction in cell numbers along the leaf-width axis. We propose that GRF1 and <em>GIF</em>1 act as transcription activator and coactivator, respectively, and that they are part of a complex involved in regulating the growth and shape of leaves and petals.

BACKGROUND

The presence of intestinal metaplasia (IM) in the columnar lined distal oesophagus defines Barrett's oesophagus with the risk of future malignant transformation. The distribution of both IM and dysplasia (low grade (LGD) and high grade (HGD)) within the columnar lined oesophagus is patchy and mosaic requiring random biopsies. Techniques that could help target areas of high yield within Barrett's mucosa would be helpful.

OBJECTIVE

To study the utility of high magnification chromoendoscopy (MCE) in the detection of IM, LGD, and HGD in patients with Barrett's oesophagus.

METHODS

Consecutive patients detected with columnar mucosa in the distal oesophagus were studied using an Olympus magnification endoscope (GIF-Q16OZ, 115x). The distal oesophagus was sprayed with indigo carmine solution and the oesophageal columnar mucosa patterns were noted under high magnification and targeted for biopsy. All biopsies were read by pathologists blinded to the endoscopic findings.

RESULTS

Eighty patients with suspected Barrett's oesophagus (that is, columnar lined distal oesophagus) were studied: mean age 62.7 years (range 35-81). Mean length of columnar mucosa was 3.7 cm (range 0.5-17). Three types of mucosal patterns were noted within the columnar mucosa after spraying indigo carmine and using MCE: ridged/villous pattern, circular pattern, and irregular/distorted pattern. The yield of IM on target biopsies according to the patterns was: ridged/villous 57/62 (97%) and circular 2/12 (17%). Six patients had an irregular/distorted pattern and all had HGD on biopsy (6/6 (100%)). Eighteen patients had LGD on target biopsies; all had the ridged/villous pattern. All patients with long segment Barrett's were identified using MCE whereas 23/28 patients (82%) with short segment Barrett's had the ridged/villous pattern.

CONCLUSIONS

MCE helps visually identify areas with IM and HGD having specific patterns but not patients with LGD (appear similar to IM). MCE may be a useful clinical tool for the increased detection of patients with IM as well as for surveillance of patients for the detection of HGD. If these preliminary results are validated, MCE would help identify high yield areas, potentially eliminating the need for random biopsies.

Cyritestin is a membrane-anchored sperm protein belonging to the ADAM (f1.gif" BORDER="0"> f2.gif" BORDER="0">isintegrin and f1.gif" BORDER="0"> f3.gif" BORDER="0">etalloprotease) family of proteins, which are proposed to be involved in cell-cell adhesion through binding to integrin receptors. Several lines of evidence support a role of cyritestin and other members of this protein family in the fusion of sperm and the egg plasma membrane. In an effort to elucidate the physiological function of cyritestin, we have disrupted its locus by homologous recombination. Male homozygous null mutants are infertile, even though spermatogenesis, mating, and migration of sperm from the uterus into the oviduct are normal. In vitro experiments showed that infertility is due to the inability of the cyritestin-deficient sperm to bind to the zona pellucida. However, after removal of the zona pellucida, sperm-egg membrane fusion monitored by the presence of pronuclei and generation of 2- and 4-cell embryos did not reveal any differences from the wild-type situation. These results demonstrate that cyritestin is crucial in the fertilization process at the level of the sperm-zona pellucida interaction.

BACKGROUND

In patients with chronic heart failure (CHF) and preserved exercise tolerance, the value of cardiopulmonary exercise testing for risk stratification is not known. Elevated slope of ventilatory response to exercise (VE/VCO(2)) predicts poor prognosis in advanced CHF. Derangement of cardiopulmonary reflexes may trigger exercise hyperpnea. We assessed the relationship between cardiopulmonary reflexes and VE/VCO(2)and investigated the prognostic value of (VE/VCO(2)) in CHF patients with preserved exercise tolerance.

RESULTS

Among 344 consecutive CHF patients, we identified 123 with preserved exercise capacity, defined as a peak oxygen consumption (PEAK VO(2))>>/=18 mL. kg(-1). min(-1) (age 56 years; left ventricular ejection fraction 28%; peak VO(2) 23.5 mL. kg(-1). min(-1)). Hypoxic and hypercapnic chemosensitivity (n=38), heart rate variability (n=34), baroreflex sensitivity (n=20), and ergoreflex activity (n=20) were also assessed. We identified 40 patients (33%) with high VE/VCO(2) (ie, >34.0). During follow-up (49+/-22 months, >3 years in all survivors), 34 patients died (3-year survival 81%). High VE/VCO(2) (hazard ratio 4.3, P<0.0001) but not peak f1.gif" BORDER="0">O(2) (P=0.7) predicted mortality. In patients with high VE/VCO(2), 3-year survival was 57%, compared with 93% in patients with normal VE/VCO(2) P<0.0001). Patients with high VE/VCO(2) demonstrated impaired reflex control, as evidenced by augmented peripheral (P=0.01) and central (P=0.0006) chemosensitivity, depressed low-frequency component of heart rate variability (P<0.0001) and baroreflex sensitivity (P=0.03), and overactive ergoreceptors (P=0.003) compared with patients with normal VE/VCO(2).

CONCLUSIONS

In CHF patients with preserved exercise capacity, enhanced ventilatory response to exercise is a simple marker of a widespread derangement of cardiovascular reflex control; it predicts poor prognosis, which VO(2) does not.

NF-kappa B regulates normal and pathological processes, including neoplasia, in a tissue-context-dependent manner. In skin, NF-kappa B is implicated in epidermal homeostasis as well as in the pathogenesis of squamous cell carcinoma; however, its function in the underlying mesenchymal dermis has been unclear. To gain insight into NF-kappa B roles in these two adjacent cutaneous tissue compartments, NF-kappa B effects on expression of 12 435 genes were determined in epidermal keratinocytes and dermal fibroblasts. Although NF-kappa B induced proinflammatory and antiapoptotic genes in both settings, it exhibited divergent effects on growth regulatory genes. In keratinocytes, but not in fibroblasts, NF-kappa B induced p21(CIP1), which was sufficient to inhibit growth of both cell types. Levels of growth inhibitory factor (GIF), in contrast, were increased by NF-kappa B in both settings but inhibited growth only in keratinocytes. These findings indicate that transcription factors such as NF-kappa B can program tissue-selective effects via both differential target gene induction as well as by inducing common targets that exert differing effects depending on cellular lineage.

Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into lineages of mesenchymal tissues that are currently under investigation for a variety of therapeutic applications. The purpose of this study was to compare cytokine gene expression in MSCs from human placenta, cord blood (CB) and bone marrow (BM). The cytokine expression profiles of MSCs from BM, CB and placenta (amnion, decidua) were compared by proteome profiler array analysis. The cytokines that were expressed differently, in each type of MSC, were analyzed by real-time PCR. We evaluated 36 cytokines. Most types of MSCs had a common expression pattern including MIF (GIF, DER6), IL-8 (CXCL8), Serpin E1 (PAI-1), GROalpha(CXCL1), and IL-6. MCP-1, however, was expressed in both the MSCs from the BM and the amnion. sICAM-1 was expressed in both the amnion and decidua MSCs. SDF-1 was expressed only in the BM MSCs. Real-time PCR demonstrated the expression of the cytokines in each of the MSCs. The MSCs from bone marrow, placenta (amnion and decidua) and cord blood expressed the cytokines differently. These results suggest that cytokine induction and signal transduction are different in MSCs from different tissues.

ParameciumDB (http://paramecium.cgm.cnrs-gif.fr) is a new model organism database associated with the genome sequencing project of the unicellular eukaryote Paramecium tetraurelia. Built with the core components of the Generic Model Organism Database (GMOD) project, ParameciumDB currently contains the genome sequence and annotations, linked to available genetic data including the Gif Paramecium stock collection. It is thus possible to navigate between sequences and stocks via the genes and alleles. Phenotypes, of mutant strains and of knockdowns obtained by RNA interference, are captured using controlled vocabularies according to the Entity-Attribute-Value model. ParameciumDB currently supports browsing of phenotypes, alleles and stocks as well as querying of sequence features (genes, UniProt matches, InterPro domains, Gene Ontology terms) and of genetic data (phenotypes, stocks, RNA interference experiments). Forms allow submission of RNA interference data and some bioinformatics services are available. Future ParameciumDB development plans include coordination of human curation of the near 40 000 gene models by members of the research community.

Although the number of antigenic sites on the rabies virus glycoprotein that have been described regularly increases with time, no attempt has been made to carefully evaluate the relative importance of each of these sites. Here we provide a more precise description of the antigenicity of the protein in mice of the H-2d haplotype; we developed this description by using 264 newly isolated monoclonal antibodies (MAbs) and a collection of neutralization-resistant (MAR) mutants. Most of the MAbs (97%) recognized antigenic sites previously described as II and III. One minor antigenic site separated from site III by three amino acids, including a proline, was identified (minor site a). Despite their proximity, there is no overlap between site III and minor site a; i.e., site III-specific MAR mutants were neutralized by the six MAbs defining minor site a, and vice versa. One of our MAbs, 1D1, reacted with sodium dodecyl sulfate-treated glycoprotein in Western blots (immunoblots) under reducing conditions and was therefore probably directed against a linear epitope, A MAR mutant selected with this MAb was still neutralized by MAbs of other specificities. This linear epitope was called G1 (G, Gif). As a general rule, we propose to reserve the term "antigenic site" (either major or minor) for regions of the protein which are defined by several MAbs originating from different fusions and to describe regions of the protein which are defined by a single MAb as epitopes. It would be interesting to test whether the same regions of the rabies virus glycoprotein are antigenic in mice of different haplotypes or in other species.

All linear accelerometers measure gravitoinertial force, which is the sum of gravitational force (tilt) and inertial force due to linear acceleration (translation). Neural strategies must exist to elicit tilt and translation responses from this ambiguous cue. To investigate these neural processes, we developed a model of human responses and simulated a number of motion paradigms used to investigate this tilt/translation ambiguity. In this model, the separation of GIF into neural estimates of gravity and linear acceleration is accomplished via an internal model made up of three principal components: 1) the influence of rotational cues (e.g., semicircular canals) on the neural representation of gravity, 2) the resolution of gravitoinertial force into neural representations of gravity and linear acceleration, and 3) the neural representation of the dynamics of the semicircular canals. By combining these simple hypotheses within the internal model framework, the model mimics human responses to a number of different paradigms, ranging from simple paradigms, like roll tilt, to complex paradigms, like postrotational tilt and centrifugation. It is important to note that the exact same mechanisms can explain responses induced by simple movements as well as by more complex paradigms; no additional elements or hypotheses are needed to match the data obtained during more complex paradigms. Therefore these modeled response characteristics are consistent with available data and with the hypothesis that the nervous system uses internal models to estimate tilt and translation in the presence of ambiguous sensory cues.

Barat, M. (Centre National de la Recherche Scientifique, Gif-sur-Yvette, Seine et Oise, France), C. Anagnostopoulos, and A.-M. Schneider. Linkage relationships of genes controlling isoleucine, valine, and leucine biosynthesis in Bacillus subtilis. J. Bacteriol.90:357-369. 1965.-In Bacillus subtilis, the genetic loci controlling isoleucine and valine biosynthesis are not all clustered. Some of them were located on two distinct transforming deoxyribonucleic acid "molecules." One of these molecules (the "ileilva(2-4)-met segment") carries the threonine deaminase and the dihydroxy acid dehydrase loci linked to methionine markers. The other (the "ilva(1-3)-leu segment") bears the reductoisomerase locus and one or more loci involved in leucine synthesis. A phenylalanine marker was also shown to be weakly linked to this latter group. In transduction mediated by phage PBS-1, these groups are transferred jointly with other gene clusters. The phage appears to convey chromosome fragments considerably longer than the transforming "molecules." The genetic maps of both the above segments were extended by transduction. Some groups previously studied by transformation can be placed in the following linear order: the ile-ilva(2-4)-met segment, the cluster of loci involved in aromatic amino acid synthesis (try segment), and a lysine locus. An arginine locus is cotransduced with the phe-ilva(1-2)-leu segment. Recombination frequencies between linked markers are much lower in transduction by this phage than in transformation.

Previously, the GRF-INTERACTING FACTOR1 (GIFGIFGIF gene family, GIFGIFgifgifgifGIFGIFGIFgifGIF gene family are functionally redundant. Kinematic analysis on leaf growth revealed that the gif triple mutant as well as other strong gif mutants developed leaf primordia with fewer cells, which was due to the low rate of cell proliferation, eventually resulting in earlier exit from the proliferative phase of organ growth. The low proliferative activity of primordial leaves was accompanied by decreased expression of cell cycle-regulating genes, indicating that GIF genes may act upstream of cell cycle regulators. Analysis of gif double and triple mutants clarified a previously undescribed role of the GIF gene family: gif mutants had small vegetative shoot apical meristems, which was correlated with the development of small leaf primordia. gif triple mutants also displayed defective structures of floral organs. Taken together, our results suggest that the GIF gene family plays important roles in the control of cell proliferation via cell cycle regulation and in other developmental properties that are associated with shoot apical meristem function.

The growth-regulating factors (GRFs) are plant-specific transcription factors. They form complexes with GRF-interacting factors (GIFs), a small family of transcriptional co-activators. In Arabidopsis thaliana, seven out of the nine GRFs are controlled by microRNA miR396. Analysis of Arabidopsis plants carrying a GRF3 allele insensitive to miR396 revealed a strong boost in the number of cells in leaves, which was further enhanced synergistically by an additional increase of GIFGIFGIFGIFGIF network impinges on different stages of leaf development. Our results integrate the post-transcriptional control of the GRF transcription factors with the progression of leaf development.

Circulating neuron-specific enolase (NSE) and chromogranin A (CgA) were measured in 128 patients with neuroendocrine tumours (NET) to compare their sensitivity and specificity, to investigate factors associated with elevated serum levels and to determine the usefulness of these markers in the follow-up of NET patients. NSE (Cispack NSE, Cis Bio International, Gif-sur-Yvette, France; normal <12.5 microg l(-1)), and chromogranin A (CgA-Riact, Cis Bio International, normal <100 microg l(-1)) were measured in 128 patients without renal insufficiency. There were 99 patients with gastroenteropancreatic (GEP) NET, 19 with medullary thyroid carcinoma and ten with phaeochromocytoma. Fifty-three patients with non-NET were studied as controls. Serum NSE and CgA levels were elevated in 48 (38%) and 76 (59%) of the 128 NET patients respectively. In all groups of NET patients, CgA proved to be more sensitive than NSE. NSE and CgA had a specificity of 73% and 68% respectively. Immunostaining for NSE was positive in three out of eight controls with elevated CgA levels, whereas immunostaining for CgA and synaptophysin was negative in all cases. Elevated CgA levels were significantly associated with two independent parameters, namely the presence of other secretions (P = 0.0001) and a heavy tumour burden (P = 0.001). Elevated NSE levels were exclusively associated with poor tumour differentiation (P = 0.01). Among six patients with NET followed for 11-37 months, CgA appeared to be a better marker of tumour evolution than NSE. We suggest that CgA ought to be the only general marker screened in NET patients.

BACKGROUND

Whether myocardial ATP content falls in heart failure is a long-standing and controversial issue. The mechanism(s) to explain any decrease in ATP content during heart failure have not been identified.

RESULTS

Cardiac dysfunction, heart failure, and a prolonged steady state of heart failure were induced by chronic right ventricular pacing for 1 to 2 weeks, 3 to 4 weeks, and 7 to 9 weeks in dogs. Cardiac function and myocardial O(2) consumption (Mf1.gif" BORDER="0">O(2)) were measured with the dogs in the conscious state. ATP, total purine, and creatine were measured in biopsy specimens obtained at each stage. ATP and the total purine pool progressively fell at rates of 0.12 and 0.15 nmol. mg protein(-1). d(-1), despite an increase in Mf1.gif" BORDER="0">O(2). The rate of loss of creatine was 1.06 nmol. mg protein(-1). d(-1), 7 times faster than the depletion of total purine.

CONCLUSIONS

(1) ATP contents progressively decreased during heart failure as a result of a loss of the total purine pool. The loss of purines may be due to inhibition of de novo purine synthesis. (2) Loss of creatine is an early marker of heart failure and may serve as a compensatory mechanism minimizing the reduction of the total purine pool in the failing heart.

BACKGROUND

There are no universally accepted diagnostic criteria for gastrointestinal failure in critically ill patients. In the present study we tested whether the occurrence of food intolerance (FI) and intra-abdominal hypertension (IAH), combined in a 5-grade scoring system for assessment of gastrointestinal function (the Gastrointestinal Failure [GIF] score), predicts mortality. The prognostic value of the GIF score alone and in combination with the Sequential Organ Failure Assessment (SOFA) score is evaluated, and the incidence and outcome of gastrointestinal failure is described relative to the GIF score.

METHODS

A total of 264 subsequently hospitalized patients, who were mechanically ventilated on admission and stayed in the intensive care unit (ICU) for longer than 24 hours, were prospectively studied. GIF score was documented daily as follows: 0 = normal gastrointestinal function; 1 = enteral feeding with under 50% of calculated needs or no feeding 3 days after abdominal surgery; 2 = FI or IAH; 3 = FI and IAH; and 4 = abdominal compartment syndrome (ACS). Admission parameters and mean GIF and SOFA scores for the first 3 days were used to predict ICU outcome.

RESULTS

FI developed in 58.3%, IAH in 27.3%, and both together in 22.7% of patients. The mean GIF score for the first 3 days in the ICU was identified as an independent risk factor for mortality (odds ratio = 3.02, 95% confidence interval = 1.63 to 5.59; P < 0.001). The GIF score integrated into the SOFA score allowed better prediction of ICU mortality than did the SOFA score alone, and was an independent predictor of mortality (odds ratio = 1.49, 95% confidence interval = 1.28 to 1.74; P < 0.001). The development of gastrointestinal failure (FI plus IAH) was associated with significantly higher ICU and 90-day mortality.

CONCLUSIONS

The GIF score is useful for classifying information on the gastrointestinal system. The mean GIF score during the first 3 days in the ICU had high prognostic value for ICU mortality. Development of gastrointestinal failure is associated with significantly impaired outcome.

The precise control of gene regulation, and hence, correct spatiotemporal tissue patterning, is crucial for plant development. Plant microRNAs can constrain the expression of their target genes at posttranscriptional levels. Recently, microRNA396 (miR396) has been characterized to regulate leaf development by mediating cleavage of its GROWTH-REGULATING FACTOR (GRF) targets. miR396 is also preferentially expressed in flowers. However, its function in flower development is unclear. In addition to narrow leaves, pistils with a single carpel were also observed in miR396 overexpression plants. The dramatically reduced expression levels of miR396 targets (GRF1, GRF2, GRF3, GRF4, GRF7, GRF8, and GRF9) caused pistil abnormalities, because the miR396-resistant version of GRF was able to rescue miR396-overexpressing plants. Both GRF and GRF-INTERACTING FACTOR (GIF) genes are highly expressed in developing pistils, and their expression patterns are negatively correlated with that of miR396. GRF interacted with GIF to form the GRF/GIF complex in plant cell nucleus. miR396 suppressed the expression of GRF genes, resulting in reduction of GRF/GIF complex. gif single mutant displayed normal pistils, whereas gif triple mutant gifgifgifGIF function as cotranscription factors, and both are required for pistil development. Our analyses reveal an important role for miR396 in controlling carpel number and pistil development via regulation of the GRF/GIF complex.

All linear accelerometers, including the otolith organs, respond equivalently to gravity and linear acceleration. To investigate how the nervous system resolves this ambiguity, we measured perceived roll tilt and reflexive eye movements in humans in the dark using two different centrifugation motion paradigms (fixed radius and variable radius) combined with two different subject orientations (facing-motion and back-to-motion). In the fixed radius trials, the radius at which the subject was seated was held constant while the rotation speed was changed to yield changes in the centrifugal force. In variable radius trials, the rotation speed was held constant while the radius was varied to yield a centrifugal force that nearly duplicated that measured during the fixed radius condition. The total gravito-inertial force (GIF) measured by the otolith organs was nearly identical in the two paradigms; the primary difference was the presence (fixed radius) or absence (variable radius) of yaw rotational cues. We found that the yaw rotational cues had a large statistically significant effect on the time course of perceived tilt, demonstrating that yaw rotational cues contribute substantially to the neural processing of roll tilt. We also found that the orientation of the subject relative to the centripetal acceleration had a dramatic influence on the eye movements measured during fixed radius centrifugation. Specifically, the horizontal vestibuloocular reflex (VOR) measured in our human subjects was always greater when the subject faced the direction of motion than when the subjects had their backs toward the motion during fixed radius rotation. This difference was consistent with the presence of a horizontal translational VOR response induced by the centripetal acceleration. Most importantly, by comparing the perceptual tilt responses to the eye movement responses, we found that the translational VOR component decayed as the subjective tilt indication aligned with the tilt of the GIF. This was true for both the fixed radius and variable radius conditions even though the time course of the responses was significantly different for these two conditions. These findings are consistent with the hypothesis that the nervous system resolves the ambiguous measurements of GIF into neural estimates of gravity and linear acceleration. More generally, these findings are consistent with the hypothesis that the nervous system uses internal models to process and interpret sensory motor cues.

BACKGROUND

Many of the anatomical changes of facial aging are still poorly understood. This study looked at the aging process in individuals linearly over time, focusing on aspects of periorbital aging and the upper midface.

METHODS

The author compared photographs of patients' friends and relatives taken 10 to 50 years before with closely matched recent follow-up pictures. The best-matching old and recent pictures were equally sized and superimposed in the computer. The images were then assembled into GIF animations, which automate the fading of one image into the other and back again indefinitely.

RESULTS

The following findings were new to the author: (1) the border of the pigmented lid skin and thicker cheek skin (the lid-cheek junction) is remarkably stable in position over time, becoming more visible by contrast, not by vertical descent as is commonly assumed. (2) Orbicularis wrinkles on the cheek and moles and other markers on the upper midface were also stable over decades. (3) With aging, there can be a distinct change in the shape of the upper eyelid. The young upper lid frequently has a medially biased peak. The upper lid peak becomes more central in the older lid. This article addresses these three issues. No evidence was seen here for descent of the globe in the orbit.

CONCLUSIONS

There seems to be very little ptosis (inferior descent) of the lid-cheek junction or of the upper midface. These findings suggest that vertical descent of skin, and by association, subcutaneous tissue, is not necessarily a major component of aging in those areas. In addition, the arc of the upper lid changes shape in a characteristic way in some patients. Other known changes of the periorbital area are visualized.

Model simulations of the squirrel monkey vestibulo-ocular reflex (VOR) are presented for two motion paradigms: constant velocity eccentric rotation and roll tilt about a naso-occipital axis. The model represents the implementation of three hypotheses: the "internal model" hypothesis, the "gravito-inertial force (GIF) resolution" hypothesis, and the "compensatory VOR" hypothesis. The internal model hypothesis is based on the idea that the nervous system knows the dynamics of the sensory systems and implements this knowledge as an internal dynamic model. The GIF resolution hypothesis is based on the idea that the nervous system knows that gravity minus linear acceleration equals GIF and implements this knowledge by resolving the otolith measurement of GIF into central estimates of gravity and linear acceleration, such that the central estimate of gravity minus the central estimate of acceleration equals the otolith measurement of GIF. The compensatory VOR hypothesis is based on the idea that the VOR compensates for the central estimates of angular velocity and linear velocity, which sum in a near-linear manner. During constant velocity eccentric rotation, the model correctly predicts that: (1) the peak horizontal response is greater while "facing-motion" than with "back-to-motion"; (2) the axis of eye rotation shifts toward alignment with GIF; and (3) a continuous vertical response, slow phase downward, exists prior to deceleration. The model also correctly predicts that a torsional response during the roll rotation is the only velocity response observed during roll rotations about a naso-occipital axis. The success of this model in predicting the observed experimental responses suggests that the model captures the essence of the complex sensory interactions engendered by eccentric rotation and roll tilt.

Kidney allograft failure is most often caused by chronic allograft nephropathy, a process of interstitial fibrosis (GIF) and tubular atrophy (TA). We assessed the pathology of living donor (LD) grafts compared to deceased donor (DD). Included are 321 recipients (245 LD; 76 DD) with protocol biopsies the first 2 years of transplant. In LD, GIF was present in 7%, 31%, 61% and 71% of grafts at 0, 4, 12 and 24 months. TA progressed in parallel to GIF. Compared to LD, more DD grafts had GIF at time 0 (29%, p = 0.002); thereafter the incidence of GIF was similar. In LD, GIF was associated with lower glomerular filtration rate (GFR)(1 year) (no GIF, 62 +/- 16; GIF, 49 +/- 15 mL/min/m(2) iothalamate clearance, p = 0.001) and reduced graft survival (HR = 2.2, p = 0.009). GIF in LD related to acute rejection (HR = 2.6, p = 0.01), polyoma nephropathy (OR = 4.4, p = 0.02) and lower levels of GFR 3 weeks post-transplant (HR = 0.961; p = 0.03, multivariate). However, GIF also developed in 53% of recipients lacking these covariates. Thus, GIF/TA develops in the majority of LD grafts, it is often mild but is associated with reduced function and survival. GIF frequently develops in the absence of risk factors. Lower GFR post-transplant identify patients at highest risk of GIF.